Shanu Modi, MD: Our patient unfortunately, has progression on the tucatinib regimen, although after a good run on it at this point, it's October of 2021. And she is now commenced on trastuzumab deruxtecan. And this is not for progression in the body, of course. It is for the CNS [central nervous system] progression. And 6 weeks later, you'll see the pre- and post-MRI scans here. She has a significant improvement in her CNS metastases. It's dramatic, actually. And so, we've all sort of alluded to it, ADCs for CNS disease. Sara, would you have considered T-DXD [trastuzumab deruxtecan] for this patient at this point in her care? And what do you think about the efficacy of T-DXD potentially for brain metastases?

Sara Tolaney, MD, MPH: Yes, no, it's a great question and I would’ve thought about T-DXD here. Again, this is now someone who's had pertuzumab, T-DM1, tucatinib and definitely would be an excellent choice. I think what we've seen from the larger studies, DESTINY-Breast01 and DESTINY-Breast03 is really data in people who've had stable treated brain mets [metastases] for the most part. And we haven't had large data sets looking at T-DXD in people with progressive or untreated brain mets. But we now are seeing some series that are coming out which is exciting. We first saw a hint in that TUXEDO-1 study which we only saw the first part so far and the first stage, but even out of those 6 patients, 5 out of 6 intracranial response rate is amazing. And then we saw the DEBRA, one of the cohorts from the DEBRA trial get presented with almost a 50% CNS response rate. And then now we see a case series from Dana-Farber [Dana Farbar Cancer Center, Boston, Massachusetts] and Duke, also very similar objective response in the CNS. In fact, more than 70% range. We are seeing this suggestion again that ADCs do get into the brain and do cause objective responses again in someone who doesn't have an intact blood-brain barrier, and we're going to get more data emerging. DESTINY-Breast12 is now enrolling with about 250 patients, progressive or untreated brain mets. We'll get large data sets. But I personally have treated people similar to this patient who've had progressive brain mets and seen tremendous benefit, it does work, which is great.

Shanu Modi, MD: Yes, it's so great to see. I'm just curious. Would you have ever considered in this woman who, just rewinding a bit, had progression on tucatinib, would you have considered maybe doing some localized radiation and continuing tucatinib? Is that something you have ever tried in a case like this?

Sara Tolaney, MD, MPH: To Tiffany's point, it's always these multidisciplinary care questions where you have to understand how complicated it is to radiate versus not. And is it going to have potential risk to the patient? But if the patient can get radiation, if it's one spot and the neuro-radiation oncologist says it's no problem to SRS, I have done that. And as you guys know, we have data with tucatinib that suggests that works. In HER2CLIMB when they allowed for that, it was pretty impressive that many patients stayed on treatment for a lot longer before they developed progression. It’s worth considering when that's an option for the patient.

Shanu Modi, MD: That's great. To continue on with this case, she had a great response to the T-DXD therapy. And a few months again follow-up scans showed that she had sustained response in multiple lesions. However, there was increase, interval increase in the size of small enhancing left frontal lesions. There were 2 of them as you'll see on the scan. And there was increased sort of uptake and peripheral sort of nodular enhancement of the large dominant left parietal lesion that she had. There was some suggestion on the scan that there was potentially viable tumor there. At this point given all the treatments that she'd had, it was decided that maybe it was worth going in to do some resection particularly of that large parietal region, which was giving her some symptoms in her leg. And surprisingly when they got the results back from the surgery, it was all necrotic tissue. There was no viable cancer, and it's a pretty alarming-looking scan, but it was all dead tissue. At that point it was decided just to leave the 2 frontal lesions alone as well and being uncertain whether they represented true viable disease or more necrosis. And she was monitored and has remained on the T-DXD with good control and symptom control up until the recent point. And I will say most recently, she had to stop the T-DXD not because of progression in the brain, but because she developed ground-glass findings on her CAT scan. So devastating. This was the worst possible scenario for a patient like this who's having such a tremendous benefit from this therapy and has been through a lot of the good options already and has found some great results with this drug but has to stop it because of some toxicity. It was asymptomatic ground-glass findings on her CAT scan. She still has no systemic recurrence, and it was a tough decision to make with her and her husband. But we elected to hold the T-DXD, and we're going to watch and see if things clear up, and with the hope of course that we can reinitiate T-DXD once again in the future. That's her status. If she were to have further CNS progression and T-DXD was not an option, meaning her CAT scan doesn't clear up, as I alluded to, she has had a lot of her best systemic therapies, I would say. Although there are other active agents potentially, and we know that some of the standard systemic therapies we use for breast cancer. The platinums for example also have some CNS penetration and if her performance status remains good and we are looking for other options – one of the things I would consider are using some of our standard systemic chemotherapies with trastuzumab. There was some nice data presented from Nancy Lin in the Dana-Farber group using high doses of trastuzumab plus pertuzumab with some penetration into the CNS, a lot of exciting things and of course clinical trials. We always remain hopeful that there is something else out there that can help keep disease under control.

Transcript edited for clarity.