Clinical Significance of Germline Cancer Predisposing Variants in Unselected Patients with Pancreatic Adenocarcinoma

Elena Fountzilas, Alexia Eliades, Georgia-Angeliki Koliou, Achilleas Achilleos, Charalambos Loizides, Kyriakos Tsangaras, Dimitrios Pectasides, Joseph Sgouros, Pavlos Papakostas, Grigorios Rallis, Amanda Psyrri, Christos Papadimitriou, Georgios Oikonomopoulos, Konstantinos Ferentinos, Anna Koumarianou, George Zarkavelis, Christos Dervenis, Gerasimos Aravantinos, Dimitrios Bafaloukos, Paris Kosmidis, George Papaxoinis, Maria Theochari, Ioannis Varthalitis, Nikolaos Kentepozidis, Georgios Rigakos, Zacharenia Saridaki, Adamantia Nikolaidi, Athina Christopoulou, Florentia Fostira, Epaminontas Samantas, Elena Kypri, Marios Ioannides, George Koumbaris, George Fountzilas, Philippos C Patsalis, Elena Fountzilas, Alexia Eliades, Georgia-Angeliki Koliou, Achilleas Achilleos, Charalambos Loizides, Kyriakos Tsangaras, Dimitrios Pectasides, Joseph Sgouros, Pavlos Papakostas, Grigorios Rallis, Amanda Psyrri, Christos Papadimitriou, Georgios Oikonomopoulos, Konstantinos Ferentinos, Anna Koumarianou, George Zarkavelis, Christos Dervenis, Gerasimos Aravantinos, Dimitrios Bafaloukos, Paris Kosmidis, George Papaxoinis, Maria Theochari, Ioannis Varthalitis, Nikolaos Kentepozidis, Georgios Rigakos, Zacharenia Saridaki, Adamantia Nikolaidi, Athina Christopoulou, Florentia Fostira, Epaminontas Samantas, Elena Kypri, Marios Ioannides, George Koumbaris, George Fountzilas, Philippos C Patsalis

Abstract

Our aim was to determine the prevalence, prognostic and predictive role of germline pathogenic/likely pathogenic variants (P/LPVs) in cancer predisposing genes in patients with pancreatic ductal adenocarcinoma (PDAC). Germline testing of 62 cancer susceptibility genes was performed on unselected patients diagnosed from 02/2003 to 01/2020 with PDAC, treated at Hellenic Cooperative Oncology Group (HeCOG)-affiliated Centers. The main endpoints were prevalence of P/LPVs and overall survival (OS). P/LPVs in PDAC-associated and homologous recombination repair (HRR) genes were identified in 22 (4.0%) and 42 (7.7%) of 549 patients, respectively. P/LPVs were identified in 16 genes, including ATM (11, 2.0%) and BRCA2 (6, 1.1%), while 19 patients (3.5%) were heterozygotes for MUTYH P/LPVs and 9 (1.6%) carried the low-risk allele, CHEK2 p.(Ile157Thr). Patients carrying P/LPVs had improved OS compared to non-carriers (22.6 vs. 13.9 months, p = 0.006). In multivariate analysis, there was a trend for improved OS in P/LPV carriers (p = 0.063). The interaction term between platinum exposure and mutational status of HRR genes was not significant (p-value = 0.35). A significant proportion of patients with PDAC carries clinically relevant germline P/LPVs, irrespectively of age, family history or disease stage. The predictive role of these P/LPVs has yet to be defined. ClinicalTrials.gov Identifier: NCT03982446.

Keywords: BRCA2; inherited; overall survival; predictive; prognostic.

