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Small groups, big answers in HER2 testing

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And for those troublesome 2+ IHC cases? “Again, additional counting by a second observer in the areas that are 2+ staining,” Dr. Allison says. In contrast to group two, because of the evidence supporting that many of these cases have co-amplification of the HER2 and centromeric control signals, the guideline’s authors wanted to give the benefit of the doubt to patients who have 2+ IHC results and high levels of HER2 copy number, but are ratio negative. Cases that are 2+ and 3+ are both considered positive. As with group two, the guideline provides a comment for inclusion in pathologists’ reports. Dr. Allison says she starts her comments by noting the results are unusual/infrequent, and that additional testing was done per the new guideline, to explain what’s been done and how that might differ from the way similar cases were previously handled.


On to group four (clinical question No. 5). Can you bear to hear the word “equivocal” one more time?

In the 2013 guideline, these cases were breast cancer’s interminable trip on a Great Plains interstate, with their often equivocal IHC results, followed by an equivocal FISH, IHC, or both. Do we retest? Do we do alternative probes? Do we do IHC? Do we take another sample to get us out of the loop of continuous equivocal results? “It seemed endless,” Dr. Allison says.

The majority of these cases (HER2/CEP17 ratio <2.0; average HER2 copy number ≥4.0 and <6.0 signals per cell) are zero to 2+ by IHC, while 3+ cases are rare. And, as with group three, their ratio negative status meant they were not included in the original trials. Based on data from other trials, however, it doesn’t appear that this group does any worse than other HER2-negative cases that are ER positive (as most of these cases are).

Retesting these cases can feel like flipping a coin multiple times, says Dr. Allison. “And if you’re close to a threshold for a result, it’s sort of chance whether you end up one side or the other.” Yet again, the recommendation is to use IHC to help decide the final ISH result. The algorithm is similar to that used for group two. IHC 3+ is called positive, though these cases “are extraordinarily rare,” says Dr. Allison. IHC negatives are called negative, with a recommended comment about the uncertainty of benefit and chance involved in retesting results. If the 2+ result persists on recount, call it negative, with an explanatory comment. “The majority of these cases will now be considered negative,” she says.

Are you now ready to pop Champagne corks? With this now rigorously defined group, “There will be no equivocal category anymore for ISH testing,” says Dr. Allison. It’s as if the Académie Française had banned the use of a loanword.

Is this as exciting as it sounds? “It is!” she says. “I think that is one of the biggest accomplishments” of the new guideline.

“‘Equivocal’ was a troublesome word,” she says. “It implied more needed to be done. And that wasn’t always the case.” The original intent wasn’t to doggedly pursue an elusive, perhaps nonexistent truth. “It’s a gray zone, and sometimes they exist, and then difficult clinical decisions need to be made within that context. So we’re trying to disperse the gray zone a bit.”

In the meantime, she adds, “We’ll continue to collect the data, and if these results need to be fine-tuned even more, we can do that.” But for now, the rallying cry is More: more IHC, more observers, more comments.

The further good news is that these are rare groups. “Infrequently frequent,” Dr. Allison calls them. “But there should be confidence that the majority of HER2 tests are clear-cut results [groups one or five]. We’re not debating those at all.”

Other areas of the guideline didn’t require a tune-up. The authors wondered whether to re-address the matter of HER2 heterogeneity—also unusual—but decided the earlier guidance, from 2013, was still sufficient: The area of interest remains clustered areas of overexpression or gene amplification. If that’s seen, the area should be counted separately by ISH and scored separately. Scattered, intermixed heterogeneity is likely not clinically relevant and doesn’t need to be reported.

Heterogeneous cases should still be reported as amplified if they have greater than 10 percent clustered heterogeneity. “But you should include in your report the percent that’s amplified overall,” Dr. Allison says. IHC is a useful technique for discovering heterogeneity (though it’s not a requirement) because it enables pathologists to more easily see it at a lower power. “And then you’d want to score a FISH area separately in that setting.”
The other two clinical questions in the new guideline could be considered semantic as well as clinical in nature.

The first was a revision of what the 2+ by IHC category meant. Dr. Allison says the 2013 guideline suffered from a somewhat confusing definition, which was addressed in an earlier correspondence (Wolff AC, et al: Reply to E.A. Rakha, et al. J Clin Oncol. 2015;33[11]:1302–1304). In 2013, says Dr. Allison, “We didn’t mean to change the definition of 2+ from the FDA definition.” The newest guideline makes clear the same descriptors should be used. “This is not controversial—it’s just fixing the wording.”

Use of the word “must” also created confusion in the 2013 guideline, evidence that three little words—“must,” “should,” and “may”—can change the course of testing, if not romance. The context here: calling for repeat HER2 testing on surgical specimens that are initially negative on core biopsy. The 2018 guideline has been revised to say repeat testing “may” be ordered.

The 2013 guideline discussed this issue in the accompanying data supplement. “The problem with the data supplement is it’s going to be the rare aficionado who’s going to read it,” says Dr. Wolff. The discussion has now moved to the body of the document, which should draw a larger readership.
Earlier concerns about false-negatives led the authors to take a conservative approach and use the word “must.” But, says Dr. Wolff, experience shows that a negative core biopsy, if done appropriately, is likely to be negative in the surgical specimen as well.

Both these changes “were easy fixes,” says Dr. Allison. “They didn’t require a lot of discussion and had already been addressed” in the earlier correspondence.


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