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• W4200217680 abstract "BackgroundGermline DDR genes mutations are the most frequently involved mechanism for inherited cancer susceptibility, and we reported that high burden of family history of cancer (FHC), namely FHC-high, was associated with prolonged OS/PFS to PD-1/PD-L1 inhibitors in a multiple-cancer cohort.MethodsWe present the outcome analysis according to FHC from two large multicentre cohorts of patients with metastatic NSCLC receiving either first-line pembrolizumab (PD-L1 expression ≥ 50%) or chemotherapy. Patients were categorized as FHC-high and FHC-low/negative, as previously reported. To explore the association between somatic DDR genes alteration and FHC, we gathered targeted DNA tumour sequencing (FoundationOne CDx assay), from a parallel cohort of patients with NSCLC identifying 24 genes of interest (MLH1-6, PMS2, ATM, ATR, CHEK1-2, BAP1, BARD1, BRCA1-2, BRIP1, PALB2, RAD51-52-51C, FANCA-C-G-L, POLD1, POLE, ERCC4, XRCC2).Results728 and 652 patients were included in the pembrolizumab/chemotherapy cohorts. We performed a perfect random case-control matching between the two cohorts and 607 patients from each cohort were randomly paired on the basis of the FHC, age, ECOG-PS, and burden of disease. As compared to FHC-low/negative patients, FHC high achieved longer OS (HR=0.67, 95%CI: 0.46-0.95; p = 0.028), longer PFS (HR=0.65, 95%CI: 0.48-0.89; p = 0.007) and higher DCR (86.4 vs 67.5, p = 0.009), within the pembrolizumab cohort. On the contrary, no significant associations were found between FHC and OS (p = 0.075), PFS (p = 0.001), and DCR (p = 0.120), within the chemotherapy cohort. 118 patients were included in the DDR cohort, of which 20 FHC-high (16.9%) and 98 FHC-low/negative (83.1%). The prevalence of at least one DDR genes somatic mutations was 20% and 24.5% for FHC-low/negative and FHC-high patients, respectively (p = 0.668). The median TMBs were 6 and 7.6 Mut/Mb for FHC-high and low/negative (p = 0.6018), no association with PD-L1 was reported.ConclusionsFHC-high identifies NSCLC with improved outcomes to pembrolizumab but not chemotherapy, suggesting its role as a surrogate marker. Somatic DDR genes are not associated with FHC and further investigations with broader germline testing are warranted.Legal entity responsible for the studyImperial College London and University of L'Aquila.FundingHas not received any funding.DisclosureA. Cortellini: Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: AstraZeneca. D.J. Pinato: Financial Interests, Personal, Invited Speaker: ViiV Healthcare; Financial Interests, Personal, Invited Speaker: Bayer; Financial Interests, Personal, Advisory Board: Mina Therapeutics; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Institutional, Funding: MSD; Financial Interests, Institutional, Funding: Bristol Myers Squibb. All other authors have declared no conflicts of interest. BackgroundGermline DDR genes mutations are the most frequently involved mechanism for inherited cancer susceptibility, and we reported that high burden of family history of cancer (FHC), namely FHC-high, was associated with prolonged OS/PFS to PD-1/PD-L1 inhibitors in a multiple-cancer cohort. Germline DDR genes mutations are the most frequently involved mechanism for inherited cancer susceptibility, and we reported that high burden of family history of cancer (FHC), namely FHC-high, was associated with prolonged OS/PFS to PD-1/PD-L1 inhibitors in a multiple-cancer cohort. MethodsWe present the outcome analysis according to FHC from two large multicentre cohorts of patients with metastatic NSCLC receiving either first-line pembrolizumab (PD-L1 expression ≥ 50%) or chemotherapy. Patients were categorized as FHC-high and FHC-low/negative, as previously reported. To explore the association