Phase II study of flutamide in patients with metastatic breast cancer. A National Cancer Institute of Canada Clinical Trials Group study

Perrault, D. J.; Logan, Diane; Stewart, David J.; Bramwell, Vivien; Paterson, Alexander; Eisenhauer, Elizabeth

doi:10.1007/bf00175399

Cited by 35 publications

(20 citation statements)

References 7 publications

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“…This fact demonstrates that AR expression is a common characteristic in breast cancer and AR could be a possible target for endocrine antitumour therapy strategies. Results of a small, phase II trial testing the efficacy of the antiandrogen drug flutamide in patients with metastatic breast cancer were disappointing [17]. However, in that study, AR status of tumour tissue was not assessed.…”

Section: Discussionmentioning

confidence: 95%

Evaluation of the prognostic significance of androgen receptor expression in metastatic breast cancer

Schippinger¹,

Regitnig²,

Dandachi³

et al. 2006

Virchows Arch

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The purpose of this study was to investigate the influence of androgen receptor (AR) expression in tumour tissue on survival of patients with metastatic breast cancer. Tumour specimens from 232 patients with metastatic breast cancer were examined for presence of AR by immunohistochemistry. According to the extent of immunostaining, AR expression was classified as score 0, 1+, 2+, or 3+. AR positivity was observed in 164 (70.7%) tumours. The median survival after disease recurrence (SAR) of patients with AR-expressing tumours was significantly longer compared to that of patients with AR-negative tumours (21.89 months, 95% CI 17.23-26.55 vs 11.99 months, 95% CI 9.36-14.62; log-rank test 0.0282). In addition, patients with AR score 3+ had a significantly longer disease-free survival (DFS) compared to patients with AR score 0, 1+, and 2+, (24.67 months, 95% CI 13.72-35.62 vs 16.36 months, 95% CI 13.18-19.54, log-rank test 0.0043). Multivariate Cox analyses showed no statistically significant influence of AR expression on DFS or SAR. In conclusion, SAR is significantly longer in patients with AR-expressing breast carcinoma. However, AR expression is not an independent prognostic factor for SAR in metastatic breast cancer.

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Section: Discussionmentioning

confidence: 95%

Evaluation of the prognostic significance of androgen receptor expression in metastatic breast cancer

Schippinger¹,

Regitnig²,

Dandachi³

et al. 2006

Virchows Arch

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show abstract

“…Previous studies that examined the use of flutamide, an oral antiandrogen, for the treatment of MBC concluded a lack of meaningful antitumor activity. However, these small phase II trials were conducted in unselected patient populations irrespective of AR, ER, or PgR (13, 14). …”

Section: Discussionmentioning

confidence: 99%

Phase II Trial of Bicalutamide in Patients with Androgen Receptor–Positive, Estrogen Receptor–Negative Metastatic Breast Cancer

Gucalp

Tolaney

Isakoff

et al. 2013

Clinical Cancer Research

623

482

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Purpose Patients with hormone receptor–negative breast cancer generally do not benefit from endocrine-targeted therapies. However, a subset with androgen receptor (AR) expression is predicted to respond to antiandrogen therapies. This phase II study explored bicalutamide in AR-positive, estrogen receptor (ER), and progesterone receptor (PgR)-negative metastatic breast cancer. Experimental Design Tumors from patients with ER/PgR-negative advanced breast cancer were tested centrally for AR [immunohistochemistry (IHC) > 10% nuclear staining considered positive]. If either the primary or a metastatic site was positive, patients were eligible to receive the AR antagonist bicalutamide at a dose of 150 mg daily. Clinical benefit rate (CBR), the primary endpoint, was defined as the total number of patients who show a complete response (CR), partial response (PR), or stable disease (SD) > 6 months; secondary endpoints included progression-free survival (PFS) and toxicity. Correlative studies included measurement of circulating endocrine markers and IHC surrogates for basal-like breast cancer. Results Of 424 patients with ER/PgR-negative breast cancer, 12% tested AR-positive. The 6-month CBR was19%[95% confidence interval (CI), 7%–39%]for bicalutamide. The median PFS was 12 weeks (95% CI, 11–22 weeks). Bicalutamide was well-tolerated with no grade 4/5 treatment-related adverse events observed. Conclusion AR was expressed in 12% of patients with ER/PgR-negative breast cancer screened for this trial. The CBR of 19% observed with bicalutamide shows proof of principle for the efficacy of minimally toxic androgen blockade in a select group of patients with ER/PgR-negative, AR-positive breast cancer.

