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Effect of Tamoxifen Or Anastrozole on Steroid Sulfatase Activity and Serum Androgen Concentrations in Postmenopausal Women with Breast Cancer

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Effect of Tamoxifen Or Anastrozole on Steroid Sulfatase Activity and Serum Androgen Concentrations in Postmenopausal Women with Breast Cancer ANTICANCER RESEARCH 31: 1367-1372 (2011) Effect of Tamoxifen or Anastrozole on Steroid Sulfatase Activity and Serum Androgen Concentrations in Postmenopausal Women with Breast Cancer S.J. STANWAY1, C. PALMIERI2, F.Z. STANCZYK3, E.J. FOLKERD4, M. DOWSETT4, R. WARD2, R.C. COOMBES2, M.J. REED1† and A. PUROHIT1 1Oncology Drug Discovery Group, Section of Investigative Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, U.K.; 2Cancer Research UK Laboratories, Department of Oncology, Hammersmith Hospital, London W12 0NN, U.K.; 3Reproductive Endocrine Research Laboratory, University of Southern California, Keck School of Medicine, Women’s and Children’s Hospital, Los Angeles, CA, U.S.A.; 4Department of Biochemistry, Royal Marsden Hospital, London, SW3 6JJ, U.K. Abstract. Background: In postmenopausal women sulfate and dehydroepiandrosterone levels. Results: Neither estrogens can be formed by the aromatase pathway, which anastrozole nor tamoxifen had any significant effect on STS gives rise to estrone, and the steroid sulfatase (STS) route activity as measured in PBLs. Anastrozole did not affect which can result in the formation of estrogens and serum androstenediol concentrations. Conclusion: androstenediol, a steroid with potent estrogenic properties. Anastrozole and tamoxifen did not inhibit STS activity and Aromatase inhibitors, such as anastrozole, are now in serum androstenediol concentrations were not reduced by clinical use whereas STS inhibitors, such as STX64, are still aromatase inhibition. As androstenediol has estrogenic undergoing clinical evaluation. STX64 was recently shown properties, it is possible that the combination of an to block STS activity and reduce serum androstenediol aromatase inhibitor and STS inhibitor may give a therapeutic concentrations in postmenopausal women with breast cancer. advantage over the use of either agent alone. In contrast, little is known about the effects of aromatase inhibitors or anti-estrogens on STS activity or serum Anti-estrogens and aromatase inhibitors are now widely used androgen levels. Patients and Methods: Study 1: Blood was for the treatment of postmenopausal women with hormone- collected from ten postmenopausal women with breast dependent breast cancer (1, 2). While anti-estrogens, such as cancer before and after two-week treatment with anastrozole tamoxifen, block the interaction of estradiol (E2) with the and serum concentrations of androstenediol and other estrogen receptor (ER), aromatase inhibitors such as androgens and estrogens were assessed. Study 2: Blood anastrozole, letrozole and exemestane inhibit the conversion samples were collected from 15 breast cancer patients before of androstenedione to estrone (E1), the major source of and after four-week treatment with anastrozole and 10 estrogen in postmenopausal women (3). Recent clinical studies patients before and after four-week treatment with tamoxifen. have revealed that third-generation aromatase inhibitors are of Blood was used to assess STS activity in peripheral blood greater clinical benefit compared with tamoxifen in lymphocytes (PBLs) and serum dehydroepiandrosterone postmenopausal women with breast cancer (4, 5). In addition to the aromatase pathway of estrogen synthesis, the steroid sulfatase (STS) route is also thought to contribute to the in situ synthesis of estrogens in breast †Deceased. tumors (6). STS is responsible for the hydrolysis of estrone sulfate (E1S) and dehydroepiandrosterone sulfate (DHEAS) Correspondence to: Dr. A. Purohit, Oncology Drug Discovery to E1 and dehydroepiandrosterone (DHEA) respectively. E1 Group, Section of Investigative Medicine, Imperial College London, and DHEA can be reduced by 17β-hydroxysteroid 6th Floor, Commonwealth Building (6N2B) Hammersmith Hospital, dehydrogenase type I (17β-HSD1) to steroids with potent Du Cane Road, London W12 0NN, U.K. Tel: +44 2083834287, i.e. Fax: +44 2083838320, e-mail: [email protected] estrogenic properties, E2 and androstenediol. 