与其他乳腺癌亚型相比，三阴乳腺癌（TNBC）预后较差且缺乏治疗靶标。我们之前报道了TBCRC009研究，是一项铂类单药治疗86名mTNBC患者的多中心单组II期临床研究：整体的客观缓解率（ORR）为25.6％，BRCA1/2携带组（N=11）ORR 为54.5％，BRCA1/2非携带组（N =66）ORR 为19.7％（P=0.02）。中位随访大约4年，6名长期应答患者保持无病生存。在这里，我们探讨TBCRC009研究中对铂治疗应答的生物标志物。
研究方法
参与者有可测量的病灶，可获得的肿瘤，≤1次进行转移治疗，之前未接受铂类化疗。患者每21天接受顺铂75mg/m2或卡铂AUC=6。主要终点：ORR和 p63/p73表达。肿瘤为基础的探索性研究包括：基因表达（GE）分析，PIK3CA和p53突变状态，与BRCA1/2失活关联的同源重组缺陷（HRD）检测。
研究结果
61例病人可评估两个共同主要终点。28例患者（46％）p63/p73比例≥2，并不能预测对铂类的反应（p63/p73≥2 vs <2 的ORR 18％ vs 27％，P =0.54）。36/54例（67％）有p53基因突变，9/55（16％）有PIK3CA突变，与ORR均不相关。PAM50分析确认60％（32/53）基底细胞样肿瘤，具有较高的ORR，但没有达到显著差异（基底 vs 非基底，28％ vs 10％，p =0.17）。所有HRD分析（包括杂合性缺失（LOH），端粒等位基因失衡（TAI），大规模状态转换（LST））中，BRCA1/2携带者比非携带者得分高。而在22个可获得组织的非携带者中，有应答者比无应答者得分高（HRD-LST 应答者 vs 无应答者，P =0.0016）。
结论
对于BRCA1/2-相关和散发mTNBC，单药铂类是有效的。虽然建立的生物标志物不能预测反应，HRD分析可以识别BRCA1/2类和对铂类化疗有反应的散发三阴性乳腺癌。临床试验信息：NCT00483223.
医脉通整理报道，转载请注明出处。
会议专题》》》2014年ASCO年会专题报道
阅读摘要原文
Identification of biomarkers to predict response to single-agent platinum chemotherapy in metastatic triple-negative breast cancer (mTNBC): Correlative studies from TBCRC009.（Abstract No:1020）
Authors: Steven J. Isakoff, Lei He, Erica L. Mayer, Paul E. Goss, et al.
Session Type: Oral Abstract Session
Background: TNBC has a poor prognosis compared to other BC subtypes and lacks therapeutic targets. We previously reported TBCRC009, a multicenter single-arm phase II study of single-agent platinum in 86 patients (pts) with mTNBC: the objective response rate (ORR) was 25.6% overall and 54.5% vs. 19.7% (p=0.02) in BRCA1/2 carriers (n=11) vs. non-carriers (n=66). Six long-term responders remain disease free at median follow up of ~4 yrs. Here we explored biomarkers of response to platinum in TBCRC009.
Methods: Participants had measurable disease, available archival tumor, ≤1 prior metastatic therapy, and no prior platinum chemotherapy. By physician choice, pts received cisplatin 75mg/m2or carboplatin AUC=6 every 21 days. Co-primary endpoints were: 1) ORR and 2) p63/p73 expression by RT-PCR as a predictor of response. Tumor-based exploratory studies included: gene expression (GE) profiling, PIK3CA and p53 mutational status, and homologous recombination deficiency (HRD) assays correlating with BRCA1/2 inactivation.
Results: Among 61 pts evaluable for co-primary endpoint 2, 28 (46%) had the pre-specified p63/p73 ratio ≥2, which did not predict response to platinum (ORR 18% vs. 27% in p63/p73 ≥2 vs. <2, respectively, p=0.54). 36/54 pts (67%) had p53 mutations, and 9/55 pts (16%) had PIK3CA mutations, but neither correlated with ORR. PAM50 analysis from global GE profiling identified 60% (32/53) basal-like tumors, which showed a higher ORR that did not reach significance (28% vs. 10% in basal vs non-basal, p=0.17). All HRD assays, including Loss Of Heterozygosity (LOH), Telomere Allelic Imbalance (TAI), and Large-scale State Transition (LST), scored higher in BRCA1/2 carriers than non-carriers, and in responders than non-responders among the small group of 22 non-carriers with available tissue (HRD-LST responders vs. nonresponders, p=0.0016).
Conclusions: Single-agent platinum is effective in both BRCA1/2-associated and sporadic mTNBC. Although established biomarkers failed to predict responses, HRD assays may identify sporadic TNBC tumors that are BRCA1/2-like and responsive to platinum chemotherapy.