between somatic DDR genes alteration and FHC, we gathered targeted DNA tumour sequencing (FoundationOne CDx assay), from a parallel cohort of patients with NSCLC identifying 24 genes of interest (MLH1-6, PMS2, ATM, ATR, CHEK1-2, BAP1, BARD1, BRCA1-2, BRIP1, PALB2, RAD51-52-51C, FANCA-C-G-L, POLD1, POLE, ERCC4, XRCC2). We present the outcome analysis according to FHC from two large multicentre cohorts of patients with metastatic NSCLC receiving either first-line pembrolizumab (PD-L1 expression ≥ 50%) or chemotherapy. Patients were categorized as FHC-high and FHC-low/negative, as previously reported. To explore the association between somatic DDR genes alteration and FHC, we gathered targeted DNA tumour sequencing (FoundationOne CDx assay), from a parallel cohort of patients with NSCLC identifying 24 genes of interest (MLH1-6, PMS2, ATM, ATR, CHEK1-2, BAP1, BARD1, BRCA1-2, BRIP1, PALB2, RAD51-52-51C, FANCA-C-G-L, POLD1, POLE, ERCC4, XRCC2). Results728 and 652 patients were included in the pembrolizumab/chemotherapy cohorts. We performed a perfect random case-control matching between the two cohorts and 607 patients from each cohort were randomly paired on the basis of the FHC, age, ECOG-PS, and burden of disease. As compared to FHC-low/negative patients, FHC high achieved longer OS (HR=0.67, 95%CI: 0.46-0.95; p = 0.028), longer PFS (HR=0.65, 95%CI: 0.48-0.89; p = 0.007) and higher DCR (86.4 vs 67.5, p = 0.009), within the pembrolizumab cohort. On the contrary, no significant associations were found between FHC and OS (p = 0.075), PFS (p = 0.001), and DCR (p = 0.120), within the chemotherapy cohort. 118 patients were included in the DDR cohort, of which 20 FHC-high (16.9%) and 98 FHC-low/negative (83.1%). The prevalence of at least one DDR genes somatic mutations was 20% and 24.5% for FHC-low/negative and FHC-high patients, respectively (p = 0.668). The median TMBs were 6 and 7.6 Mut/Mb for FHC-high and low/negative (p = 0.6018), no association with PD-L1 was reported. 728 and 652 patients were included in the pembrolizumab/chemotherapy cohorts. We performed a perfect random case-control matching between the two cohorts and 607 patients from each cohort were randomly paired on the basis of the FHC, age, ECOG-PS, and burden of disease. As compared to FHC-low/negative patients, FHC high achieved longer OS (HR=0.67, 95%CI: 0.46-0.95; p = 0.028), longer PFS (HR=0.65, 95%CI: 0.48-0.89; p = 0.007) and higher DCR (86.4 vs 67.5, p = 0.009), within the pembrolizumab cohort. On the contrary, no significant associations were found between FHC and OS (p = 0.075), PFS (p = 0.001), and DCR (p = 0.120), within the chemotherapy cohort. 118 patients were included in the DDR cohort, of which 20 FHC-high (16.9%) and 98 FHC-low/negative (83.1%). The prevalence of at least one DDR genes somatic mutations was 20% and 24.5% for FHC-low/negative and FHC-high patients, respectively (p = 0.668). The median TMBs were 6 and 7.6 Mut/Mb for FHC-high and low/negative (p = 0.6018), no association with PD-L1 was reported. ConclusionsFHC-high identifies NSCLC with improved outcomes to pembrolizumab but not chemotherapy, suggesting its role as a surrogate marker. Somatic DDR genes are not associated with FHC and further investigations with broader germline testing are warranted. FHC-high identifies NSCLC with improved outcomes to pembrolizumab but not chemotherapy, suggesting its role as a surrogate marker. Somatic DDR genes are not associated with FHC and further investigations with broader germline testing are warranted." @default.
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• W4200217680 title "10P Family history of cancer correlates with improved outcome from immunotherapy in NSCLC independent of somatic DNA damage response gene status" @default.
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