Use of a High-Throughput Genotyping Platform (OncoMap) forRASMutational Analysis to Predict Cetuximab Efficacy in Patients with Metastatic Colorectal Cancer.
OBJECTIVE
Cetuximab demonstrates improved efficacy outcomes in patients with metastatic colorectal cancer (mCRC) harboring wild-typeKRASexon 2. Resistance to cetuximab is mediated by activating less frequent mutations in theRASgenes beyondKRASexon 2. We performed extendedRASMutational analysis using a high-throughput genotyping platform (OncoMap) and evaluated extendedRASanalysis for predicting cetuximab efficacy in patients harboring wild-typeKRASexon 2 tumors following Sanger sequencing.


METHODS
ExtendedRASanalysis was performed on 227 wild-typeKRASexon 2 mCRC patients who received cetuximab as salvage treatment using OncoMap ver. 4.0. Targeted genes included exon 2, exon 3, and exon 4, both inKRASandNRAS, and includedBRAFexon 15. We assessed efficacy by the newRASmutation status.


RESULTS
The OncoMap detected 57 additional mutations (25.1%): 25 (11%) inKRASexon 2 and 32 (14.1%) beyondKRASexon 2. Survival differences were observed after dividing patients into the wild-typeRASgroup (n=170) and mutantRASgroup (n=57) using OncoMap. Progression-free survival was 4.8 months versus 1.8 months (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.32 to 0.61), and overall survival was 11.9 months versus 8.4 months (HR, 0.65; 95% CI, 0.47 to 0.88).


CONCLUSIONS
Sanger sequencing is not sufficient for selecting candidates for cetuximab treatment. High-throughput extendedRASgenotyping is a feasible approach for this purpose and identifies patients who might benefit from cetuximab treatment.
Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Dalyong
D
Kim
Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Yong Sang
YS
Hong
Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Jeong Eun
JE
Kim
Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Kyu-Pyo
KP
Kim
Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Jae-Lyun
JL
Lee
Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Sung-Min
SM
Chun
Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Jihun
J
Kim
Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Se Jin
SJ
Jang
Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Tae Won
TW
Kim
D000074322:Antineoplastic Agents, Immunological / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000068818:Cetuximab / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D004252:DNA Mutational Analysis / Q000379:methods; D019008:Drug Resistance, Neoplasm; D005091:Exons; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D012008:Recurrence; D016896:Treatment Outcome
D000074322:Antineoplastic Agents, Immunological; C117307:KRAS protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab
Cetuximab; Colorectal neoplasms; High-throughput nucleotide sequencing; RAS genes