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Clinical Trials: Targeted Therapy

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 and Scott Kopetz
Jonathan M. Loree
1BC Cancer, University of British Columbia, Vancouver, British Columbia, Canada.
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Anthony Dowers
2The University of Melbourne, Melbourne, Victoria, Australia.
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Dongsheng Tu
3Canadian Cancer Trials Group, Kingston, Ontario, Canada.
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Derek J. Jonker
4The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada.
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Daniel L. Edelstein
5Sysmex-Inostics, Baltimore, Maryland.
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Hannah Quinn
5Sysmex-Inostics, Baltimore, Maryland.
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Frank Holtrup
5Sysmex-Inostics, Baltimore, Maryland.
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Timothy Price
6Queen Elizabeth Hospital, Adelaide, South Australia, Australia.
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John R. Zalcberg
7Monash University, Melbourne, Victoria, Australia.
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Malcolm J. Moore
1BC Cancer, University of British Columbia, Vancouver, British Columbia, Canada.
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Christos S. Karapetis
8Flinders University, Adelaide, South Australia, Australia.
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Chris J. O'Callaghan
3Canadian Cancer Trials Group, Kingston, Ontario, Canada.
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Paul Waring
2The University of Melbourne, Melbourne, Victoria, Australia.
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Hagen F. Kennecke
9Virginia Mason Cancer Institute, Seattle, Washington.
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Stanley R. Hamilton
10City of Hope, Los Angeles, California.
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Scott Kopetz
11University of Texas, MD Anderson Cancer Center, Houston, Texas.
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  • For correspondence: skopetz@mdanderson.org
DOI: 10.1158/1078-0432.CCR-20-2710 Published January 2021
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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.

This article is featured in Highlights of This Issue, p. 1

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • ClinicalTrial.gov registration ID: NCT00079066.

  • Prior presentation: Presented as a poster at GI ASCO 2019.

  • Clin Cancer Res 2021;27:52–9

  • Received July 11, 2020.
  • Revision received August 31, 2020.
  • Accepted October 16, 2020.
  • Published first October 21, 2020.
  • ©2020 American Association for Cancer Research.
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Clinical Cancer Research: 27 (1)
January 2021
Volume 27, Issue 1
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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 and Scott Kopetz
Clin Cancer Res January 1 2021 (27) (1) 52-59; DOI: 10.1158/1078-0432.CCR-20-2710

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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 and Scott Kopetz
Clin Cancer Res January 1 2021 (27) (1) 52-59; DOI: 10.1158/1078-0432.CCR-20-2710
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