中国三阴性乳腺癌突变者术前白金疗法

　　乳腺癌易感基因BRCA1和BRCA2是重要的抑癌基因，一旦发生致病突变，容易引起乳腺癌等恶性肿瘤。大约三分之二的BRCA1突变乳腺癌为三阴性乳腺癌，而三阴性乳腺癌与其他乳腺癌相比，BRCA突变比例显著较高，达9.4%～11.2%。对于BRCA突变的三阴性乳腺癌，术前新辅助化疗能够提高手术的可行性和成功率、减少术后复发，目前标准方案为蒽环＋紫杉。卡铂又称碳铂、顺二氨环丁羧酸铂，即一个白金原子结合了两个氨基和一个环丁双羧基。TNT研究证实，卡铂可改善晚期三阴性乳腺癌BRCA突变亚组患者的临床缓解率和无进展生存。不过，GBG66研究表明，卡铂虽然可提高早期三阴性乳腺癌术前蒽环＋紫杉新辅助化疗的病理完全缓解率、无病生存率，但是仅见于BRCA未突变亚组患者，未见于BRCA突变亚组患者。可是，GBG66仅为二期临床研究，样本量较小，一共315例，其中有BRCA检测结果仅291例，BRCA突变亚组患者更少，仅占17.2%，而且全部是德国女性。

　　2020年7月28日，国际抗癌联盟《国际癌症杂志》在线发表北京大学肿瘤医院张娟、姚璐、刘毅强、欧阳涛、李金峰、王天峰、范照青、范铁、林本耀、解云涛的研究报告，比较了中国三阴性乳腺癌BRCA突变与未突变患者术前蒽环紫杉±卡铂新辅助化疗对生存结局的影响。

　　该单中心回顾研究对2003年6月～2015年5月北京大学肿瘤医院连续10377例乳腺癌患者进行回顾分析，其中可手术原发乳腺癌术前新辅助化疗患者1585例（蒽环→紫杉886例，蒽环→紫杉＋卡铂699例）。全部患者的BRCA1和BRCA2突变都已明确，其中102例（6.4%）患者携带BRCA致病突变。对病理完全缓解、无复发生存、无远处复发生存、总生存结局进行分析。

　　结果，中位随访81个月期间，对于全部患者，蒽环→紫杉±卡铂相比，生存结局相似。

　　不过，对于288例三阴性乳腺癌患者，蒽环→紫杉±卡铂相比，生存结局显著较好：

• 5年无复发生存比例：82.6%比47.9%（P=0.024）

• 5年无远处复发生存比例：88.5%比46.9%（P=0.010）

• 5年总生存比例：88.2%比49.9%（P=0.036）

　　通过多因素比例风险回归模型分析，对患者年龄、肿瘤大小、肿瘤分级、淋巴结状态等其他影响因素进行校正后，对于37例三阴性乳腺癌BRCA突变患者，蒽环→紫杉±卡铂相比：

• 复发死亡风险：低76%（校正后风险比：0.24，95%置信区间：0.06～0.91，P=0.035）

• 远处复发死亡风险：低83%（校正后风险比：0.17，95%置信区间：0.03～0.80，P=0.025）

• 总死亡风险：低71%（校正后风险比：0.29，95%置信区间：0.06～1.49，P=0.14）

　　因此，该研究结果表明，卡铂可以提高三阴性乳腺癌BRCA突变患者对术前蒽环＋紫杉标准新辅助化疗的生存结局获益。

相关链接

Int J Cancer. 2020 Jul 28. Online ahead of print.

Impact of the addition of carboplatin to anthracycline-taxane-based neoadjuvant chemotherapy on survival in BRCA1/2-mutated triple-negative breast cancer.

Zhang J, Yao L, Liu Y, Ouyang T, Li J, Wang T, Fan Z, Fan T, Lin B, Xie Y.

Peking University Cancer Hospital& Institute, Beijing, China.

Whether adding carboplatin to standard neoadjuvant chemotherapy improves survival in BRCA1/2 -mutated triple-negative breast cancer is unknown. In this retrospective study, we aimed to explore the efficacy of anthracycline-taxane- or anthracycline-taxane/carboplatin-based neoadjuvant chemotherapy in BRCA1/2 -mutated triple-negative breast cancer. 1,585 operable primary breast cancer patients were treated with either neoadjuvant anthracycline followed by taxane (A-T) (n=886) or anthracycline followed by taxane plus carboplatin (A-TP) regimen (n=699). BRCA1 and BRCA2 germline mutations were determined in all subjects. Pathological complete response (pCR), recurrence-free survival (RFS), distant recurrence-free survival (DRFS), and overall survival (OS) were estimated. Of the entire cohort, 102 patients (6.4%) carried a pathogenic BRCA1/2 germline mutation. After a median follow-up of 81 months, no significant differences in survival between the A-T and A-TP arms were found in the entire cohort. However, among 288 triple-negative breast cancer patients, BRCA1/2 mutation carriers had significantly better survival when treated with the A-TP regimen than with the A-T regimen (5-year RFS: 82.6% vs 47.9%; P=0.024; 5-year DRFS: 88.5% vs 46.9%; P=0.010; 5-year OS: 88.2% vs 49.9%; P=0.036). Multivariate analyses revealed that the A-TP regimen was a significantly favourable factor for RFS and DRFS and showed a trend towards better OS when compared with the A-T regimen in BRCA1/2 -mutated triple-negative breast cancer (RFS: adjusted hazard ratio [HR],0.24; 95% confidence interval [CI],0.06-0.91, P =0.035; DRFS: HR,0.17; 95% CI,0.03-0.80; P =0.025; OS: HR,0.29; 95% CI,0.06-1.49; P =0.14). Our study suggested that BRCA1/2- mutated triple-negative breast cancer patients gain a survival benefit when carboplatin is added to standard anthracycline-taxane-based neoadjuvant chemotherapy.

PMID: 32720318

DOI: 10.1002/ijc.33234