Novel combinations may lead to the future of HR+ breast cancer care.
New developments in metastatic hormone receptor (HR)-positive breast cancer are paving the way for new treatment approaches in the future, says Paul Kelly Marcom, M.D.
“It has clearly been an area that, after lying dormant for a decade, has exploded in the last five to six years with the development of targeted therapies that we combined with standard endocrine therapy,” says Marcom, an associate professor of Medicine in the Breast Cancer Program at Duke University. “That has translated into enormous clinical benefit for patients.”
Pivotal data on the selective estrogen receptor degrader Faslodex (fulvestrant) in HR-positive disease, for example, was presented at the 2016 ESMO Congress. Results of the phase 3 FALCON trial demonstrated that first-line treatment with Faslodex was associated with a better progression-free survival (PFS) versus anastrozole for patients with HR-positive advanced breast cancer. Currently, Faslodex is FDA approved for patients with advanced HR-positive breast cancer that has progressed following anti-estrogen therapy.
How has the field of HR-positive breast cancer evolved in recent years?
In an interview, Marcom discussed the future landscape of HR-positive breast cancer, highlighting the influence of CDK4/6 inhibitors and targeted agent/endocrine therapy combinations.The initial development of Afinitor (everolimus) was certainly a step forward and a rationally designed target, with a modest clinical benefit. However, I came out of a cell cycle lab and did research as a fellow to see the cell cycle mission finally being targeted in a very specific fashion and then combined with endocrine therapy.
That explained this observation that was made a good 15 years ago about cyclin D amplification of that and HR-positive disease, contrasting that with some of the alterations in other cyclins and other subtypes of breast cancer such as ER-negative disease. It really begins to point to a different part of the biology of cancer that we know has been critical at the very heart of oncology for some time; we just haven’t known how to target it.
What are the next steps researchers need to take?
We saw results of the FALCON trial at the 2016 ESMO Congress. What impact do these findings have?
Therefore, to see these drugs come forward, and to see Ibrance (palbociclib) demonstrate this doubling in PFS with a modest toxicity of neutropenia — which all oncologists are quite comfortable in dealing with — has just been very satisfying.The next steps include how we can combine these targeted therapies together, create unique combinations, and know how to sequence those. We need to know how to use the right platforms for assessing the underlying molecular alterations to really pick those agents in the appropriate patient population. That’s really where we need to go next and it is going to be a really exciting time—working through all of that biology. What is fascinating about the FALCON trial is that it was a bold attempt to identify patients who are completely endocrine naïve. These are patients who did not get adjuvant endocrine therapy and went on to develop metastatic disease, or they just didn’t get adjuvant endocrine therapy for another reason. It really is such a pristine environment of metastatic HR-positive disease to be able to look at.
CDK4/6 inhibitors such as ribociclib and abemaciclib have shown promise in clinical trials. What else will we see in this class of agents?
There is lots of correlative work that’s going to come out in the ensuing years, especially to understand the issues of de novo endocrine resistance versus secondary endocrine resistance. This is practice changing, in saying that everybody ought to get Faslodex first rather than an aromatase inhibitor. This is not necessarily on the basis of the data from the study, given the characteristics of the patient population enrolled, but given that most patients are given an aromatase inhibitor now. SERDS (Selective Estrogen Receptor Downregulators) are going to be the go-to agent in combining them with the appropriate targeted therapy; that is what we’re going to be working through.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.
What are the toxicity profiles of the CDK4/6 inhibitors?
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.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 two to three 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.