Real-world genome profiling in Japanese patients with pancreatic ductal adenocarcinoma focusing on HRD implications

Abstract

Pancreatic ductal adenocarcinoma (PDAC) poses significant challenges due to its high mortality, making it a critical area of research. This retrospective observational study aimed to analyze real-world data from comprehensive genome profiling (CGP) of Japanese patients with PDAC, mainly focusing on differences in gene detection rates among panels and the implications for homologous recombination deficiency (HRD) status. This study enrolled 2568 patients with PDAC who had undergone CGP between June 2019 and December 2021 using data from the nationwide Center for Cancer Genomics and Advanced Therapeutics database. Two types of CGP assays (tissue and liquid biopsies) were compared and a higher detection rate of genetic abnormalities in tissue specimens was revealed. HRD-related gene alterations were detected in 23% of patients, with BRCA1/2 mutations accounting for 0.9% and 2.9% of patients, respectively. Treatment outcome analysis indicated that patients with BRCA1/2 mutations had a longer time to treatment discontinuation with FOLFIRINOX than gemcitabine plus nab-paclitaxel as first-line therapy (9.3 vs. 5.6 months, p = 0.028). However, no significant differences were observed in the treatment response among the other HRD-related genes. Logistic regression analysis identified younger age and family history of breast, prostate, and ovarian cancers as predictive factors for HRD-related gene alterations. Despite the lack of progression-free survival data and the inability to discriminate between germline and somatic mutations, this study provides valuable insights into the clinical implications of CGP in Japanese patients with PDAC. Further research is warranted to optimize panel selection and elucidate the efficacy of platinum-based therapies depending on the HRD status.

Keywords: Center for Cancer Genomics and Advanced Therapeutics; comprehensive cancer genome profiling; homologous recombination deficiency; pancreatic cancer; pancreatic ductal adenocarcinoma.

FIGURE 1

Flow diagram of the study.

FIGURE 2

Overview of the prevalent genomic alteration of pancreatic ductal adenocarcinoma (PDAC).

FIGURE 3

Frequency of homologous recombination deficiency (HRD)‐related genomic alterations in pancreatic ductal adenocarcinoma (PDAC).

FIGURE 4

Frequency of major genomic changes in pancreatic ductal adenocarcinoma (PDAC) between the comprehensive genome profiling (CGP) of the tissue sample (tissue group) and liquid biopsy (liquid group). Data are shown for the (A) Top 4 and (B) 5–30 most common gene alterations. Fisher's exact test was used to evaluate comparisons among groups.

FIGURE 5

Frequency of major genomic alterations in pancreatic ductal adenocarcinoma (PDAC) between KRAS mutation (KRAS mt) and wild‐type in the comprehensive genome profiling (CGP) of tissue samples. Data are shown for the (A) Top 3 and (B) 4–29 most common gene alterations. Fisher's exact test was used to evaluate comparisons among groups.

FIGURE 6

Kaplan–Meier curves of the time to treatment discontinuation (TTD) and overall survival (OS) according to first‐line FOLFIRINOX (FFX) versus gemcitabine plus nab‐paclitaxel (GnP) therapy. (A) TTD in patients with BRCA1/2 alteration. (B) TTD in patients with BRCA1/2 wild‐type. (C) OS in patients with BRCA1/2 alteration. (D) OS in patients with the wild‐type form of BRCA1/2.

FIGURE 7

Kaplan–Meier curves of the time to treatment discontinuation (TTD) and overall survival (OS) according to the first‐line FOLFIRINOX (FFX) versus gemcitabine plus nab‐paclitaxel (GnP) therapy. (A) TTD in patients with homologous recombination deficiency (HRD) group 1 alteration. (B) TTD in patients with HRD group 1 or 2 alteration. (C) OS in patients with HRD group 1 alteration. (D) OS in patients with HRD group 1 or 2 alterations. HRD group 1: BRCA1/2, ATM, ATR, PALB2. HRD group 2: ARID1A, ATRX, BAP1, BARD1, BRIP1, CDK12, CHEK1/2, FANCA/C/G/L, MRE11A, NBN, PPP2R2A, RAD51B/C/D, RAD54 L.