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

Abstract

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. Mor...

Short-Term Biomarker Modulation Prevention Study of Anastrozole in Women at Increased Risk for Second Primary Breast Cancer

“…In contrast, another small study of 32 patients with letrozole did show a reduction in estradiol levels (14). Similarly, Bonnani and colleagues showed a reduction in estradiol levels with anastrozole when combined with tamoxifen (17). Finally, a study by Prowell and colleagues that had a very similar cohort and design to our study, showed a reduction in estradiol levels after 6 months of anastrozole therapy (19).…”

“…However, Bonanni and colleagues evaluated the effect of 2 months of tamoxifen in different doses versus placebo in 110 healthy women and showed a reduction in IGF-1/IGFBP-3 (16). In another study of 75 postmenopausal patients that were randomized to tamoxifen 10 mg/week, anastrozole at 1 mg/d or the combination for 12 months showed also a reduction in IGF-1/IGFBP-3 levels in the combination arm compared with the anastrozole arm (17). Similar to these results, our study also showed a significant modulation in the IGF pathway, specifically, a significant increase in IGFBP-1 levels.…”

The clinical effectiveness and cost-effectiveness of genotyping for CYP2D6 for the management of women with breast cancer treated with tamoxifen: a systematic review.

“…The majority (n = 12) of cohorts 41,73,83,87,93,96,97,[99][100][101]113,114 presented the rationale for the alleles tested for, with all but two 49,112 providing rationale for CYP2D6 per se. All described the test used for genotyping and/or the specific procedure, with TaqMan or AmpliChip being the most commonly used in 12 83 reported quality control methods and seven cohorts 87,91,96,97,104,114 reported on the Hardy-Weinberg equilibrium (two of these cohorts were reported in the same paper 114 ).…”

“…In around half (n = 12) of the cohorts it was clear there were missing genotype data, 41,82,83,87,[96][97][98][99][100][101]108,112 reasons being provided in seven of these. 82,83,87,97,99,108,112 Only three of the cohorts, all abstracts, 86,90,113 failed to present the number of patients contributing to each analysis.…”

Efficacy of tamoxifen based on cytochrome P450 2D6, CYP2C19 and SULT1A1 genotype in the Italian Tamoxifen Prevention Trial

“…41 A multicentric clinical study aimed at validating this approach is ongoing in Italy. Our study has some limitations.…”