Combining estrogen receptor blockade with targeted cell-cycle inhibitors increases therapeutic options for postmenopausal women with ER-positive, HER2-negative metastatic breast cancer, contributing to an evolving paradigm that is moving new regimens to the forefront of the treatment timeline.
Joyce A. O’Shaughnessy, MD
Combining estrogen receptor (ER) blockade with targeted cell-cycle inhibitors increases therapeutic options for postmenopausal women with ER-positive, HER2-negative metastatic breast cancer, contributing to an evolving paradigm that is moving new regimens to the forefront of the treatment timeline, according to Joyce A. O’Shaughnessy, MD.
O’Shaughnessy, who is co-chair of Breast Cancer Research and chair of Breast Cancer Prevention Research at Baylor-Sammons Cancer Center in Dallas and for The US Oncology Network, presented an overview of recent clinical trial findings for ER-positive metastatic breast cancer at the 14th Annual International Congress on the Future of Breast Cancer. She also chaired the meeting, which Physicians’ Education Resource hosted July 16-18 in Huntington Beach, California.
The general principle of managing postmenopausal patients with ER-positive, HER2-negative disease that is not life threatening is to hold off as long as possible on initiating chemotherapy, O’Shaughnessy said. Traditionally, that has meant up to three lines of hormonal therapy before moving to chemotherapy.
During the past decade, a growing body of evidence has established that “clamping down” on ER signaling is an effective strategy, and the emergence of new inhibitors strengthens that concept, particularly for previously untreated patients, O’Shaughnessy indicated.
“In patients with de novo metastatic, ER-driven breast cancer, optimizing blockade of that ER signal is very important for progression-free and overall survival,” said O’Shaughnessy.
Although questions of optimal sequencing remain under study, the combination of palbociclib plus letrozole is emerging as the top choice for first-line therapy for previously untreated patients whose disease is not life threatening, said O’Shaughnessy. Palbociclib, which inhibits the important cyclin dependent kinase (CDK) 4/6 cell cycle regulators, gained the FDA’s approval in February. Other first-line options include fulvestrant plus palbociclib, 500-mg fulvestrant, and fulvestrant plus an aromatase inhibitor (AI), said O’Shaughnessy.
For later lines of therapy, everolimus plus either fulvestrant or exemestane would be the primary options, although palbociclib plus fulvestrant may be considered if the patient received an AI in the first line of therapy.
Emergence of Fulvestrant
Fulvestrant first became recognized as an effective agent for ER blockade when it performed comparably to anastrozole as a second-line therapy for advanced ER-positive metastatic breast cancer.1 The CONFIRM trial2 showed that 500-mg fulvestrant improved progression-free survival (PFS) over the approved 250-mg dose, which according to O’Shaughnessy, indicated that increasing ER blockade is clinically beneficial. However, she noted that 30% to 40% of patients progressed immediately after starting fulvestrant regardless of dosage, indicating that a substantial proportion of these patients are resistant to fulvestrant.
Nevertheless, the impressive performance of the higher fulvestrant dosage led researchers to perform the FIRST study, which showed that 500-mg fulvestrant was associated with greater median PFS (23.4 months) than 1-mg anastrozole (13.1 months).3 O’Shaughnessy indicated that this trial had a relatively small number of patients (n = 205) and that results from FALCON,4 a large phase III trial, will “provide a definitive answer” regarding the effectiveness of fulvestrant versus anastrozole for optimal ER blockade, which is an essential component of treating ER-positive disease. She said results are expected within a year.
The SWOG S0226 phase III trial5 showed that addition of 250-mg fulvestrant to 1-mg anastrozole improved PFS and OS in patients with ER-positive metastatic breast cancer who had not received tamoxifen but did not improve outcomes in patients who had previous therapy with tamoxifen. According to O’Shaughnessy, the lack of response in tamoxifen-exposed patients indicates that additional therapeutic mechanisms need to be identified to effectively target these cancers.
Role for Everolimus
The BOLERO-2 trial6 showed that addition of everolimus, an inhibitor of mammalian target of rapamycin (mTOR), to exemestane significantly increased PFS in patients with ER-positive, HER2-negative metastatic breast cancer that was refractory to letrozole or anastrozole. However, PIK3CA mutation status did not predict response to everolimus in the BOLERO-2 trial, and O’Shaughnessy indicated that at the present time, no known biomarker significantly predicts response to everolimus.
“We go by clinical phenotype…those that manifest some degree of sensitivity to [ER] therapy tend to [respond better to everolimus],” said O’Shaughnessy.
Nevertheless, the clinical benefit observed with the everolimus combination versus exemestane alone (33.4% vs 18.0%, respectively; P <.0001) has introduced the phosphoinositide 3-kinase (PI3K) pathway, which incudes mTOR, as a target for development of therapeutic agents. According to O’Shaughnessy, treatment with these agents for a period of time may help resensitize the cancer to ER blockade, which may increase the effectiveness of ER blockade in future treatment cycles. She said that five categories of PI3K pathway inhibitors have been studied, with agents that target PI3Kα and AKT the most promising.
Introduction of Palbociclib
Early clinical trials investigating the addition of palbociclib to ER blockade have also shown promising results in patients with de novo ER-positive metastatic breast cancer. Addition of palbociclib to letrozole yielded a median PFS of 20.2 months in the phase II PALOMA-1 trial7 versus 10.2 months with letrozole alone (P = .0004) and “salvaged a good proportion” of the patients who progress immediately after starting fulvestrant, according to O’Shaughnessy. Similarly, the phase III PALOMA-3 trial8 showed that addition of palbociclib to fulvestrant significantly increased median PFS to 9.2 months versus 3.8 months with fulvestrant alone (HR, 0.42; P <.001), which according to O’Shaughnessy is “a very impressive result with phase III data.”
Subset analysis showed that groups of patients who had no prior systemic or endocrine therapy tended to derive a greater benefit from palbociclib. Patients who had a short disease-free interval following systemic or endocrine therapy and had undergone multiple prior therapies tended to benefit less from palbociclib.
“Patients who derive benefit from endocrine therapy may get the most benefit from [palbociclib], although we did see some salvage of patients who would have otherwise progressed right away,” said O’Shaughnessy.
Although predictors of resistance to CDK 4/6 inhibitors such as palbociclib are not completely known, O’Shaughnessy indicated that recent molecular-based studies suggest activity of pyruvate dehydrogenase kinase 1 (PDK1) may predict response to CDK 4/6. Current studies are investigating the efficacy of combining inhibition of CDK 4/6, mTOR, and PI3K for treatment of ER-driven metastatic breast cancer, building toward the general concept of combating the disease with multiple drug targets.