William J. Gradishar, MD
Despite its substantial progress, much remains unknown about endocrine therapy as a treatment for breast cancer, according to William J. Gradishar, MD. This type of treatment has come a long way since tamoxifen ruled the adjuvant therapy landscape in 1989, but oncologists still have much to learn about newer therapies and combating endocrine resistance mutations.
The current NCCN guidelines call for continuation of endocrine therapy until disease progression or unacceptable toxicity levels, noted Gradishar, deputy director of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University Feinberg School of Medicine. “We try to continue patients on endocrine therapy because of the quality of life issues and because it’s better tolerated than chemotherapy,” said Gradishar at the 2016 Lynn Sage Breast Cancer Symposium.
Sixty percent to 70% of breast cancers are hormone receptor-positive, and current treatments aim to decrease estrogen levels or block ER. While some cancer are initially resistant to such therapies (de novo resistance), others become resistant over time (acquired resistance), highlighting the need for novel therapeutics to combat endocrine therapy resistance.
In order to prolong effective treatment with these therapies, research should now focus on overcoming resistance mechanisms to endocrine therapy, he said, by exploring estrogen receptor (ER) mutations, CDK4/6 inhibitors, mTOR inhibitors, PI3K inhibitors, and HDAC inhibitors.
“Biologic information may influence the choice of therapy we offer the patient, but we just don’t know enough about yet,” he said. “When estrogen receptors stop working, it’s usually the factor that one or more molecular pathways becomes more important.”
To delay or prevent resistance, endocrine therapy is now being given in various combinations. In most instances, it is no longer considered a monotherapy, Gradishar noted.
Palbociclib, which targets CDK4/6, was first FDA approved in 2015 in combination with the endocrine therapy letrozole. It is now also approved for use with fulvestrant. Gradishar explained that in response to mitogenic signals, cyclin D1 complexes with CDK4/6, leading to the phosphorylation of RB protein, causing the protein to no longer serve as a tumor suppressor, which results in uncontrolled cell proliferation.
Two other CDK 4/6 inhibitors, ribociclib and abemaciclib, are also in development for patients with breast cancer and other malignancies. Gradishar expects these agents to be approved soon. Both abemaciclib and ribociclib have received breakthrough therapy designations from the FDA and are in phase III studies; however, abemaciclib appears unique, as it has single-agent activity.
In May, a phase III study exploring ribociclib plus letrozole was stopped, after demonstrating an improvement in progression-free survival. For abemaciclib, the agent is also being explored in phase III studies. The phase III MONARCH-2 study is looking at the agent with fulvestrant. As a single-agent, the phase II MONARCH-1 study showed a response rate of nearly 20% in heavily pretreated patients with refractory, hormone-receptor–positive, HER2-negative advanced breast cancer.
Patients given palbociclib plus letrozole showed significant improvement in progression-free survival. Unfortunately, neutropenia is one of the common side effects seen with this dual treatment, said Gradishar, adding that while it doesn’t necessarily cause a problem for the patient it can be a headache for the treating physician to monitor and manage.
Uniquely, most significant side effects of abemaciclib appear to be gastrointestinal issues, said Gradishar, with no neutropenia. “Abemaciclib seems to have some ability to benefit Cyclin D1, which may be important, but it may also have some toxicity,” said Gradishar.
Another approach once resistance has developed is the addition of an mTOR inhibitor endocrine therapy. TOR regulates metabolism in times of plenty and not, explained Gradishar, which is why it’s so prevalent in mammals.
The phase III BOLERO-2 study was instrumental in the FDA approval of the mTOR inhibitor everolimus in combination with exemestane for patients with postmenopausal advanced breast cancer following resistance to a non-steroidal aromatase inhibitor. Blocking mTOR with everolimus improved progression-free survival by 55% compared with exemestane alone; however, survival was not significantly improved.