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Gut Microbiota Condition the Therapeutic Efficacy of Trastuzumab in HER2-Positive Breast Cancer.
- Source :
-
Cancer research [Cancer Res] 2021 Apr 15; Vol. 81 (8), pp. 2195-2206. Date of Electronic Publication: 2021 Jan 22. - Publication Year :
- 2021
-
Abstract
- Emerging evidence indicates that gut microbiota affect the response to anticancer therapies by modulating the host immune system. 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. In mice, the antitumor activity of trastuzumab was impaired by antibiotic administration or fecal microbiota transplantation from antibiotic-treated donors. Modulation of the intestinal microbiota was reflected in tumors by impaired recruitment of CD4 <superscript>+</superscript> T cells and granzyme B-positive cells after trastuzumab treatment. 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. In patients, lower α-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. The transfer of fecal microbiota from R and NR into mice bearing HER2-positive breast cancer recapitulated the response to trastuzumab observed in patients. Fecal microbiota β-diversity segregated patients according to response and positively correlated with immune signature related to interferon (IFN) and NO2-IL12 as well as activated CD4 <superscript>+</superscript> T cells and activated DCs in tumors. 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. SIGNIFICANCE: Evidence of gut microbiota involvement in trastuzumab efficacy represents the foundation for new therapeutic strategies aimed at manipulating commensal bacteria to improve response in trastuzumab-resistant patients. See related commentary by Sharma, p. 1937 GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/8/2195/F1.large.jpg.<br /> (©2021 American Association for Cancer Research.)
- Subjects :
- Animals
Anti-Bacterial Agents pharmacology
Breast Neoplasms immunology
Bridged-Ring Compounds therapeutic use
CD4-Positive T-Lymphocytes
Cyclophosphamide therapeutic use
Cytokines blood
Dendritic Cells drug effects
Doxorubicin therapeutic use
Fecal Microbiota Transplantation
Female
Gastrointestinal Microbiome drug effects
Gastrointestinal Microbiome immunology
Granzymes
Humans
Immune System
Immunity, Mucosal
Interferons metabolism
Interleukin-12 metabolism
Mice
Neoadjuvant Therapy
Nitric Oxide metabolism
Streptomycin pharmacology
Taxoids therapeutic use
Treatment Outcome
Tumor Microenvironment drug effects
Tumor Microenvironment immunology
Vancomycin pharmacology
Antineoplastic Agents, Immunological therapeutic use
Breast Neoplasms chemistry
Breast Neoplasms drug therapy
Gastrointestinal Microbiome physiology
Receptor, ErbB-2
Trastuzumab therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 81
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 33483370
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-20-1659