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Small groups, big answers in HER2 testing

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Karen Titus

July 2018—Breast cancer has a way of deflating conventional wisdom:

  • Maybe it’s not about the journey.
  • Maybe more is better.
  • Maybe communication is overrated.

Take the new ASCO/CAP guideline for HER2 testing (Wolff AC, et al. Arch Pathol Lab Med. Epub ahead of print May 30, 2018. doi:10.5858/arpa.2018-0902-SA). Since the first groundbreaking joint guideline appeared 11 years ago, the authors have made a habit of addressing cases that flummox pathologists, medical oncologists, and patients. Now, in 2018, they have clarified the diagnostic approach to in situ hybridization groups two, three, and four, rare cases that nonetheless cause an outsized share of headaches and worries. It also clarifies language from the 2013 guideline that had sent some labs astray, and it addresses the use of multiple alternative chromosome 17 probe assays.

As Dr. Kimberly Allison puts the new HER2 guideline into practice at Stanford, she’s revising reporting templates and meeting with colleagues in the cytogenetics lab. “In our reporting,” she says, “we want to reflect the additional workup and that some of these result categories are unusual.” [Photo: Cindy Charles]

As Dr. Kimberly Allison puts the new HER2 guideline into practice at Stanford, she’s revising reporting templates and meeting with colleagues in the cytogenetics lab. “In our reporting,” she says, “we want to reflect the additional workup and that some of these result categories are unusual.” [Photo: Cindy Charles]

The previous guidelines turned out to be tough acts to follow—a bit like following Sean Connery in the role of James Bond—even as the new one benefits from new data. The first one plunged into the brave new world of companion diagnostics and marked the first time the CAP and ASCO joined forces on a guideline, recognizing the need for both specialties to partner on a systems level as well as in routine clinical practice, says lead author Antonio Wolff, MD, professor of oncology, Breast and Ovarian Cancer Program, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, and member, Miller Coulson Academy of Clinical Excellence at Johns Hopkins.

As the guidelines evolved, from 2007 to 2013 and now most recently, “We have learned a lot more about how HER2 testing happens in daily practice,” says Dr. Wolff, who, along with coauthor Elizabeth Hammond, MD (respectively, the lead oncologist and lead pathologist authors on all three guidelines), spearheaded the first document. That, in turn, enabled the current guideline’s authors to refine their focus.

Did someone say Daniel Craig?

Because of the broad reach of earlier documents, the authors wanted to present not only updates—obviously part and parcel of any revised guideline—but also a clear overview of the topic. They did so in the summary tables and with comprehensive figures. “We didn’t just want to say, ‘This is what we changed from last time—read the old document again,’” says coauthor Kimberly Allison, MD, professor of pathology, director of pathology residency training, and director of breast pathology and breast pathology fellowship, Stanford University School of Medicine. “We’re building on too many different things.” Dr. Allison became involved at the tail end of the 2013 update, initially in the role of patient advocate (she notes she was treated for HER2-positive breast cancer in 2008); she’s subsequently been involved because of her professional expertise.

In that sense, the guideline emphasizes what hasn’t changed. “Table 1 is an important read,” Dr. Allison says, “because it has all that laid out,” showing the summary of all recommendations, both the original and focused updates. Moreover, a number of the figures sketch out diagnostic testing algorithms, “which have become somewhat complicated for certain groups of FISH testing.”

The guideline could be summarized in the vein of the oft-recited political poem (albeit with a much happier result):

First they came for the false-positives,
Then they came for the false-negatives,
Now they come for the unusual results cases.

With the first guideline, says Dr. Wolff, “Our main concern was about an excessive number of false-positive test results,” which had become apparent with the enrollment of patients in the first generation of adjuvant trials in HER2-positive disease. Rates ran between 25 and 30 percent. “We were in that moment concerned about the need to improve specificity.”

Having succeeded in reducing the frequency of such results, “We then wanted to make sure we were not potentially missing false-negatives,” he says. The swinging pendulum—between false-positives and false-negatives, specificity and sensitivity—explains the focus the authors took with the 2013 guideline in handling difficult cases. False-negative results were estimated by some to be as high as 10 percent, though the actual frequency was difficult to estimate because only the positive cases were being submitted for central test confirmation.

Laboratories have made significant strides, particularly with preanalytical (care of specimens) and analytical (assay standardization) issues. At this point, “We may have succeeded in improving the accuracy of HER2 testing to above 95 percent,” Dr. Wolff says.
Now, in 2018, the focus has shifted once again, as more information has emerged about less common types of HER2 test results, as seen in dual-probe in situ hybridization (ISH) groups two, three, and four.

“We also began to realize that some labs were misinterpreting some of the recommendations from 2013,” he says. The most obvious example involved cases of reference labs that performed only in situ hybridization. When some of those results were initially inconclusive, labs might re-test with up to five alternative chromosome 17 probes, leading to a significant concern about false-positives, says Dr. Wolff.


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