PIK3CA mutations are not a major determinant of resistance to the epidermal growth factor receptor inhibitor cetuximab in metastatic colorectal cancer.
OBJECTIVE
It has been reported that activating KRAS mutations negatively affect response to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies in metastatic colorectal cancer. The mutation status of signaling molecules downstream of the EGFR target is thus crucial to predict clinical benefit to EGFR-targeted therapies. Other mechanisms of resistance to EGFR inhibitors could involve activating mutations of the other main EGFR effector pathway, i.e., the PI3K/PTEN/AKT pathway.


METHODS
We analyzed the PIK3CA and KRAS mutation status in a large group (n = 200) of chemorefractory metastatic colorectal cancers treated with cetuximab (Erbitux) in monotherapy or in combination with irinotecan, and correlated the mutation status with outcome.


RESULTS
Twenty-three (12%) of the 200 samples carried 1 of the PIK3CA mutations included in our assay. We found no correlation between the presence of a PIK3CA mutation and impaired response to cetuximab.


CONCLUSIONS
Our findings do not provide any evidence for a strong role of PIK3CA mutations as a single marker in determining response to cetuximab in chemorefractory metastatic colorectal cancer.
Department of Digestive Oncology, University Hospital Gasthuisberg, Leuven, Belgium.
Hans
H
Prenen
Jef
J
De Schutter
Bart
B
Jacobs
Wendy
W
De Roock
Bart
B
Biesmans
Bart
B
Claes
Diether
D
Lambrechts
Eric
E
Van Cutsem
Sabine
S
Tejpar
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000068818:Cetuximab; D058534:Class I Phosphatidylinositol 3-Kinases; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D015996:Survival Rate; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D000077146:Irinotecan; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab; D002166:Camptothecin