Inferring optimal detection of <i>MTAP</i> homozygous loss (homozygous deletion) in gastric cancer: Associations with treatment exposure, disease site, and clinical outcomes.

Abstract

327 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, the 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 gastric cancer, their prognostic associations on standard of care therapies, and their prevalence before and after such treatments. Methods: This study used the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine gastric cancer clinico-genomic database (FH-FMI CGDB), originating from approximately 280 US cancer clinics (~800 sites of care). Patients with advanced gastric cancer and tissue-based genomic testing by FoundationOne CDx were included. First-line (1L) therapy included chemotherapy alone, combined with anti- HER2 or with immune checkpoint inhibitors. Logistic regression assessed associations of prior treatment and disease site with homozygous losses. Survival outcomes were evaluated with univariable Cox proportional hazards models. Results: Among 1302 specimens, homozygous losses were most frequent in CDKN2A (18%), CDKN2B (16%), and MTAP (11%). MTAP loss nearly always co-occurred with CDKN2A (100%) and CDKN2B (92.3%) loss, while only 66.2% of cases with CDKN2A, and 71.9% with CDKN2B loss showed concurrent MTAP loss. The prevalence of homozygous losses in these genes was unaffected by prior treatment. MTAP loss occurred at similar rates in HER2 -positive and HER2 -negative but was more common in non-MSI-H than MSI-H tumors (12% vs. 4%, p = 0.01 ). Homozygous loss of CDKN2A, CDKN2B , and MTAP was associated with poorer clinical outcomes in patients treated with 1L chemotherapy, with those harboring MTAP loss experiencing a shorter median overall survival of 8.7 months [95% CI: 6.6–12.1] compared to 11.4 months [95% CI: 10.2–12.3] in MTAP wild-type (WT) cases. The prevalence of co-occurring targetable alterations, including KRAS , ERBB2 , EGFR , and FGFR2 , did not significantly differ between tumors with homozygous loss of CDKN2A , CDKN2B , and MTAP and those with WT status. Conclusions: Using an algorithm that supports a validated, FDA-approved test, homozygous losses in CDKN2A , CDKN2B , and MTAP were frequently detected in gastric cancer and were associated with poorer outcomes following 1L chemotherapy. The prevalence of these alterations was unaffected by prior treatment, indicating that biopsy timing does not impact detection. MTAP loss, present in 11% of cases, defines a clinically relevant subset of gastric cancer patients potentially eligible for MTAP -targeted therapies.