ASCO Conference Coverage

High Tumor Mutational Burden May Boost PARP Inhibitor Response in BRCA-Mutant Cancers

Kate Young

Key Highlights

  • Higher pre-treatment tumor mutational burden (pTMB) trended toward longer progression-free survival (PFS) in patients treated with PARP inhibitors (PARPi).
  • Overweight or obese patients had slightly higher median pTMB compared to those with normal BMI.
  • Somatic BRCA mutation status was independently associated with PFS.
  • BMI and diabetes mellitus (DM) status alone were not significantly linked to treatment outcomes.

Among patients with ovarian, fallopian tube (FT), or primary peritoneal carcinoma (PPC) harboring BRCA1/2 mutations and treated with PARP inhibitors (PARPi), higher pre-treatment tumor mutational burden (pTMB) was associated with a trend toward improved progression-free survival (PFS). Somatic BRCA status was also found to independently correlate with PFS. BMI and diabetes mellitus (DM), though hypothesized as possible influencers of treatment response, were not significantly associated with survival outcomes.

Obesity and hyperinsulinemia have been implicated in exacerbating DNA damage in the FT epithelium of individuals with BRCA1/2 mutations, suggesting a potential negative impact on treatment outcomes. Despite known associations between metabolic health and DNA damage, limited evidence exists on how BMI, DM, and tumor mutational burden interact with survival in BRCA-altered ovarian-related cancers treated with PARPi, prompting the need for investigation.

In this retrospective cohort study, 202 patients diagnosed with ovarian, FT, or PPC and carrying either germline or somatic BRCA1/2 mutations who received at least one dose of PARPi therapy from 2015 to 2023 were evaluated. Researchers abstracted clinical data such as BMI, DM status, histology, and pTMB measured via MSK-IMPACT. Kaplan-Meier and multivariable Cox regression analyses were utilized to assess PFS.

The study cohort had a median age of 60 years, with 57.9% classified as overweight or obese and 10% with DM. Most patients (90.1%) had high-grade serous carcinoma. pTMB values were stratified, with 6% of patients exhibiting ≥10 mutations/megabase. Overweight/obese patients demonstrated a higher median pTMB (4.9 vs 4.3 mut/Mb), although this difference did not reach statistical significance (P = .093). Most patients received PARPi as monotherapy, with olaparib being the most common agent (83%). Multivariable analysis revealed that somatic BRCA1 mutation (HR = 2.22, P = .022) was associated with poorer PFS compared to BRCA wildtype, while higher pTMB (especially ≥10 mut/Mb) was linked to improved PFS, albeit with borderline significance (P = .088). The interaction between BMI and DM status also suggested a trend toward worse PFS in overweight/obese individuals with DM (P = .094).

“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,” the researchers wrote. “Prospective trials should evaluate if TMB may predict for response to PARPi and whether obesity-mediated DNA damage alters treatment outcomes.”

Reference:
Tan R, White C, Chen Y, et al. 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. Presented at: ASCO Annual Meeting; May 30–June 3, 2025; Chicago, IL.