Tamoxifen intake in the evening/nighttime could be recommended in patients with high-risk HR+/HER2- BC while awaiting for results from further ET timing studies.

P3, N=456, Not yet recruiting, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

This study revealed dysregulation of various metabolic processes in TAMR cells, which may be crucial in elucidating the molecular basis of the mechanisms underlying acquired tamoxifen resistance.

Following this, IR-TAM is prepared by conjugating mitochondria-targeted heptamethine cyanine dye IR-68 with oxidative phosphorylation (OXPHOS) inhibitor Tamoxifen (TAM), which then self-assembled with albumin (Alb) to form IR-TAM@Alb nanoparticles. By doing this, tumor-targeting IR-TAM@Alb nanoparticle effectively reversed tumor hypoxia and depressed PD-L1 and TGF-β expression to sensitize RT. Meanwhile, due to the capacity of heptamethine cyanine dye in targeting RIPF and the function of TAM in depressing TGF-β, IR-TAM@Alb also ameliorated fibrosis development induced by RT.

P3, N=144, Recruiting, University of California, San Francisco | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

Combination of ATRA and tamoxifen is a new way for the treatment of ERα-positive ovarian cancer.

In particular, NF-κB inhibitors combined with tamoxifen were shown to significantly increase the sensitivity of breast cancer cells to tamoxifen. Combination therapy of miRNA-34a with doxorubicin was also found to synergistically inhibit the progression of doxorubicin-resistant breast cancer by inhibiting Notch/NF-κB signaling.

P2, N=23, Completed, AC Camargo Cancer Center | Active, not recruiting --> Completed

Among them, 8k, 8d, 8m, 8h, and 8f showed significantly potent IC50 values: 0.17, 5.48, 8.13, 20.51, and 23.61 µM) respectively, on MCF-7 cells compared to the positive control Raloxifene and Tamoxifen. Whereas, RMSD, RMSF, and Rg values from Molecular dynamics studies stipulated stability of the complex formed between compound 8k and receptor. All of these findings strongly indicate the antiproliferative potential of pyrazole-chalcone hybrids for the treatment of breast cancer.

This study shows the intricate epigenetic regulation of ID4 in breast cancer, highlighting subtype-specific differences in DNA methylation and chromatin accessibility.

Additionally, these compounds are being reported for the first time in this study as possible inhibitors of ERα for treating breast cancer, according to the notion of drug repurposing. Hence, these phytochemicals can be further studied and used as a parent core molecule to develop innovative lead molecules for breast cancer therapy.

All the results showed that MNPs-DPN-HA-FA-TMX can show good affinity to cancer cells using targeting agents and induce apoptosis in metastatic breast ductal carcinoma T-47D cell lines. Also, the protective effects of MNPs on hepatocytes are quite evident, and they can reduce the side effects of TMX.

P=N/A, N=5, Active, not recruiting, University Medical Center Groningen | Recruiting --> Active, not recruiting | Trial completion date: Jan 2024 --> Oct 2024 | Trial primary completion date: Jan 2024 --> Oct 2024

Inducible conditional KO mice were generated by crossing miR-23a/b clusterflox/flox mice with PlpCre-ERT2 mice; the offspring were injected with tamoxifen at 10 days or 10 weeks of age to induce a myelin-specific miR-23a/b cluster deletion...Moreover, changes in protein expression occur in KO mice, with increased leucine zipper-like transcriptional regulator 1 expression, decreased R-RAS expression, and decreased phosphorylation of extracellular signal-regulated kinases. These findings highlight the significant influence of miR-23a/b clusters on myelination during postnatal growth and aging.

Our findings elucidate that integrin α11 is upregulated by EZH2, forming a positive feedback circuit involving FAK-GLI-1 and contributing to drug resistance, cancer stem cell survival and EMT. Taken together, the results suggest integrin α11 as a promising prognostic marker and a powerful therapeutic target for drug-resistant breast cancer.

