Frontline Therapy for Triple-Positive Breast Cancer

Lisa A. Carey, MD, FASCO: Let’s move onto some other things like triple-positive breast cancer because, even from the very beginning, you’re at a fork in the road. I’d like to start with the first-line studies, PERTAIN and the SYSUCC-002 Chinese study. PERTAIN was published a year or so ago, and the Chinese study was reported a few days ago. V.K., can you comment on the decision tree for triple-positive breast cancer in the first-line setting?

Vijayakrishna Gadi, MD, PhD: Absolutely. To set the stage on the biology aspect of this, we often conflate HER2 as being 1 monolithic thing, but the truth is that it’s, at least fundamentally, 2 different diseases. You’ve got the HER2-enriched subtype, and then you have the luminal B type that has gained HER2 as a growth factor receptor. When you think about it in the ER [estrogen receptor]-positive/HER2-positive, so-called triple positives, if you suppress ER, maybe HER2 drives the disease, and if you suppress HER2, ER drives the disease. So, maybe the concept is that you need to suppress both. I know I’ve substantially oversimplified that concept, but that’s fundamentally what we’re talking about.

That’s been formally tested in a couple of trials looking at the first-line setting. I’ll start with PERTAIN, which is a primarily US-based study looking at combining in some patients an AI [aromatase inhibitor], pertuzumab, and trastuzumab. Some of these patients were induced with a taxane chemotherapy initially, and then rotated onto the AI. The concept is that you’re still going to get this dual inhibition of the ER and HER2 axis. What they showed in that trial was that the results weren’t that different from what we saw in the CLEOPATRA trial. Yes, maybe there were differences, numerically, by a couple of months, but on balance, they were very similar in terms of the outcomes. Obviously, the tolerability is greatly different when you’re talking about an AI plus pertuzumab and trastuzumab. That’s the first bit of evidence, built on 20-plus years of preclinical work, that this is a very reasonable way to approach this, and I’ll share a personal anecdote in a minute.

The Chinese study was just published. It was a headline abstract at ASCO [American Society of Clinical Oncology annual meeting] this year and was a very nicely, cleanly done study. It was trastuzumab plus ET [endocrine therapy] vs chemotherapy plus trastuzumab, and they showed very similar outcomes for the 2 arms, and a huge difference in terms of tolerability, again, favoring the endocrine therapy. The investigator was asked, on the virtual stage, the following question: Why didn’t you combine it with pertuzumab? He had a very honest and reasonable answer which was, “Well, in China, we didn’t have pertuzumab until 2017, and this trial started before then.” So, a very reasonable response. But to me, the takeaway is that the dual inhibition of the antibodies combined with the AI may be an appropriate therapy for ER+ disease.

In my personal practice, I have this anecdote. I have a lot of older, frail patients I’ve seen over the years, and they don’t want to do the chemotherapy if they can help it. One of the things I’ve done is use this therapy for them, and it has worked, and in a few cases where it hasn’t worked, I’ve been able to go back and add the taxane chemotherapy and still get a response. I’m not losing much when I start in this manner. I’ll pause before I talk about some of the other trials that are combining medications. Lee and Reshma, do you have any thoughts to share on the first-line setting?

Lee S. Schwartzberg, MD, FACP: Yes, I agree with you completely. I think we see patients who seem to be, phenotypically, a bit more estrogen-driven in terms of their presentation, so patients with long disease-free intervals, or those who have bone and soft tissue predominant, and in particular as you said, in the community, these older patients who are not really candidates, or don’t wish to have chemotherapy. I think it’s perfectly reasonable, based on the data, to take this concept of de-escalation that we’re talking about in the early setting, and potentially applying it, carefully, in the metastatic setting as well. These data are strong, that if it’s a so-called triple positive, you need to suppress both major pathways. You can get good clinical benefit out of that. I agree with you completely, V.K.

Reshma Mahtani, DO: I practice in southern Florida, and I see a lot of these older patients who are on multiple medications, have multiple comorbidities, and you get the feeling that they come in with this long disease-free interval, bone metastases, nodal metastases, and as Lee pointed out, more of perhaps an estrogen-driven type tumor. We have been utilizing this, but it was gratifying to see the trial show a benefit to support what we’ve been doing. Looking at the CLEOPATRA first-line regimen approach that we talked about earlier, with dropping the taxane quickly and continuing endocrine therapy; I think many of us were utilizing endocrine therapy in these triple-positive patients either up front or quickly after induction chemotherapy, as per CLEOPATRA.

Transcript Edited for Clarity