scholarly journals Oral Selective Estrogen Receptor Degraders (SERDs) as a Novel Breast Cancer Therapy: Present and Future from a Clinical Perspective

2021 ◽  
Vol 22 (15) ◽  
pp. 7812
Author(s):  
Cristina Hernando ◽  
Belén Ortega-Morillo ◽  
Marta Tapia ◽  
Santiago Moragón ◽  
María Teresa Martínez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Endocrine Resistance ◽  
Tamoxifen Resistance ◽  
Gene Mutations ◽  
Treatment Resistance ◽  
Progression Free Survival ◽  
Endocrine Treatment ◽  
Estrogen Production ◽  
Underlying Mechanisms

Estrogen receptor-positive (ER+) is the most common subtype of breast cancer. Endocrine therapy is the fundamental treatment against this entity, by directly or indirectly modifying estrogen production. Recent advances in novel compounds, such as cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), or phosphoinositide 3-kinase (PI3K) inhibitors have improved progression-free survival and overall survival in these patients. However, some patients still develop endocrine resistance after or during endocrine treatment. Different underlying mechanisms have been identified as responsible for endocrine treatment resistance, where ESR1 gene mutations are one of the most studied, outstanding from others such as somatic alterations, microenvironment involvement and epigenetic changes. In this scenario, selective estrogen receptor degraders/downregulators (SERD) are one of the weapons currently in research and development against aromatase inhibitor- or tamoxifen-resistance. The first SERD to be developed and approved for ER+ breast cancer was fulvestrant, demonstrating also interesting activity in ESR1 mutated patients in the second line treatment setting. Recent investigational advances have allowed the development of new oral bioavailable SERDs. This review describes the evolution and ongoing studies in SERDs and new molecules against ER, with the hope that these novel drugs may improve our patients’ future landscape.

Endocrine Treatment of Breast Cancer: Current Perspectives, Future Directions

2017 ◽  
Vol 8 (03) ◽  
Author(s):  
Tazia Irfan ◽  
Mainul Haque ◽  
Sayeeda Rahman ◽  
Russell Kabir ◽  
Nuzhat Rahman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Endocrine Therapy ◽  
Ovarian Function ◽  
Premenopausal Women ◽  
New Drugs ◽  
Effective Control ◽  
Endocrine Treatment ◽  
Estrogen Production ◽  
Hormone Sensitive

Breast cancer remains one of the major causes of death in women, and endocrine treatment is currently one of the mainstay of treatment in patients with estrogen receptor positive breast cancer. Endocrine therapy either slows down or stops the growth of hormone-sensitive tumors by blocking the body’s capability to yield hormones or by interfering with hormone action. In this paper, we intended to review various approaches of endocrine treatments for breast cancer highlighting successes and limitations. There are three settings where endocrine treatment of breast cancer can be used: neoadjuvant, adjuvant, or metastatic. Several strategies have also been developed to treat hormone-sensitive breast cancer which include ovarian ablation, blocking estrogen production, and stopping estrogen effects. Selective estrogen-receptor modulators (SERMs) (e.g. tamoxifen and raloxifene), aromatase inhibitors (AIs) (e.g. anastrozole, letrozole and exemestane), gonadotropin-releasing hormone agonists (GnRH) (e.g. goserelin), and selective estrogen receptor downregulators (SERDs) (e.g. fulvestrant) are currently used drugs to treat breast cancer. Tamoxifen is probably the first targeted therapy widely used in breast cancer treatment which is considered to be very effective as first line endocrine treatment in previously untreated patients and also can be used after other endocrine therapy and chemotherapy. AIs inhibit the action of enzyme aromatase which ultimately decrease the production of estrogen to stimulate the growth of ER+ breast cancer cells. GnRH agonists suppress ovarian function, inducing artificial menopause in premenopausal women. Endocrine treatments are cheap, well-tolerated and have a fixed single daily dose for all ages, heights and weights of patients. Endocrine treatments are not nearly as toxic as chemotherapy and frequent hospitalization can be avoided. New drugs in preliminary trials demonstrated the potential for improvement of the efficacy of endocrine therapy including overcoming resistance. However, the overall goals for breast cancer including endocrine therapy should focus on effective control of cancer, design personalized medical therapeutic approach, increase survival time and quality of life, and improve supportive and palliative care for end-stage disease.

