Breast cancer is the most common cancer in a woman with a five-year survival of patients with metastatic disease is estimated at 23%. Ado-trastuzumab emtansine (T-DM1) is a HER2-antibody drug conjugate currently approved for the treatment of HER2-positive pre-treated metastatic breast cancer (BC). We report a case of recurrent metastatic breast cancer with unusually lengthy progression-free survival (PFS) on T-DM1 chemotherapy. She was diagnosed with Triple Positive Stage IIIC multifocal invasive ductal carcinoma of the left breast. After completing neoadjuvant chemotherapy, she underwent a bilateral mastectomy. Final pathology showed partial response. Postoperatively, she received adjuvant chemotherapy and radiation therapy. She was started on Q21 days trastuzumab following completion of adjuvant chemotherapy. Systemic imaging showed liver lesions and biopsy confirmed recurrence. She was started on T-DM1, endocrine therapy with anastrozole was continued. She is currently status post 45 cycles. T-DM1 was approved for the treatment (single-agent) of HER2-positive, metastatic BC based on phase III data from the EMILIA and TH3RESA study. Median PFS in the T-DM1 arm was 9.6 months. Herein, we present a case of a woman with recurrent triple positive metastatic BC with a lengthy progression-free survival on T-DM1 chemotherapy.

HER2overexpression is associated with poor breast cancer prognosis and increased risk of metastasis. Current HER2targeted therapies include monoclonal antibody based strategies which work by reducing HER2 levels at the cell surface (trastuzumab), by preventing HER2 dimerization (pertuzumab), or via targeted delivery of a cytotoxic payload (trastuzumab emtansine). Although these therapies are successful in some cases, acquired and inherent resistance to these therapeutics remain a treatment hurdle. Oncolytic viruses (OVs) specifically target and lyse cancer cells while leaving normal cells unharmed. One such OV, VSVΔ51, replicates in interferon (IFN) defective cells, a characteristic of approximately 70% of tumours. We hypothesized that the combination of HER2 targeting therapies with VSVΔ51 could improve therapeutic efficacy. We found that HER2 overexpression was associated with increased virus sensitivity and that modulation of HER2 signaling through a subset of activating ligands and inhibitory drugs could influence infection. We further established that the HER2 monoclonal antibodies trastuzumab and pertuzumab mediate an anti-viral effect on VSVΔ51 spread. Finally, we demonstrate that conjugation of a microtubule targeting agent to trastuzumab can overcome the induced anti-viral state and enhance VSVΔ51 spread specifically in cancer cells. Overall, this work highlights the importance of HER2 signaling and activation on VSVΔ51 spread and shows that conjugation of microtubule destabilizing agents to monoclonal antibodies can enhance VSVΔ51 efficacy.