Research Spotlight: Comprehensive pan-cancer genomic landscape of KRAS altered cancers and real-world outcomes in solid tumors

Lee, J.K., Sivakumar, S., Schrock, A.B. et al. Comprehensive pan-cancer genomic landscape of KRAS altered cancers and real-world outcomes in solid tumors. npj Precis. Onc. 6, 91 (2022). https://doi.org/10.1038/s41698-022-00334-z

Mutations in the KRAS gene are among the most prevalent mutations in human cancers and are associated with tumor formation, as well as aggressive tumor growth. Recent clinical development of KRAS inhibitors has heightened interest in the genomic landscape of KRAS-altered cancers. As specific KRAS inhibitors and combination therapeutic strategies are being developed, genomic profiling to understand co-alterations and other biomarkers that may modulate response to targeted or immunotherapies will be imperative.

In this study, researchers performed a comprehensive pan-cancer genomic analysis to identify the incidence of KRAS alterations across 24 tumor types. This was the largest pan-cancer survey to date of KRAS alterations in 426,706 adult patients with solid or hematologic malignancies using comprehensive genomic profiling. Additional analyses included 62,369 liquid biopsy and 7,241 pediatric samples.

Across the 24 major tumor types studied, KRAS mutations were detected at frequencies from 1.3% to 92%. They also observed KRAS alterations in 5.5% of the pediatric samples assessed, with G13D being the most common variant. In a sub analysis of comprehensive genomic profiling of liquid biopsies, they observed a similar pan-tumor frequency and distribution of KRAS alterations and mutations compared with tissue biopsies.

The genomic co-alteration landscapes and immune biomarker patterns were evaluated in association with different KRAS mutations in terms of tumor mutational burden (TMB), PD-L1 expression, co-alterations, and mutational signatures that may modulate response to KRAS inhibitors, immunotherapies or other therapies.

The researchers also interrogated the real-world Flatiron Health-Foundation Medicine Clinico-genomic Database (CGDB) to assess prognostic implications for KRAS mutated subsets compared to other genomically defined cohorts of non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC).

The findings from this study have significant implications for the development of inhibitors targeting KRAS variants G12C, G12D, G12V and beyond. Genomic profiling to detect co-alterations and mutational signatures, and trials to understand the clinical importance of these biomarkers as predictors of response to targeted therapies and immunotherapies in patients with a wide range of KRAS altered tumor types will be imperative to improve therapy selection and outcomes.

View the full publication on Nature.com.