scholarly journals Targeted Therapies Overcoming Endocrine Resistance in Hormone Receptor-Positive Breast Cancer

Breast Care ◽  
2015 ◽  
Vol 10 (3) ◽  
pp. 168-172 ◽  
Author(s):  
Katrin Almstedt ◽  
Marcus Schmidt
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Hormone Receptor ◽  
Endocrine Resistance ◽  
Endocrine Treatment ◽  
Breast Cancer Patients ◽  
Hormone Receptor Positive ◽  
Study Results ◽  
Er Positive ◽  
Positive Breast Cancer

Breast cancer is a heterogeneous disease with different molecular subtypes. Most tumours are hormone receptor positive (luminal subtype) with potential endocrine responsiveness. Endocrine therapy is commonly used in these patients. Disease progression caused by endocrine resistance represents a significant challenge in the treatment of breast cancer. To understand the mechanisms of resistance of long-term oestrogen-deprived breast cancer cells, it is important to focus on cross-talk between steroid receptor signalling and other growth factor receptors and intracellular pathways. (Pre-)clinical trials showed that co-targeting these pathways can restore endocrine sensitivity. The focus of the current review is on the intracellular PI3K/AKT/mTOR signalling pathway and cyclin-dependant kinases (CDKs) in oestrogen receptor (ER)-positive breast cancer. Study results clearly show that both inhibition of the PI3K/AKT/mTOR pathway and CDK4/6 are promising ways to improve the efficacy of endocrine treatment in ER-positive breast cancer patients with comparably few side effects. Further clinical trials are needed to identify the patient population who would benefit most from a dual inhibition.

scholarly journals Endocrine Treatment for Breast Cancer Patients Revisited—History, Standard of Care, and Possibilities of Improvement

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5643
Author(s):  
Naiba Nabieva ◽  
Peter A. Fasching
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Hormone Receptor ◽  
Standard Of Care ◽  
Resistance Mechanisms ◽  
Endocrine Treatment ◽  
Breast Cancer Patients ◽  
Current Standard ◽  
Hormone Receptor Positive ◽  
Positive Breast Cancer

Purpose of review: Due to the findings of current studies and the approval of novel substances for the therapy of hormone-receptor-positive breast cancer patients, the established standards of endocrine treatment are changing. The purpose of this review is to give an overview of the history of endocrine treatment, to clarify its role in the present standard of care, and to discuss the possibilities of improvement. Recent findings: Tamoxifen, aromatase inhibitors, and fulvestrant are the main drugs that have been used for decades in the therapy of hormone-receptor-positive breast cancer patients. However, since a relevant number of women suffer at some point from disease recurrence or progression, several novel substances are being investigated to overcome resistance mechanisms by interfering with certain signaling pathways, such as the PI3K/AKT/mTOR or the CDK4/6 pathways. mTOR and CDK4/6 inhibitors were the first drugs approved for this purpose and many more are in development. Summary: Endocrine treatment is one of the best tolerable cancer therapies available. Continuous investigation serves to improve patients’ outcomes and modernize the current standard of care. Considering the resistance mechanisms and substances analyzed against these, endocrine treatment of hormone-receptor-positive breast cancer is on the brink of a new era.

Open label, phase II trial of neoadjuvant TAK-228 plus tamoxifen in patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor type 2 (HER2)-negative breast cancer-ANETT.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 584-584
Author(s):  
Emre Koca ◽  
Polly Ann Niravath ◽  
Joe Ensor ◽  
Tejal Amar Patel ◽  
Xiaoxian Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hormone Receptor ◽  
Phase Ii Trial ◽  
Endocrine Resistance ◽  
Newly Diagnosed ◽  
Open Label ◽  
Hormone Receptor Positive ◽  
Open Label Phase ◽  
Er Positive ◽  
Positive Breast Cancer

