Rounds with the Investigators 2012 | Breast Cancer

DR NEIL LOVE:  Okay. Here’s this one. He’s in Fresno, California, incidentally. I have a 36-year-old woman who presented with inflammatory breast cancer while pregnant. ER-, PR- and HER2-positive with metastatic disease to the spine. Wow! Received TCH, had a complete response, was placed on tamoxifen and trastuzumab. Relapsed 4 months later with brain mets. Wow, this is incredible.

Received whole brain radiation, switched to lapatinib/capecitabine. Local progression in the brain with CR continuing elsewhere. Gets stereotactic radiation. Now she’s progressing in the brain.

I’ve decided to switch her to goserelin, exemestane and everolimus and lapatinib. Wow! Any data with brain mets with pertuzumab? Any data with intrathecal injection of trastuzumab? She still has no signs of extracranial progression. Actually, this case ties into a paper that you were part of in metastatic, HER2-positive disease to the brain I was going to ask you about. What do you think, first of all, about this case?

DR ADAM BRUFSKY: It’s a tough case. It’s a really, really tough dilemma. And it’s really the cutting edge of where we are right now. And I think that we’ve gotten very good at treating systemic disease — systemic nonextracranial disease, let’s put it that way. Where we’re really having issues is brain metastases. And there’s a lot of really cool drugs out there, just to say, just up front, there’s a really neat — something called LRP, which is kind of a protein that binds to the — in fact, I have a conference call right after this about it. There’s a protein called LRP that the company Geron has figured out how to bind paclitaxel to LRP. LRP binds to the blood-brain barrier and so that’s a paclitaxel delivery. And they actually have a trial for HER2 neu-positive women that they’re — and HER2-negative. You’re going to be able to give her trastuzumab or lapatinib with this LRP.

And so that’s something that’s kind of really cool.

DR LOVE: Yes. Actually, Beth Overmoyer from Dana-Farber said she had 3 patients who’d responded to it, which is unbelievable.

DR BRUFSKY: I think it’s great. I’ve yet to try it. We’re just about to start…

DR LOVE: It’s a small molecule or what?

DR BRUFSKY: No, it’s not a small molecule. It’s a protein — it’s kind of like T-DM1 in a way.

DR LOVE: It’s an antibody-drug conjugate?

DR BRUFSKY: It’s a paclitaxel-bound LRP, basically. So this LRP protein is bound to —

DR LOVE: I mean it’s somehow specific to the brain?

DR BRUFSKY: It binds to the blood-brain barrier. Apparently there’s a receptor for this LRP on the blood-brain barrier.

DR LOVE: Because actually, here you have a 36-year-old lady with mainly brain mets — in California or I guess the patient is. How would they think about accessing this? Where are the trials going on?

DR BRUFSKY: He could email me, if he wants. If you want to email him after this and have him send his email to me.

DR LOVE: So you’re doing a trial on this?

DR BRUFSKY: Yes, we are. We’re participating in it. I think it’s a multicenter trial of a few sites.

DR LOVE: And it’s HER2-positive brain mets.

DR BRUFSKY: And negative. It’s both.

DR LOVE: Oh, both.

DR BRUFSKY: It’s for both HER2-positive and negative. You can have either one.

But I think that — off study, I’ve had success, to be honest with you, in hormonal manipulation. I think that’s a great thought. I’ve had it both with intra kind of spinal mets as well as carcinomatous meningitis, as well as parenchymal brain mets — at least stability for long periods of time. I think that’s a great kind of instinct. That’s a great thought. I would definitely do that.

I think adding the everolimus to it — there's no data whatsoever. I just don’t recall off the top of my head whether everolimus does cross the blood-brain barrier, but it is a small molecule.

DR LOVE: But you know the other thing about this that I didn’t even think about, is because he’s given her goserelin to make her postmenopausal and then given her exemestane and everolimus, I’m not even sure — can you do that on label?

DR BRUFSKY: Yes. No, it probably is off label. Although, no. You know, it just says postmenopausal.

So you’ve made her postmenopausal. If her FSH is 70, she’s postmenopausal.

I guess you’re really strictly adhering to the label, but I have no problem with that. I mean I think the instinct is a good one. I don’t know if it’s going to work, but you’ve tried just about everything else you have in your armamentarium at this point.

DR LOVE: What about — he’s asking about pertuzumab in HER2-positive brain mets.

