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Genetic and Functional Analysis of the Role of Clonal Tumor-Infiltrating Leukocytes in Breast Cancer Pathogenesis and Therapy

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[Technical Report, Final Report]

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Sloan Kettering Institute for Cancer Research

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We hypothesize that some leukocytes infiltrating breast cancers possess oncogenic mutations which affect breast cancer growth and metastasis. We are investigating this hypothesis in 3 different patient groups 1 patients with newly diagnosed breast cancer and high amounts of tumor infiltrating leukocytes, 2 patients who developed secondary leukemias after treatment for breast cancer, and 3 breast cancer patients with clonal hematopoiesis CH incidentally found on genomic screens but with no apparent hematologic disorders. We have over 4,700 breast cancer patients who have undergone genomic testing of their tumors and peripheral lymphocytes. Of these patients, 25 have CH. We have clinical information from these patients and are currently assessing whether key clinical features influence CH. For those CH patients who have primary tumor tissue available, we will also sequence the TILs in the primary breast cancer to evaluate for mutations associated with CH. 4 We are also prospectively collecting blood samples from patients prepost neoadjuvant therapy and prepost surgery to assess how chemotherapy and primary tumor presence may affect CH. From a functional standpoint, we have made progress in evaluating models to assess how mutant hematopoietic cells impact tumor growth. Specifically, we evaluated two genes, Dnmt3A and Tet2, in select models and have expanded our studies to assess the functional role of Tet2 in a second transgenic model. Additionally, we have set up our assays to investigate first, whether select leukocytes produce inflammatory cytokines which impact breast cancer progression, second, whether Tet2 expression defines response to chemotherapy, and third, whether hypomethylating agents alone or in combination with chemotherapy lead to increased therapeutic efficacy.

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[A, Approved For Public Release]