BRCA1/2 Status Affects Response to Polychemotherapy in Triple-Negative Breast Cancer

TON Web Exclusives - Breast Cancer

Up to 17% of all breast cancers are triple-negative,1 and patients with this type of disease have a high frequency of BRCA1 and BRCA2 germline mutations.2,3

The GeparSixto trial enrolled women with previously untreated, nonmetastatic, stage II-III triple-negative breast cancer (TNBC) and HER2-positive breast cancer. Patients were treated for 18 weeks with paclitaxel and nonpegylated liposomal doxorubicin. Those with TNBC received simultaneous bevacizumab, whereas those with HER2-positive disease received simultaneous trastuzumab and lapatinib. Patients were randomized in a 1:1 ratio to receive, at the same time as the backbone regimens, either carboplatin or no carboplatin.4

The secondary analysis of this trial focused on the BRCA1 and BRCA2 status of the TNBC patients and their response to polychemotherapy.5 GeparSixto included 315 patients with TNBC, of which 291 were included in the germline analysis (24 were excluded because of insufficient or unavailable DNA). All DNA samples were screened for pathogenic BRCA1 and BRCA2 germline mutations.

The primary outcome of this biomarker study was the proportion of patients who achieved pathological complete response (pCR) and disease-free survival (DFS) following neoadjuvant treatment based on mutation status and family history. DFS was defined as the time in months from randomization until invasive locoregional recurrence of disease, contralateral breast cancer, distant recurrence of disease, secondary malignant neoplasm, or death from any cause.

Results of the secondary analysis of 291 women with TNBC and a mean age of 48 years showed a 56.8% pCR rate in the carboplatin group (83 of 146 patients) and 41.4% in the noncarboplatin group (60 of 145 patients; P = .009). The investigators reported that 14.8% of the patients had pathogenic BRCA1 mutations and 2.4% had BRCA2 mutations. Another 3.4% were carriers of deleterious non-BRCA1 and BRCA2 gene mutations. In total, 17.2% of the patients with TNBC carried germline BRCA1 and BRCA2 alterations. Patients with BRCA1 and BRCA2 mutations were more likely to have pathogenic onset before age 40 years and have a positive family history for cancer.5

When looking at response based on treatment, in the noncarboplatin arm, 66.7% of the patients with BRCA1 and BRCA2 mutations showed a pCR versus 36.4% of patients without BRCA1 and BRCA2 mutations (P = .008). In the subgroup of carriers with BRCA1 and BRCA2 germline mutation, the addition of carboplatin did not improve overall pCR rates.

The investigators concluded that, “The overall increased pCR rate with carboplatin therapy appeared to be driven by elevated response rates in patients with TNBC not carrying germline BRCA1 and BRCA2 mutations; patients with TNBC without pathogenic BRCA1 and BRCA2 alterations showed a 36.4% response rate, which increased to 55% when carboplatin was added to the regimen.”5

In this study, 37.8% of patients with TNBC reported a positive family history of cancer. In patients with TNBC without a family history of cancer, carboplatin was associated with significantly higher pCR rates (53.9% vs 37% without carboplatin; P = .02).

At a 35-month median follow-up, patients treated with carboplatin demonstrated a superior DFS versus those who had no carboplatin treatment. Among patients with TNBC without pathogenic BRCA1 and BRCA2 alterations, treatment with carboplatin increased DFS rates to 85.3% versus 73.5% without carboplatin (P = .04). Among BRCA1 and BRCA2 mutation carriers, DFS rates were not significantly different based on treatment (82.5% without carboplatin vs 86.3% with carboplatin).

The investigators concluded that a less-intense treatment regimen might be considered for BRCA1 and BRCA2 mutation carriers, but further prospective studies are needed to identify the optimal regimen.5

References
1. Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med. 2010;363:1938-1948.
2. Stevens KN, Vachon CM, Couch FJ. Genetic susceptibility to triple-negative breast cancer. Cancer Res. 2013;73:2025-2030.
3. Couch FJ, Hart SN, Sharma P, et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015;33:304-311.
4. von Minckwitz G, Schneeweiss A, Loibl, et al. Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol. 2014;15:747-756.
5. Hahnen E, Lederer B, Hauke J, et al. Germline mutation status, pathological complete response, and disease-free survival in triple-negative breast cancer: secondary analysis of the GeparSixto randomized clinical trial. JAMA Oncol. 2017;3:1378-1385.

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Last modified: December 28, 2017