Detecting and Defining Residual Tumor Cell Subsets to Enable Recurrence Prevention in Early-Stage Breast Cancer Patients
Abstract
Challenge: This proposal addresses the overarching challenge of determining how breast cancer cells survive in a dormant state for years and then re-emerge as recurrent cancers, and how to prevent this from occurring. Rationale: Breast cancer is both common and treatable. Consequently, of the 14.5 million cancer survivors alive today in the U.S., nearly 1 in 4 are breast cancer survivors. Up to 30% of breast cancer patients will ultimately recur and die from their disease. These recurrences occur after a period of clinical remission that may extend decades after treatment of the primary tumor. Recurrent tumors arise from the pool of residual disseminated tumor cells (DTCs) that survive in their host following treatment of the primary breast cancer. Prior to their reemergence as metastatic disease, residual breast cancer cells lay dormant in sites such as the bone marrow; accordingly, patients who harbor DTCs have a substantially increased risk of recurrence. Unfortunately, at present methods to detect, profile, and target DTCs in the clinic are virtually non-existent. Consequently, physicians lack the tools to actively monitor breast cancer survivors for residual disease or prevent it from reemerging as incurable, recurrent disease. As a result, “watchful waiting” is the standard of care, resulting in millions of breast cancer survivors living in fear of recurrence. For these reasons, there is a pressing unmet need to develop improved methods to detect residual tumor cells before they manifest as overt, incurable recurrent cancers, and to eradicate this reservoir of cells as a means to prevent tumor recurrence and its associated mortality. Preventing this critical step in cancer progression would enable a transformational new approach to patient care. Objective: Depleting the reservoir of residual tumor cells that survive therapy would be a novel and promising approach to preventing breast cancer recurrence and the mortality associated with it. Achieving this, however, has been hindered a lack of tools to find residual tumor cells or measure whether therapies designed to kill them are effective. This proposal addresses these critical unmet needs by elucidating the relationship between residual cancer cells in the bone marrow and bloodstream, and by enabling the development of real-time markers for recurrence risk and response to therapies that target this critical population of cells. This proposal will break new ground by using novel molecular and cellular methods to analyze residual disease in blood and bone marrow samples from early-stage breast cancer patients in the ongoing PENN-SURMOUNT Surveillance study. The proposed studies focus on the detection and molecular characterization of residual tumor cells in patients as a crucial step toward designing approaches to therapeutically target this critical reservoir of cells, and thereby prevent metastatic tumor recurrence and death. Aims: This proposal will employ new methods to detect and characterize residual tumor cells in the bone marrow and blood of early-stage breast cancer patients, evaluate the molecular and genomic relationship of residual tumor cells in the blood versus bone marrow, and determine whether circulating tumor markers can accurately identify patients with DTCs in their bone marrow, which would obviate the need for bone marrow aspirates. Patient follow-up will be performed to determine the association of residual disease-related variables with clinical outcome. This application will use single cell genomic analysis to advance the development of a new diagnostic test for residual tumor cells to accurately identify women at risk for recurrence, define the specific biological features of the residual tumor cells that each woman harbors, and monitor the efficacy of therapies designed to target those cells in order to eradicate them before they can give rise to recurrent, lethal cancers. Applicability and Timeline: Results fro
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010008
Entities
People
- Lewis A Chodosh
Organizations
- United States Army
- University of Pennsylvania