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.
| Original language | English |
|---|---|
| Article number | 9 |
| Journal | Journal of Hematology and Oncology |
| Volume | 15 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 21 Jan 2022 |
Bibliographical note
Funding Information:Alessio Cortellini is supported by the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre (BRC). David J Pinato is supported by grant funding from the Wellcome Trust Strategic Fund (PS3416) and from the Associazione Italiana per la Ricerca sul Cancro (AIRC MFAG Grant ID 25697) and acknowledges support by the NIHR Imperial Biomedical Research Centre (BRC), the Imperial Experimental Cancer Medicine Centre (ECMC) and the Imperial College Tissue Bank.
Funding Information:
Dr. Alessio Cortellini received speaker fees and grant consultancies by Astrazeneca, MSD, BMS, Roche, Novartis. Dr. Sebastiano Buti received honoraria as speaker at scientific events and advisory role by Bristol-Myers Squibb (BMS), Pfizer; MSD, Ipsen, Roche, Eli-Lilly, AstraZeneca, and Novartis. Dr. Raffaele Giusti received speaker fees and grant consultancies by Astrazeneca and Roche. Dr. Joachim GJV Aerts reports receiving commercial research grants from Amphera and Roche, holds ownership interest (including patents) in Amphera BV, and is a consultant/advisory board member for Amphera, Boehringer Ingelheim, Bristol-Myers Squibb, Eli-Lilly, MSD, and Roche. Dr. Alex Friedlaender received grant consultancies by Roche, Pfizer, Astellas, and BMS. Dr. Francesca Mazzoni received grant consultancies by MSD and Takeda. Dr. Rita Chiari received speaker fees by BMS, MSD, Takeda, Pfizer, Roche, and Astrazeneca. Dr Carlo Genova received speaker fees/grant consultancies by Astrazeneca, BMS, Boehringer-Ingelheim, Roche, and MSD. Dr. Marco Russano received honoraria for scientific events by Roche, Astrazeneca, BMS, MSD and Boehringer Ingelheim. Dr. Emilio Bria received speaker and travel fees from MSD, Astra-Zeneca, Pfizer, Helsinn, Eli-Lilly, BMS, Novartis, and Roche; grant consultancies by Roche and Pfizer. Dr. Alfredo Addeo received grant consultancies by Takeda, MSD, BMJ, Astrazeneca, Roche and Pfizer. Dr. Massimo Di Maio received research funding from Tesaro-GlaxoSmithKline; acted in a consulting/advisory role for Novartis, Pfizer, Eisai, Takeda, Janssen, Astellas, Roche, AstraZeneca. Dr. Marcello Tiseo received speakers’ and consultants’ fee from Astra-Zeneca, Pfizer, Eli-Lilly, BMS, Novartis, Roche, MSD, Boehringer Ingelheim, Otsuka, Takeda, Pierre Fabre, Amgen, Merck. He also received institutional research grants from Astra-Zeneca, Boehringer Ingelheim. Dr. Gian Paolo Spinelli received advisory board/editorial collaboration fees from Novartis, Servier, Teva; Bayer; Genetic, Epionpharma. Dr. David J Pinato received lecture fees from ViiV Healthcare, Bayer Healthcare and travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, Astra Zeneca; received research funding (to institution) from MSD, BMS. All other authors declare no competing interests.
Publisher Copyright:
© 2022, The Author(s).
