HER2 as a Biomarker in Metastatic Colorectal Cancer

Transcript:

Tanios S. Bekaii-Saab, MD: HER2 [human epidermal growth factor receptor 2] is part of the HER family. EGFR [epidermal growth factor receptor] is HER1, then we have HER2, HER3, etc. HER2 overall has been known to be a driver for many cancers when amplified or overexpressed. First, its relevance was established in breast cancer, then it moved to gastric cancer. Now in colon cancer, biliary tract cancer, and other cancers as well, we see HER2 amplified. In colon cancer, it’s present in about 2% to 4% of all patients at the expressed level. HER2 as a target has become more relevant over the last few years, but mostly over the last couple of years. This year, even more so with more combinations of agents becoming available to us.

When we think about HER2 in colorectal cancer, there are many complicating elements that are important for us to understand as we plan for treatment, whether with HER2 target therapies or avoiding EGFR inhibitors. One is that the level of expression matters. IHC 3+ is a predictor of the best responses we see. IHC 2+ with FISH-positive [fluorescence in situ hybridization] is certainly clinically relevant, especially when we’re thinking about dual target things such as with tucatinib and trastuzumab. It’s important for us when we’re planning for these antibody-drug conjugates, such as trastuzumab deruxtecan, because those patients tend to not respond well to this to a lower expression of IHC 2+.

Then it’s important as we complete the picture around HER2 to have [testing for] RAS. So, RAS wild-type tumors, where most of the HER2 amplify tumors have also RAS wild type…those are the tumors that tend to be most responsive to dual therapy, such as trastuzumab and tucatinib. So, RAS wild type overexpressing HER2. In the presence of a mutation, we do not see responses with dual HER2 target strategies, which again biologically makes sense. However, we do see responses in the antibody-drug conjugates. Again, that make biological sense because antibody-drug conjugates are essentially chemotherapy that’s targeted. [An antibody-drug conjugate] doesn’t care as much about the biology of the cancer, it cares more about the expression level. So you have to have a lot of the target present. It doesn’t matter whether the receptor is active or not, as long as it’s present, it docks to it and releases the chemotherapy. For the biologic strategy, it’s more important to have the activity, so you need the RAS wild type and an active—whether it’s 3+ or 2+ and FISH-positive, you will see these levels of activity. So it’s important to have this tested and [have an] understanding of the landscape of how we deal with these tumors.

In terms of using algorithms for testing, we have a breast [cancer] algorithm and we have a gastric [cancer] algorithm that have been established. On the MOUNTAINEER [NCT03043313] study with trastuzumab-tucatinib, Andrea Cercek, MD, [Memorial Sloan Kettering Cancer Center in New York, New York,] presented that data and looked at the concordance between the gastric and the breast algorithms on our patients with colorectal cancer, through MOUNTAINEER, and the results suggest that there’s a high concordance, and almost the perfect concordance level between the gastric and the breast management in terms of predicting who may benefit from trastuzumab-tucatinib. That’s important for us to understand because our pathologists always ask, “Which algorithm do you need me to follow? How can I predict better for your patients?” The good news is that as long as it’s there, regardless of what algorithm you’re going to use, you can use the drugs.

Transcript edited for clarity.