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

1
Second Department of Medical Oncology, Euromedica General Clinic of Thessaloniki, 54645 Thessaloniki, Greece
2
European University Cyprus, 1516 Engomi, Cyprus
3
NIPD Genetics Limited, 2409 Nicosia, Cyprus
4
Section of Biostatistics, Hellenic Cooperative Oncology Group, Data Office, 11526 Athens, Greece
5
Oncology Section, Second Department of Internal Medicine, Hippokration Hospital, 11527 Athens, Greece
6
Third Department of Medical Oncology, Agii Anargiri Cancer Hospital, 14564 Athens, Greece
7
Oncology Unit, Hippokration Hospital, 11527 Athens, Greece
8
Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, 56429 Thessaloniki, Greece
9
Section of Medical Oncology, Department of Internal Medicine, Attikon University Hospital, Faculty of Medicine, National and Kapodistrian University of Athens School of Medicine, 12462 Athens, Greece
10
Oncology Unit, Aretaieion Hospital, National and Kapodistrian University of Athens School of Medicine, 11528 Athens, Greece
11
Second Department of Medical Oncology, Metropolitan Hospital, 18547 Piraeus, Greece
12
Department of Radiation Oncology, German Oncology Center, European University Cyprus, 4108 Limassol, Cyprus
13
Fourth Department of Internal Medicine, Hematology-Oncology Unit, Attikon University Hospital, National and Kapodistrian University of Athens, 12462 Athens, Greece
14
Department of Medical Oncology, University Hospital of Ioannina, Medical School, 45500 Ioannina, Greece
15
First Department of Surgery, General Hospital Konstantopouleio Agia Olga, 14233 Athens, Greece
16
Second Department of Medical Oncology, Agii Anargiri Cancer Hospital, 14564 Athens, Greece
17
First Department of Medical Oncology, Metropolitan Hospital, 18547 Piraeus, Greece
18
Second Department of Medical Oncology, Hygeia Hospital, 15123 Athens, Greece
19
Second Department of Internal Medicine, Agios Savvas Cancer Hospital, 11522 Athens, Greece
20
First Department of Medicine, Laiko General Hospital, National and Kapodistrian University of Athens School of Medicine, 11528 Athens, Greece
21
Oncology Department, General Hospital of Chania, 73300 Crete, Greece
22
Department of Medical Oncology, 251 Airforce General Hospital, 11525 Athens, Greece
23
Third Department of Medical Oncology, Hygeia Hospital, 15123 Athens, Greece
24
Asklepios Oncology Department, 71303 Heraklion, Crete, Greece
25
Oncology Clinic, Mitera Hospital, 15123 Athens, Greece
26
Medical Oncology Unit, S. Andrew Hospital, 26335 Patras, Greece
27
Molecular Diagnostics Laboratory, InRASTES, National Centre for Scientific Research “Demokritos”, 15341 Athens, Greece
28
Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, 54006 Thessaloniki, Greece
29
Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
30
Medical School, University of Nicosia, 2417 Nicosia, Cyprus
*
Author to whom correspondence should be addressed.
The authors contributed equally to this work.
Cancers 2021, 13(2), 198; https://doi.org/10.3390/cancers13020198
Received: 12 November 2020 / Revised: 24 December 2020 / Accepted: 5 January 2021 / Published: 8 January 2021
Data on the prognostic and predictive value of germline cancer predisposing pathogenic/likely pathogenic variants (P/LPVs) in patients with pancreatic ductal adenocarcinoma is limited. This research was a study of germline testing of 62 cancer susceptibility genes in 549 unselected patients with pancreatic cancer. We reported a significant proportion of European patients with pancreatic cancer carrying P/LPVs in clinically significant genes, irrespectively of age, family history or disease stage. Importantly, P/LPVs were identified in pancreatic cancer-associated genes and in homologous recombination repair genes in 4.0% and 7.7% of patients, respectively. The presence of any P/LPVs was associated with improved overall survival univariately; however, it did not retain its independent prognostic significance in multivariate analysis. The presence of P/LPVs in homologous recombination repair genes did not predict benefit from platinum-based treatment. These results should be prospectively validated through universal genetic testing of patients with pancreatic cancer, taking into consideration the administration of newer treatments.
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. View Full-Text
Keywords: BRCA2; inherited; overall survival; predictive; prognostic BRCA2; inherited; overall survival; predictive; prognostic
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Figure 1

MDPI and ACS Style

Fountzilas, E.; Eliades, A.; Koliou, G.-A.; Achilleos, A.; Loizides, C.; Tsangaras, K.; Pectasides, D.; Sgouros, J.; Papakostas, P.; Rallis, G.; Psyrri, A.; Papadimitriou, C.; Oikonomopoulos, G.; Ferentinos, K.; Koumarianou, A.; Zarkavelis, G.; Dervenis, C.; Aravantinos, G.; Bafaloukos, D.; Kosmidis, P.; Papaxoinis, G.; Theochari, M.; Varthalitis, I.; Kentepozidis, N.; Rigakos, G.; Saridaki, Z.; Nikolaidi, A.; Christopoulou, A.; Fostira, F.; Samantas, E.; Kypri, E.; Ioannides, M.; Koumbaris, G.; Fountzilas, G.; Patsalis, P.C. Clinical Significance of Germline Cancer Predisposing Variants in Unselected Patients with Pancreatic Adenocarcinoma. Cancers 2021, 13, 198. https://doi.org/10.3390/cancers13020198

AMA Style

Fountzilas E, Eliades A, Koliou G-A, Achilleos A, Loizides C, Tsangaras K, Pectasides D, Sgouros J, Papakostas P, Rallis G, Psyrri A, Papadimitriou C, Oikonomopoulos G, Ferentinos K, Koumarianou A, Zarkavelis G, Dervenis C, Aravantinos G, Bafaloukos D, Kosmidis P, Papaxoinis G, Theochari M, Varthalitis I, Kentepozidis N, Rigakos G, Saridaki Z, Nikolaidi A, Christopoulou A, Fostira F, Samantas E, Kypri E, Ioannides M, Koumbaris G, Fountzilas G, Patsalis PC. Clinical Significance of Germline Cancer Predisposing Variants in Unselected Patients with Pancreatic Adenocarcinoma. Cancers. 2021; 13(2):198. https://doi.org/10.3390/cancers13020198

Chicago/Turabian Style

Fountzilas, Elena; Eliades, Alexia; Koliou, Georgia-Angeliki; Achilleos, Achilleas; Loizides, Charalambos; Tsangaras, Kyriakos; Pectasides, Dimitrios; Sgouros, Joseph; Papakostas, Pavlos; Rallis, Grigorios; Psyrri, Amanda; Papadimitriou, Christos; Oikonomopoulos, Georgios; Ferentinos, Konstantinos; Koumarianou, Anna; Zarkavelis, George; Dervenis, Christos; Aravantinos, Gerasimos; Bafaloukos, Dimitrios; Kosmidis, Paris; Papaxoinis, George; Theochari, Maria; Varthalitis, Ioannis; Kentepozidis, Nikolaos; Rigakos, Georgios; Saridaki, Zacharenia; Nikolaidi, Adamantia; Christopoulou, Athina; Fostira, Florentia; Samantas, Epaminontas; Kypri, Elena; Ioannides, Marios; Koumbaris, George; Fountzilas, George; Patsalis, Philippos C. 2021. "Clinical Significance of Germline Cancer Predisposing Variants in Unselected Patients with Pancreatic Adenocarcinoma" Cancers 13, no. 2: 198. https://doi.org/10.3390/cancers13020198

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