Endocrine Therapy in Premenopausal Hormone Receptor Positive/Human Epidermal Growth Receptor 2 Negative Metastatic Breast Cancer: Between Guidelines and Literature

Tancredi, Richard; Furlanetto, Jenny; Loibl, Sibylle

doi:10.1634/theoncologist.2018-0077

Cited by 21 publications

(19 citation statements)

References 83 publications

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“…Patients with ER-positive tumors are treated with antiendocrine therapy inhibiting estrogen action by either aromatase inhibitors (AI) or selective estrogen receptor modulators (SERM) such as tamoxifen [5]. The latter is mainly used in premenopausal cases as aromatase inhibitors are more effective in menopausal women [6]. A major drawback of tamoxifen is therapy failure indicated by disease recurrence in about 20-30 per cent of tamoxifen-treated patients [7].…”

Section: Introductionmentioning

confidence: 99%

Time resolved gene expression analysis during tamoxifen adaption of MCF-7 cells identifies long non-coding RNAs with prognostic impact

et al. 2019

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Acquired tamoxifen resistance is a persistent problem for the treatment of estrogen receptor positive, premenopausal breast cancer patients and predictive biomarkers are still elusive. We here analyzed gene expression changes in a cellular model to identify early and late changes upon tamoxifen exposure and thereby novel prognostic biomarkers. Estrogen receptor positive MCF-7 cells were incubated with 4OHtamoxifen (10 nM) and gene expression analyzed by array hybridization during 12 weeks. Array results were confirmed by nCounter-and qRT-PCR technique. Pathway enrichment analysis revealed that early responses concerned mainly amine synthesis and NRF2-related signaling and evolved into a stable gene expression pattern within 4 weeks characterized by changes in glucuronidation-, estrogen metabolism-, nuclear receptor-and interferon signaling pathways. As a large number of long non coding RNAs was subject to regulation, we investigated 5 of these (linc01213, linc00632 linc0992, LOC101929547 and XR_133213) in more detail. From these, only linc01213 was upregulated but all were less abundant in estrogen-receptor negative cell lines (MDA-MB 231, SKBR-3 and UACC3199). In a web-based survival analysis linc01213 and linc00632 turned out to have prognostic impact. Linc01213 was investigated further by plasmid-mediated over-expression as well as siRNA down-regulation in MCF-7 cells. Nevertheless, this had no effect on proliferation or expression of tamoxifen regulated genes, but migration was increased. In conclusion, the cellular model identified a set of lincRNAs with prognostic relevance for breast cancer. One of these, linc01213 although regulated by 4OH-tamoxifen, is not a central regulator of tamoxifen adaption, but interferes with the regulation of migration.

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Section: Introductionmentioning

confidence: 99%

Time resolved gene expression analysis during tamoxifen adaption of MCF-7 cells identifies long non-coding RNAs with prognostic impact

et al. 2019

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“…Tamoxifen (TAM) is the first line of therapy for the treatment of estrogen-receptor-positive breast cancer. This type of breast cancer develops TAM resistance, promoting tumor relapse (208). Phuong et al found that the MCF-7 breast cancer cell line showed TAM resistance (TAMR/MCF-7).…”

Section: Regulation Of the Pi3k/pten/akt/mtor Signaling Pathway By Dnmentioning

confidence: 99%

Role of DNA Methylation in the Resistance to Therapy in Solid Tumors

Romero-García¹,

Prado-Garcı́a²,

Carlos‐Reyes³

2020

Front. Oncol.

