SABCS 2012

Links between EGFR/HER1 signalling and trastuzumab efficacy

Dr David Rimm – Yale University, New Haven, USA

What we found is that the measurement of EGFR or HER1 is a valuable way to determine which patients are less likely to benefit from trastuzumab, the breast cancer drug which has been shown to be very valuable, especially in the neoadjuvant or in the adjuvant setting for patients that are HER2 positive.

How does this involve EGFR as compared to HER2?

EGFR is also called HER1, binds directly to HER2 in what’s called a heterodimer and that heterodimerization causes signalling. When we measure HER2, the only thing we do as a standard of care is we look and we know that that activates a pathway that’s inhibited by the drug trastuzumab. So we look at the question what if HER2 isn’t binding just to itself but rather it’s also binding to HER1, can we measure the HER1 or the EGFR? If we measure that does that help us understand resistance to trastuzumab or response?

Part of the reason that this hasn’t been done before is twofold. One is that the antibodies that were previously available didn’t work so well and were hard to standardise because they required special techniques in the lab. A new antibody just became available in the last year or so, doesn’t require special techniques, can just use normal techniques. The other thing we did very differently is instead of having pathologists estimate the expression which is hard to standardise and hard to reproduce, we’ve used this device which we invented in the lab over ten years ago now, a technology called AQUA which stands for Automated Quantitative Analysis, which is a fluorescence based technology that allows you to more accurately assess the actual levels of protein in a cell in a very reproducible manner when the tissue is displayed on a slide. So that combination of a new test along with a new reagent has allowed us to very accurately measure HER1 or EGFR in these cells and that’s why we’ve first made this discovery just this year.

If you think about it, trastuzumab we know exactly what the target is and it’s a protein. This is a protein that interacts with the target protein so we expect that measuring protein would always be better than measuring DNA which is what FSH does. FSH just says the gene is amplified but it doesn’t tell you anything about whether the gene is expressed, whether the gene is mutated or whether the gene is actually producing functional protein. This actually looks at the protein target itself, and the protein target itself is HER2, and now HER1 or EGFR binds to the protein target and co-activates. So it has the potential to be much more sensitive and, more importantly, more specific than FSH for determining who would respond to the therapy. I think that’s particularly important now that there are other therapies. When there was just trastuzumab, well we gave what we had, but now there are therapies like lapatinib, neratinib, TDM1 and others in the pipeline that allow us to even better personalise the therapy for the patients. So in order to do that, new tests will need to come online as well and we propose this as a new test.

What were the results when testing on a cohort?

This is the NCCTG N9831 cohort, one of the three cohorts that ultimately led to the FDA approval of trastuzumab in the neoadjuvant setting. About a third of that cohort was left, but there was still tissue available from that cohort and about a third of it was put into this tissue microarray which was made available for us for testing. The results were that any patients that have high levels of EGFR expression do not benefit from adjuvant trastuzumab, that is the patients with high levels of EGFR look just like the control arm, arm A, where the patients did not receive trastuzumab.

What other therapies are available?

That’s our vision, in fact what we’ve already begun to do is there’s another trial that we’ve already accessed the tissue from called NeoALTTO. That’s a trial where they combine trastuzumab with another drug called lapatinib. Lapatinib is a small molecule inhibitor of both HER1 and HER2 and so by testing this we might find that EGFR expression, or high levels of EGFR, would be more likely to respond to lapatinib. In fact, in the trial, in the NeoALTTO trial, they found that there were different levels of response to lapatinib versus trastuzumab versus both. If you got both drugs your response went from 25% to over 50% suggesting that there was a whole set of patients that didn’t respond to just trastuzumab alone. We would argue maybe those are the patients that are expressing EGFR and in fact we hope to be able to report that next year at this very meeting since it will take me three or four months to collect the data and have the data analysed. Hopefully we’ll be able to submit that for discussion next year.