Pancreas cancer and BRCA: A critical subset of patients with improving therapeutic outcomes
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Parisa Momtaz1,2, Catherine A O'Connor1, Joanne F Chou3
1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Background:
Patients with germline/somatic BRCA1/BRCA2 mutations (g/sBRCA1/2) comprise a distinct biologic subgroup of pancreas ductal adenocarcinoma (PDAC).
Methods:
Institutional databases were queried to identify patients who had PDAC with g/sBRCA1/2. Demographics, clinicopathologic details, genomic data (annotation sBRCA1/2 according to a precision oncology knowledge base for somatic mutations), zygosity, and outcomes were abstracted. Overall survival (OS) was estimated using the Kaplan-Meier method.
Results:
In total, 136 patients with g/sBRCA1/2 were identified between January 2011 and June 2020. Germline BRCA1/2 (gBRCA1/2) mutation was identified in 116 patients (85%). Oncogenic somatic BRCA1/2 (sBRCA1/2) mutation was present in 20 patients (15%). Seventy-seven patients had biallelic BRCA1/2 mutations (83%), and 16 (17%) had heterozygous mutations. Sixty-five patients with stage IV disease received frontline platinum therapy, and 52 (80%) had a partial response. The median OS for entire cohort was 27.6 months (95% CI, 24.9-34.5 months), and the median OS for patients who had stage IV disease was 23 months (95% CI, 19-26 months). Seventy-one patients received a poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor (PARPi), and 52 received PARPi monotherapy. For maintenance PARPi, 10 patients (36%) had a partial response, 12 (43%) had stable disease, and 6 (21%) had progression of disease as their best response. Six patients (21%) received maintenance PARPi for >2 years. For those with stage IV disease who received frontline platinum, the median OS was 26 months (95% CI, 20-52 months) for biallelic patients (n = 39) and 8.66 months (95% CI, 6.2 months to not reached) for heterozygous patients (n = 4). The median OS for those who received PARPi therapy was 26.5 months (95% CI, 24-53 months) for biallelic patients (n = 25) and 8.66 months (95% CI, 7.23 months to not reached) for heterozygous patients (n = 2).
Conclusions:
g/sBRCA1/2 mutations did not appear to have different actionable utility. Platinum and PARPi therapies offer therapeutic benefit, and very durable outcomes are observed in a subset of patients who have g/sBRCA1/2 mutations with biallelic status.
Insights
Patients with BRCA1/2 mutations in pancreas cancer show benefit from platinum and PARP inhibitor therapies. Biallelic mutations are linked to durable outcomes, highlighting targeted treatment potential.
Area of Science:
- Oncology
- Genetics
- Cancer Research
Background:
- Pancreas ductal adenocarcinoma (PDAC) patients with germline/somatic BRCA1/2 mutations (g/sBRCA1/2) represent a unique biological subgroup.
- Understanding the clinical and genomic characteristics of this subgroup is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the clinical outcomes and therapeutic responses in PDAC patients with g/sBRCA1/2 mutations.
- To evaluate the efficacy of platinum-based chemotherapy and poly(adenosine diphosphate ribose) polymerase inhibitors (PARPi) in this patient population.
Main Methods:
- Retrospective analysis of institutional databases for PDAC patients with g/sBRCA1/2 mutations (January 2011-June 2020).
- Abstraction of demographic, clinicopathologic, genomic, zygosity, and outcome data.
- Overall survival (OS) estimated using Kaplan-Meier method; analysis stratified by mutation status and treatment received.
Main Results:
- 136 patients identified with g/sBRCA1/2 mutations (85% germline, 15% somatic).
- 77% had biallelic mutations, 17% had heterozygous mutations.
- Stage IV patients receiving frontline platinum therapy showed an 80% partial response rate. Median OS was 27.6 months for the cohort, 23 months for stage IV.
- Patients with biallelic mutations showed significantly longer OS with platinum and PARPi therapies compared to heterozygous patients.
Conclusions:
- g/sBRCA1/2 mutations in PDAC do not show different actionable utility.
- Platinum and PARPi therapies provide significant therapeutic benefits.
- Durable outcomes are observed in a subset of patients with g/sBRCA1/2 mutations, particularly those with biallelic status.
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