Dr. Tufia C. Haddad
Dr. Matthew Goetz
Question: What is your approach in the clinic for ER-positive, HER2-negative metastatic breast cancer, given the multiple treatment options?
Answer: An increasing number of therapeutic options are available for the management of estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer. Although this is good news for patients, the multitude of options can render treatment decisions paralyzing when striving to select the best choice for each individual patient at each stage of the journey. However, several guiding principles can provide clarity. An overarching principle for endocrine-sensitive disease is that endocrine-based regimens are preferred over chemotherapy given outstanding antitumor activity and better tolerability. In the setting of visceral crisis or severely symptomatic disease, chemotherapy should be considered given its rapid onset of activity.
As most patients have received adjuvant endocrine therapy, an important starting point is to assess endocrine sensitivity through evaluation of tumor ER and progesterone receptor (PR) levels. Additionally, recent guidelines have defined two types of endocrine resistance.1
Primary: Recurrence within the first 2 years of adjuvant endocrine therapy or progression within 6 months of initial endocrine therapy for metastatic breast cancer.
Secondary: Recurrence after year 2 of adjuvant endocrine therapy (or within 12 months of its completion) or progression after 6 months or longer after initial endocrine therapy for metastatic breast cancer.
For postmenopausal women, there is a new option for first-line therapy for the small proportion of those who present with endocrine therapy-naive disease, based on the phase III FALCON trial, which demonstrated a significant progression-free survival (PFS) improvement for fulvestrant compared with anastrozole (16.6 months vs. 13.8 months).2 In light of these results, fulvestrant is preferred first-line endocrine monotherapy for de novo metastatic breast cancer. Combining fulvestrant with an aromatase inhibitor (AI) is not considered standard given conflicting results from FACT, Southwest Oncology Group (SWOG) S0226, and SoFEA.
Most recently, combination CDK 4/6 inhibitor with endocrine therapy has challenged the decades-old norm of administering endocrine monotherapy first line. Two separate phase III trials using letrozole as a comparator resulted in substantial 10-month median PFS gains when letrozole was combined with palbociclib (PALOMA-2)3 or ribociclib (MONALEESA-2).4 Data regarding abemaciclib are expected soon (MONARCH 3; NCT02246621). In the absence of survival data and given substantial cost, a lingering question remains whether this represents a new standard of care. Using the guiding approach of first defining endocrine sensitivity, a postmenopausal woman with de novo, nonvisceral metastatic breast cancer and high ERa expression could receive fulvestrant monotherapy given the impressive median PFS of nearly 2 years. In contrast, one with non–life-threatening visceral disease who recently completed adjuvant AI could be best served with combination CDK 4/6 inhibitor and a nonsteroidal AI.
For premenopausal women, tamoxifen with ovarian suppression (a GnRH agonist or therapeutic bilateral salpingo-oophorectomy) remains a preferred, guideline-supported approach. Because PALOMA-2 and MONALEESA-2 excluded premenopausal women, the use of CDK 4/6 inhibitors in this setting remains investigational. Studies are ongoing to examine their additive benefit. Following progression, patients should be treated with postmenopausal approaches.
After progression on a nonsteroidal AI or tamoxifen, endocrine agents such as exemestane or fulvestrant have been commonly used for second-line therapy; however, the landscape for management of endocrine-resistant metastatic breast cancer has changed. Pre-clinical data suggested that long-term estrogen deprivation activates the AKT/mTOR pathway and renders ER-positive cancer cells sensitive to mTOR-targeted therapy. The BOLERO-2 trial confirmed these observations and demonstrated a median PFS improvement with combination everolimus and exemestane compared with exemestane alone (6.9 months vs. 2.8 months).5 A few years later, the PALOMA-3 trial demonstrated a median PFS improvement with combination palbociclib and fulvestrant compared with fulvestrant alone (9.5 months vs. 3.8 months).6 It is our practice to recommend this regimen for patients with metastatic relapse during or shortly after completion of adjuvant endocrine therapy or progression after first-line endocrine monotherapy. In contrast, for patients with indolent metastatic breast cancer whose disease progresses after a prolonged period of benefit from an AI, the everolimus and exemestane regimen remains an excellent option.
The optimal treatment approach after disease progression on combination palbociclib and endocrine therapy is unknown, and the mechanisms of resistance are still being defined. Clinical trial participation should be encouraged when appropriate. Subsequent lines of endocrine monotherapy should be considered, although their clinical activity and that of everolimus are unknown in this setting.
In general, chemotherapy is reserved until endocrine-based regimens have been exhausted. Combination chemotherapy should be discouraged based on results of meta-analyses suggesting no survival benefit as compared with sequential, single-agent chemotherapy. For patients with visceral crisis, however, a taxane-based combination may be considered. There are several single-agent chemotherapy options. Capecitabine is a preferred alopecia-sparing, oral regimen. Taxanes and anthracyclines (including doxorubicin liposomal) are standard, particularly for those with no prior exposure. Eribulin has been associated with improved survival compared with any of the remaining single-agent options.7 It is unknown if the order of administering these chemotherapies has any impact on clinical outcomes. Thus, it is reasonable to pursue regimens that align with patient priorities and goals of care, given that treatment is palliative in nature.