Optimal management of hormone receptor positive metastatic breast cancer in 2016

First-line treatment

ET is the preferred option for treatment of HR+ ABC, even in the presence of visceral disease, unless there is proven endocrine resistance or visceral crisis, defined as severe organ dysfunction as assessed by signs and symptoms, laboratory studies and rapid progression of disease [Cardoso et al. 2014].

Current armamentarium of ET includes selective estrogen receptor (ER) modulators (SERMs), AIs and ER downregulators (SERDs). Recently added targeted agents that modulate endocrine responses are discussed later. Although sequencing of ET is the recommended approach, few randomized trials have directly compared the effects of changing the order in which different agents are given. Unfortunately, even after many decades of trials we still lack definitive recommendations regarding the optimal ET sequencing in patients with ABC [Barrios et al. 2012].

Tamoxifen, the earliest selective ER modulator in clinical use, was first described in the treatment of ABC in 1971 [Cole et al. 1971]. For decades, tamoxifen has been the standard of care for ER+ ABC with consistent efficacy and a favorable toxicity profile. A large review of 86 clinical trials involving more than 5000 tamoxifen treated patients described an overall response rate (ORR) of 34% with an additional 19% of patients achieving stable disease for at least 6 months [Litherland and Jackson, 1988].

In postmenopausal women in whom estrogen synthesis occurs mainly in peripheral tissues, third-generation AIs (anastrozole, letrozole and exemestane) have demonstrated efficacy while decreasing circulating estrogen levels [Lonning and Eeikesal, 2013; Smith and Dowsett, 2003]. Exemestane is a steroidal AI that binds irreversibly to aromatase, whereas the nonsteroidal AIs, anastrozole and letrozole, have shown to bind reversibly to the enzyme [Buzdar et al. 2002]. Although the mechanisms remain unclear, steroidal and nonsteroidal AIs are not fully cross-resistant [Miller et al. 2008]. While there is no clinical evidence suggesting that there is a better AI, in a large meta-analysis including 8504 patients AIs documented superior survival compared with tamoxifen [hazard ratio (HR) 0.89; 95% confidence interval (CI): 0.80–0.99] [Mauri et al. 2006].

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The third available therapeutic strategy is directed against the ER itself and is exemplified by fulvestrant, a SERD that blocks ER dimerization and DNA binding, inhibits nuclear uptake and increases the turnover and degradation of ER leading to inhibition of estrogen signaling. Fulvestrant (250 mg) demonstrated it was as effective as anastrozole in tamoxifen failures [Robertson et al. 2003]. More recent data suggest that treatment with higher doses of fulvestrant improves disease control and has a survival advantage compared with anastrozole [Di Leo et al. 2010, 2014; Kuter et al. 2012; Robertson et al. 2014a]. Fulvestrant 500 mg was compared with anastrozole in the phase II FIRST trial (n = 205), which demonstrated both improvements in time to progression (TTP) [Robertson et al. 2009] and overall survival (OS) [Robertson et al. 2014b]. Median TTP was 23.4 months for fulvestrant versus 13.1 months for anastrozole with a 34% reduction in risk of progression (HR 0.66; 95% CI: 0.47–0.92; p = 0.01). Median OS was 54 months for fulvestrant versus 48 months for anastrozole (HR 0.70; 95% CI: 0.50–0.98; p = 0.041). This was the first trial to suggest that an alternative ET may be more effective than an AI in the first-line setting for ABC [Robertson et al. 2014b]. The ongoing confirmatory phase III FALCON trial [ClinicalTrials.gov identifier: {“type”:”clinical-trial”,”attrs”:{“text”:”NCT01602380″,”term_id”:”NCT01602380″}}NCT01602380] has completed accrual with results expected in 2016. Patients included in this trial are mostly treatment naïve and have not received previous ET.

References

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About the Author: Tung Chi