Abstract ES3-3: Low dose tamoxifen and other approaches to improve chemoprevention uptake
Authors: De Censi A 
Published: March 2020

Abstract
Despite strong evidence of efficacy, the uptake of cancer preventive therapy is very low. Reasons primarily include fear of side effects, including menopausal symptoms and rare serious adverse events. Moreover, physicians at least in Europe are reluctant to prescribe drugs for prevention of breast cancer for a variety of reasons, including off-label use in most countries, difficulty applying risk models in clinical practice, absence of clarity on the most appropriate physician for prevention advice, lack of reliable short-term biomarkers of effectiveness and no commercial interest in therapeutic prevention (Noonan et al Cancer Prev Res 2018). Attempts to increase uptake are focusing on decision aid tools to increase awareness of breast cancer risk and better understanding of psychological factors related to poor uptake. Strategies to increase chemoprevention uptake should attempt to better refine the so called ABC paradigm: effective and safe Agents, reliable surrogate Biomarkers and identification of high risk Cohorts. Regarding biomarkers, the use of mammographic density has been proposed based on the results of IBIS-I trial where a 10% or greater reduction of density after 1 year of tamoxifen was associated with a significant reduction of subsequent breast cancer (Cuzick et al. JNCI 2011). Regarding the identification of suitable cohorts, studies have shown a higher uptake in women with histological diagnosis of breast pre-malignant disease, including atypical ductal hyperplasia (ADH), Ductal and Lobular Carcinoma in Situ (DCIS and LCIS). In order to increase uptake of preventive agents, safer modes of administration include the use of lower doses, the combination of SERMs with estrogens, and the use of topical agents in the target organ. Biomarker studies had shown that the minimal effective dose of tamoxifen was below 20 mg/day (DeCensi et al JNCI 2003). These considerations prompted us to launch a phase-III de-escalation trial of tamoxifen, 5 mg/day, otherwise defined as “babytam”. Babytam or placebo were administered for 3 years after surgery in women with hormone sensitive or unknown breast intraepithelial neoplasia, including ADH, LCIS or DCIS. A total of 500 women aged 75 or younger were included, and after a median follow-up of 5.1 years, babytam significantly decreased recurrence by 52% and contralateral breast events by 75% (DeCensi et al JCO 2019). Serious adverse events and patient reported outcomes were not different between arms except for a slight increase in frequency of daily hot flashes on babytam, consisting of less than one extra hot flash per day. These results provide a new treatment option in the management of breast pre-invasive disorders and open the door to studies in high risk unaffected women according to the Gail, Tyrer-Cuzick or BCSC models. A similar approach is being explored with exemestane, where two lower doses are being compared with the standard dose in a window of opportunity presurgical trial in breast cancer (Guerrieri-Gonzaga et al Proc SABCS 2019). The combination of estrogen therapy and SERMs was also assessed in the HOT trial to minimize menopausal symptoms knowing that tamoxifen is safer in premenopausal women. Results were promising but the study was underpowered due to problems in the recruitment in the post WHI trial era (DeCensi et al Ann Oncol 2013). The concept is now being re-proposed with a drug that combines conjugated equine estrogens and bazedoxifene. Initial findings indicate a good drug profile on patient reported outcomes with promising biomarker modulation (Fabian et al Cancer Prev Res 2019). The use of transdermal 4-OH tamoxifen (afimoxifene) gel is also being actively pursued in clinical trials. Initial findings indicate the feasibility of this approach in attaining active concentrations in the breast and modulation of Ki-67 (Lee et al Cancer Chemother Pharmacol. 2015).
Citation Format: A De Censi. Low dose tamoxifen and other approaches to improve chemoprevention uptake [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES3-3.