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A phase II study of the histone deacetylase inhibitor vorinostat combined with tamoxifen for the treatment of patients with hormone therapy-resistant breast cancer
HORMONAL THERAPY A phase II study of the histone deacetylase inhibitor vorinostat combined with tamoxifen for the treatment of patients with hormone therapy-resistant breast cancer Munster PN, Thurn KT, Thomas S, et al (Univ of California, San Francisco; et al) Br J Cancer 104:1828-1835, 2011
Background.dHistone deacetylases (HDACs) are crucial components of the oestrogen receptor (ER) transcriptional complex. Preclinically, HDAC inhibitors can reverse tamoxifen/aromatase inhibitor resistance in hormone receptorpositive breast cancer. This concept was examined in a phase II combination trial with correlative end points. Methods.dPatients with ERpositive metastatic breast cancer progressing on endocrine therapy were treated with 400 mg of vorinostat daily for 3 of 4 weeks and 20 mg tamoxifen daily, continuously. Histone acetylation and HDAC2 expression in peripheral blood mononuclear cells were also evaluated. Results.dIn all, 43 patients (median age 56 years (31e71)) were treated, 25 (58%) received prior adjuvant tamoxifen, 29 (67%) failed one prior chemotherapy regimen, 42 (98%) progressed after one, and 23 (54%) after two aromatase inhibitors. The objective response rate by Response Evaluation Criteria in Solid Tumours criteria was 19% and the clinical benefit rate (response or stable disease >24 weeks) was 40%. The median response duration was 10.3 months (confidence interval: 8.1e12.4). Histone hyperacetylation and higher baseline HDAC2 levels correlated with response.
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Conclusion.dThe combination of vorinostat and tamoxifen is well tolerated and exhibits encouraging activity in reversing hormone resistance. Correlative studies suggest that HDAC2 expression is a predictive marker and histone hyperacetylation is a useful pharmacodynamic marker for the efficacy of this combination (Fig 2). A growing body of evidence supports the notion that epigenetic alterations and subsequent effects on gene expression drive cancer development, progression, and responsiveness to therapy.1 Gene promoter methylation and histone deacetylation are the 2 mechanisms of gene silencing
that have been targeted pharmacologically. HDAC inhibitors have been shown to reexpress silenced genes, including ER, and also to restore tamoxifen sensitivity.2 A previous phase II trial by the California Consortium showed that using the HDAC inhibitor vorinostat (suberoylanilide hydroxamic acid) as a single agent yielded a median overall survival duration of 24 months and was well tolerated in patients with both hormone receptorepositive and enegative metastatic breast cancers, but it did not produce an objective response.3 Alternatively, this phase II trial by Munster and colleagues tested preclinical observations that HDAC
FIGURE 2.dPercent change in acetyl-H4 (day 8 post-treatment pre-dose) in PBMCs by immunofluorescence normalised to pan-histone H3 expression. (A) Mean change of acetyl-H4 and (B) mean baseline HDAC2 expression relative to pan-histone H3 expression in all patients, in responders (R; response or clinical benefit $24 weeks) and in nonresponders (NR). *Statistical significance for acetyl-H4, P ¼ 0.022 (R vs NR) and HDAC2, P ¼ 0.04 (R vs NR). (C) Waterfall plot of acetyl-H4 in (-) responders and (,) non-responders (n ¼ 36). (Reprinted by permission from Macmillan Publishers Ltd: [British Journal of Cancer] Munster PN, Thurn KT, Thomas S, et al. A phase II study of the histone deacetylase inhibitor vorinostat combined with tamoxifen for the treatment of patients with hormone therapy-resistant breast cancer. Br J Cancer. 2011;104:1828-1835. Ó 2011.)
Breast Diseases: A Year BookÒ Quarterly Vol 23 No 1 2012
inhibitors could reverse tamoxifeninduced ER stabilization. Acquired tamoxifen resistance in hormonepositive breast cancer may involve growth factor pathways and signaling, which are other possible targets of HDAC inhibitors. Signaling through epidermal growth factor receptor (EGFR) and human EGFR 2 appears to bypass the estrogen requirement and to drive cells into an endocrine therapyeresistant state.4,5 Zhou and colleagues reported that HDAC inhibitors downregulate EGFR through attenuation of its messenger RNA stability. Further experiments indicated that a decrease in EGFR abolished epidermal growth factore initiated signaling pathways, including phosphorylated PAK1, p38 mitogen-activated protein kinase, and Akt.6 This study had reasonable power to exclude 10% or less of the true response rate, and vorinostat showed a promising clinical benefit rate of 40% and a response rate of 19% in patients who had recurrent or progressive disease on hormonal therapy, including tamoxifen (although tamoxifen was not used in the metastatic setting). Pharmacodynamic studies carried out on peripheral blood mononuclear cells (PBMCs) suggested a correlation between higher percent change in acetyl-H4 and response rate and duration. The authors hypothesized that HDAC2 is the primary target of vorinostat’s activity in this setting, based on similar treatment effects seen in the laboratory with HDAC2 small-
interfering RNA gene knockdown. The correlative study was limited by an insufficient number of PBMCs in the treated patients and is subject to potential bias. The utility of measuring baseline HDAC2 to predict clinical response to HDAC inhibitors needs to be further confirmed and could be an important factor in personalized therapy. A 7% incidence of deep vein thrombosis and pulmonary embolism might be more than expected with tamoxifen alone and could point to augmented thrombogenicity, which is also driven by ER-mediated transcription. In summary, Munster and colleagues achieved the objectives of the study, and their results support further randomized clinical trials. Enthusiasm is further bolstered by early results from a placebo-controlled randomized phase II trial of exemestane with or without the HDAC inhibitor entinostat (SNDX-275), which showed an improvement in progression-free and overall survival with entinostat in postmenopausal women with advanced ER-positive breast cancer who had progressive disease on a nonsteroidal aromatase inhibitor.7 D. Tripathy, MD E. Thara, DO
References 1. Esteller M. Epigenetics in cancer. N Engl J Med. 2008;358:1148-1159.