17β-HSD1 is expressed in many tissues in the body including breast Key Words: Aromatase inhibitors, anti-estrogens, breast cancer, tumors (7, 8). Several potent STS inhibitors have now been steroid sulfatase, tamoxifen, anastrozole, postmenopausal women. developed including STX64 (also known as 667 Coumate, 0250-7005/2011 $2.00+.40 1367 ANTICANCER RESEARCH 31: 1367-1372 (2011) BN83495 or Irosustat) (9, 10). In a recent phase I trial of be measured in PBLs. In addition, serum concentrations of STX64 in postmenopausal women with advanced breast androstenediol were assessed by radioimmunoassay, together cancer, treated with either 5 or 20 mg/day, STS activity in with the levels of androstenedione, testosterone, E1, E2 and peripheral blood lymphocytes (PBLs) and tumor tissues was E1S, which were measured using gas chromatographic- almost completely blocked (>90%) (11). Inhibition of STS tandem mass spectroscopy (GC-MS/MS). activity in these patients resulted in a significant decrease in serum concentration of E1 and E2. Serum concentrations of Patients and Methods androstenediol, which in postmenopausal women is mainly derived from the peripheral conversion of DHEAS, also fell Study 1. Blood was collected for the measurement of serum steroid by up to 90% (12). Unexpectedly, serum androstenedione concentrations from ten postmenopausal women with breast cancer concentration also decreased, as a result of STS inhibitor before and two weeks after starting treatment with anastrozole (1 mg/d). Three of the patients in this group achieved an objective therapy, indicating that in postmenopausal women the major response. For these patients, serum concentrations of androstenediol, part of this steroid is derived from the peripheral conversion androstenedione, testosterone, E1, E2 and E1S were measured. of DHEAS. In the phase I STX64 inhibitor trial, all patients selected Study 2. Blood samples were also collected from a further 15 for entry into the trial had previously progressed while on postmenopausal women with breast cancer before and four weeks anti-estrogen or aromatase inhibitor therapy. However, 5 out after treatment with anastrozole (1 mg/d) and ten patients before and of 14 patients still showed evidence of stable disease after four-week treatment with tamoxifen (20 mg/d). In addition, blood samples were collected from these patients before and after according to RECIST criteria. This finding suggests that STS four-week treatment for the assessment of STS activity in PBLs. For inhibitor therapy may have a role in the treatment of this blood was collected into CPT vacutainers (Beckton Dickinson, postmenopausal women with hormone-dependent breast Franklin Lakes, NJ, USA). After centrifugation (1,500 ×g at 22˚C for cancer and, in particular, for those patients progressing on 30 min), isolated PBLs were washed with phosphate-buffered saline anti-estrogen or aromatase inhibitor therapy. (PBS, 5 ml ×2) and stored at –20˚C until assayed. The STS in PBLs Although aromatase inhibitors have now been in clinical was solubilised before assaying using Triton-X 100/PBS (0.2%). STS 3 use for a number of years there is still no convincing evidence activity was assayed using [6,7- H] E1S (2-3 nmol/l, 46-57 Ci/mmol; Perkin-Elmer Life Sciences, Wellesley, MA, USA) over a 20 h period that the response to this form of endocrine therapy is related using [4-14C] E1 to monitor procedural losses (11, 22). to baseline levels of E2 or to the extent that E2 levels are The protocols for these studies were approved by the suppressed (13, 14). It is also not known why patients become Hammersmith Hospital’s Ethics Committees and all patients gave resistant to this form of therapy. Androstenediol, which is written informed consent for their participation in the study. derived from DHEA, has been shown to have potent estrogenic properties, stimulating the proliferation of ER- Steroid concentrations. For serum steroid concentration positive breast cancer cells in vitro and the growth of induced measurements in samples obtained from patients in the first study, androstenediol concentrations were measured by radioimmunoassay mammary tumors in vivo in rodents (15-17). One possible (RIA) after organic solvent extraction and Celite column partition reason why disease might progress whilst patients are treated chromatography (23). Concentrations of androstenedione, with aromatase inhibitors may be that over time tumor cells testosterone, E1, E2 and E1S were measured using a GC-MS/MS become more sensitive to the proliferative effects, not only of method by SBFC Taylor (Princeton, NJ, USA) (24, 25). The limits the low residual levels of E2, but also to steroids with potent of quantitation of E1, E2 and E1S in this assay were 5.8, 2.3 and 8.9 estrogenic properties, such as androstenediol (18). As yet, pmol/l, respectively. For samples of serum obtained from the second little is known about the effects of aromatase inhibitors on study, concentrations of DHEAS and DHEA were assayed using kits obtained from DSL (Webster, TX, USA) according to the serum concentrations of androstenediol, although in a manufacturer’s instructions. Intra-and inter-assay coefficients of previous study no effect on serum concentrations of DHEAS, variation for these assays were <15%. DHEA or androstenedione was detected (14). There is also a paucity of information about the effects of tamoxifen on Statistics. Mean and standard error of the mean (sem) levels of STS serum androgen concentrations. There are, however, a number activity and serum steroid
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