DR CAREY: This is a 45-year-old woman who had a T1N0 triple-positive breast cancer in 2010. She was treated with breast conservation, a sentinel lymphadenectomy, and then she received adjuvant TCH. She was on endocrine therapy also. She remained well until 2012 when she developed an ipsilateral breast mass that was immediately adjacent to her original tumor bed and axillary adenopathy. She underwent biopsy of this breast lesion — I’m telling you, this is like days ago — and it was now triple-negative. This is hot off the presses. What would you do regarding her treatment?
DR LOVE: Bill, what would you be thinking about in this situation? What would you do?
DR GRADISHAR: Assuming we scanned her — and I’m sure she was — and there’s nothing else except all this local stuff, then we would treat her. And the CALOR study gives us some evidence that that strategy makes sense.
I would recommend chemotherapy. And the chemotherapy, in the CALOR study, it was de jour. Whatever you wanted to do was sort of okay. It was pretty wide open. With the triple-negative breast cancer, you might think about gem/carbo. You might think about a taxane. You might even stretch it out to think about trying to get a taxane with bevacizumab for some arbitrary duration of therapy. But there would be no one set regimen that’s the standard. I think that she should get chemotherapy.
DR LOVE: Could I just ask if you could briefly comment on the CALOR study? That was really fascinating. I had heard about that years ago, and then all of a sudden it pops up with a result.
DR CAREY: Disappeared and came back. Well, it was one of those trials that almost died of poor accrual and then changed practice. I mean, we’ve had a couple of those recently, and it’s quite sobering. It was a trial looking at the role of adjuvant systemic chemotherapy in the setting of isolated local recurrent disease. And it was a combination of Breast International Group participants and NSABP.
It ultimately closed after 160-something patients because they were accruing poorly and they redid their stats and eliminated an interim analysis and went with it. Basically, patients had to have isolated local recurrence — in-breast tumor recurrence, axillary and internal mammary node or chest wall after mastectomy. They had surgery, and then they were randomized to adjuvant systemic therapy. It was poly chemotherapy, dealer’s choice, but recommended for at least 3 to 6 cycles or not. And then they followed them for outcome.
And in the end of the day, it was an interesting group. Most of the patients, the average time to relapse was 5 years out. These really were patients who had gone a long time without systemic disease. So you would think, if there was anybody in whom the systemic therapy would be least useful, it’s these ones that are 5 years out. But there was a 41% improvement in disease-free survival and a 59% improvement in overall survival. It was quite a compelling result in favor of adding chemotherapy in the setting of isolated recurrence. And about half of these patients were in-breast tumor recurrences, which is an interesting finding.
DR LOVE: Did you go back and look at the original tumor to confirm it was HER2-positive?
DR CAREY: Yeah.
DR BRUFSKY: What was the HER2 ratio and copy number? That’s a more important issue than being positive or negative.
DR CAREY: The ratio was about 3.
DR GRADISHAR: So, it’s pretty convincing at the outside —
DR BRUFSKY: You mean the copy number was 3. The ratio —
DR CAREY: The ratio —
DR BRUFSKY: No, no, no. I’m talking about the new tumor. Not the old tumor.
DR CAREY: Oh. The new tumor. It was 1.
DR BRUFSKY: It was definitely 1.
DR CAREY: Not like 1.8 or something like that, no.
DR LOVE: Edith, we clearly have a triple-negative tumor, but it seems like there was a HER2-positive tumor before.
DR PEREZ: First, I would go back to the pathologist and ask how the pathology defined that the new tumor was HER2-negative. And I would ask details. As Hope knows, we’re dealing with an email lately about this because of the misinterpretation of how to use the ASCO CAP guidelines for HER2 positivity for treatment that have occurred over the last few years. So I would nicely call the pathologist and say, “What do you mean by HER2-negative? If you did IHC, what was the percentage of cells that were positive?” Because if the IHC showed that the percentage of cells that were positive was 20%, the pathologist may be saying negative based on ASCO CAP, where that’s positive based on FDA guidelines. And that would then warrant consideration of anti-HER2 therapy. But let’s say that it’s totally negative.
DR CAREY: IHC was 1+.
DR PEREZ: 1+? Okay.
DR CAREY: 1+. FISH, 1. Ratio of 1.
DR PEREZ: So let’s figure out that it’s negative after asking.
DR CAREY: I mean, I think this is what everyone was thinking: Is this the same or is this —
DR PEREZ: Yeah. Again, I would ask the pathologist, “What percentage of cells were positive?” Not 1+/2+, but really give you the percent so that you can apply that to the FDA guidelines.
But I think if the tumor is truly negative based on current testing, then I would not use anti-HER2 therapy.
DR LOVE: Would you use chemo and, if so, what type?
DR PEREZ: I would use chemotherapy. In this particular setting, the patient had TCH just 2 years previous, and the tumor recurred quite quickly. So I would use an anthracycline regimen.
DR LOVE: And your approach to this situation in general, did it change at all because of the CALOR study? In other words, would you have done the same thing a few months ago?
DR PEREZ: Yeah. We actually have been doing this. We have been recommending adjuvant chemotherapy for these patients even before the CALOR trial became available. And there were 2 reasons for that.
Number 1, we were aware of the data with hormonal therapy based on the British study published in JCO now a few years back. And number 2, we viewed the situation of an isolated local recurrence that has been excised as essentially another adjuvant setting. That’s why we used additional chemotherapy.
DR LOVE: Monica?
