Past
RAS genetic testing is increasingly recommended to guide chemotherapy selection and prognosticate for patients with metastatic colorectal cancer (mCRC). While KRAS and NRAS mutated tumors are associated with worse overall survival and resistance to anti-EGFR therapy, few studies have assessed the impact of mutation location on outcomes.1,2 KRAS exon 4 mutations have been previously associated with a more favorable tumor phenotype, fewer recurrences, and improved overall survival in patients with mCRC.3,4 Although these prior studies are limited by sample size, the observed heterogeneity in clinical outcomes for RAS mutants suggests that biologic behavior and prognosis may vary based on mutated exon.
Present
In the current study, we sought to assess whether exon location affects pathologic and oncologic outcomes in a large sample of patients with resectable liver-dominant mCRC at a single institution over 24-years.5 The small number of NRAS and KRAS exon 3 and 4 mutants in this study indicates the rarity of these mutations in patients with resectable disease. Contrary to prior studies, there did not appear to be a significant difference in overall survival or pathologic features based on RAS exon; however, there was no overlap in the survival distributions for patients with exon 2 and 4 mutations. These findings suggest that KRAS exon 4 mutant tumors may behave more favorably, although with a smaller effect size than previously described.
Future
Our data highlight the complexity of clinical interpretation of genomic data, as it appears that not all RAS mutations share the same biologic activity and prognostic effects. While genetic tests may help inform the choice of therapy for patients with mCRC, these results should not be interpreted as binary biomarkers, and should be considered in aggregate with other clinicopathologic and treatment features, which may modulate survival. For patients with mCRC, the favorable phenotype of exon 4 mutants may help guide discussions regarding treatment planning, prognosis and decisions to pursue more aggressive surgical interventions. With the expansion of genetic testing, further studies characterizing the diverse molecular pathways of these rare mutations are warranted.
Acknowledgments
Funding: This work was funded in part by the Marie-Josée and Henry R. Kravis Center for Molecular Oncology and the National Cancer Institute Cancer Center Core Grant No. P30-CA008748.
Footnotes
Conflicts of Interest: Both authors certify that they have no affiliations with or involvement in any organization with any financial interest in the subject matter discussed in this manuscript.
Associated Manuscript: Association of RAS mutation location and oncologic outcomes after resection of colorectal liver metastases
Publisher's Disclaimer: This Author Accepted Manuscript is a PDF file of an unedited peer-reviewed manuscript that has been accepted for publication but has not been copyedited or corrected. The official version of record that is published in the journal is kept up to date and so may therefore differ from this version.
References
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