DR BRUFSKY: I don’t think pertuzumab — there’s no data on that whatsoever. That’s probably a bridge too far. I probably wouldn’t give pertuzumab in this case. But I like the LHRH. I like the exemestane. I like the, at least in theory, everolimus. I mean he’s giving it on label. Lapatinib? Why not? I mean, it’s a small molecule. It does get into the CNS. I think all of that is reasonable. Whether insurers, especially in California, are going to pay for it or not is a whole other story. But I think that there’s nothing unreasonable about that. I mean there is no data whatsoever though on everolimus.

I guess where we could look, that I’ve never looked, is go back and look at the renal cell data with everolimus to see whether people had responses in brain mets. That’s probably what I would do. Before I gave someone everolimus in that setting, I would go back to see if there’s any data on brain metastases from renal cell carcinoma that have responded to everolimus.

DR LOVE: What about this issue — and actually, your paper with, is it Dr Mata?

DR BRUFSKY: Yes.

DR LOVE: It was really cool. It said a lot — it has these cool graphics in the blood-brain barrier and all these other things.

DR BRUFSKY: Yes.

DR LOVE: It was really interesting. But you all in the paper get into the issue of what we know about trastuzumab and HER2-positive brain mets. Maybe you can reflect on that and also Dr Hagar’s question about intrathecal, although I —

DR BRUFSKY: Yes. I’ll tell you —

DR LOVE: — don’t think with brain mets you wouldn’t — I’m not sure about that.

DR BRUFSKY: Yes. It’s hard to know. I mean I think that the problem with the brain mets is where the blood supply of the met is coming from. I think there’s so much, as this paper shows, so much is unknown about the blood supply. Is it disrupted? Can you disrupt it with, say, for example, bevacizumab? Can you disrupt it [to] allow larger molecules to get through? I mean that’s kind of the gist of a lot of that paper: Do larger molecules like trastuzumab get through and can that explain some of the potential survival benefits we’ve seen in the registrar study that we presented — published a year ago. I think we’re kind of waving our hands here. There’s not a lot that’s known.

In terms of intrathecal trastuzumab, I have to say that I wanted to do it. There’s been a couple, as you know, a couple of case reports over the years with it, with varying —

DR LOVE: With brain mets?

DR BRUFSKY: No brain mets, for carcinomatous meningitis. And I wanted to do this based on that, probably 7 years ago. I went to Genentech, at the time they weren’t Roche yet, they still were Genentech, and they didn’t want to give me [the] drug. And their thought process was, one of the sugars that they use to stabilize — it’s called trehalose — is not metabolized by the brain. So in other words, you’d be giving people a load of trehalose if you gave them trastuzumab intrathecally. And somehow, potentially, you could induce CNS problems because you’re putting in a glucose substitute into the cerebral spinal fluid. That was their theory. This is why they wouldn’t give it to me. And although, I’ll tell you, I’ve been wanting to do [this] for years — never really did it myself. I think a lot of us have wanted to do it for years. There were a couple of anecdotal, nonpublished kind of thoughts that people have done it in Europe. In fact, I got an email about a week and a half ago from somebody who actually had it done to their wife at MD Anderson. And the guy told me that it worked. Again, this is a guy emailing me on the phone. I don’t [know] if I can ever use that for my own practice. But on the other hand, there’s nothing wrong with trying it. I just think that to do it, you need an Ommaya reservoir. It’s a big deal. I mean I thought about doing this —

DR LOVE: Yes. And this sounds a little experimental area.

DR BRUFSKY: — in some of my patients. A) You’ve got to put in an Ommaya. B) You have to figure out what are you suspended in. How do you inject it? If there’s an adverse event? This is something that’s truly out there. There’s a lot of things that have to go into do[ing] that, intrathecally.

So my gut feeling is, I think it would be great on a clinical trial, if anybody ever wanted to try it. Right now, people have thought about it, but I just don’t know of any clinical trials of it right now.

DR LOVE: I’ve heard this discussed for a long time, but where you see systemic therapy working on brain mets, that I’ve seen, is first we saw it with the EGFR mutant-positive lung cancer and the TKIs. And then more recently with the BRAF inhibitors like vemurafenib with melanoma. I don’t know that we really have anything like either one of those things in breast cancer. But I did mean to ask you before in terms of TKIs, whether there’s anything, in addition to — we were talking about lapatinib out there. We’ve heard about neratinib. And the other one that we’ve heard about is afatinib.