今日の臨床サポート

乳癌 浸潤性乳癌

著者: 吉田敦 聖路加国際病院 乳腺外科

監修: 中村清吾 昭和大学医学部外科学講座乳腺外科学部門

著者校正済:2021/10/06
現在監修レビュー中
参考ガイドライン:
  1. 日本乳癌学会:乳癌診療ガイドライン
  1. 全米がん情報ネットワーク(NCCN
  1. St. Gallen International Consensus Guideline(2019)
  1. ASCO Guideline breast cancer
患者向け説明資料

概要・推奨   

  1. 乳癌術前の治療方針決定に造影乳房MRIを行うことを弱く推奨する(推奨度2)。
  1. 初期治療後、定期的なマンモグラフィは有用である(推奨度1)。
  1. StageⅠ、Ⅱの浸潤性乳癌に対する局所療法では乳房温存療法と乳房切除術とでは生存率に差はなく、乳房温存療法の適応を第1選択として強く勧められる(推奨度1)。
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  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要とな
  1. 閲覧にはご契約が必要となります。閲覧にはご契
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約
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  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要と
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
吉田敦 : 未申告[2021年]
監修:中村清吾 : 講演料(アストラゼネカ,第一三共,中外製薬),研究費・助成金など(CESデカルト,第一三共,シスメックス,アストラゼネカ,島津製作所,大鵬薬品工業),奨学(奨励)寄付など(エーザイ,コニカミノルタ,大鵬薬品工業,中外製薬)[2021年]

改訂のポイント:
  1. 定期レビューを行い、ASCO Guideline breast cancerに基づいて改訂を行った。

病態・疫学・診察

疾患情報  
  1. 乳癌の罹患率・死亡率は増加傾向が続いている。
  1. 年齢別には、乳癌罹患率は30歳代から増加をはじめ、40歳代後半から50歳代前半でピークとなり、その後は緩やかに減少する。
 
年齢階級別乳癌罹患率(上皮内がんを含む)・死亡率

乳癌の罹患率・死亡率は増加傾向が続いている。
a:乳癌年齢階級別罹患率複数年(女性)(上皮内がんを含む)
b:乳癌年齢階級別死亡率複数年(女性)

 
  1. 病理学的には、乳管癌と特殊型に分類される。
  1. 浸潤性乳管癌は、さらに以下に分類される。
  1. 腺管形成型
  1. 充実型
  1. 硬性型
  1. その他
  1. 特殊型は以下に分類される。
  1. 1) 浸潤性小葉癌
  1. 2) 管状癌
  1. 3) 篩状癌
  1. 4) 粘液癌
  1. 5) 髄様癌
  1. 6) アポクリン癌
  1. 7) 化生癌
  1. i) 扁平上皮癌
  1. ii) 間葉系分化を伴う癌
  1. ①紡錘細胞癌
  1. ②骨・軟骨化生を伴う癌
  1. ③基質産生癌
  1. ④その他
  1. iii) 混合型
  1. 8) 浸潤性微小乳頭癌
  1. 9) 分泌癌
  1. 10) 腺様嚢胞癌
  1. 11) その他
  1. 治療は、手術に加え、放射線療法、内分泌療法、化学療法などを組み合わせて行う。
  1. 予後:10年生存率は、I期89.1%、 II期78.6%である。
問診・診察のポイント  
問診:
  1. 自覚症状:腫瘤、異常乳頭分泌、乳房痛、乳頭陥凹、乳頭部湿疹様変化、皮膚変化など、発症時期、経過

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

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文献 

著者: Melania Costantini, Paolo Belli, Roberta Lombardi, Gianluca Franceschini, Antonino Mulè, Lorenzo Bonomo
雑誌名: J Ultrasound Med. 2006 May;25(5):649-59; quiz 661.
Abstract/Text OBJECTIVE: The purpose of this study was to determine the reliability of sonographic American College of Radiology Breast Imaging Reporting And Data System (BI-RADS) classification in differentiating benign from malignant breast masses.
METHODS: One hundred seventy-eight breast masses studied by sonography with a known diagnosis were reviewed. All lesions were classified according to the sonographic BI-RADS lexicon. Pathologic results were compared with sonographic features. Sensitivity, specificity, accuracy, and positive predictive value (PPV) and negative predictive value (NPV) for the sonographic BI-RADS lexicon were calculated.
RESULTS: Twenty-six cases were assigned to class 3, 73 to class 4, and 79 to class 5. Pathologic results revealed 105 malignant and 73 benign lesions. The sonographic BI-RADS lexicon showed 71.3% accuracy, 98.1% sensitivity, 32.9% specificity, 67.8% PPV, and 92.3% NPV. The NPV for class 3 was 92.3%. The PPVs for classes 4 and 5 were 46.6% and 87.3%. Typical signs of malignancy were irregular shape, antiparallel orientation, noncircumscribed margin, echogenic halo, and decreased sound transmission. Typical signs of benignity were oval shape and circumscribed margin.
CONCLUSIONS: The sonographic BI-RADS lexicon is an important system for describing and classifying breast lesions.

PMID 16632790  J Ultrasound Med. 2006 May;25(5):649-59; quiz 661.
著者: Lindsay Turnbull, Sarah Brown, Ian Harvey, Catherine Olivier, Phil Drew, Vicky Napp, Andrew Hanby, Julia Brown
雑誌名: Lancet. 2010 Feb 13;375(9714):563-71. doi: 10.1016/S0140-6736(09)62070-5.
Abstract/Text BACKGROUND: MRI might improve diagnosis of breast cancer, reducing rates of reoperation. We assessed the clinical efficacy of contrast-enhanced MRI in women with primary breast cancer.
METHODS: We undertook an open, parallel group trial in 45 UK centres, with 1623 women aged 18 years or older with biopsy-proven primary breast cancer who were scheduled for wide local excision after triple assessment. Patients were randomly assigned to receive either MRI (n=816) or no further imaging (807), with use of a minimisation algorithm incorporating a random element. The primary endpoint was the proportion of patients undergoing a repeat operation or further mastectomy within 6 months of random assignment, or a pathologically avoidable mastectomy at initial operation. Analysis was by intention to treat. This study is registered, ISRCTN number 57474502.
FINDINGS: 816 patients were randomly assigned to MRI and 807 to no MRI. Addition of MRI to conventional triple assessment was not significantly associated with reduced a reoperation rate, with 153 (19%) needing reoperation in the MRI group versus 156 (19%) in the no MRI group, (odds ratio 0.96, 95% CI 0.75-1.24; p=0.77).
INTERPRETATION: Our findings are of benefit to the NHS because they show that MRI might be unnecessary in this population of patients to reduce repeat operation rates, and could assist in improved use of NHS services.
FUNDING: National Institute for Health Research's Health Technology Assessment Programme.

Copyright 2010 Elsevier Ltd. All rights reserved.
PMID 20159292  Lancet. 2010 Feb 13;375(9714):563-71. doi: 10.1016/S014・・・
著者: Uwe Fischer, Olivier Zachariae, Friedemann Baum, Dorit von Heyden, Matthias Funke, Torsten Liersch
雑誌名: Eur Radiol. 2004 Oct;14(10):1725-31. doi: 10.1007/s00330-004-2351-z. Epub 2004 Jul 10.
Abstract/Text Preoperative MRI of the breasts has been proven to be the most sensitive imaging modality in the detection of multifocal or multicentric tumor manifestations as well as simultaneous contralateral breast cancer. The aim of the presented retrospective study was to evaluate the benefit of preoperative MRI for patients with breast cancer. Preoperative MRI performed in 121 patients (group A) were compared to 225 patients without preoperative MRI (group B). Patients of group A underwent contrast-enhanced MR imaging of the breast using a 2D FLASH sequence technique (TR/TE/FA 336 ms/5 ms/90 degrees; 32 slices of 4-mm thickness, time of acquisition 1:27 min, contrast agent dosage 0.1 mmol Gd-DTPA/kg bw). All patients had histologically verified breast cancer and follow-up for more than 20 months (mean time group A: 40.3 months, group B: 41 months). Both groups received the same types of systemic treatment after breast conserving surgery. The in-breast tumor recurrence rate in group A was 1/86 (1.2%) compared to 9/133 (6.8%) in group B. Contralateral carcinoma were detected within follow-up in 2/121 (1.7%) in group A vs. 9/225 (4%) in group B. All results were statistically significant (P<0.001). Based on these results, preoperative MRI of the breasts is recommended in patients with histopathologically verified breast cancer for local staging.

Copyright 2004 Springer-Verlag
PMID 15248080  Eur Radiol. 2004 Oct;14(10):1725-31. doi: 10.1007/s0033・・・
著者: Lawrence J Solin, Susan G Orel, Wei-Ting Hwang, Eleanor E Harris, Mitchell D Schnall
雑誌名: J Clin Oncol. 2008 Jan 20;26(3):386-91. doi: 10.1200/JCO.2006.09.5448.
Abstract/Text PURPOSE: To determine the relationship of breast magnetic resonance imaging (MRI) to outcome after breast-conservation treatment (BCT) with radiation for women with early-stage invasive breast carcinoma or ductal carcinoma in situ.
PATIENTS AND METHODS: A total of 756 women with early stage invasive breast carcinoma or ductal carcinoma in situ underwent BCT including definitive breast irradiation during 1992 to 2001. At the time of initial diagnosis and evaluation, routine breast imaging included conventional mammography. Of the 756 women, 215 women (28%) had also undergone a breast MRI study, and 541 women (72%) had not undergone a breast MRI study. The median follow-up after treatment was 4.6 years (range, 0.1 to 13.5 years).
RESULTS: For the women with a breast MRI study compared with the women without a breast MRI study, there were no differences in the 8-year rates of any local failure (3% v 4%, respectively; P = .51) or local-only first failure (3% v 4%, respectively; P = .32). There were also no differences between the two groups for the 8-year rates of overall survival (86% v 87%, respectively; P = .51), cause-specific survival (94% v 95%, respectively; P = .63), freedom from distant metastases (89% v 92%, respectively; P = .16), or contralateral breast cancer (6% v 6%, respectively; P = .39).
CONCLUSION: The use of a breast MRI study at the time of initial diagnosis and evaluation was not associated with an improvement in outcome after BCT with radiation.

PMID 18202414  J Clin Oncol. 2008 Jan 20;26(3):386-91. doi: 10.1200/JC・・・
著者: Nicholas Hwang, Dan E Schiller, Pavel Crystal, Ellen Maki, David R McCready
雑誌名: Ann Surg Oncol. 2009 Nov;16(11):3000-9. doi: 10.1245/s10434-009-0607-1. Epub 2009 Jul 15.
Abstract/Text BACKGROUND: It remains uncertain whether routine preoperative breast magnetic resonance imaging (MRI) will lead to improved local outcomes after breast-conserving surgery (BCS) and radiation (RT) for invasive carcinoma. The purpose of this study was to determine whether MRI in the planning of the first lumpectomy reduces ipsilateral breast tumor recurrence (IBTR).
METHODS: Using a prospective database, 472 initial lumpectomies from 463 women between 1999 and 2005 were examined. All patients had invasive cancer excised to negative margins on BCS, received RT, and were followed. IBTR rates were calculated by Kaplan-Meier method. Univariate and multivariate analyses were performed to investigate the association between MRI for initial lumpectomies and IBTR outcomes.
RESULTS: MRI was performed before 127 (27%) lumpectomies, while 345 (73%) patients did not have a preoperative breast MRI. At median follow-up of 54 months (range 4.8-111.6 months), there was no significant difference in actuarial 8-year IBTR rates between women with preoperative MRI evaluation and women without MRI (1.8% versus 2.5%, respectively; P=0.67). After adjusting for adjuvant therapies, patient, and tumor characteristics, there continued to be no increased risk of IBTR [hazard ratio (HR) 1.7; P=0.60]. MRI visualization of tumors prior to lumpectomy did not influence the achievement of negative margins and was not associated with lower rates of re-excision (MRI: 11.8% versus no-MRI: 13.3%; P=0.50).
CONCLUSION: MRI evaluation of invasive carcinoma in the planning of initial lumpectomies was not associated with improved local outcomes after BCS with RT in this cohort of patients.

PMID 19603233  Ann Surg Oncol. 2009 Nov;16(11):3000-9. doi: 10.1245/s1・・・
著者: Benjamin T Miller, Andrea M Abbott, Todd M Tuttle
雑誌名: Ann Surg Oncol. 2012 Feb;19(2):536-40. doi: 10.1245/s10434-011-1932-8. Epub 2011 Jul 13.
Abstract/Text BACKGROUND: Breast magnetic resonance imaging (MRI) is increasingly used for breast cancer treatment planning. The aim of this study was to evaluate rates of mastectomy and breast-conserving surgery (BCS) in patients who undergo preoperative MRI.
METHODS: We retrospectively reviewed charts of patients who underwent surgical treatment of breast cancer at a single center between 2002 and 2009. Exclusion criteria included stage IV disease, previous breast cancer, Hodgkin lymphoma, and positive BRCA status. Univariate and multivariate analysis evaluated differences in patient demographics, surgical management, and tumor characteristics among women who underwent mastectomy compared to BCS.
RESULTS: Patients who underwent MRI were more likely to have mastectomy than those without MRI (43 vs. 28%; P = 0.002). Multivariate analysis revealed that younger age, larger tumor size, positive lymph node status, infiltrating lobular carcinoma, and preoperative MRI were independent predictors for mastectomy (P < 0.05). MRI detected occult contralateral breast cancer in 2.7% of patients. Among patients treated with BCS, preoperative MRI was not significantly associated with lower reexcision rates (MRI, 14%; no MRI, 18%; P = 0.34).
CONCLUSIONS: Preoperative MRI was associated with higher rates of mastectomy and detection of occult contralateral breast cancer, but was not associated with lower reexcision rates.

PMID 21751044  Ann Surg Oncol. 2012 Feb;19(2):536-40. doi: 10.1245/s10・・・
著者: Eun Sook Ko, Boo-Kyung Han, Rock Bum Kim, Eun Young Ko, Jung Hee Shin, Sang Yu Nam, Meeyoung Nam, Seok Jin Nam, Jeong Eon Lee, Won Ho Kil, Se-Kyung Lee
雑誌名: J Surg Oncol. 2013 Jun;107(8):815-21. doi: 10.1002/jso.23326. Epub 2013 Mar 15.
Abstract/Text BACKGROUND: It remains uncertain whether MRI identification of additional foci of disease leads to improved outcome. We undertook a study to evaluate the influence of breast MRI on early and long-term outcome.
METHODS: Among 1,271 patients undergone breast cancer surgery between January 2005 and December 2006, 785 patients were attempted for BCS. Operative approach and radiologic findings were compared according to MRI use. We reselected 615 patients with unilateral early-stage breast cancer treated with BCS including RT. We compared the histopathologic characteristics and outcomes according to MRI use.
RESULTS: In patients attempted for BCS (n = 785), re-excision rates were not significantly different according to MRI use (P = 1.000). Conversion to mastectomy or bilateral cancer surgery were higher in MRI group (P = 0.002). The IBTR rate was higher in the non-MRI group (P = 0.020). Difference in contralateral cancer rate and total recurrence rates failed to reach statistical significance (P = 0.168, 0.383, respectively). Multivariate study after adjustment showed no difference in recurrence rates and IBTR rates between the two groups (hazard ratios 1.34, 6.37 Ps = 0.385, 0.076).
CONCLUSION: Use of MRI in patients with early-stage breast cancer did not result in improvement of a patient's outcome.

Copyright © 2013 Wiley Periodicals, Inc.
PMID 23505028  J Surg Oncol. 2013 Jun;107(8):815-21. doi: 10.1002/jso.・・・
著者: Nehmat Houssami, Robin Turner, Petra Macaskill, Lindsay W Turnbull, David R McCready, Todd M Tuttle, Neha Vapiwala, Lawrence J Solin
雑誌名: J Clin Oncol. 2014 Feb 10;32(5):392-401. doi: 10.1200/JCO.2013.52.7515. Epub 2014 Jan 6.
Abstract/Text PURPOSE: There is little consensus regarding preoperative magnetic resonance imaging (MRI) in breast cancer (BC). We examined the association between preoperative MRI and local recurrence (LR) as primary outcome, as well as distant recurrence (DR), in patients with BC.
METHODS: An individual person data (IPD) meta-analysis, based on preoperative MRI studies that met predefined eligibility criteria, was performed. Survival analysis (Cox proportional hazards modeling) was used to investigate time to recurrence and to estimate the hazard ratio (HR) for MRI. We modeled the univariable association between LR (or DR) and MRI, and covariates, and fitted multivariable models to estimate adjusted HRs. Sensitivity analysis was based on women who had breast conservation with radiotherapy.
RESULTS: Four eligible studies contributed IPD on 3,180 affected breasts in 3,169 subjects (median age, 56.2 years). Eight-year LR-free survival did not differ between the MRI (97%) and no-MRI (95%) goups (P = .87), and the multivariable model showed no significant effect of MRI on LR-free survival: HR for MRI (versus no-MRI) was 0.88 (95% CI, 0.52 to 1.51; P = .65); age, margin status, and tumor grade were associated with LR-free survival (all P < .05). HR for MRI was 0.96 (95% CI, 0.52 to 1.77; P = .90) in sensitivity analysis. Eight-year DR-free survival did not differ between the MRI (89%) and no-MRI (93%) groups (P = .37), and the multivariable model showed no significant effect of MRI on DR-free survival: HR for MRI (v no-MRI) was 1.18 (95% CI, 0.76 to 2.27; P = .48) or 1.31 (95% CI, 0.76 to 2.27; P = .34) in sensitivity analysis.
CONCLUSION: Preoperative MRI for staging the cancerous breast does not reduce the risk of LR or DR.

PMID 24395846  J Clin Oncol. 2014 Feb 10;32(5):392-401. doi: 10.1200/J・・・
著者: Janice S Sung, Jie Li, Glenys Da Costa, Sujata Patil, Kimberly J Van Zee, D David Dershaw, Elizabeth A Morris
雑誌名: AJR Am J Roentgenol. 2014 Jun;202(6):1376-82. doi: 10.2214/AJR.13.11355.
Abstract/Text OBJECTIVE: The purpose of this study was to evaluate the effect of the use of preoperative breast MRI on surgical and long-term outcomes among women with early-stage breast cancer undergoing breast conservation therapy.
MATERIALS AND METHODS: A retrospective review yielded the cases of 174 women with stage 0, I, or II breast cancer who underwent preoperative MRI between 2000 and 2004. A control group of 174 patients who did not undergo preoperative MRI before breast conservation therapy was matched by age, histopathologic finding, stage, and surgeon. Features compared included breast density, presence of mammographically occult disease, margin status, lymph node involvement, lymphovascular invasion, extensive intraductal component, hormone receptor status, and use of adjuvant therapy. Outcomes, including rates of reexcision, ipsilateral recurrence, and disease-free survival, were compared by Kaplan-Meier methods and the log-rank test.
RESULTS: Patients referred for preoperative breast MRI were more likely to have extremely dense breasts (28% vs 6%, p < 0.0001) and mammographically occult cancer (24% vs 9%, p = 0.0003). The two groups had identical rates of final negative margins, lymph node involvement, lymphovascular invasion, extensive intraductal component status, positive hormone receptor results, and systemic adjuvant therapy. Fewer patients in the preoperative MRI group needed reexcision (29% vs 45%, p = 0.02). The median follow-up period after treatment was 8 years. There was no significant difference in locoregional recurrence (p = 0.33) or disease-free survival (p = 0.73) rates between the two groups.
CONCLUSION: Reexcision rates among patients with early breast cancer undergoing conservation therapy were lower among women who underwent preoperative breast MRI. There was no statistically significant effect of the use of preoperative MRI on rates of locoregional recurrence or disease-free survival.

PMID 24848838  AJR Am J Roentgenol. 2014 Jun;202(6):1376-82. doi: 10.2・・・
著者: Ann Yi, Nariya Cho, Kyung-Sook Yang, Wonshik Han, Dong-Young Noh, Woo Kyung Moon
雑誌名: Radiology. 2015 Sep;276(3):695-705. doi: 10.1148/radiol.2015142101. Epub 2015 Apr 27.
Abstract/Text PURPOSE: To compare breast cancer disease-free survival (DFS) outcomes of patients with newly diagnosed breast cancer without and with preoperative magnetic resonance (MR) imaging. MATERIALS AND METHODS This study was approved by an institutional review board, and informed consent was waived. From 2004 to 2009 (unilateral MR imaging from 2004 to 2006 vs bilateral MR imaging from 2007 to 2009), patients with breast cancer without preoperative MR imaging (no MR imaging group) were matched with those with preoperative MR imaging (MR imaging group) according to age, histologic grade, nuclear grade, tumor size, nodal status, stage, hormone receptor status, Ki-67 status, molecular subtype, and lymphovascular invasion. Survival analysis was performed by using Kaplan-Meier estimates. A marginal model was used to evaluate the effect of preoperative MR imaging on DFS.
RESULTS: A total of 371 patient pairs from the unilateral imaging period and 97 patient pairs from the bilateral imaging period were matched. During the unilateral imaging period, the MR imaging group had better local-regional recurrence DFS (hazard ratio [HR], 0.33; 95% confidence interval [CI]: 0.12, 0.91; P = .032) than did the no MR imaging group; however, no difference was found for contralateral breast (P = .440) or distant recurrence (P = .515) DFS. During the bilateral imaging period, the MR imaging group had better contralateral breast cancer DFS (HR, 0.03; 95% CI: 0.04, 0.21; P < .001) than the no MR imaging group; however, no difference was found for local-regional (P = .180) or distant recurrence (P = .178) DFS.
CONCLUSION: Preoperative bilateral breast MR imaging for staging of breast cancer was associated with a reduced risk of contralateral breast recurrence; however, no observed reduction in risk of local-regional or distant recurrence was shown.

PMID 25915100  Radiology. 2015 Sep;276(3):695-705. doi: 10.1148/radiol・・・
著者: Jaegyu Ryu, Hyung Seok Park, Sanghwa Kim, Jee Ye Kim, Seho Park, Seung Il Kim
雑誌名: J Breast Cancer. 2016 Dec;19(4):423-428. doi: 10.4048/jbc.2016.19.4.423. Epub 2016 Dec 23.
Abstract/Text PURPOSE: The purpose of the study was to evaluate the effect of preoperative magnetic resonance imaging (MRI) on survival outcomes for breast cancer.
METHODS: A total of 954 patients who had T1-2 breast cancer and received breast-conserving therapy (BCT) between 2007 and 2010 were enrolled. We divided the patients according to whether they received preoperative MRI or not. Survival outcomes, including locoregional recurrence-free survival (LRRFS), recurrence-free survival (RFS), and overall survival (OS), were analyzed.
RESULTS: Preoperative MRI was performed in 743 of 954 patients. Clinicopathological features were not significantly different between patients with and without preoperative MRI. In the univariate analyses, larger tumors were marginally associated with poor LRRFS compared to smaller tumors (hazard ratio [HR], 3.22; p=0.053). Tumor size, histologic grade, estrogen receptor (ER), progesterone receptor (PR), hormonal therapy, and adjuvant chemotherapy status were associated with RFS. Larger tumor size, higher histologic grade, lack of ER and PR expression, and no hormonal therapy were associated with decreased OS. Tumor size was associated with LRRFS in the multivariate analyses (HR, 4.19; p=0.048). However, preoperative MRI was not significantly associated with LRRFS, RFS, or OS in either univariate or multivariate analyses.
CONCLUSION: Preoperative MRI did not influence survival outcomes in T1-2 breast cancer patients who underwent BCT. Routine use of preoperative MRI in T1-2 breast cancer may not translate into longer RFS and OS.

PMID 28053631  J Breast Cancer. 2016 Dec;19(4):423-428. doi: 10.4048/j・・・
著者: Mai-Kim Gervais, Ellen Maki, Dan E Schiller, Pavel Crystal, David R McCready
雑誌名: J Surg Oncol. 2017 Mar;115(3):231-237. doi: 10.1002/jso.24520. Epub 2017 Jan 20.
Abstract/Text BACKGROUND: Local recurrence after breast conserving surgery is reported in 5-10% of cases. This study aims to determine if preoperative MRI is associated with reduced IBTR rates in the longer term and evaluate IBTR rates of a high risk (TN and Her-2 positive) subgroup in those receiving MRI or not.
METHODS: Between 1999 and 2005, patients with invasive breast cancer undergoing BCS and radiation were identified. Primary endpoint was IBTR rate.
RESULTS: The cohort consisted of 470 cases: 27% underwent MRI and 73% did not. Median follow-up was 97 months. Overall 10-year IBTR rate was 3.6%. There was no significant difference in IBTR rate at 10 years between those receiving MRI or not (1.6% vs. 4.2% (P = 0.37). The TN and Her-2 positive combined subgroup had a higher IBTR rate than all others (9.8% vs. 1.7%, P = 0.001). In the group without MRI, the IBTR rate of the high risk group was 11.8% compared to 1.8% in the remainder (P = 0.002).
CONCLUSION: With 10-year follow-up, there was no significant difference in IBTR rate whether preoperative MRI is performed versus not. The high risk population showed an increased IBTR rate, this was more marked in those who did not receive MRI.

