Microtubule targeting agents influence the clinical benefit of immune response in early breast cancer

Abstract

AbstractPURPOSEImmune 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.METHODSWe 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.RESULTSMTA 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).CONCLUSIONMTAs influence the clinical benefit of immune response in breast cancer. However, the limited sample size warrants additional analyses.Translational relevanceCreating 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.