Abstract P5-14-05: Phase 1 evaluation of the androgen receptor modulator CR1447 in patients with advanced breast cancer (SAKK 21/12)

2016 ◽  
Author(s):  
W Schoenfeld ◽  
M Zweifel ◽  
B Thuerlimann ◽  
S Riniker ◽  
P Weder ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Advanced Breast Cancer ◽  
Phase 1 ◽  
Advanced Breast ◽  
Receptor Modulator

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.

Is androgen receptor useful to predict the efficacy of anti-estrogen therapy in advanced breast cancer?

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1042-1042 ◽  
Author(s):  
Andrea Rocca ◽  
Giuseppe Bronte ◽  
Sara Ravaioli ◽  
Maurizio Puccetti ◽  
Maria Maddalena Tumedei ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Advanced Breast Cancer ◽  
Cox Regression ◽  
Estrogen Therapy ◽  
Advanced Breast ◽  
Categorical Variables ◽  
First Line ◽  
Primary Tumors ◽  
Best Response

1042 Background: The androgen receptor (AR) is widely expressed in breast cancers but its role in estrogen receptor (ER)-positive tumors is still controversial. However, the AR/ER ratio may impact prognosis and the response to antiestrogen endocrine therapy (ET). Methods: We assessed whether AR in primary tumors and/or matched metastases is a predictor of efficacy of first-line ET in advanced breast cancer (ABC). We evaluated patients treated with first-line ET (2002–2011), excluding those receiving concomitant chemotherapy or trastuzumab or pretreated with > 2 lines of chemotherapy. ER, progesterone receptor (PgR), Her2, Ki67 and AR expression was determined by immunohistochemistry. A cut-off of < 1% immunostained cells was used to categorize AR expression. AR expression was analyzed in relation to the other conventional biomarkers (ER, PgR, Her2 and Ki67), best response (CR, PR, SD, PD), and time to progression (TTP) (months). TTP was estimated using the Kaplan-Meier method and compared with the log-rank test. Hazard ratios and their 95% confidence intervals (95% CI) were estimated using the Cox regression model. The Chi-square test was used to evaluate correlations between categorical variables and best response. p values < 0.05 were considered statistically significant. Results: Of the 102 evaluable patients (93% were treated with an aromatase inhibitor), biomarkers were assessed in primary tumors in 70 cases, in metastases in 49 and in 17 in both). Median TTP was 17 months (95% CI 14-21.5, median follow-up 75 months). The overall concordance rate between primary tumors and metastases was 64.7% (95% CI 42%-87.4%) for AR expression. Differences in TTP according to AR status were not statistically significant. AR/PgR ≥ 0.96 was associated with a significantly shorter TTP (HR = 1.65, 95% CI 1.05-2.61, p = 0.030). AR status in primary tumors or metastases was not associated with PD as best response. In contrast, Ki67 > 20% and PgR < 10% showed a significant association with PD as best response. Using a cut off of ≤10% for AR expression, results did not change. Conclusions: AR expression does not appear to be useful to predict the efficacy of ET in ABC. Ki67 and PgR exert a greater impact on the efficacy of hormone therapy than AR.

Modeling of pharmacodynamic (PD) biomarkers (BM) related to CDK4/6 inhibition and exploratory BM-response (progression free survival [PFS]) analyses in patients with advanced breast cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14528-e14528
Author(s):  
Yanke Yu ◽  
Yuan Liu ◽  
Diane Dan Wang
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Time Course ◽  
Small Sample Size ◽  
Phase 1 ◽  
Small Sample ◽  
Advanced Breast ◽  
Longitudinal Change ◽  
Indirect Response Model ◽  
The Relationship

e14528 Background: Palbociclib (PAL) is an oral inhibitor of cyclin-dependent kinase 4 and 6 (CDK4/6) approved for advanced breast cancer (ABC). In a clinical trial, the expression levels of PD BMs related to PAL effect, including thymidine kinase (TK) in serum and phosphor-Rb (pRb) and Ki67 in skin tissues, were measured at both baseline and post-treatment in patients with ABC treated with PAL plus letrozole (LET). Pharmacokinetic (PK)/PD modeling was conducted previously to characterize the longitudinal change of pRb and Ki67. The PK/PD was further evaluated for TK and exploratory analyses were conducted to evaluate the relationship between PFS and all three BMs. Methods: The present analyses used data from a Phase 1 study evaluating the PK, PD, safety and efficacy of PAL plus LET in 26 Chinese women with ABC. A 2 compartment model was used to describe the PK of PAL. A precursor-dependent indirect response model was developed to describe the TK time course after PAL treatment. PAL effect was modeled as Imax inhibitory model. Cox proportional hazard model was used to assess the correlation of PFS with three BM metrics (baseline BM, simulated lowest BM and maximum BM change in Cycle 1). Results: The BM data included 194 TK observations from 26 patients. The PK/PD models adequately described the longitudinal change of TK, and showed PAL caused TK reduction. The estimated IC50 value was 49.5 ng/mL, similar to those for pRb and Ki67. The BM-response analyses for PFS showed that correlation was found for TK. There was a significant correlation between PFS and baseline TK (BTK) and minimum TK (MTK) in Cycle 1. A longer PFS was associated with lower BTK and lower MTK. A trend for longer PFS with higher maximum TK change in Cycle 1 was observed although the relationship was not statistically significant. Conclusions: PAL exposure had significant correlation with the reduction of all three BMs. Longer PFS was associated with lower BTK and MTK. Due to the small sample size (N = 26), this analyses result need to be confirmed in a larger study.

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