Case Report: Metachronous pancreatic adenocarcinoma following HER2-positive breast cancer and the implications of non-BRCA germline variants with TP53-mutant disease.

Metachronous pancreatic ductal adenocarcinoma (PDAC) following breast cancer is rare and often linked to pathogenic variants in high-penetrance genes such as BRCA2. We report a case of this clinical scenario lacking classic mutations, which prompted exploration of alternative genetic mechanisms. A 54-year-old woman was diagnosed with stage IIIB HER2-positive invasive breast cancer in 2017 and treated with neoadjuvant chemotherapy (TAC), modified radical mastectomy, radiotherapy, trastuzumab, and toremifene. Eight years later, elevated CA19-9 led to the detection of a pancreatic uncinate mass. Pathological examination after pancreaticoduodenectomy confirmed moderately differentiated PDAC. Germline testing revealed no BRCA1, BRCA2, PALB2, or ATM mutations but identified several variants of uncertain significance (VUS) in SIL1, SNX14, and ALOX12B. A somatic TP53 mutation was present in both malignancies. This case highlights that a hereditary cancer phenotype can occur even without classic mutations. It suggests that VUS in genes involved in cellular stress and metabolic pathways, particularly in combination with TP53 mutations, may contribute to the development of multiple primary malignancies. Furthermore, it underscores the importance of vigilant, phenotype-driven long-term surveillance in such patients, regardless of germline testing results.