© 2017 Wiley Periodicals, Inc.
PMID 28105662  J Surg Oncol. 2017 Mar;115(3):231-237. doi: 10.1002/jso・・・
著者: L Esserman, N Hylton, L Yassa, J Barclay, S Frankel, E Sickles
雑誌名: J Clin Oncol. 1999 Jan;17(1):110-9.
Abstract/Text PURPOSE: The staging and treatment for breast cancer are changing; there is an increase in the incidence of ductal carcinoma-in-situ, the use of fine-needle aspiration and stereotactic biopsy for diagnosis, and the use of neoadjuvant chemotherapy. Thus, there is a need for a tool to assess more precisely the extent of cancer in the breast before surgery. To better plan surgical and chemotherapeutic interventions, we evaluated high-resolution magnetic resonance imaging (MRI) as such a tool.
PATIENTS AND METHODS: Fifty-seven patients with 58 cases of breast cancer were evaluated preoperatively with MRI using a technique called the triple-acquisition rapid gradient echo technique to maximize anatomic detail. Imaging results were compared with mammography and subsequent pathology results.
RESULTS: Magnetic resonance imaging correctly identified residual or primary cancer in 55 of 58 cases and accurately predicted the extent of the cancer in 54 of 58 cases. The anatomic extent was more accurately defined with MRI compared with mammography (98% v 55%). Magnetic resonance imaging added the greatest value in cases of multifocal disease.
CONCLUSION: By applying MRI selectively to patients with a known diagnosis of cancer and focusing on defining the extent of malignant lesions, we were able to obtain clear and accurate anatomic information. Our results suggest that MRI could provide very valuable information for preoperative planning and single-stage resection in breast cancer. Based on preliminary data from our series, MRI would be valuable as a staging tool in the preoperative setting even if the cost is in the range of $1,300 to $2,000. It is already significantly less than the target cost, so it is reasonable to refine this technique for clinical use to help plan the most appropriate surgical intervention and possibly reduce costs as well. A careful prospective study is warranted to validate our findings.

PMID 10458224  J Clin Oncol. 1999 Jan;17(1):110-9.
著者: Takayoshi Uematsu, Sachiko Yuen, Masako Kasami, Yoshihiro Uchida
雑誌名: Breast Cancer Res Treat. 2008 Dec;112(3):461-74. doi: 10.1007/s10549-008-9890-y. Epub 2008 Jan 12.
Abstract/Text INTRODUCTION: Breast imaging modalities can assess the tumor extent and adequacy of excision, but there have been no reports comparing magnetic resonance (MR) imaging, multidetector row computed tomography (MDCT), ultrasonography (US) and mammography (MMG) for the tumor extent of breast cancer. We prospectively assessed the accuracy of MR imaging, MDCT, US and MMG for preoperative assessment of the tumor extent of breast cancer.
METHODS: Preoperative MR imaging, MDCT, US and MMG were performed for 210 breasts with breast cancer. The MR and MDCT images were independently interpreted by one of two radiologists with knowledge of the clinical and MMG findings. The US was performed with knowledge of the clinical and MMG findings by one of five US technologists. The correlation of the results of these examinations with histological findings was examined.
RESULTS: Of the 210 index breast tumors, 210 (100%) could be detected on MR, 208 (99%) were detected on MDCT, 209 (99.5%) were detected on US, and 195 (93%) were detected on MMG. For evaluating local tumor extent, the accuracy of MR imaging (76%) was significantly higher than those of MDCT, US, and MMG (71%, 56%, and 52%, respectively) (P = 0.001, P < 0.0001, and P < 0.0001). MDCT was significantly more accurate than US (P < .0001) or MMG (P < .0001), and US was significantly more accurate than MMG (P = 0.004). MR imaging and US had substantial risk (11% and 17%) of overestimation of the tumor extent. Regarding ductal carcinoma in situ (DCIS), for non-comedo DCIS, the accuracies of MR imaging (89%), MDCT (72%), and US (61%) were significantly higher than the 22% accuracy of MMG (P < 0.0001, P = 0.012, and P = 0.016), but for comedo DCIS, there were no significant differences among the four breast imaging modalities.
CONCLUSION: MR imaging was the most accurate breast imaging modality for the tumor exten of breast cancer, although MR imaging had a substantial of risk of overestimation. MR imaging, MDCT and US can complement MMG for the preoperative evaluation of patients who are candidates for breast-conserving surgery.

PMID 18193352  Breast Cancer Res Treat. 2008 Dec;112(3):461-74. doi: 1・・・
著者: C Boetes, R D Mus, R Holland, J O Barentsz, S P Strijk, T Wobbes, J H Hendriks, S H Ruys
雑誌名: Radiology. 1995 Dec;197(3):743-7. doi: 10.1148/radiology.197.3.7480749.
Abstract/Text PURPOSE: To evaluate the comparative accuracy of magnetic resonance (MR) imaging relative to mammography and ultrasonography (US) for assessing the extent of breast tumors.
MATERIALS AND METHODS: Histologic results and preoperative imaging findings (mammography, US, MR imaging) were analyzed regarding tumor size and multifocality of 61 tumors in 60 women undergoing mastectomy for carcinoma.
RESULTS: In 10% of cases, the index tumor was not seen at mammography. With US, 15% of the index tumors were not recognized, while MR imaging missed 2% of the index tumors. On mammographic and US images, tumor size was underestimated significantly (P < .005), by 14% and 18%, respectively, while MR imaging showed no significant difference in size compared with that found in a pathologic evaluation. Mammography showed 31% of the additional invasive lesions, while US showed 38% and MR imaging showed 100%.
CONCLUSION: MR imaging was the most accurate of the three preoperative imaging modalities in assessing the size and number of malignant lesions in the breast.

PMID 7480749  Radiology. 1995 Dec;197(3):743-7. doi: 10.1148/radiolog・・・
著者: Gorane Santamaría, Martín Velasco, Blanca Farrús, Gabriel Zanón, Pedro Luis Fernández
雑誌名: Breast. 2008 Apr;17(2):186-94. doi: 10.1016/j.breast.2007.09.005. Epub 2007 Oct 26.
Abstract/Text The aim of the study was to evaluate the contribution of preoperative breast magnetic resonance imaging (MRM) as an adjunct to mammography in assessing extent of pure ductal carcinoma in situ (DCIS) and to relate magnetic resonance imaging (MRI) findings to histopathological features. A retrospective analysis was conducted of 86 histologically proven cases of pure DCIS of the breast. Two experienced radiologists with knowledge of clinical and histopathological findings at the time of the review evaluated mammographic and preoperative MRI results by consensus. Compared to histopathology, mammography or MRM alone underestimated DCIS extent in 18.6% and 31.4% of cases, respectively. When both imaging modalities were considered, DCIS extent was underestimated in 8% of cases. Combined use of mammography and MRM revealed good agreement with histopathology to assess DCIS extent (kappa=0.439; P<0.001). MR enhancement of DCIS was related to histologic size (P=0.011). Mammography is more accurate than MRM in assessing cancer extent of pure DCIS, but combined use of both imaging techniques leads to improved accuracy.

PMID 17964786  Breast. 2008 Apr;17(2):186-94. doi: 10.1016/j.breast.20・・・
著者: Hidetake Yabuuchi, Toshiro Kuroiwa, Chie Kusumoto, Tatsuro Fukuya, Shinji Ohno, Yoichi Hachitanda
雑誌名: J Magn Reson Imaging. 2006 Apr;23(4):486-92. doi: 10.1002/jmri.20532.
Abstract/Text PURPOSE: To investigate the correlation between MR findings and the histological diagnosis of incidentally detected lesions in candidates for breast-conserving therapy.
MATERIALS AND METHODS: MR images of 299 patients with breast cancer were reviewed. Incidentally detected lesions were noted in 59 of 299 (20%) patients, and a histological diagnosis was obtained in 48 of 59 (81%) patients. There were 25 benign and 23 malignant lesions. The number, size, location, morphologic character, and kinetic curve assessment of the MR findings were analyzed. Statistical analyses were performed to determine whether any differences could be observed between benign and malignant lesions.
RESULTS: Lesions of over 10 mm tended to be malignant (11/16; 69%), whereas those equal or less than 5 mm tended to be benign (12/17; 71%; P < 0.05). Lesions in the same quadrant as the main lesion tended to be malignant (20/27.5; 73%), whereas those in a different quadrant tended to be benign (17.5/20.5; 85%; P < 0.001). Lesions with early peak of enhancement tended to be malignant (20/25; 80%), whereas those with persistent enhancement tended to be benign (20/23; 87%; P < 0.001).
CONCLUSION: Incidentally detected lesions that are found in a different quadrant from the main lesion, are smaller than 10 mm in diameter, and show persistent enhancement on MR imaging suggest benign lesions. Therefore, patients with such lesions should avoid unnecessary surgical procedures unless lesions are proved to be malignant by cytology or biopsy.

2006 Wiley-Liss, Inc.
PMID 16521096  J Magn Reson Imaging. 2006 Apr;23(4):486-92. doi: 10.10・・・
著者: Mitsuhiro Tozaki, Norie Yamashiro, Masaaki Sakamoto, Naomi Sakamoto, Nobuo Mizuuchi, Eisuke Fukuma
雑誌名: Jpn J Radiol. 2010 Aug;28(7):527-33. doi: 10.1007/s11604-010-0464-7. Epub 2010 Aug 27.
Abstract/Text PURPOSE: The aim of this study was to clarify the frequency of malignancy and the histopathological characteristics of the lesions in patients undergoing magnetic resonance imaging (MRI)-guided vacuum-assisted biopsy (VAB).
MATERIALS AND METHODS: A retrospective review of 100 consecutive patients with 102 lesions who had undergone MRI-guided VAB was performed. The biopsies were performed on a 1.5-T MR scanner using a commercially available biopsy system. None of the lesions seen with MRI could be detected by mammography or second-look ultrasonography.
RESULTS: The average lesion sizes of the focus, mass, and nonmass lesions before the biopsy were 4.5, 8.2, and 21 mm, respectively. Twelve patients (12%) had lesions located in the deep portion of the breast, close to the pectoral muscle. The biopsy was successfully performed without important side effects in all patients. Histopathological findings were invasive ductal carcinoma in 6 (6%), in situ carcinoma in 28 (27%), and high-risk and benign in 68 (67%). Two high-risk lesions were upgraded to ductal carcinoma in situ (DCIS), and three DCIS lesions were upgraded to invasive ductal carcinoma at surgical excision.
CONCLUSION: The high rate of DCIS might be a unique feature among Japanese women. However, MRI-guided VAB is necessary for MRI-only visible suspicious lesions in Japan.

PMID 20799018  Jpn J Radiol. 2010 Aug;28(7):527-33. doi: 10.1007/s1160・・・
著者: Shogo Nakano, Junko Kousaka, Kimihito Fujii, Kyoko Yorozuya, Miwa Yoshida, Yukako Mouri, Miwa Akizuki, Rie Tetsuka, Takahito Ando, Takashi Fukutomi, Yukihiko Oshima, Junko Kimura, Tsuneo Ishiguchi, Osamu Arai
雑誌名: Breast Cancer Res Treat. 2012 Aug;134(3):1179-88. doi: 10.1007/s10549-012-2163-9. Epub 2012 Jul 24.
Abstract/Text The aim of this study was to verify the utility of second-look sonography using real-time virtual sonography (RVS)-a coordinated sonography with an MRI system that uses an image fusion technique with magnetic navigation-on the sonographic evaluation of MRI-detected lesions of the breast. Of the 196 consecutive patients who were examined with breast MRI in our hospital from 2006 to 2009, those patients who underwent second-look sonography to identify MRI-detected lesions were enrolled in this study. MRI was performed using a 1.5-T imager with the patient in a supine position. To assess the efficacy benefits of RVS, the correlations between lesion detection rates, MRI features, distribution, and histopathological classification on second-look sonography using conventional B-mode or RVS were analyzed. Of the 196 patients, 55 (28 %) demonstrated 67 lesions initially detected by MRI, followed by second-look sonography. Of the 67 MRI-detected lesions, 18 (30 %) were identified with second-look sonography using conventional B-mode alone, whereas 60 (90 %) lesions were detected with second-look sonography using RVS (p < 0.001). The detection rates of 16 focal lesions, 46 mass lesions, 16 lesions sized <5 mm, 45 lesions sized 5-10 mm, 26 lesions situated within the mammary gland, 41 lesions situated around mammary fascia, 24 malignant lesions, and 43 benign lesions were, respectively, 25, 26, 25, 24, 42, 17, 33, and 23 % by conventional B-mode, and were significantly higher, respectively, at 94, 89, 94, 89, 88, 90, 92, and 88 % by RVS. Of the seven lesions with no sonographic correlates, five could be biopsied by marking MRI information onto the body surface using RVS. Overall, 65 of 67 (97 %) MRI-detected lesions were confirmed by histopathological results. Our results suggest that the additional use of RVS on second-look sonography significantly increases the sonographic detection rate of MRI-detected lesions without operator dependence.

PMID 22821400  Breast Cancer Res Treat. 2012 Aug;134(3):1179-88. doi: ・・・
著者: Takayoshi Uematsu, Kaoru Takahashi, Seiichiro Nishimura, Junichiro Watanabe, Seiji Yamasaki, Takashi Sugino, Takuma Oishi, Yuko Kakuda, Mutsu Sato, Tomomi Hayashi
雑誌名: Eur Radiol. 2016 Apr;26(4):1064-72. doi: 10.1007/s00330-015-3892-z. Epub 2015 Jul 3.
Abstract/Text OBJECTIVES: The purpose of our study was to assess whether there is a potential additional value of real-time virtual sonography (RVS) to second-look ultrasound (US) examination and biopsy for breast lesions identified on MRI alone.
METHODS: A retrospective review of the records of 70 consecutive patients (78 lesions) with breast abnormalities identified on MRI alone was performed. All suspicious enhancing lesions were subsequently evaluated with second-look US. Lesions not observed on second-look US underwent RVS. Pathological findings were confirmed by subsequent percutaneous biopsy or excision.
RESULTS: Of the 78 MRI-detected lesions, second-look US correlation was made in 50 (64 %), including 22 malignant and 28 benign lesions. The remaining 28 lesions (36 %) were scheduled to undergo RVS. Four lesions were not visible on the second breast MRI. The remaining 24 lesions were RVS correlated and underwent RVS-guided biopsy; these included seven malignant and 17 benign lesions. Overall, 74 of 74 (100 %) true MRI-detected lesions were confirmed by histological results without using MRI-guided breast biopsy. The cancer rate was 29 %.
CONCLUSIONS: RVS can increase the sonographic detection and biopsy rate of lesions identified on breast MRI alone.
KEY POINTS: • All 74 MRI-detected lesions were confirmed without using MRI-guided biopsy. • Four lesions were not visible on second breast MRI. • RVS can increase sonographic detection of lesions identified on breast MRI alone. • RVS-guided breast biopsy can be an alternative to MRI-guided biopsy.

PMID 26135000  Eur Radiol. 2016 Apr;26(4):1064-72. doi: 10.1007/s00330・・・
著者: Jin You Kim, Nariya Cho, Hye Ryoung Koo, Ann Yi, Won Hwa Kim, Su Hyun Lee, Jung Min Chang, Wonshik Han, Hyeong-Gon Moon, Seock-Ah Im, Dong-Young Noh, Woo Kyung Moon
雑誌名: Radiology. 2013 Apr;267(1):57-66. doi: 10.1148/radiol.12120629. Epub 2013 Jan 17.
Abstract/Text PURPOSE: To investigate the clinical effect of a single magnetic resonance (MR) imaging screening examination of the contralateral breast at preoperative evaluation in women with unilateral breast cancer.
MATERIALS AND METHODS: The institutional review board approved this study and waived informed consent. Among women with unilateral breast cancer who underwent curative surgery from 2004 to 2008, 1323 women (mean age, 46.8 years; range, 18-81 years) underwent mammography and ultrasonography (US) alone (comparison group) between January 2004 and December 2006; 1771 consecutive women (mean age, 48.2 years; range, 22-85 years) underwent mammography, US, and MR imaging (contralateral MR imaging-screened group) between January 2007 and December 2008. The incidence of synchronous cancer and the incidence of metachronous cancer in the contralateral breast were compared between groups. Multivariate Cox analysis was performed. Median follow-up was 56 months (range, 13-94 months).
RESULTS: Twenty-five synchronous contralateral cancers (13 invasive cancers, 12 ductal carcinomas in situ; mean invasive size, 14 mm [range, 1-35 mm]; 92% [12 of 13] of invasive tumors were node negative) were additionally detected with MR imaging in the MR imaging-screened group. The cumulative incidence of contralateral breast cancer at 45 months was 0.5% (nine of 1771) (95% confidence interval [CI]: 0.23%, 0.96%) for the MR imaging-screened group and 1.4% (18 of 1323) (95% CI: 0.81%, 2.14%) for the comparison group (P = .02). Contralateral MR imaging screening (hazard ratio, 0.37; 95% CI: 0.15, 0.92; P = .03) and estrogen receptor negativity (hazard ratio, 3.98; 95% CI: 1.60, 9.92; P = .003) were associated with risk of contralateral cancer diagnosis in multivariate analysis.
CONCLUSION: A single MR imaging screening examination of the contralateral breast in women with unilateral breast cancer increased synchronous cancer detection and was associated with decreased diagnosis of metachronous contralateral cancer within 45 months.

RSNA, 2013.
PMID 23329656  Radiology. 2013 Apr;267(1):57-66. doi: 10.1148/radiol.1・・・
著者: U Veronesi, B Salvadori, A Luini, M Greco, R Saccozzi, M del Vecchio, L Mariani, S Zurrida, F Rilke
雑誌名: Eur J Cancer. 1995 Sep;31A(10):1574-9.
Abstract/Text Breast conservation has become well-established in the treatment of early mammary carcinoma. However, a standardised treatment modality has not emerged. We have analysed the data from 1,973 patients treated in three consecutive randomised trials by four different radiosurgical procedures: Halsted mastectomy, quadrantectomy plus radiotherapy, lumpectomy plus radiotherapy, and quadrantectomy without radiotherapy, to compare the outcomes of these procedures in terms of local recurrence rate and overall survival. Eligibility criteria were similar in the three trials, and comparability between the four subgroups was excellent. Median follow-up for all patients was 82 months. The annual rates of local recurrence varied markedly according to the treatment. Patients treated with Halsted mastectomy and quadrantectomy plus radiotherapy had low annual rates of local recurrence (0.20 and 0.46, respectively) while both lumpectomy plus radiotherapy and quadrantectomy without radiotherapy had significantly higher rates (2.45 and 3.28, respectively). Patients under 45 years of age had a much higher incidence of local recurrences, while in women over 55 years local recurrences were much less frequent. Overall survival curves were identical in the four groups of patients, so that the three breast conserving radiosurgical procedures had the same survival rates as Halsted mastectomy. However, local recurrence rates were markedly influenced by the treatment method, patient age and specific histological features.

PMID 7488404  Eur J Cancer. 1995 Sep;31A(10):1574-9.
著者: Umberto Veronesi, Natale Cascinelli, Luigi Mariani, Marco Greco, Roberto Saccozzi, Alberto Luini, Marisel Aguilar, Ettore Marubini
雑誌名: N Engl J Med. 2002 Oct 17;347(16):1227-32. doi: 10.1056/NEJMoa020989.
Abstract/Text BACKGROUND: We conducted 20 years of follow-up of women enrolled in a randomized trial to compare the efficacy of radical (Halsted) mastectomy with that of breast-conserving surgery.
METHODS: From 1973 to 1980, 701 women with breast cancers measuring no more than 2 cm in diameter were randomly assigned to undergo radical mastectomy (349 patients) or breast-conserving surgery (quadrantectomy) followed by radiotherapy to the ipsilateral mammary tissue (352 patients). After 1976, patients in both groups who had positive axillary nodes also received adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil.
RESULTS: Thirty women in the group that underwent breast-conserving therapy had a recurrence of tumor in the same breast, whereas eight women in the radical-mastectomy group had local recurrences (P<0.001). The crude cumulative incidence of these events was 8.8 percent and 2.3 percent, respectively, after 20 years. In contrast, there was no significant difference between the two groups in the rates of contralateral-breast carcinomas, distant metastases, or second primary cancers. After a median follow-up of 20 years, the rate of death from all causes was 41.7 percent in the group that underwent breast-conserving surgery and 41.2 percent in the radical-mastectomy group (P=1.0). The respective rates of death from breast cancer were 26.1 percent and 24.3 percent (P=0.8).
CONCLUSIONS: The long-term survival rate among women who undergo breast-conserving surgery is the same as that among women who undergo radical mastectomy. Breast-conserving surgery is therefore the treatment of choice for women with relatively small breast cancers.

Copyright 2002 Massachusetts Medical Society
PMID 12393819  N Engl J Med. 2002 Oct 17;347(16):1227-32. doi: 10.1056・・・
著者: B Fisher, C Redmond, R Poisson, R Margolese, N Wolmark, L Wickerham, E Fisher, M Deutsch, R Caplan, Y Pilch
雑誌名: N Engl J Med. 1989 Mar 30;320(13):822-8. doi: 10.1056/NEJM198903303201302.
Abstract/Text In 1985 we presented results of a randomized trial involving 1843 women followed for five years that indicated that segmental breast resection (lumpectomy) followed by breast irradiation is appropriate therapy for patients with Stage I or II breast cancer (tumor size, less than or equal to 4 cm), provided that the margins of the resected specimens are free of tumor. Women with positive axillary nodes received adjuvant chemotherapy. Lumpectomy followed by irradiation resulted in a five-year survival rate of 85 percent, as compared with 76 percent for total mastectomy, a rate of survival free of distant disease of 76 percent, as compared with 72 percent, and a disease-free survival rate of 72 percent, as compared with 66 percent. In the current study, we have extended our observations through eight years of follow-up. Ninety percent of the women treated with breast irradiation after lumpectomy remained free of ipsilateral breast tumor, as compared with 61 percent of those not treated with irradiation after lumpectomy (P less than 0.001). Among patients with positive axillary nodes, only 6 percent of those treated with radiation and adjuvant chemotherapy had a recurrence of tumor in the ipsilateral breast. Lumpectomy with or without irradiation of the breast resulted in rates of disease-free survival (58 +/- 2.6 percent), distant-disease-free survival (65 +/- 2.6 percent), and overall survival (71 +/- 2.6 percent) that were not significantly different from those observed after total mastectomy (54 +/- 2.4 percent, 62 +/- 2.3 percent, and 71 +/- 2.4 percent, respectively). There was no significant difference in the rates of distant-disease-free survival (P = 0.2) or survival (P = 0.3) among the women who underwent lumpectomy (with or without irradiation), despite the greater incidence of recurrence of tumor in the ipsilateral breast in those who received no radiation. We conclude that our observations through eight years are consistent with the findings at five years and that these new findings continue to support the use of lumpectomy in patients with Stage I or II breast cancer. We also conclude that irradiation reduces the probability of local recurrence of tumor in patients treated with lumpectomy.

PMID 2927449  N Engl J Med. 1989 Mar 30;320(13):822-8. doi: 10.1056/N・・・
著者: B Fisher, S Anderson, C K Redmond, N Wolmark, D L Wickerham, W M Cronin
雑誌名: N Engl J Med. 1995 Nov 30;333(22):1456-61. doi: 10.1056/NEJM199511303332203.
Abstract/Text BACKGROUND: Previous findings from a clinical trial (Protocol B-06) conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) indicated the worth of lumpectomy and breast irradiation for treating breast cancer. After the discovery by NSABP staff members of falsified information on patients enrolled in the study by St. Luc Hospital in Montreal, separate audits were conducted at St. Luc Hospital and other participating institutions. We report the results of both audits and update the study findings through an average of 12 years of follow-up.
METHODS: Patients with either negative or positive axillary nodes and tumors 4 cm or less in diameter were randomly assigned to one of three treatments: total mastectomy, lumpectomy followed by breast irradiation, or lumpectomy without irradiation. Three cohorts of patients were analyzed. The first cohort included all 2105 randomized patients, who were analyzed according to the intention-to-treat principle. The second cohort consisted of 1851 eligible patients in the first cohort with known nodal status who agreed to be followed and who accepted their assigned therapy (among those excluded were 6 patients from St. Luc Hospital who were declared ineligible because of falsified biopsy dates). The third cohort consisted of the patients in the second cohort minus the 322 eligible patients from St. Luc Hospital (total, 1529 patients).
RESULTS: Regardless of the cohort, no significant differences were found in overall survival, disease-free survival, or survival free of disease at distant sites between the patients who underwent total mastectomy and those treated by lumpectomy alone or by lumpectomy plus breast irradiation. After 12 years of follow-up, the cumulative incidence of a recurrence of tumor in the ipsilateral breast was 35 percent in the group treated with lumpectomy alone and 10 percent in the group treated with lumpectomy and breast irradiation (P < 0.001).
CONCLUSIONS: Our findings continue to indicate that lumpectomy followed by breast irradiation is appropriate therapy for women with either negative or positive axillary nodes and breast tumors 4 cm or less in diameter.

