Estrogen Receptor Positive Breast Cancer

In addition, we have presented four enhancer reprogramming mechanisms (transcription factor cooperation, pioneer factor binding, dynamic assisted loading, and tethering) and the multiple enhancer-promoter contact models. Based on these mechanisms and models, this review proposes that the combination of multiple therapy strategies such as agonists/antagonists of SHRs plus endocrine therapy and the adoption of the latest sequencing technologies are expected to improve the efficacy of ER positive breast cancer treatment.

According to literature, and TailorX trial data, our study confirms the importance of ODX as a tool able to guide therapeutic choices and ensure patients the most appropriate adjuvant treatment.

Our findings suggest that NSDHL regulates the BCSC/tumor-initiating cell population in MCF-7 spheroids and xenograft tumors.

No abstract available

P1, N=62, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2024 --> Oct 2025

(early data and active trial) Who may benefit from the addition of anthracycline to their chemotherapy regimen (AC-T/TC)? Who may benefit from extended endocrine therapy?

The APIS ESR1 Mutations Kit demonstrated high sensitivity and specificity as a qualitative qPCR assay for detecting ESR1 mutations in varying WT backgrounds. Its performance with the SensID ESR1 Reference Set 1% AF cfDNA validated the kit's LoD at ≤1% MAF with external samples. The APIS kit is a valuable tool for assessing ESR1 mutations in both clinical and research settings, offering a more accessible alternative to traditional next-generation sequencing (NGS) and dPCR assays.

Tamoxifen is the drug of choice in ER-positive breast cancer, and several studies have shown better disease-free survival in these patients...In addition, a computational approach involving molecular modeling and simulation of phosphorylated and unphosphorylated forms of PAK1 was used to elucidate the dynamics of nuclear localization. Thus, PAK1 phosphorylation by JAK2 is a prerequisite for its nuclear localization and its tumorigenic effects on endometrial cancer cells.

P2, N=48, Suspended, City of Hope Medical Center | Recruiting --> Suspended

NOLUS positivity was observed in 20.43% of patients aged 22-50, compared to 8.93% in those over 50, though this difference was not statistically significant. NOLUS exhibits potential in predicting pCR in HR+/HER2- breast cancer, serving as a cost-effective substitute for genomic tests.

Interestingly, VCAN correlated with tumoral Ki67, while IGF1 with tumoral OCT4 that, in turn, correlated with tumoral Ki67 and patient BMI. Thus, peritumoral AT content of VCAN, and IGF1 are related to BC proliferation and aggressiveness.

P3, N=1156, Not yet recruiting, Alliance for Clinical Trials in Oncology

Our findings strengthen the evidence for a protective effect of skimmed milk consumption on ER-breast cancer risk. Further two-step MR analyses suggest that this protective effect may partly result from body mass index (BMI). There is no evidence that full cream milk consumption affects the risk of BC.

No abstract available

Pharmacologic targeting of estrogen signaling (either by HSD17B7 inhibition or with fulvestrant) and chemokine inflammation both decrease local E2 and prevent macrophage polarization. Overall, these findings suggest that chronic inflammation and hormonal disposition are critical contributors to the age-related nature of ER+ breast cancer development and growth and offer potential therapeutic insight to treat these patients. We uncover the unique underpinnings establishing how the systemic host environment contributes to the aged breast tumor microenvironment, characterized by high local estradiol and chronic inflammation with immune dysregulation, and show that targeting avenues of estrogen conversion and chronic inflammation work to restore anti-tumor immunity.

Cell interactome analysis reveals candidate signaling pathways that drive many of these cell states. This work lays a foundation for discovery of age-adapted therapeutic interventions for breast cancer.

Camizestrant at 75 and 150 mg showed a significant benefit in progression-free survival versus fulvestrant. These results support further development of camizestrant for the treatment of oestrogen receptor-positive, HER2-negative breast cancer.

Reinstating GIV alone in GIV-negative breast cancer cells reproduced approximately 20% of both the 'borrowed' and the 'intrinsic' gene induction patterns from contact co-cultures; conferred resistance to anti-estrogen drugs; and enhanced tumor dissemination. Findings provide a multiomic insight into MSC→tumor cell intercellular transport and validate how transport of one such candidate, GIV, from the haves (MSCs) to have-nots (ER+ breast cancer) orchestrates aggressive disease states.

P2, N=100, Recruiting, Mayo Clinic | Not yet recruiting --> Recruiting

P2, N=47, Active, not recruiting, City of Hope Medical Center | Recruiting --> Active, not recruiting

In multivariate MR analysis, after adjusting for total triglycerides, total cholesterol, and body mass index, the correlation between the protective relationship between 25(OH)D levels and the prognosis for ER- breast cancer remained and became increasingly significant (OR = 0.51, 95% CI = 0.31-0.83, P = .007). This study demonstrated a protective relationship between 25(OH)D levels and the prognosis of ER- breast cancer, but there was no connection between 25(OH)D levels and the prognosis of ER+ breast cancer.

Estrogen receptor-positive breast cancer patients may benefit from high levels of TGFB1 expression due to the repression of estrogen receptor signaling, inhibition of proliferation, and induction of apoptosis in cancer cells. However, some TGFB1-stimulated cells may undergo EMT, which increases the risk of metastasis.

