Efficacy and Safety of Targeting Androgen Receptor in Advanced Breast Cancer: A Systematic Review

2019 ◽  
Vol 15 (3) ◽  
pp. 197-206
Author(s):  
Loay Kassem ◽  
Kyrillus S. Shohdy ◽  
Nafie F. Makady ◽  
Dalal S. Salem ◽  
Nadia Ebrahim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Androgen Receptor ◽  
Advanced Breast Cancer ◽  
Clinical Benefit ◽  
Progression Free Survival ◽  
Advanced Breast ◽  
Receptor Modulator ◽  
Complex Signaling ◽  
Elevated Transaminases

Background::Androgen receptor (AR) upstreams complex signaling pathways that regulate cell proliferation and contribute to breast tumorignensis. Several clinical trials were initiated to investigate the clinical relevance of targeting AR especially in hormone-receptor-negative breast cancer.Methods::The search was performed in PubMed and the meeting libraries of ASCO, ESMO, SABCS, ImpakT congresses from January 2005 to July 2017. The following key words were used: Breast cancer, Androgen receptor, androgen agonist/antagonist, Flutamide, Abiraterone, Bicalutamide, Enzalutamide, Enobosarm, selective androgen receptor modulator.Results::Screening of title/abstracts yielded a total of 20 relevant results. Of those, twelve studies were found eligible: eleven clinical trials along with one case report. Response rates ranged from 0 to 12% while clinical benefit rates reached up to 35% in 2 studies (with enzalutamide and enobosarm). Progression-free survival ranged from 2.8 to 4.5 months. The most widely used cutoff for AR expression was 10%. High expression of AR was associated with more clinical benefit. Regarding safety, anti-androgens were generally well tolerated with hot flushes, elevated transaminases and fatigue being the most commonly reported across all agents.Conclusion::Androgen receptor pathway targeting in advanced breast cancer remains a valid option with reasonable clinical benefit in non-selected patients. Future studies are needed to define an AR addicted cohort with better responses and outcome.

Metronomic Cyclophosphamide and Capecitabine Combined With Bevacizumab in Advanced Breast Cancer

2008 ◽  
Vol 26 (30) ◽  
pp. 4899-4905 ◽  
Author(s):  
Silvia Dellapasqua ◽  
Francesco Bertolini ◽  
Vincenzo Bagnardi ◽  
Elisabetta Campagnoli ◽  
Eloise Scarano ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Clinical Benefit ◽  
Surrogate Marker ◽  
Metastatic Breast ◽  
Metronomic Chemotherapy ◽  
Progression Free Survival ◽  
Advanced Breast ◽  
Circulating Endothelial Cells ◽  
Overall Response

Purpose Metronomic chemotherapy has shown efficacy in patients with metastatic breast cancer. When used in association with targeted antiangiogenic drugs, it was more active than metronomic therapy alone in preclinical and clinical studies. Patients and Methods Patients with advanced breast cancer were candidates to receive metronomic oral capecitabine (500 mg thrice daily) and cyclophosphamide (50 mg daily) plus bevacizumab (10 mg/kg every 2 weeks). Results In 46 assessable patients, we observed one complete response (CR; 2%), 21 partial responses (PR; 46%), 19 patients (41%) with stable disease (SD), and five patients (11%) with progressive disease, for an overall response rate of 48% (95% CI, 33% to 63%). Additional long-term disease stabilization (SD ≥ 24 weeks) occurred in eight patients, for an overall clinical benefit (CR + PR + SD ≥ 24 weeks) of 68% (95% CI, 51% to 81%). Median time to progression was 42 weeks (95% CI, 26 to 72 weeks). Toxicity was generally mild. Grade 3 or 4 nonhematologic adverse effects included hypertension (n = 8), transaminitis (n = 2), and nausea/vomiting (n = 2). Higher baseline circulating endothelial cells (CECs) were correlated with overall response (P = .02), clinical benefit (P = .01), and improved progression-free survival (P = .04). Conclusion Treatment with metronomic capecitabine and cyclophosphamide in combination with bevacizumab was effective in advanced breast cancer and was minimally toxic. The number of baseline CECs significantly correlated with response and outcome, therefore supporting further studies on this surrogate marker for the selection of patients to be candidates for antiangiogenic treatments.

scholarly journals Circulating tumor DNA dynamics in advanced breast cancer treated with CDK4/6 inhibition and endocrine therapy

