Inferring optimal detection of <i>MTAP</i> homozygous loss (homozygous deletion) in pancreatic cancer: Association with treatment exposure, co-alterations, site of biopsy, and clinical outcomes.

Abstract

684 Background: Validated homozygous loss detection is becoming increasingly important in clinical practice, with BRCA1/2 loss portending durable PARP inhibitor benefit in prostate and ovarian cancers, recent approval of capivasertib ( AKT pathway, PTEN loss) in breast cancer, and ongoing multi-tumor trials of PRMT5 and MAT2A inhibitors (biomarker: MTAP loss). Homozygous losses are challenging to detect and require intentional NGS assay design and validations. We sought to evaluate the most common losses in advanced pancreatic cancer, their prognostic associations with standard of care therapies, and their prevalence pre- and post-treatment. Methods: This study used the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine Pancreatic cancer clinico-genomic database (FH-FMI CGDB), originating from approximately 280 US cancer clinics (~800 sites of care). Patients with advanced pancreatic cancer and tissue-based genomic testing by FoundationOne CDx were included. Logistic regression assessed associations of prior treatment and biopsy site with homozygous losses. Survival outcomes were evaluated with univariable Cox proportional hazards models. Results: Among 1525 specimens, homozygous losses were most frequently found in CDKN2A (47%), CDKN2B (44%), MTAP (34%), and SMAD4 (14%). MTAP loss nearly always co-occurred with CDKN2A loss (100%) and CDKN2B loss (96%), whereas only 72% with CDKN2A and 74% with CDKN2B loss cases showed concurrent MTAP loss. Prior chemotherapy was associated with reduced likelihood of CDKN2A / B loss ( p &lt; 0.05), but not MTAP or SMAD4 . Liver biopsies were more likely to harbor CDKN2A / B , and MTAP loss ( p &lt; 0.01) but not SMAD4 , compared to other sites. The prevalence of MTAP loss was unaffected by prior chemotherapy exposure (p &gt; 0.05). Consistent with the other genes, MTAP loss did not impact first-line (1L) treatment outcomes. Time to next treatment was similar for patients with and without MTAP loss: FOLFIRINOX, 5.4 [95% CI 4.5–6.1] vs. 6.1 months [95% CI 5.4–7]; Gemcitabine regimens, 4.6 [95% CI 3.8–5.3] vs. 4.9 months [95% CI 4.3–5.6]. MTAP loss was more frequent in KRAS -mutated (34.8%, 489/1406) than in KRAS WT tumors (22.7%, 27/119), where it occurred with or without other actionable alterations. Conclusions: Using an algorithm that supports a validated, FDA-approved test, homozygous losses were frequently detected in pancreatic cancer, with MTAP loss found in 34% of cases, defining a subset potentially eligible for MTAP -targeted therapies. MTAP loss prevalence was unaffected by prior chemotherapy, suggesting biopsy timing has minimal impact. Liver biopsies were more likely to harbor homozygous losses in CDKN2A/B and MTAP. No significant association was observed between homozygous losses and 1L treatment outcomes.