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Gut Microbiota Condition the Therapeutic Efficacy of Trastuzumab in HER2-Positive Breast Cancer
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Abstract
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+ 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+ 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
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“In breast cancer, high baseline gut microbiota alpha diversity has been associated with response to both neoadjuvant HER2 blockade and neoadjuvant chemotherapy [8, 12].”
From Gut microbiota diversity is prognostic and associated with benefit from chemo-immunotherapy in metastatic triple-negative breast cancer (2025) · cites this paper as [12]
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“Additionally, families like Lachnospiraceae, Turicibacteraceae, and Prevotellaceae are more abundant in breast cancer patients achieving pathologic complete responses to trastuzumab-containing regimens (Di Modica et al., 2021).”
From Microbiota-centered interventions to boost immune checkpoint blockade therapies (2025) · cites this paper as Di Modica et al., 2021
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Metadata
- Authors
- Di Modica, M., Gargari, G., Regondi, V., Bonizzi, A., Arioli, S., Belmonte, B., De Cecco, L., Fasano, E., Bianchi, F., Bertolotti, A., Tripodo, C., Villani, L., Corsi, F., Guglielmetti, S., Balsari, A., Triulzi, T., & Tagliabue, E.
- Affiliations
- 1Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
- Fondazione IRCCS Istituto Nazionale dei Tumori (IT)
- University of Milan (IT)
- University of Palermo (IT)
- 5Platform of Integrated Biology, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
- IFOM (IT)
- Istituti Clinici Scientifici Maugeri (IT)
- Corresponding author
- Tagliabue, Elda
- ORCID
- Venue
- Cancer Research
- Published
- 2021-01-22
- Volume
- 81
- Issue
- 8
- Pages
- 2195-2206
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W3122301327
- Cited by
- 184
- References
- 54
- Citations by year
- 2026: 29 · 2025: 42 · 2024: 45 · 2023: 38 · 2022: 23 · 2021: 7
- FWCI
- 9.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- BOA (University of Milano-Bicocca) (submittedVersion)
- Nova Science Publishers (Nova Science Publishers, Inc.) (submittedVersion)
- Funders
- AIRC (IG 2017, ID. 20264)
- FIRC-AIRC fellowship (ID. 22304)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Keywords
- gut microbiota, trastuzumab, HER2-positive breast cancer, antibiotic-induced dysbiosis, fecal microbiota transplantation, neoadjuvant therapy, treatment response biomarkers, dendritic cell activation, IL-12, CD4+ T cells, interferon signature, microbiome diversity, trastuzumab resistance, immunotherapy
- MeSH terms
- Trastuzumab, Gastrointestinal Microbiome, Fecal Microbiota Transplantation, Antineoplastic Agents, Immunological, Animals, Anti-Bacterial Agents, Breast Neoplasms, Bridged-Ring Compounds, Cyclophosphamide, Dendritic Cells, Doxorubicin, Female, Humans, Immune System, Interferons, Nitric Oxide, Streptomycin, Vancomycin, CD4-Positive T-Lymphocytes, Cytokines, Treatment Outcome, Interleukin-12, Erb-b2 Receptor Tyrosine Kinases, Immunity, Mucosal, Neoadjuvant Therapy, Taxoids, Mice, Granzymes, Tumor Microenvironment
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