scholarly journals Endocrine Resistance in Breast Cancer: The Role of Estrogen Receptor Stability

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2077
Author(s):  
Sarah A. Jeffreys ◽  
Branka Powter ◽  
Bavanthi Balakrishnar ◽  
Kelly Mok ◽  
Patsy Soon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Protein Stability ◽  
Posttranslational Modifications ◽  
Endocrine Resistance ◽  
Therapy Resistance ◽  
Disease Recurrence ◽  
Hormone Receptor Positive ◽  
Estrogen Production ◽  
Reported Data

Therapy of hormone receptor positive breast cancer (BCa) generally targets estrogen receptor (ER) function and signaling by reducing estrogen production or by blocking its interaction with the ER. Despite good long-term responses, resistance to treatment remains a significant issue, with approximately 40% of BCa patients developing resistance to ET. Mutations in the gene encoding ERα, ESR1, have been identified in BCa patients and are implicated as drivers of resistance and disease recurrence. Understanding the molecular consequences of these mutations on ER protein levels and its activity, which is tightly regulated, is vital. ER activity is in part controlled via its short protein half-life and therefore changes to its stability, either through mutations or alterations in pathways involved in protein stability, may play a role in therapy resistance. Understanding these connections and how ESR1 alterations could affect protein stability may identify novel biomarkers of resistance. This review explores the current reported data regarding posttranslational modifications (PTMs) of the ER and the potential impact of known resistance associated ESR1 mutations on ER regulation by affecting these PTMs in the context of ET resistance.

scholarly journals The PI3K/AKT/mTOR and CDK4/6 Pathways in Endocrine Resistant HR+/HER2− Metastatic Breast Cancer: Biological Mechanisms and New Treatments

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1242 ◽  
Author(s):  
Daniele Presti ◽  
Erica Quaquarini
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Endocrine Resistance ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Mtor Inhibitors ◽  
Endocrine Treatment ◽  
Response Predictors ◽  
New Treatments

Endocrine-based treatments are the normal standard-of-care in women with hormone receptor-positive/Human Epidermal growth factor Receptor 2-negative metastatic breast cancer. Despite the well-known efficacy of these drugs as first-line therapies, about 50% of women develop endocrine resistance and disease progression. The treatment of these patients has represented one of the most important research fields in the last few years, with several multicenter phase II/III trials published or still ongoing. Novel therapies, such as cyclin-dependent kinase (CDK)4/6 and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) inhibitors, have significantly changed the prognosis of patients progressing to a previous endocrine treatment, allowing a great benefit in terms of progression-free survival and, in some cases, of overall survival. However, identifying response predictors is essential for the rational use of these drugs to avoid unnecessary toxicity and costs, and to ensure the optimal therapeutic sequence is used. In this review, we analyze the PI3K/AKT/mTOR and CDK4/6 pathways and their roles in endocrine resistant metastatic breast cancer. We then focus on the new treatments developed and the roles of these drugs in overcoming endocrine resistance, describing the latest clinical trials that led to the approval of the drugs in clinical practice.

scholarly journals EMERALD: Phase III trial of elacestrant (RAD1901) vs endocrine therapy for previously treated ER+ advanced breast cancer

2019 ◽  
Vol 15 (28) ◽  
pp. 3209-3218 ◽  
Author(s):  
Aditya Bardia ◽  
Philippe Aftimos ◽  
Teeru Bihani ◽  
Alfred T Anderson-Villaluz ◽  
JungAh Jung ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Advanced Breast Cancer ◽  
Endocrine Resistance ◽  
Progression Free Survival ◽  
Advanced Breast ◽  
Phase Iii ◽  
Open Label ◽  
Er Positive ◽  
Previously Treated

