Joyce O’Shaughnessy, MD: Let's just finish with a few words about leptomeningeal disease, HER2-positive leptomeningeal disease. How do you approach that in your practice? What kind of data do we have out there to guide us, Heather?

Heather McArthur, MD: Well, it's pretty devastating complication, obviously, of this disease with important prognostic impact. The TBCRC did a study looking at the tucatinib-based regimen for patients with leptomeningeal disease, specifically presented data last year at San Antonio. Less than 20 patients on that study with modest responses. So, it's a really difficult space in which to innovate because of the poor prognosis of these patients.

Joyce O’Shaughnessy, MD: Yes, so we have a little bit of data there. Again, nothing that we have is gangbusters for these patients. But there were some patients who benefited in the study. And what about intrathecal therapies, Andrew, for these HER2-positive patients?

Andrew Brenner, MD: Yes, so I think there's a couple of points here in terms of intrathecal therapy. There are some guidelines in terms of who's ideal for intrathecal therapy. The ESMO guidelines are the ones I prefer to go by. They really break these down into nodular versus non-nodular disease. If patients have a lot of bulk along the leptomeninges, they tend to not respond to intrathecal therapy. It makes total sense because we know that when you give something into the spinal fluid, the depth of penetration is only about 2 or 3mm. So, if you have something that's bulky, you're just not going to get a good response from that. So, I think that's one thing to consider in terms of what you're going to do in terms of intrathecal or not intrathecal. And then intrathecal trastuzumab has been used. We do use that. The level of evidence is not great. But when you're talking about a relatively uncommon patient population with a four-to-five-month survival, it is really hard to get data for these patients. And so, I do tend to use that. I also tend to use the intrathecal therapies like methotrexate. I've even gone to high dose methotrexate together with intrathecal where I give the, because high dose methotrexate is active in breast cancer. It's just a real pain. But I'll do a high dose methotrexate and then on the off week to intrathecal. And I've seen good results with that. So, there are options. I think another thing that has really become known in the last four to five months is the role of proton craniospinal radiation. So, there's new data that's come out that, in a randomized study where you either treat the patient with involved field radiation for leptomeningeal disease and then do whatever you want. Versus using proton beam and then craniospinal radiation is almost a doubling in survival. So, for patients with leptomeningeal disease, whether or not to refer them for proton CSI should at least be a consideration. And then other options include intrathecal trastuzumab, intrathecal methotrexate, and then involved field radiation for symptomatic areas.

Joyce O’Shaughnessy, MD: One of my patients, she'd already had whole brain, but she just had proton spinal radiation, whole spine. She did remarkably well. Yes, so that's really, really, really good. I didn't know there were randomized data. That's really, really great. We're fortunate here in Texas we have proton therapy here, a couple of different locations.