DR MORROW: I was going to ask something that the CALOR trial leaves open in my mind. This is a fairly clear-cut setting. It’s a short interval to recurrence. Now you have triple-negative cancer. You’ve got disease in the breast and the nodes. It’s clearly bad. And I think everyone probably would have treated that before. But what if you have someone who has an in-breast recurrence at 4 or 5 years that’s still ER-positive and it’s 8 millimeters in size?
DR LOVE: Hope?
DR BRUFSKY: Hormone therapy.
DR RUGO: We don’t — in that situation —
DR BRUFSKY: Adjuvant therapy, hormone therapy.
DR RUGO: If it was a new diagnosis, we wouldn’t give chemo.
DR MORROW: You don’t really know — oh, I see what you’re saying.
DR RUGO: Yes. So, what I’m saying is that because it’s a small local recurrence, I think even if it recurred after 5 years and you’re still on hormone therapy, that most of us would probably resect and treat with hormone therapy. Just an alternate agent, and keep our fingers crossed.
DR LOVE: Sara?
DR HURVITZ: I’m sorry. I can’t address what Hope just said because I was spacing out, thinking about this case. And the reason I was spacing out is: I’m not convinced it’s a local recurrence. Everyone said that the CALOR study applies here. I would have taken the tissue and looked at it. And maybe you did this. Does it look very similar histologically to the first one? Because this could be a second primary, and then it sort of changes things. I think you can’t really apply the CALOR data. I think I still would come up with the same conclusion, that chemotherapy should be used, but you maybe have a different conclusion as to which to use.
DR CAREY: We did look at the pathology. And in truth, it looks histologically different. If you take as a given, as we all do, that receptors shift and if you take primary and recurrence, about 15% of the time you see a difference. But to have all 3 of the receptors change, it has got to be a much smaller number. To my mind, and I think therapeutically, as I approach these patients, I actually traditionally have said, “Giving them the benefit of the doubt, I think of it as a second primary and I “advantage” it as a second primary. I’d be interested in hearing how other people think of these things. But this, to me, is a patient who I treat as a second primary.
DR LOVE: So what specifically are you going to do?
DR CAREY: She is going to undergo surgery. And I’m going to use an anthracycline-based regimen. Again, I’m thinking from the standpoint of she hasn’t received it before. She had TCH previously. It’s triple-negative. I will probably use a 6-cycle CAF-type thing, which I’ve done before.
DR LOVE: I’m kind of curious what you were doing before San Antonio in terms of “adjuvant chemotherapy for local recurrence” and what you’re doing now that had changed. Ruth?
DR O'REGAN: I don’t think it’s changed that much. I mean, I actually was going to agree with Sara. To me, this sounded like a second primary. But I mean, if they’re ER-negative, depending on how far out from the original chemo, I would definitely consider it. If they’re ER-positive, maybe not so much. It’s very hard to get 21-gene Recurrence Score in recurrence, which is always an issue, trying to do that. I don’t think I’ve changed my practice that much.
DR LOVE: Bill?
DR GRADISHAR: No, I don’t think so. I mean, keeping in mind CALOR, the original accrual goal was almost 900. They got 106. This is incredibly underpowered. But nevertheless, it supports the idea that systemic therapy, at least in some subgroups, may add benefit.
DR LOVE: But you were using chemotherapy in patients with local recurrence before this?
DR GRADISHAR: I don’t think all local recurrence. You threw a couple of scenarios out, including an in-breast small — or Monica did — a small lesion that occurs a few years later, which could very well be a new primary. But something on the chest wall after a mastectomy or in the axilla a few years down the line, that makes me a bit more worried about systemic disease developing. And in those cases, I would give chemotherapy.
DR LOVE: And does that include —
DR GRADISHAR: Particularly ER-negative.
DR LOVE: What about ER-positive?
DR GRADISHAR: ER-positive, I think you have some options. And again, you individualize looking at the age of the patient. The data from the CALOR study, limited as the size of the sample was, it was less compelling in ER-positive patients, where most of those patients were going to get endocrine therapy anyway, as a foundation. So the impact of chemotherapy was less clear but trending in a favorable way. ER-negative, it was pretty convincing, I thought, even though the numbers were small.
DR LOVE: Adam, what’s your practice been in the past about the people with local recurrence? Has it changed? And do you approach it differently if it was ER-positive?
DR BRUFSKY: For in-breast recurrence, it doesn’t. I was doing everything — treating them as second primaries. I think where this really affected me would have been in the Stage IV NED. If someone comes with a chest wall recurrence, totally resected, I think in the past I probably would not have given that person adjuvant therapy. I think I’m going to going forward.
DR LOVE: Am I getting the sense that, in general, you all and people were using chemotherapy in patients with in-breast local recurrence?
DR RUGO: ER-negative.
DR HURVITZ: Yes, ER-negative. I mean, I think it depends —
DR LOVE: ER-negative.
DR RUGO: ER-negative.
DR O'REGAN: And depending how more recently they’ve had chemo. I think that’s another key thing because if this developed within 6 months of getting adjuvant chemo, I certainly wouldn’t be compelled to re-treat that patient.
DR CAREY: I have to say, CALOR actually did change my practice, particularly for patients where there was a long disease-free interval and a very localized recurrence. I used to have fights with myself. I had the 2 devils on each side, and one was saying, “It might be a new primary or it’s self-seeding.” Larry Norton would tell you this new thing can self-seed, and you need to treat it again.
On the other hand, you have a tumor that relapses in a localized setting 6 years following original therapy. The alternate argument is the systemic therapy I gave 6 years ago worked. This is a failure of radiation. And so she needs more local therapy. And I have to say I really wrestled with that exact scenario, not knowing what the right thing to do was. I think the CALOR actually did inform my practice to a large degree.