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J Clin Oncol. 2019 May 10;37(14):1217-1227. doi: 10.1200/JCO.18.01798. Epub 2019 Mar 13.

Mutational Analysis of Patients With Colorectal Cancer in CALGB/SWOG 80405 Identifies New Roles of Microsatellite Instability and Tumor Mutational Burden for Patient Outcome.

Author information

1
1 University of North Carolina at Chapel Hill, Chapel Hill, NC.
2
2 Mayo Clinic, Rochester, MN.
3
3 Genentech, South San Francisco, CA.
4
4 Duke University, Durham, NC.
5
5 West Virginia University Cancer Institute, Morgantown, WV.
6
6 Dana-Farber/Partners CancerCare, Harvard Medical School, Boston, MA.
7
7 Oregon Health & Science University, Portland, OR.
8
8 Southeast Clinical Oncology Research Consortium, Winston-Salem, NC.
9
9 University of Chicago Comprehensive Cancer Center, Chicago, IL.
10
10 University of California San Francisco, San Francisco, CA.
11
11 USC Norris Comprehensive Cancer Center, Los Angeles, CA.

Abstract

PURPOSE:

CALGB/SWOG 80405 was a randomized phase III trial that found no statistically significant difference in overall survival (OS) in patients with first-line metastatic colorectal cancer treated with chemotherapy plus either bevacizumab or cetuximab. Primary tumor DNA from 843 patients has been used to discover genetic markers of OS.

PATIENTS AND METHODS:

Gene mutations were determined by polymerase chain reaction. Microsatellite status was determined by genotyping of microsatellites. Tumor mutational burden (TMB) was determined by next-generation sequencing. Cox proportional hazard models were used, with adjusting factors. Interaction of molecular alterations with either the bevacizumab or the cetuximab arms was tested.

RESULTS:

Patients with high TMB in their tumors had longer OS than did patients with low TMB (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.95]; P = .02). In patients with microsatellite instability-high (MSI-H) tumors, longer OS was observed in the bevacizumab arm than in the cetuximab arm (HR, 0.13 [95% CI, 0.06 to 0.30]; interaction P < .001 for interaction between microsatellite status and the two arms). Patients with BRAF mutant tumors had shorter OS than did patients with wild-type (WT) tumors (HR, 2.01 [95% CI, 1.49 to 2.71]; P < .001). Patients with extended RAS mutant tumors had shorter OS than did patients with WT tumors (HR, 1.52 [95% CI, 1.26 to 1.84]; P < .001). Patients with triple-negative tumors (WT for NRAS/KRAS/BRAF) had a median OS of 35.9 months (95% CI, 33.0 to 38.8 months) versus 22.2 months (95% CI, 19.6 to 24.4 months ) in patients with at least one mutated gene in their tumors (P < .001).

CONCLUSION:

In patients with metastatic colorectal cancer treated in first line, low TMB, and BRAF and RAS mutations are negative prognostic factors. Patients with MSI-H tumors benefited more from bevacizumab than from cetuximab, and studies to confirm this effect of MSI-H are warranted.

Comment in

PMID:
30865548
PMCID:
PMC6506418
[Available on 2020-05-10]
DOI:
10.1200/JCO.18.01798

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