Circular RNAs: novel regulators of resistance to systemic treatments in breast cancer.

Systematic treatments including chemotherapy, endocrine therapy, and HER2-targeted therapy are important therapeutic approaches to breast cancer. However, drug resistance is a major barrier to achieving a cure in breast cancer (BC) patients. Hence, it is urgent to gain insight into the drug-resistance mechanisms in order to improve the prognosis of BC patients. Genetic alternations, epigenetic alternations, and other non-genetic mechanisms such as BC stem-like cells, metabolic reprogramming, and tumor microenvironment contribute to drug resistance of BC. With the development of single-cell sequencing of circulating tumor cell and next-generation sequencing of matched pre- and post- progression tumor biopsies or ctDNA from BC patients with drug resistance, new mechanisms of resistance are being discovered. An increasing number of microRNAs and long non-coding RNAs have been found to be associated with the drug resistance of BC. However, there are few reports on the role of circular RNAs (circRNAs) as master regulators of drug resistance. Therefore, there is still much to say in the field of drug resistance-related circRNAs. In this review, we mainly focus on literature evidence for the detailed mechanisms associated with systematic treatments' resistance of BC and how circRNAs intensify or weaken drug resistance. Exogenous expression of tumor suppressive circRNAs or knockdown of oncogenic circRNAs has been verified to reverse drug resistance of BC cells, which highlights that circRNAs may function as potential biomarkers and/or therapeutic targets of BC. Treatment targeting abnormally expressed circRNAs alone or combined with other systemic treatments may be a promising approach to conquering drug resistance.

An evidence-based review of the outcome of fulvestrant plus a targeted agent versus fulvestrant alone in treating hormone receptor-positive endocrine therapy-resistant metastatic breast cancer.

BACKGROUND: Fulvestrant is approved for the hormone receptor-positive advanced metastatic breast cancer (MBC) patients during or after prior endocrine treatment. The adding of a targeted agent to fulvestrant has improved the outlook for these patients from recent studies. However, these results were still under investigation, the analysis was undertaken to assess the clinical outcomes of the fulvestrant-based combination therapy compared with fulvestrant monotherapy. METHODS: I systematically searched electronic databases to identify eligible literatures till January 2019. Randomized-controlled trials (RCTs) assessing the efficacy of a targeted agent to fulvestrant with fulvestrant mono-therapy in MBC patients who are refractory to or intolerant of prior endocrine therapy were included. RESULTS: Six RCTs were included in this analysis. The group of a targeted agent to fulvestrant was significantly improved overall survival (OR = 0.86, 95%CI = 0.76-0.97, P = 0.02), progression-free survival (OR = 0.66, 95%CI = 0.54-0.81, P < 0.0001), as well with the objective response rate (OR = 2.30, 95%CI = 1.67-3.18, P < 0.00001), respectively. However, there are more adverse effects with the combination group (OR = 6.71, 95%CI = 5.58-8.06, P < 0.00001). CONCLUSIONS: Pooled results indicate that adding a targeted agent to fulvestrant prolonged OS, PFS and ORR in relapse or metastatic hormone receptor-positive breast cancer after prior endocrine therapy. Combination of fulvestrant with a targeted agent was associated with more frequent grade 3/4 toxicities. Further research is needed to develop a database of reliable biomarkers and their individual impact on the fulvestrant-based combination treatments.