新英格兰第三次发表裁缝研究结果
TAILORx是目前全球最大规模的早期乳腺癌术后辅助治疗研究，由6个国家、5大癌症研究组织、1千多个研究机构、1万多例患者参与，由美国国家癌症研究所提供资助，始于2006年。2015年9月27日，《新英格兰医学杂志》首次发表TAILORx研究的21基因乳腺癌复发风险评分0～10分、≥26分患者术后内分泌治疗±化疗结果；于是，2016年2月8日，美国临床肿瘤学会根据该研究结果，首次发布早期乳腺癌术后化疗决策指南。2018年6月3日，《新英格兰医学杂志》再次发表TAILORx研究的21基因乳腺癌复发风险评分11～25分患者术后内分泌治疗±化疗结果；于是，2019年5月31日，美国临床肿瘤学会根据该研究结果发布指南更新（相关阅读：早期乳腺癌术后化疗决策指南更新）。不过，仅仅时隔3天，《新英格兰医学杂志》第三次发表TAILORx研究结果。
TAILORx: Trial Assigning Individualized Options for Treatment - Hormone Therapy With or Without Combination Chemotherapy in Treating Women Who Have Undergone Surgery for Node-Negative Breast Cancer (NCT00310180)
Participating cancer research groups included the Alliance for Clinical Trials in Oncology, NCIC-Clinical Trials Group, NRG Oncology, and SWOG.
对于早期乳腺癌患者，可以通过临床病理因素、21基因复发风险评分预测复发风险，决定术后是否进行辅助化疗。不过，乳腺癌复发的临床风险水平，能否对21基因复发风险评分的预后信息进行补充？
2019年6月3日，美国麻省医学会《新英格兰医学杂志》在线发表纽约爱因斯坦医学院、哈佛大学医学院达纳法伯癌症研究所、德克萨斯大学圣安东尼奥分校、芝加哥洛约拉大学、芝加哥西北大学、密歇根大学、弗吉尼亚联邦大学、北卡罗来纳大学、杜克大学、梅奥医学中心、国家癌症研究所、印第安纳大学、印第安纳大学、文斯隆巴迪肿瘤医院、福克斯谷肿瘤医院、圣路易斯华盛顿大学、匹兹堡大学、埃默里大学、堪萨斯癌症中心、范德堡大学、罗格斯大学、夏威夷大学、加拿大多伦多大学、麦克马斯特大学、爱尔兰癌症研究中心、秘鲁国家肿瘤研究所的TAILORx研究第三次报告，对临床复发风险＋21基因复发风险评分指导早期乳腺癌术后内分泌治疗是否需要联合化疗进行了探讨。
该国际多中心前瞻研究对9427例激素受体阳性、HER2阴性、腋窝淋巴结阴性乳腺癌女性进行21基因复发风险评分（0～100分，评分越高，表明预后越差、化疗可能获益越大），并根据肿瘤大小和组织学分级，对乳腺癌复发临床风险低或高进行分类。通过多因素比例风险回归模型，计算内分泌治疗±化疗的远处复发风险比，对临床风险的影响进行评估。对于其中大部分年龄≤50岁的绝经前女性，初始内分泌治疗为他莫昔芬单药。
结果发现，根据基因风险（较低：0～10分，中等：11～25分，较高：26～100分）和临床风险：
对于基因风险中等女性，临床风险较高与较低相比：
单纯内分泌治疗：远处复发风险高2.73倍（95%置信区间：1.93～3.87）
化疗内分泌治疗：远处复发风险高2.41倍（95%置信区间：1.66～3.48）
对于基因风险较高女性，临床风险较高与较低相比：
化疗内分泌治疗：远处复发风险高3.17倍（95%置信区间：1.94～5.19）
对于年龄>50岁的基因风险中等女性，内分泌治疗±化疗相比：
临床风险较低：9年远处复发风险相似（4.0±0.7%比3.5±0.6%）
临床风险较高：9年远处复发风险相似（8.3±1.5%比9.3±1.9%）
对于年龄≤50岁的基因风险中等女性，内分泌治疗±化疗相比：
临床风险较低：9年远处复发风险相似（3.9+1.0%比4.7±1.0%）
临床风险较高：9年远处复发风险较低（6.1±1.8%比12.3±2.4%）
对于年龄≤50岁的基因风险较低女性，单纯内分泌治疗的9年远处复发风险极低（≤1.8±0.9%）。
对于年龄>50岁的基因风险较高女性，临床风险较高与较低相比，化疗内分泌治疗的9年远处复发风险较高（19.8±3.9%比7.0±2.4%）。
对于年龄≤50岁的基因风险较高女性，临床风险较高与较低相比，化疗内分泌治疗的9年远处复发风险较高（15.2±3.3%比6.2±2.5%）。
因此，该研究结果表明，当临床风险分层加入21基因复发风险评分时提供了预后信息，可被用于确定能够从更有效治疗获益的绝经前女性。
对此，英国牛津大学发表同期社论：实践“精准医学”所需的证据精确性。
相关阅读
N Engl J Med. 2019 Jun 3. [Epub ahead of print]
Clinical and Genomic Risk to Guide the Use of Adjuvant Therapy for Breast Cancer.
