Gut Microbiota and Trastuzumab Response in HER2- Positive Breast Cancer

The use of trastuzumab as standard treatment for HER2-positive breast carcinomas (BCs) had largely improved the clinical outcome of BCs patients. Unfortunately, many of them do not respond to the therapy and the pathological complete response (pCR) is achieved in only 50% of patients even in those with tumours classified as the most sensitive to trastuzumab (i.e. HER2-enriched and high immune infiltration). Given the relevance of the immune system in trastuzumab cytotoxicity and the immune regulatory functions of gut bacteria, this project aims at investigating the role of gut microbiota as extrinsic tumour factor that influences trastuzumab activity. We found that antibiotics abrogated trastuzumab benefit in FVB mice in a microbiota dependent manner. Vancomycin and streptomycin lowered the abundance of Clostridiales bacteria and compromised the recruitment of immune cells in tumour microenvironment. Similar results were obtained in a model of HER2-positive BC spontaneous tumorigenesis, but not in the BALB/c model. In the attempt to improve the response to trastuzumab in FVB mice, the role of lactic acid producing bacteria was explored and an improvement in the antitumor efficacy was observed. Patients treated with neoadjuvant trastuzumab, who achieved pCR (R) were characterized by higher abundance of Clostridiales bacteria and a lower representation of Bacteroidales as compared to those with residual disease (NR) at surgery. Transferring faecal material from R and NR into recipient mice recapitulated the response observed in patients indicating a causal role for commensal bacteria. Furthermore, the unsupervised analysis on patients gut microbiota composition identified two microbiota clusters that significantly discriminated patients according to trastuzumab benefit while no association between microbiota clusters and the HER2-enriched PAM50 molecular classification of tumour biopsies was observed. In conclusion, our data support the role of gut microbiota composition in the therapeutic efficacy of trastuzumab independently of tumour intrinsic characteristics.