Researchers say several key questions remain in the treatment of breast cancer: whether CDK4/6i therapy should be continued beyond progression, what the mechanisms of resistance are, and how agents should be selected.
The future for endocrine therapy in the treatment of advanced human epidermal growth factor receptor (HER)-positive/(HER)2-negative breast cancer is bright, but more research is necessary to answer several key questions. These questions include the continuation of therapy, agent selection, and biomarkers, said Erica Mayer, MD, MPH, in a session at the 2019 San Antonio Breast Cancer Symposium titled, "Future directions in endocrine therapy for advanced HER-positive/HER2-negative breast cancer."
As opposed to the endocrine monotherapy, which was popular approximately 30 years ago, Mayer said the introduction of targeted endocrine agents has significantly improved outcomes. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), which stop the development of the cell cycle, are a standard of care treatment for patients with HER-positive/HER2-negative breast cancer.
Although these treatments have advanced, Mayer said looking to the future is vital to improving patient outcomes.
"As we are in 2019 and on the cusp of a new decade, I think it's important for us to think about the years ahead," she said.
There have been 8 randomized clinical trials in the metastatic setting that evaluated the addition of CDK4/6 inhibitors to an endocrine background, Mayer said, including 5 in the first-line setting and 3 in the second-line or pretreated setting.
In these studies, there was a consistent hazard ratio between 0.5 and 0.55, which suggests that the addition of a CDK4/6i essentially doubles progression-free survival in this setting, according to Mayer. Despite the efficacy of CDK4/6 inhibitors, however, progression always inevitably occurs.
Because of this progression, Mayer said there are several key questions: should CDK4/6i therapy be continued beyond progression, what are the mechanisms of resistance, and how should these agents be selected.
There are several current studies examining whether CDK4/6i treatment is beneficial after progression, including the PACE trial. Mayer reviewed the PACE trial and said that its preclinical data suggest that a combination of endocrine therapy, CDK4/6i, and anti-PDL1 may provide synergistic efficacy.
Regarding mechanisms of resistance, research has found that there are multiple heterogeneous potential mechanisms of resistance—whether the resistance is de novo or acquired, according to Mayer. Rb1 loss is found in both types of resistance, which Mayer said is expected given that Rb is the target of CDK4/6 inhibition. There are multiple forms of resistance, she said, and although research around this area has increased, improving understanding of the mechanisms could lead to better therapies.
"Overall, a better understanding of the mechanisms of resistance may improve our ability to rationally select the next line of therapy," she said.
The real challenge, Mayer noted, is establishing which mutation has led to the patient's resistance. The gold standard of identifying this mechanism of tumor biopsy, but that presents challenges such as cost and safety. Instead, longitudinal monitoring of circulating tumor DNA may be an attractive option, according to Mayer.
In particular, there has been increased interest in using selective estrogen receptor degraders (SERDs) to target ESR1 mutations. Many oral SERDs are being studied for efficacy in estrogen receptor-positive metastatic breast cancer populations. Oral agents, Mayer said, may have greater availability and thus greater activity in the setting of endocrine resistance.
CDK4/6 inhibition with endocrine therapy is already the standard of care, but better understanding of the mechanisms of resistance and answering any lingering questions could provide keys to improving patinet outcomes, according to Mayer.
"As you've seen, there are many very exciting new agents which are currently in the pipeline in development, and we also have increasingly helpful and sophisticated methods to analyze tumors to help us assign these therapies," Mayer said. "Overall, I think the road ahead in 2020 and beyond is extremely promising for our field, and most importantly for our patients."
Mayer E. Future directions in endocrine therapy for advanced HER+/HER2- breast cancer. Presented at: 2019 San Antonio Breast Cancer Symposium; San Antonio, TX: December 10, 2019.