Background: A 57 year old female was diagnosed as having a well differentiated breast duct carcinoma through HPE analysis. Immunohistochemistry pointed to strong oestrogen receptor (ER) positivity (+++ ALLRED score 3+5=8/8) and human epidermal growth factor receptor 2 (HER2) (+++), progesterone receptor (PR) positivity + (ALLRED score 1+3=4/8), strong positivity for vascular endothelial growth factor receptor ( VEGFR) protein expression and positivity for E-cadherin. In addition the tumor showed a high mitotic index, with 1 in 4 cells showing Ki67 positivity in a P53 negative background. Being a luminal B, HER2 enriched, hormone receptor positive, highly proliferating duct carcinoma, the patient had been put on standard ER (aromatase inhibitors, letrozole) and HER2 targeted (trastuzumab) therapies. However the patient did not respond to these therapeutic interventions.

TumorSimilis study: A piece of the biopsied sample, around 1 cm3 was sent to our lab in our transport medium for a medium term TumorSimilis study. In addition to the substantial heterogeneity in tumor cell types present, we were able to capture the therapeutic insensitivity observed in the patient, with trastuzumab and ER targeted therapies showing no response in the TumorSimilis system. Further, small molecules targeted to HER2 also did not have an effect, in line with the HER2 resistance observed in the patient. The tumor also retained a high growth rate, in line with the high Ki67 index observed. However this did not result in sensitivity to cell cycle targeted small molecule inhibitors like palbociclib in culture. Similarly, VEGFR targeting through antibody (bevacizumab) or small molecule (pazopanib) inhibition did not result in a reduction in tumor growth. Single agent chemotherapy options such as adriamycin, docetaxel or mitomycin C did not result in a response at any concentration, which led us to test combination therapy options. Here we observed that combinations of doxorubin with trastuzumab and docetaxel with trastuzumab created a synergy that cause a reduction in tumor growth and metabolic activity.  These synergies were observed exclusively upon inhibition of HER2 through antibody or small molecule options together with the administration of a chemotherapeutic agent. These results were conveyed to the patient’s treatment team.

Outcomes: The patient responded to the recommended therapy options and showed volumetric shrinkage of the tumor upon PET CT imaging. She is currently alive and has recovered from her cancer.