brca mutation
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We evaluated the proportion of BRCA 1/2 germline mutations in Korean patients with sporadic pancreatic ductal adenocarcinoma (PDAC) and its effect on the chemotherapeutic response of FOLFIRINOX. This retrospective study included patients who were treated at two tertiary hospitals between 2012 and 2020, were pathologically confirmed to have PDAC, and had undergone targeted next-generation sequencing-based germline genetic testing. Sixty-six patients were included in the study (24 men; median age 57.5 years). In the germline test, BRCA 1/2 pathogenic mutations were found in nine patients (9/66, 13%, BRCA 1, n = 3; BRCA 2, n = 5; and BRCA 1/2, n = 1). There was no significant difference in the baseline characteristics according to BRCA mutation positivity. Among patients who underwent FOLFIRINOX chemotherapy, patients with a BRCA 1/2 mutation showed a higher overall response rate than those without a BRCA 1/2 mutation (71.4% vs. 13.9%, p = 0.004). Patients with a germline BRCA 1/2 mutation showed longer progression-free survival than those without a BRCA 1/2 mutation, without a significant time difference (18 months vs. 10 months, p = 0.297). Patients with a BRCA 1/2 mutation in the germline blood test had a higher response rate to FOLFIRINOX chemotherapy in PDAC. The high proportion of BRCA 1/2 germline mutations and response rate supports the need for germline testing in order to predict better treatment response.

Abstract Background: Deleterious BRCA mutations confer a significant lifetime risk of breast cancer (BC) as well as contralateral BC (CBC) in patients who do not undergo prophylactic mastectomy. Prior reports have suggested that tamoxifen reduces the risk of CBC in BRCA mutation carriers. Whether aromatase inhibitors (AI) have the same effect is unknown. Methods: This is a retrospective review of patients diagnosed with non-metastatic ER+ BC between 2004-2014 with known BRCA mutation status. Patients were followed from primary diagnosis until CBC diagnosis or death. Median follow up was 11.5 years. Risk of CBC was evaluated as time to event. Results: 935 subjects were included in this analysis, with 53 BRCA1 mutation carriers, and 94 BRCA2 mutation carriers. Median age at diagnosis was 42.7 years. Seventy-two percent (676) received tamoxifen and 43% (405) received AI. A total of 66 CBCs occurred, of which 10% (15/147) occurred in BRCA mutation carriers vs %6.5 (51/788) in BRCA wild type. Multivariate analyses indicated that BRCA status and AI use were significantly associated with CBC risk. AI use resulted in a significant reduction in risk of CBC (HR 0.44, p=0.004) regardless of the BRCA mutation status. Tamoxifen use was not associated with reduced risk of CBC. Conclusions: This is the first report showing that AIs reduce the risk of CBC in BRCA mutation carriers. The potential role of AIs as chemoprevention should be validated in larger independent cohorts.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and is known to be associated with a poor prognosis and limited therapeutic options. Poly (ADP-ribose) polymerase inhibitors (PARPi) are targeted therapeutics that have demonstrated efficacy as monotherapy in metastatic BRCA-mutant (BRCAMUT) TNBC patients. Improved efficacy of PARPi has been demonstrated in BRCAMUT breast cancer patients who have either received fewer lines of chemotherapy or in chemotherapy-naïve patients in the metastatic, adjuvant, and neoadjuvant settings. Moreover, recent trials in smaller cohorts have identified anti-tumor activity of PARPi in TNBC patients, regardless of BRCA-mutation status. While there have been concerns regarding the efficacy and toxicity of the use of PARPi in combination with chemotherapy, these challenges can be mitigated with careful attention to PARPi dosing strategies. To better identify a patient subpopulation that will best respond to PARPi, several genomic biomarkers of homologous recombination deficiency have been tested. However, gene expression signatures associated with PARPi response can integrate different pathways in addition to homologous recombination deficiency and can be implemented in the clinic more readily. Taken together, PARPi have great potential for use in TNBC patients beyond BRCAMUT status, both as a single-agent and in combination.