New approaches to treating women with advanced ER+ breast cancer are in development, which includes both hormone therapy and combinations with targeted agents. The continuing goal is to understand disease biology and individualize treatment regimens to increase survival.
Matthew Goetz, MD
Hormonal therapies that block estrogen signaling are still the most important element of therapy regimens for both pre- and postmenopausal women with advanced ER+ breast cancer. Premenopausal women are generally treated with tamoxifen, a drug that severs the tumor’s source of growth stimulation, estrogen. Tamoxifen is a selective estrogen receptor modulator (SERM) that prevents the binding of estrogen to the estrogen receptor in breast tissue. Women diagnosed prior to menopause are also given drugs that temporarily stop the ovaries from producing estrogen. An oophorectomy is also an option. Because most women are diagnosed with early-stage disease, they will have likely already been treated with adjuvant tamoxifen at the time of progression. These patients are typically treated with an aromatase inhibitor (AI) and an ovarian function suppressant.AIs are the standard of care for postmenopausal, ER+ metastatic breast cancer based on studies showing treatment with AIs results in longer survival compared with treatment with tamoxifen.1AIs inhibit the enzyme aromatase, which helps produce estrogen outside of the ovaries. Response rates for postmenopausal women to first-line hormone therapy are approximately 21% to 32%.2,3
Another hormonal agent, fulvestrant, is an anti-estrogen therapy that, unlike SERMs, has no estrogen agonist activity. Fulvestrant is not approved in the first-line metastatic setting, but follow-up data from phase II trials recently showed that treatment of postmenopausal women with ER+ breast cancer with 500 mg of fulvestrant may result in better outcomes compared with treatment with anastrozole (median time to progression, 23.4 months vs 13.1 months, respectively;P=.01).4Further studies are needed to confirm this result.Patients with metastatic ER+ breast cancer can generally be divided into those who present with de novo metastatic disease and those who have already received hormone therapy in the adjuvant setting. Postmenopausal patients with early-stage disease are most commonly started on a nonsteroidal AI, either anastrozole or letrozole, said Matthew Goetz, MD, associate professor of Oncology and Pharmacology at the Mayo Clinic, Rochester, Minnesota. Exemestane, a steroidal AI, is also an option in the adjuvant setting. Exemestane was compared with anastrozole and letrozole in 7576 women with postmenopausal, early-stage ER+ breast cancer. The adjuvant phase III trial, MA.27, showed that the distant disease-free survival for women taking either the steroidal or nonsteroidal AIs for 5 years was the same.5
Patients who progress on an initial AI in the adjuvant setting still have hormone therapy options, but the development of hormonal resistance is a concern. “The critical question clinicians face is now, will this patient respond to estrogen-targeted therapy?” said Goetz. Second-line hormone therapy options include exemestane, fulvestrant, and tamoxifen. “All three of these drugs have been tested in the hormone-refractory setting, but the time to progression is fairly quick, about 4 to 5 months,” said Goetz.
In 2010, a higher dose of fulvestrant, 500 mg, was approved for treatment of ER+ metastatic breast cancer in postmenopausal women whose disease progressed on an anti-estrogen therapy. The approval was based on the CONFIRM trial of 736 patients. A 500- mg dosage of fulvestrant was shown to decrease the risk of disease progression by 20% compared with 250 mg (P=.006).6A long-term update of the trial, presented at the 2012 San Antonio Breast Cancer Symposium (SABCS), showed a 4.1-month improvement in overall survival from 22.3 months in the 250-mg group to 26.4 months in the 500-mg group (P=.016), with no increase in toxicity.7
Still, patients who become hormonerefractory have few options. “For this reason there is a great need to understand the mechanisms of resistance to drugs that target the estrogen receptor, and to develop new drugs for patients with hormone-resistant advanced disease. It’s a big problem,” said Goetz.A recent SWOG trial of fulvestrant plus anastrozole in patients with newly diagnosed ER+ advanced breast cancer demonstrated that this combination resulted in better overall survival (OS) compared with anastrozole alone (median OS, 47.7 months vs 41.3 months, respectively;P=.05).8However, fulvestrant was given at a 250-mg dosage, lower than the currently recommended 500-mg dosage. Further confirmation of this result is needed if this combination is to be widely used. Two previous studies, the European FACT and SoFEA trials, did not show the same benefit.9-10The discrepancy may be the varying patient populations accrued to these trials, said Goetz. “There may be a subset of patients with hormonally sensitive disease that derive greater benefit from the combination, which was the finding from the SWOG group.”The first FDA-approved drug that is really designed to address one of the escape pathways that result in hormone resistance is everolimus, a mammalian target of rapamycin (mTOR) inhibitor, said Angela DeMichele, MD, associate professor of Medicine at the Hospital of the University of Pennsylvania, Philadelphia. Everolimus was approved in 2012 based on the BOLERO-2 study. The combination of everolimus with exemestane improved progression-free survival (PFS) compared with exemestane alone in postmenopausal women with ER+ metastatic breast cancer who had progressed on a nonsteroidal AI.11
Several other trials are testing combinations of endocrine therapy with targeted drugs that block signaling through the PI3K/AKT/mTOR pathway, which appears to be important in at least some of the patients’ resistant to hormone therapy. The phase III BELLE-2 trial is comparing fulvestrant with or without BKM120, a PI3K inhibitor in postmenopausal women with ER+, AI-refractory advanced breast cancer.12
“The PI3K pathway becomes important when an ER+ breast tumor is deprived of estrogen in the long term,” said Goetz. “Drugs that specifically target the PI3K enzyme appear to be promising. It is just a matter of where they fit into the treatment scheme.”
Nancy Davidson, MD
Another class of promising agents are cyclin-dependent kinases 4 and 6 (CDK 4/6) inhibitors. Studies have shown that CDK 4/6 is important for the growth of hormone-refractory breast tumors. The CDK4/6 inhibitor palbociclib blocks tumor cells in the G1 phase of the cell cycle prior to DNA replication. “This inhibitor is designed as a brake that is applied to cells. These cells are like a car without any brakes,” said DeMichele. “The drug prevents the rapid division of these tumor cells, arresting them but not killing them.”
Phase II data presented at the 2012 SABCS suggest that the drug is very promising. Patients taking the combination of palbociclib plus letrozole had a median 18.6-month longer PFS compared with letrozole alone (median PFS, 26.1 months vs 7.5 months, respectively).13A phase III trial is currently under way.14
Epigenetic modifications are another potential mechanism of resistance for ER+ breast tumors. Entinostat, a histone deacetylase (HDAC) inhibitor, has recently shown promise in women with ER+ breast cancer who had progressed following treatment with a nonsteroidal AI and one or fewer prior chemotherapy regimens. In a phase II randomized trial of 130 patients, entinostat plus exemestane treatment resulted in a significant improvement in PFS compared with the AI alone (median 4.3 months compared with 2.3 months, respectively) and in OS (28.1 months vs 19.8 months, respectively).15“These results are very promising and there are efforts now to develop a large phase III trial based on the phase II findings,” said Nancy Davidson, MD, director of the University of Pittsburgh Cancer Institute and UPMC Cancer Center in Pennsylvania.
Options for women with metastatic ER+ breast cancer are increasing, but ongoing research continues to push efforts to understand how best to sequence treatments, and to identify ways to prevent hormone resistance or to overcome resistance with novel targeted agents.