Abstract 2545: KRAS co-mutational landscape dictates treatment outcomes in pancreatic cancer (PC) patients

Abstract Background: KRAS is commonly mutated in PC patients, with a prevalence of ~80%. A holistic understanding of the landscape of KRAS mutations, co-occurring mutations (co-mutations) in other driver genes, and their impact on patient outcomes treated with current standard-of-care (SoC) therapies may inform better treatment decisions. Methods: In this study, we use a real-world clinico-genomics PC database (ConcertAI’s Genome360TM PC dataset; N=1302) to: 1. Examine the distribution of KRAS mutations. 2. Identify the genes most frequently co-mutated with KRAS, both positively and negatively, based on their odds ratios. 3. Evaluate patient outcomes (overall survival (OS) and progression-free survival (PFS) ) for the two most common first-line SoC therapies (FOLFIRINOX: folinic acid, fluorouracil, irinotecan hydrochloride, oxaliplatin, and GEMPAC: gemcitabine, paclitaxel) stratified by the mutational status of KRAS and TP53. Results: The top 5 most observed KRAS mutations and the top 3 positively (OR1) and negatively (OR1) KRAS co-mutated genes are shown in Table 1. 80%, 71%, and 65% of PC patients had pathogenic mutations in KRAS, TP53, and both genes, respectively. In the entire cohort, FOLFIRINOX (n=327, OS/PFS=1. 26/0. 58 years) was more effective (p-value0. 05) than GEMPAC (n=305, OS/PFS=0. 79/0. 44 years). However, the underlying genetic makeup (mutational status of KRAS and TP53) significantly affects these outcomes (Table 1). The KRAS+/TP53− (pathogenic mutations in KRAS, but not in TP53) cohort has the worst prognosis, and the advantage of FOLFIRINOX as the treatment of choice is not observed in this cohort. Table 1. Evaluation of KRAS mutational landscape in PC and its impact on treatment outcomes. Top 5 KRAS mutations KRAS mutations G12D G12V G12R Q61H Q61R % PC patients tested positive 42. 51 32. 52 14. 33 4. 62 1. 79 Top 3 positively and negatively co-mutated genes with KRAS KRAS co-mutated genes Positive association Negative association TP53 CDKN2A SMAD4 BRAF TERT PTEN Odds Ratio 8. 56 6. 93 6. 66 0. 05 0. 27 0. 32 Treatment outcomes for various genetic states of KRAS and TP53 Mutational status OS (years) PFS (years) FOLFIRINOX GEMPAC FOLFIRINOX GEMPAC KRAS+ TP53+ (850) 1. 13 (196) 0. 68 (188) 0. 58 (196) 0. 39 (188) KRAS− TP53− (155) 2. 08 (40) 1. 11 (27) 0. 66 (40) 0. 51 (27) KRAS+ TP53− (190) 0. 77 (33) 0. 93 (37) 0. 51 (33) 0. 33 (37) KRAS− TP53+ (81) 2. 14 (15) 0. 84 (24) 0. 54 (15) 0. 4 (24) Conclusions: This study provides insights into the genetic makeup of patients with KRAS mutations and how co-mutation with TP53 affects outcomes of SoC treatments. It highlights the need for comprehensive genetic profiling to make better therapy decisions. Citation Format: Pritha Ghosh, Rohini George, Neeraj Singh, Smita Agrawal. KRAS co-mutational landscape dictates treatment outcomes in pancreatic cancer (PC) patients abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 2545.