Refining Treatment Approaches for HER2+ Breast Cancer - Episode 2

Adjuvant Systemic Therapy Decision Factors

January 20, 2021
Joyce A. O'Shaughnessy, MD, Baylor Charles A. Sammons Cancer Center

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Lisa Carey, MD, FASCO, UNC Lineberger Comprehensive Cancer Center

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Vijayakrishna Gadi, MD, University of Illinois College of Medicine

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William Gradishar, MD, Northwestern Medicine

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Claudine Isaacs, MD, Lombardi Comprehensive Cancer Center

Joyce O’Shaughnessy, MD: Bill, how do you define patients at high risk of recurrence after their neoadjuvant therapy? What do you do with them? Who is high enough risk in your practice to get a pertuzumab up front? Do you know what I mean? When you start it, do you ever stop it? Do you just keep it going because you feel patients are high enough risk? Then in the adjuvant setting for people with residual disease.

William Gradishar, MD: Right. To piggyback on some of the other comments, we’ve more or less exclusively got away from anthracyclines preoperatively. There may be exceptions where that’s an appropriate thing to do. For most patients, they are getting TCHP [docetaxel, trastuzumab, pertuzumab, carboplatin] upfront, particularly if they have bigger disease at the outset. We do use TCH [docetaxel, carboplatin, trastuzumab] for those where we’re trying to avoid some of the excess toxicity.

In my mind, the fundamental thing that defines risk after receiving neoadjuvant therapy is what the residual disease burden looks like. If there’s significant disease, particularly in nodes, that would be very worrisome, as it would be if there’s a significant amount of disease in the breast. I would also say as a caveat, quite frankly, I haven’t seen that many patients in my own personal experience getting TCH or TCHP who actually progressed on that preoperatively. I know it happens, but I don’t see it very often.

For those that have significant residual disease, and Lisa was already alluding to KATHERINE with those patients switching to T-DM1 [trastuzumab emtansine] and good results, even in those patients where the subsequent HER2 [human epidermal growth factor receptor 2] assessment is negative, we continued the idea to switching to T-DM1 in those with residual disease makes sense.

That’s the strategy we employ. With respect to those who get a pCR [pathologic complete response] at the outset, for most patients—not all—we’ve continued or at least started with the idea that they would complete HP [trastuzumab, pertuzumab]. Who would we not do that in? Certainly, anybody who’s having excessive toxicity. Anybody who’s ER+ [estrogen receptor positive] I would be reluctant to do that in because I don’t think they’re getting as much benefit. There are some nuances to how it would be used.

Joyce O’Shaughnessy, MD: Bill, do you think that if somebody has residual disease after a TCHP or occasionally a AC-THP [doxorubicin, cyclophosphamide, paclitaxel, trastuzumab, pertuzumab], that T-DM1 is really the real standard of care? I say that because not long ago, say a few weeks ago, I saw a patient who had some residual disease and didn’t get T-DM1. Frankly, I was surprised, you know what I mean? It’s become a must-do standard. What do you think? Do you think there’s some room for maneuver with a tiny amount of cancer left?

William Gradishar, MD: I think it is the standard. Just as we can find exceptions to everything we do if we look hard enough, I suppose if somebody had a millimeter of disease, would I feel obligated that they must get T-DM1? Maybe not. Maybe if they’re a little older. For most patients, it really is the standard. Most patients do OK with it, so I would try to leverage that benefit that we saw in KATHERINE and confer to whoever has residual disease.

Joyce O’Shaughnessy, MD: Yeah. Does anyone else want to make any comments about KATHERINE? We’re going to come back and go into it a little more deeply, but any other issues around the adjuvant?

Vijayakrishna Gadi, MD: I’ll share a struggle. In our patients who are node-positive preoperative therapy and get a pCR, what’s the thinking around continuing HP? Even in those pCR patients who were node positive, knowing that there’s a little benefit there when they’re node positive. I found a presentation at San Antonio Breast Cancer Symposium by a very young scientist from Europe looking at pCR rates across a lot of different diseases and saying, “pCR equals pCR.” These are people who have good outcomes. You look at some of the trials, and you start picking at them a little. There seems to be a suggestion that maybe you should continue the HP. I have to be honest. I don’t find that data compelling, but I’m always curious what others think.

Lisa Carey, MD, FASCO: Now you just continue H [trastuzumab]?

Vijayakrishna Gadi, MD: I often just continue H yes.

Lisa Carey, MD, FASCO: I have to say, I don’t think we know the right thing to do. I stay with whatever brought you. You know? If I got a pCR out of an HP-based regimen, I tend to continue the HP. Your point is well taken. The patients can do very well. In our experience, CALGB-40601—which was designed deliberately—is very similar to the European analog Neo ALTTO; the pCR is different. It’s about a 10% absolute benefit difference between the 2 of them in the pCR group, with the event-free survival around 90%-plus for the American trial. But it’s in the 80s for European trials, without a particularly good explanation if you dive into it. I’m not sure that I have, because I don’t feel I can take a pCR to the bank. And so if I gave HP up front, I’d give HP out back, but I don’t know if that’s right.

Claudine Isaacs, MD: I tend to continue HP as well if somebody is tolerating it and there’s no compelling reason to stop it. I have Lisa’s take on it that. If it’s not causing much harm—and I’m not sure what it would do for me to take it back—I’ll continue it. I agree. I wonder about de-escalating from the patient’s perspective and then the time and the inconvenience and everything that goes with it to continuing the therapy.

William Gradishar, MD: I also think that the other thing that figures into it is APHINITY, though we can’t jump up and down about this huge gap between the lines. That gap was identified with a full year of therapy, particularly in node-positive patients. That has to figure into it at least a little. It is a struggle for the patient.

Joyce O’Shaughnessy, MD: Yeah, I did also want to point out that the FDA label for pertuzumab talks about the neoadjuvant. In the label there’s a section called neoadjuvant, and talks about pertuzumab preoperatively. What it says is interesting. It says that if you start it preoperatively, you should finish the year of it. It’s really interesting. Even though we honestly don’t know. If somebody has a pCR, do they really need it, or you don’t even know. If they’re clinically node negative, they start off with it, but they’ve got a big cancer. You decide to use it; we just don’t know this so much.

Bill does the NCCN [National Comprehensive Cancer Network] have a statement about this anywhere, if somebody starts with pertuzumab preoperatively and gets a pCR, are there any recommendations in NCCN Guidelines?

William Gradishar, MD: No, we haven’t gone to that granular level. We wanted to let doctors be doctors.

Joyce O’Shaughnessy, MD: That’s a beautiful thing. I love that. Thank you. It’s refreshing.

Vijayakrishna Gadi, MD: Joyce, I’ll point out 1 thing that does make giving both therapies in the adjuvant setting now—and we’re going to talk about this later this evening—is the ability to give both as a single injection.

Joyce O’Shaughnessy, MD: Yeah, there you go. That might help too, VK.

Transcript Edited for Clarity