TY - JOUR
T1 - Expanded low allele frequency RAS and BRAF V600E testing in metastatic colorectal cancer as predictive biomarkers for cetuximab in the randomized CO.17 trial
AU - Loree, Jonathan M.
AU - Dowers, Anthony
AU - Tu, Dongsheng
AU - Jonker, Derek J.
AU - Edelstein, Daniel L.
AU - Quinn, Hannah
AU - Holtrup, Frank
AU - Price, Timothy
AU - Zalcberg, John R.
AU - Moore, Malcolm J.
AU - Karapetis, Christos S.
AU - O’Callaghan, Chris J.
AU - Waring, Paul
AU - Kennecke, Hagen F.
AU - Hamilton, Stanley R.
AU - Kopetz, Scott
PY - 2021/1/1
Y1 - 2021/1/1
N2 - 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 ¼ 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 ¼ 0.0002) and NRAS (P ¼ 0.006) as predictive, while BRAF mutations were not (P ¼ 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 ¼ 2%) responded to cetuximab. More NRAS than KRAS mutations were low MAF (OR, 20.50; 95% CI, 3.88—96.85; P ¼ 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.
AB - 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 ¼ 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 ¼ 0.0002) and NRAS (P ¼ 0.006) as predictive, while BRAF mutations were not (P ¼ 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 ¼ 2%) responded to cetuximab. More NRAS than KRAS mutations were low MAF (OR, 20.50; 95% CI, 3.88—96.85; P ¼ 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.
KW - Low Allele Frequency
KW - Metastatic Colorectal Cancer
KW - Cetuximab
UR - http://www.scopus.com/inward/record.url?scp=85100356038&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-20-2710
DO - 10.1158/1078-0432.CCR-20-2710
M3 - Article
AN - SCOPUS:85100356038
SN - 1078-0432
VL - 27
SP - 52
EP - 59
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 1
ER -