TY - JOUR
T1 - High familial burden of cancer correlates with improved outcome from immunotherapy in patients with NSCLC independent of somatic DNA damage response gene status
AU - Cortellini, Alessio
AU - Giusti, Raffaele
AU - Filetti, Marco
AU - Citarella, Fabrizio
AU - Adamo, Vincenzo
AU - Santini, Daniele
AU - Buti, Sebastiano
AU - Nigro, Olga
AU - Cantini, Luca
AU - Di Maio, Massimo
AU - Aerts, Joachim G.J.V.
AU - Bria, Emilio
AU - Bertolini, Federica
AU - Ferrara, Miriam Grazia
AU - Ghidini, Michele
AU - Grossi, Francesco
AU - Guida, Annalisa
AU - Berardi, Rossana
AU - Morabito, Alessandro
AU - Genova, Carlo
AU - Mazzoni, Francesca
AU - Antonuzzo, Lorenzo
AU - Gelibter, Alain
AU - Marchetti, Paolo
AU - Chiari, Rita
AU - Macerelli, Marianna
AU - Rastelli, Francesca
AU - Della Gravara, Luigi
AU - Gori, Stefania
AU - Tuzi, Alessandro
AU - De Tursi, Michele
AU - Di Marino, Pietro
AU - Mansueto, Giovanni
AU - Pecci, Federica
AU - Zoratto, Federica
AU - Ricciardi, Serena
AU - Migliorino, Maria Rita
AU - Passiglia, Francesco
AU - Metro, Giulio
AU - Spinelli, Gian Paolo
AU - Banna, Giuseppe L.
AU - Friedlaender, Alex
AU - Addeo, Alfredo
AU - Ficorella, Corrado
AU - Porzio, Giampiero
AU - Tiseo, Marcello
AU - Russano, Marco
AU - Russo, Alessandro
AU - Pinato, David James
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
KW - DDR genes
KW - Family history of cancer
KW - Immune checkpoint inhibitors
KW - Immunotherapy
KW - NSCLC
KW - Pembrolizumab
UR - http://www.scopus.com/inward/record.url?scp=85123438477&partnerID=8YFLogxK
U2 - 10.1186/s13045-022-01226-2
DO - 10.1186/s13045-022-01226-2
M3 - Letter
SN - 1756-8722
VL - 15
JO - Journal of Hematology and Oncology
JF - Journal of Hematology and Oncology
IS - 1
M1 - 9
ER -