Trastuzumab, has played a major role in improving treatment outcomes in HER-2 positive gastric cancer. However, once there is disease progression there is a paucity of evidence for second line therapy. Patient-derived xenografts (PDXs) in combination with liquid biopsies can help guide individual therapeutic decisions and have now started to be studied. In the present case we established a PDX model from a metastatic HER-2+ gastric cancer patient and after the first engraftment passage we performed a mouse clinical trial to test T-DM1 as an alternative therapy for the patient. The PDX tumor response served as a guide to administer T-DM1 therapy to the patient who responded to treatment before relapsing 6 months later. Throughout out the clinical follow up of the patient, ctDNA levels of HER-2 copy number and a PIK3CA mutation were monitored and we found their correlation with drug response and disease progression to outperform that of CEA levels. This study highlights the utility of applying precision medicine tools combining PDX models to guide therapy with circulating tumor DNA (ctDNA) to monitor treatment response and disease progression.