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Olga Martínez-Sáez ◽  
Tomás Pascual ◽  
Fara Brasó-Maristany ◽  
Nuria Chic ◽  
Blanca González-Farré ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Endocrine Therapy ◽  
Methodological Approach ◽  
Progression Free Survival ◽  
Circulating Tumor Dna ◽  
Advanced Breast ◽  
Dna Dynamics ◽  
Ca 15.3 ◽  
Tumor Dna

AbstractCirculating tumor DNA (ctDNA) levels may predict response to anticancer drugs, including CDK4/6 inhibitors and endocrine therapy combinations (CDK4/6i+ET); however, critical questions remain unanswered such as which assay or statistical method to use. Here, we obtained paired plasma samples at baseline and week 4 in 45 consecutive patients with advanced breast cancer treated with CDK4/6i+ET. ctDNA was detected in 96% of cases using the 74-gene Guardant360 assay. A variant allele fraction ratio (VAFR) was calculated for each of the 79 detected mutations between both timepoints. Mean of all VAFRs (mVAFR) was computed for each patient. In our dataset, mVAFR was significantly associated with progression-free survival (PFS). Baseline VAF, on-treatment VAF or absolute changes in VAF were not associated with PFS, nor were CA-15.3 levels at baseline, week 4 or the CA-15.3 ratio. These findings demonstrate that ctDNA dynamics using a standardized multi-gene panel and a unique methodological approach predicts treatment outcome. Clinical trials in patients with an unfavorable ctDNA response are needed.

AMEERA-5: A randomized, double-blind phase III study of amcenestrant (SAR439859) + palbociclib versus letrozole + palbociclib for previously untreated ER+/HER2- advanced breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS1104-TPS1104
Author(s):  
Aditya Bardia ◽  
Javier Cortes ◽  
Sara A. Hurvitz ◽  
Suzette Delaloge ◽  
Hiroji Iwata ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Phase I ◽  
Advanced Breast Cancer ◽  
Progression Free Survival ◽  
Advanced Breast ◽  
Phase Iii ◽  
Double Blind ◽  
Free Survival ◽  
Phase Iii Study

TPS1104 Background: Selective estrogen receptor degraders (SERDs) block estrogen receptor (ER) associated signaling and have created interest for treating patients (pts) with advanced ER+ breast cancer (BC). Fulvestrant is currently the only SERD available for advanced BC but requires intramuscular administration, limiting the applied dose, exposure and receptor engagement. Amcenestrant (SAR439859) is an oral SERD that binds with high affinity to both wild-type and mutant ER, blocking estradiol binding and promoting up to 98% ER degradation in preclinical studies. In the phase I AMEERA-1 study of pretreated pts with ER+/HER2- advanced BC, amcenestrant 150–600 mg once daily (QD) showed a mean ER occupancy of 94% with plasma concentrations > 100 ng/mL and a favorable safety profile (Bardia, 2019; data on file). Combination therapy with amcenestrant + palbociclib (palbo) was also evaluated as part of this ongoing phase I study. CDK 4/6 inhibitors (CDK4/6i) combined with an aromatase inhibitor (AI), the gold standard for first line treatment for advanced breast cancer, prolong progression free survival (PFS) in pts with no prior treatment for ER+/HER2- advanced BC, but OS benefit has not been shown yet in postmenopausal pts. There remains a clinical need for more effective treatments in this setting. Methods: AMEERA-5 (NCT04478266) is an ongoing, prospective, randomized, double-blind phase III study comparing the efficacy and safety of amcenestrant + palbo with that of letrozole + palbo in pts with advanced, locoregional recurrent or metastatic ER+/HER2- BC who have not received prior systemic therapy for advanced disease. The study includes men, pre/peri-menopausal (with goserelin) and post-menopausal women. Pts with progression during or within 12 months of (neo)adjuvant endocrine therapy using any of the following agents are excluded: AI, selective estrogen receptor modulators, CDK4/6i. Pts are randomized 1:1 to either continuous amcenestrant 200 mg or letrozole 2.5 mg QD orally with matching placebos; both combined with palbo 125 mg QD orally (d1–21 every 28-d cycle). Randomization is stratified according to disease type (de novo metastatic vs recurrent disease), the presence of visceral metastasis, and menopausal status. The primary endpoint is investigator assessed progression free survival (PFS) (RECIST v1.1). Secondary endpoints are overall survival, PFS2, objective response rate, duration of response, clinical benefit rate, pharmacokinetics of amcenestrant and palbo, health-related quality of life, time to chemotherapy, and safety. Biomarkers will be measured in paired tumor biopsies and cell free deoxyribonucleic acid (cfDNA) over time. Target enrolment = 1066 pts; enrolment as of 1/2021 = 33 pts. Bardia A, et al., J Clin Oncol. 2019; 37 (15 suppl):1054 Clinical trial information: NCT04478266 .

