Emerging combination endocrine therapies for advanced breast cancer

For hormone receptor positive breast cancer, for decades the concept was that combining endocrine agents was not more effective than using them individually. However, emerging combinations have been shown to enhance endocrine therapy effectiveness. We provide an illustrative case and updated results for endocrine therapy in this setting. A 44 year-old, premenopausal woman initially presented in 2006 with stage III, estrogen receptor (ER) positive, HER2 negative breast cancer. Following initial surgery, she received adjuvant chemotherapy with docetaxel, doxorubicin, and cyclophosphamide, radiation therapy, and tamoxifen. In 2009, bone and lung metastases developed and biopsy revealed ER positive, HER2 negative disease. Subsequent sequential single agent chemotherapies included capecitabine, gemcitabine, vinorelbine, and ixabepilone, followed by goserelin plus fulvestrant and palliative radiation therapy. After progression on weekly paclitaxel, hospice was discussed. Alternatively, exemestane (25 mg/d) and everolimus (10 mg/d) were initiated. Toxicity required dose reduction of everolimus (5 mg/d) in August 2012. The patient continues on the combination as of March 2016, with a 52 month course of stable disease that highlights the changing nature of endocrine therapy. Everolimus, a PI3K/AKT/mTOR pathway inhibitor, was evaluated in the TAMRAD phase II trial in which postmenopausal women with ER positive, HER2 negative breast cancer progressing after non-steroidal aromatase inhibitor (AI) were randomized to tamoxifen everolimus (10 mg/d). With the everolimus combination, clinical benefit was greater (61% vs 42%, P=.045) as was overall survival (P=.007). In the randomized phase III BOLERO-2 trial, with similar eligibility and study design, everolimus addition significantly increased RFS by over 50%. With everolimus, immune suppression-related side effects were rare. While stomatitis was common (60%-70%), prophylactic corticosteroid mouthwash drastically reduced stomatitis incidence in a recent trial. While results of using companion diagnostics to detect PI3K/ AKT/mTOR pathway activating mutations to select targeting agents have been mixed, PIK3CA mutation status determination using circulating DNA was successful in the phase III BELLE-2 trial evaluating the mTOR inhibitor buparlisib. In this trial, 1147 postmenopausal women with ER positive, HER2 negative advanced breast cancer progressing after AI were randomized to fulvestrant buparlisib. Overall, the improvement in progression-free survival (PFS) for buparlisib was of marginal clinical relevance. However, in PIK3CA mutant subgroups, a substantial clinical benefit was seen (PFS; 7.0 vs 3.2 months, P<.001). A FDA application for buparlisib approval is pending. Palbociclib, a cyclin-dependent 4/6 kinase inhibitor, was evaluated in PALOMA1, a phase II randomized clinical trial comparing letrozole palbociclib in 165 postmenopausal women with ER positive, HER2 negative advanced breast cancer with no prior endocrine therapy for advanced disease. Palbociclib addition nearly doubled PFS (20.2 vs 10.2 months, P=.0004; Table 1) and was granted accelerated approval by the FDA. The phase III PALOMA2 study evaluating letrozole palbociclib had closely comparable results where palbociclib addition significantly improved PFS (P<.0001; Table 1). While grade 3 neutropenia was common, febrile neutropenia was rare. In the PALOMA3 trial, in which 521 patients with prior endocrine therapy were randomized to fulvestrant palbociclib, PFS benefit was seen with palbociclib-fulvestrant (9.2 vs 3.8 months, P<.001). With similar findings in premenopausal women (who also received goserelin) and postmenopausal women, the combination is FDA approved for both groups. Ribociclib, another CDK 4/6 inhibitor, was recently granted Breakthrough Therapy designation based on MONALEESA-2 trial results. In 668 postmenopausal women with ER positive advanced breast cancer, the ribociclib-letrozole combination significantly improved PFS (HR 0.56, 95% CI 0.43-0.72). In summary, new standards of care for ER positive, HER2 negative advanced breast have emerged. Additional therapy combinations are anticipated to expand therapeutic options in the future. Received: 30 October 2016 | Revised: 18 November 2016 | Accepted: 18 November 2016 DOI: 10.1111/tbj.12876