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大部分早期三阴性乳腺癌患者在手术前需要进行新辅助化疗，有助于缩小肿瘤、提高手术的可行性和成功率。其中，大约三分之一患者可以获得病理完全缓解、生存结局较好。不过，其余三分之二患者仍然残留病变、复发风险较高。手术后对外周血液进行循环肿瘤DNA测序和循环肿瘤细胞计数（又被称为液体活检）可以从分子水平和细胞水平检测微量残留病变，早期预测哪些患者可能复发，以便及时采取措施强化治疗。 2020年7月9日，《美国医学会杂志》肿瘤学分册在线发表印第安纳大学、威斯康星医学院、芝加哥大学、阿拉巴马大学、乔治城大学、佛罗里达好莱坞纪念医院、埃默里大学、印第安纳波利斯地区肿瘤医院、佛罗里达大学、佛罗里达西尔维斯特综合癌症中心、威斯康星奥罗拉医院、田纳西厄兰格医院、马萨诸塞剑桥基础医学、戴维斯加利福尼亚大学、普渡大学的BRE12-158研究预设二次分析报告，探讨了早期三阴性乳腺癌患者术前新辅助化疗后循环肿瘤DNA和循环肿瘤细胞与复发和生存结局是否独立相关。 NCT02101385: A Phase II Randomized Controlled Trial of Genomically Directed Therapy After Preoperative Chemotherapy in Patients With Triple Negative Breast Cancer: Hoosier Oncology Group BRE12-158 该多中心随机对照二期临床研究于2014年3月26日～2018年12月18日入组早期三阴性乳腺癌术前新辅助化疗后残留病变患者196例（平均年龄49.6±11.1岁）按1∶1随机分为两组，一组针对新辅助化疗后基因组进行治疗，一组根据医师选择进行治疗。入组时，收集患者血液标本，对142例患者进行循环肿瘤DNA与生存结局分析，对123例患者进行循环肿瘤细胞与生存结局分析。主要结局为无远处病变生存期、无病生存、总生存。 结果，中位随访17.2个月（范围0.3～58.3个月），循环肿瘤DNA阳性与阴性的患者相比：
24个月时，循环肿瘤DNA阳性与阴性的患者相比：
循环肿瘤DNA＋循环肿瘤细胞，可以为提高敏感性和特异性提供更多信息。 循环肿瘤DNA＋循环肿瘤细胞双阳性与循环肿瘤DNA＋循环肿瘤细胞双阴性的患者相比：
24个月时，循环肿瘤DNA＋循环肿瘤细胞双阳性与循环肿瘤DNA＋循环肿瘤细胞双阴性的患者相比：
因此，该随机临床研究预设二次分析结果表明，早期三阴性乳腺癌患者新辅助化疗后循环肿瘤DNA和循环肿瘤细胞阳性与病变复发独立相关，高于常规临床指标，对于将来的新辅助研究，可以成为新的重要分层因素。 对此，西北大学费恩伯格医学院罗伯特·卢里综合癌症中心发表同期评论：早期三阴性乳腺癌患者微量残留病变阳性、阴性或更复杂？  Presence of ctDNA and CTCs After Chemotherapy and Recurrence of Triple-Negative Breast Cancer. Interview with Bryan P. Schneider, MD, and Milan Radovich, PhD JAMA Oncol. 2020 Jul 9. Online ahead of print. Association of Circulating Tumor DNA and Circulating Tumor Cells After Neoadjuvant Chemotherapy With Disease Recurrence in Patients With Triple-Negative Breast Cancer: Preplanned Secondary Analysis of the BRE12-158 Randomized Clinical Trial. Radovich M, Jiang G, Hancock BA, 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, Shen F, Storniolo AMV, Badve S, Ballinger TJ, Chang CL, Zhong Y, Savran C, Miller KD, Schneider BP. Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis; Medical College of Wisconsin, Milwaukee; University of Chicago, Chicago, Illinois; University of Alabama at Birmingham, Birmingham; Georgetown University, Washington, DC; Memorial Healthcare System, Hollywood, Florida; Winship Cancer Institute of Emory University, Atlanta, Georgia; Community Regional Cancer Care, Indianapolis, Indiana; University of Florida, Gainesville; Sylvester Comprehensive Cancer Center, Deerfield Beach, Florida; Advocate Aurora Health Care, Milwaukee, Wisconsin; Erlanger Health System, Chattanooga, Tennessee; Foundation Medicine Inc, Cambridge, Massachusetts; University of California at Davis, Davis; Purdue University School of Mechanical Engineering, West Lafayette, Indiana. This preplanned secondary analysis of a randomized clinical trial examines whether the presence of circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) after neoadjuvant chemotherapy in patients with early-stage triple-negative breast cancer is independently associated with recurrence and clinical outcomes. QUESTION: Is the presence of circulating tumor DNA and circulating tumor cells after surgery associated with inferior outcomes for patients with early-stage triple-negative breast cancer? FINDINGS: This large preplanned secondary analysis of 196 female patients from a recently completed randomized clinical trial found that the presence of circulating tumor DNA and circulating tumor cells after neoadjuvant chemotherapy in patients with early-stage triple-negative breast cancer was associated with significantly inferior distant disease-free survival, disease-free survival, and overall survival. MEANING: Detection of circulating tumor DNA and circulating tumor cells after neoadjuvant chemotherapy in patients with early-stage triple-negative breast cancer is independently