Trastuzumab-based treatment of HER2-positive breast cancer: an antibody-dependent cellular cytotoxicity mechanism?

TLDR

The study assessed immune cell responses during neoadjuvant trastuzumab therapy in HER2‑positive breast cancer patients. Twenty‑three HER2‑positive patients received trastuzumab plus docetaxel, while matched controls received docetaxel alone or no taxane/trastuzumab; tumor specimens were blindly scored for B/T lymphocytes, macrophages, dendritic cells, NK cells, and cytolytic markers Granzyme B and TiA1, with HER2 expression also evaluated. Trastuzumab plus docetaxel produced 39 % pathological complete and 61 % partial responses, and was associated with increased tumor‑associated NK cells and cytolytic marker expression, supporting an immune‑mediated mechanism that may underlie its synergistic effect with docetaxel.

Abstract

This study evaluated by immunohistochemistry (IHC) immune cell response during neoadjuvant primary systemic therapy (PST) with trastuzumab in patients with HER2-positive primary breast cancer. In all, 23 patients with IHC 3+ primary breast cancer were treated with trastuzumab plus docetaxel. Pathological complete and partial responses were documented for nine (39%) and 14 (61%) patients, respectively. Case-matched controls comprised patients treated with docetaxel-based PST without trastuzumab (D; n=23) or PST without docetaxel or trastuzumab (non-taxane, non-trastuzumab, NT–NT; n=23). All surgical specimens were blind-analysed by two independent pathologists, with immunohistochemical evaluation of B and T lymphocytes, macrophages, dendritic cells and natural killer (NK) cells. Potential cytolytic cells were stained for Granzyme B and TiA1. HER2 expression was also evaluated in residual tumour cells. Trastuzumab treatment was associated with significantly increased numbers of tumour-associated NK cells and increased lymphocyte expression of Granzyme B and TiA1 compared with controls. This study supports an in vivo role for immune (particularly NK cell) responses in the mechanism of trastuzumab action in breast cancer. These results suggest that trastuzumab plus taxanes lead to enhanced NK cell activity, which may partially account for the synergistic activity of trastuzumab and docetaxel in breast cancer.