Fulvestrant (FUL), a selective estrogen receptor degrader used to treat AI-resistant ERα-positive postmenopausal BC, was found to induce degradation of ERα together with a decrease in ER-mediated transcription; however, FA2H protein expression and migration remained unchanged. Overall, the findings of this study suggest that FA2H is one of the drivers of LTED cell migration, and that LTED cells resistant to FUL therapy may be involved in malignancy and metastatic mechanisms.

We conducted the first breast-tissue-based PWAS and identified seven proteins associated with breast cancer, including five proteins not previously implicated. These findings help improve our understanding of the underlying genetic mechanism of breast cancer development.

P1, N=2, Terminated, University of Utah | Trial completion date: Apr 2026 --> Jul 2024 | Recruiting --> Terminated; It was not feasible to perform FES PET/CT

P3, N=4220, Recruiting, Stemline Therapeutics, Inc. | Not yet recruiting --> Recruiting

P=N/A, N=128, Enrolling by invitation, University of Pennsylvania

These findings suggest that PRODH regulates tamoxifen resistance by regulating ferroptosis in tamoxifen-resistant cells.

P2, N=32, Completed, Peter Mac Callum Cancer Centre | Active, not recruiting --> Completed

Treating a sensitive luminal BC PDX with the CDK4/6i palbociclib revealed that, despite initial tumor shrinkage, some tumors might eventually regrow under drug treatment..

Due to discordant imaging findings, the patient then underwent 18F-FES PET/CT, which demonstrated over 90 metastatic osseous lesions. This study highlights the utility of 18F-FES PET/CT over 18F-FDG PET/CT in diagnosis of metastatic osseous lesions in a patient with metastatic estrogen receptor-positive breast cancer.

In this comprehensive review, we systematically summarize the critical role and intricate molecular mechanisms by which lncRNAs influence the development of tamoxifen resistance in breast cancer. Furthermore, we propose the potential clinical significance of lncRNAs as innovative therapeutic targets and prognostic biomarkers for breast cancer.

P2, N=137, Recruiting, Dartmouth-Hitchcock Medical Center | Trial completion date: Sep 2024 --> Aug 2029 | Trial primary completion date: Sep 2024 --> Feb 2026

This study confirms a bidirectional genetic link between ER+BC and EC, suggesting shared genetic etiologies and possibly linked pathophysiological pathways. Understanding the genetic interplay between ER+BC and EC can enhance strategies for the precise prevention and screening of these prevalent cancers, potentially leading to improved clinical outcomes and management of secondary primary malignancies.

In this study, we employed formaldehyde cross-linking followed by ERα immunoprecipitation and mass spectrometry to reveal that fulvestrant, the first FDA-approved SERD, induces the interaction between ERα and SUMO E3 ligases PIAS1 and PIAS2. In addition, raloxifene (a SERM) and elacestrant (the first FDA-approved oral SERD) were identified as compounds that similarly induce ERα SUMOylation and inhibit its chromatin interaction. Our findings reveal a mechanism by which select ERα inhibitors disrupt ERα function through SUMOylation, offering insights for the development of next-generation ERα-targeted therapies.

The multi-model approach achieved an AUC of 0.91 (95% CI: 0.87-0.95) on the internal set and an AUC of 0.84 (95% CI: 0.78-0.89) on the external cohort for predicting low- and high-breast cancer recurrence risk categories based on the Oncotype DX recurrence score. With further validation, the proposed methodology could provide an alternative to assist clinicians in personalizing treatment for breast cancer patients and potentially improving their outcomes.

For patients whose disease progressed on a prior CDK4/6i, we demonstrated comparable median TTFs for patients rechallenged with the same CDK4/6i (4.3 months, 95%CI 3.2-5.5) and with a different CDK4/6i (4.7 months, 95%CI 3.7-6.0) when compared to the recent PACE, PALMIRA, and MAINTAIN trials. Exploratory genomic analysis suggested that the presence of mutations known to confer CDK4/6i resistance, such as TP53 mutations, CDK4 amplifications, and RB1 or FAT1 loss of function mutations may be molecular biomarkers predictive of CDK4/6i retrial failure.

Dedicated FES brain PET represents a promising adjunct modality, noting limitations of small sample size, retrospective nature of our study, and the possibility of ER expression heterogeneity. Our findings merit future prospective clinical trials incorporating dedicated brain FES PET/CT and PET/MRI in the management of patients with ER-positive disease and BCBM.

Neoadjuvant endocrine therapy is associated with a reduction in mastectomy rate. Given the moderate methodological quality of previous studies, further RCTs are required.

However, further research is warranted to establish optimal dosing regimens, identify predictive biomarkers, and delineate its role within combination treatment strategies. Clarifying these aspects could refine MC's application, potentially reshaping treatment paradigms and enhancing patient outcomes in breast cancer management.

Integrating cell-based ChIP-sequencing with motif analysis and TCGA RNA-seq data, we identified a set of candidate NF-kB target genes upregulated with loss of DAB2IP linked with several oncogenic phenotypes, including altered RNA processing. This study provides insight into mechanisms associated with aggressiveness and recurrence within a subset of the typically less aggressive Luminal A breast cancer intrinsic subtype.

In this paper, we show that peritumor breast adipose-derived secretome (ADS) from patients with a high (>30) BMI is a stronger inducer of TNBC cell invasiveness and JAG1 expression than peritumor breast ADS from patients with low (<30) BMI. These findings indicate that patient BMI-associated changes in peritumor AT induce changes in peritumor ADS, which in turn acts on TNBC cells to stimulate JAG1 expression and cancer cell invasiveness.