AACR 2026 | HER2 amplification predicts response in rectal cancer studies

Yeah, so HER2 amplification was assessed on the study based mostly on immunohistochemistry. This was done because it’s pretty accurate. It does a pretty good job of assessing for HER2 amplification, and also it’s feasible. So you can do it on tissue pretty quickly as opposed to extended sequencing, which typically can take a couple of weeks. Patients that had HER2 amplification as defined by immunohistochemistry score of three or more were allowed on the study, or if the patients had two plus staining on immunohistochemistry plus an amplified FISH study, they were allowed on the study. We also did next-generation sequencing on all folks, and we assessed patients for KRAS mutations. I didn’t mention this, but patients that had KRAS mutations were not allowed on study. We actually didn’t find any patients in our screening that had a RAS mutation as well as the HER2 amplification, which is pretty interesting. We screened over 500 people. So in the stage four setting, you see RAS mutations in, you know, between 20 and 40% of people with HER2 amplification. So that in itself was an interesting finding that maybe RAS mutations happen after HER2 amplification or maybe in the early stage setting, they’re not as relevant. But to go back to your question, HER2 has been studied in a number of different cancers. The things you have to keep in mind are there can be heterogeneity in the tumor. So we didn’t find that in our study because we only have one tumor site that we biopsied. And most of the patients had three plus or more staining. But that can be a phenomenon that is witnessed in other cancers, such as esophageal gastric cancer, and theoretically could be seen in rectal cancer, too. If we see more patients, maybe we would find that. We also did next-generation sequencing to evaluate for DNA amplification, so not doing the protein staining but looking for DNA. Interestingly, we had a couple patients on the study that had immunohistochemistry positive, but their DNA sequencing was what we called normal, which was very interesting. And that wasn’t an inclusion criteria for the study, but we think, and it’s one of the messages of the trial, that maybe the DNA amplification is actually more important. And to prove this point, we looked at patients that had a complete clinical response, and we compared those four patients to the four patients that did not have a complete clinical response with only the chemotherapy and HER2 treatments alone. And what we found is the biggest predictor of the clinical complete response was actually the genomic amplification of the DNA, which is really interesting. All of the patients with a complete clinical response had high amplification of their DNA. There was one patient, which is still pending. On patients who did not have a complete clinical response, those patients had significantly less DNA amplification as done by external sequencing. Interestingly, too, all the patients with a complete clinical response also had HER2 3-plus amplification. The folks that did not have a clinical response, many of those patients had 2-plus amplification on the protein staining. They had a positive FISH, so they were eligible for the study, but their level of amplification was lower. So hence the title of the talk, we think that the genomic amplification of HER2 is very important in this setting.

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