Association of SLC12A1 and GLUR4 Ion Transporters with Neoadjuvant Chemoresistance in Luminal Locally Advanced Breast Cancer.

Chemoresistance to standard neoadjuvant treatment commonly occurs in locally advanced breast cancer, particularly in the luminal subtype, which is hormone receptor-positive and represents the most common subtype of breast cancer associated with the worst outcomes. Identifying the genes associated with chemoresistance is crucial for understanding the underlying mechanisms and discovering effective treatments. In this study, we aimed to identify genes linked to neoadjuvant chemotherapy resistance in 62 retrospectively included patients with luminal breast cancer. Whole RNA sequencing of 12 patient biopsies revealed 269 differentially expressed genes in chemoresistant patients. We further validated eight highly correlated genes associated with resistance. Among these, solute carrier family 12 member 1 (SLC12A1) and glutamate ionotropic AMPA type subunit 4 (GRIA4), both implicated in ion transport, showed the strongest association with chemoresistance. Notably, SLC12A1 expression was downregulated, while protein levels of glutamate receptor 4 (GLUR4), encoded by GRIA4, were elevated in patients with a worse prognosis. Our results suggest a potential link between SLC12A1 gene expression and GLUR4 protein levels with chemoresistance in luminal breast cancer. In particular, GLUR4 protein could serve as a potential target for drug intervention to overcome chemoresistance.

CNVs in 8q24.3 do not influence gene co-expression in breast cancer subtypes.

Gene co-expression networks are a useful tool in the study of interactions that have allowed the visualization and quantification of diverse phenomena, including the loss of co-expression over long distances in cancerous samples. This characteristic, which could be considered fundamental to cancer, has been widely reported in various types of tumors. Since copy number variations (CNVs) have previously been identified as causing multiple genetic diseases, and gene expression is linked to them, they have often been mentioned as a probable cause of loss of co-expression in cancerous networks. In order to carry out a comparative study of the validity of this statement, we took 477 protein-coding genes from chromosome 8, and the CNVs of 101 genes, also protein-coding, belonging to the 8q24.3 region, a cytoband that is particularly active in the appearance of breast cancer. We created CNVS-conditioned co-expression networks of each of the 101 genes in the 8q24.3 region using conditional mutual information. The study was carried out using the four molecular subtypes of breast cancer (Luminal A, Luminal B, Her2, and Basal), as well as a case corresponding to healthy samples. We observed that in all cancer cases, the measurement of the Kolmogorov-Smirnov statistic shows that there are no significant differences between one and other values of the CNVs for any case. Furthermore, the co-expression interactions are stronger in all cancer subtypes than in the control networks. However, the control network presents a homogeneously distributed set of co-expression interactions, while for cancer networks, the highest interactions are more confined to specific cytobands, in particular 8q24.3 and 8p21.3. With this approach, we demonstrate that despite copy number alterations in the 8q24 region being a common trait in breast cancer, the loss of long-distance co-expression in breast cancer is not determined by CNVs.

Combined endocrine and targeted therapy in luminal breast cancer.

Introduction: For decades, endocrine therapy has been the cornerstone of management for luminal breast cancer. Despite the substantial benefit derived by patients from endocrine therapy, primary and secondary resistances to endocrine therapy are serious clinical issues.Areas covered: Today, in the advanced setting, three distinct classes of targeted agents mTOR, CDK 4/6, and PI3K inhibitors, are approved for use. CDK 4/6 inhibitors have improved outcomes substantially, changing the natural history of advanced luminal breast cancer. Current studies seek to bring CDK 4/6 inhibitors to the early setting. This review will cover all available data on target therapy combinations with endocrine therapy for both the early and advanced settings, including approved drugs and agents in development.Expert opinion: Combined endocrine and target therapy has changed the landscape in advanced disease. In early disease, it is possible to have a large impact, particularly in patients with higher risk of relapse. Trials like ADAPTCYCLE seek to leverage neoadjuvant data to de-escalate treatment, substituting chemotherapy for CDK 4/6 inhibitors. In advanced diseases, studies such as PADA-1 point toward a future in which ctDNA will be used to define management before clinical progression occurs.

Managing Common Estrogen Deprivation Side Effects in HR+ Breast Cancer: an Evidence-Based Review.

PURPOSE OF REVIEW: The article reviews the consequences of estrogen deprivation during endocrine therapy for breast cancer and provides an update on alternative therapies for the management of symptoms. RECENT FINDINGS: Endocrine therapy has progressed substantially in recent years, and its use is recommended for all breast cancer patients expressing hormone receptors. The main adverse events of this treatment can be controlled with medications and nonpharmacological measures. Antidepressants are effective in controlling vasomotor symptoms. Vaginal discomfort can be treated with local lubricants and pelvic floor physiotherapy, which may help in sexual dysfunction. Pathophysiological mechanisms of musculoskeletal symptoms during aromatase inhibitors treatment are not well understood, but some studies evaluating treatment with duloxetine, yoga, and acupuncture have shown some benefits. For prevention of bone loss, patients with risk factors should be offered bisphosphonates or denosumab. Individualization of treatment is crucial. Consideration should be given to therapy effects on quality of life, and strategies for controlling associated symptoms should be offered.

Neoadjuvant endocrine therapy in breast cancer: current role and future perspectives.

Luminal breast cancer, as defined by oestrogen and/or progesterone expression by immunohistochemistry, accounts for up to 75% of all breast cancers. In this population, endocrine therapy is likely to account for most of the gains obtained with the administration of adjuvant systemic treatment. The role of adjuvant chemotherapy in these patients remains debatable since it is known that only a small fraction of patients will derive meaningful benefit from this treatment whilst the majority will be exposed to significant and unnecessary chemotherapy-related toxicities, in particular the elderly and frail. Therefore, neoadjuvant endocrine therapy (NET) becomes an attractive option for selected patients with hormonal-receptor positive locally advanced breast cancer. In this review, we discuss the current role of NET and future perspectives in the field.