Improving Endocrine Therapy for Breast Cancer: It's Not That Simple

Dees, Elizabeth Claire; Carey, Lisa A.

doi:10.1200/jco.2012.46.2655

Cited by 28 publications

(19 citation statements)

References 22 publications

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“…However, there is accumulating evidence that androgen signaling and AR are involved in resistance to ER-directed endocrine therapies. De novo or acquired resistance to anti-estrogen therapies is a frequent occurrence, and ultimately all metastatic ER+ breast cancers are resistant (6,7). In ER+ tumors responsive to neoadjuvant aromatase inhibitor (AI) therapy, AR mRNA and nuclear AR protein decreased, whereas in non-responsive tumors it remained elevated (8,9).…”

Section: Introductionmentioning

confidence: 99%

Cooperative Dynamics of AR and ER Activity in Breast Cancer

D’Amato

Gordon

Babbs

et al. 2016

Molecular Cancer Research

122

152

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Androgen receptor (AR) is expressed in 90% of estrogen receptor alpha positive (ER+) breast tumors, but its role in tumor growth and progression remains controversial. Use of two anti-androgens that inhibit AR nuclear localization, enzalutamide and MJC13, revealed that AR is required for maximum ER genomic binding. Here, a novel global examination of AR chromatin binding found that estradiol induced AR binding at unique sites compared to dihydrotestosterone (DHT). Estradiol-induced AR binding sites were enriched for estrogen response elements and had significant overlap with ER binding sites. Furthermore, AR inhibition reduced baseline and estradiol-mediated proliferation in multiple ER+/AR+ breast cancer cell lines, and synergized with tamoxifen and fulvestrant. In vivo, enzalutamide significantly reduced viability of tamoxifen-resistant MCF7 xenograft tumors and an ER+/AR+ patient-derived model. Enzalutamide also reduced metastatic burden following cardiac injection. Lastly, in a comparison of ER+/AR+ primary tumors versus patient-matched local recurrences or distant metastases, AR expression was often maintained even when ER was reduced or absent. These data provide pre-clinical evidence that anti-androgens that inhibit AR nuclear localization affect both AR and ER, and are effective in combination with current breast cancer therapies. In addition, single agent efficacy may be possible in tumors resistant to traditional endocrine therapy, since clinical specimens of recurrent disease demonstrate AR expression in tumors with absent or refractory ER. Implications This study suggests that AR plays a previously-unrecognized role in supporting E2-mediated ER activity in ER+/AR+ breast cancer cells, and that enzalutamide may be an effective therapeutic in ER+/AR+ breast cancers.

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Section: Introductionmentioning

confidence: 99%

Cooperative Dynamics of AR and ER Activity in Breast Cancer

D’Amato

Gordon

Babbs

et al. 2016

Molecular Cancer Research

122

152

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“…Preclinical studies have shown that the phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of the rapamycin (mTOR) signaling pathway is important to endocrine resistance [3, 4]. In preclinical models, combining everolimus (Afinitor ® ), an mTOR inhibitor, with an AI produced synergistic anti-tumor activity [5].…”

Section: Introductionmentioning

confidence: 99%

Cost-effectiveness analysis of everolimus plus exemestane versus exemestane alone for treatment of hormone receptor positive metastatic breast cancer

Diaby

Adunlin

Zeichner

et al. 2014

Breast Cancer Res Treat

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Everolimus in combination with exemestane significantly improved progression-free survival compared to exemestane alone in patients previously treated with non-steroidal aromatase inhibitors in the BOLERO-2 trial. As a result, this combination has been approved by the food and drug administration to treat postmenopausal women with hormone receptor positive and HER2 negative metastatic breast cancer. A cost-effectiveness analysis was conducted to determine whether everolimus represents good value for money, utilizing data from BOLERO-2. A decision-analytic model was used to estimate the incremental cost-effectiveness ratio between treatment arms of the BOLERO-2 trial. Costs were obtained from the Center for Medicare Services drug payment table and physician fee schedule. Benefits were expressed as quality-adjusted progression-free survival weeks (QAPFW) and quality-adjusted progression-free years (QAPFY), with utilities/disutilities derived from the literature. Deterministic and probabilistic sensitivity analyses were performed. A willingness to pay threshold of 1–3 times the per capita gross domestic product was adopted, as per the definition of the World Health Organization. The U.S. per capita gross domestic product in 2013 was $49,965; thus, a threshold varying between $49,965 and $149,895 was considered. Everolimus/exemestane had an incremental benefit of 11.88 QAPFW (0.22 QAPFY) compared to exemestane and an incremental cost of $60,574. This translated into an ICER of $265,498.5/QAPFY. Univariate sensitivity analyses showed important variations of the ICER, ranging between $189,836.4 and $530,947/QAPFY. A tornado analysis suggested that the key drivers of our model, by order of importance, included health utility value for stable disease, everolimus acquisition costs, and transition probabilities from the stable to the progression states. The Monte-Carlo simulation showed results that were similar to the base-case analysis. This cost-effectiveness analysis showed that everolimus plus exemestane is not cost-effective compared to exemestane alone. Further research is needed to investigate the cost-effectiveness of the drug combination within sub-groups of the population studied in BOLERO-2.

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“…Specifically, the disease may be using alternative pathways, such as the mTOR pathway, to continue cancer cell growth and proliferation in the presence of endocrine interventions. These alternative pathways are less likely to be active in patients with minimal or no prior exposure to systemic endocrine therapy [29, 30]. Nonetheless, disease relapse during standard adjuvant endocrine therapy remains a concern, and might involve similar signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Everolimus plus exemestane as first-line therapy in HR+, HER2− advanced breast cancer in BOLERO-2

Beck

Hortobágyi

Campone

et al. 2013

Breast Cancer Res Treat

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The present exploratory analysis examined the efficacy, safety, and quality-of-life effects of everolimus (EVE) + exemestane (EXE) in the subgroup of patients in BOLERO-2 whose last treatment before study entry was in the (neo)adjuvant setting. In BOLERO-2, patients with hormone-receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2−) advanced breast cancer recurring/progressing after a nonsteroidal aromatase inhibitor (NSAI) were randomly assigned (2:1) to receive EVE (10 mg/day) + EXE (25 mg/day) or placebo (PBO) + EXE. The primary endpoint was progression-free survival (PFS) by local assessment. Overall, 137 patients received first-line EVE + EXE (n = 100) or PBO + EXE (n = 37). Median PFS by local investigator assessment nearly tripled to 11.5 months with EVE + EXE from 4.1 months with PBO + EXE (hazard ratio = 0.39; 95 % CI 0.25–0.62), while maintaining quality of life. This was confirmed by central assessment (15.2 vs 4.2 months; hazard ratio = 0.32; 95 % CI 0.18–0.57). The marked PFS improvement in patients receiving EVE + EXE as first-line therapy for disease recurrence during or after (neo)adjuvant NSAI therapy supports the efficacy of this combination in the first-line setting. Furthermore, the results highlight the potential benefit of early introduction of EVE + EXE in the management of HR+, HER2− advanced breast cancer in postmenopausal patients.

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Improving Endocrine Therapy for Breast Cancer: It's Not That Simple

Cited by 28 publications

References 22 publications

Cooperative Dynamics of AR and ER Activity in Breast Cancer

Cooperative Dynamics of AR and ER Activity in Breast Cancer

Cost-effectiveness analysis of everolimus plus exemestane versus exemestane alone for treatment of hormone receptor positive metastatic breast cancer

Everolimus plus exemestane as first-line therapy in HR+, HER2− advanced breast cancer in BOLERO-2

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