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Simple Summary: Receptor for hyaluronan-mediated motility (RHAMM) is a hyaluronan receptor involved in various functions, including in breast cancer. Chemoresistance in breast cancer is a major clinical issue, and the role of RHAMM and hyaluronan in this process is not well understood. Our study found that RHAMM and hyaluronan are linked to increased aggressiveness and recurrence in breast cancer after chemotherapy. In lab experiments, epirubicin-resistant breast cancer cells had higher RHAMM levels than non-resistant cells. Knockdown of RHAMM decreased the growth and migration of both cell types. It also lowered CD44 levels, a marker of cancer stem cells, and changed N-cadherin and E-cadherin, resulting in more typical epithelial cell behavior. These findings suggest that abnormal RHAMM activity contributes to chemoresistance by enhancing cancer stem cell properties and altering cell characteristics, promoting cancer growth and spread. This research could lead to new ways to combat breast cancer chemoresistance. Background/Objectives: Receptor for hyaluronan-mediated motility (RHAMM) is a hyaluronan (HA) receptor, which exerts diverse biological functions in not only physiological but also pathological conditions in human malignancies, including breast cancer. Although chemoresistance is a significant clinical challenge in breast cancer, a possible contribution of RHAMM and hyaluronan to breast cancer chemoresistance has remained unclear. Methods: We immunolocalized RHAMM and HA in breast carcinoma tissues. Also, we utilized epirubicin-sensitive (parental) and rpirubicin-resistant (EPIR) breast cancer cell lines to explore the role of RHAMMM in breast cancer progression. Results: We found out that RHAMM and HA were cooperatively correlated with breast cancer aggressiveness and recurrence after chemotherapy. In vitro studies demonstrated that RHAMM was overexpressed in EPIR cells compared to parental cells. In addition, the knockdown of RHAMM significantly suppressed proliferation and migration of both parental and EPIR cells. On the other hand, the expression level of cancer stem cell marker CD44, which was overexpressed in M-EPIR (epirubicin-resistant MCF-7 subline) compared to MCF-7, was significantly suppressed by knockdown of RHAMM. In addition, the knockdown of RHAMM significantly altered the expression of N-cadherin and E-cadherin, leading to an epithelial phenotype. Conclusions: Aberrant RHAMM signaling were considered to cause chemoresistance related to cancer stemness and epithelial to mesenchymal transition, and increased cell proliferation and migration of both chemo-sensitive and chemo-resistant breast cancer cells. [ABSTRACT FROM AUTHOR]

Introduction: This multicenter, phase II randomized, non-inferiority study reports from the first prospective two-armed randomized control trial that compared the efficacy, safety, and quality of life (QoL) of pegylated liposomal doxorubicin (PLD)-based and epirubicin-based as adjuvant chemotherapy for stage I-II human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Methods: Patients with stage I/II HER2-negative breast cancer received PLD (37.5 mg/m2, Q3W, 5 cycles, LC arm) plus cyclophosphamide (600 mg/m2) or epirubicin (90 mg/m2, Q3W, 4 cycles, EC arm) plus cyclophosphamide (600 mg/m2). Randomization was stratified by lymph node and ER and PR status. The primary endpoint was disease-free survival (DFS), and secondary endpoints were overall survival (OS), safety profiles, and QoL. QoL was assessed using the EORTC-QLQ-C30 and QLQ-BR23 questionnaires. Results: A total of 256 patients were assigned to LC (n = 148) and EC (n = 108). There was no difference in 5-year DFS and OS rate between the two groups. LC-based adjuvant regimens had significantly less alopecia and low-grade 3–4 hematologic adverse events (AEs). Significantly improved QoL was observed in the LC arm during and after treatment for symptoms including fatigue, nausea and vomiting, and systemic therapy side effects. Conclusion: Comparable efficacy and safety between adjuvant PLD and epirubicin for stage I-II HER2-negative breast cancer was observed. There was no difference in the 5-year DFS and OS rates between the two treatment arms. However, low-grade 3–4 AEs and a trend of favorable QoL symptom scales were observed in the LC arm, suggesting that PLD-containing regimen could become a new standard treatment for early-stage HER2-negative breast cancer patients. Plain Language Summary: This study compared two chemotherapy treatments for human epidermal growth factor receptor 2 (HER2)-negative early-stage breast cancer: one using a drug called pegylated liposomal doxorubicin (PLD) and the other using epirubicin. A total of 256 women with stage I or II breast cancer from multiple medical centers in Taiwan were included in this study. They were randomly assigned to receive either PLD or epirubicin along with another drug called cyclophosphamide. Traditional treatments like anthracyclines (including doxorubicin and epirubicin) have been widely used but can have serious side effects. PLD is a newer drug that seems to work as well as traditional anthracyclines but with fewer harmful effects. The study found that both treatments were equally effective in 5-year disease-free survival and overall survival. However, the PLD treatment caused fewer severe side effects, such as hair loss and blood-related problems. Also, patients who received PLD reported feeling better during and after treatment compared to those who received epirubicin. This study is one of the first to directly compare PLD and epirubicin in a randomized trial for HER2-negative early-stage breast cancer patients. The results suggest that PLD could be a treatment option for these patients, offering similar effectiveness with fewer side effects to epirubicin treatments. [ABSTRACT FROM AUTHOR]

