RESUMEN
The drug's activity at the target tissue could help to define the minimal effective dose to promote cancer preventive therapy. Here we present exemestane and sex hormone concentrations within breast tissue from a pre-surgical study of alternative exemestane schedules. Postmenopausal women candidate for breast surgery for estrogen receptor-positive breast cancer were randomized to exemestane 25 mg once daily (QD), 25 mg three times/week (TIW), or 25 mg per/week (QW) for 4-6 weeks before surgery. Drug and sex hormones were analyzed from homogenized frozen tissue using a QTRAP 6500+ LC-MS/MS System. Tissue drug concentrations were detectable only in the QD arm with higher concentrations in non-malignant tissue. Estradiol was nearly suppressed in all groups in the non-malignant tissue (QD vs TIW p = .364 and QD vs QW p = .693). In contrast, a dose-response trend was observed in cancer tissue. Based on estradiol suppression in non-malignant tissue, lower exemestane schedules should be explored for breast cancer preventive therapy.
RESUMEN
Importance: The effects of breast cancer incidence changes and advances in screening and treatment on outcomes of different screening strategies are not well known. Objective: To estimate outcomes of various mammography screening strategies. Design, Setting, and Population: Comparison of outcomes using 6 Cancer Intervention and Surveillance Modeling Network (CISNET) models and national data on breast cancer incidence, mammography performance, treatment effects, and other-cause mortality in US women without previous cancer diagnoses. Exposures: Thirty-six screening strategies with varying start ages (40, 45, 50 years) and stop ages (74, 79 years) with digital mammography or digital breast tomosynthesis (DBT) annually, biennially, or a combination of intervals. Strategies were evaluated for all women and for Black women, assuming 100% screening adherence and "real-world" treatment. Main Outcomes and Measures: Estimated lifetime benefits (breast cancer deaths averted, percent reduction in breast cancer mortality, life-years gained), harms (false-positive recalls, benign biopsies, overdiagnosis), and number of mammograms per 1000 women. Results: Biennial screening with DBT starting at age 40, 45, or 50 years until age 74 years averted a median of 8.2, 7.5, or 6.7 breast cancer deaths per 1000 women screened, respectively, vs no screening. Biennial DBT screening at age 40 to 74 years (vs no screening) was associated with a 30.0% breast cancer mortality reduction, 1376 false-positive recalls, and 14 overdiagnosed cases per 1000 women screened. Digital mammography screening benefits were similar to those for DBT but had more false-positive recalls. Annual screening increased benefits but resulted in more false-positive recalls and overdiagnosed cases. Benefit-to-harm ratios of continuing screening until age 79 years were similar or superior to stopping at age 74. In all strategies, women with higher-than-average breast cancer risk, higher breast density, and lower comorbidity level experienced greater screening benefits than other groups. Annual screening of Black women from age 40 to 49 years with biennial screening thereafter reduced breast cancer mortality disparities while maintaining similar benefit-to-harm trade-offs as for all women. Conclusions: This modeling analysis suggests that biennial mammography screening starting at age 40 years reduces breast cancer mortality and increases life-years gained per mammogram. More intensive screening for women with greater risk of breast cancer diagnosis or death can maintain similar benefit-to-harm trade-offs and reduce mortality disparities.
Asunto(s)
Neoplasias de la Mama , Detección Precoz del Cáncer , Mamografía , Adulto , Anciano , Femenino , Humanos , Persona de Mediana Edad , Factores de Edad , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/diagnóstico por imagen , Técnicas de Apoyo para la Decisión , Reacciones Falso Positivas , Incidencia , Tamizaje Masivo , Uso Excesivo de los Servicios de Salud , Guías de Práctica Clínica como Asunto , Estados Unidos/epidemiología , Modelos EstadísticosRESUMEN
In a 3-arm presurgical trial, four-six weeks exemestane 25 mg three times/week (TIW) was non-inferior to 25 mg/day (QD) in suppressing circulating estradiol in postmenopausal women with ER-positive breast cancer. Since obesity may decrease exemestane efficacy, we analyzed changes in sex steroids, adipokines, Ki-67, and drug levels in relation to obesity. Postmenopausal women with early-stage ER-positive breast cancer were randomized to either exemestane 25 mg QD (n = 57), 25 mg TIW (n = 57), or 25 mg/week (QW, n = 62) for 4-6 weeks before breast surgery. Serum and tissue pre- and post-treatment biomarkers were stratified by body mass index (BMI)< or ≥30 kg/m2. Post-treatment median exemestane and 17-OH exemestane levels were 5-6 times higher in the QD arm compared to the TIW arm. For obese women, TIW maintained comparable reductions to QD in systemic estradiol levels, although the reduction in estrone was less with the TIW regimen. There was less suppression of SHBG with the TIW versus the QD dose schedule in obese women which should result in less systemic bioavailable estrogens. Metabolically, the effect of the TIW regimen was similar to the QD regimen for obese women in terms of leptin suppression and increase in the adiponectin-leptin ratio. Reduction in tissue Ki-67 was less for obese women on the TIW regimen than QD, although changes were similar for non-obese women. Our findings suggest that TIW exemestane should be explored further for primary cancer prevention in both normal weight and obese cohorts.
RESUMEN
Breast cancer prevention only requires local exposure of the breast to active drug. However, oral preventive agents entail systemic exposure, causing adverse effects that limit acceptance by high-risk women. Drug-delivery through the breast skin is an attractive option, but requires demonstration of dermal safety and drug distribution throughout the breast. We formulated the tamoxifen metabolite (E/Z)-endoxifen for transdermal delivery and tested it in a placebo-controlled, double-blinded Phase I trial with dose escalation from 10 to 20 mg daily. The primary endpoint was dermal toxicity. Thirty-two women planning mastectomy were randomized (2:1) to endoxifen-gel or placebo-gel applied to both breasts for 3-5 weeks. Both doses of endoxifen-gel incurred no dermal or systemic toxicity compared to placebo. All endoxifen-treated breasts contained the drug at each of five sampling locations; the median per-person tissue concentration in the treated participants was 0.6 ng/g (IQR 0.4-1.6), significantly higher (p < 0.001) than the median plasma concentration (0.2 ng/mL, IQR 0.2-0.2). The median ratio of the more potent (Z)-isomer to (E)-isomer at each breast location was 1.50 (IQR 0.96-2.54, p < 0.05). No discernible effects of breast size or adiposity on tissue concentrations were observed. At the endoxifen doses and duration used, and the tissue concentration achieved, we observed a non-significant overall reduction of tumor proliferation (Ki67 LI) and significant downregulation of gene signatures known to promote cancer invasion (FN1, SERPINH1, PLOD2, PDGFA, ITGAV) (p = 0.03). Transdermal endoxifen is an important potential breast cancer prevention agent but formulations with better dermal penetration are needed.