Insights From: Hope S. Rugo, MD, UCSF Helen Diller Family Comprehensive Cancer Center; Sara Hurvitz, MD, UCLA Jonsson Comprehensive Cancer Center
Hope S. Rugo, MD: The rationale for targeting cyclin-dependent kinases (CDK) 4/6 is really quite interesting because we’ve known that the cell cycle is important in tumor cell growth forever. That was the basis of understanding how rapidly growing cells were an issue and how they lose control over the cell cycle and lose the normal regulatory factors. Of course, in the recent years, we’ve understood this better, but I think what has been most interesting recently is the role that estrogen plays, the estrogen receptor pathway in the cell cycle, and the cell cycling in cancer cells.
So, cyclin-dependent kinase inhibitors, of course, were of interest for a long time in the treatment of cancer because of the importance of the cell cycle, but they had a lot of off-target toxicity. It’s actually on-target but normal cell toxicity where you would get low blood counts, cytopenias, were a problem. But with these more selective cyclin-dependent kinase 4/6 inhibitors and an understanding of how CDK4/6, cyclin-D1, and RB interact, it actually led to an interest in trying to understand how those inhibitors would work in breast cancer cells.
Really elegant preclinical work, done by Dennis Slamon and Rich Finn at UCLA, in cell lines that had already been well-characterized showed that these agents could suppress cancer cell growth in luminal-like cancers and HER2-positive cancers. And at the same time, there was preclinical work showing the relationship between ER and signaling through the estrogen receptor and CDK4/6. And so, the rationale really came about from the fact that CDK4/6 inhibitors could actually potentially have single-agent activity, but that more importantly, estrogen could actually overcome that inhibition in preclinical settings. And so, combining an estrogen antagonist or an aromatase inhibitor, for example, with the CDK4/6 inhibitor made perfect sense for treating these luminal-like or hormone receptor positive cancers.
We’ve seen a real revolution in the treatment paradigm for patients with hormone receptor-positive metastatic breast cancer where CDK4/6 inhibitors have really impacted our treatment planning and our guidelines as well. In fact, the use of CDK4/6 inhibitors has been incorporated into guidelines, nationally and internationally. So, what has happened is we understand that if you give a CDK4/6 with a variety of different hormonal agents, you can improve progression-free survival and response rates. In many situations, either you don’t adversely impact health-related quality of life or you improve aspects of health-related quality of life at the same time.
Based on these data, the agents have been incorporated into both the first-line and subsequent line combinations with hormone therapy. So, the impact in terms of the treatment paradigm is that now when you have a patient who has hormone receptor-positive metastatic breast cancer, the decision is, “I’m going to give hormone therapy, should I also give a CDK4/6 inhibitor?” And in most cases, that answer is yes in the first-line or subsequent line setting, depending on the individual patient setting and situation and the organs that are involved.