Liquid Biopsy Biomarkers of Targeted Therapy Resistance in Metastatic ER+ Breast Cancer

At a Glance

This project will pioneer a liquid biopsy approach to identify treatment-resistant and aggressive features in estrogen receptor-positive (ER+) metastatic breast cancer. The innovative technique, using blood samples, aims to predict the efficacy of standard regimens early, enabling personalized treatment strategies and improving outcomes for breast cancer patients in Wisconsin.

The Challenge

Breast cancer is the most common cancer in Wisconsin, with over 4,600 new cases annually. Metastatic breast cancer (MBC), the lethal form of the disease, is the second most common cause of cancer mortality for Wisconsin women, with 5-year survival of less than 30 percent. Over 70 percent of breast cancers are estrogen receptor positive (ER+), and endocrine therapy (ET) inhibiting the estrogen receptor ER pathway driving tumor growth is the standard treatment for women with estrogen receptor positive metastatic breast cancer (ER+MBC). ET is typically used in combination with CDK4/6 inhibitors (CDKi) which target cell cycle progression, slowing tumor progression. However, even with these regiments, 1 in 5 patients experience upfront ET resistance and most patients acquire resistance within 25 to 28 months of treatment. There are currently no clinical or molecular biomarkers of ET resistance.

Project Goals

The research team hypothesizes that tumor-derived DNA (ctDNA) fragmentation patterns will distinguish endocrine resistant from endocrine responsive tumor phenotypes and identify patients with aggressive disease biology after first line CDKi therapy. This hypothesis will be tested through the following aims:

1. Identify ctDNA genomic alterations and fragmentomic patterns associated with earlier progression on first line ET/CDKi in ER+MBC.
2. Identify ctDNA genomic alterations and fragmentomic patterns associated with a rapid progression phenotype after first line ET/CDKi in ER+MBC.