Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate of 3–15% and limited effective treatment options for most patients. Approximately 5–10% of cases are wild-type KRAS and are more likely to harbor rare alterations, including gene fusions involving anaplastic lymphoma kinase (ALK), ROS Proto-Oncogene 1 (ROS1), neurotrophic tyrosine receptor kinase (NTRK), Rearranged During Transfection (RET), Fibroblast Growth Factor Receptor (FGFR), or Neuregulin 1 (NRG1) genes, as well as germline mutations in DNA repair genes. This review integrates current evidence on the prevalence, molecular profile, and clinical significance of gene fusions, amplification, and somatic/germline mutations in PDAC, with a particular focus on the wild-type KRAS subgroup. Clinical trial data and case reports indicate that these alterations can enhance patient susceptibility to targeted therapies. Currently, selpercatinib, larotrectinib, and repotrectinib are approved by the FDA for the treatment of certain solid tumors harboring specific gene fusions. Recent studies on zenocutuzumab resulted in the FDA-accelerated approval forNGR1fusion-positive NSCLC and PDAC. Germline mutations may specifically increase responsiveness to poly(ADP-ribose) polymerase (PARP) inhibitors or platinum-based treatments. Comprehensive genomic profiling, incorporating fusion detection and germline testing, is essential to identify patients who may benefit from precision-based approaches.
胰腺导管腺癌（PDAC）是一种高度致命的恶性肿瘤，五年生存率仅为3-15%，且大多数患者缺乏有效的治疗选择。约5-10%的病例为KRAS野生型，这类肿瘤更可能携带罕见变异，包括涉及间变性淋巴瘤激酶（ALK）、ROS原癌基因1（ROS1）、神经营养性酪氨酸受体激酶（NTRK）、转染重排（RET）、成纤维细胞生长因子受体（FGFR）或神经调节蛋白1（NRG1）等基因的融合，以及DNA修复基因的胚系突变。本综述整合了当前关于PDAC中基因融合、扩增及体细胞/胚系突变的流行率、分子特征和临床意义的证据，特别聚焦于KRAS野生型亚组。临床试验数据和病例报告表明，这些变异可能增强患者对靶向治疗的敏感性。目前，塞尔帕替尼、拉罗替尼和瑞普替尼已获美国食品药品监督管理局批准用于治疗携带特定基因融合的某些实体瘤。近期关于泽诺妥珠单抗的研究促使美国食品药品监督管理局加速批准其用于治疗NRG1融合阳性的非小细胞肺癌和PDAC。胚系突变可能特别增强患者对聚腺苷二磷酸核糖聚合酶（PARP）抑制剂或铂类治疗的敏感性。全面的基因组分析，包括融合检测和胚系突变测试，对于识别可能受益于精准治疗方法的患者至关重要。
KRAS-Wild Pancreatic Cancer—More Targets than Treatment Possibilities?
肿瘤(癌症)患者之家