PMID 7477145  N Engl J Med. 1995 Nov 30;333(22):1456-61. doi: 10.1056・・・
著者: Bernard Fisher, Stewart Anderson, John Bryant, Richard G Margolese, Melvin Deutsch, Edwin R Fisher, Jong-Hyeon Jeong, Norman Wolmark
雑誌名: N Engl J Med. 2002 Oct 17;347(16):1233-41. doi: 10.1056/NEJMoa022152.
Abstract/Text BACKGROUND: In 1976, we initiated a randomized trial to determine whether lumpectomy with or without radiation therapy was as effective as total mastectomy for the treatment of invasive breast cancer.
METHODS: A total of 1851 women for whom follow-up data were available and nodal status was known underwent randomly assigned treatment consisting of total mastectomy, lumpectomy alone, or lumpectomy and breast irradiation. Kaplan-Meier and cumulative-incidence estimates of the outcome were obtained.
RESULTS: The cumulative incidence of recurrent tumor in the ipsilateral breast was 14.3 percent in the women who underwent lumpectomy and breast irradiation, as compared with 39.2 percent in the women who underwent lumpectomy without irradiation (P<0.001). No significant differences were observed among the three groups of women with respect to disease-free survival, distant-disease-free survival, or overall survival. The hazard ratio for death among the women who underwent lumpectomy alone, as compared with those who underwent total mastectomy, was 1.05 (95 percent confidence interval, 0.90 to 1.23; P=0.51). The hazard ratio for death among the women who underwent lumpectomy followed by breast irradiation, as compared with those who underwent total mastectomy, was 0.97 (95 percent confidence interval, 0.83 to 1.14; P=0.74). Among the lumpectomy-treated women whose surgical specimens had tumor-free margins, the hazard ratio for death among the women who underwent postoperative breast irradiation, as compared with those who did not, was 0.91 (95 percent confidence interval, 0.77 to 1.06; P=0.23). Radiation therapy was associated with a marginally significant decrease in deaths due to breast cancer. This decrease was partially offset by an increase in deaths from other causes.
CONCLUSIONS: Lumpectomy followed by breast irradiation continues to be appropriate therapy for women with breast cancer, provided that the margins of resected specimens are free of tumor and an acceptable cosmetic result can be obtained.

Copyright 2002 Massachusetts Medical Society
PMID 12393820  N Engl J Med. 2002 Oct 17;347(16):1233-41. doi: 10.1056・・・
著者: J A van Dongen, H Bartelink, I S Fentiman, T Lerut, F Mignolet, G Olthuis, E van der Schueren, R Sylvester, D Tong, J Winter
雑誌名: Eur J Cancer. 1992;28A(4-5):801-5.
Abstract/Text A (modified) radical mastectomy (RM) was compared with breast-conserving therapy (BCT) in stage I and stage II breast cancer patients. Treatment of the study arm comprised lumpectomy, axillary clearance and radiotherapy to the breast (50 Gy in 5 weeks external irradiation and a boost with iridium implant of 25 Gy). 902 patients were included. There were 734 TNM stage II patients. Patients with microscopically incomplete excision of the tumour were not excluded. After a median follow-up of 6 years, overall survival and local recurrence rates do not differ significantly between the two study arms. Actuarial survival at 8 years was 73% after RM and 71% after BCT; actuarial local recurrence at 8 years was 9% and 15%, respectively. In the mastectomy group tumour size did not affect local relapse, but after BCT the incidence of local recurrences was higher for tumours of 2-5 cm (16%) than for smaller tumours (7%) (at 8 years, P = 0.08). Results of salvage treatment for local recurrence so far were similar in both the BCT and the mastectomy group.

PMID 1524898  Eur J Cancer. 1992;28A(4-5):801-5.
著者: J A van Dongen, A C Voogd, I S Fentiman, C Legrand, R J Sylvester, D Tong, E van der Schueren, P A Helle, K van Zijl, H Bartelink
雑誌名: J Natl Cancer Inst. 2000 Jul 19;92(14):1143-50.
Abstract/Text BACKGROUND: Breast-conserving therapy (BCT) has been shown to be as effective as mastectomy in the treatment of tumors 2 cm or smaller. However, evidence of its efficacy, over the long term, in patients with tumors larger than 2 cm is limited. From May 1980 to May 1986, the European Organization for Research and Treatment of Cancer carried out a randomized, multicenter trial comparing BCT with modified radical mastectomy for patients with tumors up to 5 cm. In this analysis, we investigated whether the treatments resulted in different overall survival, time to distant metastasis, or time to locoregional recurrence.
METHODS: Of 868 eligible breast cancer patients randomly assigned to the BCT arm or to the modified radical mastectomy arm, 80% had a tumor of 2.1-5 cm. BCT comprised lumpectomy with an attempted margin of 1 cm of healthy tissue and complete axillary clearance, followed by radiotherapy to the breast and a supplementary dose to the tumor bed. The median follow-up was 13.4 years. All P values are two-sided.
RESULTS: At 10 years, there was no difference between the two groups in overall survival (66% for the mastectomy patients and 65% for the BCT patients; P =.11) or in their distant metastasis-free rates (66% for the mastectomy patients and 61% for the BCT patients; P =.24). The rate of locoregional recurrence (occurring before or at the same time as distant metastasis) at 10 years did show a statistically significant difference (12% of the mastectomy and 20% of the BCT patients; P =. 01).
CONCLUSIONS: BCT and mastectomy demonstrate similar survival rates in a trial in which the great majority of the patients had stage II breast cancer.

PMID 10904087  J Natl Cancer Inst. 2000 Jul 19;92(14):1143-50.
著者: Matthew M Poggi, David N Danforth, Linda C Sciuto, Sharon L Smith, Seth M Steinberg, David J Liewehr, Cynthia Menard, Marc E Lippman, Allen S Lichter, Rosemary M Altemus
雑誌名: Cancer. 2003 Aug 15;98(4):697-702. doi: 10.1002/cncr.11580.
Abstract/Text BACKGROUND: Between 1979-1987, the National Cancer Institute conducted a randomized, prospective study of mastectomy (MT) versus breast conservation therapy (BCT) in the treatment of patients with early-stage breast carcinoma. After a median potential follow-up of 18.4 years, the authors present the updated results.
METHODS: After informed consent was obtained from each patient, 237 evaluable women with clinical AJCC Stage I and Stage II breast carcinoma were enrolled on an institutionally reviewed protocol and randomly assigned to undergo modified radical MT (116 patients) or BCT (121 patients), which was comprised of lumpectomy, axillary lymph node dissection, and radiation therapy. Negative surgical margins in the lumpectomy arm were not required. The 237 randomized patients were followed for a median potential follow-up of 18.4 years. The primary endpoints were overall survival and disease-free survival.
RESULTS: At a median follow-up of 18.4 years, there was no detectable difference with regard to overall survival between patients treated with MT and those treated with BCT (58% vs. 54%; P = 0.67 overall). Twenty-seven women in the BCT arm (22%) experienced an in-breast event. After censoring in-breast events in the BCT arm that were salvaged successfully by MT, disease-free survival also was found to be statistically similar (67% in the MT arm vs. 63% in the BCT arm; P = 0.64 overall). There was no statistically significant difference with regard to contralateral breast carcinoma between the two treatment arms (P = 0.70).
CONCLUSIONS: After nearly 20 years of follow-up, there was no detectable difference in overall survival or disease-free survival in patients with early-stage breast carcinoma who were treated with MT compared with those treated with BCT. For BCT patients, long-term in-breast failures continued to occur throughout the duration of follow-up. There was no statistically significant difference in the incidence of contralateral breast carcinoma between the two treatment groups.

PMID 12910512  Cancer. 2003 Aug 15;98(4):697-702. doi: 10.1002/cncr.11・・・
著者: M Blichert-Toft, C Rose, J A Andersen, M Overgaard, C K Axelsson, K W Andersen, H T Mouridsen
雑誌名: J Natl Cancer Inst Monogr. 1992;(11):19-25.
Abstract/Text The Danish Breast Cancer Cooperative Group (DBCG) conducted a randomized trial comparing breast conservation with mastectomy in patients with invasive mammary carcinoma. From January 1983 to March 1989, the trial accrued a total of 1153 women. Of this number, 905 patients (79%) were randomly assigned to one of the two treatment options, whereas 248 patients (21%) did not accept randomization. Of the randomly assigned patients, 90% received the surgical option to which they had been originally assigned. In the breast conservation arm the tumor was excised with the intention of obtaining free margins determined at gross examination, and radiotherapy was subsequently administered to residual breast tissue. The axilla was dissected in all instances. Patient and tumor characteristics were similar in the two randomization arms. The median follow-up time was 40 months. At 6 years of life-table analysis the probability of recurrence-free survival was 70% in the breast conservation arm against 66% in the mastectomy arm. Survival figures were 79% against 82%, respectively.

PMID 1627427  J Natl Cancer Inst Monogr. 1992;(11):19-25.
著者: R Arriagada, M G Lê, F Rochard, G Contesso
雑誌名: J Clin Oncol. 1996 May;14(5):1558-64.
Abstract/Text PURPOSES: A randomized trial was conducted to compare tumorectomy and breast irradiation with modified radical mastectomy. We have analyzed the patterns of failure in each arm of the trial and the prognostic factors that have an independent effect on treatment failures and overall survival.
PATIENTS AND METHODS: The trial included 179 patients with breast cancer of up to 20 mm in diameter at macroscopic examination. Eighty-eight patients had conservative management and 91 a mastectomy. All patients had axillary dissection with frozen-section examination. For patients with positive axillary nodes (N+), a second randomization was performed: lymph node irradiation versus no further regional treatment. Patterns of failure were determined by a competing-risk approach and multivariate analysis. A prognostic-score was determined by multivariate analysis.
RESULTS: Overall survival, distant metastasis, contralateral breast cancer, new primary malignancy, and locoregional recurrence rates were not significantly different between the two surgical groups, or between lymph node irradiation groups. Most recurrences appeared during the first 10 years. Three distinct prognostic groups were determined taking into account age, tumor size, histologic grading, and number of positive axillary nodes.
CONCLUSION: Long-term results support conservative treatment with limited surgery and systematic breast irradiation as a safe procedure for the management of small breast cancers. Four easily obtainable clinical and histologic factors may be combined in a prognostic score that is highly predictive of overall and event-free survival.

PMID 8622072  J Clin Oncol. 1996 May;14(5):1558-64.
著者:
雑誌名: J Natl Cancer Inst Monogr. 1992;(11):1-5.
Abstract/Text
PMID 1627416  J Natl Cancer Inst Monogr. 1992;(11):1-5.
著者: M Clarke, R Collins, S Darby, C Davies, P Elphinstone, E Evans, J Godwin, R Gray, C Hicks, S James, E MacKinnon, P McGale, T McHugh, R Peto, C Taylor, Y Wang, Early Breast Cancer Trialists' Collaborative Group (EBCTCG)
雑誌名: Lancet. 2005 Dec 17;366(9503):2087-106. doi: 10.1016/S0140-6736(05)67887-7.
Abstract/Text BACKGROUND: In early breast cancer, variations in local treatment that substantially affect the risk of locoregional recurrence could also affect long-term breast cancer mortality. To examine this relationship, collaborative meta-analyses were undertaken, based on individual patient data, of the relevant randomised trials that began by 1995.
METHODS: Information was available on 42,000 women in 78 randomised treatment comparisons (radiotherapy vs no radiotherapy, 23,500; more vs less surgery, 9300; more surgery vs radiotherapy, 9300). 24 types of local treatment comparison were identified. To help relate the effect on local (ie, locoregional) recurrence to that on breast cancer mortality, these were grouped according to whether or not the 5-year local recurrence risk exceeded 10% (<10%, 17,000 women; >10%, 25,000 women).
FINDINGS: About three-quarters of the eventual local recurrence risk occurred during the first 5 years. In the comparisons that involved little (<10%) difference in 5-year local recurrence risk there was little difference in 15-year breast cancer mortality. Among the 25,000 women in the comparisons that involved substantial (>10%) differences, however, 5-year local recurrence risks were 7% active versus 26% control (absolute reduction 19%), and 15-year breast cancer mortality risks were 44.6% versus 49.5% (absolute reduction 5.0%, SE 0.8, 2p<0.00001). These 25,000 women included 7300 with breast-conserving surgery (BCS) in trials of radiotherapy (generally just to the conserved breast), with 5-year local recurrence risks (mainly in the conserved breast, as most had axillary clearance and node-negative disease) 7% versus 26% (reduction 19%), and 15-year breast cancer mortality risks 30.5% versus 35.9% (reduction 5.4%, SE 1.7, 2p=0.0002; overall mortality reduction 5.3%, SE 1.8, 2p=0.005). They also included 8500 with mastectomy, axillary clearance, and node-positive disease in trials of radiotherapy (generally to the chest wall and regional lymph nodes), with similar absolute gains from radiotherapy; 5-year local recurrence risks (mainly at these sites) 6% versus 23% (reduction 17%), and 15-year breast cancer mortality risks 54.7% versus 60.1% (reduction 5.4%, SE 1.3, 2p=0.0002; overall mortality reduction 4.4%, SE 1.2, 2p=0.0009). Radiotherapy produced similar proportional reductions in local recurrence in all women (irrespective of age or tumour characteristics) and in all major trials of radiotherapy versus not (recent or older; with or without systemic therapy), so large absolute reductions in local recurrence were seen only if the control risk was large. To help assess the life-threatening side-effects of radiotherapy, the trials of radiotherapy versus not were combined with those of radiotherapy versus more surgery. There was, at least with some of the older radiotherapy regimens, a significant excess incidence of contralateral breast cancer (rate ratio 1.18, SE 0.06, 2p=0.002) and a significant excess of non-breast-cancer mortality in irradiated women (rate ratio 1.12, SE 0.04, 2p=0.001). Both were slight during the first 5 years, but continued after year 15. The excess mortality was mainly from heart disease (rate ratio 1.27, SE 0.07, 2p=0.0001) and lung cancer (rate ratio 1.78, SE 0.22, 2p=0.0004).
INTERPRETATION: In these trials, avoidance of a local recurrence in the conserved breast after BCS and avoidance of a local recurrence elsewhere (eg, the chest wall or regional nodes) after mastectomy were of comparable relevance to 15-year breast cancer mortality. Differences in local treatment that substantially affect local recurrence rates would, in the hypothetical absence of any other causes of death, avoid about one breast cancer death over the next 15 years for every four local recurrences avoided, and should reduce 15-year overall mortality.

PMID 16360786  Lancet. 2005 Dec 17;366(9503):2087-106. doi: 10.1016/S0・・・
著者: A D Morris, R D Morris, J F Wilson, J White, S Steinberg, P Okunieff, R Arriagada, M G Lê, M Blichert-Toft, J A van Dongen
雑誌名: Cancer J Sci Am. 1997 Jan-Feb;3(1):6-12.
Abstract/Text BACKGROUND: The randomized trials comparing breast-conserving therapy (BCT), i.e., surgery and radiation to the breast, with mastectomy in early-stage breast cancer use a variety of protocols. Meta-analysis may assist in understanding the impact of these differences on survival.
PURPOSE: To evaluate the possible variations of the relative efficacy of BCT and mastectomy in terms of overall survival according to tumor size, nodal status, and use of adjuvant radiation therapy.
METHODS: The most recent published results and, where available, updated patient-level data from randomized controlled trials of BCT and mastectomy for early-stage breast cancer were combined in a meta-analysis using a random effects model. Pooled survival rates and odds ratios were generated according to subgroups of nodal status and tumor size. Five- and 10-year odds ratios were also determined according to adjuvant radiation protocol.
RESULTS: The pooled odds ratio comparing 10-year survival for BCT and mastectomy was 0.91. The odds ratios comparing the two treatment regimens were not significant after grouping according to tumor size and nodal status. When more than 50% of node-positive patients in both the mastectomy and BCT arms received adjuvant radiation, both arms had similar survival rates. When less than 50% of node-positive patients in both arms received adjuvant nodal radiation, the odds ratio was 0.69, and patients receiving BCT had a survival advantage.
CONCLUSIONS: Patients allocated to BCT have survival rates at least as high as patients allocated to mastectomy. When all protocols were combined, nodal status and tumor size did not significantly alter the relative survival rates. However, under some conditions, particularly for node-positive patients, BCT may confer a relative survival advantage over mastectomy. In particular, mastectomy without adjuvant radiation appears to be inferior to BCT for node-positive patients.

PMID 9072310  Cancer J Sci Am. 1997 Jan-Feb;3(1):6-12.
著者: Armando E Giuliano, Kelly K Hunt, Karla V Ballman, Peter D Beitsch, Pat W Whitworth, Peter W Blumencranz, A Marilyn Leitch, Sukamal Saha, Linda M McCall, Monica Morrow
雑誌名: JAMA. 2011 Feb 9;305(6):569-75. doi: 10.1001/jama.2011.90.
Abstract/Text CONTEXT: Sentinel lymph node dissection (SLND) accurately identifies nodal metastasis of early breast cancer, but it is not clear whether further nodal dissection affects survival.
OBJECTIVE: To determine the effects of complete axillary lymph node dissection (ALND) on survival of patients with sentinel lymph node (SLN) metastasis of breast cancer.
DESIGN, SETTING, AND PATIENTS: The American College of Surgeons Oncology Group Z0011 trial, a phase 3 noninferiority trial conducted at 115 sites and enrolling patients from May 1999 to December 2004. Patients were women with clinical T1-T2 invasive breast cancer, no palpable adenopathy, and 1 to 2 SLNs containing metastases identified by frozen section, touch preparation, or hematoxylin-eosin staining on permanent section. Targeted enrollment was 1900 women with final analysis after 500 deaths, but the trial closed early because mortality rate was lower than expected.
INTERVENTIONS: All patients underwent lumpectomy and tangential whole-breast irradiation. Those with SLN metastases identified by SLND were randomized to undergo ALND or no further axillary treatment. Those randomized to ALND underwent dissection of 10 or more nodes. Systemic therapy was at the discretion of the treating physician.
MAIN OUTCOME MEASURES: Overall survival was the primary end point, with a noninferiority margin of a 1-sided hazard ratio of less than 1.3 indicating that SLND alone is noninferior to ALND. Disease-free survival was a secondary end point.
RESULTS: Clinical and tumor characteristics were similar between 445 patients randomized to ALND and 446 randomized to SLND alone. However, the median number of nodes removed was 17 with ALND and 2 with SLND alone. At a median follow-up of 6.3 years (last follow-up, March 4, 2010), 5-year overall survival was 91.8% (95% confidence interval [CI], 89.1%-94.5%) with ALND and 92.5% (95% CI, 90.0%-95.1%) with SLND alone; 5-year disease-free survival was 82.2% (95% CI, 78.3%-86.3%) with ALND and 83.9% (95% CI, 80.2%-87.9%) with SLND alone. The hazard ratio for treatment-related overall survival was 0.79 (90% CI, 0.56-1.11) without adjustment and 0.87 (90% CI, 0.62-1.23) after adjusting for age and adjuvant therapy.
CONCLUSION: Among patients with limited SLN metastatic breast cancer treated with breast conservation and systemic therapy, the use of SLND alone compared with ALND did not result in inferior survival.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00003855.

PMID 21304082  JAMA. 2011 Feb 9;305(6):569-75. doi: 10.1001/jama.2011.・・・
著者: Armando E Giuliano, Linda McCall, Peter Beitsch, Pat W Whitworth, Peter Blumencranz, A Marilyn Leitch, Sukamal Saha, Kelly K Hunt, Monica Morrow, Karla Ballman
雑誌名: Ann Surg. 2010 Sep;252(3):426-32; discussion 432-3. doi: 10.1097/SLA.0b013e3181f08f32.
Abstract/Text BACKGROUND AND OBJECTIVE: Sentinel lymph node dissection (SLND) has eliminated the need for axillary dissection (ALND) in patients whose sentinel node (SN) is tumor-free. However, completion ALND for patients with tumor-involved SNs remains the standard to achieve locoregional control. Few studies have examined the outcome of patients who do not undergo ALND for positive SNs. We now report local and regional recurrence information from the American College of Surgeons Oncology Group Z0011 trial.
METHODS: American College of Surgeons Oncology Group Z0011 was a prospective trial examining survival of patients with SN metastases detected by standard H and E, who were randomized to undergo ALND after SLND versus SLND alone without specific axillary treatment. Locoregional recurrence was evaluated.
RESULTS: There were 446 patients randomized to SLND alone and 445 to SLND + ALND. Patients in the 2 groups were similar with respect to age, Bloom-Richardson score, estrogen receptor status, use of adjuvant systemic therapy, tumor type, T stage, and tumor size. Patients randomized to SLND + ALND had a median of 17 axillary nodes removed compared with a median of only 2 SN removed with SLND alone (P < 0.001). ALND also removed more positive lymph nodes (P < 0.001). At a median follow-up time of 6.3 years, there were no statistically significant differences in local recurrence (P = 0.11) or regional recurrence (P = 0.45) between the 2 groups.
CONCLUSIONS: Despite the potential for residual axillary disease after SLND, SLND without ALND can offer excellent regional control and may be reasonable management for selected patients with early-stage breast cancer treated with breast-conserving therapy and adjuvant systemic therapy.

PMID 20739842  Ann Surg. 2010 Sep;252(3):426-32; discussion 432-3. doi・・・
著者: Armando E Giuliano, Karla V Ballman, Linda McCall, Peter D Beitsch, Meghan B Brennan, Pond R Kelemen, David W Ollila, Nora M Hansen, Pat W Whitworth, Peter W Blumencranz, A Marilyn Leitch, Sukamal Saha, Kelly K Hunt, Monica Morrow
雑誌名: JAMA. 2017 Sep 12;318(10):918-926. doi: 10.1001/jama.2017.11470.
Abstract/Text Importance: The results of the American College of Surgeons Oncology Group Z0011 (ACOSOG Z0011) trial were first reported in 2005 with a median follow-up of 6.3 years. Longer follow-up was necessary because the majority of the patients had estrogen receptor-positive tumors that may recur later in the disease course (the ACOSOG is now part of the Alliance for Clinical Trials in Oncology).
Objective: To determine whether the 10-year overall survival of patients with sentinel lymph node metastases treated with breast-conserving therapy and sentinel lymph node dissection (SLND) alone without axillary lymph node dissection (ALND) is noninferior to that of women treated with axillary dissection.
Design, Setting, and Participants: The ACOSOG Z0011 phase 3 randomized clinical trial enrolled patients from May 1999 to December 2004 at 115 sites (both academic and community medical centers). The last date of follow-up was September 29, 2015, in the ACOSOG Z0011 (Alliance) trial. Eligible patients were women with clinical T1 or T2 invasive breast cancer, no palpable axillary adenopathy, and 1 or 2 sentinel lymph nodes containing metastases.
Interventions: All patients had planned lumpectomy, planned tangential whole-breast irradiation, and adjuvant systemic therapy. Third-field radiation was prohibited.
Main Outcomes and Measures: The primary outcome was overall survival with a noninferiority hazard ratio (HR) margin of 1.3. The secondary outcome was disease-free survival.
Results: Among 891 women who were randomized (median age, 55 years), 856 (96%) completed the trial (446 in the SLND alone group and 445 in the ALND group). At a median follow-up of 9.3 years (interquartile range, 6.93-10.34 years), the 10-year overall survival was 86.3% in the SLND alone group and 83.6% in the ALND group (HR, 0.85 [1-sided 95% CI, 0-1.16]; noninferiority P = .02). The 10-year disease-free survival was 80.2% in the SLND alone group and 78.2% in the ALND group (HR, 0.85 [95% CI, 0.62-1.17]; P = .32). Between year 5 and year 10, 1 regional recurrence was seen in the SLND alone group vs none in the ALND group. Ten-year regional recurrence did not differ significantly between the 2 groups.
Conclusions and Relevance: Among women with T1 or T2 invasive primary breast cancer, no palpable axillary adenopathy, and 1 or 2 sentinel lymph nodes containing metastases, 10-year overall survival for patients treated with sentinel lymph node dissection alone was noninferior to overall survival for those treated with axillary lymph node dissection. These findings do not support routine use of axillary lymph node dissection in this patient population based on 10-year outcomes.
Trial Registration: clinicaltrials.gov Identifier: NCT00003855.

