What is really going to happen that will be exciting is the BELLE-2 trial—even though it’s a different class of drugs. It does point to the right platform for looking at molecular alterations in the current state of the cancer for predicting what agents someone will respond to. We will be sorting out the platform technology for assessing genetic mutation status and combining not just CDK4/6 inhibitors by themselves or with endocrine therapy, but looking at those endocrine-resistant mechanisms and the molecular pathways that compensate or contribute to that resistance and having targeted agents that go after those pathways.
Combinations with targeted therapies with or without endocrine therapy will translate into significant prolongation of the duration of disease control. Even things such as using estradiol for treating metastatic estrogen receptor-positive breast cancer get overlooked in a lot of situations. Using it in the appropriate patient population, with an understanding of who is the appropriate population following progression on or through an aromatase inhibitor, will create a broader range of options for endocrine treatment of breast cancer.What are the toxicity profiles of the CDK4/6 inhibitors?
Even though medical oncologists are quite comfortable with neutropenia as a side effect, we are beginning to appreciate that neutropenia with these agents is different. It is not cytotoxic neutropenia—it is cell cycle rest—and once patients go into that off-week, they generally do recover those counts very quickly.
You do have to assess over the first several cycles and get somebody on the right dose that they can tolerate without getting neutropenia. Most oncologists have learned that, if you are not careful, you can have some patients who will stay low for 2 to 3 weeks. Then, they would be at risk for complications. However, like any new drug, you will learn over time how to use it, how often you need to check counts, who you need to follow closely, and who you can get to a stable dose quickly. It’s a manageable side effect.