Approximately 60–80% of breast cancer cases in Western countries are hormone receptor-positive (HR+). Given the complexity of HR+ advanced breast cancer (ABC), it represents a significant clinical challenge that is responsible for most breast cancer deaths. Yet for many years, patients with HR+ ABC have been faced with few treatment options and limited prospects. Whilst endocrine therapy constitutes the therapeutic backbone for patients with this cancer subtype, not all patients benefit equally. Endocrine resistance occurs in approximately 40% of patients with HR+ breast cancer, and even patients who do respond eventually exhibit acquired resistance.
Fortunately, in recent years there has been considerable progress in developing new treatment options for ABC patients, including the use of combination therapies. Challenges nevertheless remain. New guidelines on treatment strategies must now be put in place to ensure the right treatment is given at the right time to optimise outcomes for HR+ ABC patients.
What treatment options are available to HR+ ABC patients?
Currently, there are three broad categories of first-line treatment options available: endocrine monotherapy, such as fulvestrant, recently approved for use in first-line setting for HR+ ABC patients in the EU and the US, and aromatase inhibitors; combination therapy (commonly targeted therapy, such as CDK4 /6 inhibitors, plus endocrine therapy) and chemotherapy.
Of these three, endocrine monotherapy has been the preferred treatment option even in the presence of visceral disease, until recently, when randomised clinical trials demonstrated significant benefit in HR+ ABC patients with the combination of targeted therapy and endocrine therapy. One example of this approach is the PALOMA-3 study in which the combination of the CDK4/6 inhibitor palbociclib and fulvestrant was associated with significant and consistent improvement in progression-free survival compared with fulvestrant plus placebo. Based on these results, in March 2016 the US FDA approved the use of palbociclib plus fulvestrant for first-line treatment in patients with HR+ ABC.
Additionally, cytotoxic chemotherapy is also considered a first-line treatment option. However, chemotherapy is much more commonly used in this setting, despite clear guidelines on the use of chemotherapy - namely its use only as the treatment of choice when patients are in symptomatic visceral crisis, meaning that clear metastasis from the breast to other sites has occurred putting the patient’s life in danger (incidence less than 1%), or in patients who have clear evidence of endocrine resistance.
The challenge of optimising treatment selection by physicians
With the evolving treatment landscape, physicians must now determine treatment strategies that are most beneficial to patients, e.g. whether all patients who are suitable for endocrine treatment should receive combination therapy, or whether endocrine monotherapy remains the best option.
Key challenges identified in the management of advanced breast cancer include the need for biologically driven criteria to guide treatment choice, i.e. predictive biomarkers are needed to guide more personalised care, identification of the optimal combinations or sequences of targeted agents and integration of new agents into current regimens. Further research is also needed into the appropriate means of monitoring disease progression. The cost of long-term treatment for patients with advanced breast cancer is also a pressing concern for the future, since welcome recent advances in treatment mean that such patients may receive treatment for a considerable length of time.
Overall, in the absence of clear guidelines on the new treatment options, physicians have limited objective means to ensure that the strategies they choose are the most appropriate. Filling the gap, physicians have been using a range of approaches to inform treatment choices, including assessments of the patient’s characteristics on age, fitness level, comorbidities, physical characteristics, and response to previous treatment, which nevertheless remain subjective and disjointed across clinical practice. Even when more effective and safer treatment options are available, the traditional ‘one-size-fits-all’ approach may still contribute to the overuse of chemotherapy and an increased tendency of the shift towards combination therapy, whereby the benefit of monotherapy may be greater in some patients.
Experts within the clinical community have begun to set out proposals that could push for the development of assessment tools for physicians treating HR+ ABC patients. One suggested treatment algorithm was discussed by Professor Peter Schmid of the Centre for Experimental Cancer Medicine at Barts Cancer Institute, at the ESMO 2016 Conference, which centred around patient stratification by disease activity and the likelihood of response to endocrine therapy. Patients with low disease burden, slow progression and presumed endocrine sensitivity might still be considered for endocrine monotherapy, whereas patients with more aggressive disease e.g. visceral metastases, could benefit from combination therapy (Figure 1). While representing one opinion, this could form the basis of renewed thinking on how to best approach treating HR+ ABC patients.
The advancement of treatments for HR+ ABC patients is undoubtedly welcome, but their true value to patients will not be realised until physicians can optimally form an appropriate treatment strategy. To advance the treatment of patients with HR+ ABC, we must develop meaningful tools and guidelines that empower physicians to objectively select the right treatments for the right patients.
Figure 1: [VY1] Treatment algorithm suggested by Professor Peter Schmid
Veeva ID: Z4-6952
Date of next review: September 2018