Abstract:

Pancreatic cancer is a highly dismal malignancy and has a poor response to major treatments. Patients with pancreatic cancer usually have poor prognosis. Precision therapy has a great potential to improve the outcome of pancreatic cancer. Over 25% of patients have druggable targets, which mainly involve in KRAS mutation status, homologous recombination repair deficiency, gene fusions, and immunotherapy related pathways. Patients with familial or personal history of malignancy, younger patients, or patients with acinar cell carcinoma may benefit from precision therapy. However, only 4% of patients have received precision therapy, and thus precision therapy is still not a major therapeutic method for pancreatic cancer. It is common that genetic/molecular reports are lack of critical information, such as KRAS mutation status, tumor cell content, fusions and germline mutations. It is necessary to promote precision therapy from streamlet towards mainstream by formulating detection technique, establishing expertise team and stressing cooperation to accumulate evidence, thereby providing benefits for the patients. Recent reports have shown that precision treatments could improve the outcome and survival of patients with pancreatic cancer. In 2019, The New England Journal of Medicine published the POLO study which investigated olaparib, an inhibitor of poly (ADP-ribose) polymerase (PARP), in patients with metastatic pancreatic cancer and BRCA1 or BRCA2 germline mutation. This is the first clinical trial of precision therapy based on therapeutic targets in pancreatic cancer. In 2020, Pishvaian et al. from the University of Texas MD Anderson Cancer Center published the results of “Know Your Tumor (KYT)”. In this study, among 1 856 patients with pancreatic cancer, patients with actionable molecular alterations who received a matched therapy (n = 46, 2.58 years) had longer median overall survival than did those patients who only received unmatched therapies [n = 143; 1.51 years; hazard ratio (HR) was 0.42, P = 0.004]. The patients who received a matched therapy also had longer overall survival compared with the patients who did not have an actionable molecular alteration (n=488; 1.32 years; HR was 0.34, P<0.000 1). This real-world study indicates that matched treatments for patients with pancreatic cancer and actionable molecular alterations could prolong the overall survival of patients for more than one year. To date, therapeutic targets in pancreatic cancer include KRAS mutation status (KRAS wild-type and KRAS G12C mutation), homologous recombination repair deficiency (BRCA1/2, PALB2, ATM/ATR/ATRX, CHEK2, CDK12, RAD51, NBN, BLM, FANC, RAD51/51C, RAD50, BAP1, BARD1, BRIP1, MRE11), gene fusions (NTRK, NRG1, ALK, RAF, RET, MET, FGFR2/3, ROS), immunotherapy related pathways [MSI-H, TMB, MMR-D (MLH1, MLH3, MSH2, MSH3, MSH6, PMS1, PMS2, POLE, EPCAM)] and others [BRAF, human epidermal growth factor receptor 2 (HER2)]. It is necessary to establish specialized team which focuses on precision treatments in pancreatic cancer for the reasons that only limited proportion of patients have therapeutic targets which are widely distributed. The overall survival of patients with pancreatic cancer is poor. It is hard to acquire tumor specimens from advanced pancreatic cancer. As great importance has been attached, we believe that there will be a bright future for the precision treatment in pancreatic cancer.

Key words: Pancreatic cancer, Targeted therapy, Immunotherapy, KRAS, Fusion gene