Genomic profiling unlocks new treatment opportunities for ampullary carcinoma

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^WT 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^WT tumors, and could particularly benefit from precision oncology-based approaches.