Clinical usefulness of KRAS, BRAF, and PIK3CA mutations as predictive markers of cetuximab efficacy in irinotecan- and oxaliplatin-refractory Japanese patients with metastatic colorectal cancer.
BACKGROUND
Anti-epidermal growth factor receptor (EGFR) antibodies, cetuximab, and panitumumab are established as a new treatment option for metastatic colorectal cancer (mCRC). Among activating mutations downstream of EGFR, the KRAS mutation, which is present in 30-45 % of CRC patients, has shown to be a predictive biomarker of resistance to anti-EGFR antibody therapy based on Caucasian studies.


METHODS
Forty-three chemotherapy-refractory Japanese patients with mCRC were treated with cetuximab monotherapy or cetuximab plus irinotecan. KRAS, BRAF, and PIK3CA mutational status of tumors was assessed. The association between mutational status and treatment outcome was evaluated.


RESULTS
Of 43 tumors, KRAS, BRAF, and PIK3CA mutations were identified in 12 (27.9 %), 2 (4.7 %), and 2 (4.7 %) tumors, respectively. The wild-type KRAS subgroup showed better clinical outcomes than the mutant KRAS subgroup in terms of response rate (RR) (31.3 % vs. 0 %, P = 0.034) and progression-free survival (PFS) (5.1 vs. 3.0 months, P = 0.017). No responder to treatment was shown in 16 (37.2 %) patients with tumors harboring mutations in any one of the three genes (KRAS, BRAF, and PIK3CA). The wild-type subgroup without any mutations in KRAS, BRAF, and PIK3CA had a better RR (37.0 %) and PFS (6.4 months) than did the wild-type KRAS subgroup.


CONCLUSIONS
Our data indicated that KRAS status is predictive of cetuximab response in the Japanese population. The additional analysis of BRAF and PIK3CA genes in wild-type KRAS patients could improve selection of patients who are most likely to benefit from anti-EGFR antibody therapy.
Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aobaku, Sendai, 980-8575, Japan.
Hiroshi
H
Soeda
Hideki
H
Shimodaira
Mika
M
Watanabe
Takao
T
Suzuki
Makio
M
Gamoh
Takahiro
T
Mori
Keigo
K
Komine
Noriyuki
N
Iwama
Shunsuke
S
Kato
Chikashi
C
Ishioka
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D044466:Asian People / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000068818:Cetuximab; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics*
D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D002166:Camptothecin; D000068818:Cetuximab; D058534:Class I Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D000077146:Irinotecan; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D019869:Phosphatidylinositol 3-Kinases; D011518:Proto-Oncogene Proteins; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; C117307:KRAS protein, human; C484760:PIK3CA protein, human; C482119:BRAF protein, human