Predicting response to PARP inhibition in difficult-to-treat triple-negative breast cancer patients

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that lacks expression of hormone and growth factor receptors.  Patients with early TNBC currently receive up to six types of treatments, including chemotherapy, immunotherapy, and targeted therapy. Although immunotherapy, when administered in combination with chemotherapy has been shown to decrease the overall rate of recurrence, there are still a significant proportion of patients that do not respond to these treatments.  Patients with tumors that do no melt completely with these treatments (i.e. have residual disease at the time of surgery) have a high chance of recurrence.  

To improve the outcomes of these patients after surgery, clinicians are offering more treatments, but there is a lack of clinical and biological rationale to guide which treatments should be offered, albeit as single-agents or two-drug combinations. We need to better predict which patients are at high-risk and low-risk, so that patients and clinicians can better decide subsequent treatment.    

To achieve this goal, we need to better understand the potential utility of PARP inhibitors, an orally-available targeted therapeutic agent, that has been shown to be effective in improving overall survival amongst patients with commonly hereditary risk of developing breast cancer, that is a mutation in the BRCA1/2 gene.  Patients with BRCA1/2 mutations consist of only 15% of all patients with triple-negative breast cancer.  However, my group and others have identified gene tests or signatures (compilation of multiple genetic defects) that could identify up to 60% of triple-negative breast cancer patients that could benefit from PARP inhibitors.  These tests need to be validated using patient samples and in a prospective manner.  Therefore, using samples at the time of surgery from patients who did not respond completely to chemotherapy plus immunotherapy, we will conduct whole-genome sequencing, and analyze the data to identify the presence of these gene signatures.  From a subset of these patients, we will also develop a three-dimensional laboratory model, called patient-derived organoids, to test the accuracy of the genomic predictions by evaluating the efficacy of PARP inhibitors.  

Importantly, our study aims to mitigate two of the most challenging aspects of triple-negative breast cancer, the lack of biomarkers to select patient populations who may or may not benefit from therapies, and the paucity of targeted therapies.  In a manner similar to which a genetic test has revolutionized the treatment paradigm in which patients with estrogen-receptor positive breast cancer are offered chemotherapy versus anti-hormonal therapy, our study aims to identify such a test that can risk-stratify triple-negative breast cancer patients.   Therefore, our proposal will lead to important changes in the therapeutic strategy for TNBC patients, resulting in much-needed improvements in long-term outcomes.