These alterations in genes associated with a Th2 and regulatory response coincided with a noteworthy increase in drug-associated cytotoxicity but only at concentrations far beyond those achieved in pharmacological therapy. These findings suggest that the effects of TAM, as described in preclinical studies on asthmatic horses, may not be attributed to the modification of the adaptive response.

The downregulation of SOX2OT in TAMR breast cancer indicates its involvement in resistance mechanisms. Further studies should explore the intricate interactions between SOX2OT, SOX2, and TME in breast cancer subtypes.

P2, N=238, Active, not recruiting, Seoul National University Hospital | Recruiting --> Active, not recruiting | Trial primary completion date: Dec 2023 --> Dec 2024

This study aimed to explore the underlying mechanisms of histone deacetylase (HDAC) inhibitor trichostatin A (TSA) to overcome resistance to tamoxifen in breast cancer cells...Finally, expression of vascular endothelial growth factor (VEGF), E-cadherin, Vimentin, phosphorylated phosphatidylinositol kinase (p-PI3k), phosphorylated protein kinase B (p-AKT), and phosphorylated mammalian target protein of rapamycin (p-mTOR) was evaluated by western blotting...However, HDAC inhibitor combined with PI3K inhibitor exerts more profound effects on the cancer cells as compared to HDAC inhibitor monotherapy. HDAC inhibitors inhibited the survival of breast cancer drug-resistant cells, invasion, migration, and angiogenesis by inhibiting the PI3k/Akt/mTOR signaling pathway.

Mice with MDA-MB-231 tumors and treated with tamoxifen (TAM), E2, or TAM/E2 exhibited increased osteolysis, cortical bone breakdown, pathologic fracture, and tumor volume; the combined E2/TAM group also had reduced bone volume. These results suggest that E2 increased osteolytic lesions in TNBC through a membrane-mediated PLC/PKC pathway involving ERα36, which was enhanced by TAM, demonstrating the role of ERα36 and its membrane-associated signaling pathway in bone tumors. This work suggests that ERα36 may be a potential therapeutic target in patients with TNBC.

Lastly, we demonstrate that the community cohesion scores can predict tamoxifen responses in ER+ breast cancer and suggest potential combination therapies (e.g. NAMPT and RXRA inhibitors) to reduce endocrine therapy resistance based on individualized characteristics. Our method opens new perspectives for the biomarker development in precision oncology.

Medication persistence for 4 years and more was good and similar between patients initiating aromatase inhibitor (AI) and tamoxifen (75.7% and 72.0%, respectively, P = .43)...Adherence to ET in BC is high in Western Sweden. Less regular nurse-initiated contacts between BC patients and nursesled surprisingly to a better adherence than a more regular nurse-initiated contact.

P2, N=160, Not yet recruiting, Andrea DeCensi

Chronic oral tamoxifen treatment resulted in a decrease in BDNF expression across several regions of the hippocampus. These findings provide a novel method of modeling and measuring chronic oral tamoxifen exposure and suggest a putative mechanism by which tamoxifen may cause cognitive and behavioral changes reported by patients.

Synergies between MELK inhibition with 4OH-tamoxifen (Tam) and ALK inhibition with HER2 inhibitors revealed potential therapeutic avenues for ERα-positive/PR-positive/HER2-negative and ERα-positive/PR-negative/HER2-positive tumors, respectively. Our findings propose MELK as a promising target for ERα-positive/PR-positive/HER2-negative BC and highlight ALK as a potential focus for ERα-positive/PR-negative/HER2-positive BC. The synergistic anti-proliferative effects of MELK with Tam and ALK with HER2 inhibitors underscore kinase inhibitors' potential for selective treatment in diverse BC subtypes, paving the way for personalized and effective therapeutic strategies in BC management.

Tamoxifen administration seems to increase estradiol and SHBG levels and reduce CRP and IGF-1 levels in women with breast cancer or at risk of developing breast cancer. Further studies are needed to determine whether these changes have any clinical relevance.

These methods can all identify patients that benefit from 2 years of tamoxifen with equal performance, indicating that GEX data might be used to guide adjuvant tamoxifen therapy.