Elacestrant is a novel, nonsteroidal, orally bioavailable selective estrogen receptor degrader (SERD) that has demonstrated activity in patients with estrogen receptor (ER)-positive/HER2-negative breast cancer previously treated with endocrine therapies including fulvestrant and/or CDK 4/6 inhibitor therapy, and in those with ESR1 mutations ( ESR1-mut) known to confer endocrine resistance. Herein, we describe the design and methodology of EMERALD, an international, multicenter, randomized, open-label, active-controlled, Phase III clinical study comparing the efficacy and safety of elacestrant to standard-of-care endocrine monotherapy treatment (fulvestrant or an aromatase inhibitor, per investigator’s choice) in patients with ER-positive/HER2-negative advanced breast cancer. Primary end points are progression-free survival in ESR1-mut patients and in all patients (NCT03778931; EudraCT 2018-002990-24).

Relationship between endocrine resistance and the periods of adjuvant endocrine treatment for hormone receptor-positive, HER2-negative breast cancer

2021 ◽  
pp. 1-6
Author(s):  
Jun Yamamura ◽  
Yukiko Miyamura ◽  
Shunji Kamigaki ◽  
Junya Fujita ◽  
Hiroki Osato ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hormone Receptor ◽  
Endocrine Resistance ◽  
Progression Free Survival ◽  
Primary Treatment ◽  
Endocrine Treatment ◽  
First Year ◽  
Hormone Receptor Positive ◽  
First Recurrence ◽  
The Relationship

BACKGROUND: Current guidelines define primary and secondary endocrine resistance according to the periods of adjuvant endocrine therapy (adj-ET); however, the relationship between adj-ET period and endocrine resistance remains unclear. OBJECTIVE: We examined progression-free survival (PFS) after primary ET for recurrent hormone receptor-positive/HER2-negative breast cancer, and evaluated the relationship between endocrine resistance and the periods of adj-ET. METHODS: We assessed PFS among 183 patients who received ET as primary treatment for the first recurrence, according to the period of adj-ET (adj-ET < 1 year, 1–2 years, ≥2 years, and completion). RESULTS: Patients who relapsed during the first year of adj-ET had the significantly shortest PFS. PFS did not significantly differ between patients who relapsed at 1–2 years of adj-ET and patients who relapsed while on adj-ET but after the first 2 years. CONCLUSIONS: Relapse at 1–2 years after adj-ET initiation might be better classified as secondary endocrine resistance rather than primary endocrine resistance.

scholarly journals Endocrine Therapeutic Strategies for Patients with Hormone Receptor-positive Advanced Breast Cancer

2017 ◽  
Vol 13 (02) ◽  
pp. 127
Author(s):  
Peter Schmid ◽  
Keyword(s):  
Breast Cancer ◽  
Combination Therapy ◽  
Endocrine Therapy ◽  
Cancer Biology ◽  
Single Agent ◽  
Endocrine Resistance ◽  
Progression Free Survival ◽  
Endocrine Treatment ◽  
Receive Combination Therapy ◽  
Mutational Status

Endocrine treatment constitutes the therapeutic backbone for patients with oestrogen and/or progesterone receptor-positive breast cancer unless there is visceral crisis or suspected or known endocrine resistance. Whether all patients who are suitable for endocrine therapy should receive combination therapy or whether there remains a role for single-agent endocrine therapy is yet to be determined. Cancer biology (ESR1 mutational status) and disease pattern determine the choice of single-agent endocrine treatment. Possibly, patients with low disease burden, slow progression and presumed endocrine sensitivity might still be considered for single-agent endocrine therapy, whereas patients with more aggressive disease including visceral metastases might benefit from combination therapy. Improved guidance on selection and sequencing of treatments should become available once overall survival (OS) and progression-free survival (PFS) data have been reported from the ongoing trials in breast cancer, principally, FALCON (NCT01602380), PALOMA-2 (NCT01740427) and MONALEESA-2 (NCT01958021), which include different patient groups and, probably, different endocrine sensitivity.

scholarly journals MCM3 upregulation confers endocrine resistance in breast cancer and is a predictive marker of diminished tamoxifen benefit