PMID 28898379  JAMA. 2017 Sep 12;318(10):918-926. doi: 10.1001/jama.20・・・
著者: Marieke E Straver, Philip Meijnen, Geertjan van Tienhoven, Cornelis J H van de Velde, Robert E Mansel, Jan Bogaerts, Nicole Duez, Luigi Cataliotti, Jean H G Klinkenbijl, Helen A Westenberg, Huub van der Mijle, Marko Snoj, Coen Hurkmans, Emiel J T Rutgers
雑誌名: Ann Surg Oncol. 2010 Jul;17(7):1854-61. doi: 10.1245/s10434-010-0945-z. Epub 2010 Mar 19.
Abstract/Text BACKGROUND: The randomized EORTC 10981-22023 AMAROS trial investigates whether breast cancer patients with a tumor-positive sentinel node biopsy (SNB) are best treated with an axillary lymph node dissection (ALND) or axillary radiotherapy (ART). The aim of the current substudy was to evaluate the identification rate and the nodal involvement.
METHODS: The first 2,000 patients participating in the AMAROS trial were evaluated. Associations between the identification rate and technical, patient-, and tumor-related factors were evaluated. The outcome of the SNB procedure and potential further nodal involvement was assessed.
RESULTS: In 65 patients, the sentinel node could not be identified. As a result, the sentinel node identification rate was 97% (1,888 of 1,953). Variables affecting the success rate were age, pathological tumor size, histology, year of accrual, and method of detection. The SNB results of 65% of the patients (n = 1,220) were negative and the patients underwent no further axillary treatment. The SNB results were positive in 34% of the patients (n = 647), including macrometastases (n = 409, 63%), micrometastases (n = 161, 25%), and isolated tumor cells (n = 77, 12%). Further nodal involvement in patients with macrometastases, micrometastases, and isolated tumor cells undergoing an ALND was 41, 18, and 18%, respectively.
CONCLUSIONS: With a 97% detection rate in this prospective international multicenter study, the SNB procedure is highly effective, especially when the combined method is used. Further nodal involvement in patients with micrometastases and isolated tumor cells in the sentinel node was similar-both were 18%.

PMID 20300966  Ann Surg Oncol. 2010 Jul;17(7):1854-61. doi: 10.1245/s1・・・
著者: Mila Donker, Geertjan van Tienhoven, Marieke E Straver, Philip Meijnen, Cornelis J H van de Velde, Robert E Mansel, Luigi Cataliotti, A Helen Westenberg, Jean H G Klinkenbijl, Lorenzo Orzalesi, Willem H Bouma, Huub C J van der Mijle, Grard A P Nieuwenhuijzen, Sanne C Veltkamp, Leen Slaets, Nicole J Duez, Peter W de Graaf, Thijs van Dalen, Andreas Marinelli, Herman Rijna, Marko Snoj, Nigel J Bundred, Jos W S Merkus, Yazid Belkacemi, Patrick Petignat, Dominic A X Schinagl, Corneel Coens, Carlo G M Messina, Jan Bogaerts, Emiel J T Rutgers
雑誌名: Lancet Oncol. 2014 Nov;15(12):1303-10. doi: 10.1016/S1470-2045(14)70460-7. Epub 2014 Oct 15.
Abstract/Text BACKGROUND: If treatment of the axilla is indicated in patients with breast cancer who have a positive sentinel node, axillary lymph node dissection is the present standard. Although axillary lymph node dissection provides excellent regional control, it is associated with harmful side-effects. We aimed to assess whether axillary radiotherapy provides comparable regional control with fewer side-effects.
METHODS: Patients with T1-2 primary breast cancer and no palpable lymphadenopathy were enrolled in the randomised, multicentre, open-label, phase 3 non-inferiority EORTC 10981-22023 AMAROS trial. Patients were randomly assigned (1:1) by a computer-generated allocation schedule to receive either axillary lymph node dissection or axillary radiotherapy in case of a positive sentinel node, stratified by institution. The primary endpoint was non-inferiority of 5-year axillary recurrence, considered to be not more than 4% for the axillary radiotherapy group compared with an expected 2% in the axillary lymph node dissection group. Analyses were by intention to treat and per protocol. The AMAROS trial is registered with ClinicalTrials.gov, number NCT00014612.
FINDINGS: Between Feb 19, 2001, and April 29, 2010, 4823 patients were enrolled at 34 centres from nine European countries, of whom 4806 were eligible for randomisation. 2402 patients were randomly assigned to receive axillary lymph node dissection and 2404 to receive axillary radiotherapy. Of the 1425 patients with a positive sentinel node, 744 had been randomly assigned to axillary lymph node dissection and 681 to axillary radiotherapy; these patients constituted the intention-to-treat population. Median follow-up was 6·1 years (IQR 4·1-8·0) for the patients with positive sentinel lymph nodes. In the axillary lymph node dissection group, 220 (33%) of 672 patients who underwent axillary lymph node dissection had additional positive nodes. Axillary recurrence occurred in four of 744 patients in the axillary lymph node dissection group and seven of 681 in the axillary radiotherapy group. 5-year axillary recurrence was 0·43% (95% CI 0·00-0·92) after axillary lymph node dissection versus 1·19% (0·31-2·08) after axillary radiotherapy. The planned non-inferiority test was underpowered because of the low number of events. The one-sided 95% CI for the underpowered non-inferiority test on the hazard ratio was 0·00-5·27, with a non-inferiority margin of 2. Lymphoedema in the ipsilateral arm was noted significantly more often after axillary lymph node dissection than after axillary radiotherapy at 1 year, 3 years, and 5 years.
INTERPRETATION: Axillary lymph node dissection and axillary radiotherapy after a positive sentinel node provide excellent and comparable axillary control for patients with T1-2 primary breast cancer and no palpable lymphadenopathy. Axillary radiotherapy results in significantly less morbidity.
FUNDING: EORTC Charitable Trust.

Copyright © 2014 Elsevier Ltd. All rights reserved.
PMID 25439688  Lancet Oncol. 2014 Nov;15(12):1303-10. doi: 10.1016/S14・・・
著者: Á Sávolt, G Péley, C Polgár, N Udvarhelyi, G Rubovszky, E Kovács, B Győrffy, M Kásler, Z Mátrai
雑誌名: Eur J Surg Oncol. 2017 Apr;43(4):672-679. doi: 10.1016/j.ejso.2016.12.011. Epub 2017 Jan 16.
Abstract/Text INTRODUCTION: The National Institute of Oncology, Budapest conducted a single centre randomized clinical study. The OTOASOR (Optimal Treatment Of the Axilla - Surgery Or Radiotherapy) trial compares completion of axillary lymph node dissection (cALND) to regional nodal irradiation (RNI) in patients with sentinel lymph node metastasis (pN1sn) in stage I-II breast cancer.
PATIENTS AND METHODS: Patients with primary invasive breast cancer (cN0 and cT ≤ 3 cm) were randomized before surgery for cALND (standard treatment) or RNI (investigational treatment). Sentinel lymph nodes (SN) were investigated with serial sectioning at 0.5 mm levels by hematoxylin-eosin staining. Investigational treatment arm patients received 50 Gy RNI instead of cALND. Adjuvant treatment and follow up were performed according to the actual guidelines. Between August 2002 and June 2009, 1054 patients were randomized for cALND and 1052 patients for RNI. SN was evaluated in 2073 patients and was positive in 526 patients (25.4%). 474 cases were evaluable (244 in the cALND and 230 in the RNI arm), and in the cALND group 94 of 244 patients (38.5%) who underwent completion axillary surgery has additional positive nodes. The two arms were well balanced according to the majority of main prognostic factors. Primary endpoint was axillary recurrence and secondary endpoints were overall survival (OS) and disease-free survival (DFS).
RESULTS: Mean follow-up was 97 months (Q1-Q3: 80-120). Axillary recurrence was 2.0% in cALND arm vs. 1.7% in RNI arm (p = 1.00). OS at 8 years was 77.9% vs. 84.8% (p = 0.060), and DFS was 72.1% in cALND arm and 77.4% after RNI (p = 0.51). The results show that RNI is statistically not inferior to cALND treatment.
CONCLUSIONS: The long term follow-up results of this prospective-randomized trial suggest that RNI without cALND does not increase the risk of axillary failure in selected patients with early-stage invasive breast cancer (cT ≤ 3 cm, cN0) and pN1(sn). Axillary radiotherapy should be an alternative treatment for selected patients with sentinel lymph node metastases.

Copyright © 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.
PMID 28139362  Eur J Surg Oncol. 2017 Apr;43(4):672-679. doi: 10.1016/・・・
著者: Gary H Lyman, Armando E Giuliano, Mark R Somerfield, Al B Benson, Diane C Bodurka, Harold J Burstein, Alistair J Cochran, Hiram S Cody, Stephen B Edge, Sharon Galper, James A Hayman, Theodore Y Kim, Cheryl L Perkins, Donald A Podoloff, Visa Haran Sivasubramaniam, Roderick R Turner, Richard Wahl, Donald L Weaver, Antonio C Wolff, Eric P Winer, American Society of Clinical Oncology
雑誌名: J Clin Oncol. 2005 Oct 20;23(30):7703-20. doi: 10.1200/JCO.2005.08.001. Epub 2005 Sep 12.
Abstract/Text PURPOSE: To develop a guideline for the use of sentinel node biopsy (SNB) in early stage breast cancer.
METHODS: An American Society of Clinical Oncology (ASCO) Expert Panel conducted a systematic review of the literature available through February 2004 on the use of SNB in early-stage breast cancer. The panel developed a guideline for clinicians and patients regarding the appropriate use of a sentinel lymph node identification and sampling procedure from hereon referred to as SNB. The guideline was reviewed by selected experts in the field and the ASCO Health Services Committee and was approved by the ASCO Board of Directors.
RESULTS: The literature review identified one published prospective randomized controlled trial in which SNB was compared with axillary lymph node dissection (ALND), four limited meta-analyses, and 69 published single-institution and multicenter trials in which the test performance of SNB was evaluated with respect to the results of ALND (completion axillary dissection). There are currently no data on the effect of SLN biopsy on long-term survival of patients with breast cancer. However, a review of the available evidence demonstrates that, when performed by experienced clinicians, SNB appears to be a safe and acceptably accurate method for identifying early-stage breast cancer without involvement of the axillary lymph nodes.
CONCLUSION: SNB is an appropriate initial alternative to routine staging ALND for patients with early-stage breast cancer with clinically negative axillary nodes. Completion ALND remains standard treatment for patients with axillary metastases identified on SNB. Appropriately identified patients with negative results of SNB, when done under the direction of an experienced surgeon, need not have completion ALND. Isolated cancer cells detected by pathologic examination of the SLN with use of specialized techniques are currently of unknown clinical significance. Although such specialized techniques are often used, they are not a required part of SLN evaluation for breast cancer at this time. Data suggest that SNB is associated with less morbidity than ALND, but the comparative effects of these two approaches on tumor recurrence or patient survival are unknown.

PMID 16157938  J Clin Oncol. 2005 Oct 20;23(30):7703-20. doi: 10.1200/・・・
著者: Theodore Kim, Armando E Giuliano, Gary H Lyman
雑誌名: Cancer. 2006 Jan 1;106(1):4-16. doi: 10.1002/cncr.21568.
Abstract/Text BACKGROUND: Lymphatic mapping with sentinel lymph node biopsy has the potential for reducing the morbidity associated with breast carcinoma staging. It has become a widely used technology despite limited data from controlled clinical trials.
METHODS: A systematic review of the world's literature of sentinel lymph node (SLN) biopsy in patients with early-stage breast carcinoma was undertaken by using electronic and hand searching techniques. Only studies that incorporated full axillary lymph node dissection (ALND), regardless of SLN results, were included. Individual study results along with weighted summary measures were estimated using the Mantel-Haenszel method. The correlations of outcomes with the study size, the proportion of positive lymph nodes, the technique used, and the study quality were evaluated.
RESULTS: Between 1970 and 2003, 69 trials were reported that met eligibility criteria. Of the 8059 patients who were studied, 7765 patients (96%) had successfully mapped SLNs. The proportion of patients who had successfully mapped SLNs ranged from 41% to 100%, with > 50% of studies reporting a rate < 90%. Lymph node involvement was found in 3132 patients (42%) and ranged from 17% to 74% across studies. The false-negative rate (FNR) ranged from 0% to 29%, averaging 7.3% overall. Eleven trials (15.9%) reported an FNR of 0.0, whereas 26 trials (37.7%) reported an FNR > 10%. Significant inverse correlations were observed between the FNR and both the number of patients studied (r = - 0.42; P < 0.01) and the proportion of patients who had successfully mapped SLNs nodes (r = - 0.32; P = 0.009).
CONCLUSIONS: Lymphatic mapping with SLN biopsy is used widely to reduce the complications associated with ALND in patients with low-risk breast carcinoma. This systematic review revealed a wide variation in test performance.

Copyright 2005 American Cancer Society.
PMID 16329134  Cancer. 2006 Jan 1;106(1):4-16. doi: 10.1002/cncr.21568・・・
著者: David N Krag, Stewart J Anderson, Thomas B Julian, Ann M Brown, Seth P Harlow, Takamaru Ashikaga, Donald L Weaver, Barbara J Miller, Lynne M Jalovec, Thomas G Frazier, R Dirk Noyes, André Robidoux, Hugh M C Scarth, Denise M Mammolito, David R McCready, Eleftherios P Mamounas, Joseph P Costantino, Norman Wolmark, National Surgical Adjuvant Breast and Bowel Project
雑誌名: Lancet Oncol. 2007 Oct;8(10):881-8. doi: 10.1016/S1470-2045(07)70278-4.
Abstract/Text BACKGROUND: The goals of axillary-lymph-node dissection (ALND) are to maximise survival, provide regional control, and stage the patient. However, this technique has substantial side-effects. The purpose of the B-32 trial is to establish whether sentinel-lymph-node (SLN) resection can achieve the same therapeutic goals as conventional ALND but with decreased side-effects. The aim of this paper is to report the technical success and accuracy of SLN resection plus ALND versus SLN resection alone.
METHODS: 5611 women with invasive breast cancer were randomly assigned to receive either SLN resection followed by immediate conventional ALND (n=2807; group 1) or SLN resection without ALND if SLNs were negative on intraoperative cytology and histological examination (n=2804; group 2) in the B-32 trial. Patients in group 2 underwent ALND if no SLNs were identified or if one or more SLNs were positive on intraoperative cytology or subsequent histological examination. Primary endpoints, including survival, regional control, and morbidity, will be reported later. Secondary endpoints are accuracy and technical success and are reported here. This trial is registered with the Clinical Trial registry, number NCT00003830.
FINDINGS: Data for technical success were available for 5536 of 5611 patients; 75 declined protocol treatment, had no SLNs removed, or had no SLN resection done. SLNs were successfully removed in 97.2% of patients (5379 of 5536) in both groups combined. Identification of a preincision hot spot was associated with greater SLN removal (98.9% [5072 of 5128]). Only 1.4% (189 of 13171) of SLN specimens were outside of axillary levels I and II. 65.1% (8571 of 13 171) of SLN specimens were both radioactive and blue; a small percentage was identified by palpation only (3.9% [515 of 13 171]). The overall accuracy of SLN resection in patients in group 1 was 97.1% (2544 of 2619; 95% CI 96.4-97.7), with a false-negative rate of 9.8% (75 of 766; 95% CI 7.8-12.2). Differences in tumour location, type of biopsy, and number of SLNs removed significantly affected the false-negative rate. Allergic reactions related to blue dye occurred in 0.7% (37 of 5588) of patients with data on toxic effects.
INTERPRETATION: The findings reported here indicate excellent balance in clinical patient characteristics between the two randomised groups and that the success of SLN resection was high. These findings are important because the B-32 trial is the only trial of sufficient size to provide definitive information related to the primary outcome measures of survival and regional control. Removal of more than one SLN and avoidance of excisional biopsy are important variables in reducing the false-negative rate.

PMID 17851130  Lancet Oncol. 2007 Oct;8(10):881-8. doi: 10.1016/S1470-・・・
著者: Umberto Veronesi, Giovanni Paganelli, Giuseppe Viale, Alberto Luini, Stefano Zurrida, Viviana Galimberti, Mattia Intra, Paolo Veronesi, Patrick Maisonneuve, Giovanna Gatti, Giovanni Mazzarol, Concetta De Cicco, Gianfranco Manfredi, Julia Rodríguez Fernández
雑誌名: Lancet Oncol. 2006 Dec;7(12):983-90. doi: 10.1016/S1470-2045(06)70947-0.
Abstract/Text BACKGROUND: In women with breast cancer, sentinel-lymph-node biopsy (SLNB) provides information that allows surgeons to avoid axillary-lymph-node dissection (ALND) if the SLN does not have metastasis, and has a favourable effect on quality of life. Results of our previous trial showed that SLNB accurately screens the ALN for metastasis in breast cancers of diameter 2 mm or less. We aimed to update this trial with results from longer follow-up.
METHODS: Women with breast tumours of diameter 2 cm or less were randomly assigned after breast-conserving surgery either to SLNB and total ALND (ALND group), or to SLNB followed by ALND only if the SLN was involved (SLN group). Analysis was restricted to patients whose tumour characteristics met eligibility criteria after treatment. The main endpoints were the number of axillary metastases in women in the SLN group with negative SLNs, staging power of SLNB, and disease-free and overall survival.
FINDINGS: Of the 257 patients in the ALND group, 83 (32%) had a positive SLN and 174 (68%) had a negative SLN; eight of those with negative SLNs were found to have false-negative SLNs. Of the 259 patients in the SLN group, 92 (36%) had a positive SLN, and 167 (65%) had a negative SLN. One case of overt clinical axillary metastasis was seen in the follow-up of the 167 women in the SLN group who did not receive ALND (ie, one false-negative). After a median follow-up of 79 months (range 15-97), 34 events associated with breast cancer occurred: 18 in the ALND group, and 16 in the SLN group (log-rank p=0.6). The overall 5-year survival of all patients was 96.4% (95% CI 94.1-98.7) in the ALND group and 98.4% (96.9-100) in the SLN group (log-rank p=0.1).
INTERPRETATION: SLNB can allow total ALND to be avoided in patients with negative SLNs, while reducing postoperative morbidity and the costs of hospital stay. The finding that only one overt axillary metastasis occurred during follow-up of patients who did not receive ALND (whereas eight cases were expected) could be explained by various hypotheses, including those from cancer-stem-cell research.

PMID 17138219  Lancet Oncol. 2006 Dec;7(12):983-90. doi: 10.1016/S1470・・・
著者: Arpana M Naik, Jane Fey, Mary Gemignani, Alexandra Heerdt, Leslie Montgomery, Jeanne Petrek, Elisa Port, Virgilio Sacchini, Lisa Sclafani, Kimberly VanZee, Raquel Wagman, Patrick I Borgen, Hiram S Cody
雑誌名: Ann Surg. 2004 Sep;240(3):462-8; discussion 468-71.
Abstract/Text OBJECTIVE: We sought to identify the rate of axillary recurrence after sentinel lymph node (SLN) biopsy for breast cancer.
SUMMARY BACKGROUND DATA: SLN biopsy is a new standard of care for axillary lymph node staging in breast cancer. Nevertheless, most validated series of SLN biopsy confirm that the SLN is falsely negative in 5-10% of node-positive cases, and few studies report the rate of axillary local recurrence (LR) for that subset of patients staged by SLN biopsy alone.
METHODS: Through December of 2002, 4008 consecutive SLN biopsy procedures were performed at Memorial Sloan-Kettering Cancer Center for unilateral invasive breast cancer. Patients were categorized in 4 groups: SLN-negative with axillary lymph node dissection (ALND; n = 326), SLN-negative without ALND (n = 2340), SLN-positive with ALND (n = 1132), and SLN-positive without ALND (n = 210). Clinical and pathologic characteristics and follow-up data for each of the 4 cohorts were evaluated with emphasis on patterns of axillary LR.
RESULTS: With a median follow-up of 31 months (range, 1-75), axillary LR occurred in 10/4008 (0.25%) patients overall. In 3 cases (0.07%) the axillary LR was the first site of treatment failure, in 4 (0.1%) it was coincident with breast LR, and in 3 (0.07%) it was coincident with distant metastases. Axillary LR was more frequent among the unconventionally treated SLN-positive/no ALND patients than in the other 3 conventionally treated cohorts (1.4% versus 0.18%, P = 0.013).
CONCLUSIONS: Axillary LR after SLN biopsy, with or without ALND, is a rare event, and this low relapse rate supports wider use of SLN biopsy for breast cancer staging. There is a low-risk subset of SLN-positive patients in whom completion ALND may not be required.

PMID 15319717  Ann Surg. 2004 Sep;240(3):462-8; discussion 468-71.
著者: Igor Langer, Walter Richard Marti, Ulrich Guller, Holger Moch, Felix Harder, Daniel Oertli, Markus Zuber
雑誌名: Ann Surg. 2005 Jan;241(1):152-8.
Abstract/Text OBJECTIVE: To assess the axillary recurrence rate in breast cancer patients with negative sentinel lymph node (SLN) or SLN micrometastases (>0.2 mm to SUMMARY BACKGROUND DATA: Under controlled study conditions, the SLN procedure proved to be a reliable method for the evaluation of the axillary nodal status in patients with early-stage invasive breast cancer. Axillary dissection of levels I and II can thus be omitted if the SLN is free of macrometastases. The prognostic value and potential therapeutic consequences of SLN micrometastases, however, remain a matter of great debate. We present the follow-up data of our prospective SLN study, particularly focusing on the axillary recurrence rate in patients with negative SLN and SLN micrometastases.
METHODS: In this prospective study, 236 SLN procedures were performed in 234 patients with early-stage breast cancer between April 1998 and September 2002. The SLN were marked and identified with 99m technetium-labeled colloid and blue dye (Isosulfanblue 1%). The excised SLNs were examined by step sectioning and stained with hematoxylin and eosin and immunohistochemistry (cytokeratin antibodies Lu-5 or CK 22). Only patients with SLN macrometastases received formal ALND of levels I and II, while patients with negative SLN or SLN micrometastases did not undergo further axillary surgery.
RESULTS: The SLN identification rate was 95% (224/236). SLN macrometastases were found in 33% (74/224) and micrometastases (>0.2 mm to CONCLUSIONS: Axillary recurrences in patients with negative SLN or SLN micrometastases did not occur more frequently after SLN biopsy alone compared with results from the recent literature regarding breast cancer patients undergoing formal ALND. Based on a median follow-up of 42 months-one of the longest so far in the literature-the present investigation does not provide evidence that the presence of SLN micrometastases leads to axillary recurrence or distant disease and supports the theory that formal ALND may be omitted in these patients.

PMID 15622003  Ann Surg. 2005 Jan;241(1):152-8.
著者: Robert E Mansel, Lesley Fallowfield, Mark Kissin, Amit Goyal, Robert G Newcombe, J Michael Dixon, Constantinos Yiangou, Kieran Horgan, Nigel Bundred, Ian Monypenny, David England, Mark Sibbering, Tholkifl I Abdullah, Lester Barr, Utheshtra Chetty, Dudley H Sinnett, Anne Fleissig, Dayalan Clarke, Peter J Ell
雑誌名: J Natl Cancer Inst. 2006 May 3;98(9):599-609. doi: 10.1093/jnci/djj158.
Abstract/Text BACKGROUND: Sentinel lymph node biopsy in women with operable breast cancer is routinely used in some countries for staging the axilla despite limited data from randomized trials on morbidity and mortality outcomes. We conducted a multicenter randomized trial to compare quality-of-life outcomes between patients with clinically node-negative invasive breast cancer who received sentinel lymph node biopsy and patients who received standard axillary treatment.
METHODS: The primary outcome measures were arm and shoulder morbidity and quality of life. From November 1999 to October 2003, 1031 patients were randomly assigned to undergo sentinel lymph node biopsy (n = 515) or standard axillary surgery (n = 516). Patients with sentinel lymph node metastases proceeded to delayed axillary clearance or received axillary radiotherapy (depending on the protocol at the treating institution). Intention-to-treat analyses of data at 1, 3, 6, and 12 months after surgery are presented. All statistical tests were two-sided.
RESULTS: The relative risks of any lymphedema and sensory loss for the sentinel lymph node biopsy group compared with the standard axillary treatment group at 12 months were 0.37 (95% confidence interval [CI] = 0.23 to 0.60; absolute rates: 5% versus 13%) and 0.37 (95% CI = 0.27 to 0.50; absolute rates: 11% versus 31%), respectively. Drain usage, length of hospital stay, and time to resumption of normal day-to-day activities after surgery were statistically significantly lower in the sentinel lymph node biopsy group (all P < .001), and axillary operative time was reduced (P = .055). Overall patient-recorded quality of life and arm functioning scores were statistically significantly better in the sentinel lymph node biopsy group throughout (all P < or = .003). These benefits were seen with no increase in anxiety levels in the sentinel lymph node biopsy group (P > .05).
CONCLUSION: Sentinel lymph node biopsy is associated with reduced arm morbidity and better quality of life than standard axillary treatment and should be the treatment of choice for patients who have early-stage breast cancer with clinically negative nodes.

