By Joan Mancuso
- Despite the FDA’s approval of several medications to treat endocrine resistance in metastatic breast cancer, scientists persist in examining other avenues of potential resistance, in order to develop new drugs.
- Researchers are conducting clinical trials that combine already-approved medications as well as approved drugs and experimental compounds.
- Oncologists are optimizing treatments by how they sequence and combine existing medications to treat resistance.
Resistance to chemotherapy and targeted treatments is a challenge in treating metastatic breast cancer (MBC). Development of therapies for patients with luminal A or B MBC who have become resistant to standard endocrine therapies such as tamoxifen, aromatase inhibitors (AIs) and fulvestrant, has become a clear medical need. Even though some patients have a durable response to endocrine drugs, scientists continue to examine avenues of endocrine resistance (ER), in order to develop additional therapies.
In an area already identified by scientists in the lab as promoting ER in MBC, the Food and Drug Administration (FDA) recently approved two inhibitors that hone in on CDK4/6 cell cycle progression. In September, the FDA gave a go-ahead to amebaciclib as either a stand-alone treatment or given with fulvestrant, and in April they approved ribociclib for use with an AI. The first in this class of drugs for MBC was palbociclib, which the FDA approved in 2015. The addition of CDK4/6 inhibitors can potentially double response time over endocrine therapy alone, Dr. Angela DeMichele said during a presentation at a session titled Challenges in Advanced/Metastatic Breast Cancer, given at the 2017 annual meeting of the San Antonio Breast Cancer Symposium in December. Dr. DeMichele is professor of epidemiology in biostatistics and epidemiology at Abramson Cancer Center, University of Pennsylvania.
The luminal subtype of breast cancer is biologically distinct, Dr. DeMichele said. It is characterized by endocrine- and estrogen-related genes. Clinically, it tends to be estrogen-receptor positive and/or progesterone-receptor positive, and HER2 negative. Luminal B has less endocrine expression and greater proliferation.
Optimization of therapies
Oncologists can optimize treatments depending on how they sequence or combine medications, Dr. DeMichele said. For example, the FALCON and FIRST clinical trials showed that fulvestrant, rather than the AI anastrozole, improves durable response for post-menopausal women who are treatment naïve.
Further, a switch in a combination of already approved drugs as well as adding additional agents under investigation can be tested in clinical trials for efficacy. For example, researchers are combining three approved drugs—ribociclib, the AI exemestane and everolimus—in the TRINITI-1 trial. However, patients would be concerned about the potential toxiciteis of combining three drugs, and those results will be reported. In the PASTOR trial, they are combining the experimental drug, vistuserib, with everolimus. This trial is active but no longer recruiting.
Along with everolimus, vistusertib is an inhibitor that targets mTOR along the PIK3/AKT/mTOR signaling pathway within a cell. Although the PIK3CA mutation itself occurs in 40% of breast cancers, few agents that target PIK3CA have reached phase III clinical trials due to toxicity and lack of efficacy, according to Dr. DeMichele.
Everolimus was FDA approved in 2010 for use with the exemestane. It was the first drug of its class for controlling resistance to endocrine drugs in MBC.
Balancing quality of life and treatment toxicities
All cancer treatments have toxicities, which affect the quality of life (QOL) of MBC patients. A good QOL is important, and patients are always weighing the benefits and risks of different treatments. Patients can help control toxicities by recruiting a doctor who specializes in palliative care. And they should not be afraid or reluctant to ask their oncologist for a recommendation. A palliative care physician can help control side effects.
Neutropenia is a Grade 3/4 toxicity that occurs among the CDK4/6 inhibitors. However, CDK4/6 neutropenia is reversible with a rapid recovery, in comparison to a delayed recovery in chemotherapy-induced neutropenia, Dr. DeMichele noted. Neutropenia can be potentially decreased by lowering the dosage level of palbociclib without compromising efficacy. There was no difference in efficacy between patients in the PALOMA-3 trial who had a dose reduction of palbociclib of ≥ one and patients who did not have a reduction, she said. Neutropenia is a low, white blood cell count. Grades range from a low toxicity of 1 to a high toxicity of 4.
Amebaciclib and ribociclib show Grade 3/4 fatigue and diarrhea, and ribociclib also has Grade 3/4 QTc prolongation, which can cause problems with electrical activity of the heart. Diarrhea can be controlled by medications.
Stomatitis is a Grade 3/4 toxicity of everolimus. However, it is treatable with alcohol-free dexamethasone, as was shown in the SWISH trial. Stomatitis is inflammation of the mucosa of the mouth.
Scientists continue to move forward
In branching out to continue to find treatments for ER resistance, scientists are researching other areas of resistance such as the role of:
- *Histone deacetylase (HDAC): HDACs are a class of enzymes. HDAC inhibitors can arrest cancer growth and induce death of cancer cells.
- *Fibroblast growth factor receptor 1 (FGFR1): FGFR1 belongs to the family of fibroblast growth factor proteins (FGFR1–4). They are proteins involved in cell division, regulation of cell growth and maturation, formation of blood vessels and wound healing
- p53-mouse double minute 2 homolog (p53-MDM2): The tumor suppressor gene p53 acts as an important defense mechanism against the onset of cancer and cancer progression. It is negatively regulated by interaction with the oncoprotein, MDM2. That interaction results in an inability of p53 to suppress cancer cells. An oncogene is a gene that can transform a cell into a tumor cell, under certain circumstances.
- Immunoglobulin IgG1: Immunoglobulin G is a type of antibody that helps to protect the body from infection. It has four subclasses (IgG1–4). IgG1 is the most abundant. The newly opened PACE clinical trial will test the efficacy of an antibody of IgG1.