Carriers of germline variants in the BRCA1 and BRCA2 genes are more likely to experience a pathologic complete response to two different chemotherapy regimens, according to a retrospective study now published in JAMA Oncology.
This study was a secondary analysis of data from the GeparOcto multicenter prospective clinical trial, in which 945 women with different subtypes of high-risk, early-stage breast cancer were randomized to receive either sequential intense dose-dense epirubicin/paclitaxel/cyclophosphamide (iddEPC) or weekly paclitaxel and non-PEGylated liposomal doxorubicin (PM); patients with triple-negative breast cancer (TNBC) who had been randomized to receive PM also received carboplatin (PMCb). Although GeparOcto results showed that overall, there was no difference between the two treatment arms in the trial's primary end point of pathologic complete response rate, they left unanswered the question of whether there was any association between treatment outcome and germline variations in BRCA1/2 and other breast cancer predisposition genes.
For the current study, genetic analyses assessing for variants in BRCA1/2 and 16 other breast cancer predisposition genes were performed in 914 of the 945 women who participated in the trial.
Overall, carriers of BRCA1/2 variants had a higher pathologic complete response rate (60.4%) than those without BRCA1/2 mutations (46.7%). Variations in other breast cancer predisposition genes had no association with therapeutic response. Patients with TNBC had the highest pathologic complete response rates among carriers of BRCA1/2 mutations, with substantial effects in both the PMCb arm (74.3% for BRCA1/2 carriers vs 47.0% for those without BRCA1/2 mutations) and the iddEPC arm (64.7% vs 45.0%). In patients with human epidermal growth factor receptor 2 (HER2)-negative, hormone receptor-positive breast cancer, those with BRCA1/2 mutations also experienced a higher pathologic complete response rate (31.8% vs 11.9%).
"Patients with germline BRCA1/2 variants benefited most from both treatment regimens, while variants in non-BRCA1/2 breast cancer predisposition genes were not associated with therapy response," remark the researchers in their publication in JAMA Oncology, led by first author Esther Pohl-Rescigno, PhD, of the Faculty of Medicine and the Center for Integrated Oncology's Center for Familial Breast and Ovarian Cancer at University Hospital Cologne in Cologne, Germany.
The investigators note that their results confirm those of previous studies indicating that the most effective chemotherapy for germline BRCA1/2-mutated TNBC is platinum based. "In germline BRCA1/2-mutated TNBC, we demonstrate that iddEPC appears to also be effective," they remark, "although with a pathologic complete response rate approximately 10 percentage points lower than that observed in the PMCb arm."
"Of further interest is the high germline BRCA1/2 variant prevalence in [HER2]-negative, hormone receptor-positive breast cancer along with the elevated pathologic complete response rate of germline BRCA1/2 variant carriers compared to noncarriers," add Dr. Pohl-Rescigno and colleagues. "Although [this] subgroup of patients… was small in our study (n=156), we suggest that patients with [HER2]-negative, hormone-receptor positive breast cancer may benefit from BRCA1/2 testing prior to treatment start."
For More Information
Pohl-Rescigno E, Hauke J, Loibl S, et al (2020). Association of germline variant status with therapy response in high-risk early-stage breast cancer: a secondary analysis of the GeparOcto randomized clinical trial. JAMA Oncol. [Epub ahead of print] DOI:10.1001/jamaoncol.2020.0007
Image credit: Tom Misteli and Karen Meaburn. Courtesy of the National Cancer Institute