Purpose: Cyclophosphamide, Epirubicin/Doxorubicin, 5-fluorouracil (CEF or CAF) chemotherapy has long been a standard first-line treatment for breast cancer. The genetic variations of enzymes that are responsible for the metabolism of these drugs have been linked to altered treatment response and toxicity. Two drug-metabolizing enzymes ALDH1A1 and NQO1 are critically involved in the pathways of CEF/CAF metabolism. This study aimed to evaluate the effect of ALDH1A1 (rs13959) and NQO1 (rs1800566) polymorphisms on treatment response and toxicities caused by adjuvant (ACT) and neoadjuvant chemotherapy (NACT) where CEF/CAF combination was used to treat Bangladeshi breast cancer patients. Methods: A total of 330 patients were recruited from various hospitals, with 150 receiving neoadjuvant chemotherapy and 180 receiving adjuvant chemotherapy. To extract genomic DNA, a non-enzymatic simple salting out approach was adopted. The polymerase chain reaction-restriction fragment length polymorphism method was used to detect genetic polymorphisms. Unconditional logistic regression was used to derive odds ratios (ORs) with 95% confidence intervals (CIs) to study the association between genetic polymorphisms and clinical outcome and toxicity. Results: A statistically significant association was observed between ALDH1A1 (rs13959) polymorphism and treatment response (TT vs. CC: aOR = 6.40, p = 0.007; recessive model: aOR = 6.38, p = 0.002; allele model: p = 0.032). Patients with the genotypes TT and CT + TT of the NQO1 (rs1800566) polymorphism had a significantly higher risk of toxicities such as anemia (aOR = 0.34, p = 0.006 and aOR = 0.58, p = 0.021), neutropenia (aOR = 0.42, p = 0.044 and aOR = 0.57, p = 0.027), leukopenia (aOR = 0.33, p = 0.010 and aOR = 0.46, p = 0.005), and gastrointestinal toxicity (aOR = 0.30, p = 0.02 and aOR = 0.38, p = 0.006) when compared to the wild CC genotype, while patients with the genotype CT had a significant association with gastrointestinal toxicity (aOR = 0.42, p = 0.02) and leukopenia (aOR = 0.52, p = 0.010). The TT and CT + TT genotypes of rs13959 had a significantly higher risk of anemia (aOR = 2.00, p = 0.037 and aOR = 1.68, p = 0.029). There was no significant association between rs1800566 polymorphism and treatment response. Conclusion: Polymorphisms in ALDH1A1 (rs13959) and NQO1 (rs1800566) may be useful in predicting the probability of treatment response and adverse effects from CEF or CAF-based chemotherapy in breast cancer patients. [ABSTRACT FROM AUTHOR]

