| Contributors: |
Cortellini, A.; Giusti, R.; Filetti, M.; Citarella, F.; Adamo, V.; Santini, D.; Buti, S.; Nigro, O.; Cantini, L.; Di Maio, M.; Aerts, J. G. J. V.; Bria, E.; Bertolini, F.; Ferrara, M. G.; Ghidini, M.; Grossi, F.; Guida, A.; Berardi, R.; Morabito, A.; Genova, C.; Mazzoni, F.; Antonuzzo, L.; Gelibter, A.; Marchetti, P.; Chiari, R.; Macerelli, M.; Rastelli, F.; Della Gravara, L.; Gori, S.; Tuzi, A.; De Tursi, M.; Di Marino, P.; Mansueto, G.; Pecci, F.; Zoratto, F.; Ricciardi, S.; Migliorino, M. R.; Passiglia, F.; Metro, G.; Spinelli, G. P.; Banna, G. L.; Friedlaender, A.; Addeo, A.; Ficorella, C.; Porzio, G.; Tiseo, M.; Russano, M.; Russo, A.; Pinato, D. J. |
| Description: |
Family history of cancer (FHC) is a hallmark of cancer risk and an independent predictor of outcome, albeit with uncertain biologic 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/negative, 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/negative, 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. |