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Detection of Minimal Residual Disease in Triple-Negative Breast Cancer

Research by Shane R. Stecklein, M.D., Ph.D., Junior Faculty, Kansas Institute for Precision Medicine COBRE.

Triple-negative breast cancer (TNBC) accounts for 15% of breast cancers and is defined by its lack of expression of estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2). As a disease defined by what it lacks, TNBC is a collection of biologically heterogeneous tumors. Because there is no unifying biology in TNBC, responses to standard-of-care chemoimmunotherapy are highly variable and compared to other subtypes of breast cancer, TNBC has the worst prognosis.

We are using a variety of in vitro, in vivo, human tissue-based, and computational approaches to understand the biological heterogeneity of TNBC, how this heterogeneity shapes the tumor-immune microenvironment, and how we can use biology and molecular biomarkers to personalize treatment for individual TNBC patients.

Recent work has shown that TNBC patients who exhibit plasma circulating tumor DNA (ctDNA) after definitive treatment are significantly more likely to develop recurrent disease and die of TNBC compared to patients with undetectable ctDNA. This suggests that the presence of ctDNA is a marker of systemic minimal residual disease (MRD) and that stratifying TNBC patients based on molecular markers of MRD is an optimal paradigm by which to personalize adjuvant intensification approaches in high-risk TNBC patients. Though ctDNA status is a significant predictor of disease-free survival, its concordance with disease recurrence is imperfect and additional and/or complementary biomarkers are required to improve the sensitivity and specificity of MRD detection and enable the most accurate and personalized adjuvant treatment intensification strategies.

Extracellular vesicles (EVs or “exosomes”) and circulating tumor cells (CTCs) are two additional biomarkers that have been shown to have prognostic value in TNBC. In this work, we hypothesize that integrated analysis of ctDNA, CTCs, and EVs will improve our ability to detect MRD and allow us to define MRD categories that better correlate with recurrence risk. This will in turn enable better identification of patients who benefit from standard adjuvant therapy or are candidates for adjuvant intensification strategies.

illustration of process involved in using post-treament biomarker analysis to personalize treatment for individual TNBC patients