This study introduces a new electrochemical platform for the rapid and sensitive detection of the potent anticancer drug epirubicin (EPB) in blood plasma. The platform utilizes a graphene/Zinc Oxide (ZnO) nanoparticle nanocomposite modified glassy carbon electrode (GCE), which was synthesized through a simple one-pot method where ZnO nanoparticles were dispersed onto graphene sheets. The graphene/ZnO/GCE nanocomposite was characterized using advanced techniques such as FE-SEM, EDS, XRD, FT-IR, and XPS in order to analyze its structural properties. The graphene/ZnO/GCE electrode exhibited minimal interference and demonstrated high selectivity and sensitivity in detecting EPB. The sensor's selectivity was validated by a recovery rate exceeding 98.40 % and a relative standard deviation below 4.65 %. The limits of detection and quantification were determined to be 6.0 nM and 9.0 nM, respectively, indicating the sensor's high sensitivity within a practical concentration range. With a sensitivity of 1.09509 µA/µM, the sensor exhibited a linear response to EPB concentrations ranging from 4.0 to 730.0 μM. Furthermore, successful detection of EPB in serum samples with a recovery rate exceeding 98.40 % underscores the practical utility of the graphene/ZnO/GCE sensor. The detailed characterization of the graphene/ZnO/GCE nanocomposite provides insights into its structural and chemical attributes, furthering its potential for biomedical applications.

Background: Anthracycline-taxane is the standard chemotherapy strategy for treating high-risk early breast cancer despite the potentially life-threatening adverse events caused by anthracyclines. Commonly, the combination of docetaxel and cyclophosphamide (TC) is considered an alternative option. However, the efficacy of TC compared to anthracycline-taxane chemotherapy is unclear. This study compares disease-free survival (DFS), overall survival (OS) and cardiotoxicity between adjuvant TC and anthracycline-taxane for stages I–III, HER2-negative breast cancer. Methods: A systematic search on MEDLINE, Embase and Cochrane CENTRAL for randomized-controlled trials published until 11 March 2024, yielded 203 studies with 11,803 patients, and seven trials were included. Results: TC results in little to no difference in DFS (HR 1.09, 95% CI 0.98–1.20; moderate-certainty of evidence); OS (1.02, 95% CI 0.89–1.16; high-certainty of evidence); and cardiotoxicity (RR 0.54, 95% CI 0.16–1.76; high-certainty of evidence), compared to anthracycline-taxane. In the subgroup analysis, patients with ≥4 lymph nodes had improved DFS from anthracycline-taxane over TC. Conclusions: Overall, there was no difference between TC and anthracycline-taxane in DFS, OS and cardiotoxicity. In women with ≥4 nodes, anthracycline-taxane was associated with a substantial reduction in relapse events, compared to TC. Our study supports the current standard of practice, which is to use anthracycline-taxane and TC chemotherapy as a reasonable option in select cases. [ABSTRACT FROM AUTHOR]

The new adjuvant chemotherapy of docetaxel, epirubicin, and cyclophosphamide has been recommended for treating breast cancer. It is necessary to investigate the potential drug-drug Interactions (DDIs) since they have a narrow therapeutic window in which slight differences in exposure might result in significant differences in treatment efficacy and tolerability. To guide clinical rational drug use, this study aimed to evaluate the DDI potentials of docetaxel, cyclophosphamide, and epirubicin in cancer patients using physiologically based pharmacokinetic (PBPK) models. The GastroPlus™ was used to develop the PBPK models, which were refined and validated with observed data. The established PBPK models accurately described the pharmacokinetics (PKs) of three drugs in cancer patients, and the predicted-to-observed ratios of all the PK parameters met the acceptance criterion. The PBPK model predicted no significant changes in plasma concentrations of these drugs during co-administration, which was consistent with the observed clinical phenomenon. Besides, the verified PBPK models were then used to predict the effect of other Cytochrome P450 3A4 (CYP3A4) inhibitors/inducers on these drug exposures. In the DDI simulation, strong CYP3A4 modulators changed the exposure of three drugs by 0.71–1.61 fold. Therefore, patients receiving these drugs in combination with strong CYP3A4 inhibitors should be monitored regularly to prevent adverse reactions. Furthermore, co-administration of docetaxel, cyclophosphamide, or epirubicin with strong CYP3A4 inducers should be avoided. In conclusion, the PBPK models can be used to further investigate the DDI potential of each drug and to develop dosage recommendations for concurrent usage by additional perpetrators or victims. [ABSTRACT FROM AUTHOR]