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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.

Munster PN, Thurn KT, Thomas S, Raha P, Lacevic M, Miller A, Melisko M, Ismail-Khan R, Rugo H, Moasser M, Minton SE - Br. J. Cancer (2011)

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology and Oncology, University of California, San Francisco, 1600 Divisadero, Rm A719 Box 1711, San Francisco, CA 94143, USA. pmunster@medicine.ucsf.edu

ABSTRACT

Background: Histone deacetylases (HDACs) are crucial components of the oestrogen receptor (ER) transcriptional complex. Preclinically, HDAC inhibitors can reverse tamoxifen/aromatase inhibitor resistance in hormone receptor-positive breast cancer. This concept was examined in a phase II combination trial with correlative end points.

Methods: Patients with ER-positive 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: In all, 43 patients (median age 56 years (31-71)) 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: 8.1-12.4). Histone hyperacetylation and higher baseline HDAC2 levels correlated with response.

Conclusion: The 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.

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(A) Scatter plot of baseline histone deacetylase 2 (HDAC2) expression vs percent change in acetyl-H4 in PBMCs (day 8 post-treatment pre-dose) by immunofluorescence normalised to pan-histone H3 expression, analysed by Pearson's correlation (P=0.004, correlation coefficient of 0.470). (B) Percent change in acetyl-H4 in patients with less severe (grade 1/2) and more severe (grade 3/4) haematological or non-haematological toxicities (P=0.49).
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fig3: (A) Scatter plot of baseline histone deacetylase 2 (HDAC2) expression vs percent change in acetyl-H4 in PBMCs (day 8 post-treatment pre-dose) by immunofluorescence normalised to pan-histone H3 expression, analysed by Pearson's correlation (P=0.004, correlation coefficient of 0.470). (B) Percent change in acetyl-H4 in patients with less severe (grade 1/2) and more severe (grade 3/4) haematological or non-haematological toxicities (P=0.49).

Mentions: In previous studies, we have shown that the change in histone acetylation correlates with baseline expression of HDAC2 (Munster et al, 2007, 2009a) in PBMC and tumour cells. In this study, higher baseline expression of HDAC2 in PBMCs was associated with a more pronounced increase in histone H4 acetylation (Figure 3A) (P=0.003, Pearson's correlation coefficient=0.519).


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, Raha P, Lacevic M, Miller A, Melisko M, Ismail-Khan R, Rugo H, Moasser M, Minton SE - Br. J. Cancer (2011)

(A) Scatter plot of baseline histone deacetylase 2 (HDAC2) expression vs percent change in acetyl-H4 in PBMCs (day 8 post-treatment pre-dose) by immunofluorescence normalised to pan-histone H3 expression, analysed by Pearson's correlation (P=0.004, correlation coefficient of 0.470). (B) Percent change in acetyl-H4 in patients with less severe (grade 1/2) and more severe (grade 3/4) haematological or non-haematological toxicities (P=0.49).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3111195&req=5

fig3: (A) Scatter plot of baseline histone deacetylase 2 (HDAC2) expression vs percent change in acetyl-H4 in PBMCs (day 8 post-treatment pre-dose) by immunofluorescence normalised to pan-histone H3 expression, analysed by Pearson's correlation (P=0.004, correlation coefficient of 0.470). (B) Percent change in acetyl-H4 in patients with less severe (grade 1/2) and more severe (grade 3/4) haematological or non-haematological toxicities (P=0.49).
Mentions: In previous studies, we have shown that the change in histone acetylation correlates with baseline expression of HDAC2 (Munster et al, 2007, 2009a) in PBMC and tumour cells. In this study, higher baseline expression of HDAC2 in PBMCs was associated with a more pronounced increase in histone H4 acetylation (Figure 3A) (P=0.003, Pearson's correlation coefficient=0.519).

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology and Oncology, University of California, San Francisco, 1600 Divisadero, Rm A719 Box 1711, San Francisco, CA 94143, USA. pmunster@medicine.ucsf.edu

ABSTRACT

Background: Histone deacetylases (HDACs) are crucial components of the oestrogen receptor (ER) transcriptional complex. Preclinically, HDAC inhibitors can reverse tamoxifen/aromatase inhibitor resistance in hormone receptor-positive breast cancer. This concept was examined in a phase II combination trial with correlative end points.

Methods: Patients with ER-positive 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: In all, 43 patients (median age 56 years (31-71)) 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: 8.1-12.4). Histone hyperacetylation and higher baseline HDAC2 levels correlated with response.

Conclusion: The 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.

Show MeSH
Related in: MedlinePlus