Abstract C074: Clinico-genomic characterization of N=2,460 pancreatic adenocarcinoma identifies KRASMUT dosage as prognostic of overall survival across disease stages
Authors: Varghese Anna M. , Perry Maria A. , Muldoon Daniel , Nandakumar Subhiksha , Erakky Amanda , Nguyen Bastien , Zucker Amanda , Ozkan Hulya Sahin , Basturk Olca , Chakravarty Debyani , Kelsen David P. , Park Wungki , Yu Kenneth H. , Wei Alice C. , Schultz Nikolaus , Berger Michael F. , Iacobuzio-Donahue Christine , Bandlamudi Chaitanya , O'Reilly Eileen M. 
Published: January 2024

Abstract
Background: The majority (~80%) of patients (pts) with pancreatic adenocarcinomas (PDAC) present with advanced disease. Most sequencing efforts to date have focused on early stage disease. Herein, we leverage a large clinical sequencing cohort of N= 2460 pts with PDAC to characterize the clinico-genomic landscape across different disease stages. Methods: Tumors from 2460 pts were sequenced using MSK-IMPACT clinical sequencing assay and mutations called via CLIA-approved pipelines. Detailed clinical descriptors including lines of treatment and response were abstracted for N=1451 (59%) pts. Intratumor heterogeneity estimates including allele-specific copy number were inferred using FACETS. Results: Of N=2460, at diagnosis 34% of pts had resectable tumors, and 24% and 42% had locally advanced and metastatic disease, respectively. 94% of pts had KRASMUT tumors. Expectedly, MAPK pathway alterations were significantly enriched in KRASWT tumors (60% vs. 7% in KRASMUT, p &lt; 0.001) with gain-of-function kinase oncogene fusions exclusively observed in these tumors (p&lt;0.001). In addition, GNAS, PTEN, FOXP1, SMARCB1 and CREBBP were enriched in the KRASWT tumors (q &lt; 0.05). Collectively, pts with KRASWT/MAPK MUT and KRASWT/MAPK WT tumors comprise 4% and 2% of all pts PDAC, respectively. Germline pathogenic variants in high/moderate penetrance genes were more common in pts with KRASWT tumors compared to pts with KRASMUT tumors (20% vs. 10%, p &lt; 0.001). Pathogenic germline alterations in BRCA1/2 and PALB2 were observed in 6% (N=144) of cohort. Biallelic inactivation of BRCA2 specifically was associated with prolonged response of metastatic pts to PARP-inhibitor maintenance therapy with 10.3 months on treatment prior to progression compared to 3.4 months for those with biallelic inactivation of other HRD genes and 2.2 months for those with non-biallelic inactivation. Among KRASMUT tumors assessed for KRAS copy-number allelic imbalance (AI) (N=1097), 41% (N=452) had AI at the KRAS locus with mutant-allele selected for in 94% of tumors with imbalance. Among KRASMUT tumors with normal genome ploidy, overall, 20% had a mutant allele gain ranging from 10% in resectable to 29% of metastatic tumors. We observe significantly lower OS among pts with KRASMUT dosage gain compared to heterozygous KRASMUT across pts with resectable (HR: 0.66, 95% CI: 0.18-1.15, p&lt;0.01) and metastatic (HR: 0.39, 95% CI: 0.16-0.63, p=0.001) diseases with statistical significance not reached among the locally advanced disease (HR: 0.4, 95% CI: -0.01-0.81, p=0.056). Notably, the OS of pts with loss of the wild-type allele and no mutant copy gain was indistinguishable from that of heterozygous KRASMUT tumors (HR: -0.11, 95% CI: -0.37-0.15, p=0.4). Conclusion: In this large cohort of 2460 pts with PDAC, we observed that KRASMUT dosage gain is a significant negative predictor of OS. These findings highlight the importance of incorporating allelic-dosage into comprehensive molecular testing in PDAC given prognostic importance and the emerging era of direct RAS targeting.
Citation Format: Anna M. Varghese, Maria A. Perry, Daniel Muldoon, Subhiksha Nandakumar, Amanda Erakky, Bastien Nguyen, Amanda Zucker, Hulya Sahin Ozkan, Olca Basturk, Debyani Chakravarty, David P. Kelsen, Wungki Park, Kenneth H. Yu, Alice C. Wei, Nikolaus Schultz, Michael F. Berger, Christine Iacobuzio-Donahue, Chaitanya Bandlamudi, Eileen M. O'Reilly. Clinico-genomic characterization of N=2,460 pancreatic adenocarcinoma identifies KRASMUT dosage as prognostic of overall survival across disease stages [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C074.