High dehydroepiandrosterone-sulfate predicts breast cancer progression during new aromatase inhibitor therapy and stimulates breast cancer cell growth in tissue culture: A renewed role for adrenalectomy

doi:10.1067/msy.2001.118378

Surgery

Volume 130, Issue 6, December 2001, Pages 947-953

Presented at the 22nd Annual Meeting of the American Association of Endocrine Surgeons, Atlanta, Ga, April 28-May 1, 2001.

https://doi.org/10.1067/msy.2001.118378 Get rights and content

Abstract

Background. Stage IV hormone-sensitive breast cancer is often treated with aromatase inhibitors (anastrozole, letrozole, exemestane), which block the conversion of dehydroepiandrosterone (DHEA) to estrone and estradiol. This is intended to obviate the need for steroid replacement and antiquate adrenalectomy. Methods. Patients who underwent oophorectomy and were being treated with new aromatase inhibitor therapy received serial measurements of serum estrone, estradiol, and DHEA-sulfate (DHEA-S). Steroid values during responsive and progressive phases of disease were compared. In vitro, human breast cancer cell lines T-47D (estrogen-receptor and progesterone-receptor positive) and HCC 1937 (estrogen-receptor and progesterone-receptor negative) were treated with DHEA-S. Proliferation rates were measured by colorimetric assay. Results. Disease in 12 of the 19 patients progressed. DHEA-S was less than 89 μg/dL in patients during the responsive phase and more than or equal to 89 μg/dL during disease progression, with 1 exception (P <.0005). Estrone and estradiol remained suppressed. After disease progression, the condition of 9 patients stabilized with aminoglutethimide therapy (n = 8) or adrenalectomy (n = 1), and their DHEA-S levels were reduced to less than 89 μg/dL. In vitro, elevated DHEA-S induced cell proliferation in T-47D cells. Conclusions. DHEA-S levels more than or equal to 89 μg/dL predicted disease progression in states of low estrogen. Tissue culture results supported the role of DHEA-S as an estrogenic agent. Oophorectomies with either aminoglutethimide therapy or adrenalectomy were effective remedies for breast cancer progression due to high DHEA-S. (Surgery 2001;130:947-53.)

Section snippets

Clinical data

Women with hormone-sensitive stage IV breast cancer referred to our surgical oncology clinics were treated with endocrine ablation therapy consisting of oophorectomy and adrenal blockade of estrogen precursors. All women in this study were treated with 1 of the new AI medications as the adrenal blockade component. Serial measurements of the patients, sex steroids, including estrone (E1), estradiol (E2), and DHEA-S, were made every 3 months and at the time of progression to assess the degree of

Clinical data

Nineteen women with an average age of 59 years (range, 39-79 years) were studied. Fourteen women were treated with anastrozole, 3 with letrozole, and 2 with exemestane. The mean follow-up for all patients was 14 months. Disease in 7 of the 19 women remained stable. Their mean follow-up was 23 months (range, 2-49 months). The remaining 12 women had progression of their disease during new AI therapy. Average time from initiation of new AI therapy to progression was 9 months (range, 1-33 months).

Conclusions

In the group of patients with progression of disease and negligible serum estrogen levels, elevated DHEA-S appeared to stimulate tumor progression. The 7 women whose disease remained stable during new AI therapy consistently had serum DHEA-S levels of less than 89 μg/dL, whereas all but 1 of the women with disease progression had DHEA-S levels greater than 89 μg/dL. Most importantly, we were able to stabilize progressing disease in 9 patients by converting treatment to either aminoglutethimide

Discussion

Dr Clive Grant (Rochester, Minn). These aromatase inhibitors may well exceed the efficacy of tamoxifen. All of your patients had stage IV disease. Have you any experience with monitoring DHEA levels of patients receiving aromatase inhibitors in the adjuvant setting? And does the cut-off of a DHEA level of > 89 mg/dL predict disease relapse in this situation?

Dr Morris (Portland, Ore). As far as I know, we haven't been using the new aromatase inhibitors as adjuvant therapy for women who don't

Acknowledgements

This research was supported by women's golf clubs in Oregon and the Oregon Chapter of the Order of the Eastern Star.

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Estrogen is synthesized from androgen thus agents which inhibit androgen biosynthesis may also be a good candidate to treat breast cancer. Furthermore, clinical findings indicate that elevated serum dehydroepiandrosterone-sulfate (DHEA-S) levels predict disease progression in states of low estrogen (such as that produced by aromatase inhibitors) and that after disease progression, the condition is stabilized by reduction of DHEA-S levels by aminoglutethimide therapy or adrenalectomy [8]. In line with this finding, it has been reported that adrenal androgen and its metabolites directly activate ER in vitro [9].
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^*: Reprint requests: Rodney F. Pommier, MD, Oregon Health Sciences University, Department of Surgery, Section of Surgical Oncology, Mail Code-L223A, 3181 SW Sam Jackson Park Rd, Portland, OR 97201.

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American Association of Endocrine SurgeonsHigh dehydroepiandrosterone-sulfate predicts breast cancer progression during new aromatase inhibitor therapy and stimulates breast cancer cell growth in tissue culture: A renewed role for adrenalectomy*

Abstract

Section snippets

Clinical data

Clinical data

Conclusions

Discussion

Acknowledgements

Am J Surg

Surg Oncol

Eur J Cancer

J Immunol Methods

Cancer Lett

J Steroid Biochem Mol Biol

The role of major endocrine ablation

Endocrine therapy of metastatic breast cancer

American Association of Endocrine Surgeons
High dehydroepiandrosterone-sulfate predicts breast cancer progression during new aromatase inhibitor therapy and stimulates breast cancer cell growth in tissue culture: A renewed role for adrenalectomy*