584 Background: Neoadjuvant endocrine therapy is standard care for women with hormone receptor-positive breast cancer. However, both primary and acquired endocrine resistance is not uncommon, thereby limiting efficacy. [1] The PI3K-Akt-mTOR pathway is a major mediator of endocrine resistance. [2,3] Therefore, we determined the efficacy and safety of the mTORC1/2 inhibitor TAK-228 in combination with tamoxifen in neoadjuvant setting. Methods: In this single-arm, open-label phase II trial, newly diagnosed patients with stage I−III ER-positive, HER2-negative breast cancer received TAK-228 (30 mg weekly) and tamoxifen (20 mg daily) for 16 weeks until 2-4 weeks prior to surgery. The primary endpoint was the change in Ki67 after 6 weeks. Secondary endpoints included pathological complete response rate (pCR), preoperative endocrine prognostic index (PEPI) score, and safety. Results: Of the 28 patients enrolled in the study, 3 were excluded due to non-compliance. Mean patient age was 51.7 years. Most patients had stage I or II disease (12 [43%] each); 4 (14%) had stage III disease. Mean Ki67 was significantly lowered from baseline to Week 6 (17.2% vs. 15.2%, p = 0.0023). Interestingly, mean Ki67 increased to 20.1% from baseline to the time of surgery. This may have been due to a rebound effect, as TAK-228 was discontinued 2-4 weeks prior to surgery. Tumor size also significantly decreased from baseline to surgery, with a median decrease of 0.75 centimeters (p < 0.0001). PEPI score was intermediate risk (score 1−3) in 6 patients and high risk group (score ≥4) in 15 patients. No patients achieved a PEPI score of 0 and no pCR was achieved. Overall, the combination was well tolerated, the most common side effects were nausea (72%), vomiting (72%), fatigue (72%), mucositis (45%), and headache (45%). The any Grade 3 AE rate was 7.7%. Conclusions: The TAK-228 and tamoxifen combination was found to be an effective neoadjuvant strategy with a favorable safety profile in newly diagnosed patients with hormone receptor-positive breast cancer. Further molecular analysis (PI3K-Akt-mTOR pathway) are pending and will be presented. Clinical trial information: NCT02988986.

Aromatase Inhibitors in Postmenopausal Breast Cancer Patients

2005 ◽  
Vol 3 (3) ◽  
pp. 309-314 ◽  
Author(s):  
Alyssa G. Rieber ◽  
Richard L. Theriault
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Cancer Patients ◽  
Aromatase Inhibitors ◽  
Hormone Receptor ◽  
Metastatic Breast ◽  
Postmenopausal Breast Cancer ◽  
Breast Cancer Patients ◽  
Hormone Receptor Positive ◽  
Positive Breast Cancer

Aromatase inhibitors (AIs) have greatly enriched the treatment of hormone receptor-positive breast cancer in postmenopausal patients. Before the introduction of the well-tolerated third-generation AIs, tamoxifen was the mainstay of endocrine therapy for hormone receptor-positive breast cancer. Many clinical trials have shown the superiority of AIs compared with tamoxifen in adjuvant breast cancer treatment, as well as their benefit in metastatic breast cancer. NCCN guidelines recommendations for their use are based on the evidence provided by these clinical trials. This discussion reviews the evidence supporting the current guidelines for use of AI therapy in the treatment of hormone receptor-positive postmenopausal breast cancer patients.

scholarly journals Clinical CYP2D6 Genotyping to Personalize Adjuvant Tamoxifen Treatment in ER-Positive Breast Cancer Patients: Current Status of a Controversy

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 771
Author(s):  
Tessa A. M. Mulder ◽  
Mirjam de With ◽  
Marzia del Re ◽  
Romano Danesi ◽  
Ron H. J. Mathijssen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Outcome ◽  
Cancer Patients ◽  
Plasma Concentrations ◽  
Tamoxifen Treatment ◽  
Current Status ◽  
Endocrine Treatment ◽  
Breast Cancer Patients ◽  
Er Positive ◽  
Positive Breast Cancer

Tamoxifen is a major option for adjuvant endocrine treatment in estrogen receptor (ER) positive breast cancer patients. The conversion of the prodrug tamoxifen into the most active metabolite endoxifen is mainly catalyzed by the enzyme cytochrome P450 2D6 (CYP2D6). Genetic variation in the CYP2D6 gene leads to altered enzyme activity, which influences endoxifen formation and thereby potentially therapy outcome. The association between genetically compromised CYP2D6 activity and low endoxifen plasma concentrations is generally accepted, and it was shown that tamoxifen dose increments in compromised patients resulted in higher endoxifen concentrations. However, the correlation between CYP2D6 genotype and clinical outcome is still under debate. This has led to genotype-based tamoxifen dosing recommendations by the Clinical Pharmacogenetic Implementation Consortium (CPIC) in 2018, whereas in 2019, the European Society of Medical Oncology (ESMO) discouraged the use of CYP2D6 genotyping in clinical practice for tamoxifen therapy. This paper describes the latest developments on CYP2D6 genotyping in relation to endoxifen plasma concentrations and tamoxifen-related clinical outcome. Therefore, we focused on Pharmacogenetic publications from 2018 (CPIC publication) to 2021 in order to shed a light on the current status of this debate.

scholarly journals Analytical validation of CanAssist-Breast: an immunohistochemistry based prognostic test for hormone receptor positive breast cancer patients

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Arun Kumar Attuluri ◽  
Chandra Prakash V. Serkad ◽  
Aparna Gunda ◽  
Charusheila Ramkumar ◽  
Chetana Basavaraj ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Hormone Receptor ◽  
Breast Cancer Patients ◽  
Analytical Validation ◽  
Prognostic Test ◽  
Hormone Receptor Positive ◽  
Positive Breast Cancer
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