However, despite the high sensitivity of HER2-enriched tumors, no more than 50% of these patients respond to trastuzumab (reviewed in ref. By using the PAM50 classifier to define different tumor intrinsic subtypes within HER2-positive breast cancer, patients with tumors classified as HER2-enriched (i.e., characterized by the high expression of ERBB2 and other genes of the 17q amplicon and low to intermediate expression of luminal genes, such as ESR1 and PGR) are more likely than the others to benefit from anti-HER2 treatment ( 4). Several attempts have been made to understand the reason for the lack of efficacy and to identify biomarkers that predict patients who will benefit from trastuzumab treatment (reviewed in ref. Although trastuzumab substantially improves the clinical outcomes of patients with HER2-positive breast cancer, a large number of patients present or develop resistance to this treatment, underlying the need to optimize the response rate in resistant patients. Trastuzumab, a recombinant humanized mAb that binds to the extracellular domain of HER2, represents the first treatment option for women with early and advanced stages of HER2-positive breast cancer ( 2). The aggressive biological behavior of breast cancer overexpressing HER2 and the consequent worse clinical outcomes of patients with these tumors ( 1) have largely been addressed by targeting HER2. Overall, our data reveal the direct involvement of the gut microbiota in trastuzumab efficacy, suggesting that manipulation of the gut microbiota is an optimal future strategy to achieve a therapeutic effect or to exploit its potential as a biomarker for treatment response.

Fecal microbiota ОІ-diversity segregated patients according to response and positively correlated with immune signature related to interferon (IFN) and NO2-IL12 as well as activated CD4 + T cells and activated DCs in tumors. The transfer of fecal microbiota from R and NR into mice bearing HER2-positive breast cancer recapitulated the response to trastuzumab observed in patients. In patients, lower О±-diversity and lower abundance of Lachnospiraceae, Turicibacteraceae, Bifidobacteriaceae, and Prevotellaceae characterized nonresponsive patients (NR) compared with those who achieved pathologic complete response (R), similar to antibiotic-treated mice. Antibiotics caused reductions in dendritic cell (DC) activation and the release of IL12p70 upon trastuzumab treatment, a mechanism that was necessary for trastuzumab effectiveness in our model.

Modulation of the intestinal microbiota was reflected in tumors by impaired recruitment of CD4 + T cells and granzyme BвЂ“positive cells after trastuzumab treatment. In mice, the antitumor activity of trastuzumab was impaired by antibiotic administration or fecal microbiota transplantation from antibiotic-treated donors. In this study, we investigated the impact of gut microbiota on immune-mediated trastuzumab antitumor efficacy in preclinical models of HER2-positive breast cancer and in 24 patients with primary HER2-positive breast cancer undergoing trastuzumab-containing neoadjuvant treatment. Emerging evidence indicates that gut microbiota affect the response to anticancer therapies by modulating the host immune system.

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