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DNA Mutational Profiling in Patients With Colorectal Cancer Treated With Standard of Care Reveals Differences in
Federico Innocenti1,2, Wancen Mu3, Xueping Qu4
1Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC.
Purpose:
CALGB (Alliance)/SWOG 80405 was a randomized phase III trial that in first-line patients with metastatic colorectal cancer (mCRC) treated with bevacizumab or cetuximab with chemotherapy. We aimed to discover novel mutated genes associated with prognosis and differential response to therapy with the biologics.
Methods:
Primary tumor DNA from 548 patients was sequenced using FoundationOne. The effect of mutated genes and mutations on overall survival (OS) was tested adjusting for microsatellite instability status, BRAF V600E, all RAS mutations, arm, sex, and age.
Results:
The median number (lower-upper quartile) of mutated genes was 5 (3-7), 5 (3-6) in microsatellite stable and 12.5 (4.5-32) in microsatellite instability-high tumors. Mutated KRAS and APC were more frequent in Black (53% and 85%) than White (27% and 65%, respectively) patients while BRAF V600E was less frequent in Black (5%) than White (14%) patients. The median OS in patients with BRAF non-V600E (2.2% of patients) was 31.9 months (95% CI, 15.1 to not applicable [NA]) similar to that of BRAF wild-type (WT) patients (31.2 months [95% CI, 29.0 to 33.9]). Mutated LRP1B (10.7% of patients) was associated with improved OS compared with WT LRP1B (hazard ratio, 0.57 [95% CI, 0.40 to 0.80]). RNF43 (5.6% of patients) interacted with treatment arms as, in the cetuximab arm, patients with mutated RNF43 had a median OS of 11.5 (95% CI, 10.8 to NA) months compared with 30.1 (95% CI, 24.9 to 35.3) months in patients with WT RNF43, whereas in the bevacizumab arm, patients with mutated RNF43 had a median OS of 25.0 (95% CI, 14.2 to NA) months compared with 31.3 (95% CI, 29.0 to 34.3) months in patients with WT RNF43.
Conclusion:
These results can provide new tools to predict patient outcome and improve therapeutic decisions and trial participation in patient minorities. The molecular alterations identified in this study may direct biomarker-driven studies.
Insights
Novel gene mutations in metastatic colorectal cancer (mCRC) impact patient survival and response to bevacizumab or cetuximab. Identifying these biomarkers can improve treatment strategies and clinical trial design for diverse patient groups.
Area of Science:
- Oncology
- Genetics
- Clinical Trials
Background:
- Metastatic colorectal cancer (mCRC) treatment involves chemotherapy combined with biologics like bevacizumab or cetuximab.
- Identifying genetic markers can personalize treatment and improve outcomes for mCRC patients.
Purpose of the Study:
- To discover novel mutated genes linked to prognosis in mCRC.
- To identify genes associated with differential treatment responses to bevacizumab and cetuximab in first-line mCRC.
Main Methods:
- Whole exome sequencing of primary tumor DNA from 548 mCRC patients in the CALGB (Alliance)/SWOG 80405 trial.
- Statistical analysis to correlate gene mutations with overall survival (OS), adjusting for known prognostic factors like microsatellite instability and RAS/BRAF mutations.
Main Results:
- Microsatellite instability-high tumors exhibited a higher median number of mutated genes (12.5) compared to microsatellite-stable tumors (5).
- Mutations in KRAS and APC were more prevalent in Black patients, while BRAF V600E was less common.
- Mutated LRP1B was associated with improved OS (HR, 0.57). RNF43 mutations showed differential impact on OS depending on the treatment arm (cetuximab vs. bevacizumab).
Conclusions:
- Identified molecular alterations in mCRC can serve as predictive biomarkers for patient outcomes.
- These findings may enhance therapeutic decision-making and guide future biomarker-driven clinical trials, particularly for underrepresented patient populations.
