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Cracking the many mysteries of HER2 GEA

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Karen Titus

January 2017—Only a sadist would want to see gastroesophageal adenocarcinoma become as common as breast cancer. GEA wreaks enough destruction already as the fifth (stomach) and eighth (esophageal) most common cancers worldwide.

Dr. Angela Bartley, lead author of the HER2 GEA guideline, says she and colleagues concluded from a review of the literature that  using biopsy or resection specimens for testing is acceptable. “And if these two are not available, an FNA specimen can be used from the primary or metastatic tumor.”

Dr. Angela Bartley, lead author of the HER2 GEA guideline, says she and colleagues concluded from a review of the literature that using biopsy or resection specimens for testing is acceptable. “And if these two are not available, an FNA specimen can be used from the primary or metastatic tumor.”

“It will never be as common as breast cancer—well, I hope it will never be as common as breast cancer is now,” says Mary Kay Washington, MD, PhD, co-chair and coauthor of a new CAP/ASCP/ASCO guideline on HER2 testing in GEA.

Nevertheless, it’s nearly impossible to consider the role of HER2 in GEA without thinking about breast cancer—not with envy, surely, but with an odd covetousness, knowing that accompanying breast cancer’s many more cases are many more studies, and, as a result, much deeper knowledge of how and when to test for the biomarker. With GEA, many mysteries still linger.

But now when pathologists and their clinical colleagues assess HER2 in patients with GEA, they will be better prepared for what they see and how to respond. The new guideline (Bartley AN, et al. Arch Pathol Lab Med. 2016;140[12]:1345–1363) should, say its three co-chairs, be useful to general pathologists as well as those with GI expertise, and to medical oncologists in community and academic settings.

Whatever information had been available to physicians was fragmented, scattered throughout the literature. “This guideline brings everything together,” says Jaffer Ajani, MD, guideline co-chair (representing the American Society of Clinical Oncology) and coauthor.

Many physicians “don’t know a whole lot about this subject as individuals,” continues Dr. Ajani, professor of medicine, and member, Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston. “Their experiences are based on their work in breast cancer and the literature on breast cancer.”

Until recently, the most widely  understood piece of knowledge about HER2 testing in GEA could fill a shot glass: It is the only biomarker established for selecting trastuzumab (Herceptin) to treat advanced GEA.

But then what? For clinicians in particular, “We’re always wondering, should we get a biopsy from a metastatic site, or get a lymph node, or should we go to the primary? This has not been clear,” Dr. Ajani says.

Angela Bartley, MD, another co-chair (representing the CAP) and lead author, adds other questions. Should labs perform immunohistochemistry and in situ hybridization simultaneously? Should pathologists use specific antibodies or probes? When validating a test, how many specimens should be used? Can they be breast specimens, or must they be GEA specimens?

And on the most basic level, “Who should be tested?” asks Dr. Washington (American Society for Clinical Pathology co-chair), professor of pathology, Vanderbilt University Medical Center, Nashville, Tenn.

For some, the answer to that last question is nothing short of critical. It’s no secret that GEA has a poor prognosis, with disease often diagnosed at an advanced stage. As the guideline’s authors note, at this point in a patient’s status—unresectable local-regional, recurrent, or metastatic disease—therapies are limited.

The well-known Trastuzumab for Gastric Cancer Trial (ToGA) stirred a vigorous dash of hope into matters, showing that Herceptin prolonged overall survival compared with chemotherapy-only regimens in those with HER2-positive advanced GEA. Those with IHC scores of 3+ experienced more benefit than those with IHC of 2+ (and concurrent HER2 ISH amplification).

A trio of recommendations from the new guideline reinforce the clinical implications of the ToGA trial. Treating physicians should request HER2 testing on tumor tissue for patients with advanced GEA who are good candidates for combination chemotherapy plus trastuzumab. “It’s kind of a simple recommendation,” says Dr. Bartley—but an important one. Physicians can also banish concerns about trastuzumab’s side effects, the guideline notes. In the ToGA trial, the adverse cardiac event rate was six percent and did not differ between the treatment groups. Patients who received Herceptin had slightly higher rates of other events (including diarrhea, anemia, thrombocytopenia, fatigue) though frequency of side effects was the same.

