Abstract ES5-3: ES5-3 Targeting the breast, locally: Old and new approaches
Authors: Khan SA 
Published: March 2017

Abstract
The oldest local approach to breast cancer prevention is surgery. The largest and most rigorous description of this procedure in a high risk population comes from the Mayo Clinic, where 639 women underwent bilateral mastectomy for prevention between 1960 and 1993. Of these procedures, 90% were subcutaneous mastectomies, i.e. ∼90% of the breast was removed, with preservation of the nipple and areola. The breast cancer incidence in this population, with 13 year follow-up, was 90% of the expected incidence. A subset was tested for BRCA1/2 mutations, and among 26 mutations carriers, no cancers were observed. Subsequent studies have focused on more defined high risk populations, mainly carriers of BRCA1/2 mutations. In one recent meta-analysis, the pooled relative risk (RR) was 0.11; 95% CI, 0.04-0.32. However, all-cause mortality was unaffected by mastectomy. Nipple-sparing mastectomy has emerged as an option for mutation carriers recently, and data are beginning to accumulate that overall satisfaction with reconstruction results, and sexual well-being, are greater with the nipple-sparing procedures. The long-term cancer risk data following nipple-sparing procedures are not yet mature.
However, mastectomy carries a large physical and emotional cost, which could be avoided if effective non-surgical prevention options were available. Breast cancer prevention in high risk women and those with carcinoma in situ requires that the breast be exposed to an effective agent; systemic exposure is unnecessary, and its harms lead many eligible women to decline preventive therapy. Local transdermal therapy (LTT) to the breast involves the application of active drugs to the breast skin, resulting in high concentrations in the breast but low systemic exposure. It is non-invasive, self-delivered, and not dependent on hepatic metabolism. Existing data on LTT include two pre-surgical window trials of topical 4-hydroxytamoxifen (an active tamoxifen metabolite) in women with invasive breast cancer, and duct carcinoma in situ (DCIS). These demonstrate that LTT with 4-OHT decreases proliferation of invasive and non-invasive cancer cells to a similar degree as oral tamoxifen, with low systemic levels, and no effect on coagulation proteins. These data are promising regarding the use of LTT with 4-OHT for breast cancer prevention, and for therapy of DCIS, but also suggest that LTT could be developed for any small, lipophilic molecule with good dermal permeation, thus greatly expanding the menu of drugs that could be tested for breast cancer prevention. Another locally targeted approach involves the intraductal delivery of active drugs, using a catheter to cannulate the nipple duct orifice. Preliminary studies using Doxil in rodents and in humans have shown this is feasible, but concerns have been raised regarding carcinogenicity of cytotoxic drugs. More recently, RNA interference therapy, and trastuzumab conjugated to a cytotoxic alpha-emitter 225Ac, have been tried in mouse models of DCIS with some success. A trial of intraductal fulvestrant is on-going. Both transdermal and intraductal local therapy approaches hold promise, but are challenging in distinct ways. Nevertheless, ongoing research suggests that local therapy options for breast cancer prevention can move beyond surgical resection of breast tissue.
Citation Format: Khan SA. ES5-3 Targeting the breast, locally: Old and new approaches [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr ES5-3.