Fabregat-Franco C, Castet F, Castillo G, Salcedo M, Sierra A, López-Valbuena D, Pando E, Tian T V, Macarulla T
Medical Oncology Department, Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, Barcelona, Spain.
Upper Gastrointestinal and Endocrine Tumor Unit, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain.
ESMO Open. 2025 May;10(5):104480. doi: 10.1016/j.esmoop.2025.104480. Epub 2025 May 12.
Ampullary carcinoma (AC) is a rare disease with an abysmal prognosis and few treatment options. The molecular landscape and its therapeutic implications remain inadequately understood. This study aims to provide a clinical and genomic characterization of AC and explore opportunities for precision oncology.
We carried out a retrospective analysis of clinical and genomic features in patients with AC treated in our institution. Gene mutations were categorized into molecular pathways, and potentially targetable alterations were classified according to the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT). Key molecular findings were validated in an external cohort.
We included 78 patients with a median age of 66 years; 51.6% were women, and most were treated with surgery (81.2%). Histologically, they were classified as pancreaticobiliary (58.3%), intestinal (INT, 33.3%), and mixed (8.3%). The percentages of patients diagnosed at stages I, II, III, and IV disease were 18.8%, 23.4%, 32.8%, and 25.0%, respectively. Of note, the INT subtype was enriched in transforming growth factor-β pathway alterations (25.9% versus 6.1%, P = 0.03). Potentially actionable molecular alterations were found in 52% of the patients. Importantly, KRAS tumors were enriched in potentially targetable alterations ESCAT I-IIIA both in our cohort (37.2% versus 9.4%, P = 0.006) and external validation cohort (23.0% versus 9.3%, P = 0.01), including 25.6% ERBB2 amplification/mutation, 14.0% homologous recombination deficiency status, and 7.4% microsatellite instability status. Six patients received matched targeted therapies after progression to chemotherapy, with a response rate of 50% and two patients surviving for >1 year.
AC patients are enriched in targetable alterations, especially KRAS tumors, and could particularly benefit from precision oncology-based approaches.
壶腹癌（AC）是一种罕见疾病，预后极差且治疗选择有限。其分子特征及其治疗意义仍未得到充分了解。本研究旨在对AC进行临床和基因组特征分析，并探索精准肿瘤学的机会。
我们对在本机构接受治疗的AC患者的临床和基因组特征进行了回顾性分析。基因突变被归类到分子途径中，潜在可靶向改变根据欧洲医学肿瘤学会（ESMO）分子靶点临床可操作性量表（ESCAT）进行分类。关键分子发现在外部队列中得到验证。
我们纳入了78例患者，中位年龄为66岁；51.6%为女性，大多数接受了手术治疗（81.2%）。组织学上，它们被分类为胰胆管型（58.3%）、肠型（INT，33.3%）和混合型（8.3%）。I期、II期、III期和IV期疾病诊断患者的百分比分别为18.8%、23.4%、32.8%和25.0%。值得注意的是，INT亚型在转化生长因子-β途径改变中富集（25.9%对6.1%，P = 0.03）。52%的患者发现了潜在可操作的分子改变。重要的是，KRAS肿瘤在我们的队列（37.2%对9.4%，P = 0.006）和外部验证队列（23.0%对9.3%，P = 0.01）中均在ESCAT I-IIIA级潜在可靶向改变中富集，包括25.6%的ERBB2扩增/突变、14.0%的同源重组缺陷状态和7.4%的微卫星不稳定状态。6例患者在化疗进展后接受了匹配的靶向治疗，缓解率为50%，2例患者存活超过1年。
AC患者在可靶向改变中富集，尤其是KRAS肿瘤，可能特别受益于基于精准肿瘤学的方法。
