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HR+ mBC: Factors in Selecting CDK4/6 Inhibitions

Panelists: Joyce A. OShaughnessy, MD, Baylor-Sammons Cancer Center; Andrew D. Seidman, MD, Memorial Sloan Kettering Cancer Center
Published: Tuesday, Dec 04, 2018



Transcript:

Joyce A. O’Shaughnessy, MD: And the only other kind of caveat I would say that I find myself thinking about in practice—whether it be first-line or second-line choice, mostly first-line these days—is the patient where I’m teetering on chemotherapy. Like, uh-oh, am I almost at the chemotherapy? What’s the liver function looking like here?

Andrew D. Seidman, MD: Has the increased efficacy of CDK4/6 inhibitors changed the way you calibrate that decision? Am I brave enough to lead with chemotherapy when I’m staring at a PET scan or a CT scan with 10 or 12 liver lesions or pulmonary metastasis? There are times where we might go to chemotherapy.

Joyce A. O’Shaughnessy, MD: Absolutely. And I think historically, with heavy tumor burdens and a lot of symptoms in particular, like you said—vital structures, the liver, the lungs—we’ve gone with chemotherapy. We really had no choice. Endocrine therapy response tempo is too short. All of these trials showed very fast results, just as good as chemotherapy. And the only way I look at it, Andy, is that I guess I’m increasingly convinced that they’re going to get a response within 6, 8 weeks in terms of just enough tumor reduction that you’re going to get some symptomatic improvement. But then the median PFS, even with combination chemotherapy first line is just—let’s be generous here—8 or 9 months with combination. And we’re looking at medians that are far longer with the PFS with the CDKs.

Andrew D. Seidman, MD: Right. So, there were some interesting subset analyses of the sort of worrisome patient. Maybe you can comment on who these patients are who we might expect a shorter PFS from.

Joyce A. O’Shaughnessy, MD: Liver metastasis, they definitely have shorter PFS. Patients who have the shorter disease-free interval or the shorter treatment-free interval from when they stop their adjuvant endocrine therapy to when they recur, or duration from diagnosis to when they recur, have higher tumor grade, primary breast cancer tumor grade, and then progesterone receptor negativity. And where I tend to think about abemaciclib is that you don’t have to take that week off, not that we have a head-to-head comparison to see if it makes a difference. It may not, at the end of the day, make a difference. We have to have head-to-head because 21 days on, 7 days off, maybe the pharmacodynamic effects really do hold out during that 7, where we know that there will be rebound with all of the CDK4/6 inhibitors. When you stop them, there’s a rebound of the proliferation. We know that, but in the highly proliferative cancer where there are very strong multiple pathways converging on that growth, it seems to me that you should keep the brakes on that thing as much as you can in the patient who’s in trouble. So, that is where I would choose it. Even though there are more side effects for abemaciclib, that’s where I would go with the abemaciclib in the first-line setting.

Andrew D. Seidman, MD: Interesting.

Joyce A. O’Shaughnessy, MD: For the relatively heavy liver or if I don’t like the biology, if there has been a short disease-free interval and I know this is a luminal B breast cancer, I will go with the abemaciclib.

Andrew D. Seidman, MD: So, you wouldn’t just give 400 mg of ribociclib and give it continuously?

Joyce A. O’Shaughnessy, MD: Good, yes.

Andrew D. Seidman, MD: That’s a joke not to do this at home.

Joyce A. O’Shaughnessy, MD: Yes. Obviously, it’s a really, really good question. But we don’t really know truthfully what the pharmacodynamics are that we got; we don’t know. But we are just trying to keep the lid on that thing.

Andrew D. Seidman, MD: I was going to save this story for a later moment in the program, but I think this is a good moment to make this point. When I was interviewing for my Fellowship training, I was in Upstate New York at Strong Memorial Hospital, University of Rochester. And a doctor named John Bennett had me in his office, and he put up a CAT scan on the view box. This is when we actually still had films that we could slide up on the view box. There was a liver full of metastatic lesions, and then he put up another one next to it, and it was a liver that looked really pristine. And he said, “So, you want to train here at University of Rochester. This is the before scan; this is the after scan. I want you to tell me what’s the disease and what’s the treatment.”

I’m looking at this scan like is this a trick question. I realized he was having fun with me, and I thought I’d give it my best third-year medical resident answer, and I said, “Maybe it’s metastatic colon cancer and the treatment is 5-fluorouracil.” Dr. Bennett looked at me, and he said, “Good guess, but you’re wrong. The disease is breast cancer, and the treatment is tamoxifen.” So, Dr. Bennett was trying to impress upon me that he had real belief in endocrine therapy. Now, I think that kind of a CAT scan would probably motivate a lot of doctors to go to chemotherapy. I tell this story because it’s the kind of scenario where I’m really thinking about leading with endocrine CDK4/6 inhibitor, assuming the bilirubin isn’t 3 and the transaminases aren’t 8-fold above the upper limit of normal.

Joyce A. O’Shaughnessy, MD: Right, exactly. Interestingly, Andy, the time may come that we—even in that scenario, because we worry so much about toxicity of chemotherapy with the abnormal liver function—it may be that we find out that even there, the CDK4/6 inhibitors are even better than chemotherapy. I think this is a major sea change we’re seeing in practice. In addition to the marvelous PFS that we’re seeing for patients, as you said, for years, the other thing is that there’s going to be less and less chemotherapy utilization in the first-line setting. We’re going to get increasingly comfortable in an incremental fashion, I think.

Andrew D. Seidman, MD: Which is a really good thing.

Joyce A. O’Shaughnessy, MD: Which is a really, really good thing.

Andrew D. Seidman, MD: Yes, until we can put cytotoxic chemotherapy away for good, right?

