TY - JOUR
T1 - Association of CTLA-4 Gene Variants with Response to Therapy and Long-term Survival in Metastatic Melanoma Patients Treated with Ipilimumab
T2 - An Italian Melanoma Intergroup Study
AU - Queirolo, Paola
AU - Dozin, Beatrice
AU - Morabito, Anna
AU - Banelli, Barbara
AU - Piccioli, Patrizia
AU - Fava, Cristiana
AU - Leo, Claudio
AU - Carosio, Roberta
AU - Laurent, Stefania
AU - Fontana, Vincenzo
AU - Ferrucci, Pier Francesco
AU - Martinoli, Chiara
AU - Cocorocchio, Emilia
AU - Battaglia, Angelo
AU - Ascierto, Paolo A
AU - Capone, Mariaelena
AU - Simeone, Ester
AU - De Galitiis, Federica
AU - Pagani, Elena
AU - Antonini Cappellini, Gian Carlo
AU - Marchetti, Paolo
AU - Guida, Michele
AU - Tommasi, Stefania
AU - Mandalà, Mario
AU - Merelli, Barbara
AU - Quaglino, Pietro
AU - Fava, Paolo
AU - Guidoboni, Massimo
AU - Romani, Massimo
AU - Spagnolo, Francesco
AU - Pistillo, Maria Pia
PY - 2017
Y1 - 2017
N2 - Ipilimumab (IPI) blocks CTLA-4 immune checkpoint resulting in T cell activation and enhanced antitumor immunity. IPI improves overall survival (OS) in 22% of patients with metastatic melanoma (MM). We investigated the association of CTLA-4 single nucleotide variants (SNVs) with best overall response (BOR) to IPI and OS in a cohort of 173 MM patients. Patients were genotyped for six CTLA-4 SNVs (-1661A>G, -1577G>A, -658C>T, -319C>T, +49A>G, and CT60G>A). We assessed the association between SNVs and BOR through multinomial logistic regression (MLR) and the prognostic effect of SNVs on OS through Kaplan-Meier method. Both -1577G>A and CT60G>A SNVs were found significantly associated with BOR. In particular, the proportion of responders was higher in G/G genotype while that of stable patients was higher in A/A genotype. The frequency of patients experiencing progression was similar in all genotypes. MLR evidenced a strong downward trend in the probability of responsiveness/progression, in comparison to disease stability, as a function of the allele A "dose" (0, 1, or 2) in both SNVs with reductions of about 70% (G/A vs G/G) and about 95% (A/A vs G/G). Moreover, -1577G/G and CT60G/G genotypes were associated with long-term OS, the surviving patients being at 3 years 29.8 and 30.8%, respectively, as compared to 12.9 and 14.4% of surviving patients carrying -1577G/A and CT60G/A, respectively. MM patients carrying -1577G/G or CT60G/G genotypes may benefit from IPI treatment in terms of BOR and long-term OS. These CTLA-4 SNVs may serve as potential biomarkers predictive of favorable outcome in this subset of patients.
AB - Ipilimumab (IPI) blocks CTLA-4 immune checkpoint resulting in T cell activation and enhanced antitumor immunity. IPI improves overall survival (OS) in 22% of patients with metastatic melanoma (MM). We investigated the association of CTLA-4 single nucleotide variants (SNVs) with best overall response (BOR) to IPI and OS in a cohort of 173 MM patients. Patients were genotyped for six CTLA-4 SNVs (-1661A>G, -1577G>A, -658C>T, -319C>T, +49A>G, and CT60G>A). We assessed the association between SNVs and BOR through multinomial logistic regression (MLR) and the prognostic effect of SNVs on OS through Kaplan-Meier method. Both -1577G>A and CT60G>A SNVs were found significantly associated with BOR. In particular, the proportion of responders was higher in G/G genotype while that of stable patients was higher in A/A genotype. The frequency of patients experiencing progression was similar in all genotypes. MLR evidenced a strong downward trend in the probability of responsiveness/progression, in comparison to disease stability, as a function of the allele A "dose" (0, 1, or 2) in both SNVs with reductions of about 70% (G/A vs G/G) and about 95% (A/A vs G/G). Moreover, -1577G/G and CT60G/G genotypes were associated with long-term OS, the surviving patients being at 3 years 29.8 and 30.8%, respectively, as compared to 12.9 and 14.4% of surviving patients carrying -1577G/A and CT60G/A, respectively. MM patients carrying -1577G/G or CT60G/G genotypes may benefit from IPI treatment in terms of BOR and long-term OS. These CTLA-4 SNVs may serve as potential biomarkers predictive of favorable outcome in this subset of patients.
KW - Journal Article
U2 - 10.3389/fimmu.2017.00386
DO - 10.3389/fimmu.2017.00386
M3 - Article
C2 - 28446908
VL - 8
SP - 386
JO - Frontiers in Immunology
JF - Frontiers in Immunology
SN - 1664-3224
ER -