The study showed that a subgroup of patients with a clinical high risk and a genomic low risk ER+/HER2-breast cancer benefits from NET resulting in BCS instead of a mastectomy. Additionally, NET may enable de-escalation in axillary treatment.

Conversely, overexpression of MFN1 alleviated TAM-induced mitochondrial apoptosis and promoted TAM resistance in sensitive cells. These results revealed that dysregulated mitochondrial dynamics contributes to the development of TAM resistance, suggesting that targeting MFN1-mediated mitochondrial fusion is a promising strategy to circumvent TAM resistance.

Low UTRN expression may contribute to tamoxifen resistance and a poor prognosis. Specifically, UTRN can improve clinical decision-making and raise the diagnosis accuracy of breast cancer.

Cathepsin D expression significantly predicts poor prognosis in breast cancer and is associated with variables of poor prognosis and shorter outcome. The strong association of Cathepsin D with aggressive tumour characteristics and poor outcomes warrants further research of its potential as a therapeutic target The results also suggest a possible interaction between Cathepsin D and tamoxifen therapy in ER-positive breast cancer which needs further investigation to elucidate the underlying mechanisms.

P=N/A, N=180, Not yet recruiting, International Research Training Group 2804

The lead compound was found to have a significant effect on the signaling pathways in parental and 4-hydroxytamoxifen-resistant cells...Accumulation of cleaved poly(ADP-ribose) polymerase in cells treated with compound 2f indicated induction of apoptosis. The selectivity analysis showed that lead compound 2f produces no significant effects on cytochromes P450, CYP19A1, CYP21A2, and CYP7B1.

The induction of FAT10 by IKKα is mediated by the transcription factor Pax5, and coordinated via an IKKα-p53-miR-23a circuit in which activation of IKKα attenuates p53-directed repression of FAT10. Thus, our findings establish IKKα-to-FAT10 pathway as a new therapeutic target for the treatment of Tam-resistant ER+ breast cancer.

Taken together, we introduce a number of novel promising diagnostic biomarkers for breast cancer. The use of garlic and ginger in the treatment of cancer can be useful. This action is probably through the antioxidant mechanism, and regulation of the expression of cancer related genes such as PTEN.

Women who responded to tamoxifen with a density decrease had on average 17% higher baseline density and a 2.2-fold higher PR expression compared to non-responders. Our results indicate that features in the normal breast tissue before tamoxifen exposure influences the tamoxifen-associated density decrease, and that the age-associated difference in density change may be related to age-dependant differences in expression of Ki67 and PR.

Although the acelERA BC study did not reach statistical significance for its primary INV-PFS end point, there was a consistent treatment effect with giredestrant across most key subgroups and a trend toward favorable benefit among patients with ESR1-mutated tumors. Giredestrant was well tolerated, with a safety profile comparable to PCET and consistent with known endocrine therapy risks. Overall, these data support the continued investigation of giredestrant in other studies.

This tamoxifen preference of TERRA was maintained in mammalian cells and mice, even when fused to Cre recombinase, expanding the mammalian synthetic biology toolbox. Not only is our platform transferable to engineer ligand preference of any steroid receptor, it can also profile drug-resistance landscapes for steroid receptor-targeted therapies.

Notably, the cancer inhibition efficacy of NCG was superior to that of both NAR and the positive control tamoxifen, and was accompanied by increased hepatic EST expression and reduced estradiol levels in the liver, blood, and tumor tissue. Moreover, few side effects were observed after NCG treatment. Our findings reveal NCG as a promising candidate for endocrine therapy and highlight hepatic EST targeting as a novel therapeutic strategy for HR+ breast cancer.

P3, N=3966, Active, not recruiting, NSABP Foundation Inc | Trial completion date: Dec 2038 --> Apr 2025

P=N/A, N=200, Recruiting, Institut Claudius Regaud | Trial completion date: Feb 2024 --> Feb 2026 | Trial primary completion date: Feb 2024 --> Feb 2026

P3, N=3966, Active, not recruiting, NSABP Foundation Inc | Trial completion date: Dec 2023 --> Dec 2038