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 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 ¼ 5) and low protein expression of 53BP1 (n ¼ 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. Mol Cancer Ther; 15(1); 190-8. Ó2015 AACR.

Cytotoxic and targeted therapy for hereditary cancers

“…However, retrospective analysis of women with metastatic BC revealed several instances of unexpectedly long remission of the disease; importantly, these survivors are enriched by BRCA1/2 germ-line mutation carriers, which is in good agreement with the data on increased chemosensitivity of BRCA-driven BC [119]. Furthermore, patients with BRCA1-like stage III BC show substantial benefit from adjuvant high-dose therapy [91, 120], and this effect correlates with the molecular status of BRCA1-related pathways [115]. There is also a number of case reports describing patients with germ-line BRCA1/2 mutations, who were treated by high-dose chemotherapy for the metastatic disease and remained tumor-free for years [121, 122].…”

“…There are some other proposed mechanisms of the resistance of BRCA1/2-mutated cells to the specific therapy, such as inactivation of TP53BP1 protein, efflux of platinum drugs or PARP inhibitors, or some other molecular events [25, 112–115]. However, they were demonstrated mainly in laboratory models, and their actual clinical relevance remains uncertain.…”

The Long Non-Coding RNA XIST Interacted with MiR-124 to Modulate Bladder Cancer Growth, Invasion and Migration by Targeting Androgen Receptor (AR)

“…LncRNA XIST has been reported to be up-regulated in many cancers [15, 36-38]. In cell lines created from the tissue of a patient with collecting duct carcinoma of the kidney, the XIST gene was found to have an increase in copy number [39].…”

Non-coding RNAs: long non-coding RNAs and microRNAs in endocrine-related cancers

“…Patients with high XIST mRNA and low protein expression of 53BP1 in BRCA1-like breast tumors showed no benefit from high-dose alkylating chemotherapy and lower disease-free and overall survival (Schouten, et al 2016). XIST expression was also decreased in uterine papillary serous carcinoma accompanied by wide-spread X chromosome demethylation ).…”