PMID 16670385  J Natl Cancer Inst. 2006 May 3;98(9):599-609. doi: 10.1・・・
著者: Giorgio Zavagno, Gian Luca De Salvo, Giuliano Scalco, Fernando Bozza, Luca Barutta, Paola Del Bianco, Marco Renier, Carlo Racano, Paolo Carraro, Donato Nitti, GIVOM Trialists
雑誌名: Ann Surg. 2008 Feb;247(2):207-13. doi: 10.1097/SLA.0b013e31812e6a73.
Abstract/Text OBJECTIVE: The aim of this multicenter randomized trial was to assess the efficacy and safety of sentinel lymph node (SLN) biopsy compared with axillary lymph node dissection (ALND).
BACKGROUND: All studies on SLN biopsy in breast cancer report a variable false negative rate, whose prognostic consequences are still unclear.
METHODS: From May 1999 to December 2004, patients with breast cancer < or =3 cm were randomly assigned to receive SLN biopsy associated with ALND (ALND arm) or SLN biopsy followed by ALND only if the SLN was metastatic (SLN arm). The main aim was the comparison of disease-free survival in the 2 arms.
RESULTS: A total of 749 patients were randomized and 697 were available for analysis. SLNs were identified in 662 of 697 patients (95%) and positive SLNs were found in 189 of 662 patients (28.5%). In the ALND group, positive non-SLNs were found in 18 patients with negative SLN, giving a false negative rate of 16.7% (18 of 108). Postoperative side effects were significantly less in the SLN group and there was no negative impact of the SLN procedure on psychologic well being. At a median follow-up of 56 months, there were more locoregional recurrences in the SLN arm, and the 5-year disease-free survival was 89.9% in the ALND arm and 87.6% in the SLN arm, with a difference of 2.3% (95% confidence interval: -3.1% to 7.6%). However, the number of enrolled patients was not sufficient to draw definitive conclusions.
CONCLUSION: SLN biopsy is an effective and well-tolerated procedure. However, its safety should be confirmed by the results of larger randomized trials and meta-analyses.

PMID 18216523  Ann Surg. 2008 Feb;247(2):207-13. doi: 10.1097/SLA.0b01・・・
著者: David N Krag, Stewart J Anderson, Thomas B Julian, Ann M Brown, Seth P Harlow, Joseph P Costantino, Takamaru Ashikaga, Donald L Weaver, Eleftherios P Mamounas, Lynne M Jalovec, Thomas G Frazier, R Dirk Noyes, André Robidoux, Hugh Mc Scarth, Norman Wolmark
雑誌名: Lancet Oncol. 2010 Oct;11(10):927-33. doi: 10.1016/S1470-2045(10)70207-2.
Abstract/Text BACKGROUND: Sentinel-lymph-node (SLN) surgery was designed to minimise the side-effects of lymph-node surgery but still offer outcomes equivalent to axillary-lymph-node dissection (ALND). The aims of National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-32 were to establish whether SLN resection in patients with breast cancer achieves the same survival and regional control as ALND, but with fewer side-effects.
METHODS: NSABP B-32 was a randomised controlled phase 3 trial done at 80 centres in Canada and the USA between May 1, 1999, and Feb 29, 2004. Women with invasive breast cancer were randomly assigned to either SLN resection plus ALND (group 1) or to SLN resection alone with ALND only if the SLNs were positive (group 2). Random assignment was done at the NSABP Biostatistical Center (Pittsburgh, PA, USA) with a biased coin minimisation approach in an allocation ratio of 1:1. Stratification variables were age at entry (≤ 49 years, ≥ 50 years), clinical tumour size (≤ 2·0 cm, 2·1-4·0 cm, ≥ 4·1 cm), and surgical plan (lumpectomy, mastectomy). SLN resection was done with a blue dye and radioactive tracer. Outcome analyses were done in patients who were assessed as having pathologically negative sentinel nodes and for whom follow-up data were available. The primary endpoint was overall survival. Analyses were done on an intention-to-treat basis. All deaths, irrespective of cause, were included. The mean time on study for the SLN-negative patients with follow-up information was 95·6 months (range 70·1-126·7). This study is registered with ClinicalTrials.gov, number NCT00003830.
FINDINGS: 5611 women were randomly assigned to the treatment groups, 3989 had pathologically negative SLN. 309 deaths were reported in the 3986 SLN-negative patients with follow-up information: 140 of 1975 patients in group 1 and 169 of 2011 in group 2. Log-rank comparison of overall survival in groups 1 and 2 yielded an unadjusted hazard ratio (HR) of 1·20 (95% CI 0·96-1·50; p=0·12). 8-year Kaplan-Meier estimates for overall survival were 91·8% (95% CI 90·4-93·3) in group 1 and 90·3% (88·8-91·8) in group 2. Treatment comparisons for disease-free survival yielded an unadjusted HR of 1·05 (95% CI 0·90-1·22; p=0·54). 8-year Kaplan-Meier estimates for disease-free survival were 82·4% (80·5-84·4) in group 1 and 81·5% (79·6-83·4) in group 2. There were eight regional-node recurrences as first events in group 1 and 14 in group 2 (p=0·22). Patients are continuing follow-up for longer-term assessment of survival and regional control. The most common adverse events were allergic reactions, mostly related to the administration of the blue dye.
INTERPRETATION: Overall survival, disease-free survival, and regional control were statistically equivalent between groups. When the SLN is negative, SLN surgery alone with no further ALND is an appropriate, safe, and effective therapy for breast cancer patients with clinically negative lymph nodes.
FUNDING: US Public Health Service, National Cancer Institute, and Department of Health and Human Services.

Copyright © 2010 Elsevier Ltd. All rights reserved.
PMID 20863759  Lancet Oncol. 2010 Oct;11(10):927-33. doi: 10.1016/S147・・・
著者: G G Steger, R Greil, A Lang, M Rudas, F Fitzal, B Mlineritsch, B L Hartmann, R Bartsch, E Melbinger, M Hubalek, H Stoeger, P Dubsky, S Ressler, A L Petzer, C F Singer, C Muss, R Jakesz, S P Gampenrieder, C C Zielinski, C Fesl, M Gnant, Austrian Breast and Colorectal Study Group (ABCSG)
雑誌名: Ann Oncol. 2014 Feb;25(2):366-71. doi: 10.1093/annonc/mdt508. Epub 2013 Dec 16.
Abstract/Text BACKGROUND: This randomized phase III trial compared pathologic complete response (pCR) rates of early breast cancer (EBC) following neoadjuvant epirubicin-docetaxel (ED)±capecitabine (C), and evaluated the addition of trastuzumab in HER2-positive tumors.
PATIENTS AND METHODS: Patients with invasive breast cancer (except T4d) were randomly assigned to receive six 3-weekly cycles of ED (both 75 mg/m2)±C (1000 mg/m2, twice daily, days 1-14). Patients with HER2-positive disease were further randomized to receive trastuzumab (8 mg/kg, then 6 mg/kg every 3 weeks) or not. Primary end point: pCR rate at the time of surgery.
RESULTS: Five hundred thirty-six patients were randomized to ED (n=266) or EDC (n=270); 93 patients were further randomized to trastuzumab (n=44) or not (n=49). pCR rate was significantly increased with EDC (23.0% versus 15.4% ED, P=0.027), and nonsignificantly further increased with trastuzumab (38.6% EDC versus 26.5% ED, P=0.212). Rates of axillary node involvement at surgery and breast conservation were improved with EDC versus ED, but not significantly; the addition of trastuzumab had no further impact. Hormone receptor status, tumor size, grade, and C (all P≤0.035) were independent prognostic factors for pCR. Trastuzumab added to ED±C significantly increased the number of serious adverse events (35 versus 18; P=0.020), mainly due to infusion-related reactions.
CONCLUSION: These findings show that the integration of C into a neoadjuvant taxane-/anthracycline-based regimen is a feasible, safe, and effective treatment option, with incorporation of trastuzumab in HER2-positive disease.
CLINICAL TRIAL NUMBER: NCT00309556, www.clinicaltrials.gov.

PMID 24347519  Ann Oncol. 2014 Feb;25(2):366-71. doi: 10.1093/annonc/m・・・
著者: Aman U Buzdar, Nuhad K Ibrahim, Deborah Francis, Daniel J Booser, Eva S Thomas, Richard L Theriault, Lajos Pusztai, Marjorie C Green, Banu K Arun, Sharon H Giordano, Massimo Cristofanilli, Debra K Frye, Terry L Smith, Kelly K Hunt, Sonja E Singletary, Aysegul A Sahin, Michael S Ewer, Thomas A Buchholz, Donald Berry, Gabriel N Hortobagyi
雑誌名: J Clin Oncol. 2005 Jun 1;23(16):3676-85. doi: 10.1200/JCO.2005.07.032. Epub 2005 Feb 28.
Abstract/Text PURPOSE: The objective of this study was to determine whether the addition of trastuzumab to chemotherapy in the neoadjuvant setting could increase pathologic complete response (pCR) rate in patients with human epidermal growth factor receptor 2 (HER2) -positive disease.
PATIENTS AND METHODS: Forty-two patients with HER2-positive disease with operable breast cancer were randomly assigned to either four cycles of paclitaxel followed by four cycles of fluorouracil, epirubicin, and cyclophosphamide or to the same chemotherapy with simultaneous weekly trastuzumab for 24 weeks. The primary objective was to demonstrate a 20% improvement in pCR (assumed 21% to 41%) with the addition of trastuzumab to chemotherapy. The planned sample size was 164 patients.
RESULTS: Prognostic factors were similar in the two groups. After 34 patients had completed therapy, the trial's Data Monitoring Committee stopped the trial because of superiority of trastuzumab plus chemotherapy. pCR rates were 25% and 66.7% for chemotherapy (n = 16) and trastuzumab plus chemotherapy (n = 18), respectively (P = .02). The decision was based on the calculation that, if study continued to 164 patients, there was a 95% probability that trastuzumab plus chemotherapy would be superior. Of the 42 randomized patients, 26% in the chemotherapy arm achieved pCR compared with 65.2% in the trastuzumab plus chemotherapy arm (P = .016). The safety of this approach is not established, although no clinical congestive heart failure was observed. A more than 10% decrease in the cardiac ejection fraction was observed in five and seven patients in the chemotherapy and trastuzumab plus chemotherapy arms, respectively.
CONCLUSION: Despite the small sample size, these data indicate that adding trastuzumab to chemotherapy, as used in this trial, significantly increased pCR without clinical congestive heart failure.

PMID 15738535  J Clin Oncol. 2005 Jun 1;23(16):3676-85. doi: 10.1200/J・・・
著者: Aman U Buzdar, Vicente Valero, Nuhad K Ibrahim, Deborah Francis, Kristine R Broglio, Richard L Theriault, Lajos Pusztai, Marjorie C Green, Sonja E Singletary, Kelly K Hunt, Aysegul A Sahin, Francisco Esteva, William F Symmans, Michael S Ewer, Thomas A Buchholz, Gabriel N Hortobagyi
雑誌名: Clin Cancer Res. 2007 Jan 1;13(1):228-33. doi: 10.1158/1078-0432.CCR-06-1345.
Abstract/Text PURPOSE: Findings from our previously published phase III randomized trial showed a high pathologic complete remission (CR) rate in patients with human epidermal growth factor receptor 2-positive breast cancer after the concurrent administration of trastuzumab and paclitaxel, followed by concurrent trastuzumab and 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) preoperative chemotherapy. The safety and efficacy data of initial population were updated, with inclusion of additional experience with the same therapy. Study Design: The initial randomized study population of 42 patients were randomly assigned to either four cycles of paclitaxel followed by four cycles of FEC or to the same chemotherapy with simultaneous weekly trastuzumab for 24 weeks. All data were updated through November 2005.
RESULTS: Pretreatment characteristics of the initial patients and of the second cohort were similar. In the second cohort, pathologic CR rate was 54.5% (95% confidence interval, 32.2-75.6%) and the pathologic CR rate among all patients treated with chemotherapy plus trastuzumab was 60% (95% confidence interval, 44.3-74.3%). Three patients in the chemotherapy only group have recurred, and one has died. There has been no recurrences in the patients randomized to chemotherapy plus trastuzumab, and the estimated disease-free survival at 1 and 3 years was 100% (P = 0.041). In additional cohort treated with chemotherapy and trastuzumab at the median follow-up of 16.3 months, no patients had recurred. No new safety concerns were observed in this study.
CONCLUSION: Our expanded cardiac safety data and the updated efficacy data showed that the natural history of this subset of breast cancer patients can be substantially modified by this treatment approach.

PMID 17200359  Clin Cancer Res. 2007 Jan 1;13(1):228-33. doi: 10.1158/・・・
著者: Luca Gianni, Wolfgang Eiermann, Vladimir Semiglazov, Ana Lluch, Sergei Tjulandin, Milvia Zambetti, Angela Moliterni, Federico Vazquez, Mikhail J Byakhov, Mikhail Lichinitser, Miguel Angel Climent, Eva Ciruelos, Belen Ojeda, Mauro Mansutti, Alla Bozhok, Domenico Magazzù, Dominik Heinzmann, Jutta Steinseifer, Pinuccia Valagussa, Jose Baselga
雑誌名: Lancet Oncol. 2014 May;15(6):640-7. doi: 10.1016/S1470-2045(14)70080-4. Epub 2014 Mar 20.
Abstract/Text BACKGROUND: In our randomised, controlled, phase 3 trial NeOAdjuvant Herceptin (NOAH) trial in women with HER2-positive locally advanced or inflammatory breast cancer, neoadjuvant trastuzumab significantly improved pathological complete response rate and event-free survival. We report updated results from our primary analysis to establish the long-term benefit of trastuzumab-containing neoadjuvant therapy.
METHODS: We did this multicentre, open-label, randomised trial in women with HER2-positive locally advanced or inflammatory breast cancer. Participants were randomly assigned (1:1), by computer program with a minimisation technique, to receive neoadjuvant chemotherapy alone or with 1 year of trastuzumab (concurrently with neoadjuvant chemotherapy and continued after surgery). A parallel group with HER2-negative disease was included and received neoadjuvant chemotherapy alone. Our primary endpoint was event-free survival. Analysis was by intention to treat. This study is registered at www.controlled-trials.com, ISRCTN86043495.
FINDINGS: Between June 20, 2002, and Dec 12, 2005, we enrolled 235 patients with HER2-positive disease, of whom 118 received chemotherapy alone and 117 received chemotherapy plus trastuzumab. 99 additional patients with HER2-negative disease were included in the parallel cohort. After a median follow-up of 5.4 years (IQR 3.1-6.8) the event-free-survival benefit from the addition of trastuzumab to chemotherapy was maintained in patients with HER2-positive disease. 5 year event-free survival was 58% (95% CI 48-66) in patients in the trastuzumab group and 43% (34-52) in those in the chemotherapy group; the unadjusted hazard ratio (HR) for event-free survival between the two randomised HER2-positive treatment groups was 0.64 (95% CI 0.44-0.93; two-sided log-rank p=0.016). Event-free survival was strongly associated with pathological complete remission in patients given trastuzumab. Of the 68 patients with a pathological complete response (45 with trastuzumab and 23 with chemotherapy alone), the HR for event-free survival between those with and without trastuzumab was 0.29 (95% CI 0.11-0.78). During follow-up only four cardiovascular adverse events were regarded by the investigator to be drug-related (grade 2 lymphostasis and grade 2 lymphoedema, each in one patient in the trastuzumab group, and grade 2 thrombosis and grade 2 deep vein thrombosis, each in one patient in the chemotherapy-alone group).
INTERPRETATION: These results show a sustained benefit in event-free survival from trastuzumab-containing neoadjuvant therapy followed by adjuvant trastuzumab in patients with locally advanced or inflammatory breast cancer, and provide new insight into the association between pathological complete remission and long-term outcomes in HER2-positive disease.

Copyright © 2014 Elsevier Ltd. All rights reserved.
PMID 24657003  Lancet Oncol. 2014 May;15(6):640-7. doi: 10.1016/S1470-・・・
著者: Luca Gianni, Wolfgang Eiermann, Vladimir Semiglazov, Alexey Manikhas, Ana Lluch, Sergey Tjulandin, Milvia Zambetti, Federico Vazquez, Mikhail Byakhow, Mikhail Lichinitser, Miguel Angel Climent, Eva Ciruelos, Belén Ojeda, Mauro Mansutti, Alla Bozhok, Roberta Baronio, Andrea Feyereislova, Claire Barton, Pinuccia Valagussa, Jose Baselga
雑誌名: Lancet. 2010 Jan 30;375(9712):377-84. doi: 10.1016/S0140-6736(09)61964-4.
Abstract/Text BACKGROUND: The monoclonal antibody trastuzumab has survival benefit when given with chemotherapy to patients with early, operable, and metastatic breast cancer that has HER2 (also known as ERBB2) overexpression or amplification. We aimed to assess event-free survival in patients with HER2-positive locally advanced or inflammatory breast cancer receiving neoadjuvant chemotherapy with or without 1 year of trastuzumab.
METHODS: We compared 1 year of treatment with trastuzumab (given as neoadjuvant and adjuvant treatment; n=117) with no trastuzumab (118), in women with HER2-positive locally advanced or inflammatory breast cancer treated with a neoadjuvant chemotherapy regimen consisting of doxorubicin, paclitaxel, cyclophosphamide, methotrexate, and fluorouracil. Randomisation was done with a computer program and minimisation technique, taking account of geographical area, disease stage, and hormone receptor status. Investigators were informed of treatment allocation. A parallel cohort of 99 patients with HER2-negative disease was included and treated with the same chemotherapy regimen. Primary endpoint was event-free survival. Analysis was by intention to treat. This study is registered, number ISRCTN86043495.
FINDINGS: Trastuzumab significantly improved event-free survival in patients with HER2-positive breast cancer (3-year event-free survival, 71% [95% CI 61-78; n=36 events] with trastuzumab, vs 56% [46-65; n=51 events] without; hazard ratio 0.59 [95% CI 0.38-0.90]; p=0.013). Trastuzumab was well tolerated and, despite concurrent administration with doxorubicin, only two patients (2%) developed symptomatic cardiac failure. Both responded to cardiac drugs.
INTERPRETATION: The addition of neoadjuvant and adjuvant trastuzumab to neoadjuvant chemotherapy should be considered for women with HER2-positive locally advanced or inflammatory breast cancer to improve event-free survival, survival, and clinical and pathological tumour responses.
FUNDING: F Hoffmann-La Roche.

Copyright 2010 Elsevier Ltd. All rights reserved.
PMID 20113825  Lancet. 2010 Jan 30;375(9712):377-84. doi: 10.1016/S014・・・
著者: Jean-Yves Pierga, Suzette Delaloge, Marc Espié, Etienne Brain, Brigitte Sigal-Zafrani, Marie-Christine Mathieu, Philippe Bertheau, Jean Marc Guinebretière, Marc Spielmann, Alexia Savignoni, Michel Marty
雑誌名: Breast Cancer Res Treat. 2010 Jul;122(2):429-37. doi: 10.1007/s10549-010-0939-3. Epub 2010 May 18.
Abstract/Text To assess anti-tumor activity of sequential epirubicin/cyclophosphamide followed by docetaxel with the randomized addition of celecoxib in HER2 negative patients or trastuzumab in HER2 positive patients. From May 2004 till October 2007, 340 patients with stage II and III breast adenocarcinoma, ineligible for breast conserving surgery, received eight sequential three weekly cycles of EC-D [epirubicin (75 mg/m(2))-cyclophosphamide (750 mg/m(2)) for four cycles followed by docetaxel (100 mg/m(2)) for four cycles]. HER2-negative patients (N = 220) were randomized to receive concomitantly with docetaxel celecoxib 800 mg/day during cycles 5-8 or no additional treatment, while HER2-positive patients confirmed by FISH (N = 120) were randomized to trastuzumab concomitant to docetaxel (8 mg/kg then 6 mg/kg IV every 3 weeks) or no additional preoperative treatment. In the HER2 negative group, pCR (grade 1 and 2 of Chevallier's classification) was observed in 11.5 and 13% of patients treated without and with neoadjuvant Celecoxib, respectively. In the HER2 positive group, pCR rate reached 26% in those who received neoadjuvant trastuzumab versus 19% in the others. There was no unexpected toxicity, no cardiac toxicity, and no toxic death. Triple negative breast cancers experience the highest pCR rate of 30%. Celecoxib is not likely to improve pCR rates in addition to EC-D in patients with HER2-negative tumor. In HER2-positive tumor patients, trastuzumab added to ECD leads to increased pCR rates. It was the only combination to deserve further study according to the two-stage Fleming's design used in this trial.

PMID 20480225  Breast Cancer Res Treat. 2010 Jul;122(2):429-37. doi: 1・・・
著者: Luca Gianni, Tadeusz Pienkowski, Young-Hyuck Im, Laslo Roman, Ling-Ming Tseng, Mei-Ching Liu, Ana Lluch, Elżbieta Staroslawska, Juan de la Haba-Rodriguez, Seock-Ah Im, Jose Luiz Pedrini, Brigitte Poirier, Paolo Morandi, Vladimir Semiglazov, Vichien Srimuninnimit, Giulia Bianchi, Tania Szado, Jayantha Ratnayake, Graham Ross, Pinuccia Valagussa
雑誌名: Lancet Oncol. 2012 Jan;13(1):25-32. doi: 10.1016/S1470-2045(11)70336-9. Epub 2011 Dec 6.
Abstract/Text BACKGROUND: Studies with pertuzumab, a novel anti-HER2 antibody, show improved efficacy when combined with the established HER2-directed antibody trastuzumab in breast cancer therapy. We investigated the combination of pertuzumab or trastuzumab, or both, with docetaxel and the combination of pertuzumab and trastuzumab without chemotherapy in the neoadjuvant setting.
METHODS: In this multicentre, open-label, phase 2 study, treatment-naive women with HER2-positive breast cancer were randomly assigned (1:1:1:1) centrally and stratified by operable, locally advanced, and inflammatory breast cancer, and by hormone receptor expression to receive four neoadjuvant cycles of: trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) plus docetaxel (75 mg/m(2), escalating, if tolerated, to 100 mg/m(2) every 3 weeks; group A) or pertuzumab (loading dose 840 mg, followed by 420 mg every 3 weeks) and trastuzumab plus docetaxel (group B) or pertuzumab and trastuzumab (group C) or pertuzumab plus docetaxel (group D). The primary endpoint, examined in the intention-to-treat population, was pathological complete response in the breast. Neither patients nor investigators were masked to treatment. This study is registered with ClinicalTrials.gov, number NCT00545688.
FINDINGS: Of 417 eligible patients, 107 were randomly assigned to group A, 107 to group B, 107 to group C, and 96 to group D. Patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate (49 of 107 patients; 45·8% [95% CI 36·1-55·7]) compared with those given trastuzumab plus docetaxel (group A; 31 of 107; 29·0% [20·6-38·5]; p=0·0141). 23 of 96 (24·0% [15·8-33·7]) women given pertuzumab plus docetaxel (group D) had a pathological complete response, as did 18 of 107 (16·8% [10·3-25·3]) given pertuzumab and trastuzumab (group C). The most common adverse events of grade 3 or higher were neutropenia (61 of 107 women in group A, 48 of 107 in group B, one of 108 in group C, and 52 of 94 in group D), febrile neutropenia (eight, nine, none, and seven, respectively), and leucopenia (13, five, none, and seven, respectively). The number of serious adverse events was similar in groups A, B, and D (15-20 serious adverse events per group in 10-17% of patients) but lower in group C (four serious adverse events in 4% of patients).
INTERPRETATION: Patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate compared with those given trastuzumab plus docetaxel, without substantial differences in tolerability. Pertuzumab and trastuzumab without chemotherapy eradicated tumours in a proportion of women and showed a favourable safety profile. These findings justify further exploration in adjuvant trials and support the neoadjuvant approach for accelerating drug assessment in early breast cancer.
FUNDING: F Hoffmann-La Roche.

