三阴性乳腺癌是一种高度异质性和侵袭性的疾病，至今无有效靶向疗法，故与其他乳腺癌亚型相比，患者的复发和死亡风险仍然较高。虽然约三分之一的三阴性乳腺癌患者对标准蒽环类和紫杉类化疗可获得病理学完全缓解，但是这些肿瘤的异质性，阻碍了识别对化疗有效患者的生物标志。
2016年12月13日，美国《公共科学图书馆·医学》在线发表美国耶鲁大学、匈牙利自然科学研究中心、匈牙利塞麦尔维斯大学、美国德克萨斯大学MD安德森癌症中心、美国耶鲁癌症中心的研究报告《三阴性乳腺癌化疗敏感性的预测方法：综合基因组分析》，发现一种三阴性乳腺癌亚型显示出显著改善的化疗效果，这种乳腺癌易感基因（BRCA）缺失三阴性乳腺癌亚型患者化疗后的生存率较高。
该研究利用全外显子组测序技术，对MD安德森癌症中心（MDACC）29例新辅助化疗后三阴性乳腺癌患者（病理学完全缓解18例，广泛残留病灶11例）基因组所有表达基因进行测序，并将144例癌症基因组图谱（TCGA）和278例国际乳腺癌联盟分子分类（METABRIC）队列病例作为验证队列，分析可能提示对标准蒽环类和紫杉类化疗有效或耐药的特异基因或信号通路突变。
结果发现，AR和FOXA1调控网络的突变，尤其BRCA1起了关键作用。MDACC队列的AR和FOXA1通路突变者与未突变者相比，病理学完全缓解率显著较高（94.1%比16.6%，校正后P=0.02），生存结局优于TCGA三阴性乳腺癌队列（对数秩检验P=0.05）。
DNA测序、DNA甲基化、RNA测序组合分析显示，功能性BRCA缺失三阴性乳腺癌（以野生型BRCA1/2表达水平低为特征）患者，对标准化疗的生存优于非BRCA缺失三阴性乳腺癌患者（对数秩检验P=0.021），突变率显著较高（P＜0.001），并出现与免疫细胞活性增加相关的新生抗原。
经过独立验证，METABRIC数据队列BRCA缺失三阴性乳腺癌的转录标志与生存改善有显著相关性（对数秩检验P=0.009）。
因此，该研究通过综合分子分析，发现了BRCA缺失与突变增加、新生抗原产生、三阴性乳腺癌（蒽环类和紫杉类）化疗敏感性显著增强的直接相关性，而这些都有可能为新的免疫靶向疗法提供靶点，有助于为三阴性乳腺癌患者提供新的治疗策略。
不过，该回顾性研究的局限性包括前期队列样本量小（29例）以及可能存在选择偏倚。
PLoS Med. 2016 Dec 13;13(12):e1002193.
Predictors of Chemosensitivity in Triple Negative Breast Cancer: An Integrated Genomic Analysis.
Jiang T, Shi W, Wali VB, Pongor LS, Li C, Lau R, Gyorffy B, Lifton RP, Symmans WF, Pusztai L, Hatzis C.
Yale University, New Haven, Connecticut, United States of America; Research Center for Natural Sciences, Budapest, Hungary; Semmelweis University, Budapest, Hungary; University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America; Yale Cancer Center, New Haven, Connecticut, United States of America.
BACKGROUND: Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive disease, and although no effective targeted therapies are available to date, about one-third of patients with TNBC achieve pathologic complete response (pCR) from standard-of-care anthracycline/taxane (ACT) chemotherapy. The heterogeneity of these tumors, however, has hindered the discovery of effective biomarkers to identify such patients.
METHODS AND FINDINGS: We performed whole exome sequencing on 29 TNBC cases from the MD Anderson Cancer Center (MDACC) selected because they had either pCR (n = 18) or extensive residual disease (n = 11) after neoadjuvant chemotherapy, with cases from The Cancer Genome Atlas (TCGA; n = 144) and METABRIC (n = 278) cohorts serving as validation cohorts. Our analysis revealed that mutations in the AR- and FOXA1-regulated networks, in which BRCA1 plays a key role, are associated with significantly higher sensitivity to ACT chemotherapy in the MDACC cohort (pCR rate of 94.1% compared to 16.6% in tumors without mutations in AR/FOXA1 pathway, adjusted p = 0.02) and significantly better survival outcome in the TCGA TNBC cohort (log-rank test, p = 0.05). Combined analysis of DNA sequencing, DNA methylation, and RNA sequencing identified tumors of a distinct BRCA-deficient (BRCA-D) TNBC subtype characterized by low levels of wild-type BRCA1/2 expression. Patients with functionally BRCA-D tumors had significantly better survival with standard-of-care chemotherapy than patients whose tumors were not BRCA-D (log-rank test, p = 0.021), and they had significantly higher mutation burden (p < 0.001) and presented clonal neoantigens that were associated with increased immune cell activity. A transcriptional signature of BRCA-D TNBC tumors was independently validated to be significantly associated with improved survival in the METABRIC dataset (log-rank test, p = 0.009). As a retrospective study, limitations include the small size and potential selection bias in the discovery cohort.
CONCLUSIONS: The comprehensive molecular analysis presented in this study directly links BRCA deficiency with increased clonal mutation burden and significantly enhanced chemosensitivity in TNBC and suggests that functional RNA-based BRCA deficiency needs to be further examined in TNBC.
PMID: 27959926
DOI: 10.1371/journal.pmed.1002193
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