Understanding HER2 Testing in Oncology

High-quality pre-analytical handling of all specimens and nuanced interpretation are essential.

Recent development of powerful new drugs, for example the HER2

antibody drug Conjugase, has shown efficiencies in tumor that are HER2 low or even ultra low.

Hello and welcome back to the Oncology Brothers podcast. Today, the topic at hand we'll be

rather binary classification that is positive or negative has rather evolved into significantly

something more profound. That is what we're using for HER2 status being reported as positive

negative. Now we are also reporting that as positive or low or even ultra low.

It is important to appreciate the shift and these nuances in testing because HER2 has now become

not just a classic oncogenic driver but also a target for antibody drug conjugates such as

Mavderak's decan. We have come to recognize that the biology of the disease is much more complex

than we usually recognized before.

A number of different new biomarkers have emerged.

So essentially the importance of these biomarkers

is that they do have a significant impact

in the way we manage patients and we select treatment.

So it is crucial to test for HER2 expression

in breast cancer.

We can look for the gene amplification

by doing in situ hybridization.

The other way to do is to look at HER2 protein expression

by immunohistochemistry.

So by looking at this,

we score the tumor cells expression from zero to three plus.

Only three plus strong staining correlates

with gene amplification and thus considered positive.

And for cases that are scored zero,

but they show very, very weak staining,

we call this HER2 ultra low.

Recent development of powerful new drugs,

for example, HER2 antibody drug conjugates

has shown efficacy in tumor

that are HER2 low or even ultra low.

because some of the new therapies, as you mentioned,

for example, in the DB06 trial,

okay, also work in patients that are not HER2 3+.

They also work in 1+, 2+,

and in the ultra-low, as Gary mentioned.

So this concept of moving from a binary result,

positive or negative,

is extremely important for the community oncology

to learn that we are changing.

High-quality pre-analytical handling of all specimens

and nuanced interpretation are essential.

The first problem is metastatic diseases.

Biopsies are always taken from distant sites,

multiple sites, bone, liver, lymph nodes,

and many of these are very difficult to assess.

So unlike the primary tumor, which is much easier to assess.

So this will limit the materials

that we were able to perform our tests.

In clinical practice, of course, we always try to...

obtain tissue from the most accessible or adequately preserved specimens.

Once the specimen is obtained, there are specific things that we need to do or have to observe.

The first is to avoid delays in fixation. Secondly, the use of fixative and duration

for the fixation. Overall, pre-analytical errors usually would lead to reduction

of the antigen expression, and thus it would lead to false negative results rather than false

positive results. So this is particularly important in a low or ultra-low setting,

because when they are already very low, if you lost your sensitivity, then it would become

decreased from ultra-low to negative. One of the questions I ask myself whenever I

receive a pathology report

is does this pathology report actually speaks to the clinical picture this patient is presenting or not?

Because from that moment on, everything I do is going to be based on that piece of paper.

So what the roles we play would, apart from giving very accurate reports,

we would also highlight the difficulties and also to understand the clinical scenarios.

We can highlight sample limitations and potential errors. We could also bring to our colleagues

the possibility of issues related to hereditary heterogeneity and the subtleties of low-level

expression. Oncology is becoming so complex, okay, that we cannot manage this kind of

disease without help and without discussing this with other people. So I think that the

key message is that we need to recognize this complexity. The understanding of the disease,

the resistant mechanisms, actually leads to one very important concept. We improve patient outcomes.

Why we are doing this is all because there is meaning to it,

because there are clinical implications tied to it.

Gary and Carlos, thanks so much

for both of your insights today.

We are the Oncology Brothers.