Virginia Kaklamani, MD: This is a case of a 60-year-old patient, semi-retired real estate agent who was diagnosed with stage three ERPR negative and HER2 positive breast cancer. She received adjuvant chemotherapy with pertuzumab and trastuzumab and then five years after completion of the adjuvant therapy she developed pulmonary metastasis. The patient was treated with a CLEOPATRA regimen with frontline pertuzumab, trastuzumab, and docetaxel for six cycles and then she was placed on pertuzumab, trastuzumab maintenance for four years and that's really what I do as well. After the six cycles I will drop the docetaxel and continue with the doublet of antibodies. But after the four years she developed brain metastasis. She complained of intractable headache, routine clinical visit. She had scans that showed a 1.5cm lesion in the brain and that was treated with SRS. Two months after completing the SRS the patient had stable brain lesions but now her pulmonary metastasis was noted to progress. And so, the question is how would we treat the patient? Andrew, let me start with you.

Andrew Brenner, MD: So, this is a second line setting for a patient with stable brain metastasis who was just treated with the CLEOPATRA regimen. In this particular patient I would probably go to TDXD for this patient based on the level of activity and that it's, as we've mentioned previously, that it's superior to TDM1 in the setting. The patient does not have active brain metastasis right now, so I really don't see a reason to move tucatinib in this setting given the stable brain metastasis.

Virginia Kaklamani, MD: And one thing that I've thought about, we talk about these antibody drug conjugates that are large molecules, right, but somehow, they do treat brain metastasis. So, to me, especially if you've treated a brain met, that blood brain barrier we all love talking about probably doesn't exist anymore, right?

Andrew Brenner, MD: Yes, this is a very active area of research. So, there's the blood brain barrier and what we also call the blood tumor barrier. And the blood tumor barrier is usually denuded of a lot of the other structures such as astrocytes and parasites which help to keep things from getting across. There are some studies with radioactive labeled antibodies that show that the concentration within brain metastasis is certainly much higher than in the normal brain. So, they do get across. The question is, to what extent do they get across? It's obviously not going to be the same as in areas and other parts of the body where we have the finestra where the larger molecules can pass. So yes, it is disrupted. Some does get across, but the amount getting across is different from the rest of the body and it may or may not be sufficient to result in activity.

Joyce O’Shaughnessy, MD: It's a really interesting question because this patient had a solitary met. It had SRS, so she may well have microscopic subclinical met, but whether the blood tumor barrier is still very much intact there, it's like the TDM1 didn't work in the adjuvant setting in CATHERINE because maybe you were just treating microscopic disease there. And so, it's just really an important question. I don't think we know the answer when it's a definite established brain metastasis, the antibody drug conjugate, the TDXD, TDM1 may be better. So, it's a really, really interesting question.

Virginia Kaklamani, MD: And I think it may matter whether it's established but also treated versus established and untreated. And DeAndre's point, I think once you've treated that brain metastasis, then you're freer to give your favorite systemic agent than having to worry about the brain getting out of control.

Joyce O’Shaughnessy, MD: Yes, yes. So, sounds like, yes, Andrew, you would just treat the brain and then go on to your TDXD thinking you want to use that highest level one evidence for the second line setting for a systemic control.

Andrew Brenner, MD: And there is a serious question about what you should do in the second line setting for a patient who has active brain metastasis. In this case, since the patient had stable brain metastasis, I'd be very comfortable going with just the best available systemic regimen, which in this setting, the best data seems to be TDXD.