Combined assessment of epidermal [corrected] growth factor receptor dual color in situ hybridization and immunohistochemistry with downstream gene mutations in prediction of response to the anti-EGFR therapy for patients with metastatic colorectal cancer.
OBJECTIVE
Biomarkers associated with anti-EGFR antibodies therapy have been investigated in metastatic colorectal cancer (CRC). We conducted this study to evaluate the clinical utility of a combined assessment of EGFR status and genomic mutations of the EGFR downstream signal pathway in predicting the efficacy of anti-EGFR antibody treatment.


METHODS
We collected formalin-fixed paraffin-embedded tumor tissues and evaluated the EGFR status by immunohistochemistry (IHC), dual color in situ hybridization (DISH) and genomic analyses of KRAS, BRAF, PIK3CA and NRAS by direct sequencing.


RESULTS
A total of 129 patients were evaluated in our study. Among KRAS wild-type patients, EGFR DISH positivity was associated with a higher response rate than DISH negativity (56.3 vs. 21.1%, p = 0.011). A subgroup with EGFR DISH positivity plus IHC3+ and wild-type of EGFR downstream gene mutations achieved higher response rate and disease control rate. EGFR DISH positivity, KRAS codon 146 mutation and NRAS codon 61 mutation were prognostic factors in both progression-free survival and overall survival by multivariate analyses.


CONCLUSIONS
Combined assessment of DISH plus IHC and EGFR downstream gene mutations was useful to predict the response to anti-EGFR antibodies treatment in metastatic colorectal cancer patients in our study.
Department of Gastrointestinal Oncology, National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, Japan. Electronic address: naoki19800623@gmail.com.
Naoki
N
Takahashi
Department of Gastrointestinal Oncology, National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, Japan.
Yasuhide
Y
Yamada
Department of Pathology, National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, Japan.
Hirokazu
H
Taniguchi
Department of Gastrointestinal Oncology, National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, Japan.
Yoshitaka
Y
Honma
Department of Gastrointestinal Oncology, National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, Japan.
Satoru
S
Iwasa
Department of Gastrointestinal Oncology, National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, Japan.
Ken
K
Kato
Department of Gastrointestinal Oncology, National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, Japan.
Tetsuya
T
Hamaguchi
Department of Gastrointestinal Oncology, National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, Japan.
Yasuhiro
Y
Shimada
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000068818:Cetuximab; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization / Q000379:methods*; D000077146:Irinotecan; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation; D000077544:Panitumumab; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism*; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D002166:Camptothecin; D000068818:Cetuximab; D058534:Class I Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D020558:GTP Phosphohydrolases; D000077146:Irinotecan; D008565:Membrane Proteins; D000077544:Panitumumab; D019869:Phosphatidylinositol 3-Kinases; D011518:Proto-Oncogene Proteins; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D040262:Receptors, Vascular Endothelial Growth Factor; D018631:ras Proteins; C117307:KRAS protein, human; C484760:PIK3CA protein, human; C482119:BRAF protein, human; C579846:NRAS protein, human
BRAF; Colon cancer; DISH; EGFR therapy; KRAS; NRAS; PIK3CA