Questions and Controversies in Treating Breast Cancer - Episode 1
Transcript:Adam M. Brufsky, MD, PhD: Hello, and thank you for joining us in this OncLive Peer Exchange® titled “Questions and Controversies in Treating Breast Cancer.” Evidence-based management of breast cancer has become increasingly complex owing to gains in understanding disease biology, as well as the introduction of newly approved drugs. As we continue to refine the use of systemic therapy, we are faced with the challenge of integrating newly approved agents into our current practice patterns.
In this OncLive Peer Exchange® panel discussion, my colleagues and I will contemplate some of the yet-unresolved questions in breast biology to provide guidance in treating your own patients. We’ll discuss the newest FDA approvals and emerging data. I am Dr Adam Brufsky, and I am a professor of medicine at the University of Pittsburgh and associate director for Clinical Investigation at the University of Pittsburgh Cancer Institute.
Participating today on our very distinguished panel are Dr Carlos Arteaga, director for the Center of Targeted Therapies and director of the Breast Cancer Program at Vanderbilt University in Nashville, Tennessee; Dr José Baselga, physician-in-chief and chief medical officer at Memorial Sloan Cancer Center in New York, New York; Dr Kimberly Blackwell, professor of medicine and assistant professor in radiation oncology at the Duke Cancer Institute in Durham, North Carolina; Dr Debu Tripathy, professor and chair for the Department of Breast Medical Oncology at the University of Texas MD Anderson Cancer Center in Houston, Texas; and finally, Dr Denise Yardley, senior investigator of the Breast Cancer Research Program and principal investigator at the Sarah Cannon Research Institute in Nashville, Tennessee. Thank you so much for joining us, and let’s begin.
We really have a plethora of riches in breast cancer. I think that we now—in all 3 really, but clearly in ER-positive disease and in HER2-positive disease—have a lot of things that are new. Even now, we’re starting to approach triple-negative disease. But let’s start with ER-positive metastatic breast cancer and really talk about CDK4/6 inhibitors and, in particular, ribociclib. It’s the new kid on the block; it’s second to market. What’s going on with ribociclib? Denise, what do you think?
Denise A. Yardley, MD: Well, I think the MONALEESA-2 data were quite exciting and really resonated with the enthusiasm that we have now for combining targeted agents with endocrine therapy, which used to be a standard as monotherapy. I think the MONALEESA-2 trial demonstrated much of what we had seen with palbociclib, that adding a CDK4/6 inhibitor to first-line postmenopausal women who are ER-positive demonstrated an improvement in progression-free survival—almost doubling it.
And while the median survival for the ribociclib group has still not been reached, what we saw in the control arm with letrozole seems to be very consistent with a median survival at about 14.57 months—what we saw with the PALOMA-2 data. I think that we are able to enrich what we’re offering our first-time endocrine patients, with delaying the role of chemotherapy, adding another novel agent to endocrine therapy, and extending patient outcomes.
Adam M. Brufsky, MD, PhD: Again, it’s second to market. I’m going to go back a little bit and just ask all of you a question. It was at a meeting several years ago, the San Antonio Breast Cancer Symposium 2012, where Rich Finn presented the phase II data from PALOMA-1. Did people believe that when it first came out? What was your thought? Carlos, when you first saw those data, were you familiar with the CDK4/6 pathway?
Carlos L. Arteaga, MD: It turns out that at the time—and José knows this paper—we had published a paper supporting the idea that when tumors escape from being hormone dependent, they rely on CDK4.
Adam M. Brufsky, MD, PhD: Really?
Carlos L. Arteaga, MD: So, I found those data quite plausible, but I think that it was a small study—not enough to change patterns of care, but enough to do the randomized studies that were preceded by it.
José Baselga, MD, PhD: Yes, but to be honest, I think the management of the data was something that at least I did not expect initially. It was really spectacular, and when the first 2 randomized data came out, we said, “This is too good to be true, because it’s not blinded, and maybe there’s a bias in that.” And now we have the data with ribociclib. Now we have the PALOMA studies, and the story is a very clear one. This has forever changed the way we treat patients with breast cancer. And the magnitude of the size, as you mentioned—we’re talking about hazard ratios of 0.5.
Adam M. Brufsky, MD, PhD: You’re doubling. You take whatever hormone therapy you have, and you just double it.
Carlos L. Arteaga, MD: The point I was making was that there was a basis for the combination to be better.
Adam M. Brufsky, MD, PhD: Yes, it was.
Kimberly L. Blackwell, MD: The other thing I’m surprised about is that there was no toxicity. There’s toxicity with each of these CDK inhibitors, but you see that rate of neutropenia in the 160-patient study, which is PALOMA-1, and you’re thinking now, “Why didn’t they see febrile neutropenia?” Now we have several large phase III studies, both in combination with AI and fulvestrant, and the rate of febrile neutropenia in most of these studies was less than 2%.
So, I think not only of the magnitude of the benefit when Rich Finn presented PALOMA-1 and that separation of curves we love to see at these national meetings, but also of the fact that patients aren’t necessarily paying a price to get this additional benefit. There are a lot of drugs emerging that have small differences in the curves, but there’s a fair amount of toxicity, whereas, in my opinion, that’s just not the case with the CDK inhibitors.
Debu Tripathy, MD: We have to keep in mind that the natural history of hormone receptor—positive breast cancer is quite long, and so I’m as encouraged as everyone else is with the differences in PFS. There’s no difference in overall survival that has emerged yet, but the number of deaths in all of these trials is still pretty low, so we will have to wait and see if that emerges.
Adam M. Brufsky, MD, PhD: But could it be conceivable that you now have a PFS of 24 months—30 months even, if you believe the investigator—and even higher in some of these trials? You have a PFS of almost more than 2 years, and you’re not going to see a survival benefit, really? We don’t know that yet, but seriously?
Debu Tripathy, MD: We don’t know why patients escape sensitivity to CDK4/6 inhibitors. Are there fundamental defects in cell-cycle control? Is there loss of retinoblastoma function? That could be something…
Adam M. Brufsky, MD, PhD: Or use of cyclin E. That seems to be the latest theory.
Debu Tripathy, MD: We’re seeing cyclin E isoforms and other putative mechanisms of resistance that may not necessarily be specific to CDK4/6 inhibitors but may render the tumor differently in some way. We can’t really guess what’s going to happen. We actually have to see what happens with all of these patients. Now, most of the trials do not follow these patients indefinitely. There are a couple of registries that are getting set up that will follow patients through multiple lines of therapy.
Adam M. Brufsky, MD, PhD: Those will be nice.
Debu Tripathy, MD: We will learn from those, yes.
Transcript Edited for Clarity