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Germline mutation status, pathological complete response, and disease-free survival in triple-negative breast cancer: Secondary analysis of the GeparSixto randomized clinical trial

JAMA Oncology Oct 24, 2017

Hahnen E, et al. - This study aimed to determine whether BRCA1 and BRCA2 germline mutation status affects therapy response in patients with triple-negative breast cancer (TNBC). In patients without BRCA1 and BRCA2 germline mutations, the addition of carboplatin to the nonstandard GeparSixto polychemotherapy regimen proved advantageous and in those with BRCA1 and BRCA2 mutations superior response rates were evident without additive effects observed for carboplatin.

Methods

  • A randomized clinical trial was secondarily analyzed utilizing 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.
  • This multicenter prospective investigation included 291 participants in all.
  • Analysis of DNA samples was performed for germline mutations in BRCA1, BRCA2, and 16 other cancer predisposition genes.
  • Researchers compared the pathological complete response (pCR) rates between the carboplatin and noncarboplatin arms.
  • They performed genetic analyses at the Center for Familial Breast and Ovarian Cancer in Cologne, Germany; data analysis, November 1 through December 31, 2015.
  • They determined proportion of patients who achieved pCR and disease-free survival after neoadjuvant treatment according to BRCA1 and BRCA2 germline mutation status.
  • For pCR rates, they used the ypT0/is ypN0 definition as a primary end point.

Results

  • The 291 patients with TNBC were all women; the mean (SD) age was 48 (11) years.
  • In the carboplatin group, the pCR rate was 56.8% (83 of 146) and in the noncarboplatin group, it was 41.4% (60 of 145) (odds ratio [OR], 1.87; 95% CI, 1.17-2.97; P = .009).
  • Observations revealed pathogenic BRCA1 and BRCA2 germline mutations in 50 of the 291 patients (17.2%).
  • In the noncarboplatin arm, the pCR rates were 66.7% (16 of 24) and 36.4% (44 of 121) for patients with BRCA1 and BRCA2 mutations and for patients without (OR, 3.50; 95% CI, 1.39-8.84; P = .008), respectively.
  • The high pCR rate was not increased further by adding carboplatin (17 of 26 [65.4%]) in BRCA1 and BRCA2 mutation carriers (16 of 24 [66.7%]) .
  • On the other hand, increased response rates were observed with carboplatin 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 exhibited increased 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).

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