Joseph A. Sparano, Robert J. Gray, Peter M. Ravdin, Della F. Makower, Kathleen I. Pritchard, Kathy S. Albain, Daniel F. Hayes, Charles E. Geyer, Jr., Elizabeth C. Dees, Matthew P. Goetz, John A. Olson, Jr., Tracy Lively, Sunil S. Badve, Thomas J. Saphner, Lynne I. Wagner, Timothy J. Whelan, Matthew J. Ellis, Soonmyung Paik, William C. Wood, Maccon M. Keane, Henry L. Gomez Moreno, Pavan S. Reddy, Timothy F. Goggins, Ingrid A. Mayer, Adam M. Brufsky, Deborah L. Toppmeyer, Virginia G. Kaklamani, Jeffrey L. Berenberg, Jeffrey Abrams, George W. Sledge, Jr.
Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY; Dana-Farber Cancer Institute, Boston; University of Texas, San Antonio; Sunnybrook Research Institute, Toronto; McMaster University, Hamilton, ON, Canada; Loyola University Medical Center, Maywood; Northwestern University, Chicago, Illinois; University of Michigan, Ann Arbor; Virginia Commonwealth University School of Medicine and the Massey Cancer Center, Richmond; University of North Carolina, Chapel Hill; Duke University Medical Center, Durham, North Carolina; Mayo Clinic, Jacksonville, FL; National Institutes of Health, National Cancer Institute, Bethesda, MD; Indiana University School of Medicine, Indiana University Hospital, Indianapolis; Vince Lombardi Cancer Clinic, Two Rivers; Fox Valley Hematology and Oncology, Appleton, Wisconsin; Washington University, St. Louis; the National Surgical Adjuvant Breast and Bowel Project Pathology Office, University of Pittsburgh, Pittsburgh; Emory University, Atlanta; Cancer Trials Ireland, Dublin; Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru; Cancer Center of Kansas, Wichita; Vanderbilt University, Nashville; Rutgers Cancer Institute of New Jersey, New Brunswick; University of Hawaii Cancer Center, Honolulu.
BACKGROUND: The use of adjuvant chemotherapy in patients with breast cancer may be guided by clinicopathological factors and a score based on a 21-gene assay to determine the risk of recurrence. Whether the level of clinical risk of breast cancer recurrence adds prognostic information to the recurrence score is not known.
METHODS: We performed a prospective trial involving 9427 women with hormone-receptor-positive, human epidermal growth factor receptor 2-negative, axillary node-negative breast cancer, in whom an assay of 21 genes had been performed, and we classified the clinical risk of recurrence of breast cancer as low or high on the basis of the tumor size and histologic grade. The effect of clinical risk was evaluated by calculating hazard ratios for distant recurrence with the use of Cox proportional-hazards models. The initial endocrine therapy was tamoxifen alone in the majority of the premenopausal women who were 50 years of age or younger.
RESULTS: The level of clinical risk was prognostic of distant recurrence in women with an intermediate 21-gene recurrence score of 11 to 25 (on a scale of 0 to 100, with higher scores indicating a worse prognosis or a greater potential benefit from chemotherapy) who were randomly assigned to endocrine therapy (hazard ratio for the comparison of high vs. low clinical risk, 2.73; 95% confidence interval [CI], 1.93 to 3.87) or to chemotherapy plus endocrine (chemoendocrine) therapy (hazard ratio, 2.41; 95% CI, 1.66 to 3.48) and in women with a high recurrence score (a score of 26 to 100), all of whom were assigned to chemoendocrine therapy (hazard ratio, 3.17; 95% CI, 1.94 to 5.19). Among women who were 50 years of age or younger who had received endocrine therapy alone, the estimated (±SE) rate of distant recurrence at 9 years was less than 5% (≤1.8±0.9%) with a low recurrence score (a score of 0 to 10), irrespective of clinical risk, and 4.7±1.0% with an intermediate recurrence score and low clinical risk. In this age group, the estimated distant recurrence at 9 years exceeded 10% among women with a high clinical risk and an intermediate recurrence score who received endocrine therapy alone (12.3±2.4%) and among those with a high recurrence score who received chemoendocrine therapy (15.2±3.3%).
CONCLUSIONS: Clinical-risk stratification provided prognostic information that, when added to the 21-gene recurrence score, could be used to identify premenopausal women who could benefit from more effective therapy.
Funded by the National Cancer Institute and others
ClinicalTrials.gov number: NCT00310180
DOI: 10.1056/NEJMoa1904819
N Engl J Med. 2019 Jun 3. [Epub ahead of print]
The Precision of Evidence Needed to Practice "Precision Medicine".
David J. Hunter, Dan L. Longo.
University of Oxford, Oxford, United Kingdom.
DOI: 10.1056/NEJMe1906088