Copyright © 2012 Elsevier Ltd. All rights reserved.
PMID 22153890  Lancet Oncol. 2012 Jan;13(1):25-32. doi: 10.1016/S1470-・・・
著者: Luca Gianni, Tadeusz Pienkowski, Young-Hyuck Im, Ling-Ming Tseng, Mei-Ching Liu, Ana Lluch, Elżbieta Starosławska, Juan de la Haba-Rodriguez, Seock-Ah Im, Jose Luiz Pedrini, Brigitte Poirier, Paolo Morandi, Vladimir Semiglazov, Vichien Srimuninnimit, Giulia Valeria Bianchi, Domenico Magazzù, Virginia McNally, Hannah Douthwaite, Graham Ross, Pinuccia Valagussa
雑誌名: Lancet Oncol. 2016 Jun;17(6):791-800. doi: 10.1016/S1470-2045(16)00163-7. Epub 2016 May 11.
Abstract/Text BACKGROUND: In the primary analysis of the NeoSphere trial, patients given neoadjuvant pertuzumab, trastuzumab, and docetaxel showed a significantly improved pathological complete response compared with those given trastuzumab and docetaxel after surgery. Here, we report 5-year progression-free survival, disease-free survival, and safety.
METHODS: In this multicentre, open-label, phase 2 randomised trial in hospitals and medical clinics, treatment-naive adults with locally advanced, inflammatory, or early-stage HER2-positive breast cancer were randomly assigned (1:1:1:1) to receive four neoadjuvant cycles of trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) plus docetaxel (75 mg/m(2) every 3 weeks, increasing to 100 mg/m(2) from cycle 2 if tolerated; group A), pertuzumab (840 mg loading dose, followed by 420 mg every 3 weeks) and trastuzumab plus docetaxel (group B), pertuzumab and trastuzumab (group C), or pertuzumab and docetaxel (group D). After surgery, patients received three cycles of FEC (fluorouracil 600 mg/m(2), epirubicin 90 mg/m(2), and cyclophosphamide 600 mg/m(2)) every 3 weeks (patients in group C received four cycles of docetaxel prior to FEC), and trastuzumab 6 mg/kg every 3 weeks to complete 1 year's treatment (17 cycles in total). Randomisation was done by a central centre using dynamic allocation, stratified by operable, locally advanced, and inflammatory breast cancer, and by oestrogen and/or progesterone receptor positivity. Safety analyses were done according to treatment received. The primary endpoint (pathological complete response) was previously reported; secondary endpoints reported here are 5-year progression-free survival (analysed in the intention-to-treat population) and disease-free survival (analysed in patients who had surgery). Secondary and exploratory analyses were not powered for formal statistical hypothesis testing, and therefore results are for descriptive purposes only. The study ended on Sept 22, 2014 (last patient, last visit). This study is registered with ClinicalTrials.gov, number NCT00545688.
FINDINGS: Between Dec 17, 2007, and Dec 22, 2009, 417 eligible patients were randomly assigned to group A (107 patients), group B (107 patients), group C (107 patients), or group D (96 patients). One patient in group A withdrew before treatment. One patient assigned to group D received group A treatment, one patient assigned to group D received group B treatment, and one patient assigned to group B received group C treatment. At clinical cutoff, 87 patients had progressed or died. 5-year progression-free survival rates were 81% (95% CI 71-87) for group A, 86% (77-91) for group B, 73% (64-81) for group C, and 73% (63-81) for group D (hazard ratios 0·69 [95% CI 0·34-1·40] group B vs group A, 1·25 [0·68-2·30] group C vs group A, and 2·05 [1·07-3·93] group D vs group B). Disease-free survival results were consistent with progression-free survival results and were 81% (95% CI 72-88) for group A, 84% (72-91) for group B, 80% (70-86) for group C, and 75% (64-83) for group D. Patients who achieved total pathological complete response (all groups combined) had longer progression-free survival compared with patients who did not (85% [76-91] in patients who achieved total pathological response vs 76% [71-81] in patients who did not achieve total pathological response; hazard ratio 0·54 [95% CI 0·29-1·00]). There were no new or long-term safety concerns and tolerability was similar across groups (neoadjuvant and adjuvant treatment periods combined). The most common grade 3 or worse adverse events were neutropenia (group A: 71 [66%] of 107 patients; group B: 59 [55%] of 107; group C: 40 [37%] of 108; group D: 60 [64%] of 94), febrile neutropenia (group A: 10 [9%]; group B: 12 [11%]; group C: 5 [5%]; group D: 15 [16%]), and leucopenia (group A: 13 [12%]; group B: 6 [6%]; group C: 4 [4%]; group D: 8 [9%]). The number of patients with one or more serious adverse event was similar across groups (19-22 serious adverse events per group in 18-22% of patients).
INTERPRETATION: Progression-free survival and disease-free survival at 5-year follow-up show large and overlapping CIs, but support the primary endpoint (pathological complete response) and suggest that neoadjuvant pertuzumab is beneficial when combined with trastuzumab and docetaxel. Additionally, they suggest that total pathological complete response could be an early indicator of long-term outcome in early-stage HER2-positive breast cancer.
FUNDING: F Hoffmann-La Roche.

Copyright © 2016 Elsevier Ltd. All rights reserved.
PMID 27179402  Lancet Oncol. 2016 Jun;17(6):791-800. doi: 10.1016/S147・・・
著者: A Schneeweiss, S Chia, T Hickish, V Harvey, A Eniu, R Hegg, C Tausch, J H Seo, Y-F Tsai, J Ratnayake, V McNally, G Ross, J Cortés
雑誌名: Ann Oncol. 2013 Sep;24(9):2278-84. doi: 10.1093/annonc/mdt182. Epub 2013 May 22.
Abstract/Text BACKGROUND: Pertuzumab (P) combined with trastuzumab (H)-based chemotherapy improves efficacy in early and advanced HER2-positive breast cancer. We assessed the tolerability, with particular focus on cardiac safety, of H and P with chemotherapy in the neoadjuvant treatment of HER2-positive early breast cancer.
PATIENTS AND METHODS: In this multicenter, open-label phase II study, patients with operable, locally advanced, or inflammatory breast cancer were randomized 1 : 1 : 1 to receive six neoadjuvant cycles q3w (Arm A: 5-fluorouracil, epirubicin, cyclophosphamide [FEC] + H + P ×3 → docetaxel [T] + H + P ×3; Arm B: FEC ×3 → T + H + P ×3; Arm C: T + carboplatin + H [TCH]+P ×6). pCR was assessed at surgery and adjuvant therapy given to complete 1 year of H.
RESULTS: Two hundred twenty-five patients were randomized. During neoadjuvant treatment, two patients (2.7%; Arm B) experienced symptomatic left ventricular systolic dysfunction (LVSD) and 11 patients (Arm A: 4 [5.6%]; Arm B: 4 [5.3%]; Arm C: 3 [3.9%]) had declines in left ventricular ejection fraction of ≥10% points from baseline to <50%. Diarrhea was the most common adverse event. pCR (ypT0/is) was reported for 61.6% (Arm A), 57.3% (Arm B), and 66.2% (Arm C) of patients.
CONCLUSION: The combination of P with H and standard chemotherapy resulted in low rates of symptomatic LVSD.

PMID 23704196  Ann Oncol. 2013 Sep;24(9):2278-84. doi: 10.1093/annonc/・・・
著者: S M Swain, M S Ewer, G Viale, S Delaloge, J-M Ferrero, M Verrill, R Colomer, C Vieira, T L Werner, H Douthwaite, D Bradley, M Waldron-Lynch, A Kiermaier, J Eng-Wong, C Dang, BERENICE Study Group
雑誌名: Ann Oncol. 2018 Mar 1;29(3):646-653. doi: 10.1093/annonc/mdx773.
Abstract/Text Background: Anti-HER2 therapies are associated with a risk of increased cardiac toxicity, particularly when part of anthracycline-containing regimens. We report cardiac safety of pertuzumab, trastuzumab, and chemotherapy in the neoadjuvant treatment of HER2-positive early breast cancer.
Patients and methods: BERENICE (NCT02132949) is a nonrandomized, phase II, open-label, multicenter, multinational study in patients with normal cardiac function. In the neoadjuvant period, cohort A patients received four cycles of dose-dense doxorubicin and cyclophosphamide, then 12 doses of standard paclitaxel plus four standard trastuzumab and pertuzumab cycles. Cohort B patients received four standard fluorouracil/epirubicin/cyclophosphamide cycles, then four docetaxel cycles with four standard trastuzumab and pertuzumab cycles. The primary end point was cardiac safety during neoadjuvant treatment, assessed by the incidence of New York Heart Association class III/IV heart failure and of left ventricular ejection fraction declines (≥10 percentage-points from baseline and to a value of <50%). The main efficacy end point was pathologic complete response (pCR, ypT0/is ypN0). Results are descriptive.
Results: Safety populations were 199 and 198 patients in cohorts A and B, respectively. Three patients [1.5%; 95% confidence interval (CI) 0.31% to 4.34%] in cohort A experienced four New York Heart Association class III/IV heart failure events. Thirteen patients (6.5%; 95% CI 3.5% to 10.9%) in cohort A and four (2.0%; 95% CI 0.6% to 5.1%) in cohort B experienced at least one left ventricular ejection fraction decline. No new safety signals were identified. pCR rates were 61.8% and 60.7% in cohorts A and B, respectively. The highest pCR rates were in the HER2-enriched PAM50 subtype (75.0% and 73.7%, respectively).
Conclusion: Treatment with pertuzumab, trastuzumab, and common anthracycline-containing regimens for the neoadjuvant treatment of early breast cancer resulted in cardiac and general safety profiles, and pCR rates, consistent with prior studies with pertuzumab.
Clinical Trial Information: NCT02132949.

PMID 29253081  Ann Oncol. 2018 Mar 1;29(3):646-653. doi: 10.1093/annon・・・
著者: Sara A Hurvitz, Miguel Martin, W Fraser Symmans, Kyung Hae Jung, Chiun-Sheng Huang, Alastair M Thompson, Nadia Harbeck, Vicente Valero, Daniil Stroyakovskiy, Hans Wildiers, Mario Campone, Jean-François Boileau, Matthias W Beckmann, Karen Afenjar, Rodrigo Fresco, Hans-Joachim Helms, Jin Xu, Yvonne G Lin, Joseph Sparano, Dennis Slamon
雑誌名: Lancet Oncol. 2018 Jan;19(1):115-126. doi: 10.1016/S1470-2045(17)30716-7. Epub 2017 Nov 23.
Abstract/Text BACKGROUND: HER2-targeted treatments have improved outcomes in patients with HER2-positive breast cancer in the neoadjuvant, adjuvant, and metastatic settings; however, some patients remain at risk of relapse or death for many years after treatment of early-stage disease. Therefore, new strategies are needed. We did a phase 3 trial to assess a neoadjuvant regimen for HER2-positive breast cancer that replaces traditional systemic chemotherapy with targeted treatment.
METHODS: We did a randomised, open-label phase 3 KRISTINE trial in 68 Translational Research In Oncology centres (hospitals and specialty cancer centres in Asia, Europe, USA, and Canada). Eligible participants were aged 18 years or older with centrally confirmed HER2-positive stage II-III operable breast cancer (>2 cm tumour size), an Eastern Cooperative Oncology Group performance status of 0-1, and a baseline left ventricular ejection fraction of at least 55% (by echocardiogram or multiple-gated acquisition scan). We randomly assigned participants (1:1) to receive either trastuzumab emtansine plus pertuzumab or docetaxel, carboplatin, and trastuzumab plus pertuzumab. We did the randomisation via an interactive response system under a permuted block randomisation scheme (block size of four), stratified by hormone receptor status, stage at diagnosis, and geographical location. Patients received six cycles (every 3 weeks) of neoadjuvant trastuzumab emtansine plus pertuzumab (trastuzumab emtansine 3·6 mg/kg; pertuzumab 840 mg loading dose, 420 mg maintenance doses) or docetaxel, carboplatin, and trastuzumab plus pertuzumab (docetaxel 75 mg/m2; carboplatin area under the concentration-time curve 6 mg/mL × min; trastuzumab 8 mg/kg loading dose, 6 mg/kg maintenance doses) plus pertuzumab [same dosing as in the other group]). All treatments were administered intravenously. The primary objective was to compare the number of patients who achieved a pathological complete response (ypT0/is, ypN0), between groups in the intention-to-treat population (two-sided assessment), based on local evaluation of tumour samples taken at breast cancer surgery done between 14 days and 6 weeks after completion of neoadjuvant therapy. Safety was analysed in patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT02131064, and follow-up of the adjuvant phase is ongoing.
FINDINGS: Between June 25, 2014, and June 15, 2015, we randomly assigned 444 patients to neoadjuvant treatment with trastuzumab emtansine plus pertuzumab (n=223) or docetaxel, carboplatin, and trastuzumab plus pertuzumab (n=221). A pathological complete response was achieved by 99 (44·4%) of 223 patients in the trastuzumab emtansine plus pertuzumab group and 123 (55·7%) of 221 patients in the docetaxel, carboplatin, and trastuzumab plus pertuzumab group (absolute difference -11·3 percentage points, 95% CI -20·5 to -2·0; p=0·016). During neoadjuvant treatment, compared with patients receiving docetaxel, carboplatin, and trastuzumab plus pertuzumab, fewer patients receiving trastuzumab emtansine plus pertuzumab had a grade 3-4 adverse event (29 [13%] of 223 vs 141 [64%] of 219) or a serious adverse event (11 [5%] of 223 vs 63 [29%] of 219). The most common grade 3-4 adverse events in the trastuzumab emtansine plus pertuzumab group were decreased platelet count (three [1%] of 223 patients vs 11 [5%] of 219 with docetaxel, carboplatin, and trastuzumab plus pertuzumab), fatigue (three [1%] vs seven [3%]), alanine aminotransferase increase (three [1%] vs four [2%]), and hypokalaemia (three [1%] vs five [2%]). The most common grade 3-4 adverse events in the docetaxel, carboplatin, and trastuzumab plus pertuzumab group were neutropenia (55 [25%] of 219 vs one [<1%] of 223 with trastuzumab emtansine plus pertuzumab), diarrhoea (33 [15%] vs 2 [<1%]), and febrile neutropenia (33 [15%] vs 0). No deaths were reported during neoadjuvant treatment.
INTERPRETATION: Traditional neoadjuvant systemic chemotherapy plus dual HER2-targeted blockade (docetaxel, carboplatin, and trastuzumab plus pertuzumab) resulted in significantly more patients achieving a pathological complete response than HER2-targeted chemotherapy plus HER2-targeted blockade (trastuzumab emtansine plus pertuzumab); however, numerically more grade 3-4 and serious adverse events occurred in the chemotherapy plus trastuzumab and pertuzumab group. Further efforts to improve the efficacy of chemotherapy without imparting more toxicity are warranted.
FUNDING: F Hoffmann-La Roche and Genentech.

Copyright © 2018 Elsevier Ltd. All rights reserved.
PMID 29175149  Lancet Oncol. 2018 Jan;19(1):115-126. doi: 10.1016/S147・・・
著者: Kristine R Broglio, Melanie Quintana, Margaret Foster, Melissa Olinger, Anna McGlothlin, Scott M Berry, Jean-François Boileau, Christine Brezden-Masley, Stephen Chia, Susan Dent, Karen Gelmon, Alexander Paterson, Daniel Rayson, Donald A Berry
雑誌名: JAMA Oncol. 2016 Jun 1;2(6):751-60. doi: 10.1001/jamaoncol.2015.6113.
Abstract/Text IMPORTANCE: The expense and lengthy follow-up periods for randomized clinical trials (RCTs) of adjuvant systemic therapy in breast cancer make them impractical and even impossible to conduct. Randomized clinical trials of neoadjuvant systemic therapy for breast cancer may help resolve this dilemma.
OBJECTIVE: To assess the utility of pathologic complete response (pCR) for neoadjuvant drug development in human epidermal growth factor receptor 2 (HER2 [also referred to as ERBB2])-positive breast cancer.
DATA SOURCES: We searched MEDLINE (Ovid), Embase (Ovid), CENTRAL (Wiley), and Northern Light Life Sciences Conference Abstracts (Ovid) in December 2014. Searches combined terms for "breast cancer" and "neoadjuvant therapy," with no limit on publication date.
STUDY SELECTION: Cohort studies and RCTs were selected that met following criteria: stages I to III HER2-positive breast cancer, neoadjuvant therapy, and reports of both pCR and an event-free survival (EFS)-type outcome. The initial search identified 2614 publications, of which 38 studies met the selection criteria.
DATA EXTRACTION AND SYNTHESIS: Two authors independently screened each study for inclusion and extracted the data. Data were analyzed using Bayesian hierarchical models.
MAIN OUTCOMES AND MEASURES: Event-free survival and overall survival (OS) hazard ratios (HRs) for pCR vs non-pCR. For RCTs, main outcome measures were treatment benefits in pCR and the corresponding treatment HRs for EFS and OS.
RESULTS: A total of 36 studies with EFS by pCR status representing 5768 patients with HER2-positive breast cancer were included in the patient-level analysis. Overall, the improvement in EFS for pCR vs non-pCR was substantial: HR, 0.37 (95% probability interval [PI], 0.32-0.43). This association was greater for patients with hormone receptor-negative disease (HR, 0.29 [95% PI, 0.24-0.36]) than hormone receptor-positive disease (HR, 0.52 [95% PI, 0.40-0.66]). In RCTs, the R2 correlations between odds ratios for pCR and HRs were 0.63 for EFS and 0.29 for OS. Based on absolute treatment improvements in pCR rate, predicted HRs for EFS for RCTs were concordant with observed HRs.
CONCLUSIONS AND RELEVANCE: Pathologic complete response in HER2-positive breast cancer is associated with substantially longer times to recurrence and death. This relationship is maintained in RCTs. For any particular new therapy the relationship between pCR and survival may differ. Quantifying the importance of pCR is necessary for designing efficient clinical trials, which should adapt to the relationship between pCR and survival for the therapy under investigation.

PMID 26914222  JAMA Oncol. 2016 Jun 1;2(6):751-60. doi: 10.1001/jamaon・・・
著者: J S D Mieog, J A van der Hage, C J H van de Velde
雑誌名: Cochrane Database Syst Rev. 2007 Apr 18;(2):CD005002. doi: 10.1002/14651858.CD005002.pub2. Epub 2007 Apr 18.
Abstract/Text BACKGROUND: Currently, preoperative chemotherapy is the standard of care in locally advanced breast cancer to achieve local tumour downsizing in order to make surgery possible. Since the early 1980s, the role of preoperative chemotherapy in early stage (or operable) breast cancer has been the subject of study. Potential advantages are early introduction of systemic therapy, determination of chemosensitivity, reduction of tumour volume and downstaging of surgical requirement. Concerns exist about local control after downsized surgery and the delay of local treatment in patients with tumours resistant to chemotherapy.
OBJECTIVES: To assess the effectiveness of preoperative chemotherapy in women with operable breast cancer when compared to postoperative chemotherapy.
SEARCH STRATEGY: The Specialised Register maintained by the Editorial Base of the Cochrane Breast Cancer Group was searched on 4th of August 2005.
SELECTION CRITERIA: Randomised trials comparing preoperative chemotherapy with postoperative in women with operable breast cancer.
DATA COLLECTION AND ANALYSIS: Studies were assessed for eligibility and quality, and data were extracted by two independent review authors. Hazard ratios were derived for time-to-event outcomes directly or indirectly using the methods described by Parmar. Relative risks were derived for dichotomous outcomes. Meta-analyses were performed using fixed effect model.
MAIN RESULTS: We identified 14 eligible studies which randomised a total of 5,500 women. Median follow-up ranged from 18 to 124 months. Eight studies described a satisfactory method of randomisation.Data, based on 1139 estimated deaths in 4620 women available for analysis, show equivalent overall survival rates with a HR of 0.98 (95% CI, 0.87 to 1.09; p, 0.67; no heterogeneity). Preoperative chemotherapy increases breast conservation rates, yet at the associated cost of increased loco regional recurrence rates. However, this rate was not increased as long as surgery remains part of the treatment even after complete tumour regression (HR, 1.12; 95% CI, 0.92 to 1.37; p, 0.25; no heterogeneity. Preoperative chemotherapy was associated with fewer adverse effects. Pathological complete response is associated with better survival than residual disease (HR, 0.48; 95% CI, 0.33 to 0.69; p, < 10-4).
AUTHORS' CONCLUSIONS: This review suggests safe application of preoperative chemotherapy in the treatment of women with early stage breast cancer in order to down-stage surgical requirement, to evaluate chemosensitivity and to facilitate translational research.

PMID 17443564  Cochrane Database Syst Rev. 2007 Apr 18;(2):CD005002. d・・・
著者: Early Breast Cancer Trialists' Collaborative Group (EBCTCG)
雑誌名: Lancet Oncol. 2018 Jan;19(1):27-39. doi: 10.1016/S1470-2045(17)30777-5. Epub 2017 Dec 11.
Abstract/Text BACKGROUND: Neoadjuvant chemotherapy (NACT) for early breast cancer can make breast-conserving surgery more feasible and might be more likely to eradicate micrometastatic disease than might the same chemotherapy given after surgery. We investigated the long-term benefits and risks of NACT and the influence of tumour characteristics on outcome with a collaborative meta-analysis of individual patient data from relevant randomised trials.
METHODS: We obtained information about prerandomisation tumour characteristics, clinical tumour response, surgery, recurrence, and mortality for 4756 women in ten randomised trials in early breast cancer that began before 2005 and compared NACT with the same chemotherapy given postoperatively. Primary outcomes were tumour response, extent of local therapy, local and distant recurrence, breast cancer death, and overall mortality. Analyses by intention-to-treat used standard regression (for response and frequency of breast-conserving therapy) and log-rank methods (for recurrence and mortality).
FINDINGS: Patients entered the trials from 1983 to 2002 and median follow-up was 9 years (IQR 5-14), with the last follow-up in 2013. Most chemotherapy was anthracycline based (3838 [81%] of 4756 women). More than two thirds (1349 [69%] of 1947) of women allocated NACT had a complete or partial clinical response. Patients allocated NACT had an increased frequency of breast-conserving therapy (1504 [65%] of 2320 treated with NACT vs 1135 [49%] of 2318 treated with adjuvant chemotherapy). NACT was associated with more frequent local recurrence than was adjuvant chemotherapy: the 15 year local recurrence was 21·4% for NACT versus 15·9% for adjuvant chemotherapy (5·5% increase [95% CI 2·4-8·6]; rate ratio 1·37 [95% CI 1·17-1·61]; p=0·0001). No significant difference between NACT and adjuvant chemotherapy was noted for distant recurrence (15 year risk 38·2% for NACT vs 38·0% for adjuvant chemotherapy; rate ratio 1·02 [95% CI 0·92-1·14]; p=0·66), breast cancer mortality (34·4% vs 33·7%; 1·06 [0·95-1·18]; p=0·31), or death from any cause (40·9% vs 41·2%; 1·04 [0·94-1·15]; p=0·45).
INTERPRETATION: Tumours downsized by NACT might have higher local recurrence after breast-conserving therapy than might tumours of the same dimensions in women who have not received NACT. Strategies to mitigate the increased local recurrence after breast-conserving therapy in tumours downsized by NACT should be considered-eg, careful tumour localisation, detailed pathological assessment, and appropriate radiotherapy.
FUNDING: Cancer Research UK, British Heart Foundation, UK Medical Research Council, and UK Department of Health.

Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
PMID 29242041  Lancet Oncol. 2018 Jan;19(1):27-39. doi: 10.1016/S1470-・・・
著者: Jack Cuzick, Ivana Sestak, Michael Baum, Aman Buzdar, Anthony Howell, Mitch Dowsett, John F Forbes, ATAC/LATTE investigators
雑誌名: Lancet Oncol. 2010 Dec;11(12):1135-41. doi: 10.1016/S1470-2045(10)70257-6. Epub 2010 Nov 17.
Abstract/Text BACKGROUND: The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial was designed to compare the efficacy and safety of anastrozole (1 mg) with tamoxifen (20 mg), both given orally every day for 5 years, as adjuvant treatment for postmenopausal women with early-stage breast cancer. In this analysis, we assess the long-term outcomes after a median follow-up of 120 months.
METHODS: We used a proportional hazards model to assess the primary endpoint of disease-free survival, and the secondary endpoints of time to recurrence, time to distant recurrence, incidence of new contralateral breast cancer, overall survival, and death with or without recurrence in all randomised patients (anastrozole n=3125, tamoxifen n=3116) and hormone-receptor-positive patients (anastrozole n=2618, tamoxifen n=2598). After treatment completion, we continued to collect data on fractures and serious adverse events in a masked fashion (safety population: anastrozole n=3092, tamoxifen n=3094). This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN18233230.
FINDINGS: Patients were followed up for a median of 120 months (range 0-145); there were 24,522 woman-years of follow-up in the anastrozole group and 23,950 woman-years in the tamoxifen group. In the full study population, there were significant improvements in the anastrozole group compared with the tamoxifen group for disease-free survival (hazard ratio [HR] 0·91, 95% CI 0·83-0·99; p=0·04), time to recurrence (0·84, 0·75-0·93; p=0·001), and time to distant recurrence (0·87, 0·77-0·99; p=0·03). For hormone-receptor-positive patients, the results were also significantly in favour of the anastrozole group for disease-free survival (HR 0·86, 95% CI 0·78-0·95; p=0·003), time to recurrence (0·79, 0·70-0·89; p=0·0002), and time to distant recurrence (0·85, 0·73-0·98; p=0·02). In hormone-receptor-positive patients, absolute differences in time to recurrence between anastrozole and tamoxifen increased over time (2·7% at 5 years and 4·3% at 10 years) and recurrence rates remained significantly lower on anastrozole than tamoxifen after treatment completion (HR 0·81, 95% CI 0·67-0·98; p=0·03), although the carryover benefit was smaller after 8 years. There was weak evidence of fewer deaths after recurrence with anastrozole compared with tamoxifen treatment in the hormone-receptor-positive subgroup (HR 0·87, 95% CI 0·74-1·02; p=0·09), but there was little difference in overall mortality (0·95, 95% CI 0·84-1·06; p=0·4). Fractures were more frequent during active treatment in patients receiving anastrozole than those receiving tamoxifen (451 vs 351; OR 1·33, 95% CI 1·15-1·55; p<0·0001), but were similar in the post-treatment follow-up period (110 vs 112; OR 0·98, 95% CI 0·74-1·30; p=0·9). Treatment-related serious adverse events were less common in the anastrozole group than the tamoxifen group (223 anastrozole vs 369 tamoxifen; OR 0·57, 95% CI 0·48-0·69; p<0·0001), but were similar after treatment completion (66 vs 78; OR 0·84, 95% CI 0·60-1·19; p=0·3). No differences in non-breast cancer causes of death were apparent and the incidence of other cancers was similar between groups (425 vs 431) and continue to be higher with anastrozole for colorectal (66 vs 44) and lung cancer (51 vs 34), and lower for endometrial cancer (six vs 24), melanoma (eight vs 19), and ovarian cancer (17 vs 28). No new safety concerns were reported.
INTERPRETATION: These data confirm the long-term superior efficacy and safety of anastrozole over tamoxifen as initial adjuvant therapy for postmenopausal women with hormone-sensitive early breast cancer.