associated with disease recurrence, above and beyond standard clinical parameters, and represents an important novel stratification factor for future postneoadjuvant trials. IMPORTANCE: A significant proportion of patients with early-stage triple-negative breast cancer (TNBC) are treated with neoadjuvant chemotherapy. Sequencing of circulating tumor DNA (ctDNA) after surgery, along with enumeration of circulating tumor cells (CTCs), may be used to detect minimal residual disease and assess which patients may experience disease recurrence. OBJECTIVE: To determine whether the presence of ctDNA and CTCs after neoadjuvant chemotherapy in patients with early-stage TNBC is independently associated with recurrence and clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS: A preplanned secondary analysis was conducted from March 26, 2014, to December 18, 2018, using data from 196 female patients in BRE12-158, a phase 2 multicenter randomized clinical trial that randomized patients with early-stage TNBC who had residual disease after neoadjuvant chemotherapy to receive postneoadjuvant genomically directed therapy vs treatment of physician choice. Patients had blood samples collected for ctDNA and CTCs at time of treatment assignment; ctDNA analysis with survival was performed for 142 patients, and CTC analysis with survival was performed for 123 patients. Median clinical follow-up was 17.2 months (range, 0.3-58.3 months). INTERVENTIONS: Circulating tumor DNA was sequenced using the FoundationACT or FoundationOneLiquid Assay, and CTCs were enumerated using an epithelial cell adhesion molecule-based, positive-selection microfluidic device. MAIN OUTCOMES AND MEASURES: Primary outcomes were distant disease-free survival (DDFS), disease-free survival (DFS), and overall survival (OS). RESULTS: Among 196 female patients (mean [SD] age, 49.6 [11.1] years), detection of ctDNA was significantly associated with inferior DDFS (median DDFS, 32.5 months vs not reached; hazard ratio [HR], 2.99; 95% CI, 1.38-6.48; P = .006). At 24 months, DDFS probability was 56% for ctDNA-positive patients compared with 81% for ctDNA-negative patients. Detection of ctDNA was similarly associated with inferior DFS (HR, 2.67; 95% CI, 1.28-5.57; P = .009) and inferior OS (HR, 4.16; 95% CI,1.66-10.42; P = .002). The combination of ctDNA and CTCs provided additional information for increased sensitivity and discriminatory capacity. Patients who were ctDNA positive and CTC positive had significantly inferior DDFS compared with those who were ctDNA negative and CTC negative (median DDFS, 32.5 months vs not reached; HR, 5.29; 95% CI, 1.50-18.62; P = .009). At 24 months, DDFS probability was 52% for patients who were ctDNA positive and CTC positive compared with 89% for those who were ctDNA negative and CTC negative. Similar trends were observed for DFS (HR, 3.15; 95% CI, 1.07-9.27; P = .04) and OS (HR, 8.60; 95% CI, 1.78-41.47; P = .007). CONCLUSIONS AND RELEVANCE: In this preplanned secondary analysis of a randomized clinical trial, detection of ctDNA and CTCs in patients with early-stage TNBC after neoadjuvant chemotherapy was independently associated with disease recurrence, which represents an important stratification factor for future postneoadjuvant trials. ClinicalTrials.gov Identifier: NCT02101385 PMID: 32644110 DOI: 10.1001/jamaoncol.2020.2295  JAMA Oncol. 2020 Jul 9. Online ahead of print. Minimal Residual Disease in Patients With Nonmetastatic Triple-Negative Breast Cancer: Positive, Negative, or a More Complex Issue? Davis AA, Cristofanilli M. Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois. PMID: 32644099 DOI: 10.1001/jamaoncol.2020.2285
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