PURPOSE Immune response to tumors is associated with clinical benefits in breast cancer. Preclinically, disruption of microtubule dynamics affect the functionality of immune cells. We investigate the impact of microtubule targeting agents (MTA) on the clinical benefit of immune response in early breast cancer.

METHODS We used the gene expression dataset associated with the randomized FinHER adjuvant phase III trial, which compared Docetaxel (stabilizing MTA) to Vinorelbine (destabilizing MTA), and an integrated non-randomized GEO neoadjuvant dataset with regimens containing stabilizing MTA or without any MTA. Cox/logistic interaction models assessed the interaction between MTAs and immune response on clinical benefit. Immune response was measured using histopathology (TIL-H&E), gene module scores, and immune cell-type estimation methods.

RESULTS MTA and immune responses interact significantly in breast cancer, particularly in TNBC, affecting patient survival. In the randomized FinHER adjuvant TNBC setting, a unit increase in interferon score is associated with a death hazard-ratio (HR) of 10.97 (95% confidence interval, 0.79 to 151.78) in the Docetaxel arm (n=60), and a death HR of 0.16 (0.03 to 0.97) in the Vinorelbine arm (n=60), P-interaction = 0.008 (FDR-adjusted, 0.039). In the non-randomized neoadjuvant TNBC setting, a unit increase in interferon score is associated with a pathological-complete-response (pCR) odds-ratio (OR) of 1.3 (0.6 to 3.1) in stabilizing MTA regimens (n=293), and a pCR OR of 46.8 (3.9 to 557.7) in non-MTA regimens (n=83), P-interaction = 0.004 (FDR-adjusted, 0.032).

CONCLUSION MTAs influence the clinical benefit of immune response in breast cancer. However, the limited sample size warrants additional analyses.

Translational relevance Creating combination regimens with immune system stimulation, such as immunotherapy, requires classification of cancer therapies by their effects on immune cells. The finding that microtubule-destabilizing agents respond better to immunogenic TNBCs than stabilizing agents (taxanes), and vice-versa, has different implications. Firstly, destabilizing agents, currently recommended in metastatic settings, can be brought into early settings for immunogenic TNBCs while limiting stabilizing agents to non-immunogenic tumors. Secondly, stabilizing agents may be more effective as backbone therapy for immunotherapy in non-immunogenic tumors than destabilizing agents and vice-versa. Furthermore, the potential use of destabilizing agents as checkpoint inhibitors in immunogenic TNBC is warranted from the present non-immunotherapy dataset. Finally, since routine evaluation of immune response is recommended from tumor biopsies, the heterogeneity observed between TIL counts from histopathology and gene signatures of immune response calls for additional research into the objectivity of different measures of immune response.

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Roberto Salgado reports non-financial support from Merck and Bristol Myers Squibb (BMS), research support from Merck, Puma Biotechnology and Roche, and personal fees from Roche, BMS and Exact Sciences for advisory boards. Stefan Michiels reports fees outside the scope of the submitted work for statistical advice to IDDI, Amaris, Roche, and data and safety monitoring member of clinical trials: IQVIA, Sensorion, Biophytis, Servier, Yuhan. Sherene Loi receives research funding to her institution from Novartis, Bristol Meyers Squibb, Merck, Puma Biotechnology, Eli Lilly, Nektar Therapeutics, Astra Zeneca, Roche-Genentech and Seattle Genetics. She has acted as consultant (not compensated) to Seattle Genetics, Novartis, Bristol Meyers Squibb, Merck, AstraZeneca, Eli Lilly, Pfizer, Gilead Therapeutics and Roche-Genentech. She has acted as consultant (paid to her institution) to Aduro Biotech, Novartis, GlaxoSmithKline, Roche-Genentech, Astra Zeneca, Silverback Therapeutics, G1 Therapeutics, PUMA Biotechnologies, Pfizer, Gilead Therapeutics, Seattle Genetics, Daiichi Sankyo, Merck, Amunix, Tallac Therapeutics, Eli Lilly and Bristol Meyers Squibb. Heikki Joensuu has had a leadership role in Orion Pharma, Neutron Therapeutics, and Sartar Therapeutics, has a consulting/advisory role in Orion Pharma and Neutron Therapeutics, has received honoraria for scientific meetings from Deciphera Pharmaceuticals, and has stock ownership in Orion Pharma and Sartar Therapeutics. Christos Sotiriou has received research grants from Astellas, Cepheid, Vertex, Seattle Genetics, Puma, Amgen, and Merck & has support for attending meetings and/or travel from Roche, Genentech, and received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Eisai, Prime Oncology, Teva, and Exact Sciences.

Vinu Jose received funding from the F.R.S-FNRS grant "Fonds de la Recherche Scientifique"-Televie (Belgium), for this work (Credit no: 7461813F). The funders had no role in the study design, data collection, analysis, publication decision, or manuscript preparation. Roberto Salgado is supported by the Breast Cancer Research Foundation (BCRF, grant nr. 17-194). Sherene Loi is supported by the National Breast Cancer Foundation of Australia Endowed Chair and the Breast Cancer Research Foundation, New York. Heikki Joensuu is supported by the Sigrid Juselius Foundation, Finland.

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