scholarly journals Subjective health estimations (SHE) in patients with advanced breast cancer: an adapted utility concept for clinical trials

1998 ◽  
Vol 77 (6) ◽  
pp. 985-991 ◽  
Author(s):  
C Hürny ◽  
B van Wegberg ◽  
M Bacchi ◽  
J Bernhard ◽  
B Thürlimann ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Advanced Breast Cancer ◽  
Subjective Health ◽  
Advanced Breast ◽  
Utility Concept

Review of Cyclin-Dependent Kinase 4/6 Inhibitors for the Treatment of Hormone Receptor–Positive Advanced Breast Cancer

2018 ◽  
Vol 53 (2) ◽  
pp. 195-203
Author(s):  
Keith A. Hecht ◽  
Christopher Selby
Keyword(s):  
Breast Cancer ◽  
Adverse Effects ◽  
Advanced Breast Cancer ◽  
Hormone Receptor ◽  
Progression Free Survival ◽  
Advanced Breast ◽  
Cdk Inhibitors ◽  
Cyclin Dependent Kinase ◽  
Hormone Receptor Positive ◽  
Positive Breast Cancer

Objective: To evaluate the existing literature regarding the use of cyclin-dependent kinase (CDK) 4/6 inhibitors in the treatment of hormone receptor–positive advanced breast cancer (ABC). Data Sources: A search of the medical literature was performed using PubMed (2014 to June 2018). Search terms included cyclin-dependent kinase, CDK, breast cancer, palbociclib, ribociclib, abemaciclib, PD0332991, LEE011, and LY2835219. Clinicaltrials.gov was also searched. Study Selection and Data Extraction: Trials with clinical efficacy outcomes evaluating CDK 4/6 inhibitors in the treatment of advanced hormone-positive breast cancer were considered. Data Synthesis: Palbociclib, abemaciclib, and ribociclib each demonstrated significant benefit when combined with an aromatase inhibitor, the benefit to patients was similar for each, with an improvement of 42% to 51% in median progression-free survival (PFS). In combination with fulvestrant, CDK 4/6 inhibitors used for the treatment of hormone receptor–positive ABC resulted in a 43% to 58% improvement in median PFS versus fulvestrant alone. CDK inhibitors are relatively well tolerated; however, discontinuation as a result of adverse effects was highest with abemaciclib. Relevance to Patient Care and Clinical Practice: This review considers the use of the 3 commercially available CDK 4/6 inhibitors for treatment of hormone receptor–positive breast cancer, including data on each of the 3 agents in newly advanced and treatment refractory disease. Conclusions: The CDK inhibitors should be used in combination with endocrine therapies for the treatment of ABC. Efficacy of the 3 agents is similar. Selection within the class should include consideration of adverse effects and drug interactions.

scholarly journals The role of abemaciclib in treatment of advanced breast cancer

2018 ◽  
Vol 10 ◽  
pp. 175883591877692 ◽  
Author(s):  
Amelia McCartney ◽  
Erica Moretti ◽  
Giuseppina Sanna ◽  
Marta Pestrin ◽  
Emanuela Risi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Single Agent ◽  
Endocrine Resistance ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Advanced Breast ◽  
Significant Activity ◽  
Epidermal Growth

Until recently, the mainstay of treatment in the majority of hormone receptor (HR)-positive, human epidermal growth factor 2 receptor (HER2)-negative advanced breast cancer (ABC) has consisted of single-agent endocrine therapy (ET). However, as understanding of endocrine resistance has grown, newer targeted agents have come to the fore. Inhibition of cyclin-dependent kinase complexes 4 and 6 (CDK4/6) combined with ET has shown significant activity in HR+ HER2− ABC, with impressive results in terms of progression-free survival (PFS) when compared with ET alone. This review summarizes the seminal findings pertaining to CDK4/6 inhibition in this population, specifically focusing on abemaciclib, contrasted with palbociclib and ribociclib. Potential directions for future studies are discussed, as a way of addressing outstanding issues such as establishing optimal treatment sequencing and agent combinations, appropriate patient selection to derive maximal benefits, predictive biomarkers and the employment of CDK4/6 inhibition beyond the ABC setting.

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