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Background <p><i>KRAS</i><sup><i>G12D</i></sup> is one of the most prevalent driver mutations in patients with pancreatic ductal adenocarcinoma (PDAC) and colorectal adenocarcinoma (CRC). Although this genetic alteration is associated with poor prognosis and resistance to chemotherapy, additional genomic features may contribute to the behavior of <i>KRAS</i>-mutant PDACs and CRCs.</p> Objective <p>Here, we aimed at defining the landscape of these additional genomic features of <i>KRAS</i><sup><i>G12D</i></sup>-mutant PDAC and CRC, and their impact on clinical outcomes.</p> Patients and Methods <p>This retrospective analysis utilized circulating tumor DNA data from two cohorts with advanced CRC and PDAC: a national cohort from Guardant (<i>n</i> = 27,497) and a Mayo Clinic cohort (<i>n</i> = 1434). Patients were categorized into three groups: <i>KRAS</i><sup><i>G12D</i></sup> alone, <i>KRAS</i><sup><i>G12D</i></sup> with putative resistance alterations, and <i>KRAS</i> not detected (ND). Genomic co-occurrences were summarized. Overall survival (OS) was compared among groups using Kaplan–Meier and multivariable survival analysis.</p> Results <p>Among patients with <i>KRAS</i><sup><i>G12D</i></sup> mutation, additional oncogenic alterations were detected in 34.5% of CRC and 11.5% of PDAC in the national cohort; 38.9% of CRC, and 17.4% of PDAC in the Mayo cohort. Common additional oncogenic alterations included <i>EGFR</i> amplifications, additional <i>KRAS</i> point mutations, and alterations in <i>NRAS</i>, <i>BRAF</i>, and <i>PIK3CA</i>. Patients with <i>KRAS</i><sup><i>G12D</i></sup> and these alterations had significantly shorter median OS compared with those with <i>KRAS</i><sup><i>G12D</i></sup> alone and <i>KRAS</i> ND for CRC (<i>p</i> &lt; 0.0001) and PDAC (<i>p</i> &lt; 0.0001). Presence of <i>KRAS</i><sup><i>G12D</i></sup> and additional oncogenic alterations was the only variable significantly associated with OS outcomes in both CRC and PDAC.</p> Conclusions <p>We described the genomic landscape of <i>KRAS</i><sup><i>G12D</i></sup>-mutant CRC and PDAC, demonstrating that cases often have additional oncogenic alterations linked to resistance to KRAS inhibition. These alterations are also associated with a worse prognosis. Recognizing these alterations may inform new therapeutic strategies. Further studies are warranted to validate these findings in ongoing clinical trials.</p>

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Translational Relevance of the Genomic Landscape of KRASG12D-Mutant Colorectal and Pancreatic Cancers

  • 期刊论文

  • 发表日期：

    2025年12月11日

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  • Khalid Jazieh,
  • Jill Tsai,
  • Sheila Solomon,
  • Mojun Zhu,
  • Katrina S. Pedersen,
  • Martin E. Fernandez-Zapico,
  • Hao Xie

摘要

Background

KRASG12D is one of the most prevalent driver mutations in patients with pancreatic ductal adenocarcinoma (PDAC) and colorectal adenocarcinoma (CRC). Although this genetic alteration is associated with poor prognosis and resistance to chemotherapy, additional genomic features may contribute to the behavior of KRAS-mutant PDACs and CRCs.

Objective

Here, we aimed at defining the landscape of these additional genomic features of KRASG12D-mutant PDAC and CRC, and their impact on clinical outcomes.

Patients and Methods

This retrospective analysis utilized circulating tumor DNA data from two cohorts with advanced CRC and PDAC: a national cohort from Guardant (n = 27,497) and a Mayo Clinic cohort (n = 1434). Patients were categorized into three groups: KRASG12D alone, KRASG12D with putative resistance alterations, and KRAS not detected (ND). Genomic co-occurrences were summarized. Overall survival (OS) was compared among groups using Kaplan–Meier and multivariable survival analysis.

Results

Among patients with KRASG12D mutation, additional oncogenic alterations were detected in 34.5% of CRC and 11.5% of PDAC in the national cohort; 38.9% of CRC, and 17.4% of PDAC in the Mayo cohort. Common additional oncogenic alterations included EGFR amplifications, additional KRAS point mutations, and alterations in NRAS, BRAF, and PIK3CA. Patients with KRASG12D and these alterations had significantly shorter median OS compared with those with KRASG12D alone and KRAS ND for CRC (p < 0.0001) and PDAC (p < 0.0001). Presence of KRASG12D and additional oncogenic alterations was the only variable significantly associated with OS outcomes in both CRC and PDAC.

Conclusions

We described the genomic landscape of KRASG12D-mutant CRC and PDAC, demonstrating that cases often have additional oncogenic alterations linked to resistance to KRAS inhibition. These alterations are also associated with a worse prognosis. Recognizing these alterations may inform new therapeutic strategies. Further studies are warranted to validate these findings in ongoing clinical trials.