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Multitargeting Ovarian Epithelial Cancer: Adding the Old to the New

Comprehensive Cancer Center, University of Colorado, Aurora, CO

To the Editor:

The recent editorial by Kaye¹ addresses the numerous possibilities of combining the antiangiogenesis agent, bevacizumab, with other targeted agents in patients with advanced epithelial ovarian carcinoma. A regimen not mentioned is the combination of antiestrogen therapy with bevacizumab. It has been shown that in patients with metastatic breast cancer, those whose human epidermal growth factor 2 (HER2)–negative tumors were estrogen receptor (ER)–positive had a better response to the combination of capecitabine plus bevacizumab than patients whose tumors were HER2/ER-negative.² This could due to the mechanism of normalization of tumor vasculature by bevacizumab in ER-positive tumors, allowing more of the cytotoxic agent to reach the tumor. However, this has not been proven. Alternatively, it could be due to disruption by bevacizumab of the crosstalk between the vascular endothelial growth factor (VEGF) and ER pathways.³

Estrogen receptors are expressed in the majority (61% to 79%) of ovarian cancers, with endometrioid and serous types having the highest ER expression.⁴ There is precedence for the use of antiestrogen therapy in ovarian cancer but, unfortunately, most studies have not considered ER status of the tumor. In an earlier study that did, tamoxifen (40 mg/d) demonstrated an 18% response rate in 105 patients. Of the nine patients who had a complete response, eight patients (89%) had tumors that were ER-positive.⁵ In a more recent study of 42 patients with ER-positive ovarian cancers, the nonsteroidal aromatase inhibitor, letrozole, produced a response in nine patients (17%).⁶ Therefore, if disrupting a pathway, such as VEGF, is desirable in tumors with an intact ER pathway, as seen in breast and ovarian cancers, simultaneously blocking its crosstalk partner, ER, may be even more desirable. In that regard, estradiol can induce hypoxia-inducible factor 1- (HIF-1) and its downstream target gene, VEGF-A, in ovarian tumor cells.⁷ Estradiol would be targeted by the antiestrogen and VEGF by bevacizumab, for dual inhibition of the two cross-talking pathways, a relatively less costly regimen.

If vascular occlusion is a concern, since both tamoxifen and bevacizumab have such an association, perhaps one of the multitargeting tyrosine kinase inhibitors could be used as the VEGFR blocking agent in place of the latter. These oral agents do not appear to have such adverse effects and would give a completely oral regimen.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Kaye SB: Bevacizumab for the treatment of epithelial ovarian cancer: Will this be its finest hour? J Clin Oncol 25:5150-5152, 2007[Free Full Text]

2. Sledge G, Miller K, Moisa C, et al: Safety and efficacy of capecitabine (C) plus bevacizumab (B) as first-line in metastatic breast cancer. J Clin Oncol 25:18S-, 2007 (suppl; abstr 1013)

3. Menendez D, Inga A, Snipe J, et al: A single-nucleotide polymorphism in a half-binding site creates p53 and estrogen receptor control of vascular growth factor receptor 1. Mol Cell Biol 27:2590-2600, 2007[Abstract/Free Full Text]

4. Zheng H, Kavanagh JJ, Hu W, et al: Hormonal therapy in ovarian cancer. Int J Gynecol Cancer 17:325-338, 2007[CrossRef][Medline]

5. Hatch KD, Beecham JB, Blessing JA, et al: Responsiveness of patients with advanced ovarian carcinoma to tamoxifen. Cancer 68:269-271, 1991[CrossRef][Medline]

6. Smyth JF, Gourley C, Walker G, et al: Antiestrogen therapy is active in selected ovarian cancer cases: The use of letrozole in estrogen receptor-positive patients. Clin Cancer Res 13:3617-3622, 2007[Abstract/Free Full Text]

7. Gao N, Nester RA, Sarkar MA: 4-Hydroxy estradiol but not 2-hydroxy estradiol induces expression of hypoxia-inducible factor 1-alpha and vascular endothelial growth A through phosphatidylinositol 3-kinase/Akt/FRAP pathway in OVCAR-3 and A2780-CP70 human ovarian cancer cells. Toxicol Appl Pharmacol 196:124-135, 2004[CrossRef][Medline]

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• Bevacizumab for the Treatment of Epithelial Ovarian Cancer: Will This Be Its Finest Hour?
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  JCO 2007 25: 5150-5152 [Full Text]

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Garfield, D. H. Search for Related Content PubMed PubMed Citation Articles by Garfield, D. H. Related Articles Related Article Social Bookmarking                            What's this?