TY - JOUR
T1 - The clinical significance of PD-L1 in advanced gastric cancer is dependent on ARID1A mutations and ATM expression
AU - Buglioni, Simonetta
AU - Melucci, Elisa
AU - Sperati, Francesca
AU - Pallocca, Matteo
AU - Terrenato, Irene
AU - De Nicola, Francesca
AU - Goeman, Frauke
AU - Casini, Beatrice
AU - Amoreo, Carla Azzurra
AU - Gallo, Enzo
AU - Diodoro, Maria Grazia
AU - Pescarmona, Edoardo
AU - Vici, Patrizia
AU - Sergi, Domenico
AU - Pizzuti, Laura
AU - Di Lauro, Luigi
AU - Mazzotta, Marco
AU - Barba, Maddalena
AU - Fanciulli, Maurizio
AU - Vitale, Ilio
AU - De Maria Marchiano, Ruggero
AU - Ciliberto, Gennaro
AU - Maugeri-Saccà, Marcello
PY - 2018
Y1 - 2018
N2 - Whether PD-L1 expression is associated with survival outcomes in gastric cancer (GC) is controversial. The inhibition of the PD-1/PD-L1 pathway is effective against genomically unstable tumors. Hypothesizing that also the clinical significance of PD-L1 might be dependent on the activation of molecular circuits ensuring genomic stability, we evaluated PD-L1 expression in tissue samples from 72 advanced GC patients treated with first-line chemotherapy. Samples were already characterized for DNA damage repair (DDR) component expression (pATM, pChk1, pWee1, γ-H2AX and pRPA2) along with mutations in DDR-linked genes (TP53 and ARID1A). Overall, PD-L1 expression was not associated with progression-free survival (PFS) and overall survival (OS), independently on whether we considered its expression in tumor cells (PD-L1-TCs) or in the immune infiltrate (PD-L1-TILs). In subgroup analysis, positive PD-L1-TC immunostaining was associated with better PFS in patients whose tumors did not carry DDR activation (multivariate Cox: HR 0.34, 95%CI: 0.15–0.76, p = 0.008). This subset (DDRoff) was characterized by negative pATM expression or the presence of ARID1A mutations. Conversely, the relationship between PD-L1-TC expression and PFS was lost in a molecular scenario denoting DDR activation (DDRon), as defined by concomitant pATM expression and ARID1A wild-type form. Surprisingly, while PD-L1-TC expression was associated with better OS in the DDRoffsubset (multivariate Cox: HR 0.41, 95% CI: 0.17–0.96, p = 0.039), in the DDRonsubgroup we observed an opposite impact on OS (multivariate Cox: HR 2.56, 95%CI: 1.06–6.16, p = 0.036). Thus, PD-L1-TC expression may impact survival outcomes in GC on the basis of the activation/inactivation of genome-safeguarding pathways.
AB - Whether PD-L1 expression is associated with survival outcomes in gastric cancer (GC) is controversial. The inhibition of the PD-1/PD-L1 pathway is effective against genomically unstable tumors. Hypothesizing that also the clinical significance of PD-L1 might be dependent on the activation of molecular circuits ensuring genomic stability, we evaluated PD-L1 expression in tissue samples from 72 advanced GC patients treated with first-line chemotherapy. Samples were already characterized for DNA damage repair (DDR) component expression (pATM, pChk1, pWee1, γ-H2AX and pRPA2) along with mutations in DDR-linked genes (TP53 and ARID1A). Overall, PD-L1 expression was not associated with progression-free survival (PFS) and overall survival (OS), independently on whether we considered its expression in tumor cells (PD-L1-TCs) or in the immune infiltrate (PD-L1-TILs). In subgroup analysis, positive PD-L1-TC immunostaining was associated with better PFS in patients whose tumors did not carry DDR activation (multivariate Cox: HR 0.34, 95%CI: 0.15–0.76, p = 0.008). This subset (DDRoff) was characterized by negative pATM expression or the presence of ARID1A mutations. Conversely, the relationship between PD-L1-TC expression and PFS was lost in a molecular scenario denoting DDR activation (DDRon), as defined by concomitant pATM expression and ARID1A wild-type form. Surprisingly, while PD-L1-TC expression was associated with better OS in the DDRoffsubset (multivariate Cox: HR 0.41, 95% CI: 0.17–0.96, p = 0.039), in the DDRonsubgroup we observed an opposite impact on OS (multivariate Cox: HR 2.56, 95%CI: 1.06–6.16, p = 0.036). Thus, PD-L1-TC expression may impact survival outcomes in GC on the basis of the activation/inactivation of genome-safeguarding pathways.
KW - ARID1A
KW - ATM
KW - DNA damage repair
KW - Gastric cancer
KW - Immunology
KW - Immunology and Allergy
KW - Oncology
KW - PD-L1
KW - chemotherapy
KW - genomic stability
KW - ARID1A
KW - ATM
KW - DNA damage repair
KW - Gastric cancer
KW - Immunology
KW - Immunology and Allergy
KW - Oncology
KW - PD-L1
KW - chemotherapy
KW - genomic stability
UR - http://hdl.handle.net/10807/126731
UR - http://www.tandfonline.com/loi/koni20
U2 - 10.1080/2162402X.2018.1457602
DO - 10.1080/2162402X.2018.1457602
M3 - Article
SN - 2162-4011
VL - 7
SP - N/A-N/A
JO - OncoImmunology
JF - OncoImmunology
ER -