Improving long-term adjuvant anti-oestrogenic therapy for breast cancer

Long-term (five years) adjuvant tamoxifen treatment for oestrogen receptor-positive, or ER-positive, breast cancer post-surgery is recognised as a major advance in healthcare. Clinical trials comparing standard and extended tamoxifen therapy found a major decrease in mortality occurred in the ten years following a decade of adjuvant therapy. Studies in premenopausal breast cancer patients showed that ovarian function suppression (OFS) plus an aromatase inhibitor (AI), such as exemestane, which compared to tamoxifen has fewer serious side effects and decreases mortality rates further, is superior to OFS plus tamoxifen in reducing breast cancer recurrence. Current studies using AIs in combination with the selective ER downregulator (SERD) fulvestrant to treat ER-positive metastatic breast cancer (MBC) may provide clinical benefit over AI alone. Preliminary studies suggest that high-dose fulvestrant is superior to anastrazole (an AI) as first-line treatment in MBC, and has prompted the search for new orally-active SERDs. The development of acquired resistance to AIs and fulvestrant led to the development of a treatment strategy with either an mTOR inhibitor or a cyclin-dependent kinase (CDK) 4/6 inhibitor. An mTOR inhibitor (e.g. everolimus) improves responsiveness to an AI over an AI alone and a CDK 4/6 inhibitor (e.g. palbociclib), either with an AI or fulvestrant versus the endocrine therapy alone, demonstrates significant improvements in progression-free survival. Unfortunately, both mTOR and CDK 4/6 inhibitors have considerable toxic adverse effects and are expensive. It is logical to predict that the novel targeted therapeutics used in combination with either an AI or tamoxifen (or indeed in the future with a new SERD) would dramatically improve response rates when used in the adjuvant setting. Nevertheless, the success of adjuvant therapy depends on compliance, and compliance depends upon the severity of side effects.