The question most pressing to Dr. Ajani and fellow clinicians was, what sort of specimen should be tested? “We went through and exhaustively looked at the literature, and determined that using biopsy or resection specimens is acceptable,” says Dr. Bartley, who is the division chair of pathology and laboratory medicine, section head of molecular diagnostics, and gastrointestinal pathologist, St. Joseph Mercy Hospital, Ann Arbor, Mich. “And if those two are not available, an FNA specimen can be used from the primary or metastatic tumor.” A (limited) number of studies suggest a fair amount of concordance between primary and metastatic tumors, she says.

It’s worth noting that resections aren’t always available in GEA cases, though hopes had been high for using this type of material. The thinking was that since gastroesophageal tumors have great heterogeneity compared with breast, says Dr. Bartley, resection specimens would be better in GEA testing, “because we’d have more neoplastic tissue to evaluate.” As it turns out, “The biopsy specimens correlate pretty well with resection specimens.” Since biopsies are more readily available, this is good news.

That’s not to say doing a biopsy guarantees adequate material. “It’s absolutely imperative that you talk to your gastroenterologists or surgeons to get an adequate specimen,” Dr. Bartley says. “The chance of that occurring is, obviously, higher if you communicate with them than if you don’t.” The new guideline doesn’t provide a recommendation but notes that one study recommends testing at least five biopsy fragments of tumor, and the National Comprehensive Cancer Network and other guidelines recommend six to eight. Ideally, she says, clinicians are reading the same guidelines as pathologists and are familiar with these optimal numbers. “But it doesn’t always happen,” she concedes. “Not every institution has a GI advisory board.” (Hers does.)

As the guideline moves to pathology-specific recommendations, including the testing algorithm itself, a theme emerges. Were Chicago Cubs manager Joe Maddon to turn it into a slogan for one of his infamous T-shirts, it might read, “Try not to miss.”

The best way to identify patients who are likely to benefit from trastuzumab is to perform IHC testing first, followed by ISH when IHC results are 2+, or equivocal. “If the IHC is 0, 1+, or 3+, you’re done,” Dr. Washington says.

But recalling the early, unsettled days of qualifying breast cancer patients for Herceptin, when there was pressure to test by all possible means, this straightforward approach for GEA might create flickers of doubt for some. Why not test every specimen using IHC and ISH, just to be sure?

Today, there’s no shortage of data on qualifying breast cancer patients, but the GEA data are less plenteous. The authors had two randomized controlled trials on which to base their algorithm recommendation. That could sow uncertainty: “Some people are thinking, ‘Oh, you’re going to miss people who would be candidates for trastuzumab if you don’t do concurrent IHC and ISH,’” Dr. Bartley says. Especially since there’s evidence—though there’s contradictory data as well—to suggest some negative IHC samples might be positive on ISH.

Based on the ToGA trial, however, it appears that those who were negative by IHC, i.e. 0 or 1+, did not respond to trastuzumab even if they were ISH amplified. “So that’s why for now we’re recommending that people do IHC first, and then do ISH only in examples of 2+/equivocal cases of IHC,” Dr. Bartley says.

It’s hardly a secret that laws often are created in response to what’s happening (as well as to what some fear might happen). And while a practice guideline is hardly law, it’s fair to assume that at least a small percentage of laboratories are performing IHC and ISH on all specimens, rather than waiting to do the latter only on 2+/equivocal specimens.

At Dr. Bartley’s institution, pathologists follow the new guideline “to the letter,” she says. This includes doing IHC first, on all specimens, and following up with ISH on 2+ specimens.

The clinicians cede GEA HER2 testing decisions to the pathologists. That’s put her and her colleagues in the unusual position of not having to communicate closely with clinicians. “I can honestly say I have never had a call from a clinician questioning a result or asking if we should do something else.” Lest some poor business consultant’s head implode at this revelation, she adds, “It’s probably the only testing situation I can think of that clinicians don’t call us and say, ‘Hey, what’s going on with this?’ ”

Some physicians might have hoped the guideline would “do more,” as Dr. Washington puts it. “We know,” she says, “that there were advocates for doing FISH on everything, along with IHC. But I think overall, when you look at the data, most people were happy to accept the final guideline.”

Reflex testing for every patient with esophageal, gastroesophageal junction, or gastric adenocarcinoma is not recommended. “Many of those patients are not recommended for HER2-targeted therapy,” Dr. Washington says. The guideline gives physicians leeway in deciding how and when to test.

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