High XIST and Low 53BP1 Expression Predict Poor Outcome after High-Dose Alkylating Chemotherapy in Patients with a BRCA1-like Breast Cancer

Abstract

In previous studies high expression of XIST and low expression of 53BP1 were respectively associated with poor systemic therapy outcome in patients and therapy resistance in BRCA1-deficient mouse tumor models, but have not been evaluated in BRCA1-deficient patients. Previously we demonstrated that classifying breast cancer copy number profiles as BRCA1-like or non-BRCA1-like identified patients enriched for defects in BRCA1 that benefit from high dose (HD) alkylating chemotherapy compared to a conventional standard regimen. We investigated whether XIST and 53BP1 expression predicted poor outcome of HD chemotherapy within 28 BRCA1-like patients from a trial randomizing between HD (4 cycles 5-fluorouracil, epirubicin, cyclophosphamide (FEC) followed by 1 cycle high dose carboplatin, thiotepa, cyclophosphamide (CTC)) or conventional chemotherapy (5 cycles FEC), for which both XIST and 53BP1 status were available. High RNA expression of XIST (n=5) and low protein expression of 53BP1 (n=3) expression did not coincide. Patients with either one had poor outcome after treatment with HD chemotherapy, whereas patients with low expression of XIST and high expression of 53BP1 derived substantial benefit of this regimen on recurrence free, disease free and overall survival, corroborating pre-clinical findings. XIST and 53BP1 may be predictive biomarkers in BRCA1-like breast cancer.