- 作者: Siao Muk Cheng, Yung-Yeh Su, Nai-Jung Chiang, Chih-Jung Wang, Ying-Jui Chao, Chien-Jui Huang, Hui-Jen Tsai, Shang-Hung Chen, Chi-Yen Chang, Chia-Rung Tsai, Yi-Jie Li, Chia-Jui Yen, Shih-Chang Chuang, Jeffrey Shu-Ming Chang, Yan-Shen Shan, Daw-Yang Hwang & Li-Tzong Chen
- 作者服務機構: 1.Center for Biomarkers and Biotech Drugs, Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan 2.Deparment of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan 3.Department of Internal Medicine, Kaohsiung Medical University Hospital and Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan 4.Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan 5.Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan 6.Department of Surgery, Faculty of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 7.Department of Surgery, National Cheng-Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan 8.Division of General and Digestive Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 9.Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 10.Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan 11.National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan 12.Precision Medicine Ph.D. Program, National Tsing Hua University, Hsinchu, Taiwan 13.School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- 中文摘要:
- 英文摘要:
Background
Cancer susceptibility germline mutations are associated with pancreatic ductal adenocarcinoma (PDAC). However, the hereditary status of PDAC and its impact on survival is largely unknown in the Asian population.
Methods
Exome sequencing was performed on 527 blood samples from PDAC individuals and analyzed for mutations in 80 oncogenic genes. Pathogenic and likely pathogenic (P/LP) germline variants were diagnosed according to the ACMG variant classification categories. The association between germline homologous recombination gene mutations (gHRmut, including BAP1, BRCA1, BRCA2, PALB2, ATM, BLM, BRIP1, CHEK2, NBN, MUTYH, FANCA and FANCC) and the treatment outcomes was explored in patients with stage III/IV diseases treated with first-line (1L) platinum-based versus platinum-free chemotherapy.
Results
Overall, 104 of 527 (19.7%) patients carried germline P/LP variants. The most common mutated genes were BRCA2 (3.60%), followed by ATR (2.66%) and ATM (1.9%). After a median follow-up duration of 38.3-months (95% confidence interval, 95% CI 35.0–43.7), the median overall survival (OS) was not significantly different among patients with gHRmut, non-HR germline mutations, or no mutation (P = 0.43). Among the 320 patients with stage III/IV disease who received 1L combination chemotherapy, 32 (10%) had gHRmut. Of them, patients receiving 1L platinum-based chemotherapy exhibited a significantly longer median OS compared to those with platinum-free chemotherapy, 26.1 months (95% CI 12.7–33.7) versus 9.6 months (95% CI 5.9–17.6), P = 0.001. However, the median OS of patients without gHRmut was 14.5 months (95% CI 13.2–16.9) and 12.6 months (95% CI 10.8–14.7) for patients receiving 1L platinum-based and platinum-free chemotherapy, respectively (P = 0.22). These results were consistent after adjusting for potential confounding factors including age, tumor stage, performance status, and baseline CA 19.9 in the multivariate Cox regression analysis.
Conclusions
Our study showed that nearly 20% of Taiwanese PDAC patients carried germline P/LP variants. The longer survival observed in gHRmut patients treated with 1L platinum-based chemotherapy highlights the importance of germline testing for all patients with advanced PDAC at diagnosis. - 中文關鍵字:
- 英文關鍵字: Next-generation sequencing, Homologous recombination, Platinum, Chemotherapy