Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.
Am Soc Clin Oncol Educ Book. 2021 Mar;41:1-13. doi: 10.1200/EDBK_321255.
Performing germline and somatic sequencing in locally advanced and metastatic pancreatic cancer can identify potentially targetable genomic aberrations that impact current standard treatment options or eligibility for biomarker-targeted clinical trials. Testing for deleterious germline mutations in impacts patient selection for platinum-based chemotherapy regimens and selection of patients who are candidates to receive maintenance therapy with olaparib. Additional germline mutations also similarly introduce potential vulnerabilities to the cancers that arise and may be targeted by clinical trials. Somatic mutation testing also provides opportunities for optimal selection of patients for biomarker-driven clinical trials. Although mutations are found in 90% to 93% of pancreatic cancers, there are increasing opportunities for therapies against particular mutant KRAS isoforms, especially with the advent of KRAS G12C-specific small molecule inhibitors, and KRAS targeting trials will increasingly require identification of the specific mutation present. There are also a range of tumor site-agnostic molecular features, such as microsatellite instability and NTRK fusions that, although rarely found in pancreatic cancers, impact selection of patients who have the potential for dramatic benefit with immune checkpoint inhibitors such as pembrolizumab or TRK inhibitors such as larotrectinib or entrectinib, respectively, and thus motivate broader somatic mutation and fusion testing for patients with locally advanced and metastatic pancreatic cancers. Multiple other rare actionable aberrations, particularly gene fusions in the 8% to 10% of KRAS wild-type pancreatic cancers, are also known, and enrollment in basket trials for these rare patient cohorts is highly encouraged.
在局部晚期和转移性胰腺癌中进行种系和体细胞测序，可以识别出潜在的可靶向基因组异常，这些异常会影响当前的标准治疗选择或生物标志物靶向临床试验的资格。对 的有害种系突变进行检测，会影响到铂类化疗方案患者的选择，以及选择适合奥拉帕利维持治疗的患者。其他种系突变也同样为新出现的癌症引入了潜在的弱点，并可能成为临床试验的靶点。体细胞突变检测也为患者最佳选择生物标志物驱动的临床试验提供了机会。尽管 突变在 90%至 93%的胰腺癌中被发现，但针对特定突变 KRAS 异构体的治疗机会越来越多，特别是随着 KRAS G12C 特异性小分子抑制剂的出现，以及 KRAS 靶向试验将越来越需要确定存在的特定 突变。还有一系列肿瘤部位不可知的分子特征，如微卫星不稳定性和 NTRK 融合，虽然在胰腺癌中很少见，但影响到免疫检查点抑制剂如 pembrolizumab 或 TRK 抑制剂如 larotrectinib 或 entrectinib 潜在获益的患者选择，因此强烈鼓励对局部晚期和转移性胰腺癌患者进行更广泛的体细胞突变和融合检测。还已知其他多种罕见的可靶向异常，特别是在 8%至 10% KRAS 野生型胰腺癌中的基因融合，也强烈鼓励这些罕见患者队列参加篮子试验。
