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*
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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Cited by (53)
Androgen receptor in estrogen receptor positive breast cancer: Beyond expression
2017, Cancer Treatment ReviewsEstrone sulfate and dehydroepiandrosterone sulfate: Transactivation of the estrogen and androgen receptor
2016, SteroidsCitation Excerpt :Some compounds may enhance or counteract each other’s biological effects when combined [22], and we believe that the combined effect of DHEAS, E1S and the PFAAs on the ER and AR transactivity might be relevant in studies of adverse human health effects. For example, we recently found that high levels of the PFAAs were associated with an increased risk of breast cancer in Greenlandic and Danish women [23,24], and a similar association have been reported for the sulfated steroids [25,26]. We conclude that DHEAS and E1S can induce ER and AR transactivity in the used cell cultures at concentrations comparable with levels found in human serum.
Breast cancer: Current and future endocrine therapies
2014, Molecular and Cellular EndocrinologyCitation Excerpt :Androstenediol (Adiol), has potent oestrogenic effects, and can stimulate the growth of hormone-dependent breast cancer cells in vitro and carcinogen-induced mammary tumours in rodents (Poulin and Labrie, 1986; Dauvois and Labrie, 1989). While Dehydroepiandrosterone (DHEA) has also been shown to stimulate the proliferation of breast cancer cell lines (Maggiolini et al., 1999) and its sulfated version dehydroepiandrosterone sulfate (DHEAS), which can be converted to DHEA, has been shown to be significantly elevated in women who failed to derive benefit from an AI in the metastatic setting (Morris et al., 2001). In light of the potential importance of adrenal derived steroidoal hormones in endocrine resistance, the utility of two agents which can modulate these hormones, namely abiraterone acetate (herein referred to as abiraterone) and Irosustat, are currently being explored in breast cancer.
Effect of an investigational CYP17A1 inhibitor, orteronel (TAK-700), on estrogen- and corticoid-synthesis pathways in hypophysectomized female rats and on the serum estradiol levels in female cynomolgus monkeys
2013, Journal of Steroid Biochemistry and Molecular BiologyCitation Excerpt :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].
Treatment of metastatic breast cancer: State-of-the-art, subtypes and perspectives
2011, Critical Reviews in Oncology/HematologySteroid sulfatase: A pivotal player in estrogen synthesis and metabolism
2011, Molecular and Cellular EndocrinologyCitation Excerpt :A raised serum DHEAS has been demonstrated in postmenopausal women with breast cancer when compared to controls (Aspinall et al., 2003), suggesting that increased adrenal secretion of this androgen may have a role in the pathogenesis of breast cancer, possibly due to its conversion to Adiol. Higher concentrations of DHEAS and DHEA have also been associated with an increased risk of breast cancer in postmenopausal women, especially in ER+/PR+ cases (Key et al., 2002; Dorgan et al., 1997; Missmer et al., 2004; Morris et al., 2001). At this junction, it is important to emphasise that the affinities of the substrates for the aromatase or STS are very different.
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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.