Joyce A. O’Shaughnessy, MD: Yes, absolutely, absolutely.

Transcript Edited for Clarity

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Transcript:

Joyce A. O’Shaughnessy, MD: And the only other kind of caveat I would say that I find myself thinking about in practice—whether it be first-line or second-line choice, mostly first-line these days—is the patient where I’m teetering on chemotherapy. Like, uh-oh, am I almost at the chemotherapy? What’s the liver function looking like here?

Andrew D. Seidman, MD: Has the increased efficacy of CDK4/6 inhibitors changed the way you calibrate that decision? Am I brave enough to lead with chemotherapy when I’m staring at a PET scan or a CT scan with 10 or 12 liver lesions or pulmonary metastasis? There are times where we might go to chemotherapy.

Joyce A. O’Shaughnessy, MD: Absolutely. And I think historically, with heavy tumor burdens and a lot of symptoms in particular, like you said—vital structures, the liver, the lungs—we’ve gone with chemotherapy. We really had no choice. Endocrine therapy response tempo is too short. All of these trials showed very fast results, just as good as chemotherapy. And the only way I look at it, Andy, is that I guess I’m increasingly convinced that they’re going to get a response within 6, 8 weeks in terms of just enough tumor reduction that you’re going to get some symptomatic improvement. But then the median PFS, even with combination chemotherapy first line is just—let’s be generous here—8 or 9 months with combination. And we’re looking at medians that are far longer with the PFS with the CDKs.

Andrew D. Seidman, MD: Right. So, there were some interesting subset analyses of the sort of worrisome patient. Maybe you can comment on who these patients are who we might expect a shorter PFS from.

Joyce A. O’Shaughnessy, MD: Liver metastasis, they definitely have shorter PFS. Patients who have the shorter disease-free interval or the shorter treatment-free interval from when they stop their adjuvant endocrine therapy to when they recur, or duration from diagnosis to when they recur, have higher tumor grade, primary breast cancer tumor grade, and then progesterone receptor negativity. And where I tend to think about abemaciclib is that you don’t have to take that week off, not that we have a head-to-head comparison to see if it makes a difference. It may not, at the end of the day, make a difference. We have to have head-to-head because 21 days on, 7 days off, maybe the pharmacodynamic effects really do hold out during that 7, where we know that there will be rebound with all of the CDK4/6 inhibitors. When you stop them, there’s a rebound of the proliferation. We know that, but in the highly proliferative cancer where there are very strong multiple pathways converging on that growth, it seems to me that you should keep the brakes on that thing as much as you can in the patient who’s in trouble. So, that is where I would choose it. Even though there are more side effects for abemaciclib, that’s where I would go with the abemaciclib in the first-line setting.

Andrew D. Seidman, MD: Interesting.

Joyce A. O’Shaughnessy, MD: For the relatively heavy liver or if I don’t like the biology, if there has been a short disease-free interval and I know this is a luminal B breast cancer, I will go with the abemaciclib.

Andrew D. Seidman, MD: So, you wouldn’t just give 400 mg of ribociclib and give it continuously?

Joyce A. O’Shaughnessy, MD: Good, yes.

Andrew D. Seidman, MD: That’s a joke not to do this at home.

Joyce A. O’Shaughnessy, MD: Yes. Obviously, it’s a really, really good question. But we don’t really know truthfully what the pharmacodynamics are that we got; we don’t know. But we are just trying to keep the lid on that thing.

Andrew D. Seidman, MD: I was going to save this story for a later moment in the program, but I think this is a good moment to make this point. When I was interviewing for my Fellowship training, I was in Upstate New York at Strong Memorial Hospital, University of Rochester. And a doctor named John Bennett had me in his office, and he put up a CAT scan on the view box. This is when we actually still had films that we could slide up on the view box. There was a liver full of metastatic lesions, and then he put up another one next to it, and it was a liver that looked really pristine. And he said, “So, you want to train here at University of Rochester. This is the before scan; this is the after scan. I want you to tell me what’s the disease and what’s the treatment.”

I’m looking at this scan like is this a trick question. I realized he was having fun with me, and I thought I’d give it my best third-year medical resident answer, and I said, “Maybe it’s metastatic colon cancer and the treatment is 5-fluorouracil.” Dr. Bennett looked at me, and he said, “Good guess, but you’re wrong. The disease is breast cancer, and the treatment is tamoxifen.” So, Dr. Bennett was trying to impress upon me that he had real belief in endocrine therapy. Now, I think that kind of a CAT scan would probably motivate a lot of doctors to go to chemotherapy. I tell this story because it’s the kind of scenario where I’m really thinking about leading with endocrine CDK4/6 inhibitor, assuming the bilirubin isn’t 3 and the transaminases aren’t 8-fold above the upper limit of normal.

Joyce A. O’Shaughnessy, MD: Right, exactly. Interestingly, Andy, the time may come that we—even in that scenario, because we worry so much about toxicity of chemotherapy with the abnormal liver function—it may be that we find out that even there, the CDK4/6 inhibitors are even better than chemotherapy. I think this is a major sea change we’re seeing in practice. In addition to the marvelous PFS that we’re seeing for patients, as you said, for years, the other thing is that there’s going to be less and less chemotherapy utilization in the first-line setting. We’re going to get increasingly comfortable in an incremental fashion, I think.

Andrew D. Seidman, MD: Which is a really good thing.

Joyce A. O’Shaughnessy, MD: Which is a really, really good thing.

Andrew D. Seidman, MD: Yes, until we can put cytotoxic chemotherapy away for good, right?

Joyce A. O’Shaughnessy, MD: Yes, absolutely, absolutely.

Transcript Edited for Clarity
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