KRAS mutation status and clinical outcome of preoperative chemoradiation with cetuximab in locally advanced rectal cancer: a pooled analysis of 2 phase II trials.
OBJECTIVE
Cetuximab-containing chemotherapy is known to be effective for KRAS wild-type metastatic colorectal cancer; however, it is not clear whether cetuximab-based preoperative chemoradiation confers an additional benefit compared with chemoradiation without cetuximab in patients with locally advanced rectal cancer.


METHODS
We analyzed EGFR, KRAS, BRAF, and PIK3CA mutation status with direct sequencing and epidermal growth factor receptor (EGFR) and Phosphatase and tensin homolog (PTEN) expression status with immunohistochemistry in tumor samples of 82 patients with locally advanced rectal cancer who were enrolled in the IRIX trial (preoperative chemoradiation with irinotecan and capecitabine; n=44) or the ERBIRIX trial (preoperative chemoradiation with irinotecan and capecitabine plus cetuximab; n=38). Both trials were similarly designed except for the administration of cetuximab; radiation therapy was administered at a dose of 50.4 Gy/28 fractions and irinotecan and capecitabine were given at doses of 40 mg/m2 weekly and 1650 mg/m2/day, respectively, for 5 days per week. In the ERBIRIX trial, cetuximab was additionally given with a loading dose of 400 mg/m2 on 1 week before radiation, and 250 mg/m2 weekly thereafter.


RESULTS
Baseline characteristics before chemoradiation were similar between the 2 trial cohorts. A KRAS mutation in codon 12, 13, and 61 was noted in 15 (34%) patients in the IRIX cohort and 5 (13%) in the ERBIRIX cohort (P=.028). Among 62 KRAS wild-type cancer patients, major pathologic response rate, disease-free survival and pathologic stage did not differ significantly between the 2 cohorts. No mutations were detected in BRAF exon 11 and 15, PIK3CA exon 9 and 20, or EGFR exon 18-24 in any of the 82 patients, and PTEN and EGFR expression were not predictive of clinical outcome.


CONCLUSIONS
In patients with KRAS wild-type locally advanced rectal cancer, the addition of cetuximab to the chemoradiation with irinotecan plus capecitabine regimen was not associated with improved clinical outcome compared with chemoradiation without cetuximab.
Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Korea.
Sun Young
SY
Kim
Eun Kyung
EK
Shim
Hyun Yang
HY
Yeo
Ji Yeon
JY
Baek
Yong Sang
YS
Hong
Dae Yong
DY
Kim
Tae Won
TW
Kim
Jee Hyun
JH
Kim
Seock-Ah
SA
Im
Kyung Hae
KH
Jung
Hee Jin
HJ
Chang
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use; D000069287:Capecitabine; D000068818:Cetuximab; D059248:Chemoradiotherapy / Q000379:methods*; D058534:Class I Phosphatidylinositol 3-Kinases; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives / Q000627:therapeutic use; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011300:Preoperative Care; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D011879:Radiotherapy Dosage; D012004:Rectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D003841:Deoxycytidine; D000069287:Capecitabine; D000077146:Irinotecan; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D000068818:Cetuximab; D005472:Fluorouracil; D002166:Camptothecin