Impact of body mass index, diabetes, and tumor mutational burden in ovarian, fallopian tube, and primary peritoneal carcinoma with BRCA1/2 alteration on poly(ADP-ribose) polymerase inhibitors.

5585 Background: Obesity and hyperinsulinemia are associated with increased fallopian tube (FT) epithelial DNA damage in women carrying germline BRCA1/2 mutations. Whether these states impact survival in patients with ovarian, FT, or primary peritoneal carcinoma (PPC) with BRCA1/2 mutations, particularly when treated with Poly (ADP-ribose) polymerase inhibitor (PARPi), remains unclear. Research on tumor mutational burden (TMB) in these malignancies and survival have yielded inconsistent results. Methods: Ovarian/FT/PPC patients with germline/somatic BRCA1/2 mutation who received ≥1 dose of PARPi therapy between 2015-2023 were included in this retrospective cohort. Clinical characteristics abstracted include age, ethnicity, histology, DM status, pre-treatment TMB (pTMB) on MSK-IMPACT, PARPi use. Progression-free survival (PFS) was estimated using Kaplan-Meier. Cox regression was used to evaluate associations with PFS. Results: 202 patients treated between March 2015 – Aug 2024 were included; median age was 60 (interquartile range 50.3-67.2), 117 (57.9%) were overweight/obese (body mass index [BMI] ≥ 25) and 21 (10%) had DM. 160 (79%) and 33 (16%) had ovarian and FT cancer respectively. 182 (90.1%) had high grade serous carcinoma. 80 (40%) had germline BRCA1, 48 (24%) had germline BRCA2, 50 (25%) had somatic BRCA1 and 28 (14%) had somatic BRCA2 mutations. 91 (58%) had pTMB ≤5 mutations/megabase [mut/Mb], 56 (36%) had pTMB >5 to <10 mut/Mb and 9 (6%) had pTMB ≥10 mut/Mb. Median pTMB was higher in overweight/obese than normal BMI (4.9 vs 4.3 mut/Mb, p=0.093). 118 (58%) received PARPi as first-line and 59 (29%) received PARPi as second-line maintenance. 190 (94%) received PARPi as monotherapy, 6 (3%) in combination with bevacizumab and 6 (3%) in combination with immunotherapy +/- bevacizumab on a clinical trial. 168 (83%) received olaparib, 24 (12%) received niraparib and 9 (4.5%) received rucaparib. In multivariable (MV) Cox regression analysis, somatic BRCA status (BRCA1 hazard ratio [HR]=2.22, 95% confidence interval [95% CI]: 0.55-8.98; BRCA2 HR=0.66, 95% CI: 0.12-3.77; p=0.022; reference was somatic BRCA wildtype) was independently associated with PFS, pTMB (>5 to <10 mut/Mb HR=0.62, 95% CI: 0.32-1.19; ≥10 mut/Mb HR=0.19 95% CI: 0.02-1.56; p=0.088) had borderline significance while BMI and DM status were not associated. A MV Cox model additionally including the interaction between BMI and DM illustrated worse PFS in overweight/obese DM patients with borderline significance (p=0.094). Conclusions: Higher pTMB trended toward longer PFS in ovarian/FT/PPC patients with BRCA1/2 mutations receiving maintenance PARPi and was more common in overweight/obese. Prospective trials should evaluate if TMB may predict for response to PARPi and whether obesity-mediated DNA damage alters treatment outcomes.