DR RUGO: The PALOMA-2 data is very supportive of the PALOMA-1 and PALOMA-3. We saw some fascinating data that’s published now on fulvestrant and palbociclib from the PALOMA-3 trial in patients who had ESR1 or estrogen receptor mutations. We know these increase overexposure to hormone therapy.

And one of the really fascinating things that they were able to show was that patients who had responded to an AI were more likely to have an ESR1 mutation than those who hadn’t responded, because the ones who never respond to hormone therapy have an alternate mechanism of resistance most likely, not identified. But the ones who’ve responded, the tumor learns to grow in an estrogen-deprived environment and learns to have its own signaling through ER that’s independent of the ligand, so to speak — ligand-independent signaling. So that was fascinating.

And what they showed in PALOMA-3 was that again, it’s a subset. It was looking at blood markers, all sorts of caveats. But that fulvestrant seemed to work just as well whether you had an ESR1 mutation or not, and palbociclib added as much whether you had an ESR1 mutation. So the reason why I think that’s so interesting is, (1), obviously these drugs seem to help even when you have some resistance to AIs, but also the data from the FALCON trial is eagerly awaited. That’s looking at anastrozole versus current dosing of fulvestrant as first-line therapy for patients who are completely hormone therapy-naïve, never had hormone therapy at all.

If you could delay the development of ESR1 mutations in patients who have hormone-responsive disease, if you started with fulvestrant, that would make a good argument for using fulvestrant first in patients who have hormone therapy completely naïve disease. And, in fact, there was a press release suggesting that they had met their primary endpoint of PFS. And I suspect we’ll see that data at the European oncology meeting, ESMO, in the fall. So I think that that’s kind of exciting.

There was a press release on ribociclib, the CDK4/6 inhibitor, suggesting its first-line trial, MONALEESA, met its endpoint. And then there was data on abemaciclib as a single agent in metastatic disease in a trial I was involved with that Maura Dickler presented suggesting that there is some low-level, single-agent response to abemaciclib, different from palbo and ribo, and that the toxicity is different — more diarrhea, less bone marrow suppression. It blocks CDK4 more than CDK6. So it may be yet another agent that we have that works a little bit differently. And it crosses the blood-brain barrier.

And there was a fascinating poster that showed that in patients who’d gotten abemaciclib and then had a brain met resected that you actually could see there was activity in the brain of this drug, which is incredibly elegant and nice. It was part of the poster discussion session. So really intriguing data, I think, that leads us to further investigations that are ongoing.

DR LOVE: Just one more question about the ESR1 mutations. Are these like driver mutations, or is it kind of like the tumor mutations you see in lung cancer, EGFR, for example, or is this different?

DR RUGO: I don't know that we can really compare it to lung, but FGFR mutations appear to occur somewhat less frequently than PI3 kinase inhibitors but more frequently than many others. So somewhere in the 20% range. And there are different kinds of mutations that can occur. It definitely seems to correspond with resistance to hormone therapy and a worse outcome.

There’s an interesting agent — I mean, there have been agents before, dovitinib, et cetera. But there’s an interesting agent, lucitanib, that has shown some single-agent efficacy with Phase II data coming up that will be presented in the not-too-distant future. But a lot of the problems we’ve had with FGFR inhibitors are off-target toxicities.

So, for example, lucitanib also is a VEGF inhibitor. And the problem with being a VEGF inhibitor is that it causes VEGF-like toxicity. And then you have FGFR-like toxicity, so you’re combined. So people have a lot of trouble using it, because they have to manage the hypertension, the hypothyroidism, the proteinuria. And it’s kind of messy, right? So I think that it’ll remain to be seen where we go with these agents.

Genomic assays and (neo)adjuvant treatment decision-making

Early-stage breast cancer in the adjuvant and neoadjuvant settings

Management of metastatic breast cancer (mBC)

CDK4/6 inhibitors for the treatment of breast cancer

Checkpoint inhibitors and other novel immunotherapeutic approaches to breast cancer

Triple-negative and BRCA mutation-positive breast cancers