High familial burden of cancer correlates with improved outcome from immunotherapy in patients with NSCLC independent of somatic DNA damage response gene status.

Abstract

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.

• Authors: Alessio Cortellini, Raffaele Giusti, Marco Filetti, Fabrizio Citarella, Vincenzo Adamo, Daniele Santini, Sebastiano Buti, Olga Nigro, Luca Cantini, Massimo Di Maio, Joachim G J V Aerts, Emilio Bria, Federica Bertolini, Miriam Grazia Ferrara, Michele Ghidini, Francesco Grossi, Annalisa Guida, Rossana Berardi, Alessandro Morabito, Carlo Genova, Francesca Mazzoni, Lorenzo Antonuzzo, Alain Gelibter, Paolo Marchetti, Rita Chiari, Marianna Macerelli, Francesca Rastelli, Luigi Della Gravara, Stefania Gori, Alessandro Tuzi, Michele De Tursi, Pietro Di Marino, Giovanni Mansueto, Federica Pecci, Federica Zoratto, Serena Ricciardi, Maria Rita Migliorino, Francesco Passiglia, Giulio Metro, Gian Paolo Spinelli, Giuseppe L Banna, Alex Friedlaender, Alfredo Addeo, Corrado Ficorella, Giampiero Porzio, Marcello Tiseo, Marco Russano, Alessandro Russo, David James Pinato
• Journal: Journal of hematology & oncology (J Hematol Oncol) Vol. 15 Issue 1 Pg. 9 (01 21 2022) ISSN: 1756-8722 [Electronic] England
• PMID: 35062993 (Publication Type: Letter, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Immune Checkpoint Inhibitors

Topics

• Carcinoma, Non-Small-Cell Lung (genetics, therapy)
• DNA Damage
• Female
• Humans
• Immune Checkpoint Inhibitors (therapeutic use)
• Immunotherapy
• Lung Neoplasms (genetics, therapy)
• Male
• Treatment Outcome