Abstract 1965P
Background
BRCA1 and BRCA2 (BRCA1/2) are involved in the DNA damage response (DDR) and homologous recombination repair (HRR). PAPR inhibitors (PARPis) have shown higher therapeutic efficacy in ovarian and breast cancer patients harboring pathogenic germline or somatic BRCA1/2 (gBRCA1/2 or sBRCA1/2) mutations. Emerging evidence suggests that prostate, pancreatic and endometrial cancer patients harboring BRCA1/2 mutations could potentially benefit from the PARPis or platinum-based therapies. The aim of this study was to evaluate the prevalence of BRCA1/2 deleterious mutations in an unselected cohort of Asian patients with advanced solid tumors who will potentially benefit from PARPis.
Methods
This study included 1312 formalin-fixed paraffin-embedded (FFPE) tumor tissues and 133 blood samples from cancer patients in Taiwan, Hong Kong, Southeast Asia and Middle-East countries. Two targeted gene panels (440 cancer-related genes and BRCA1/2) were used to identify gBRCA1/2 and sBRCA1/2 mutations. Variants were classified into pathogenic (P), likely pathogenic (LP) and the variant of uncertain significance (VUS), based on the standards and guidelines of the American College of Medical Genetics (ACMG) and Association for Molecular Pathology (AMP) for the interpretation of sequence variants.
Results
Combined 1312 Next Generation Sequencing (NGS) data identified 62 P/LP variants, twenty-seven in BRCA1 and 35 in BRCA2, in 60 FFPE tumor samples, yielding a positivity rate of 4.5%. These deleterious variants were found in 16.0% (29/181) ovarian, 7.5% (13/173) breast, 5.6% (4/71) pancreatic, 3.4% (3/58) cholangiocarcinoma, 2.6% (6/233) lung, and 1.0% (1/97) colorectal cancer patients. Eight P/LP mutations identified in the gastrointestinal cancers were all within BRCA2. Three recurrent P/LP germline BRCA1 variants, including p.Arg1495Lys, p.Thr1691Lys and p.Pro1749Arg were identified in 6 (5 ovarian and 1 breast cancer) Taiwanese patients, suggesting the possibility of founder effects in the Han Chinese population.
Conclusions
NGS performed with a small or large panel can efficiently identify PARPi responders across various tumor types whose tumor harbors gBRCA1/2 or sBRCA1/2 aberration.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.