Digging into the NGS Information from a Large-Scale South European Population with Metastatic/Unresectable Pancreatic Ductal Adenocarcinoma: A Real-World Genomic Depiction

Dimitrios C Ziogas; Eirini Papadopoulou; Helen Gogas; Stratigoula Sakellariou; Evangellos Felekouras; Charalampos Theocharopoulos; Dimitra T Stefanou; Maria Theochari; Ioannis Boukovinas; Dimitris Matthaios; Anna Koumarianou; Eleni Zairi; Michalis Liontos; Konstantinos Koutsoukos; Vasiliki Metaxa-Mariatou; George Kapetsis; Angeliki Meintani; Georgios N Tsaousis; George Nasioulas

doi:10.3390/cancers16010002

Digging into the NGS Information from a Large-Scale South European Population with Metastatic/Unresectable Pancreatic Ductal Adenocarcinoma: A Real-World Genomic Depiction

Cancers (Basel). 2023 Dec 19;16(1):2. doi: 10.3390/cancers16010002.

Authors

Dimitrios C Ziogas¹, Eirini Papadopoulou², Helen Gogas¹, Stratigoula Sakellariou³, Evangellos Felekouras⁴, Charalampos Theocharopoulos¹, Dimitra T Stefanou¹, Maria Theochari¹, Ioannis Boukovinas⁵, Dimitris Matthaios⁶, Anna Koumarianou⁷, Eleni Zairi⁸, Michalis Liontos⁹, Konstantinos Koutsoukos⁹, Vasiliki Metaxa-Mariatou², George Kapetsis², Angeliki Meintani², Georgios N Tsaousis², George Nasioulas²

Affiliations

¹ First Department of Internal Medicine, Laikon General Hospital, School of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece.
² GeneKor Medical S.A., 15344 Gerakas, Greece.
³ First Department of Pathology, School of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece.
⁴ First Department of Surgery, Laikon General Hospital, School of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece.
⁵ Department of Medical Oncology, Bioclinic Hospital, 54622 Thessaloniki, Greece.
⁶ Oncology Department, General Hospital of Rhodes, 85133 Rhodes, Greece.
⁷ Hematology Oncology Unit, Fourth Department of Internal Medicine, School of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece.
⁸ Oncology Department, St. Lukes Hospital, 55236 Thessaloniki, Greece.
⁹ Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece.

Abstract

Despite ongoing oncological advances, pancreatic ductal adenocarcinoma (PDAC) continues to have an extremely poor prognosis with limited targeted and immunotherapeutic options. Its genomic background has not been fully characterized yet in large-scale populations all over the world. Methods: Replicating a recent study from China, we collected tissue samples from consecutive Greek patients with pathologically-confirmed metastatic/unresectable PDAC and retrospectively investigated their genomic landscape using next generation sequencing (NGS). Findings: From a cohort of 409 patients, NGS analysis was successfully achieved in 400 cases (56.50% males, median age: 61.8 years). Consistent with a previous study, KRAS was the most frequently mutated gene in 81.50% of tested samples, followed by TP53 (50.75%), CDKN2 (8%), and SMAD4 (7.50%). BRCA1/2 variants with on-label indications were detected in 2%, and 87.50% carried a variant associated with off-label treatment (KRAS, ERBB2, STK11, or HRR-genes), while 3.5% of the alterations had unknown/preliminary-studied actionability (TP53/CDKN2A). Most of HRR-alterations were in intermediate- and low-risk genes (CHEK2, RAD50, RAD51, ATM, FANCA, FANCL, FANCC, BAP1), with controversial actionability: 8% harbored a somatic non-BRCA1/2 alteration, 6 cases had a high-risk alteration (PALB2, RAD51C), and one co-presented a PALB2/BRCA2 alteration. Elevated LOH was associated with HRR-mutated status and TP53 mutations while lowered LOH was associated with KRAS alterations. Including TMB/MSI data, the potential benefit from an NGS-oriented treatment was increased from 1.91% to 13.74% (high-MSI: 0.3%, TMB > 10 muts/MB: 12.78%). TMB was slightly increased in females (4.75 vs. 4.46 muts/MB) and in individuals with age > 60 (4.77 vs. 4.40 muts/MB). About 28.41% showed PD-L1 > 1% either in tumor or immune cells, 15.75% expressed PD-L1 ≥ 10%, and only 1.18% had PD-L1 ≥ 50%. This is the largest depiction of real-world genomic characteristics of European patients with PDAC, which offers some useful clinical and research insights.

Keywords: HRR; KRAS; genomic mutation; next generation sequencing; pancreatic ductal adenocarcinoma.

Grants and funding

This research received no external funding.