KRAS, Cancer and Precision Medicine
Precision medicine has revolutionized cancer treatment, but clinical-grade genomic biomarkers of drug response are lacking. In a recent study published in Nature Medicine, van de Haar et. al. used whole-genome analysis of 37 patients with metastatic colorectal cancer (mCRC) treated with the chemotherapy trifluridine/tipiracil (FTD/TPI) to identify KRAS codon G12 (KRASG12) mutations as potential biomarkers of resistance.
KRAS mutations, and their resulting gene products, are a hallmark across many cancers, but are notoriously difficult drug targets. However, with the advent of computer modeling and AI-based structural biology, progress has been made in creating a small-molecule that inhibits a mutant KRAS protein. However, these mutational signatures also hold promise as biomarkers for predicting treatment response.
KRAS Biomarkers Predict FTD/TPI Efficacy
The authors collected data from 960 patients with mCRC receiving FTD/TPI chemotherapy and validated that KRASG12 mutations were significantly associated with poor survival. For patients with KRASG12 mutations, overall survival (OS) was not prolonged with FTD/TPI versus placebo, but patients with a different mutation, KRASG13, showed significantly improved OS with FTD/TPI versus placebo.
Although durable responses to FTD/TPI have been observed in some patients with mCRC, the median overall survival benefit in the general population with mCRC is modest (1.8 months), highlighting the unmet need for patient stratification tools. Precision medicine is widely used to select patients for targeted therapies and immunotherapies, and could be applied to mCRC according to the presence or absence of genomic biomarkers.
Clinical Implications of KRASG12 VS KRASG13
KRAS mutations are found in 44% of patients with mCRC, and they most frequently occur at codon G12 (KRASG12; 28% of patients) or codon G13 (KRASG13; 8% of patients). Although KRASG12 and KRASG13 mutations are regarded as a single entity in clinical practice guidelines, they clearly have different biochemical properties and result in different treatment outcomes.
Taken together, these findings suggest that genomics-based precision medicine may be possible for a subset of chemotherapies in addition to their existing use for immunotherapies, and highlight the importance of identifying genomic biomarkers of response and resistance to improve patient outcomes in mCRC. With the use of whole-genome analysis, researchers can identify potential biomarkers of resistance and validate their findings in real-world cohorts and clinical trials. These advances in precision medicine will continue to enhance cancer treatment and improve patient outcomes.
Outsourcing Bioinformatics Analysis: How Bridge Informatics Can Help
Genomics analysis for precision medicine requires comprehensive data storage and pipeline development expertise. As experts across data types from cutting-edge sequencing platforms, we can help you tackle the challenging computational tasks of storing, analyzing and interpreting genomic and transcriptomic data. Bridge Informatics’ bioinformaticians have a strong background in bench research, so they understand the biological questions driving your analysis needs. From pipeline development and software engineering to deploying existing bioinformatic tools, Bridge Informatics can help you at every step of your research journey. Click here to schedule a free introductory call with a member of our team.
Jane Cook, Biochemist & Content Writer, Bridge Informatics
Jane Cook, leading Content Writer for Bridge Informatics, has written over 100 articles on the latest topics and trends for the bioinformatics community. Jane’s broad and deep interdisciplinary molecular biology experience spans developing biochemistry assays to genomics. Prior to joining Bridge, Jane held research assistant roles in biochemistry research labs across a variety of therapeutic areas. While obtaining her B.A. in Biochemistry from Trinity College in Dublin, Ireland, Jane also studied journalism at New York University’s Arthur L. Carter Journalism Institute. As a native Texan, she embraces any challenge that comes her way. Jane hails from Dallas but returns to Ireland any and every chance she gets. If you’re interested in reaching out, please email jennifer.martinez@old.bridgeinformatics.com or dan.ryder@old.bridgeinformatics.com.
