Abstract 4959: The gut microbiota contributes to the effectiveness of HER2-targeted therapy
Authors: Modica Martina Di , Regondi Viola , Gargari Giorgio , Bonizzi Arianna , Arioli Stefania , Belmonte Beatrice , Tripodo Claudio , Guglielmetti Simone , Corsi Fabio , Triulzi Tiziana , Tagliabue Elda 
Published: August 2019

Abstract
Recently, the composition of the gut microbiota, due to its influence on host immune system, has been linked to the effectiveness of chemotherapy and immunotherapy. Since trastuzumab, besides inhibiting the HER2 signaling, recruits innate and adaptive immune cells that mediate its cytotoxic activity in the tumor, we hypothesized that commensal bacteria can be a source of heterogeneity for the response to therapy in patients with HER2-positive breast cancer (HER2+BC).
The impact of the gut microbiota on anti-HER2 therapy was studied in mice with the intestinal flora alterated by the treatment with vancomycin or streptomycin-two broad spectrum antibiotics poorly absorbed in the intestine. The association between commensal bacteria composition and clinical efficacy of trastuzumab was investigated in a cohort of HER2+BC patients treated with neoadjuvant trastuzumab.
Administration of antibiotics impaired the efficacy of anti-HER2 monoclonal antibodies both in FVB and BALB/c mice bearing syngeneic mammary carcinomas expressing HER2. 16S rRNA gene profiling of FVB mouse feces showed that both antibiotics decreased bacterial α-diversity in the gut as evaluated by Chao1, Simpson and Shannon indices, lowering the abundance of Clostridiales bacteria. Mice transplanted with feces from antibiotic treated mice did not benefit from the anti-HER2 treatment supporting a direct relation between intestinal bacteria and therapeutic efficacy. Analysis by flow cytometry and immunohistochemistry of tumors grown in mice showed that alteration of gut microbiota compromised the recruitment of CD4+ T cells and Natural Killer (CD49b+, GZMB+) cells upon anti-HER2 administration. Fecal 16S rRNA gene sequencing demonstrated a significantly higher microbial α-diversity in patients who achieved a pathological complete response compared to non-responders using several indices. Moreover, a clustering effect by patient’s response was observed visualizing the β-diversity. OTUs belonging to the Clostridiales and Bacteroidales orders were reduced and enriched, respectively, in non-responders.
Our data support that the composition of the gut microbiota, especially as regards the abundance of Clostridiales bacteria, has a role in the therapeutic efficacy of trastuzumab both in mice and patients. Therefore, the manipulation of intestinal bacteria may represent a new strategy to improve the cure of HER2+BC patients.
(Supported by Associazione Italiana per la Ricerca sul Cancro).
Citation Format: Martina Di Modica, Viola Regondi, Giorgio Gargari, Arianna Bonizzi, Stefania Arioli, Beatrice Belmonte, Claudio Tripodo, Simone Guglielmetti, Fabio Corsi, Tiziana Triulzi, Elda Tagliabue. The gut microbiota contributes to the effectiveness of HER2-targeted therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4959.