胰腺癌精准治疗：从小众走向主流

胰腺癌恶性程度高，预后差，治疗手段有限，精准治疗是提高胰腺癌患者疗效的大势所趋。超过1/4的胰腺癌患者存在可治疗的靶点，主要包括KRAS突变、同源重组修复缺陷、融合基因改变、免疫微环境等四大类分子靶标，其中有恶性肿瘤家族史或个人史、年轻患者及腺泡细胞癌等胰腺癌患者更可能从精准治疗中获益。然而目前胰腺癌患者最终接受精准治疗的不足4%，肿瘤分子谱检测每有KRAS突变状态、肿瘤细胞含量、融合基因、胚系突变等关键信息缺失，精准治疗仍是一种小众治疗手段。因而有必要建立精准检测技术规范，打造专业化的精准分析团队，强调多中心协作从而积累循证医学证据，推动胰腺癌精准治疗从小众走向主流，造福于广大胰腺癌患者。最新的研究结果表明，胰腺癌精准治疗可改善患者预后，延长生存期。2019年，《新英格兰医学杂志》（New England Journal of Medicine）报道了针对具有BRCA1或BRCA2胚系突变的晚期胰腺癌进行多聚二磷酸腺苷核糖聚合酶[poly (ADP-ribose) polymerase，PARP]抑制剂奥拉帕利维持治疗的POLO研究，从而拉开了胰腺癌精准治疗的序幕。2020年，得克萨斯大学MD安德森癌症中心（The University of Texas MD Anderson Cancer Center）Pishvaian等报道了“知道您的肿瘤（Know Your Tumor，KYT）”计划。结果表明，在1 856例胰腺癌患者中，具有可治疗靶点且匹配对应治疗的患者（46例，中位生存期为2.58年）其预后明显优于具有可治疗靶点但未匹配对应治疗的患者[143例，中位生存期为1.51年，风险比（hazard ratio，HR） = 0.42，P = 0.004]以及无可治疗靶点的患者（488例，中位生存期为1.32年，HR = 0.34，P<0.000 1）。然而，具有可治疗靶点但未匹配对应治疗的患者的预后却与无可治疗靶点的患者差异无统计学意义（P = 0.10）。这项真实世界研究表明，对有可治疗靶点的胰腺癌实施精准治疗可将胰腺癌患者的生存期延长1年以上。目前胰腺癌精准治疗的靶标包括KRAS突变状态（KRAS野生型，KRAS G12C突变）、同源重组修复缺陷（BRCA1/2、PALB2、ATM/ATR/ATRX、CHEK2、CDK12、RAD51、NBN、BLM、FANC、RAD51/51C、RAD50、BAP1、BARD1、BRIP1和MRE11）、融合基因改变（NTRK、NRG1、ALK、RAF、RET、MET、FGFR2/3和ROS）、免疫微环境[MSI-H、TMB和MMR-D（MLH1、MLH3、MSH2、MSH3、MSH6、PMS1、PMS2、POLE和EPCAM）]、其他[BRAF、 人表皮生长因子受体2（human epidermal growth factor receptor 2，HER2）]等。由于胰腺癌精准治疗靶点相对有限且分布不集中，患者存在生存期短以及标本难获得等劣势，因而有必要建立专业化的精准分析团队，进而推动胰腺癌精准治疗的发展。相信随着业内对精准治疗的重视，胰腺癌的精准治疗必将迎来春天。

Precision therapy in pancreatic cancer: from streamlet towards mainstream

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.