Pathogenic variants of homologous recombination repair-related genes in advanced pancreatic cancer and oxaliplatin-based chemotherapy: Prospective multicenter observational study.
Authors: Tomohiro Kondo, Daisuke Yamaguchi, Junichi Matsubara, Takashi Ura, Motoo Nomura, Taro Funakoshi, Akira Yokoyama, Keitaro Doi, Masashi Tamaoki, Tadayuki Kou, Toshinao Itani, Michio Yoshimura, Norimitsu Uza, Takahiro Yamada, Toshihiko Masui, Sachiko Minamiguchi, Hideki Ishikawa, Shigemi Matsumoto, Manabu Muto, Masashi Kanai
Journal: Journal of Clinical Oncology (2022)

555 Background: The latest National Comprehensive Cancer Network Guidelines for pancreatic adenocarcinoma recommended platinum-based chemotherapy for the patients with germline BRCA1/2 or PALB2 variants based on retrospective studies. However, the association between the efficacy of oxaliplatin-based chemotherapy and homologous recombination repair (HRR)-related gene variants has not yet been evaluated in a prospective study. Methods: This was a multicenter, prospective, observational study. Key inclusion criteria were: histologically confirmed pancreatic adenocarcinoma or adenosquamous carcinoma; candidates for systemic chemotherapy or currently under systemic chemotherapy for unresectable disease; age ≥ 20 years; Eastern Cooperative Oncology Group Performance Status 0–2; formalin-fixed paraffin-embedded cancer tissue available for genomic sequencing; and adequate hematological, liver, and renal function. Patients were assessed with the next generation sequencing (NGS)-based ACT-repair panel (ACT genomics; Taipei, Taiwan). ACT-repair panel is accredited by College of American Pathologists and is designed to detect short variants (SVs) including substitutions, insertions, deletions, and copy number variants of 35 genes including 8 HRR-related genes ( ATM, ATR, BRCA1, BRCA2, PALB2, RAD51B, RAD51C, RAD51D). The primary endpoint was the one-year overall survival rate (1yr-OS%) after the initiation of oxaliplatin-based chemotherapy in patients who harbored pathogenic HRR gene variants. On the basis of published retrospective data, expected 1yr-OS% was set at ≥ 60% in this study. Results: Forty patients were enrolled from August 2018 to March 2020. Median age was 67 years (range, 49–81 years). Sequencing data were obtained from 39 patients (NGS success rate = 97.5%). Nine patients (22.5%) harboring HRR gene; ATM SVs (n = 4), BRCA2 loss of heterozygosity (LOH) (n = 3), BRCA2 SVs (n = 1), and PALB2 LOH (n = 1). Three patients received oxaliplatin-based chemotherapy as first-line chemotherapy, while the remaining six patients received it as second- or later-line oxaliplatin-based chemotherapy. The 1yr-OS% was 44.4%, and the median overall survival was 221 days (95% confidence interval, 79–NA days) after the initiation of oxaliplatin-based chemotherapy. In three patients who received oxaliplatin-based chemotherapy as first-line treatment, overall survivals were 703 (alive), 694 (alive), and 405 (dead) days, respectively. Conclusions: Efficacy of oxaliplatin-based chemotherapy on advanced pancreatic cancer harboring HRR-related gene variants did not meet the primary endpoint of 1yr-OS% (≥ 60%). Clinical trial information: UMIN000033655.