Addition of Anti-estrogen Therapy to Anti-HER2 Dendritic Cell Vaccination Improves Regional Nodal Immune Response and Pathologic Complete Response Rate in Patients with ER/HER2 Early Breast Cancer

HER2-directed therapies are less effective in patients with ER compared to ER breast cancer, possibly reflecting bidirectional activation between HER2 and estrogen signaling pathways. We investigated dual blockade using anti-HER2 vaccination and anti-estrogen therapy in HER2/ER early breast cancer patients. In pre-clinical studies of HER2 breast cancer cell lines, ER cells were partially resistant to CD4 Th1 cytokine-induced metabolic suppression compared with ER cells. The addition of anti-estrogen treatment significantly enhanced cytokine sensitivity in ER, but not ER, cell lines. In two pooled phase-I clinical trials, patients with HER2 early breast cancer were treated with neoadjuvant anti-HER2 dendritic cell vaccination; HER2/ER patients were treated with or without concurrent anti-estrogen therapy. The anti-HER2 Th1 immune response measured in the peripheral blood significantly increased following vaccination, but was similar across the three treatment groups (ER vaccination alone, ER vaccination alone, ER vaccination + anti-estrogen therapy). In the sentinel lymph nodes, however, the anti-HER2 Th1 immune response was significantly higher in ER patients treated with combination anti-HER2 vaccination plus anti-estrogen therapy compared to those treated with anti-HER2 vaccination alone. Similar rates of pathologic complete response (pCR) were observed in vaccinated ER patients and vaccinated ER patients treated with concurrent anti-estrogen therapy (31.4% vs. 28.6%); both were significantly higher than the pCR rate in vaccinated ER patients who did not receive anti-estrogen therapy (4.0%, = 0.03). Since pCR portends long-term favorable outcomes, these results support additional clinical investigations using HER2-directed vaccines in combination with anti-estrogen treatments for ER/HER2 DCIS and invasive breast cancer.