MDR1 polymorphism role in patients treated with cetuximab and irinotecan in irinotecan refractory colorectal cancer.
The aim of the study was to evaluate the influence of the MDR1 C3435T polymorphism on the therapeutic response in 23 patients treated with cetuximab plus irinotecan for irinotecan refractory liver metastatic colorectal cancer considering their KRAS status. Indeed, irinotecan and its active metabolite (SN-38) are both substrates of P-glycoprotein (P-gp) encoded by MDR1. Patients received cetuximab and irinotecan up to progression. The overall survival was 55% at 10 months. Overall, four patients had an undetermined KRAS status and two patients with mutated KRAS were in progression disease. The response to treatment was observed after 3 months among the 17 wild-type KRAS patients. Two patients presented a progressive disease (1 TT and 1 CT), eight patients had a stable disease (5 CC and 3CT) and five patients had a partial response (3 CC and 2 CT). Importantly, 2 patients (2 TT) were in complete response and still alive 5 years after starting the treatment, which suggests that the combination of wild-type KRAS and MDR1 3435 TT may be a factor of good prognosis. These results suggest that EGFR inhibition by cetuximab may overcome this irinotecan resistance by abrogating drug efflux depending on MDR1 3435 polymorphism. Among patients resistant to irinotecan, it is still possible to use the association of cetuximab plus irinotecan to obtain a complete resection of hepatic metastases that is necessary to improve their survival.
Centre Hépatobiliaire, Department of Pharmacy-Pharmacology, Paul Brousse University Hospital, AP-HP, 12-14, avenue Paul Vaillant-Couturier, Villejuif, France.
Bernard
B
Paule
Vincent
V
Castagne
Véronique
V
Picard
Raphaël
R
Saffroy
René
R
Adam
Catherine
C
Guettier
Robert
R
Farinotti
Laurence
L
Bonhomme-Faivre
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; 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; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D000077146:Irinotecan; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011110:Polymorphism, Genetic / Q000187:drug effects*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D015996:Survival Rate; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D000077146:Irinotecan; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab; D002166:Camptothecin