作者: Cortellini, Alessio ; Giusti, Raffaele ; Filetti, Marco ; Citarella, Fabrizio ; Adamo, Vincenzo ; Santini, Daniele ; Buti, Sebastiano ; Nigro, Olga ; Cantini, Luca ; Di Maio, Massimo ; Aerts, Joachim G. J. V. ; Bria, Emilio ; Bertolini, Federica ; Ferrara, Miriam Grazia ; Ghidini, Michele ; Grossi, Francesco ; Guida, Annalisa ; Berardi, Rossana ; Morabito, Alessandro ; Genova, Carlo ; Mazzoni, Francesca ; Antonuzzo, Lorenzo ; Gelibter, Alain ; Marchetti, Paolo ; Chiari, Rita ; Macerelli, Marianna ; Rastelli, Francesca ; Della Gravara, Luigi ; Gori, Stefania ; Tuzi, Alessandro ; De Tursi, Michele ; Di Marino, Pietro ; Mansueto, Giovanni ; Pecci, Federica ; Zoratto, Federica ; Ricciardi, Serena ; Migliorino, Maria Rita ; Passiglia, Francesco ; Metro, Giulio ; Spinelli, Gian Paolo ; Banna, Giuseppe L. ; Friedlaender, Alex ; Addeo, Alfredo ; Ficorella, Corrado ; Porzio, Giampiero ; Tiseo, Marcello ; Russano, Marco ; Russo, Alessandro ; Pinato, David James
Abstract: Family history of cancer (FHC) is a hallmark of cancer risk and an independent predictor of outcome, albeit with uncertain biol. foundations. We previously showed that FHC-high patients experienced prolonged overall (OS) and progression-free survival (PFS) following PD-1/PD-L1 checkpoint inhibitors. To validate our findings in patients with NSCLC, we evaluated two multicenter cohorts of patients with metastatic NSCLC receiving either first-line pembrolizumab or chemotherapy. From each cohort, 607 patients were randomly case-control matched accounting for FHC, age, performance status, and disease burden. Compared to FHC-low/neg., FHC-high patients experienced longer OS (HR 0.67 [95% CI 0.46-0.95], p = 0.0281), PFS (HR 0.65 [95% CI 0.48-0.89]; p = 0.0074) and higher disease control rates (DCR, 86.4% vs 67.5%, p = 0.0096), within the pembrolizumab cohort. No significant associations were found between FHC and OS/PFS/DCR within the chemotherapy cohort. We explored the association between FHC and somatic DNA damage response (DDR) gene alterations as underlying mechanism to our findings in a parallel cohort of 118 NSCLC, 16.9% of whom were FHC-high. The prevalence of ≥ 1 somatic DDR gene mutation was 20% and 24.5% (p = 0.6684) in FHC-high vs. FHC-low/neg., with no differences in tumor mutational burden (6.0 vs. 7.6 Mut/Mb, p = 0.6018) and tumor cell PD-L1 expression. FHC-high status identifies NSCLC patients with improved outcomes from pembrolizumab but not chemotherapy, independent of somatic DDR gene status. Prospective studies evaluating FHC alongside germline genetic testing are warranted.