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Despite the recent advances in chemotherapeutic treatments against cancer, some types of highly aggressive and invasive cancer develop drug resistance against conventional therapies, which continues to be a major problem in the fight against cancer. In recent years, studies of alterations of DNA methylome have given us a better understanding of the role of DNA methylation in the development of tumors. DNA methylation (DNAm) is an epigenetic change that promotes the covalent transfer of methyl groups to DNA. This process suppresses gene expression through the modulation of the transcription machinery access to the chromatin or through the recruitment of methyl binding proteins. DNAm is regulated mainly by DNA methyltransferases. Aberrant DNAm contributes to tumor progression, metastasis, and resistance to current anti-tumoral therapies. Aberrant DNAm may occur through hypermethylation in the promoter regions of tumor suppressor genes, which leads to their silencing, while hypomethylation in the promoter regions of oncogenes can activate them. In this review, we discuss the impact of dysregulated methylation in certain genes, which impact signaling pathways associated with apoptosis avoidance, metastasis, and resistance to therapy. The analysis of methylome has revealed patterns of global methylation, which regulate important signaling pathways involved in therapy resistance in different cancer types, such as breast, colon, and lung cancer, among other solid tumors. This analysis has provided gene-expression signatures of methylated region-specific DNA that can be used to predict the treatment outcome in response to anti-cancer therapy. Additionally, changes in cancer methylome have been associated with the acquisition of drug resistance. We also review treatments with demethylating agents that, in combination with standard therapies, seem to be encouraging, as tumors that are in early stages can be successfully treated. On the other hand, tumors that are in advanced stages can be treated with these combination schemes, which could sensitize tumor cells that are resistant to the therapy. We propose that rational strategies, which combine specific demethylating agents with conventional treatment, may improve overall survival in cancer patients.

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“…As for other combinations used in post-menopausal women, the application of such combinations in pre-menopausal setting needs proof of benefit and multiple trials are ongoing (161). For instance, regarding the use of mTORinhibitors + non-steroidal aromatase inhibitors in addition to GnRH agonist in premenopausal patients, data is still scarce.…”

Section: Pre-menopausal Vs Post-menopausalmentioning

confidence: 99%

Endocrine and Targeted Therapy for Hormone-Receptor-Positive, HER2-Negative Advanced Breast Cancer: Insights to Sequencing Treatment and Overcoming Resistance Based on Clinical Trials

et al. 2019

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Background: Advanced hormone-receptor positive HER2 negative breast cancer is a common and a very heterogeneous disease. Hormone therapy is the main first line treatment of choice, given alone or in combination with other agents that have shown to improve patient outcomes, Nevertheless, treatment remains generally palliative rather than curative. Sequencing of such treatment remains challenging, especially with resurgence of variable resistance patterns. Multiple attempts have been made to overcome resistance and improve patient survival, yet resistance remains not very well understood and metastatic cancer remains a disease with dismal prognosis. Methods: In this paper, we searched pubmed database as well as local and international meetings for all studies discussing advanced and metastatic hormone-receptor-positive, her2-negative breast cancer, hormonal treatment, resistance to hormonal treatment, mechanism of resistance, and means to overcome such resistance. Conclusion: There does not exist an optimal treatment sequence for hormone-receptor-positive, her2-negative advanced breast cancer. However, after review of literature, a reasonable approach may be starting with tamoxifen, aromatase inhibitors, or fulvestrant in absence of visceral crisis, in addition to ensuring adequate ovarian function suppression in pre/peri-menopausal women. Aromatase inhibitors and fulvestrant seem to be superior. Resistance to such agents is increasing, mostly attributed to genetic and molecular changes. Multiple modalities are addressed to overcome such resistance including use of CKD4/6 inhibitors, mTOR inhibitors and PI3K inhibitors in addition to other agents under study, all with promising results. CDK4/6 inhibitors work best when used in frontline setting. Finally, treatment of breast cancer remains a growing field, and more studies are to be awaited.

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Endocrine Therapy in Premenopausal Hormone Receptor Positive/Human Epidermal Growth Receptor 2 Negative Metastatic Breast Cancer: Between Guidelines and Literature

Cited by 21 publications

References 83 publications

Time resolved gene expression analysis during tamoxifen adaption of MCF-7 cells identifies long non-coding RNAs with prognostic impact

Time resolved gene expression analysis during tamoxifen adaption of MCF-7 cells identifies long non-coding RNAs with prognostic impact

Role of DNA Methylation in the Resistance to Therapy in Solid Tumors

Endocrine and Targeted Therapy for Hormone-Receptor-Positive, HER2-Negative Advanced Breast Cancer: Insights to Sequencing Treatment and Overcoming Resistance Based on Clinical Trials

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