sensitivity in estrogen receptornegative breast cancer cells: tamoxifenbound reactivated ER recruits distinctive corepressor complexes. Cancer Res. 2006;66:6370-6378. 3. Luu TH, Morgan RJ, Leong L, et al. A phase II trial of vorinostat (suberoylanilide hydroxamic acid) in metastatic breast cancer: a California Cancer Consortium study. Clin Cancer Res. 2008;14:7138-7142. 4. Osborne CK, Bardou V, Hopp TA, et al. Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER2/neu in tamoxifen resistance in breast cancer. J Natl Cancer Inst. 2003;95:353-361. 5. El-Ashry D, Miller DL, Kharbanda S, Lippman ME, Kern FG. Constitutive Raf-1 kinase activity in breast cancer cells induces both estrogenindependent growth and apoptosis. Oncogene. 1997;15:423-435. 6. Zhou Q, Shaw PG, Davidson NE. Inhibition of histone deacetylase suppresses EGF signaling pathways by destabilizing EGFR mRNA in ER-negative human breast cancer cells. Breast Cancer Res Treat. 2009; 117:443-451. 7. Yardley DAQ, Ismail-Khan R, Klein P. Results of ENCORE 301, a randomized, phase II, double-blind, placebocontrolled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on a nonsteroidal aromatase inhibitor (abstract 268). J Clin Oncol. 2011:29.
2. Sharma D, Saxena NK, Davidson NE, Vertino PM. Restoration of tamoxifen
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Background.dHistone deacetylases (HDACs) are crucial components of the oestrogen receptor (ER) transcriptional complex. Preclinically, HDAC inhibitors can reverse tamoxifen/aromatase inhibitor resistance in hormone receptorpositive breast cancer. This concept was examined in a phase II combination trial with correlative end points. Methods.dPatients with ERpositive metastatic breast cancer progressing on endocrine therapy were treated with 400 mg of vorinostat daily for 3 of 4 weeks and 20 mg tamoxifen daily, continuously. Histone acetylation and HDAC2 expression in peripheral blood mononuclear cells were also evaluated. Results.dIn all, 43 patients (median age 56 years (31e71)) were treated, 25 (58%) received prior adjuvant tamoxifen, 29 (67%) failed one prior chemotherapy regimen, 42 (98%) progressed after one, and 23 (54%) after two aromatase inhibitors. The objective response rate by Response Evaluation Criteria in Solid Tumours criteria was 19% and the clinical benefit rate (response or stable disease >24 weeks) was 40%. The median response duration was 10.3 months (confidence interval: 8.1e12.4). Histone hyperacetylation and higher baseline HDAC2 levels correlated with response.
88
Conclusion.dThe combination of vorinostat and tamoxifen is well tolerated and exhibits encouraging activity in reversing hormone resistance. Correlative studies suggest that HDAC2 expression is a predictive marker and histone hyperacetylation is a useful pharmacodynamic marker for the efficacy of this combination (Fig 2). A growing body of evidence supports the notion that epigenetic alterations and subsequent effects on gene expression drive cancer development, progression, and responsiveness to therapy.1 Gene promoter methylation and histone deacetylation are the 2 mechanisms of gene silencing
that have been targeted pharmacologically. HDAC inhibitors have been shown to reexpress silenced genes, including ER, and also to restore tamoxifen sensitivity.2 A previous phase II trial by the California Consortium showed that using the HDAC inhibitor vorinostat (suberoylanilide hydroxamic acid) as a single agent yielded a median overall survival duration of 24 months and was well tolerated in patients with both hormone receptorepositive and enegative metastatic breast cancers, but it did not produce an objective response.3 Alternatively, this phase II trial by Munster and colleagues tested preclinical observations that HDAC
FIGURE 2.dPercent change in acetyl-H4 (day 8 post-treatment pre-dose) in PBMCs by immunofluorescence normalised to pan-histone H3 expression. (A) Mean change of acetyl-H4 and (B) mean baseline HDAC2 expression relative to pan-histone H3 expression in all patients, in responders (R; response or clinical benefit $24 weeks) and in nonresponders (NR). *Statistical significance for acetyl-H4, P ¼ 0.022 (R vs NR) and HDAC2, P ¼ 0.04 (R vs NR). (C) Waterfall plot of acetyl-H4 in (-) responders and (,) non-responders (n ¼ 36). (Reprinted by permission from Macmillan Publishers Ltd: [British Journal of Cancer] Munster PN, Thurn KT, Thomas S, et al. A phase II study of the histone deacetylase inhibitor vorinostat combined with tamoxifen for the treatment of patients with hormone therapy-resistant breast cancer. Br J Cancer. 2011;104:1828-1835. Ó 2011.)