Copyright © 2010 Elsevier Ltd. All rights reserved.
PMID 21087898  Lancet Oncol. 2010 Dec;11(12):1135-41. doi: 10.1016/S14・・・
著者: Meredith M Regan, Patrick Neven, Anita Giobbie-Hurder, Aron Goldhirsch, Bent Ejlertsen, Louis Mauriac, John F Forbes, Ian Smith, István Láng, Andrew Wardley, Manuela Rabaglio, Karen N Price, Richard D Gelber, Alan S Coates, Beat Thürlimann, BIG 1-98 Collaborative Group, International Breast Cancer Study Group (IBCSG)
雑誌名: Lancet Oncol. 2011 Nov;12(12):1101-8. doi: 10.1016/S1470-2045(11)70270-4. Epub 2011 Oct 20.
Abstract/Text BACKGROUND: Postmenopausal women with hormone receptor-positive early breast cancer have persistent, long-term risk of breast-cancer recurrence and death. Therefore, trials assessing endocrine therapies for this patient population need extended follow-up. We present an update of efficacy outcomes in the Breast International Group (BIG) 1-98 study at 8·1 years median follow-up.
METHODS: BIG 1-98 is a randomised, phase 3, double-blind trial of postmenopausal women with hormone receptor-positive early breast cancer that compares 5 years of tamoxifen or letrozole monotherapy, or sequential treatment with 2 years of one of these drugs followed by 3 years of the other. Randomisation was done with permuted blocks, and stratified according to the two-arm or four-arm randomisation option, participating institution, and chemotherapy use. Patients, investigators, data managers, and medical reviewers were masked. The primary efficacy endpoint was disease-free survival (events were invasive breast cancer relapse, second primaries [contralateral breast and non-breast], or death without previous cancer event). Secondary endpoints were overall survival, distant recurrence-free interval (DRFI), and breast cancer-free interval (BCFI). The monotherapy comparison included patients randomly assigned to tamoxifen or letrozole for 5 years. In 2005, after a significant disease-free survival benefit was reported for letrozole as compared with tamoxifen, a protocol amendment facilitated the crossover to letrozole of patients who were still receiving tamoxifen alone; Cox models and Kaplan-Meier estimates with inverse probability of censoring weighting (IPCW) are used to account for selective crossover to letrozole of patients (n=619) in the tamoxifen arm. Comparison of sequential treatments to letrozole monotherapy included patients enrolled and randomly assigned to letrozole for 5 years, letrozole for 2 years followed by tamoxifen for 3 years, or tamoxifen for 2 years followed by letrozole for 3 years. Treatment has ended for all patients and detailed safety results for adverse events that occurred during the 5 years of treatment have been reported elsewhere. Follow-up is continuing for those enrolled in the four-arm option. BIG 1-98 is registered at clinicaltrials.govNCT00004205.
FINDINGS: 8010 patients were included in the trial, with a median follow-up of 8·1 years (range 0-12·4). 2459 were randomly assigned to monotherapy with tamoxifen for 5 years and 2463 to monotherapy with letrozole for 5 years. In the four-arm option of the trial, 1546 were randomly assigned to letrozole for 5 years, 1548 to tamoxifen for 5 years, 1540 to letrozole for 2 years followed by tamoxifen for 3 years, and 1548 to tamoxifen for 2 years followed by letrozole for 3 years. At a median follow-up of 8·7 years from randomisation (range 0-12·4), letrozole monotherapy was significantly better than tamoxifen, whether by IPCW or intention-to-treat analysis (IPCW disease-free survival HR 0·82 [95% CI 0·74-0·92], overall survival HR 0·79 [0·69-0·90], DRFI HR 0·79 [0·68-0·92], BCFI HR 0·80 [0·70-0·92]; intention-to-treat disease-free survival HR 0·86 [0·78-0·96], overall survival HR 0·87 [0·77-0·999], DRFI HR 0·86 [0·74-0·998], BCFI HR 0·86 [0·76-0·98]). At a median follow-up of 8·0 years from randomisation (range 0-11·2) for the comparison of the sequential groups with letrozole monotherapy, there were no statistically significant differences in any of the four endpoints for either sequence. 8-year intention-to-treat estimates (each with SE ≤1·1%) for letrozole monotherapy, letrozole followed by tamoxifen, and tamoxifen followed by letrozole were 78·6%, 77·8%, 77·3% for disease-free survival; 87·5%, 87·7%, 85·9% for overall survival; 89·9%, 88·7%, 88·1% for DRFI; and 86·1%, 85·3%, 84·3% for BCFI.
INTERPRETATION: For postmenopausal women with endocrine-responsive early breast cancer, a reduction in breast cancer recurrence and mortality is obtained by letrozole monotherapy when compared with tamoxifen montherapy. Sequential treatments involving tamoxifen and letrozole do not improve outcome compared with letrozole monotherapy, but might be useful strategies when considering an individual patient's risk of recurrence and treatment tolerability.
FUNDING: Novartis, United States National Cancer Institute, International Breast Cancer Study Group.

Copyright © 2011 Elsevier Ltd. All rights reserved.
PMID 22018631  Lancet Oncol. 2011 Nov;12(12):1101-8. doi: 10.1016/S147・・・
著者: Tomohiko Aihara, Yuichi Takatsuka, Shozo Ohsumi, Kenjiro Aogi, Yasuo Hozumi, Shigeru Imoto, Hirofumi Mukai, Hiroji Iwata, Toru Watanabe, Chikako Shimizu, Kazuhiko Nakagami, Motoshi Tamura, Toshikazu Ito, Norikazu Masuda, Nobuo Ogino, Kazufumi Hisamatsu, Shoshu Mitsuyama, Hajime Abe, Shiro Tanaka, Takuhiro Yamaguchi, Yasuo Ohashi
雑誌名: Breast Cancer Res Treat. 2010 Jun;121(2):379-87. doi: 10.1007/s10549-010-0888-x.
Abstract/Text Clinical trials conducted in Western countries have shown that aromatase inhibitors are associated with better disease-free survival (DFS) than tamoxifen in postmenopausal early breast cancer. Because pharmacogenetic differences in drug-metabolizing genes may cause ethnic differences, assessment of the efficacy and tolerability of aromatase inhibitors in non-white women is warranted. This open-label, randomized clinical trial included 706 postmenopausal Japanese women with hormone-receptor-positive breast cancer, who had received tamoxifen for 1 to 4 years as adjuvant therapy. This study was closed early after entry of approximately 28% of the initially planned patients. They were randomly assigned to either switch to anastrozole or to continue tamoxifen for total treatment duration of 5 years. Primary endpoints were DFS and adverse events. At a median follow-up of 42 months, the unadjusted hazard ratio was 0.69 (95% confidence interval, 0.42-1.14; P = 0.14) for DFS and 0.54 (95% CI, 0.29-1.02; P = 0.06) for relapse-free survival (RFS), both in favor of anastrozole. The incidence of thromboembolic events in the tamoxifen group and bone fractures in the anastrozole group was not excessively high. Switching from tamoxifen to anastrozole was likely to decrease disease recurrence in postmenopausal Japanese breast cancer patients. Ethnic differences in major adverse events may be attributable to a low baseline risk of these events in Japanese.

PMID 20390343  Breast Cancer Res Treat. 2010 Jun;121(2):379-87. doi: 1・・・
著者: BIG 1-98 Collaborative Group, Henning Mouridsen, Anita Giobbie-Hurder, Aron Goldhirsch, Beat Thürlimann, Robert Paridaens, Ian Smith, Louis Mauriac, John F Forbes, Karen N Price, Meredith M Regan, Richard D Gelber, Alan S Coates
雑誌名: N Engl J Med. 2009 Aug 20;361(8):766-76. doi: 10.1056/NEJMoa0810818.
Abstract/Text BACKGROUND: The aromatase inhibitor letrozole, as compared with tamoxifen, improves disease-free survival among postmenopausal women with receptor-positive early breast cancer. It is unknown whether sequential treatment with tamoxifen and letrozole is superior to letrozole therapy alone.
METHODS: In this randomized, phase 3, double-blind trial of the treatment of hormone-receptor-positive breast cancer in postmenopausal women, we randomly assigned women to receive 5 years of tamoxifen monotherapy, 5 years of letrozole monotherapy, or 2 years of treatment with one agent followed by 3 years of treatment with the other. We compared the sequential treatments with letrozole monotherapy among 6182 women and also report a protocol-specified updated analysis of letrozole versus tamoxifen monotherapy in 4922 women.
RESULTS: At a median follow-up of 71 months after randomization, disease-free survival was not significantly improved with either sequential treatment as compared with letrozole alone (hazard ratio for tamoxifen followed by letrozole, 1.05; 99% confidence interval [CI], 0.84 to 1.32; hazard ratio for letrozole followed by tamoxifen, 0.96; 99% CI, 0.76 to 1.21). There were more early relapses among women who were assigned to tamoxifen followed by letrozole than among those who were assigned to letrozole alone. The updated analysis of monotherapy showed that there was a nonsignificant difference in overall survival between women assigned to treatment with letrozole and those assigned to treatment with tamoxifen (hazard ratio for letrozole, 0.87; 95% CI, 0.75 to 1.02; P=0.08). The rate of adverse events was as expected on the basis of previous reports of letrozole and tamoxifen therapy.
CONCLUSIONS: Among postmenopausal women with endocrine-responsive breast cancer, sequential treatment with letrozole and tamoxifen, as compared with letrozole monotherapy, did not improve disease-free survival. The difference in overall survival with letrozole monotherapy and tamoxifen monotherapy was not statistically significant. (ClinicalTrials.gov number, NCT00004205.)

2009 Massachusetts Medical Society
PMID 19692688  N Engl J Med. 2009 Aug 20;361(8):766-76. doi: 10.1056/N・・・
著者: Judith M Bliss, Lucy S Kilburn, Robert E Coleman, John F Forbes, Alan S Coates, Stephen E Jones, Jacek Jassem, Thierry Delozier, Jørn Andersen, Robert Paridaens, Cornelis J H van de Velde, Per E Lønning, James Morden, Justine Reise, Laura Cisar, Thomas Menschik, R Charles Coombes
雑誌名: J Clin Oncol. 2012 Mar 1;30(7):709-17. doi: 10.1200/JCO.2010.33.7899. Epub 2011 Oct 31.
Abstract/Text PURPOSE: Intergroup Exemestane Study (IES), an investigator-led study in 4,724 postmenopausal patients with early-stage breast cancer has demonstrated clinically important benefits from switching adjuvant endocrine therapy after 2 to 3 years of tamoxifen to exemestane. Now, with longer follow-up, a large number of non-breast cancer-related events have been reported. Exploratory analyses describe breast cancer-free survival (BCFS) and explore incidence and patterns of the different competing events.
PATIENTS AND METHODS: Patients who were disease-free after 2 to 3 years of adjuvant tamoxifen were randomly assigned to continue tamoxifen or switch to exemestane to complete 5 years of adjuvant endocrine therapy. At this planned analysis, the median follow-up was 91 months. Principal analysis focuses on 4,052 patients with estrogen receptor (ER) -positive and 547 with ER-unknown tumors.
RESULTS: In all, 930 BCFS events have been reported (exemestane, 423; tamoxifen, 507), giving an unadjusted hazard ratio (HR) of 0.81 (95% CI, 0.71 to 0.92; P = .001) in favor of exemestane in the ER-positive/ER unknown group. Analysis partitioned at 2.5 years after random assignment showed that the on-treatment benefit of switching to exemestane (HR, 0.60; 95% CI, 0.48 to 0.75; P < .001) was not lost post-treatment, but that there was no additional gain once treatment had ceased (HR, 0.94; 95% CI, 0.80 to 1.10; P = .60). Improvement in overall survival was demonstrated, with 352 deaths in the exemestane group versus 405 deaths in the tamoxifen group (HR, 0.86; 95% CI, 0.75 to 0.99; P = .04). Of these, 222 were reported as intercurrent deaths (exemestane, 107; tamoxifen, 115).
CONCLUSION: The protective effect of switching to exemestane compared with continuing on tamoxifen on risk of relapse or death was maintained for at least 5 years post-treatment and was associated with a continuing beneficial impact on overall survival.

PMID 22042946  J Clin Oncol. 2012 Mar 1;30(7):709-17. doi: 10.1200/JCO・・・
著者: Walter Jonat, Michael Gnant, Francesco Boccardo, Manfred Kaufmann, Alessandra Rubagotti, Ivan Zuna, Mike Greenwood, Raimund Jakesz
雑誌名: Lancet Oncol. 2006 Dec;7(12):991-6. doi: 10.1016/S1470-2045(06)70948-2.
Abstract/Text BACKGROUND: For more than 20 years, tamoxifen has been the mainstay of adjuvant endocrine therapy for women with hormone-sensitive early-stage breast cancer. However, not only does tamoxifen have potential side-effects such as an increased risk of endometrial cancer and thromboembolic events, but patients can also develop resistance to the drug. We aimed to investigate whether switching treatment of postmenopausal women with such breast cancer to anastrozole after 2-3 years of tamoxifen would be more effective than continuing on tamoxifen for a total of 5 years.
METHODS: We did a meta-analysis of three clinical trials--the Austrian Breast and Colorectal Cancer Study Group (ABCSG 8), Arimidex-Nolvadex (ARNO 95), and the Italian Tamoxifen Anastrozole (ITA) studies--in which postmenopausal women with histologically confirmed, hormone-sensitive early-stage breast cancer were randomised to 1 mg/day anastrozole (n=2009) after 2-3 years of tamoxifen treatment or to continued 20 or 30 mg/day tamoxifen (n=1997). We analysed the data with a stratified Cox proportional hazards model with the covariates of age, tumour size, nodal status, grade, surgery, and chemotherapy.
FINDINGS: Patients who switched to anastrozole had fewer disease recurrences (92 vs 159) and deaths (66 vs 90) than did those who remained on tamoxifen, resulting in significant improvements in disease-free survival (hazard ratio 0.59 [95% CI 0.48-0.74]; p<0.0001), event-free survival (0.55 [0.42-0.71]; p<0.0001), distant recurrence-free survival (0.61 [0.45-0.83]; p=0.002), and overall survival (0.71 [0.52-0.98]; p=0.04).
INTERPRETATION: Our results show that the clinical benefits in terms of event-free survival seen in individual trials for those patients who switched to anastrozole translate into a benefit in overall survival. These findings confirm that clinicians should consider switching postmenopausal women who have taken adjuvant tamoxifen for 2-3 years to anastrozole.

PMID 17138220  Lancet Oncol. 2006 Dec;7(12):991-6. doi: 10.1016/S1470-・・・
著者: Early Breast Cancer Trialists' Collaborative Group (EBCTCG), C Davies, J Godwin, R Gray, M Clarke, D Cutter, S Darby, P McGale, H C Pan, C Taylor, Y C Wang, M Dowsett, J Ingle, R Peto
雑誌名: Lancet. 2011 Aug 27;378(9793):771-84. doi: 10.1016/S0140-6736(11)60993-8. Epub 2011 Jul 28.
Abstract/Text BACKGROUND: As trials of 5 years of tamoxifen in early breast cancer mature, the relevance of hormone receptor measurements (and other patient characteristics) to long-term outcome can be assessed increasingly reliably. We report updated meta-analyses of the trials of 5 years of adjuvant tamoxifen.
METHODS: We undertook a collaborative meta-analysis of individual patient data from 20 trials (n=21,457) in early breast cancer of about 5 years of tamoxifen versus no adjuvant tamoxifen, with about 80% compliance. Recurrence and death rate ratios (RRs) were from log-rank analyses by allocated treatment.
FINDINGS: In oestrogen receptor (ER)-positive disease (n=10,645), allocation to about 5 years of tamoxifen substantially reduced recurrence rates throughout the first 10 years (RR 0·53 [SE 0·03] during years 0-4 and RR 0·68 [0·06] during years 5-9 [both 2p<0·00001]; but RR 0·97 [0·10] during years 10-14, suggesting no further gain or loss after year 10). Even in marginally ER-positive disease (10-19 fmol/mg cytosol protein) the recurrence reduction was substantial (RR 0·67 [0·08]). In ER-positive disease, the RR was approximately independent of progesterone receptor status (or level), age, nodal status, or use of chemotherapy. Breast cancer mortality was reduced by about a third throughout the first 15 years (RR 0·71 [0·05] during years 0-4, 0·66 [0·05] during years 5-9, and 0·68 [0·08] during years 10-14; p<0·0001 for extra mortality reduction during each separate time period). Overall non-breast-cancer mortality was little affected, despite small absolute increases in thromboembolic and uterine cancer mortality (both only in women older than 55 years), so all-cause mortality was substantially reduced. In ER-negative disease, tamoxifen had little or no effect on breast cancer recurrence or mortality.
INTERPRETATION: 5 years of adjuvant tamoxifen safely reduces 15-year risks of breast cancer recurrence and death. ER status was the only recorded factor importantly predictive of the proportional reductions. Hence, the absolute risk reductions produced by tamoxifen depend on the absolute breast cancer risks (after any chemotherapy) without tamoxifen.
FUNDING: Cancer Research UK, British Heart Foundation, and Medical Research Council.

Copyright © 2011 Elsevier Ltd. All rights reserved.
PMID 21802721  Lancet. 2011 Aug 27;378(9793):771-84. doi: 10.1016/S014・・・
著者: Prudence A Francis, Meredith M Regan, Gini F Fleming, István Láng, Eva Ciruelos, Meritxell Bellet, Hervé R Bonnefoi, Miguel A Climent, Gian Antonio Da Prada, Harold J Burstein, Silvana Martino, Nancy E Davidson, Charles E Geyer, Barbara A Walley, Robert Coleman, Pierre Kerbrat, Stefan Buchholz, James N Ingle, Eric P Winer, Manuela Rabaglio-Poretti, Rudolf Maibach, Barbara Ruepp, Anita Giobbie-Hurder, Karen N Price, Marco Colleoni, Giuseppe Viale, Alan S Coates, Aron Goldhirsch, Richard D Gelber, SOFT Investigators, International Breast Cancer Study Group
雑誌名: N Engl J Med. 2015 Jan 29;372(5):436-46. doi: 10.1056/NEJMoa1412379. Epub 2014 Dec 11.
Abstract/Text BACKGROUND: Suppression of ovarian estrogen production reduces the recurrence of hormone-receptor-positive early breast cancer in premenopausal women, but its value when added to tamoxifen is uncertain.
METHODS: We randomly assigned 3066 premenopausal women, stratified according to prior receipt or nonreceipt of chemotherapy, to receive 5 years of tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression. The primary analysis tested the hypothesis that tamoxifen plus ovarian suppression would improve disease-free survival, as compared with tamoxifen alone. In the primary analysis, 46.7% of the patients had not received chemotherapy previously, and 53.3% had received chemotherapy and remained premenopausal.
RESULTS: After a median follow-up of 67 months, the estimated disease-free survival rate at 5 years was 86.6% in the tamoxifen-ovarian suppression group and 84.7% in the tamoxifen group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.83; 95% confidence interval [CI], 0.66 to 1.04; P=0.10). Multivariable allowance for prognostic factors suggested a greater treatment effect with tamoxifen plus ovarian suppression than with tamoxifen alone (hazard ratio, 0.78; 95% CI, 0.62 to 0.98). Most recurrences occurred in patients who had received prior chemotherapy, among whom the rate of freedom from breast cancer at 5 years was 82.5% in the tamoxifen-ovarian suppression group and 78.0% in the tamoxifen group (hazard ratio for recurrence, 0.78; 95% CI, 0.60 to 1.02). At 5 years, the rate of freedom from breast cancer was 85.7% in the exemestane-ovarian suppression group (hazard ratio for recurrence vs. tamoxifen, 0.65; 95% CI, 0.49 to 0.87).
CONCLUSIONS: Adding ovarian suppression to tamoxifen did not provide a significant benefit in the overall study population. However, for women who were at sufficient risk for recurrence to warrant adjuvant chemotherapy and who remained premenopausal, the addition of ovarian suppression improved disease outcomes. Further improvement was seen with the use of exemestane plus ovarian suppression. (Funded by Pfizer and others; SOFT ClinicalTrials.gov number, NCT00066690.).

PMID 25495490  N Engl J Med. 2015 Jan 29;372(5):436-46. doi: 10.1056/N・・・
著者: Amye J Tevaarwerk, Molin Wang, Fengmin Zhao, John H Fetting, David Cella, Lynne I Wagner, Silvana Martino, James N Ingle, Joseph A Sparano, Lawrence J Solin, William C Wood, Nicholas J Robert
雑誌名: J Clin Oncol. 2014 Dec 10;32(35):3948-58. doi: 10.1200/JCO.2014.55.6993. Epub 2014 Oct 27.
Abstract/Text PURPOSE: The effects of ovarian function suppression (OFS) on survival and patient-reported outcomes were evaluated in a phase III trial in which premenopausal women were randomly assigned to tamoxifen with or without OFS.
PATIENTS AND METHODS: Premenopausal women with axillary node-negative, hormone receptor-positive breast cancer tumors measuring ≤ 3 cm were randomly assigned to tamoxifen alone versus tamoxifen plus OFS; adjuvant chemotherapy was not permitted. Primary end points were disease-free survival (DFS) and overall survival (OS). Secondary end points included toxicity and patient-reported outcomes. Patient-reported outcome data included health-related quality of life, menopausal symptoms, and sexual function. These were evaluated at baseline, 6 months, 12 months, and then annually for up to 5 years after registration.
RESULTS: In all, 345 premenopausal women were enrolled: 171 on tamoxifen alone and 174 on tamoxifen plus OFS. With a median follow-up of 9.9 years, there was no significant difference between arms for DFS (5-year rate: 87.9% v 89.7%; log-rank P = .62) or OS (5-year rate: 95.2% v 97.6%; log-rank P = .67). Grade 3 or higher toxicity was more common in the tamoxifen plus OFS arm (22.4% v 12.3%; P = .004). Patients treated with tamoxifen plus OFS had more menopausal symptoms, lower sexual activity, and inferior health-related quality of life at 3-year follow-up (P < .01 for all). Differences diminished with further follow-up.
CONCLUSION: When added to tamoxifen, OFS results in more menopausal symptoms and sexual dysfunction, which contributes to inferior self-reported health-related quality of life. Because of early closure, this study is underpowered for drawing conclusions about the impact on survival when adding OFS to tamoxifen.

© 2014 by American Society of Clinical Oncology.
PMID 25349302  J Clin Oncol. 2014 Dec 10;32(35):3948-58. doi: 10.1200/・・・
著者: Poornima Saha, Meredith M Regan, Olivia Pagani, Prudence A Francis, Barbara A Walley, Karin Ribi, Jürg Bernhard, Weixiu Luo, Henry L Gómez, Harold J Burstein, Vani Parmar, Roberto Torres, Josephine Stewart, Meritxell Bellet, Antonia Perelló, Faysal Dane, Antonio Moreira, Daniel Vorobiof, Michelle Nottage, Karen N Price, Alan S Coates, Aron Goldhirsch, Richard D Gelber, Marco Colleoni, Gini F Fleming, SOFT, TEXT Investigators, International Breast Cancer Study Group
雑誌名: J Clin Oncol. 2017 Sep 20;35(27):3113-3122. doi: 10.1200/JCO.2016.72.0946. Epub 2017 Jun 27.
Abstract/Text Purpose To describe benefits and toxicities of adjuvant endocrine therapies in women younger than 35 years with breast cancer (n = 582) enrolled in the Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT). Methods In SOFT, women still premenopausal after surgery with or without chemotherapy were randomly assigned to tamoxifen alone, tamoxifen plus ovarian function suppression (OFS), or exemestane plus OFS. In TEXT, all received OFS with or without concomitant chemotherapy and were randomly assigned to exemestane plus OFS or tamoxifen plus OFS. We summarize treatment efficacy, quality of life, and adherence of the cohort of women younger than 35 years in SOFT and TEXT, alongside data from the cohort of older premenopausal women. Results For 240 human epidermal growth factor receptor 2-negative patients younger than 35 years enrolled in SOFT after receiving chemotherapy, the 5-year breast cancer-free interval (BCFI) was 67.1% (95% CI, 54.6% to 76.9%) with tamoxifen alone, 75.9% with tamoxifen plus OFS (95% CI, 64.0% to 84.4%), and 83.2% with exemestane plus OFS (95% CI, 72.7% to 90.0%). For 145 human epidermal growth factor receptor 2-negative patients younger than 35 years in TEXT, 5-year BCFI was 79.2% (95% CI, 66.2% to 87.7%) with tamoxifen plus OFS and 81.6% (95% CI, 69.8% to 89.2%) with exemestane plus OFS. The most prominent quality of life symptom for patients younger than 35 years receiving OFS was vasomotor symptoms, with the greatest worsening from baseline at 6 months (on the order of 30 to 40 points), but loss of sexual interest and difficulties in becoming aroused were also clinically meaningful (≥ 8-point change). The level of symptom burden was similar in older premenopausal women. A total of 19.8% of women younger than 35 years stopped all protocol-assigned endocrine therapy early. Conclusion In women younger than 35 years with hormone receptor-positive breast cancer, adjuvant OFS combined with tamoxifen or exemestane produces large improvements in BCFI compared with tamoxifen alone. Menopausal symptoms are significant but are not worse than those seen in older premenopausal women.

