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 with 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 HD carboplatin, thiotepa, cyclophosphamide] or conventional chemotherapy (5 cycles FEC), for which both XIST and 53BP1 statuses 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 survival, disease-free survival, and overall survival, corroborating preclinical findings. XIST and 53BP1 may be predictive biomarkers in BRCA1-like breast cancer.
Highlights
Germline mutations in the BRCA1 gene confer a substantially increased breast cancer risk [1, 2]
We assessed whether the expression of X inactive–specific transcript (XIST) and 53BP1 can be used to identify a population of patients with a BRCA1-like breast cancer that do not benefit from HD chemotherapy
We investigated the influence of XIST and 53BP1 to predict outcome after HD chemotherapy compared with conventional chemotherapy by dividing them into two groups: (i) "XIST-lowand-53BP1-high," predicted to be sensitive, and (ii) "XIST-highor-53BP1-low," predicted to be resistant
Summary
Germline mutations in the BRCA1 gene confer a substantially increased breast cancer risk [1, 2]. XIST and 53BP1 may be predictive biomarkers in BRCA1-like breast cancer. BRCA1 deficiency and low XIST expression identify a similar group of patients [12, 16,17,18,19,20,21]. We previously investigated a BRCA1-like copy number classifier as predictive biomarker for benefit of HD alkylating chemotherapy [25, 26]. Patients with a BRCA1-like tumor had a 6fold lower risk of recurrence and death when treated with HD chemotherapy compared with conventional chemotherapy. We assessed whether the expression of XIST and 53BP1 can be used to identify a population of patients with a BRCA1-like breast cancer that do not benefit from HD chemotherapy. Our hypothesis was that matching the targetable defect of the model system to patients with that defect would result in good concordance of the preclinical and clinical findings and create opportunities for translation toward patients
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