Endocrine Therapies in the treatment of Hormone Sensitive Breast Cancer- Understanding Toxicities and Optimising Utility

Abstract

Hormone sensitive (HS) breast cancer (BC) comprises approximately 70% of all BCs and endocrine therapies (ETs) are well established as a mainstay of multimodal treatment for HSBC. Tamoxifen (TAM), a selective oestrogen receptor modulator, and aromatase inhibitors (AIs) are dosed daily as tablets for five to ten years in the adjuvant setting. In the metastatic setting, treatment continues until disease progression or unacceptable toxicity for TAM, AIs or Fulvestrant (F). F is a selective oestrogen receptor downregulator that is administered via intramuscular injection and is used in advanced HSBC. Though effective, F is not on the Pharmaceutical Benefits Scheme and is not readily accessible in Australia. ETs, while generally well tolerated, do have potential side effects (toxicities) that can be a barrier to effective treatment. This research sought to further our understanding of ETs, their metabolism (TAM), efficacy (F) and toxicities (TAM, AIs and F) in order to optimize their use and our understanding of toxicities in the treatment of women with HSBC. AIs cause bone density loss and arthralgias as the predominant toxicities that can limit treatment. This thesis reviewed the published literature regarding these two potentially problematic toxicities. TAM, the oldest ET, has highly variable inter-patient metabolism to produce its active metabolite endoxifen. There are discordant published data on the impact this complex and variable metabolism has on efficacy, mechanism of action, and toxicities. This thesis examined the literature to date and reports three studies conducted on prospectively recruited cohorts of women treated with TAM. Two studies pertained to toxicities of TAM; the first examining the efficacy of dose reduction in ameliorating hot flush toxicity and examining the impact of this on active metabolite levels. We found that this manoeuvre reduces endoxifen levels whilst subjectively improving hot flushes at the lower dose. The second study sought correlations and associations of hot flush toxicity and this study found none despite previous heterogeneous reports in the literature. The third study regarding TAM examines phenotyping methods for classifying CYP2D6 metabolism to understand drug activity. This is currently borrowed from that of other drugs. We tested the existing system and devised a new TAM-specific phenotyping method to better understand TAM metabolism. Finally, we examined the role of F in treating metastatic HSBC by conducting a systematic review and meta-analysis. This thesis reports the results regarding the benefits, roles and toxicities of F with our resultant recommendation that F is a valid option in the treatment of metastatic HSBC. This work provides insights and furthers understanding of endocrine therapies to optimize their use in the treatment of women with HSBC.