对于肿瘤较大、淋巴结转移、尚未远处转移的三阴性乳腺癌，术前新辅助化疗有助于缩小肿瘤和淋巴结，为手术创造条件，并减少术后复发风险。不过，如果术后病理检查发现肿瘤和淋巴结并未完全消失，那么复发风险较高。CREATE-X研究数据表明，术后卡培他滨辅助治疗可显著减少残癌患者的复发风险。根据多基因检测结果个体化选择靶向药物，也被证实对多种癌症患者有效。那么，对于残癌患者，应该根据医师经验选择治疗方案？还是应该根据多基因检测结果选择个体化靶向治疗？
2022年2月1日，美国临床肿瘤学会《临床肿瘤学杂志》正式发表印第安纳大学梅尔文布伦西蒙综合癌症中心、威斯康星医学院、芝加哥大学、阿拉巴马大学伯明翰分校、乔治城大学、佛罗里达好莱坞纪念医疗中心、埃默里大学温希普癌症研究所、印第安纳波利斯地区癌症中心、佛罗里达大学、西尔维斯特综合癌症中心、密尔沃基医疗中心、厄兰格医疗中心、戴维斯加利福尼亚大学的BRE12-158研究报告，对三阴性乳腺癌术前新辅助治疗后残癌患者的多基因检测结果指导个体化靶向治疗与医师选择治疗进行了比较。
BRE12-158 (NCT02101385): A Postneoadjuvant, Randomized Phase II Trial of Personalized Therapy Versus Treatment of Physician's Choice for Patients With Residual Triple-Negative Breast Cancer. 该多中心随机对照二期临床研究于2014年3月至2018年12月从全国29家医院入组三阴性乳腺癌术前新辅助治疗后残癌患者193例，采用大规模并行测序对残癌进行多基因检测，由印第安纳大学分子肿瘤专家委员会对全部检测结果进行判断。将多基因检测结果，有药物靶点的144例患者按1∶1的比例分入两组：
A组71例：基因指导治疗4个周期
B组73例：医师选择治疗4个周期
无药物靶点的49例患者也被分入B组。
主要终点为2年无病生存。次要和探索性终点包括远处无病生存、总生存、毒性评定、治疗随时间的变化、药物对应结局。
结果，A组与B组相比：
2年无病生存率：56.6%比62.4%（95%置信区间：0.45～0.70、0.52～0.75）
无病生存：相似（风险比：0.69，95%置信区间：0.40～1.19，P=0.18）
远处无病生存：相似（风险比：0.73，95%置信区间：0.41～1.29，P=0.28）
总生存：相似（风险比：0.72，95%置信区间：0.38～1.38，P=0.32）
随着时间的推移，卡培他滨用于医师选择治疗有所增加，并且显著获益。后期随机入组患者的远处复发较少。循环肿瘤DNA状态仍然是结局的重要预测因素，一些患者术前新辅助治疗后循环肿瘤DNA被清除。
因此，该小样本随机对照二期临床研究结果表明，对于三阴性乳腺癌术前新辅助化疗后残癌患者，多基因指导治疗并不优于医师选择治疗。不应进行多基因测序指导临床研究以外的早期三阴性乳腺癌术后辅助治疗，应该继续将卡培他滨作为治疗标准；不过，其他药物对于此类患者的活性，为检验改善结局的最佳组合奠定了基础。对于此类患者，循环肿瘤DNA应被视为术前新辅助治疗后临床研究的标准影响因素之一。
相关链接
J Clin Oncol. 2022 Feb 1;40(4):345-355.
BRE12-158: A Postneoadjuvant, Randomized Phase II Trial of Personalized Therapy Versus Treatment of Physician's Choice for Patients With Residual Triple-Negative Breast Cancer.Schneider BP, Jiang G, Ballinger TJ, Shen F, Chitambar C, Nanda R, Falkson C, Lynce FC, Gallagher C, Isaacs C, Blaya M, Paplomata E, Walling R, Daily K, Mahtani R, Thompson MA, Graham R, Cooper ME, Pavlick DC, Albacker LA, Gregg J, Solzak JP, Chen YH, Bales CL, Cantor E, Hancock BA, Kassem N, Helft P, O'Neil B, Storniolo AMV, Badve S, Miller KD, Radovich M.Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN; Medical College of Wisconsin, Milwaukee, WI; University of Chicago, Chicago, IL; University of Alabama at Birmingham, Birmingham, AL; Georgetown University, Washington, DC; Memorial Healthcare System, Hollywood, FL; Winship Cancer Institute of Emory University, Atlanta, GA; Community Regional Cancer Care, Indianapolis, IN; University of Florida, Gainesville, FL; Sylvester Comprehensive Cancer Center, Deerfield Beach, FL; Advocate Aurora Health, Milwaukee, WI; Erlanger Health System, Chattanooga, TN; Foundation Medicine Inc, Cambridge, MA; University of California at Davis, Sacramento, CA.PURPOSE: Patients with triple-negative breast cancer (TNBC) with residual disease after neoadjuvant chemotherapy (NAC) have high risk of recurrence with prior data suggesting improved outcomes with capecitabine. Targeted agents have demonstrated activity across multiple cancer types. BRE12-158 was a phase II, multicenter trial that randomly allocated patients with TNBC with residual disease after NAC to genomically directed therapy versus treatment of physician choice (TPC).PATIENTS AND METHODS: From March 2014 to December 2018, 193 patients were enrolled. Residual tumors were sequenced using a next-generation sequencing test. A molecular tumor board adjudicated all results. Patients were randomly allocated to four cycles of genomically directed therapy (arm A) versus TPC (arm B). Patients without a target were assigned to arm B. Primary end point was 2-year disease-free survival (DFS) among randomly assigned patients. Secondary/exploratory end points included distant disease-free survival, overall survival, toxicity assessment, time-based evolution of therapy, and drug-specific outcomes.RESULTS: One hundred ninety-three patients were randomly allocated or were assigned to arm B. The estimated 2-year DFS for the randomized population only was 56.6% (95% CI, 0.45 to 0.70) for arm A versus 62.4% (95% CI, 0.52 to 0.75) for arm B. No difference was seen in DFS, distant disease-free survival, or overall survival for the entire or randomized populations. There was increased uptake of capecitabine for TPC over time. Patients randomly allocated later had less distant recurrences. Circulating tumor DNA status remained a significant predictor of outcome with some patients demonstrating clearance with postneoadjuvant therapy.CONCLUSION: Genomically directed therapy was not superior to TPC for patients with residual TNBC after NAC. Capecitabine should remain the standard of care; however, the activity of other agents in this setting provides rationale for testing optimal combinations to improve outcomes. Circulating tumor DNA should be considered a standard covariate for trials in this setting.KEY OBJECTIVE: Patients with triple-negative breast cancer with residual disease after standard preoperative therapy have a poor prognosis despite the use of capecitabine and/or pembrolizumab in the postneoadjuvant setting. BRE12-158 was a multicenter, randomized, phase II trial testing treatment of physician's choice (TPC) versus genomically guided therapy and represents one of the first randomized trials to test for superiority of a personalized approach (at the patient level) in the curative setting.KNOWLEDGE GENERATED: Genomically guided therapy did not improve outcomes compared with TPC. Capecitabine uptake increased over time in the TPC arm with clear benefit. Circulating tumor DNA positivity remained a significant predictor of outcome.RELEVANCE: Genomic sequencing should not be performed to guide therapy in the curative setting outside of a clinical trial. Circulating tumor DNA should be considered a standard covariate in postneoadjuvant clinical trials for triple-negative breast cancer.DOI: 10.1200/JCO.21.01657
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