Synergized Immune and Tumor Cell Bone Marrow Biomarkers to Predict Recurrence in Triple Negative Breast Cancer

Project Summary/Abstract
Triple negative breast cancer (TNBC) is aggressive and a large percentage of patients develop metastatic
disease. Disseminated tumor cells (DTCs) found in the bone marrow (BM) of TNBC patients may be the
intermediaries of the metastatic process. Data from our lab as well as others suggest that the immune landscape
of BM may influence DTC latency, treatment resistance, and metastatic potential. We have already defined and
validated an 8 gene expression-based biomarker panel that can detect DTCs in the BM of treatment naïve TNBC
patients and that predicts development of distant metastatic disease. Our recent data indicate that TNBC patients
with DTC-positive BM have altered populations of immune cell precursors and this is associated with recurrent
disease development. Based on these findings, we hypothesize that immune checkpoint inhibitors will
facilitate the elimination of BM DTCs in TNBC patients by altering the immune microenvironment in
patients with specific DTC and/or BM immune cell populations, and that cell population-specific gene
expression signatures can predict which patients will benefit most from aggressive immunotherapy to
prevent metastatic disease relapse.
We will test this hypothesis using our extensive biorepository of BM specimens collected from TNBC patients
who received conventional chemotherapy, as well as prospectively collected specimens from TNBC patients
participating in an independently funded institutional phase II immune checkpoint inhibitor (ICI) trial of
carboplatin/paclitaxel/nivolumab with or without cabiralizumab. Our goals are: 1. To evaluate the ability of our 8-
gene DTC gene panel to predict distant disease development in TNBC patients enrolled in our ICI therapeutic
trial of carboplatin/paclitaxel/nivolumab with or without cabiralizumab; 2. To understand the specific
subpopulations of BM DTCs in TNBC patients treated with conventional chemotherapy and ICI therapy which
are resistant to therapy, and; 3. To understand alterations in specific T cell and conventional dendritic cell (cDC)
populations in the BM when DTCs are present, and how this is impacted by conventional and ICI therapy. The
results of this proposal will lead to a greater understanding of immune escape and heterogeneity of BM
micrometastatic disease as well as biomarkers for improving conventional and ICI therapy in TNBC patients.

Grant Number: 5R01CA262555-05
NIH Institute/Center: NIH
Principal Investigator: Rebecca Aft