Gwen’s best of SABCS 2011: Don’t be a victim of HER2 errors!

by Gwen on January 24, 2012

© 2012 Carl H. Stritter All rights reserved.

You can find an overview of the most important presentations of the 2011 San Antonio Breast Cancer Symposium here.

A couple of weeks ago, a client of mine was diagnosed with ER-positive, HER2-negative breast cancer. At the time of our consultation, I could not find the report that gave any details – only that she was HER2-negative.

I encouraged her to get a copy of the full HER2 report. With difficulty, her second opinion oncologist managed to obtain it – he found that my client was actually HER2-equivocal (a.k.a. HER2-borderline). This is absolutely critical since trastuzumab (Herceptin, an anti-HER2 receptor antibody) works just as well in HER2-equivocal cases as it does in those that are strongly HER2-positive.

There are roughly 250,000 new cases of breast cancer diagnosed every year in the US. About 1/4 are HER2-positive. By some accounts, up to 5% of the specimens could be falsely labeled as HER2-negative. When you think of the number of women who may be missing out on potentially life-saving anti-HER2 treatment, it really does boggle the imagination.

The science behind HER2 measurement is simple: when there is an excessive number of HER2 genes in a breast cancer specimen, the chance for cancer cure goes up dramatically when trastuzumab, is administered.

There was a San Antonio Breast Cancer Symposium (SABCS) session this year that explained the discrepancy in HER2 reporting. Read on to peek behind the scenes of gene copy measurement. Once you see how this “sausage” is made, you will have a healthy respect for the limitations of this science. But don’t worry – at the end of my post, there are several tips to help you avoid being erroneously labeled as HER2-negative.

One the first day of the conference Angelo Di Leo, an MD PhD from Italy, gave a riveting talk on the measurement of HER2. Basically, he had three points to make:

1) We don’t really know what to measure

2) We really don’t know how to measure it

3) And more controversially, we don’t really know if we need to measure it in the first place

Let’s review Dr. Di Leo’s talk. Hold on to your hat! This story has a few twists and turns.

Unlike ER or PR measurement, the HER2 gene copy test (called the HER2 FISH test) is quite expensive, so a cheaper test was found where they just measured the amount of HER2 protein found on the cancer cells instead (the HER2 IHC test). If a large amount (3+) of it was found, trastuzumab treatment was in order. If only a small amount (0 to 1+) was found, it wasn’t prescribed. The gene test was only done when there was a middling amount of HER2 (2+) by IHC.

This introduced a level a discrepancy since a small number of IHC negative tests end up being FISH positive (about 4%).

The next difficulty lies in that fact that doing the FISH test accurately is like rocket science – it’s hard to do well. So, when researchers want to make absolutely sure of precise testing, they will send their samples only to a few highly regarded “central labs” as opposed to letting the local pathology staff perform the test.

But even if you use a perfectly accurate FISH testing laboratory, there still are some hurdles to be crossed. First, there is about 20% disagreement between expert FISH testers[1]. How can this be? It turns out that a single breast cancer specimen contains a heterogeneous population of cells – some cells have a much higher FISH copy number than others. So the test result, even when very accurate, can vary depending on which population of cancer cells is tested. (I was very interested to see a couple of biotech companies at the SABCS conference developing rigorous specimen analysis algorithms to compensate for this FISH test weakness. I will be following their development with much interest.)

And if that were not enough of a challenge, there is debate as how to best quantify HER2 FISH. Some labs use the standard technique where the CEP17 gene is the reference. But, because anomalies in the CEP17 gene number can result in misclassifying cancers as HER2 negative, many of the more advanced labs are using additional reference genes such as the RARA gene or p53.

The next problem is that, when presented with the same FISH test result, some experts will call it HER2 positive while others say the opposite. Why don’t the experts agree? It turns out that two groups have developed different definitions of what constitutes HER2 positivity. The ASCO/CAP criteria are more strict than that used by the FDA. So a small number of ASCO HER-negative cases become HER2-positive when the FDA criteria is applied[2].

Now here is where the story takes a real left turn. We may not need to do the test in the first place! It turns out that there are not one but two large, gold-standard clinical trials (NSABP-B31and N9831) showing that HER2-negative patients erroneously labeled as HER2-positive by local labs, derived almost as much benefit from Herceptin as HER2-positive patients! Even some NSABP researchers theorize that trastuzumab effectiveness may not be limited to only those with extra HER2 gene copies[3]. It really makes one think…

After hearing Di Leo’s talk and learning about all the pitfalls in HER2 measurement, one could logically ask, why spend the time and the money doing this test in the first place? Amazingly, the HER2 FISH test works a lot of time despite its inherent inaccuracies. And, until more research comes along that points to a better way to predict trastuzumab effectiveness, it’s all we have.

With that in mind, here are a few tips to minimize your risk of HER2 error.

1) If you are told you are HER2-negative, ALWAYS get a 2nd pathology opinion from a lab that is recognized for their expertise in HER-2 testing. Phenopath an example of such a lab. There are others.

2) Make sure the lab uses an additional reference gene rather than just relying on CEP17.

3) If you are just below the cut-off point for being designated HER2-equivocal, ask the lab to analyze an additional 20 – 40 cells in your specimen.

4) If you’re told you are HER2 equivocal (a.k.a. HER2-borderline or HER2-indeterminant), ask your oncologist if there is a good reason to NOT take trastuzumab in your case. In general, a FISH HER2 copy number between 1.8 and 2.2 is considered equivocal.

So, get a close look at your full HER2 test report. For those who were told they were HER2-negative and they want to retest their cancer specimen at a central lab (the most recent biopsy specimen is the one that is usually best to use), the process will be as simple asking your oncologist to order it for you. But make sure the test is not ordered from the same lab as tested it originally.

Please see references below.

Was this information useful? If so, please help Gwen continue to bring unbiased breast information to the people. Donate now!

*Information on the Breast Equity blog is provided on an “as is” basis for general information only. It is not intended as medical advice and should not be relied upon as a substitute for consultation with a qualified health professional.*

© 2012 Gwendolyn M Stritter, MD. All rights reserved.


© 2012, Gwen. All rights reserved.

Leave a Comment

Previous post:

Next post: