Periampullary adenocarcinomas are rare neoplasm that originates from the 
pancreatic head, the ampulla of vater, the distal bile duct or the duodenum. 
Surgical resection followed by adjuvant therapy is considered as the standard of 
care treatment for these carcinomas. Despite several advances in diagnostics and 
therapeutics, only 5% of these patients have an overall survival of five years 
or more. Currently, there is a dearth of viable therapeutic targets for this 
disease. The role of HER2 in cancer biology has been studied extensively in 
several tumour subtypes, and HER2 based targeted therapies have shown to have 
therapeutic benefits on different cancers. In this case report, we present a 
case of HER2 positive distal common bile duct carcinoma - a subtype of 
periampullary carcinoma with multiple relapses where multi-analyte testing with 
Encyclopedic Tumor Analysis (ETA) (Exacta®) identified amplification and over 
expression of HER2 gene which was used as a potential target to treat the 
patient with trastuzumab. Synchronous in vitro chemosensitivity profiling on 
Circulating Tumor Asscociated Cells (C-TACs) isolated from blood aided us to 
design the personalized chemotherapeutic regimen with cyclophosphamide and 
methotrexate. The combination of trastuzumab with cyclophosphamide and 
methotrexate yielded excellent treatment response with the patient remaining in 
complete response till the last follow-up. Our study suggests HER2 directed 
therapy as a potent pathway for treatment in the subset of HER-2 amplified 
distal common bile duct carcinomas.