Center for Hereditary Breast and Ovarian Cancer, Medical Faculty, University Hospital Cologne, Cologne, Germany.
Center for Integrated Oncology, Medical Faculty, University Hospital Cologne, Cologne, Germany.
JAMA Oncol. 2017 Oct 1;3(10):1378-1385. doi: 10.1001/jamaoncol.2017.1007.
The GeparSixto trial provided evidence that the addition of neoadjuvant carboplatin to a regimen consisting of anthracycline, taxane, and bevacizumab increases pathological complete response (pCR) rates in patients with triple-negative breast cancer (TNBC). Whether BRCA1 and BRCA2 germline mutation status affects treatment outcome remains elusive.
To determine whether BRCA1 and BRCA2 germline mutation status affects therapy response in patients with TNBC.
DESIGN, SETTING, AND PARTICIPANTS: This secondary analysis of a randomized clinical trial used archived DNA samples and cancer family history of 315 patients with TNBC enrolled between August 1, 2011, and December 31, 2012, in the GeparSixto trial. In all, 291 participants (92.4%) were included in this multicenter prospective investigation. DNA samples were analyzed for germline mutations in BRCA1, BRCA2, and 16 other cancer predisposition genes. The pCR rates between the carboplatin and noncarboplatin arms were compared. Genetic analyses were performed at the Center for Familial Breast and Ovarian Cancer in Cologne, Germany; data analysis, November 1 through December 31, 2015.
Proportion of patients who achieved pCR and disease-free survival after neoadjuvant treatment according to BRCA1 and BRCA2 germline mutation status. For pCR rates, the ypT0/is ypN0 definition was used as a primary end point.
Of the 291 patients with TNBC, all were women; the mean (SD) age was 48 (11) years. The pCR rate in the carboplatin group was 56.8% (83 of 146) and 41.4% (60 of 145) in the noncarboplatin group (odds ratio [OR], 1.87; 95% CI, 1.17-2.97; P = .009). Pathogenic BRCA1 and BRCA2 germline mutations were present in 50 of the 291 patients (17.2%). In the noncarboplatin arm, the pCR rate was 66.7% (16 of 24) for patients with BRCA1 and BRCA2 mutations and 36.4% (44 of 121) for patients without (OR, 3.50; 95% CI, 1.39-8.84; P = .008). The high pCR rate observed in BRCA1 and BRCA2 mutation carriers (16 of 24 [66.7%]) was not increased further by adding carboplatin (17 of 26 [65.4%]). In contrast, carboplatin increased response rates in patients without BRCA1 and BRCA2 mutations: 66 of the 120 patients (55%) without BRCA1 and BRCA2 mutations achieved pCR in the carboplatin arm vs 44 of the 121 patients (36.4%) in the noncarboplatin arm (OR, 2.14; 95% CI, 1.28-3.58; P = .004). Patients without pathogenic BRCA1 and BRCA2 alterations showed elevated disease-free survival rates when carboplatin was added (without carboplatin, 73.5%; 95% CI, 64.1%-80.8% vs with carboplatin, 85.3%; 95% CI, 77.0%-90.8%; hazard ratio, 0.53; 95% CI, 0.29-0.96; P = .04).
Under the nonstandard GeparSixto polychemotherapy regimen, patients without BRCA1 and BRCA2 germline mutations benefited from the addition of carboplatin and those with BRCA1 and BRCA2 mutations showed superior response rates without additive effects observed for carboplatin.
clinicaltrials.gov Identifier: NCT01426880.
重要性：GeparSixto 试验提供了证据，表明在包含蒽环类药物、紫杉烷和贝伐珠单抗的方案中加入新辅助卡铂可增加三阴性乳腺癌（TNBC）患者的病理完全缓解（pCR）率。BRCA1 和 BRCA2 种系突变状态是否影响治疗结果仍不清楚。
目的：确定 BRCA1 和 BRCA2 种系突变状态是否影响 TNBC 患者的治疗反应。
设计、地点和参与者：这是对 GeparSixto 试验中 315 例 TNBC 患者的随机临床试验的二次分析，这些患者于 2011 年 8 月 1 日至 2012 年 12 月 31 日入组。共有 291 例（92.4%）参与者纳入本多中心前瞻性研究。分析了 BRCA1、BRCA2 和其他 16 个癌症易感性基因的种系突变。比较了卡铂组和非卡铂组的 pCR 率。遗传分析在德国科隆家族性乳腺癌和卵巢癌中心进行；数据分析于 2015 年 11 月 1 日至 12 月 31 日进行。
主要结果和措施：根据 BRCA1 和 BRCA2 种系突变状态，新辅助治疗后达到 pCR 和无病生存的患者比例。对于 pCR 率，ypT0/is ypN0 定义为主要终点。
结果：在 291 例 TNBC 患者中，均为女性；平均（SD）年龄为 48（11）岁。卡铂组的 pCR 率为 56.8%（83/146），非卡铂组为 41.4%（60/145）（优势比[OR]，1.87；95%CI，1.17-2.97；P=0.009）。291 例患者中有 50 例（17.2%）存在致病性 BRCA1 和 BRCA2 种系突变。在非卡铂组，BRCA1 和 BRCA2 突变患者的 pCR 率为 66.7%（16/24），无突变患者为 36.4%（44/121）（OR，3.50；95%CI，1.39-8.84；P=0.008）。BRCA1 和 BRCA2 突变携带者（16/24 [66.7%]）的高 pCR 率并未因加用卡铂而进一步增加（17/26 [65.4%]）。相比之下，卡铂增加了无 BRCA1 和 BRCA2 突变患者的反应率：在卡铂组，120 例无 BRCA1 和 BRCA2 突变患者中有 66 例（55%）达到 pCR，而非卡铂组 121 例患者中有 44 例（36.4%）（OR，2.14；95%CI，1.28-3.58；P=0.004）。无致病性 BRCA1 和 BRCA2 改变的患者在加用卡铂时显示出更高的无病生存率（无卡铂组为 73.5%；95%CI，64.1%-80.8% vs 卡铂组为 85.3%；95%CI，77.0%-90.8%；风险比，0.53；95%CI，0.29-0.96；P=0.04）。
结论和相关性：在非标准的 GeparSixto 多化疗方案下，无 BRCA1 和 BRCA2 种系突变的患者从加用卡铂中获益，而有 BRCA1 和 BRCA2 突变的患者在无卡铂的情况下反应率更高，而无卡铂的情况下反应率更高。
试验注册：clinicaltrials.gov 标识符：NCT01426880。
