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. 2022 Dec 9;27(12):1025-1033.
doi: 10.1093/oncolo/oyac179.

KRAS Mutation Variants and Co-occurring PI3K Pathway Alterations Impact Survival for Patients with Pancreatic Ductal Adenocarcinomas

Adam C Diehl  1   2 , Lindsay M Hannan  1   2 , David B Zhen  1   2 , Andrew L Coveler  1   2 , Gentry King  1   2 , Stacey A Cohen  1   2 , William P Harris  1   2 , Veena Shankaran  1   2 , Kit M Wong  1   2 , Steven Green  2 , Natasha Ng  2 , Venu G Pillarisetty  3 , Jonathan G Sham  3 , James O Park  3 , Deepti Reddi  4 , Eric Q Konnick  4 , Colin C Pritchard  4   5 , Kelsey Baker  2 , Mary Redman  2 , E Gabriela Chiorean  1   2
Affiliations

KRAS Mutation Variants and Co-occurring PI3K Pathway Alterations Impact Survival for Patients with Pancreatic Ductal Adenocarcinomas

Adam C Diehl et al. Oncologist. .

Abstract

Background: KRAS variant alleles may have differential biological properties which impact prognosis and therapeutic options in pancreatic ductal adenocarcinomas (PDA).

Materials and methods: We retrospectively identified patients with advanced PDA who received first-line therapy and underwent blood and/or tumor genomic sequencing at the University of Washington between 2013 and 2020. We examined the incidence of KRAS mutation variants with and without co-occurring PI3K or other genomic alterations and evaluated the association of these mutations with clinicopathological characteristics and survival using a Cox proportional hazards model.

Results: One hundred twenty-six patients had genomic sequencing data; KRAS mutations were identified in 111 PDA and included the following variants: G12D (43)/G12V (35)/G12R (23)/other (10). PI3K pathway mutations (26% vs. 8%) and homologous recombination DNA repair (HRR) defects (35% vs. 12.5%) were more common among KRAS G12R vs. non-G12R mutated cancers. Patients with KRAS G12R vs. non-G12R cancers had significantly longer overall survival (OS) (HR 0.55) and progression-free survival (PFS) (HR 0.58), adjusted for HRR pathway co-mutations among other covariates. Within the KRAS G12R group, co-occurring PI3K pathway mutations were associated with numerically shorter OS (HR 1.58), while no effect was observed on PFS.

Conclusions: Patients with PDA harboring KRAS G12R vs. non-G12R mutations have longer survival, but this advantage was offset by co-occurring PI3K alterations. The KRAS/PI3K genomic profile could inform therapeutic vulnerabilities in patients with PDA.

Keywords: KRAS; PI3K; pancreatic cancer.

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Conflict of interest statement

David B. Zhen: Merck, Daiichi-Sankyo, AstraZeneca, SeaGen (RF); William P. Harris: Neotherma, Eisai, Exelixis, AstraZeneca, Zymeworks, Boston Scientific, Bard Medical, Merck (C/A); Venu G. Pillarisetty: Takeda, Umoja (C/A), AstraZeneca, Ipsen, Merck, OncoResponse, NGM (RF), TriSalus Life Sciences (SAB); E. Gabriela Chiorean: BioNTech, Noxxon (C/A), BioMed Valley, Boehringer-Ingelheim, Clovis, Corcept, Fibrogen, Lonza, Merck, Rafael (RF), Bayer, Cardiff, Ipsen, Merck, Novartis, Pfizer, Stemline (SAB). The other authors indicated no financial relationships.

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board.

Figures

Figure 1.
Figure 1.
Pathogenic co-mutations in PDA with KRAS G12R and non-G12R mutations. Only the 19 most common co-mutations are shown. Homologous recombination repair (HRR), core HRR (BRCA1, BRCA2, PALB2), and PI3K pathway mutations are shown on the right side.
Figure 2.
Figure 2.
(A) Overall survival for KRAS G12R vs. non-G12R mutated PDA. (B) Progression-free survival for KRAS G12R vs. non-G12R mutated PDA.
Figure 3.
Figure 3.
(A) Overall survival for PI3K pathway mutated vs. wild type PDA. (B) Overall survival for KRAS G12R mutated PDA with vs. without PI3K pathway mutations. (C) Overall survival for KRAS non-G12R mutated PDA with vs. without PI3K pathway mutations. (D) Progression-free survival for PI3K pathway mutated versus wildtype PDA. (E) Progression-free survival for KRAS G12R mutated PDA with vs. without PI3K pathway mutations. (F) Progression-free survival for KRAS non-G12R mutated PDA with vs. without PI3K pathway mutations. P values based on the log rank test to detect differences in survival.
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