TNBC accounts for approximately 15% of all breast cancers in American women, and it is over-represented in young women, Black women, and women with inherited mutations in the BRCA1 tumor suppressor gene. This type of breast cancer is called “triple-negative” because it lacks expression of estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2). Among all subtypes of breast cancer, TNBC has the worst prognosis. Because it is a disease that is defined by what it is not, TNBC is effectively a collection of heterogeneous tumors that have different biological drivers and therefore different therapeutic susceptibilities
Genetic or epigenetic inactivation of the homologous recombination (HR) DNA double-strand break repair pathway is common in TNBC, and such tumors are said to have homologous recombination deficiency (HRD). The presence of HRD is associated with hypersensitivity to DNA damaging chemotherapy, some targeted agents (e.g., poly(ADP)ribose polymerase inhibitors), and ionizing radiation. The overarching goal of the Stecklein Lab is to understand how genomic instability broadly, and HRD specifically, regulates intrinsic and extrinsic (i.e., microenvironmental) therapeutic vulnerabilities. His research team employs in vitro, in vivo, human tissue, and computational strategies to address these questions.
Dr. Stecklein is also active in clinical translational research. He has ongoing projects sequencing TNBC tumor tissue from innovative neoadjuvant systemic therapy trials, and is using circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and extracellular vesicles (EVs) to assess treatment response and guide adjuvant therapy in a prospective clinical trial. This work will allow his team to identify predictive and prognostic biomarkers that will enable personalized neoadjuvant and adjuvant therapy for individual TNBC patients.
The long-term goals of he and his lab team are to define and optimize personalized treatment strategies for TNBC and translate promising pre-clinical findings into early-stage therapeutic trials.