Genetic diversity of the KIR/HLA system and outcome of patients with metastatic colorectal cancer treated with chemotherapy.
OBJECTIVE
To explore genes of the killer-cell immunoglobulin-like receptor (KIR) and of the HLA ligand and their relationship with the outcome of metastatic colorectal cancer (mCRC) patients treated with first-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI).


METHODS
A total of 224 mCRC patients were screened for KIR/HLA typing. The determination of the KIR/HLA combinations was based upon the gene content and variants. Genetic associations with complete response (CR), time to progression (TTP) and overall survival (OS) were evaluated by calculating odds and hazard ratios. Multivariate modeling with prognostic covariates was also performed.


RESULTS
For CR, the presence of KIR2DL5A, 2DS5, 2DS1, 3DS1, and KIR3DS1/HLA-Bw4-I80 was associated with increased CR rates, with median ORs ranging from 2.1 to 4.3, while the absence of KIR2DS4 and 3DL1 was associated with increased CR rates (OR 3.1). After univariate analysis, patients that underwent resective surgery of tumor, absence of KIR2DS5, and presence of KIR3DL1/HLA-Bw4-I80 showed a significant better OS (HR 1.5 to 2.8). Multivariate analysis identified as parameters independently related to OS the type of treatment (surgery; HR 2.0) and KIR3DL1/HLA-Bw4-I80 genotype (HR for T-I80 2.7 and for no functional KIR/HLA interaction 1.8). For TTP, no association with KIR/HLA genes was observed.


CONCLUSIONS
This study, for the first time, evidences that the genotyping for KIR-HLA pairs are found predictive markers associated with complete response and improves overall survival prediction of FOLFIRI treatment response in metastatic colorectal cancer. These results suggest a role of the KIR/HLA system in patient outcome, and guide new research on the immunogenetics of mCRC through mechanistic studies and clinical validation.
Translational Research, CRO National Cancer Institute, IRCCS, Aviano, Pordenone, Italy.
Valli
V
De Re
Translational Research, CRO National Cancer Institute, IRCCS, Aviano, Pordenone, Italy.
Laura
L
Caggiari
Translational Research, CRO National Cancer Institute, IRCCS, Aviano, Pordenone, Italy.
Mariangela
M
De Zorzi
Epidemiology and Biostatistics, CRO National Cancer Institute, IRCCS, Aviano, Pordenone, Italy.
Renato
R
Talamini
Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy.
Vito
V
Racanelli
Medical Oncology Unit, San Filippo Neri Hospital, Rome, Italy.
Mario
M
D' Andrea
Medical Oncology, CRO National Cancer Institute, IRCCS, Aviano, Pordenone, Italy.
Angela
A
Buonadonna
Medical Oncology, Istituto Oncologico Veneto, IRCCS, Padova, Italy.
Vittorina
V
Zagonel
Translational Research, CRO National Cancer Institute, IRCCS, Aviano, Pordenone, Italy.
Erika
E
Cecchin
University of North Carolina, Institute for Pharmacogenomics and Individualized Therapy, Eshelman School of Pharmacy, School of Medicine, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, United States of America.
Federico
F
Innocenti
Translational Research, CRO National Cancer Institute, IRCCS, Aviano, Pordenone, Italy.
Giuseppe
G
Toffoli
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006680:HLA Antigens / Q000145:classification / Q000235:genetics*; D015235:HLA-B Antigens / Q000235:genetics; D006801:Humans; D000077146:Irinotecan; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009362:Neoplasm Metastasis; D011379:Prognosis; D054340:Receptors, KIR / Q000145:classification / Q000235:genetics*; D054341:Receptors, KIR3DL1 / Q000235:genetics; D016896:Treatment Outcome
D006680:HLA Antigens; D015235:HLA-B Antigens; C042388:HLA-Bw4 antigen; C531595:KIR2DS5 protein, human; C515083:KIR3DL1 protein, human; D054340:Receptors, KIR; D054341:Receptors, KIR3DL1; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin