Expanded Low Allele Frequency RAS and BRAF V600E Testing in Metastatic Colorectal Cancer as Predictive Biomarkers for Cetuximab in the Randomized CO.17 Trial

Jonathan M Loree, Anthony Dowers, Dongsheng Tu, Derek J Jonker, Daniel L Edelstein, Hannah Quinn, Frank Holtrup, Timothy Price, John R Zalcberg, Malcolm J Moore, Christos S Karapetis, Chris J O'Callaghan, Paul Waring, Hagen F Kennecke, Stanley R Hamilton, Scott Kopetz, Jonathan M Loree, Anthony Dowers, Dongsheng Tu, Derek J Jonker, Daniel L Edelstein, Hannah Quinn, Frank Holtrup, Timothy Price, John R Zalcberg, Malcolm J Moore, Christos S Karapetis, Chris J O'Callaghan, Paul Waring, Hagen F Kennecke, Stanley R Hamilton, Scott Kopetz

Abstract

Purpose: Expanded RAS/BRAF mutations have not been assessed as predictive for single-agent cetuximab in metastatic colorectal cancer (mCRC), and low mutant allele frequency (MAF) mutations are of unclear significance. We aimed to establish cetuximab efficacy in optimally selected patients using highly sensitive beads, emulsion, amplification, and magnetics (BEAMing) analysis, capable of detecting alterations below standard clinical assays.

Patients and methods: CO.17 trial compared cetuximab versus best supportive care (BSC) in RAS/BRAF-unselected mCRC. We performed RAS/BRAF analysis on microdissected tissue of 242 patients in CO.17 trial using BEAMing for KRAS/NRAS (codons 12/13/59/61/117/146) and BRAF V600E. Patients without BEAMing but with previous Sanger sequencing-detected mutations were included.

Results: KRAS, NRAS, and BRAF mutations were present in 53%, 4%, and 3% of tumors, respectively. Cetuximab improved overall survival [OS; HR, 0.51; 95% confidence interval (CI), 0.32-0.81; P = 0.004] and progression-free survival (PFS; HR, 0.25; 95% CI, 0.15-0.41; P < 0.0001) compared with BSC in RAS/BRAF wild-type patients. Cetuximab did not improve OS/PFS for KRAS-, NRAS-, or BRAF-mutated tumors, and tests of interaction confirmed expanded KRAS (P = 0.0002) and NRAS (P = 0.006) as predictive, while BRAF mutations were not (P = 0.089). BEAMing identified 14% more tumors as RAS mutant than Sanger sequencing, and cetuximab lacked activity in these patients. Mutations at MAF < 5% were noted in 6 of 242 patients (2%). One patient with a KRAS A59T mutation (MAF = 2%) responded to cetuximab. More NRAS than KRAS mutations were low MAF (OR, 20.50; 95% CI, 3.88-96.85; P = 0.0038).

Conclusions: We establish single-agent cetuximab efficacy in optimally selected patients and show that subclonal RAS/BRAF alterations are uncommon and remain of indeterminate significance.

Trial registration: ClinicalTrials.gov NCT00079066.

Conflict of interest statement

Conflicts of Interest: Daniel Edelstein, Hannah Quinn and Frank Holtrup disclose potential conflicts of interest as employees of Sysmex-Inostics.

©2020 American Association for Cancer Research.

Figures

Figure 1.
Figure 1.
Impact of cetuximab on overall survival in patients with (A) RAS/BRAF V600E wild type metastatic colorectal cancer compared to best supportive care in the CO.17 trial and stratified by (B) molecular subgroup.
Figure 2.
Figure 2.
Impact of cetuximab on progression free survival in patients with (A) RAS/BRAF V600E wild type metastatic colorectal cancer compared to best supportive care in the CO.17 trial and stratified by (B) molecular subgroup.
Figure 3.
Figure 3.
Violin plot displaying the mutant allele frequency distribution density of detected mutations in KRAS, NRAS and BRAF.
Figure 4.
Figure 4.
Objective response rate of patients in CO.17 receiving cetuximab or best supportive care (BSC).

Source: PubMed

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