PMID 28654365  J Clin Oncol. 2017 Sep 20;35(27):3113-3122. doi: 10.120・・・
著者: Olivia Pagani, Meredith M Regan, Barbara A Walley, Gini F Fleming, Marco Colleoni, István Láng, Henry L Gomez, Carlo Tondini, Harold J Burstein, Edith A Perez, Eva Ciruelos, Vered Stearns, Hervé R Bonnefoi, Silvana Martino, Charles E Geyer, Graziella Pinotti, Fabio Puglisi, Diana Crivellari, Thomas Ruhstaller, Eric P Winer, Manuela Rabaglio-Poretti, Rudolf Maibach, Barbara Ruepp, Anita Giobbie-Hurder, Karen N Price, Jürg Bernhard, Weixiu Luo, Karin Ribi, Giuseppe Viale, Alan S Coates, Richard D Gelber, Aron Goldhirsch, Prudence A Francis, TEXT and SOFT Investigators, International Breast Cancer Study Group
雑誌名: N Engl J Med. 2014 Jul 10;371(2):107-18. doi: 10.1056/NEJMoa1404037. Epub 2014 Jun 1.
Abstract/Text BACKGROUND: Adjuvant therapy with an aromatase inhibitor improves outcomes, as compared with tamoxifen, in postmenopausal women with hormone-receptor-positive breast cancer.
METHODS: In two phase 3 trials, we randomly assigned premenopausal women with hormone-receptor-positive early breast cancer to the aromatase inhibitor exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 years. Suppression of ovarian estrogen production was achieved with the use of the gonadotropin-releasing-hormone agonist triptorelin, oophorectomy, or ovarian irradiation. The primary analysis combined data from 4690 patients in the two trials.
RESULTS: After a median follow-up of 68 months, disease-free survival at 5 years was 91.1% in the exemestane-ovarian suppression group and 87.3% in the tamoxifen-ovarian suppression group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.72; 95% confidence interval [CI], 0.60 to 0.85; P<0.001). The rate of freedom from breast cancer at 5 years was 92.8% in the exemestane-ovarian suppression group, as compared with 88.8% in the tamoxifen-ovarian suppression group (hazard ratio for recurrence, 0.66; 95% CI, 0.55 to 0.80; P<0.001). With 194 deaths (4.1% of the patients), overall survival did not differ significantly between the two groups (hazard ratio for death in the exemestane-ovarian suppression group, 1.14; 95% CI, 0.86 to 1.51; P=0.37). Selected adverse events of grade 3 or 4 were reported for 30.6% of the patients in the exemestane-ovarian suppression group and 29.4% of those in the tamoxifen-ovarian suppression group, with profiles similar to those for postmenopausal women.
CONCLUSIONS: In premenopausal women with hormone-receptor-positive early breast cancer, adjuvant treatment with exemestane plus ovarian suppression, as compared with tamoxifen plus ovarian suppression, significantly reduced recurrence. (Funded by Pfizer and others; TEXT and SOFT ClinicalTrials.gov numbers, NCT00066703 and NCT00066690, respectively.).

PMID 24881463  N Engl J Med. 2014 Jul 10;371(2):107-18. doi: 10.1056/N・・・
著者: M Gnant, B Mlineritsch, H Stoeger, G Luschin-Ebengreuth, M Knauer, M Moik, R Jakesz, M Seifert, S Taucher, V Bjelic-Radisic, M Balic, H Eidtmann, W Eiermann, G Steger, W Kwasny, P Dubsky, U Selim, F Fitzal, G Hochreiner, V Wette, P Sevelda, F Ploner, R Bartsch, C Fesl, R Greil, Austrian Breast and Colorectal Cancer Study Group, Vienna, Austria
雑誌名: Ann Oncol. 2015 Feb;26(2):313-20. doi: 10.1093/annonc/mdu544. Epub 2014 Nov 17.
Abstract/Text BACKGROUND: Zoledronic acid (ZOL) plus adjuvant endocrine therapy significantly improved disease-free survival (DFS) at 48- and 62-month follow-up in the ABCSG-12 trial. We present efficacy results of a final additional analysis after 94.4 months.
PATIENTS AND METHODS: Patients were premenopausal women who had undergone primary surgery for stage I/II estrogen-receptor-positive and/or progesterone-receptor-positive breast cancer with <10 positive lymph nodes, and were scheduled for standard goserelin therapy. All 1803 patients received goserelin (3.6 mg every 28 days) and were randomized to tamoxifen (20 mg/days) or anastrozole (1 mg/days), both with or without ZOL (4 mg every 6 months) for 3 years. The primary end point was DFS; recurrence-free survival and overall survival (OS) were secondary end points.
RESULTS: After 94.4-month median follow-up (range, 0-114 months), relative risks of disease progression [hazard ratio (HR) = 0.77; 95% confidence interval (CI) 0.60-0.99; P = 0.042] and of death (HR = 0.66; 95% CI 0.43-1.02; P = 0.064) are still reduced by ZOL although no longer significant at the predefined significance level. Overall, 251 DFS events and 86 deaths were reported. Absolute risk reductions with ZOL were 3.4% for DFS and 2.2% for OS. There was no DFS difference between tamoxifen alone versus anastrozole alone, but there was a pronounced higher risk of death for anastrozole-treated patients (HR = 1.63; 95% CI 1.05-1.45; P = 0.030). Treatments were generally well tolerated, with no reports of renal failure or osteonecrosis of the jaw.
CONCLUSION: These final results from ABCSG 12 suggest that twice-yearly ZOL enhances the efficacy of adjuvant endocrine treatment, and this benefit is maintained long-term.
CLINICALTRIALSGOV: NCT00295646 (http://www.clinicaltrials.gov/ct2/results?term=00295646).

© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
PMID 25403582  Ann Oncol. 2015 Feb;26(2):313-20. doi: 10.1093/annonc/m・・・
著者: Michael Gnant, Brigitte Mlineritsch, Herbert Stoeger, Gero Luschin-Ebengreuth, Dietmar Heck, Christian Menzel, Raimund Jakesz, Michael Seifert, Michael Hubalek, Gunda Pristauz, Thomas Bauernhofer, Holger Eidtmann, Wolfgang Eiermann, Guenther Steger, Werner Kwasny, Peter Dubsky, Gerhard Hochreiner, Ernst-Pius Forsthuber, Christian Fesl, Richard Greil, Austrian Breast and Colorectal Cancer Study Group, Vienna, Austria
雑誌名: Lancet Oncol. 2011 Jul;12(7):631-41. doi: 10.1016/S1470-2045(11)70122-X. Epub 2011 Jun 5.
Abstract/Text BACKGROUND: Analysis of the Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12) at 48 months' follow-up showed that addition of zoledronic acid to adjuvant endocrine therapy significantly improved disease-free survival. We have now assessed long-term clinical efficacy including disease-free survival and disease outcomes in patients receiving anastrozole or tamoxifen with or without zoledronic acid.
METHODS: ABSCG-12 is a randomised, controlled, open-label, two-by-two factorial, multicentre trial in 1803 premenopausal women with endocrine-receptor-positive early-stage (stage I-II) breast cancer receiving goserelin (3.6 mg every 28 days), comparing the efficacy and safety of anastrozole (1 mg per day) or tamoxifen (20 mg per day) with or without zoledronic acid (4 mg every 6 months) for 3 years. Randomisation (1:1:1:1 ratio) was computerised and based on the Pocock and Simon minimisation method to balance the four treatment arms across eight prognostic variables (age, neoadjuvant chemotherapy, pathological tumour stage; lymph-node involvement, type of surgery or locoregional therapy, complete axillary dissection, intraoperative radiation therapy, and geographical region). Treatment allocation was not masked. The primary endpoint was disease-free survival (defined as disease recurrence or death) and analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00295646; follow-up is ongoing.
FINDINGS: At a median follow-up of 62 months (range 0-114.4 months), more than 2 years after treatment completion, 186 disease-free survival events had been reported (53 events in 450 patients on tamoxifen alone, 57 in 453 patients on anastrozole alone, 36 in 450 patients on tamoxifen plus zoledronic acid, and 40 in 450 patients on anastrozole plus zoledronic acid). Zoledronic acid reduced risk of disease-free survival events overall (HR 0.68, 95% CI 0.51-0.91; p=0.009), although the difference was not significant in the tamoxifen (HR 0.67, 95% CI 0.44-1.03; p=0.067) and anastrozole arms (HR 0.68, 95% CI 0.45-1.02; p=0.061) assessed separately. Zoledronic acid did not significantly affect risk of death (30 deaths with zoledronic acid vs 43 deaths without; HR 0.67, 95% CI 0.41-1.07; p=0.09). There was no difference in disease-free survival between patients on tamoxifen alone versus anastrozole alone (HR 1.08, 95% CI 0.81-1.44; p=0.591), but overall survival was worse with anastrozole than with tamoxifen (46 vs 27 deaths; HR 1.75, 95% CI 1.08-2.83; p=0.02). Treatments were generally well tolerated, with no reports of renal failure or osteonecrosis of the jaw. Bone pain was reported in 601 patients (33%; 349 patients on zoledronic acid vs 252 not on the drug), fatigue in 361 (20%; 192 vs 169), headache in 280 (16%; 147 vs 133), and arthralgia in 266 (15%; 145 vs 121).
INTERPRETATION: Addition of zoledronic acid improved disease-free survival in the patients taking anastrozole or tamoxifen. There was no difference in disease-free survival between patients receiving anastrozole and tamoxifen overall, but those on anastrozole alone had inferior overall survival. These data show persistent benefits with zoledronic acid and support its addition to adjuvant endocrine therapy in premenopausal patients with early-stage breast cancer.
FUNDING: AstraZeneca; Novartis.

Copyright © 2011 Elsevier Ltd. All rights reserved.
PMID 21641868  Lancet Oncol. 2011 Jul;12(7):631-41. doi: 10.1016/S1470・・・
著者: Meredith M Regan, Prudence A Francis, Olivia Pagani, Gini F Fleming, Barbara A Walley, Giuseppe Viale, Marco Colleoni, István Láng, Henry L Gómez, Carlo Tondini, Graziella Pinotti, Karen N Price, Alan S Coates, Aron Goldhirsch, Richard D Gelber
雑誌名: J Clin Oncol. 2016 Jul 1;34(19):2221-31. doi: 10.1200/JCO.2015.64.3171. Epub 2016 Apr 4.
Abstract/Text PURPOSE: Risk of recurrence is the primary consideration in breast cancer adjuvant therapy recommendations. The TEXT (Tamoxifen and Exemestane Trial) and SOFT (Suppression of Ovarian Function Trial) trials investigated adjuvant endocrine therapies for premenopausal women with hormone receptor-positive breast cancer, testing exemestane plus ovarian function suppression (OFS), tamoxifen plus OFS, and tamoxifen alone. We examined absolute treatment effect across a continuum of recurrence risk to individualize endocrine therapy decision making for premenopausal women with human epidermal growth factor receptor 2 (HER2) -negative disease.
PATIENTS AND METHODS: The TEXT and SOFT hormone receptor-positive, HER2-negative analysis population included 4,891 women. The end point was breast cancer-free interval (BCFI), defined as time from random assignment to first occurrence of invasive locoregional, distant, or contralateral breast cancer. A continuous, composite measure of recurrence risk for each patient was determined from a Cox model incorporating age, nodal status, tumor size and grade, and estrogen receptor, progesterone receptor, and Ki-67 expression levels. Subpopulation treatment effect pattern plot methodology revealed differential treatment effects on 5-year BCFI according to composite risk.
RESULTS: SOFT patients who remained premenopausal after chemotherapy experienced absolute improvement of 5% or more in 5-year BCFI with exemestane plus OFS versus tamoxifen plus OFS or tamoxifen alone, reaching 10% to 15% at intermediate to high composite risk; the benefit of tamoxifen plus OFS versus tamoxifen alone was apparent at the highest composite risk. The SOFT no-chemotherapy cohort-for whom composite risk was lowest on average-did well with all endocrine therapies. For TEXT patients, the benefit of exemestane plus OFS versus tamoxifen plus OFS in 5-year BCFI ranged from 5% to 15%; patients not receiving chemotherapy and with lowest composite risk did well with both treatments.
CONCLUSION: Premenopausal women with hormone receptor-positive, HER2-negative disease and high recurrence risk, as defined by clinicopathologic characteristics, may experience improvement of 10% to 15% in 5-year BCFI with exemestane plus OFS versus tamoxifen alone. An improvement of at least 5% may be achieved for women at intermediate risk, and improvement is minimal for those at lowest risk.

© 2016 by American Society of Clinical Oncology.
PMID 27044936  J Clin Oncol. 2016 Jul 1;34(19):2221-31. doi: 10.1200/J・・・
著者: W A Mellink, R Holland, J H Hendriks, P H Peeters, E J Rutgers, W A van Daal
雑誌名: Cancer. 1991 Apr 1;67(7):1844-8.
Abstract/Text The role of routine mammography was assessed in the early detection of asynchronous contralateral breast cancer (ACBC). The breast cancer patient populations of two cities, Nijmegen and Eindhoven, The Netherlands, which were subjected to a well-defined follow-up program, were compared. The program consisted of regular physical examination and annual mammography in Nijmegen and physical examination only in Eindhoven. From 1975 until 1987, 24 ACBC patients were detected within a group of 880 breast cancer patients in Nijmegen (3%) and, from 1971 until 1984, 14 ACBC patients within a group of 411 patients in Eindhoven (3%). In Nijmegen, eight of the 23 evaluable patients (35%) had a contralateral tumor with a histologic size smaller than 10 mm or an in situ carcinoma, compared with one of the 14 of the Eindhoven patients (7%), whereas 18 of the 24 (75%) versus eight of the 14 patients (57%) were node-negative. Thus annual mammography is very likely a contribution in the early detection of contralateral breast cancer as compared with follow-up by regular physical examination only.

PMID 1848469  Cancer. 1991 Apr 1;67(7):1844-8.
著者: T K Yau, H Sze, I S Soong, W Wong, K Chan, A Chang, K Y Lau, A Lee
雑誌名: Breast. 2008 Apr;17(2):132-7. doi: 10.1016/j.breast.2007.08.001. Epub 2007 Oct 1.
Abstract/Text Annual surveillance mammography is commonly recommended after breast conservation therapy (BCT). We retrospectively reviewed its effectiveness on 511 invasive and non-invasive breast cancers treated with BCT between 1994 and 2003. The median follow-up was 5.9 years. The 5-year actuarial ipsilateral breast tumour recurrence (IBTR) rate was 4.5% and contralateral breast cancer (CBC) rate was 2.0% (representing eight times increase in risk). IBTR of 43% and 62% CBC were first detected by surveillance mammography. The IBTR detection rates per 1000 mammograms were 5.2 for patients (n=349) with one or more IBTR risk factors (age 45, positive/close margins or histological grade 3) and 0.6 for patients (n=162) without. No survival difference was observed between different modes of IBTR detection (p=0.342). In conclusion, a risk-adapted approach of limiting ipsilateral surveillance to patients with IBTR risk is possible but its implementation will be complicated by the continued need of contralateral surveillance.

PMID 17905584  Breast. 2008 Apr;17(2):132-7. doi: 10.1016/j.breast.200・・・
著者: D A Montgomery, K Krupa, W J L Jack, G R Kerr, I H Kunkler, J Thomas, J M Dixon
雑誌名: Br J Cancer. 2007 Jun 18;96(12):1802-7. doi: 10.1038/sj.bjc.6603815. Epub 2007 May 29.
Abstract/Text The guidelines for follow-up of breast cancer patients concentrate on the first 3-5 years, with either reduced frequency of visits or discharge after this. They also recommend mammography, but no evidence exists to inform frequency. We analyse treatable relapses in our unit from 1312 patients with early stage breast cancer treated by breast conserving surgery (BCS) and postoperative radiotherapy between 1991 and 1998 to assess appropriateness of the guidelines. A total of 110 treatable relapses were analysed. Treatable relapse developed at 1-1.5% per year throughout follow-up. Forty-eight relapses were in ipsilateral breast, 25 ipsilateral axilla, 35 contralateral breast, 2 both breasts simultaneously. Thirty-seven relapses (33.5%) were symptomatic, 56 (51%) mammographically detected, 15 (13.5%) clinically detected, 2 (2%) diagnosed incidentally. Mammography detected 5.37 relapses per 1000 mammograms. Patients with symptomatic or mammographically detected ipsilateral breast relapse had significantly longer survival from original diagnosis (P=0.0002) and from recurrence (P=0.0014) compared with clinically detected. Treatable relapse occurs at a constant rate for at least 10 years. Clinical examination detects a minority (13.5%). Relapse diagnosed clinically is associated with poorer outcome. Long-term follow-up based on regular mammography is warranted for all patients treated by BCS.

PMID 17533401  Br J Cancer. 2007 Jun 18;96(12):1802-7. doi: 10.1038/sj・・・
著者: S G Orel, B L Fowble, L J Solin, D J Schultz, E F Conant, R H Troupin
雑誌名: Radiology. 1993 Jul;188(1):189-94.
Abstract/Text The prognostic implications of detection mode in local recurrence after lumpectomy and radiation therapy were assessed. Seventy-two women treated with lumpectomy and irradiation for American Joint Committee on Cancer stages I and II invasive breast cancer developed recurrent cancer in the ipsilateral breast, had physical examination and mammography performed at the time of recurrence, and underwent salvage mastectomy. There was a statistically significant association between detection with mammography alone and lower T stage (P = .05), and there was a nonstatistically significant trend toward noninvasive histologic findings. No significant association was noted between detection method and site of recurrent current cancer in the breast, interval to recurrence, or patient age. There were nonstatistically significant trends toward improved relapse-free survival and overall survival for patients with recurrences detected solely with mammography. that postirradiation surveillance mammography is important for the early detection of recurrent cancer. While the trend did not reach statistical significance, detection with mammography alone had a clinically apparent impact on relapse-free and overall survival.

PMID 8511295  Radiology. 1993 Jul;188(1):189-94.
著者: E Grunfeld, H Noorani, L McGahan, L Paszat, D Coyle, C van Walraven, J Joyce, C Sawka
雑誌名: Breast. 2002 Jun;11(3):228-35. doi: 10.1054/brst.2001.0404.
Abstract/Text As the prevalence of diagnosed breast cancer increases, it is important to define how best to provide long-term follow-up. Whereas many aspects of follow-up remain controversial, guidelines recommend surveillance mammograms as the only investigation to be performed routinely. We conducted a systematic review of the literature to elucidate the effect of routine surveillance mammograms on detecting ipsilateral recurrence (IR) and contralateral breast cancers (CBC). The systematic review yielded 15 articles. All were observational studies and ranked as level II-2 or III evidence. There were no randomized controlled trials identified. Most of the ten studies on detection of IR did not report on outcomes after detection. When reported, most studies found that the method of detection of IR did not influence overall survival or disease-free survival. Two of the nine studies on detection of CBC found that the CBC was detected at an earlier stage than the initial breast cancer, but did not report on long-term outcomes. This systematic review highlights the need for further research to help better define the optimum surveillance mammography regimen.

PMID 14965672  Breast. 2002 Jun;11(3):228-35. doi: 10.1054/brst.2001.0・・・
著者: Timothy L Lash, Matthew P Fox, Diana S M Buist, Feifei Wei, Terry S Field, Floyd J Frost, Ann M Geiger, Virginia P Quinn, Marianne Ulcickas Yood, Rebecca A Silliman
雑誌名: J Clin Oncol. 2007 Jul 20;25(21):3001-6. doi: 10.1200/JCO.2006.09.9572. Epub 2007 Jun 4.
Abstract/Text PURPOSE: There are more than 2,000,000 breast cancer survivors in the United States today. While surveillance for asymptomatic recurrence and second primary is included in consensus recommendations, the effectiveness of this surveillance has not been well characterized. Our purpose is to estimate the effectiveness of surveillance mammography in a cohort of breast cancer survivors with complete ascertainment of surveillance mammograms and negligible losses to follow-up.
PATIENTS AND METHODS: We enrolled 1,846 stage I and II breast cancer patients who were at least 65 years old at six integrated health care delivery systems. We used medical record review and existing databases to ascertain patient, tumor, and therapy characteristics, as well as receipt of surveillance mammograms. We linked personal identifiers to the National Death Index to ascertain date and cause of death. We matched four controls to each breast cancer decedent to estimate the association between receipt of surveillance mammogram and breast cancer mortality.
RESULTS: One hundred seventy-eight women died of breast cancer during 5 years of follow-up. Each additional surveillance mammogram was associated with a 0.69-fold decrease in the odds of breast cancer mortality (95% CI, 0.52 to 0.92). The protective association was strongest among women with stage I disease, those who received mastectomy, and those in the oldest age group.
CONCLUSION: Given existing recommendations for post-therapy surveillance, trials to compare surveillance with no surveillance are unlikely. This large observational study provides support for the recommendations, suggesting that receipt of surveillance mammograms reduces the rate of breast cancer mortality in older patients diagnosed with early-stage disease.

PMID 17548838  J Clin Oncol. 2007 Jul 20;25(21):3001-6. doi: 10.1200/J・・・
著者: Lawrence Paszat, Rinku Sutradhar, Eva Grunfeld, Corona Gainford, Veronique Benk, Susan Bondy, Doug Coyle, Claire Holloway, Carol Sawka, Rene Shumak, Katherine Vallis, Carl van Walraven
雑誌名: Breast Cancer Res Treat. 2009 Mar;114(1):169-78. doi: 10.1007/s10549-008-9986-4. Epub 2008 Mar 27.
Abstract/Text GOAL: To ascertain outcomes of surveillance mammography (SM) following treatment of early stage unilateral primary breast cancer (PBC) in a population based case series.
METHODS: Random samples from all 12,279 women having breast surgery within 4 months after diagnosis of PBC, between July 1991 and December 1993 in Ontario, were drawn from a database created by deterministic linkage of PBC files from the Ontario Cancer Registry (OCR) with episodes of breast surgery extracted from the hospital Discharge Abstract Database (DAD), and mammography from the Ontario physician billings database (OHIP). Among women having >or=1 episode(s) of breast surgery subsequent (SBS) to the date of diagnosis up to December 2000, a sample of 1,200/5,064 (23.7%) was drawn, and among women with no SBS, a sample of 400/7,215 (5.5%). Among these two samples, operative, pathology, and mammography reports were abstracted from original charts. Treatments were abstracted and categorized. Women with complete data for Stages 1 and 2 unilateral PBC were included. From the subsequent surgery sample, 609/1,200 (50.8%) were excluded because of simultaneous or sequential bilateral breast cancers or mastectomies within 6 months, missing stage information, Stage 3 or 4 PBC, or missing primary charts. From the no subsequent surgery sample, 90/400 (22.5%) were excluded by the same criteria. Episodes of bilateral 2-view X-ray mammography, beginning >or=6 months after the diagnosis of unilateral PBC, and if multiple, at least 11 months apart, and not prompted by a clinical concern or symptom, were classified as SM. We confirmed episodes of cancer recurrence within the ipsilateral conserved breast (CRICB) and metachronous contralateral primary breast cancer (CPBC) >or=6 months after the diagnosis of the unilateral PBC from original operative and pathology reports. We used Cox models to describe the association of exposure to >or=1 episode(s) of SM with the risk of death from breast cancer among the study population, and separately among women experiencing CRICB or CPBC.
RESULTS: Eligible women comprising 591/1,200 and 310/400 produced a combined case series of 901/1,600 (56.3%). Women with >or=1 episode(s) of SM numbered 721/901 (80.0%). We confirmed 84 CRICB events among 584 women initially treated by lumpectomy (14.4%), and 49 CPBC events among all 901 women in the study population (5.4%). Among women having >or=1 episode(s), the 25th percentile of observed follow up was 1,631 days, the 50th, 4,287 days, and the 75th 5,011 days. Among women without any SM, the 25th percentile of observed follow-up was 440 days, the 50th, 891 days, and the 75th, 1,849 days. Hazard ratio (HR) for death due to breast cancer associated with >or=1 episode of SM was 0.28 (95% CI 0.22-0.37), adjusted for age, stage, type of surgery, adjuvant chemotherapy, and tamoxifen. Among 84/584 women with CRICB, unadjusted HR = 0.36 (95%CI 0.13, 1.00) and among 49/901 women with CPBC, unadjusted HR = 0.86 (0.20-3.77).
CONCLUSION: SM was associated with a significant reduction in the hazard for breast cancer death. Among women who experienced CRICB, the reduction was of borderline significance, and the reduction was not significant among women who experienced CPBC.

PMID 18368477  Breast Cancer Res Treat. 2009 Mar;114(1):169-78. doi: 1・・・

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