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.