Broad Detection of Alterations Predicted to Confer Lack of Benefit From EGFR Antibodies or Sensitivity to Targeted Therapy in Advanced Colorectal Cancer.
BACKGROUND
AKRASmutation represented the first genomic biomarker to predict lack of benefit from anti-epidermal growth factor receptor (EGFR) antibody therapy in advanced colorectal cancer (CRC). ExpandedRAStesting has further refined the treatment approach, but understanding of genomic alterations underlying primary and acquired resistance is limited and further study is needed.


METHODS
We prospectively analyzed 4,422 clinical samples from patients with advanced CRC, using hybrid-capture based comprehensive genomic profiling (CGP) at the request of the individual treating physicians. Comparison with prior molecular testing results, when available, was performed to assess concordance.


RESULTS
We identified a RAS/RAF pathway mutation or amplification in 62% of cases, including samples harboringKRASmutations outside of the codon 12/13 hotspot region in 6.4% of cases. Among cases withKRASnon-codon 12/13 alterations for which prior test results were available, 79 of 90 (88%) were not identified by focused testing. Of 1,644RAS/RAFwild-type cases analyzed by CGP, 31% harbored a genomic alteration (GA) associated with resistance to anti-EGFR therapy in advanced CRC including mutations inPIK3CA,PTEN,EGFR, andERBB2. We also identified other targetable GA, including novel kinase fusions, receptor tyrosine kinase amplification, activating point mutations, as well as microsatellite instability.


CONCLUSIONS
Extended genomic profiling reliably detects alterations associated with lack of benefit to anti-EGFR therapy in advanced CRC, while simultaneously identifying alterations potentially important in guiding treatment. The use of CGP during the course of clinical care allows for the refined selection of appropriate targeted therapies and clinical trials, increasing the chance of clinical benefit and avoiding therapeutic futility.


CONCLUSIONS
Comprehensive genomic profiling (CGP) detects diverse genomic alterations associated with lack of benefit to anti-epidermal growth factor receptor therapy in advanced colorectal cancer (CRC), as well as targetable alterations in many other genes. This includes detection of a broad spectrum of activatingKRASalterations frequently missed by focused molecular hotspot testing, as well as otherRAS/RAFpathway alterations, mutations shown to disrupt antibody binding, RTK activating point mutations, amplifications, and rearrangements, and activating alterations in downstream effectors including PI3K and MEK1. The use of CGP in clinical practice is critical to guide appropriate selection of targeted therapies for patients with advanced CRC.
Foundation Medicine Inc., Cambridge, Massachusetts, USA.
Andrew
A
Rankin
The Angeles Clinic & Research Institute, Los Angeles, California, USA.
Samuel J
SJ
Klempner
Foundation Medicine Inc., Cambridge, Massachusetts, USA.
Rachel
R
Erlich
Foundation Medicine Inc., Cambridge, Massachusetts, USA.
James X
JX
Sun
Mayo Clinic Cancer Center, Rochester, Minnesota, USA.
Axel
A
Grothey
City of Hope Comprehensive Cancer Center, Duarte, California, USA.
Marwan
M
Fakih
College of Medicine, University of Florida, Gainesville, Florida, USA.
Thomas J
TJ
George
Department of Hematology and Oncology, Samsung Medical Center, SungKyunKwan University School of Medicine, Seoul, Republic of Korea.
Jeeyun
J
Lee
Foundation Medicine Inc., Cambridge, Massachusetts, USA.|Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
Jeffrey S
JS
Ross
Foundation Medicine Inc., Cambridge, Massachusetts, USA.
Philip J
PJ
Stephens
Foundation Medicine Inc., Cambridge, Massachusetts, USA.
Vincent A
VA
Miller
Foundation Medicine Inc., Cambridge, Massachusetts, USA.
Siraj M
SM
Ali
Foundation Medicine Inc., Cambridge, Massachusetts, USA aschrock@Foundationmedicine.com.
Alexa B
AB
Schrock
Biomarker; Cetuximab; Colon cancer; Epidermal growth factor receptor; Genomic profiling; KRAS
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