KRAS mutated colorectal cancers with or without PIK3CA mutations: Clinical and molecular profiles inform current and
1Algoma District Cancer Program, Sault Area Hospital, Sault Ste. Marie, Ontario, Canada; Section of Internal Medicine, Division of Clinical Sciences, Northern Ontario School of Medicine, Sudbury, Ontario, Canada.
Background:
Colorectal cancer is one of the most prevalent malignancies and its molecular pathogenesis has been intensely investigated for several decades. As a result, great progress has been made and targeted therapies have been introduced in the clinic. This paper examines colorectal cancers based on two of the most common molecular alterations, KRAS and PIK3CA mutations as a basis for therapeutic targeting.
Methods:
Two publicly available genomic series with clinical data were evaluated for prevalence and characteristics of cases with and without KRAS and PIK3CA mutations and the literature was reviewed for relevant information on the therapeutic implication of these alterations as well as other coincident alterations to derive therapeutic individualized options of targeted treatments.
Results:
Colorectal cancers without KRAS and PIK3CA mutations represent the most prevalent group (48-58 % of patients) and present therapeutic targeted opportunities with BRAF inhibitors and immune checkpoint inhibitors in the subsets with BRAF mutations (15-22 %) and Microsatellite Instability (MSI, 14-16 %), respectively. The second most prevalent sub-set, with KRAS mutations and PIK3CA wild type, representing 20-25 % of patients, has currently few targeted options, besides specific KRAS G12C inhibitors for the small percentage of cases (9-10 %) that bear this mutation. Cancers with KRAS wild type and PIK3CA mutations are observed in 12-14 % of colorectal cancer patients, harbor the highest percentage of cases with BRAF mutations and Microsatellite Instability (MSI), and are candidates for the respective targeted therapies. New targeted therapies in development, such as ATR inhibitors could be effective in cases with ATM mutations and ARID1A mutations that are also most prevalent in this sub-group (14-22 % and 30 %, respectively). KRAS and PIK3CA double mutant cancers have also few targeted options currently and could benefit from combination therapies with PI3K inhibitors and new KRAS inhibitors in development.
Conclusion:
The backbone of common KRAS and PIK3CA mutations is a rational frame for development of therapeutic algorithms in colorectal cancer and can help guide new drug therapies development. In addition, the prevalence of different molecular groups presented here may help with planning of combination clinical trials by providing estimations of sub-sets with more than one alteration.
Insights
Colorectal cancer treatment can be guided by KRAS and PIK3CA mutations. Identifying these molecular alterations helps in developing targeted therapies and planning clinical trials for better patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Colorectal cancer is a prevalent malignancy with complex molecular underpinnings.
- Decades of research have led to significant advancements and the development of targeted therapies.
- This study focuses on KRAS and PIK3CA mutations, two common alterations in colorectal cancer.
Purpose of the Study:
- To examine colorectal cancers based on KRAS and PIK3CA mutations.
- To identify therapeutic targeting opportunities based on these molecular alterations.
- To inform the development of individualized targeted treatment strategies.
Main Methods:
- Analysis of two public genomic datasets with clinical data.
- Evaluation of the prevalence and characteristics of KRAS and PIK3CA mutations.
- Comprehensive literature review on therapeutic implications and co-occurring alterations.
Main Results:
- Colorectal cancers lacking KRAS/PIK3CA mutations (48-58%) offer opportunities for BRAF and MSI-targeted therapies.
- KRAS-mutated, PIK3CA-wild-type cancers (20-25%) have limited options, with KRAS G12C inhibitors for a subset.
- Cancers with PIK3CA mutations (12-14%) show high rates of BRAF mutations and MSI, and potential benefit from new therapies like ATR inhibitors.
- KRAS/PIK3CA double mutations have few current options, suggesting a need for combination therapies.
Conclusions:
- KRAS and PIK3CA mutations provide a framework for developing therapeutic algorithms in colorectal cancer.
- Understanding mutation prevalence aids in guiding new drug development and clinical trial design.
- This molecular classification can help plan combination trials for subsets with multiple alterations.
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