Comprehensive profiling of EGFR PACC mutations and their co-mutation landscape in Chinese patients with non–small cell lung cancer: A large-scale NGS study of 2,360 cases.

Abstract

8650 Background: EGFR PACC (P-loop and αC-helix compressing) mutations represent a group of noncanonical alterations located in critical structural regions of the EGFR kinase domain and have recently been implicated in reduced sensitivity to EGFR TKIs and treatment resistance. However, the prevalence, mutational spectrum, and co-mutation landscape of EGFR PACC mutations in Chinese patients with non–small cell lung cancer (NSCLC) remain poorly characterized. This study aimed to systematically delineate the molecular features of EGFR PACC mutations to inform molecular testing strategies and clinical decision-making. Methods: A total of 2,360 patients with NSCLC were enrolled. All tumor samples underwent NGS covering 733 cancer-related genes. The overall prevalence of EGFR PACC mutations, the distribution of individual PACC variants, and their co-occurrence with other EGFR alterations and non-EGFR driver mutations were comprehensively analyzed. Results: Among the 2,360 NSCLC patients, 112 harbored EGFR PACC mutations, yielding an overall prevalence of 4.74%. EGFR PACC mutations exhibited marked site heterogeneity. The most frequent variants were S768I (18/112), G719A (15/112), G719S (12/112), and G719C (8/112), followed by C797S (6/112), E709A (6/112), E709V (5/112), and E709K (5/112). The remaining PACC variants—including I740_K745dup, R776H, S752_I759del, V774M, E709_T710delinsD, G779F, K757R, L747P, L718V, R776C, A647T, K757M, L718Q, T751_I759delinsN, V769L, and V769M—were low-frequency events, underscoring substantial molecular diversity. In total, 61 PACC-associated co-mutation events were identified. Co-mutation analysis revealed that classic EGFR-sensitizing mutations predominated, with L858R as the most common co-occurring alteration (n = 10), followed by exon 19 deletion E746_A750del (n = 4) and L861Q (n = 3). Notably, T790M (n = 2) co-occurred with C797S PACC mutations, suggesting a potential role of PACC variants in the evolution of EGFR-TKI resistance. Beyond EGFR-intrinsic co-mutations, cross-driver co-mutations were also observed, including ROS1 (V1002A, I1685L), MET (V145A), and NRG1 (V516M) (each n = 2), indicating that a subset of EGFR PACC–mutant tumors may harbor more complex oncogenic signaling. Conclusions: EGFR PACC mutations occur at a non-negligible frequency in Chinese patients with NSCLC and display pronounced site heterogeneity. These mutations frequently co-exist with classic EGFR-sensitizing or resistance-associated alterations and, in some cases, with additional non-EGFR driver mutations, highlighting their potential biological and clinical relevance. Our findings underscore the importance of comprehensive NGS-based profiling for accurate detection of EGFR PACC mutations and their co-mutation landscape, thereby supporting precision treatment strategies.