germline mutation

An analysis of germline mutation status predicting therapy response results from the GeparSixto trial looked into the efficacy of the treatment regimen for patients with triple-negative breast cancer.

Triple-negative breast cancer (TNBC) patients carrying a germline mutation demonstrate better pathological complete response (pCR) and disease-free survival (DFS) rates under the anthracycline, taxane, and bevacizumab regimen. The addition of neoadjuvant carboplatin, beneficial for the overall TNBC group, had no contribution on the response rate among the BCRA1, BCRA2 carriers. The overall benefit of adding neoadjuvant carboplatin to a regimen of anthracycline, taxane, and bevacizumab was previously observed from the results of GeparSixto randomized clinical trial (2011-2012). The GeparSixto trial assessed the safety and efficacy of the addition of the neoadjuvant carboplatin to the chemotherapy standard regimen in a group of TNBC and HER2 positive breast cancer patients and had a secondary analysis published in JAMA Oncology.

The TNBC patients in carboplatin group demonstrated superior response – 57% achieved pCR compared to 42.7% in the non-carboplatin group. Among HER2 positive tumors, 52.6% benefited from carboplatin compared to 49.7% without carboplatin. Thus, the addition of neoadjuvant was significantly efficient in achieving a pathological complete response in TNBC patients, but not in the HER2 positive group.

The objectives of the current study taken place a few years later (2014-2015) were to assess the contribution of the BCRA germline mutations on the response rate in the GeparSixto trial. Archived DNA samples were sequenced using specific BCRA1/BCRA2 oligonucleotides and the response rate to the adjuvant addition and the medical history of the patients were retrieved for the analysis.

BCRA1 and BCRA2 are critical genes in the DNA repair pathway, and mutations in these genes are frequently found in TNBC tumors (70% of TNBC tumors contain a mutation in BCRA1 gene), and used as markers for breast cancer predisposition. Tumors lacking the ability to repair DNA damage (carriers of BCRA1/2 mutated genes) are usually better responsive for chemotherapy that targeted to damage DNA.  Carboplatin and Doxorubicin (anthracycline group chemotherapy agent) both interfere with DNA synthesis and can potentially show a better response in BCRA1/2 germline mutation carriers. Thus, the question raised in the study, published in the JAMA Oncology, is whether the breast cancer patients carrying BCRA1/2 germline mutations are demonstrating a better response to the addition of carboplatin on top of the standard chemotherapy.

The archived genomic DNA derived from 291 GeparSixto trial patients (all women, mean age 48) were sequenced and assessed for the presence of BCRA1/2 aberrations (all patients consented for study). Pathogenic BRCA1 mutations were present in43of 291 cases (14.8%), BRCA2 mutations were found in 7 of 291 cases (2.4%) – 50 samples with BCRA mutations in total.

As many as 66.7% of BCRA1/2 germline mutation carriers (16 out of 24) innon-carboplatin arm achieved pCR compared to 36.4% (44 of 121 patients)without BRCA1 and BRCA2 germline mutations, indicating that BCRA carriers show better responsiveness to the standard chemotherapy regimen. Addition of carboplatin did not increase overall pCR rates in the group of BRCA1 and BRCA2mutation carriers: 65.4% (17 of 26 patients) carrying the BRCA1 and BRCA2 mutations achieved a pCR with adjuvant carboplatin therapy compared with 66.7% without carboplatin therapy. Patients without pathogenic BRCA1 and BRCA2 alterations showed an increase in response from 36.4% to 55% following carboplatin addition.

The possible explanation for the high initial response of BCRA1 carriers, which wasn’t improved by adding possible raises from the vulnerability of the BCRA1/2 mutated tumors to DNA damaging agent doxorubicin included in the standard chemotherapy regimen. The maximal response was probably achieved with doxorubicin, so additional DNA-damaging agent – carboplatin, wasn’t needed for a better response.

As any chemotherapy agent is associated with adverse events, it is important to minimize the dose whenever is possible. The knowledge of BCRA1/2 response to the addition of carboplatin should be integrated into personalized therapy adjustments.

A limitation of this study is the small representation of only 50 BCRA1/2 carriers. Thus, more data should be collected to assess benefits of several DNA-damaging compounds on BCRA1/2 mutated tumors. This important study shows, however, that patients without BRCA1 and BRCA2  germline mutations benefit from the addition of carboplatin while those with BRCA1 and BRCA2 germline mutations show superior response rates without additive effects observed for carboplatin.  Clinicians should take these results into consideration when designing treatment regimes.

Written by Bella Groisman, PhD

Reference: Hahnen, E., Lederer, B., Hauke, J., et al. (2017). Germline Mutation Status, Pathological Complete Response, and Disease-Free Survival in Triple-Negative Breast Cancer. JAMA Oncology.

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