Conflict of interest statement

E.F.: Stock ownership: GENPREX INC, ARIAD, Deciphera Pharmaceuticals, Inc. Travel grant: Merck, Pfizer, and K.A.M Oncology/Hematology. Advisory: LEO Pharma. Speaker fees: Roche, Pfizer; AE: Employed by NIPD Genetics; has filed a PCT patent application for the Target-enriched multiplexed parallel analysis for assessment of tumor biomarkers (WO2019/008172A1). A.A.: Employed by NIPD Genetics; has filed a PCT patent application for the Target-enriched multiplexed parallel analysis for assessment of tumor biomarkers (WO2019/008172A1); has filed a PCT patent application for the Enrichment of Targeted Genomic Regions for Multiplexed Parallel Analysis (WO2019/008148A9). C.L.: Employed by NIPD Genetics. K.T.: Employed by NIPD Genetics, has filed a PCT patent application for the Target-enriched multiplexed parallel analysis for assessment of tumor biomarkers (WO2019/008172A1), has filed a PCT patent application for the Enrichment of Targeted Genomic Regions for Multiplexed Parallel Analysis (WO2019/008148A9). D.P.: Advisory Role: Roche, MSD, Astellas. Honoraria: Roche, MSD, Astellas. P.P.: Advisory Role: Roche, Merck, Genesis Pharmaceuticals, Honoraria: Roche, Merck. A.P.: Consultation Fees: Amgen, Merck Serono, Roche, BMS, Astra Zeneca, MSD. Honoraria: Amgen, Merck Serono, Roche, BMS, Astra Zeneca, MSD, Research funds: BMS, Kura. C.P.: Speaker honoraria and honoraria for consultancy in advisory boards: Novartis, AstraZeneca, Genesis, MSD, Amgen, Pfizer, Merck, Roche; Research grants: BMS, Roche. A.K.: Advisory Role: Genesis Pharma. Honoraria: Pfizer. Speaker’s bureau: Roche, Research Funding: Merck, Travel: MSD, Educational grants: Novartis, Pfizer, Merck, Roche, BMS, MSD, Genesis, and Ipsen. G.A.: Advisory Boards: Novartis, BMS, Roche Hellas, Astra Zeneca, Sanofi, Amgen, Genesis Pharma, Merck, Pfizer; PK: Honoraria: Novartis, MSD, Pfizer. Travel: Pfizer, MSD, Genesis. A.N.: Advisory Board and Speaker fees: Pfizer, Novartis. E.S.: Advisory Board of Merck, MSD, Asta-Zeneca, Roche, Amgen and Genesis. E.K.: Employed by NIPD Genetics; has filed a PCT patent application for the Target-enriched multiplexed parallel analysis for assessment of tumor biomarkers (WO2019/008172A1); has filed a PCT patent application for the Enrichment of Targeted Genomic Regions for Multiplexed Parallel Analysis (WO2019/008148A9). M.I.: Employed by NIPD Genetics; has filed a PCT patent application for the Target-enriched multiplexed parallel analysis for assessment of tumor biomarkers (WO2019/008172A1), has filed a PCT patent application for the Enrichment of Targeted Genomic Regions for Multiplexed Parallel Analysis (WO2019/008148A9). G.K.: Employed by NIPD Genetics; has filed a PCT patent application for the Target-enriched multiplexed parallel analysis for assessment of tumor biomarkers (WO2019/008172A1); has filed a PCT patent application for the Enrichment of Targeted Genomic Regions for Multiplexed Parallel Analysis (WO2019/008148A9). G.F.: Advisory Board: Pfizer, Sanofi and Roche. Honoraria: Astra Zeneca. Stock ownership: ARIAD and GENPREX. P.C.P.: Employed by NIPD Genetics; has filed a PCT patent application for the Target-enriched multiplexed parallel analysis for assessment of tumor biomarkers (WO2019/008172A1); has filed a PCT patent application for the Enrichment of Targeted Genomic Regions for Multiplexed Parallel Analysis (WO2019/008148A9); The rest of the authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Prevalence of P/LPVs in 549 patients of the study. Single nucleotide variants (SNV), insertions/deletions (Indels) and copy number variant (CNV) detection was performed for the following genes: APC, ATM, BAP1, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, (CDKN2Ap16(INK4A), CDKN2Ap14(ARF)), CHEK2, DDB2, DICER1, EPCAM, ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, GREM1, HOXB13, MEN1, MLH1, MRE11, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, POLD1, POLE, POLH, PTEN, RAD50, RAD51C, RAD51D, RB1, RET, SDHAF2, SDHB, SDHC, SDHD, SLX4, SMAD4, SMARCA4, STK11, TP53, VHL, XPA, XPC. Overall, 62 patients (11.3%) carried ≥1 P/LPV in at least 1 of 16 genes. Three patients carried two P/LPVs; two carried P/LPVs in CHEK2 and MUTYH and one in BRCA1 and MUTYH. The rest of the patients (59) had one P/LPV detected. The percentage of patients carrying a P/LPV in each gene is shown on top of each bar.
Figure 2
Figure 2
Overall survival (OS) in patients with and without P/LPVs; analysis was performed in 540 patients with available outcome data.

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