학술논문
Digging into the NGS Information from a Large-Scale South European Population with Metastatic/Unresectable Pancreatic Ductal Adenocarcinoma: A Real-World Genomic Depiction
Document Type
Academic Journal
Author
Ziogas, Dimitrios C.; Papadopoulou, Eirini; Gogas, Helen; Sakellariou, Stratigoula; Felekouras, Evangellos; Theocharopoulos, Charalampos; Stefanou, Dimitra T.; Theochari, Maria; Boukovinas, Ioannis; Matthaios, Dimitris; Koumarianou, Anna; Zairi, Eleni; Liontos, Michalis; Koutsoukos, Konstantinos; Metaxa-Mariatou, Vasiliki; Kapetsis, George; Meintani, Angeliki; Tsaousis, Georgios N.; Nasioulas, George
Source
Cancers. December 2023, Vol. 16 Issue 1
Subject
Language
English
ISSN
2072-6694
Abstract
Author(s): Dimitrios C. Ziogas (corresponding author) [1,*,†]; Eirini Papadopoulou [2,†]; Helen Gogas [1]; Stratigoula Sakellariou [3]; Evangellos Felekouras [4]; Charalampos Theocharopoulos [1]; Dimitra T. Stefanou [1]; Maria Theochari [1]; Ioannis [...]
Even in the era of precision medicine, the genomic background of pancreatic ductal adenocarcinoma has not yet been fully elucidated in large-scale populations all over the world, including Europe. The genomic characteristics from 409 Greek/South European patients with PDAC were detected by panel-based NGS and confirmed recurrent somatic alterations in KRAS (81.20%), TP53 (50.75%), CDKN2B (8%) SMAD4 (7.50%), and BRCA1/2 variants (2%), among others. The majority of HRR-alterations were in intermediate- and low-risk genes (CHEK2, RAD50, RAD51, ATM, FANCA, FANCL, FANCC, BAP1), with controversial actionability. Elevated genomic LOH (gLOH) was associated with HRR-mutated status and TP53 mutations, while the lowered gLOH was associated with KRAS alterations. The comprehensive knowledge of NGS status, including TMB, MSI, and PD-L1, increased the possibility of immunotherapy use from 1.91% to 13.74%. TMB was slightly increased in females and in elderly individuals. PD-L1 > 1% either in tumor or immune cells was detected in 28.41%, PD-L1 ≥ 10% in 15.75%, PD-L1 ≥ 50% in 1.18% of cases. This is the largest NGS depiction of real-world genomic characteristics of South European patients with PDAC, which offers some useful clinical and research insights, describing the incidence of potentially targetable and predictive biomarkers and identifying genetic subtypes more susceptible to respond to specific treatments. 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.
Even in the era of precision medicine, the genomic background of pancreatic ductal adenocarcinoma has not yet been fully elucidated in large-scale populations all over the world, including Europe. The genomic characteristics from 409 Greek/South European patients with PDAC were detected by panel-based NGS and confirmed recurrent somatic alterations in KRAS (81.20%), TP53 (50.75%), CDKN2B (8%) SMAD4 (7.50%), and BRCA1/2 variants (2%), among others. The majority of HRR-alterations were in intermediate- and low-risk genes (CHEK2, RAD50, RAD51, ATM, FANCA, FANCL, FANCC, BAP1), with controversial actionability. Elevated genomic LOH (gLOH) was associated with HRR-mutated status and TP53 mutations, while the lowered gLOH was associated with KRAS alterations. The comprehensive knowledge of NGS status, including TMB, MSI, and PD-L1, increased the possibility of immunotherapy use from 1.91% to 13.74%. TMB was slightly increased in females and in elderly individuals. PD-L1 > 1% either in tumor or immune cells was detected in 28.41%, PD-L1 ≥ 10% in 15.75%, PD-L1 ≥ 50% in 1.18% of cases. This is the largest NGS depiction of real-world genomic characteristics of South European patients with PDAC, which offers some useful clinical and research insights, describing the incidence of potentially targetable and predictive biomarkers and identifying genetic subtypes more susceptible to respond to specific treatments. 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.