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^pos/HER2^pos early breast cancer

HER2-directed therapies are less effective in patients with ER^pos compared to ER^neg 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^pos/ER^pos early breast cancer patients. In pre-clinical studies of HER2^pos breast cancer cell lines, ER^pos cells were partially resistant to CD4⁺ Th1 cytokine-induced metabolic suppression compared with ER^neg cells. The addition of anti-estrogen treatment significantly enhanced cytokine sensitivity in ER^pos, but not ER^neg, cell lines. In two pooled phase-I clinical trials, patients with HER2^pos early breast cancer were treated with neoadjuvant anti-HER2 dendritic cell vaccination; HER2^pos/ER^pos 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^neg vaccination alone, ER^pos vaccination alone, ER^pos vaccination + anti-estrogen therapy). In the sentinel lymph nodes, however, the anti-HER2 Th1 immune response was significantly higher in ER^pos 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^neg patients and vaccinated ER^pos patients treated with concurrent anti-estrogen therapy (31.4% vs. 28.6%); both were significantly higher than the pCR rate in vaccinated ER^pos patients who did not receive anti-estrogen therapy (4.0%, p = 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^pos/HER2^pos DCIS and invasive breast cancer.