Intratumoral heterogeneity of <i>MTAP</i> loss by immunohistochemistry in non–small cell lung cancer: Implications for clinical outcomes.

Abstract

8025 Background: MTAP-cooperative PRMT5 inhibitors are under development for MTAP-loss solid tumors including non-small cell lung cancer (NSCLC). However, the intratumoral heterogeneity of MTAP loss in NSCLC and its potential implications for clinical outcomes remain incompletely understood. Methods: Tumor specimens from patients with NSCLC who underwent surgical resection between January 2019 and October 2019 in our institution were retrospectively collected. MTAP expression status was evaluated in surgically resected specimens using MTAP immunohistochemistry (IHC) 2G5 and categorized as retained (100% positive tumor cells), partial loss (1–99%), or complete loss (0%). MTAP status was confirmed by fluorescence in situ hybridization (FISH). Clinicopathological characteristics and survival outcomes were analyzed according to MTAP expression status. Results: MTAP expression status was successfully analyzed in 196 specimens from primary lesion of patients with NSCLC. MTAP expression status was classified as retained in 131 specimens (67%), partial loss in 43 (22%), and complete loss in 22 (11%). Of 14 specimens of which MTAP status was evaluated by FISH, the MTAP status by IHC and FISH were completely consistent. Compared to the patients with retained, the patients with complete loss showed no significant differences in the clinicopathological characteristics, but the patients with partial loss were significantly more frequently associated with adenocarcinoma histology (93% vs 74%, P = 0.02) and never-smoker status (51% vs 22%, P &lt; 0.001). Among specimens diagnosed as adenocarcinoma, those with partial loss showed a significantly higher frequency of lepidic and papillary predominant patterns compared to those with complete loss (83% vs 50%, P = 0.02). Among specimens of which EGFR mutation status was analyzed, the frequency of EGFR mutations was significantly higher in specimens with MTAP complete/partial loss compared to MTAP retained (59% vs 30%, P = 0.03). There were no significant differences in the recurrence-free survival (RFS) and the overall survival (OS) among the patients with complete loss, partial loss and retained (5-year RFS rates: 82%, 83% vs 76%, 5-year OS rates: 90%, 81% vs 77%). MTAP expression status of corresponding metastatic lymph node (mLN) was evaluated in 6 patients with MTAP partial loss. MTAP expression status for corresponding mLN were consistent with predominant MTAP expression status for primary lesion in 4 patients (67%). Conclusions: Intratumoral heterogeneity of MTAP expression was observed in 22% of NSCLC, particularly with adenocarcinoma histology and in never-smokers. Intratumoral heterogeneity of MTAP loss may contribute to inaccurate assessment of MTAP status on small biopsy samples. MTAP expression status was not associated with the prognosis in patients with surgically resected NSCLC.