Next-Generation Sequencing in HER2+ Breast Cancer

Mark Pegram, MD: Next, let’s talk about new technologies for detection of the HER2 [human epidermal growth factor receptor 2] gene alteration. I understand that at the ASCO [American Society of Clinical Oncology] 2020 Annual Meeting, there was some update at next-generation sequencing methodologies to detect HER2. Can you comment on those abstracts, please?

Julie R. Gralow, MD: There are a couple of abstracts looking at next-generation sequencing, trying to make the point that maybe we could more accurately assign HER2 status based on next-generation sequencing. They found interesting cut points, but what we haven’t seen is would next-gen sequencing do any better at picking out a population who benefits from HER2-targeted therapy? Maybe we can define levels of amplification and overexpression. But the real thing that matters is, are they going to respond to HER2 drugs?

One of the most important things next-gen sequencing can do is to find an ERBB2-activating mutation. As we know, that happens probably more commonly in the classic HER2-negative population, yet we’ve seen responses and we’ve had trials with neratinib. In a classic HER2-negative population but with an ERBB2-activating mutation, that tyrosine kinase inhibitor to HER2 can have efficacy.

From my perspective, right now where I would use next-gen sequencing is I’d be looking for an ERBB2-activating mutation. I did have a recent case where it was present in a HER2-positive early stage patient. She was enrolled in a clinical trial of trastuzumab and pertuzumab, a TBCRC [Translational Breast Cancer Research Consortium] trial, and had no response at all to TRASTUZ-PERTUZ [trastuzumab-pertuzumab]. It didn’t make any sense to me. Her tumor highly overexpressed HER2. Then I added chemotherapy and had some response. At that point, at the time she went to surgery, we ran next-gen sequencing and found an ERBB2 mutation, which I think explains why she hadn’t had a sense of response to the HER2 antibodies. So this is something to look for.

A problem with next-gen sequencing is that we’re learning that HER2 heterogeneity is important. In some recent trials that we’ve seen, populations where there’s a clear population of tumor cells that are HER2 negative that’s 30% or greater don’t do so well with HER2 approaches. Also, is this HER2 2-plus and FISH [fluorescence in situ hybridization]–positive population might not be doing so well as the HER2 3-pluses when we look at the results of some recent trials.

So I think we have a lot of work to do. But as we define the way we are testing for HER2, we have to remember that the bottom line is that we are doing it so we can assign treatment. There have been some exciting early data that maybe trastuzumab deruxtecan might work better in a HER2-lower population. But we had the NSABP-B-47 trial that enrolled the HER2, 1-plus and 2-plus FISH-negative population that showed that trastuzumab didn’t work there. Maybe we need to repeat that trial with trastuzumab deruxtecan as well.

Actually, we have a very interesting trial going on with our colleagues at the Uganda Cancer Institute looking at using a platform that’s commonly available in sub-Saharan Africa that they use in terms of TB [tuberculosis] and HIV analysis. The platform is there, and they’ve got cartridge that can do RT-PCR [reverse transcription–polymerase chain reaction] tumors for ER [estrogen receptor] and PR [progesterone receptor] HER2, so you don’t need a complicated lab setup to do immunohistochemistry [IHC] or FISH. We’re comparing this African version, which is very practical, very doable with the gold standard that we do in Seattle right now, and we are finding a very tight correlation. For the rest of the world, which doesn’t have access to labs with not just next-gen sequencing but a lot of places they can’t do immunohistochemistry or fluorescence in situ hybridization, we might have some interesting new assays here as well.

Mark Pegram, MD: That’s really interesting that you bring up the issue of this real-time PCR [polymerase chain reaction] cartridge that’s actually from some colleagues that are near us here in Northern California, in Sunnyvale, from Cepheid. And in a paper by Natalie Wu and Mike Press, who was a coauthor on that paper—it’s really interesting if you look at their HER2-low subgroups. That is, for the patients who are 0 or 1-plus by IHC, if you look at their transcript level, it’s not dissimilar to HER2 2-plus, FISH negative. In the development of trastuzumab deruxtecan—currently the HER2-low definition is IHC1 or 2-plus, FISH-negative—I wonder whether we should also include HER2 0 IHC based on these transcript levels that are about the same as 1 or 2-plus IHC. That could be a missed opportunity, and we should look into that in future clinical trials, indeed.

Julie R. Gralow, MD: Let’s partner in a trial.

Transcript edited for clarity.