Abstract ES5-1: Tumor dormancy and recurrence

Abstract

Abstract Despite early detection and adjuvant therapy, breast cancer remains the leading cause of cancer mortality in women, largely due to distant, incurable recurrences that arise years, or even decades, after treatment of the primary tumor. Recurrent, metastatic tumors arise from the pool of residual local and disseminated tumor cells (DTCs) that survive primary treatment in tissues at sites throughout the body where they persist in a presumed dormant state. Early studies demonstrated that an immunohistochemical assay can detect cytokeratin-positive DTCs in bone marrow aspirates of a substantial fraction of breast cancer patients lacking any clinical signs of metastasis. Importantly, women who harbor detectable DTCs in their bone marrow have a substantially increased risk of distant recurrence, as well as poorer breast cancer-specific and overall survival, and this measure has repeatedly been shown to be an independent predictor of recurrence-free survival and overall survival in multivariate analysis. Since DTCs constitute the reservoir from which recurrent cancers arise, understanding their biology is a critical priority in cancer research. We hypothesize that effectively disabling the survival mechanisms by which DTCs persist in breast cancer patients following treatment will deplete this critical reservoir of cells, reduce tumor recurrence, and thereby improve survival. At present, however, the mechanisms enabling these cells to survive in a dormant state and ultimately recur are poorly understood and clinical methods to detect DTCs, as well as DTC-directed therapeutic approaches, are still in their infancy. To address this critical gap and elucidate critical pathways in dormant tumor cell survival, we and others have developed a variety of mouse models for human breast cancer that recapitulate key features of human breast cancer progression, including metastasis, residual disease, dormancy and recurrence. Investigation of these models using both genetic and pharmacological approaches has identified several mediators of dormant DTC survival and recurrence, demonstrated their relevance to pathways that contribute to therapeutic resistance in human breast cancers following targeted therapy or chemotherapy, and revealed that pharmacological targets for dormancy and recurrence may be unique to these stages of tumor progression. These findings have, in turn, led to the initiation of clinical trials to test the ability of targeted therapies to deplete the burden of DTCs in the bone marrow of breast cancer patients and thereby decrease risk of relapse. If successful, the ability to therapeutically target survival mechanisms utilized by DTCs would constitute a powerful, paradigm-shifting approach to preventing cancer recurrence and the mortality associated with it. Citation Format: Chodosh L. Tumor dormancy and recurrence [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr ES5-1.