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Small groups, big answers in HER2 testing

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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.”n

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

Resources are online to help laboratories implement the recommendations ( 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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