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Small groups, big answers in HER2 testing

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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.

As she puts the guideline into clinical practice at Stanford, Dr. Allison says she’s revising reporting templates and meeting with colleagues in the cytogenetics lab. “And then it’s a little more complicated reporting for these rare cases, because you’re folding in another test to your final result.”

On a practical level, such testing might already be happening, in a hidden-part-of-the-iceberg sort of way. “I think a lot of ISH labs already did this in the background, without reporting it,” she suggests. She plans to include the IHC findings for cases in the unusual results categories, although the guideline does not make this a requirement. By showing how she arrived at the final result, “Everybody understands what your workup is,” she says.

“In our reporting we want to reflect the additional workup and that some of these result categories are unusual,” Dr. Allison says. That makes for a more complex report, with an additional result in some cases, and more comments.

Based on the group’s discussions, she’s confident that clinicians will find this useful. “They didn’t like treating the group-two cases that had ratio positive but really low signals per cell, usually IHC negative,” she says. These were more often low-grade cancers, more often in older patients. “You don’t want to treat a low-grade biology with chemotherapy plus Herceptin if it’s unclear there’s going to be benefit. Potentially you’re harming them.”
On the other hand, they like the idea of giving the benefit of the doubt to ISH group three, IHC 2+ and 3+ cases, she says, since these appear to be more aggressive cancers.

And for patients, it should help alleviate the angst that often accompanies an equivocal result. While it will mean fewer patients will be considered HER2 positive, it also means nonaggressive cases won’t be overtreated. And more aggressive cases will be treated accordingly.

“Everybody should be happy there’s no equivocal anymore,” she says.

Dr. Wolff

Dr. Wolff

Dr. Wolff agrees the added information in the reports will likely be helpful, especially for medical oncologists who aren’t breast specialists. Faced with unusual results groups, “they need even more guidance from the pathologist about whether the patient is likely to benefit from HER2-targeted therapy.”
A bit facetiously, Dr. Wolff says that as the guideline is refined, “The best situation is you don’t need to talk to anybody, right?” He laughs. “You can simply get on with the job you need to do, comfortable with the information you have and that everything is working well.” Indeed, if the test is done optimally each and every time, “then to a degree the system is working”—the goal of that first joint guideline. “We would expect actually a lesser need for oncologists to pick up the phone and call the pathologist. The number of times there’s a difficult case, that emails will be flying back and forth between oncologists and pathologists, or among oncologists at different institutions, asking for help on how to deal with these more complex cases—I think we’re going to make things a lot easier for everybody.”

The equivocal category, he says, was in the beginning viewed as a tool to increase communication, to alert pathologists to the need for additional testing. “But what we realized after the fact is we were being left with an occasional case that the pathologist wasn’t able to resolve.”

Searching for answers, pathologists would then perform additional tests, hoping to get an answer. The test of choice: alternative probes. “When you do that, especially when you are close to the line of positive/negative, it doesn’t take much for a single test by chance alone to give you an answer that is different from the one before.” And by default, that testing population was enriched for more complex cases. Using an aphorism he favors, he says, “Multiple equivocals do not add up to a positive.” It’s simply a positive by chance, which meant uncertain oncologists ran the risk of treating even triple-negative patients with HER2-targeted therapy.

There was debate about how much to focus on single-probe versus dual-probe assays. Since the guideline doesn’t recommend the use of single-probe assays, the authors wanted to minimize discussion. One-probe assays appear to be heading the way of the checkbook; dual-probe assays might be useful for labs that have limited resources.

The new guideline, says Dr. Wolff, strongly discourages the routine use of alternative probes. Some expert labs will continue to use them on very difficult cases, he acknowledges. “But in that case these labs are likely to be the exception, not the norm, and they’re going to report more carefully, which is going to hopefully curtail the epidemic of alternative probe testing that occurred after 2013, which was really not our intention—was truly kind of an unintended consequence of how some labs interpreted what to do.”

Not to be overlooked is the reminder that regardless of the HER2 testing result, anatomic pathology still rides shotgun. The authors emphasized this point in 2013, and Dr. Allison says it remains important. No one should look at a case strictly through the HER2 peephole. “If you’re resulting a grade-one cancer as HER2 positive, you need to stop and rework your case,” is how she puts it. “A pure mucinous carcinoma shouldn’t be HER2 positive.

“You should still be a responsible pathologist,” she says.

In the meantime, as new HER2-targeted therapies are developed, HER2 testing will continue to be the standard to qualify patients for these drugs, says Dr. Allison. “You want the HER2 testing to be able to apply to all HER2-targeted therapies. I don’t think we’re going to be revising the way we test based on just more drugs on the market.”

There may be a role for add-on tests based on certain combinations of therapies. And HER2 testing will remain crucial as medical oncologists explore deescalation and other approaches. “We now can begin to explore additional biomarkers that can help identify what we believe is a group of patients who appear to have disease that is exquisitely sensitive to HER2-targeting manipulations,” she says. “At the end of the day, having very tight assays for HER2 assessment allows us to test all of these strategies going forward. It’s a big deal.”

But for now, HER2 serum testing and gene expression arrays—to name just two possibilities—are more promise than product.

This is not a disappointment. Dr. Allison calls it “comforting to know we’ve come such a long way and standardized this HER2 testing really well. We don’t want to throw that by the wayside.

“It’s an amazing story, actually,” she continues. It’s good, she says, to be reminded of that first burst of glory—the light hasn’t dimmed. She still recalls the excitement of having a test that qualified patients for a targeted therapy, and the many steps along the way to make the process even better, including multiple guidelines. “It’s nice to see we’re really at the point of fine-tuning rather than reworking the whole system over and over.”

Karen Titus is CAP TODAY contributing editor and co-managing editor.

Resources are online to help laboratories implement the recommendations (http://bit.ly/cap-asco-her2). In addition, the 2018 Laboratory Accreditation Program checklists (anatomic pathology, cytogenetics, molecular pathology), to be released in August, will contain the guideline updates, as will the breast biomarker reporting template.

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