Joyce A. O’Shaughnessy, MD: So, Claudine, if somebody does not have a path CR to preoperative therapy with the triple-negative—which, unfortunately, is still quite common, in the 40%-to-50% range even with the best therapy we have—what do you do with those patients?

Claudine Isaacs, MD: Well, as Tiffany said earlier, we know that that is a high-risk group of patients, so we obviously have the data from pCR from lots of different trials. But one of the other interesting presentations at San Antonio was a presentation from the I-SPY 2 trial looking at the event-free survival—so looking at a solid outcome in terms of what happened to the patients and really validating what I think we’re increasingly believing: that achieving a path CR makes a huge difference. This was across different drugs, because the I-SPY 2 trial was looking at different targeted therapies for different subtypes of breast cancer.

For patients who achieved path CR, the event-free survival was about 94% to 96%, regardless of what group they were in, regardless of what drug they got, for those patients at 3 years. And that’s a high-risk group of patients that that trial selects for a high-risk group of patients. Whereas if they didn’t achieve a path CR, again, the numbers varied. So, for patients with triple-negative disease, it was more like 65% to 69% event-free survival at 3 years and a little bit better for the hormone receptor—positives, but really distinguishing those groups.

So, as Tiffany said, the neoadjuvant setting allows us to triage our patients. And I think that we’re all hoping for our patients to get a path CR, but we also realize that this is where we need novel therapies and this is where we need something else. So, that area is very rich now in terms of clinical trials. But we also have some data. The data from the CREATE-X trial were published last year in the New England Journal of Medicine, and that looked at the role of capecitabine in patients who, again, were HER2-negative—so it included triple-negative but also hormone receptor—positive/HER2-negative patients who did not achieve a path CR or had node-positive disease. And it randomized them to either get capecitabine for 6 to 8 cycles or no further therapy. And I think, somewhat surprisingly to many of us, it showed an improvement in outcome in the patients who got the capecitabine.

It wasn’t an easy regimen. A lot of patients were not able to complete it on the dose, or somewhere around one-quarter of patients actually stopped early and did not complete all of their intended cycles. But there was an event-free and an overall survival benefit that was particularly marked in the triple-negative subset. So, I think that has really become something that we think of and I would think of as what we have the highest level of evidence for in terms of what to do in a patient who does not achieve a path CR. I think what we’re also grappling with in those patients who didn’t get a platinum, should we be incorporating a platinum? Should we be thinking of immunotherapy, checkpoint inhibitor therapy, in those patients? Should we be thinking of some sort of combinations? And, again, there are a number of large intergroup trials that are addressing some of those questions.

Joyce A. O’Shaughnessy, MD: They did use the label dose of the capecitabine there, which I always have to remind myself of that because I don’t start ever with that, but I do think the onus is on us to push the dose as much as we can. Like maybe starting with the 2 g/m and divide the doses 14, 7 and get as much as we can because that disease-free and overall survival benefit was had with a very, very high dose. It wasn’t even tolerable for some patients.

Claudine Isaacs, MD: I do think the other point, and this was a trial that was done in an Asian population, there’s a lot of debate and a lot of differences between what we see in terms of tolerability and efficacy with some drugs in the Asian population compared with the non-Asian population. So, we really don’t know how that translates to the population that we might be seeing more commonly in our clinics.

Joyce A. O’Shaughnessy, MD: Yes, and your point about the fact that the whole trial was positive, meaning the ER-positive was there, too, the point estimate wasn’t as impressive in the ER-positive subset, but like around the 0.83 or something. And I’ll just point out that we did one of the negative adjuvant capecitabine trials, one of the several, unfortunately; everybody was on a selected high-risk subset.

Tiffany Traina, MD: Right, it was so enriched.

Joyce A. O’Shaughnessy, MD: But we did central Ki-67 and showed through a hypothesis-generating subset analysis that it was the higher Ki-67 patients, 20% or more, that really had a larger benefit from adjuvant capecitabine than not. In my practice from a practical standpoint, if someone gets preoperative, is ER-positive, and they have a residual disease that the Ki-67 is less than 10%, personally, I’m not adding in the capecitabine to those patients—but they still have some proliferation on them. Then I am using the CREATE-X data. That’s what I’m doing, from a practical standpoint, in mine. How about you, Tiffany? Are you using much in ER-positive?

Tiffany Traina, MD: So, I also try to risk stratify there to end up with a large burden of nodal disease, even despite best. Another point in CREATE-X: The vast majority of those patients did have anthracycline/taxane-based neoadjuvant regimens; sort of high 90% receive that. So, with a high-risk residual disease, I am inclined to offer it even in my ER-positive patients.

Joyce A. O’Shaughnessy, MD: Yes.

Claudine Isaacs, MD: I think in that group, as well, the other thing we’re grappling with is the role of improving our endocrine therapy, right? So, there are a lot of trials that are addressing that. There’s the addition of CDK4/6 inhibitors as options for those patients within the setting of clinical trials or the role of ovarian suppression, or adding other things on top of that, how that might further improve outcome in that group of patients.

Tiffany Traina, MD: Actually, a logistical question, which wasn’t clear from the manuscript, is, what do we do about our ER-positive patients who also need to get on to their adjuvant endocrine therapy, may need postmastectomy radiation or radiation, in and of itself, with breast conservation? And I don’t know that we have much guidance from what has been published. I could say in my practice that we do go right on to radiation and get that done, and I’ve been overlapping my endocrine therapy with my adjuvant capecitabine because I would hate to delay starting that for 6 months or longer because of the radiation time.

Joyce A. O’Shaughnessy, MD: Yes. I actually emailed Professor Masuda to ask, and they gave the radiation first and then they gave the capecitabine. But you’re right, you’ve got to get your endocrine therapy going. And it gets tricky on the CDK4/6 trials because there’s only a certain amount of endocrine that you can get before they have to be randomized, so it is a little tricky. But capecitabine really has come into the forefront, I think, for that, for the high-risk, no-path CR patients.

Transcript Edited for Clarity