Cancer Therapy: Clinical Randomized Biomarker Trial of Anastrozole or Low-Dose Tamoxifen or Their Combination in Subjects with Breast Intraepithelial Neoplasia

Purpose: In the Anastrozole, Tamoxifen Alone or in Combination trial, the combination arm was inferior to anastrozole alone in terms of disease-free survival possibly due to an adverse pharmacokinetic interaction or a predominant estrogenic effect of tamoxifen under estrogen deprivation. We assessed whether the addition of a lower dose of tamoxifen influenced anastrozole bioavailability and favorably modulated biomarkers of bone fracture, breast cancer, cardiovascular disease, and endometrial cancer risk. The influence of CYP2D6 genotype on tamoxifen effects was also determined. Experimental Design: Seventy-five postmenopausal women with breast intraepithelial neoplasia were randomly allocated to either 1 mg/d anastrozole or 10 mg/wk tamoxifen or their combination for 12 months. Study endpoints were plasma drug concentrations and changes of C-telopeptide, osteocalcin, estradiol/sex hormone binding globulin (SHBG) ratio, estrone sulfate, insulin-like growth factor-I (IGF-I)/insulin-like growth factor binding protein-3 (IGFBP-3), C-reactive protein, antithrombin-III, endometrial Ki-67 expression, and thickness. Results: Anastrozole concentrations were not affected by the combination with lowdose tamoxifen, whereas endoxifen levels were lower in poor CYP2D6 metabolizers. C-telopeptide increased by 20% with anastrozole and decreased by 16% with tamoxifen and by 7% with their combination (P < 0.001); osteocalcin showed similar changes. Compared with anastrozole, the combination arm showed lower IGF-I/IGFBP-3 levels (-17% versus -9%; P = 0.004) and lower estradiol/SHBG and estrone sulfate reductions (-15% versus -29% and -30% versus 38%, respectively). However, IGF-I/IGFBP-3 and estradiol/SHBG did not decrease in poor CYP2D6 metabolizers. Endometrial thickness was not greater in the combination than in the anastrozole arm. Conclusions: The addition of a weekly tamoxifen administration did not impair anastrozole bioavailability and modulated favorably its safety profile, providing the rationale for further studies. (Clin Cancer Res 2009;15(22):7053–60) Aromatase inhibitors are a standard treatment of estrogen receptor–positive breast cancer in postmenopausal patients (1–4) and are being tested as chemopreventive agents in at-risk women (5). However, these agents are associated with increased bone fracture rate, joint and tendon disorders, and possibly increased cardiovascular risk due to their profound estrogen-suppressive effect rising concern on their long-term safety, especially in the prevention setting. Moreover, prolonged aromatase inhibitor treatment may lead to the onset of endocrine resistance with the emergence of estrogen hypersensitive cell clones (6). One potential way to counteract these phenomena is to add tamoxifen to exploit its partial estrogenicity. In the Anastrozole, Tamoxifen Alone or in Combination study, a phase III adjuvant trial with three arms (1 mg anastrozole, 20 mg tamoxifen, and their combination), anastrozole significantly prolonged disease-free survival versus tamoxifen. Moreover, the combination of anastrozole and tamoxifen at the dose of 20 mg/d was inferior to anastrozole alone and slightly, albeit Authors' Affiliations: Divisions of Cancer Prevention and Genetics, Epidemiology and Biostatistics, Breast Surgery, Breast Diagnostics, Gynaecology, Pathology, European Institute of Oncology, Milan, University of Milan School of Medicine, Milan, Italy; Hormone Laboratory, Haukeland University Hospital, Bergen; Section for Endocrinology, Institute ofMedicine, University of Bergen, Bergen, Norway; and Division ofMedical Oncology, E.O. Ospedali Galliera, Genoa, Italy Received5/28/09; revised8/11/09; accepted8/24/09; publishedOnlineFirst 11/3/09. The costs of publication of this article were defrayed in part by the payment of page charges. This articlemust therefore be herebymarked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Andrea Decensi, Division of Medical Oncology, E.O. Ospedali Galliera, Mura delle Cappuccine 14, 16128 Genoa, Italy. Phone: 39105634501; Fax: 39-1057481090; E-mail: [email protected]. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-09-1354 7053 Clin Cancer Res 2009;15(22) November 15, 2009 www.aacrjournals.org Published Online First on November 3, 2009 as 10.1158/1078-0432.CCR-09-1354 Research. on April 15, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst November 3, 2009; DOI: 10.1158/1078-0432.CCR-09-1354