中国发现转移性三阴性乳腺癌顺铂一线化疗方案效果较好的生物标志

　　编者按：2015年，英国《柳叶刀》肿瘤学分册发表中国抗癌协会（CACA）乳腺癌专业委员会（CBCS）中国乳腺癌临床研究协作组（CBCSG）多中心随机非盲对照三期临床研究（CBCSG006），报告了顺铂＋吉西他滨与紫杉醇＋吉西他滨相比，一线治疗转移性三阴性乳腺癌的效果较好。

　　2018年6月14日，欧洲肿瘤内科学会（ESMO）官方期刊、牛津大学出版社旗下《肿瘤学年鉴》在线发表复旦大学附属肿瘤医院、复旦大学上海医学院、复旦大学公共卫生学院的研究报告，更新了CBCSG006研究的生存数据，并且探讨了治疗效果的潜在生物标志。

　　该研究于2011年1月14日～2013年11月14日从中国12家医院入组尚未接受治疗的转移性三阴性乳腺癌患者240例，按1∶1随机分配接受顺铂＋吉西他滨或紫杉醇＋吉西他滨（两组各120例），其中236例（两组各118例）接受了至少一次治疗，对其中132例（55.9%）检测了种系（生殖细胞）同源重组基因（包括BRCA）突变，对其中114例（48.3%）检测了PD-L1表达。通过无参数滑动窗亚组治疗效果模式图（STEPP）对绝对生存获益进行分析。所有统计学检验均为双侧。

　　结果发现，顺铂＋吉西他滨与紫杉醇＋吉西他滨相比，无进展生存较长（中位：7.73比6.07个月，95%置信区间：6.46～9.00、5.32～6.83，P=0.005），总生存未见显著差异。

　　同源重组基因突变状态与治疗无进展生存之间存在显著相互影响，顺铂＋吉西他滨与紫杉醇＋吉西他滨相比：

同源重组基因有突变

• 客观有效率较高（71.9%比38.7%，P=0.008）

• 无进展生存较长（10.37比4.3个月，P=0.011）

  同源重组基因无突变

• 客观有效率相似（55.6%比60.6%，P=0.671）

• 无进展生存相似（6.03比7.10个月，P=0.154）

　　种系BRCA基因突变状态与治疗无进展生存之间未见显著相互影响，顺铂＋吉西他滨与紫杉醇＋吉西他滨相比：

种系BRCA基因有突变

• 客观有效率相似（83.3%比37.5%，P=0.086）

• 无进展生存相似（8.90比3.20个月，P=0.459）

  种系BRCA基因无突变

• 客观有效率相似（61.3%比51.8%，P=0.298）

• 无进展生存相似（6.97比5.97个月，P=0.347）

　　PD-L1状态与治疗无进展生存之间未见显著相互影响，顺铂＋吉西他滨与紫杉醇＋吉西他滨相比：

PD-L1阳性

• 客观有效率相似（72.7%比62.5%，P=0.636）

• 无进展生存相似（9.63比5.60个月，P=0.459）

  PD-L1阴性

• 客观有效率相似（71.1%比55.0%，P=0.123）

• 无进展生存相似（7.97比7.03个月，P=0.459）

　　此外，该研究还建立了一种复合风险模型。根据STEPP分析，复合风险较低与较高的患者相比，无进展生存的绝对获益较高。

　　因此，该研究结果表明，顺铂＋吉西他滨与紫杉醇＋吉西他滨相比，对于转移性三阴性乳腺癌患者一线化疗效果较好。BRCA和同源重组基因种系突变，可能成为预测顺铂方案效果较好的生物标志。该研究制定的复合风险模型可以指导选择哪些三阴性乳腺癌患者接受顺铂＋吉西他滨治疗。

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Ann Oncol. 2018 Jun 14. [Epub ahead of print]

Biomarker assessment of the CBCSG006 trial: A randomized phase III trial of cisplatin plus gemcitabine compared with paclitaxel plus gemcitabine as first-line therapy for patients with metastatic triple-negative breast cancer.

J Zhang, Y Lin, X J Sun, B Y Wang, Z H Wang, J F Luo, L P Wang, S Zhang, J Cao, Z H Tao, J Wu, Z M Shao, W T Yang, X C Hu.

Fudan University Shanghai Cancer Center; Shanghai Medical College, Fudan University, Shanghai, China; School of Public Health, Fudan University, Shanghai, China.

BACKGROUND: CBCSG006 trial reported the superior efficacy of cisplatin plus gemcitabine (GP) regimen than paclitaxel plus gemcitabine (GT) regimen as first-line treatment of metastatic triple-negative breast cancer (mTNBC). This study focused on the updated survival data and the explorations of potential biomarkers for efficacy.

PATIENTS AND METHODS: Germ-line mutations of homologous recombination (HR) panel, BRCA1/2 included, were evaluated in 55.9% (132/236) patients. PD-L1 expression was evaluated in in 48.3% (114/236) patients. A nonparametric sliding-window subpopulation treatment effect patter plot (STEPP) methodology was used to analyze the absolute survival benefits. All statistical tests were two-sided.

RESULTS: Median progression-free survival was 7.73 (95% CI 6.46-9.00) months for GP arm and 6.07 (95% CI 5.32-6.83) months for GT arm (P = 0.005). No significant difference in overall survival was observed. There was significant interaction between HR status and treatment for PFS and status of HR deficient significantly correlated with higher ORR and longer PFS in GP than GT arm (71.9% vs. 38.7%, P = 0.008; 10.37 vs. 4.30 months, P = 0.011). There was no significant interaction between gBRCA1/2 status and treatment for PFS. Patients with gBRCA1/2 mutation had numerically higher ORR and prolonged PFS in GP than GT arm (83.3% vs. 37.5%, p = 0.086; 8.90 vs. 3.20 months, P = 0.459). There was no significant interaction between PD-L1 status and treatment for PFS, and no significant differences in ORR, PFS or OS between two arms regardless of PD-L1 status. In STEPP analysis, patients with lower composite risks had more absolute benefits in PFS than those with higher composite risks.

CONCLUSIONS: GP regimen has superior efficacy than GT regimen as first-line chemotherapy for mTNBC patients. Germ-line mutations of BRCA1/2 and HR panel are possible biomarkers for better performance of cisplatin-based regimens. A composite risk model was developed to guide patient selection for GP treatment in TNBC patients.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT01287624

KEYWORDS: Metastatic triple-negative breast cancer, Progression-free survival, Overrall survival, Biomarker, Cisplatin

DOI: 10.1093/annonc/mdy209

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