Breast Diseases: A Year BookÒ Quarterly Vol 23 No 1 2012
inhibitors could reverse tamoxifeninduced ER stabilization. Acquired tamoxifen resistance in hormonepositive breast cancer may involve growth factor pathways and signaling, which are other possible targets of HDAC inhibitors. Signaling through epidermal growth factor receptor (EGFR) and human EGFR 2 appears to bypass the estrogen requirement and to drive cells into an endocrine therapyeresistant state.4,5 Zhou and colleagues reported that HDAC inhibitors downregulate EGFR through attenuation of its messenger RNA stability. Further experiments indicated that a decrease in EGFR abolished epidermal growth factore initiated signaling pathways, including phosphorylated PAK1, p38 mitogen-activated protein kinase, and Akt.6 This study had reasonable power to exclude 10% or less of the true response rate, and vorinostat showed a promising clinical benefit rate of 40% and a response rate of 19% in patients who had recurrent or progressive disease on hormonal therapy, including tamoxifen (although tamoxifen was not used in the metastatic setting). Pharmacodynamic studies carried out on peripheral blood mononuclear cells (PBMCs) suggested a correlation between higher percent change in acetyl-H4 and response rate and duration. The authors hypothesized that HDAC2 is the primary target of vorinostat’s activity in this setting, based on similar treatment effects seen in the laboratory with HDAC2 small-
interfering RNA gene knockdown. The correlative study was limited by an insufficient number of PBMCs in the treated patients and is subject to potential bias. The utility of measuring baseline HDAC2 to predict clinical response to HDAC inhibitors needs to be further confirmed and could be an important factor in personalized therapy. A 7% incidence of deep vein thrombosis and pulmonary embolism might be more than expected with tamoxifen alone and could point to augmented thrombogenicity, which is also driven by ER-mediated transcription. In summary, Munster and colleagues achieved the objectives of the study, and their results support further randomized clinical trials. Enthusiasm is further bolstered by early results from a placebo-controlled randomized phase II trial of exemestane with or without the HDAC inhibitor entinostat (SNDX-275), which showed an improvement in progression-free and overall survival with entinostat in postmenopausal women with advanced ER-positive breast cancer who had progressive disease on a nonsteroidal aromatase inhibitor.7 D. Tripathy, MD E. Thara, DO
References 1. Esteller M. Epigenetics in cancer. N Engl J Med. 2008;358:1148-1159.
sensitivity in estrogen receptornegative breast cancer cells: tamoxifenbound reactivated ER recruits distinctive corepressor complexes. Cancer Res. 2006;66:6370-6378. 3. Luu TH, Morgan RJ, Leong L, et al. A phase II trial of vorinostat (suberoylanilide hydroxamic acid) in metastatic breast cancer: a California Cancer Consortium study. Clin Cancer Res. 2008;14:7138-7142. 4. Osborne CK, Bardou V, Hopp TA, et al. Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER2/neu in tamoxifen resistance in breast cancer. J Natl Cancer Inst. 2003;95:353-361. 5. El-Ashry D, Miller DL, Kharbanda S, Lippman ME, Kern FG. Constitutive Raf-1 kinase activity in breast cancer cells induces both estrogenindependent growth and apoptosis. Oncogene. 1997;15:423-435. 6. Zhou Q, Shaw PG, Davidson NE. Inhibition of histone deacetylase suppresses EGF signaling pathways by destabilizing EGFR mRNA in ER-negative human breast cancer cells. Breast Cancer Res Treat. 2009; 117:443-451. 7. Yardley DAQ, Ismail-Khan R, Klein P. Results of ENCORE 301, a randomized, phase II, double-blind, placebocontrolled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on a nonsteroidal aromatase inhibitor (abstract 268). J Clin Oncol. 2011:29.
2. Sharma D, Saxena NK, Davidson NE, Vertino PM. Restoration of tamoxifen
Breast Diseases: A Year BookÒ Quarterly Vol 23 No 1 2012
89