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“…The concept of introducing AR blockade as a therapeutic option for breast cancer has received more attention recently [6-9,50-54]. Older trials of AR blockade did not select for patients with AR dependent signaling or AR expression and therefore may not have addressed the question with an optimal cohort [55]. Based upon our interaction studies, we also recommend that any therapeutic strategies for the molecular apocrine subgroup consider combinatorial targeted therapy to include ErbB family targets, particularly EGFR targeted therapy for the entire molecular apocrine subtype and ErbB2 therapy for those tumors that overexpress ErbB2.…”

Section: Discussionmentioning

confidence: 99%

Gene expression meta-analysis supports existence of molecular apocrine breast cancer with a role for androgen receptor and implies interactions with ErbB family

et al. 2009

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BackgroundPathway discovery from gene expression data can provide important insight into the relationship between signaling networks and cancer biology. Oncogenic signaling pathways are commonly inferred by comparison with signatures derived from cell lines. We use the Molecular Apocrine subtype of breast cancer to demonstrate our ability to infer pathways directly from patients' gene expression data with pattern analysis algorithms.MethodsWe combine data from two studies that propose the existence of the Molecular Apocrine phenotype. We use quantile normalization and XPN to minimize institutional bias in the data. We use hierarchical clustering, principal components analysis, and comparison of gene signatures derived from Significance Analysis of Microarrays to establish the existence of the Molecular Apocrine subtype and the equivalence of its molecular phenotype across both institutions. Statistical significance was computed using the Fasano & Franceschini test for separation of principal components and the hypergeometric probability formula for significance of overlap in gene signatures. We perform pathway analysis using LeFEminer and Backward Chaining Rule Induction to identify a signaling network that differentiates the subset. We identify a larger cohort of samples in the public domain, and use Gene Shaving and Robust Bayesian Network Analysis to detect pathways that interact with the defining signal.ResultsWe demonstrate that the two separately introduced ER- breast cancer subsets represent the same tumor type, called Molecular Apocrine breast cancer. LeFEminer and Backward Chaining Rule Induction support a role for AR signaling as a pathway that differentiates this subset from others. Gene Shaving and Robust Bayesian Network Analysis detect interactions between the AR pathway, EGFR trafficking signals, and ErbB2.ConclusionWe propose criteria for meta-analysis that are able to demonstrate statistical significance in establishing molecular equivalence of subsets across institutions. Data mining strategies used here provide an alternative method to comparison with cell lines for discovering seminal pathways and interactions between signaling networks. Analysis of Molecular Apocrine breast cancer implies that therapies targeting AR might be hampered if interactions with ErbB family members are not addressed.

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Phase II study of flutamide in patients with metastatic breast cancer. A National Cancer Institute of Canada Clinical Trials Group study

Cited by 35 publications

References 7 publications

Evaluation of the prognostic significance of androgen receptor expression in metastatic breast cancer

Evaluation of the prognostic significance of androgen receptor expression in metastatic breast cancer

Phase II Trial of Bicalutamide in Patients with Androgen Receptor–Positive, Estrogen Receptor–Negative Metastatic Breast Cancer

Gene expression meta-analysis supports existence of molecular apocrine breast cancer with a role for androgen receptor and implies interactions with ErbB family

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