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Sanne Løkkegaard ◽  
Daniel Elias ◽  
Carla L. Alves ◽  
Martin V. Bennetzen ◽  
Anne-Vibeke Lænkholm ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cancer Patients ◽  
Endocrine Therapy ◽  
Endocrine Resistance ◽  
Predictive Marker ◽  
Endocrine Treatment ◽  
Breast Cancer Patients ◽  
Minichromosome Maintenance ◽  
Primary Tumors

AbstractResistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer is a major clinical problem with poorly understood mechanisms. There is an unmet need for prognostic and predictive biomarkers to allow appropriate therapeutic targeting. We evaluated the mechanism by which minichromosome maintenance protein 3 (MCM3) influences endocrine resistance and its predictive/prognostic potential in ER+ breast cancer. We discovered that ER+ breast cancer cells survive tamoxifen and letrozole treatments through upregulation of minichromosome maintenance proteins (MCMs), including MCM3, which are key molecules in the cell cycle and DNA replication. Lowering MCM3 expression in endocrine-resistant cells restored drug sensitivity and altered phosphorylation of cell cycle regulators, including p53(Ser315,33), CHK1(Ser317), and cdc25b(Ser323), suggesting that the interaction of MCM3 with cell cycle proteins is an important mechanism of overcoming replicative stress and anti-proliferative effects of endocrine treatments. Interestingly, the MCM3 levels did not affect the efficacy of growth inhibitory by CDK4/6 inhibitors. Evaluation of MCM3 levels in primary tumors from four independent cohorts of breast cancer patients receiving adjuvant tamoxifen mono-therapy or no adjuvant treatment, including the Stockholm tamoxifen (STO-3) trial, showed MCM3 to be an independent prognostic marker adding information beyond Ki67. In addition, MCM3 was shown to be a predictive marker of response to endocrine treatment. Our study reveals a coordinated signaling network centered around MCM3 that limits response to endocrine therapy in ER+ breast cancer and identifies MCM3 as a clinically useful prognostic and predictive biomarker that allows personalized treatment of ER+ breast cancer patients.

scholarly journals From Micro to Long: Non-Coding RNAs in Tamoxifen Resistance of Breast Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3688
Author(s):  
Jéssica Fernanda Barazetti ◽  
Tayana Shultz Jucoski ◽  
Tamyres Mingorance Carvalho ◽  
Rafaela Nasser Veiga ◽  
Ana Flávia Kohler ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hormone Receptor ◽  
Estrogen Receptor Alpha ◽  
Expression Patterns ◽  
Tamoxifen Resistance ◽  
Hormone Receptor Positive ◽  
Current State ◽  
Main Driver ◽  
Underlying Mechanisms ◽  
Multiple Signaling

Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer mortality among women. Two thirds of patients are classified as hormone receptor positive, based on expression of estrogen receptor alpha (ERα), the main driver of breast cancer cell proliferation, and/or progesterone receptor, which is regulated by ERα. Despite presenting the best prognosis, these tumors can recur when patients acquire resistance to treatment by aromatase inhibitors or antiestrogen such as tamoxifen (Tam). The mechanisms that are involved in Tam resistance are complex and involve multiple signaling pathways. Recently, roles for microRNAs and lncRNAs in controlling ER expression and/or tamoxifen action have been described, but the underlying mechanisms are still little explored. In this review, we will discuss the current state of knowledge on the roles of microRNAs and lncRNAs in the main mechanisms of tamoxifen resistance in hormone receptor positive breast cancer. In the future, this knowledge can be used to identify patients at a greater risk of relapse due to the expression patterns of ncRNAs that impact response to Tam, in order to guide their treatment more efficiently and possibly to design therapeutic strategies to bypass mechanisms of resistance.

scholarly journals G-protein-coupled estrogen receptor GPR30 and tamoxifen resistance in breast cancer

2011 ◽  
Vol 128 (2) ◽  
pp. 457-466 ◽  
Author(s):  
Atanas Ignatov ◽  
Tanja Ignatov ◽  
Christine Weißenborn ◽  
Holm Eggemann ◽  
Joachim Bischoff ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
G Protein ◽  
Tamoxifen Resistance ◽  
G Protein Coupled
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