Functional Tissue-based Therapy Response Prediction for Breast Cancer Patients

Breast cancer is a heterogeneous disease that can be classified into several subtypes. Triple-negative breast cancers (TNBC) lack estrogen and progesterone receptors and do not harbor HER2 amplification. TNBC accounts for 10-15% of all breast cancer cases and show great overlap with BRCA1/2 mutated breast cancers. BRCA1/2 mutations occur in 3% of breast cancer cases and cause defects in the homologous recombination (HR) pathway, leading to ineffective repair of double strand DNA breaks. Targeted therapy with Poly ADP Ribose Polymerase (PARP) inhibitors can specifically kill cells with impaired HR activity. The RECAP (homologous recombination REpair CAPacity) test, is a functional ex vivo assay that assesses whether the HR pathway is functioning, using RAD51 foci as a read-out. In a first cohort of primary breast cancer tumors, approximately 15% showed HR deficiency (HRD). The RECAP test is now also feasible on core needle biopsies from metastatic breast cancer, where 35% of the tumors showed HRD. Selection of patients for PARP inhibitor therapy using the functional RECAP test, as opposed to selection based on germline BRCA1/2 mutation, could enhance the number of patients benefiting from this therapy. Predictive value of the RECAP test for in vivo response to PARP inhibition requires validation, for which clinical trials are ongoing.

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