Optimal management of hormone receptor positive metastatic breast cancer in 2016

Abstract

Hormone receptor positive tumors represent the most common form of breast cancer and account for most of the deaths from the disease. Endocrine therapy represents the main initial therapeutic strategy for these patients and has been associated with significant clinical benefits in a majority of patients. While in early stages endocrine therapy is administered as part of a curative approach once clinical metastases develop, the disease is considered incurable and the main management objectives are tumor control and quality of life. The two major clinical paradigms of always indicating endocrine therapy in the absence of visceral crises and sequencing endocrine treatments have been guiding our therapeutic approach to these patients. However, for many decades, we have delivered endocrine therapy with a 'one size fits all' approach by applying agents that interfere with hormone receptor signaling equally in every clinical patient scenario. We have been unable to incorporate the well-known biologic principle of different degrees of hormone receptor dependency in our therapeutic recommendations. Recent developments in the understanding of molecular interactions of hormone signaling with other important growth factor, metabolic and cell division pathways have opened the possibility of improving results by modulating hormone signaling and interfering with resistance mechanisms yet to be fully understood. Unfortunately, limitations in the design of trials conducted in this area have made it difficult to develop predictive biomarkers and most of the new combinations with targeted agents, even though showing improvements in clinical endpoints, have been directed to an unselected population of patients. In this review we explore some of the current and most relevant literature in the management of hormone receptor positive advance breast cancer.

Keywords: advanced breast cancer; breast neoplasms; drug resistance; hormone receptor.

Figure 1.

Suggested endocrine therapy sequencing alternatives in patients with HR+ advanced breast cancer. General comments to interpret Figure 1

1. The sequence of the treatment alternatives in each line text box does not represent a particular preference order.

2. Subsequent use of ET should always take into account previous lines of treatment as well as the type and duration of response to previous ET.

3. Intrinsic or primary resistance has been defined as recurrence within the first 2 years of adjuvant ET or progressive disease within 6 months of starting ET in the advanced setting.

4. Acquired or secondary resistance has been defined as recurrence after the first 2 years of adjuvant ET or disease progression more than 6 months after initiation of ET in the advanced setting. These definitions, although imperfect and somewhat arbitrary, have been useful in some clinical trials to analyze and stratify patient populations.

5. These suggestions refer to postmenopausal patients. Specific management of the premenopausal population is addressed in the text.

6. These suggestions do not take into consideration acess and regulatory issues in the dfferent regions of the world.

Specific comments ^aFulvestrant (500 mg) use in the first-line treatment of HR+ ABC is based on the randomized phase II FIRST trial. The ongoing confirmatory phase III FALCON trial has completed accrual. ^bLetrozole in combination with palbociclib in the first-line treatment of HR+ ABC is based on the randomized phase II PALOMA-1 trial. The ongoing confirmatory phase III PALOMA 2 trial has completed accrual. ^cDespite the evidence of superior outcomes with other alternatives, our personal opinion is that an AI or tamoxifen remain reasonable options as first-line or second-line ET for selected patients with HR+ ABC, particularly in the very endocrine sensitive population. ^dThis combination demonstrated significant PFS advantage in a second-line phase III trial. ^eIn this setting patients may have more endocrine resistant disease and would probably benefit more from treatment strategies that could modulate endocrine resistance rather than sequential single agent ET. ^fThe sequential use of the combinations with CDK4/6 inhibitors and mTOR inhibitors has not been addressed in clinical trials and there is no definitive information on response rates or benefit in this setting. Chemotherapy remains an alternative for these most endocrine resistant situations. However, the occasional patient that remains clinically stable with slowly progressive disease in spite previous ET failure could still be considered for treatment with a combination with CDK4/6 or mTOR inhibitor depending on previous exposure. ABC, advanced breast cancer; AI, aromatase inhibitor; CDK, cyclin-dependent kinase; DFI, disease-free interval; ET, endocrine therapy; HR, hormone receptor; mTOR, mammalian target of rapamycin; PFS, progression-free survival; [1] Robertson et al. [2014b] [2] Finn et al. [2015] [3] Mauri et al. [2006] [4] Litherland and Jackson [1988] [5] Di Leo et al. [2014] [6] Baselga et al., [2012] [7] Turner et al. [2015] [8] Buzdar et al. [1998] [9] Bachelot et al. [2012]