Second act for HER2, in gastric cancers

In fact, says Dr. Streutker, that group actually did worse in the ToGA trial. “But it’s such a small group,” the implications are hard to assess. (Researchers are now revisiting the data from breast cancer studies, Dr. Whitney-Miller says, and early reports suggest this might be the case for breast cancer as well.)

Some clinicians may look at discrepant cases and suggest the IHC failed in some way. “We don’t have a lot of those cases, but I see no reason we should doubt ourselves,” assuming the test was done carefully, says Dr. Streutker. “Why can’t there be a genetic problem where there’s something wrong with the protein, so that it doesn’t get to the membrane?” Or, she says perhaps rare cases that are IHC 3+ and ISH negative might be caused by increased gene transcription—the result of a promoter that’s been turned on, say—rather than by an increase in copy numbers. And that doesn’t even take into account issues associated with chromosome 17 polysomy, which in breast has emerged as a controversial and important area of discussion, she says. In short, this dissonance may not be a lab problem, but rather an unanswered question, at least for the time being.

Not that there aren’t other lab challenges.

One of the biggest ones, says Dr. Whitney-Miller, is that in breast cancer, the emphasis is on complete membrane staining and obvious circumferential distribution. Gastric cancer, on the other hand, frequently has an intestinal phenotype, as noted. Such cases may show only basolateral or even lateral staining. “When you FISH those cases, they’re amplified.”

Heterogeneity also rears its head in GI cases, which seem to have more heterogeneous HER2 overexpression than in breast cases (though Dr. Hicks suggests “it’s probably more common than we thought” in breast cancer). That can make things tricky. As Rüschoff, et al., found, cell clusters of ≥ 5 cohesive stained tumor cells must have a moderate-strong complete, basolateral, or lateral membrane reactivity, says Dr. Whitney-Miller. But those cells may not account for 10 percent of the total cellularity.

While in Germany, Dr. Streutker noticed that the breast pathologists struggled with the lower thresholds used for GI cancers. They appeared to have an easier time accepting that GI samples didn’t require complete membrane staining or circumferential distribution. “But the patchiness, I think, was very unnerving to people who focused on breast.” (See Fig.3, page 40.)

Adequate sampling has posed issues for pathologists doing GI HER2 reads. Typically they work with tiny endoscopic mucosal biopsies, which have sufficient tissue to identify presence of a malignancy. But is it enough to rule out HER2-positive disease? Given the issue of intertumoral heterogeneity, it probably isn’t. “If the mucosal biopsy is negative, I don’t think you’ve excluded a HER2-driven gastric cancer,” says Dr. Hicks.

The Canadians have emphasized the need for adequate sampling. Dr. Streutker says she tells her clinical colleagues, “The more the better. I’ve had a few cases sent in for testing where the tumor’s gone.” While she concedes that many of her colleagues are trying valiantly and supplying her with multiple biopsies, there may be tumor in only one specimen. “Honestly, they need to biopsy the heck out of these things.”

The message is clear: “If you’re suspicious of gastric cancer, get as much tissue as possible,” says Dr. Hsieh. Ideally, they’d like to see six to eight pieces, though they concede this can be difficult to obtain. Many are willing to do so when asked. Says Dr. Hsieh: “Generally, the endoscopists we have interacted with are quite receptive. However, it may be more difficult to reach endoscopists who primarily scope at the private clinics.”

Dr. Hezel agrees, adding that he and his medical oncologist colleagues are well aware that pathologists need sufficient, high-quality samples to work with. “A clear test result is of such significance that I think most oncologists would consider getting more tissue—redoing a biopsy—if asked,” he says.

Dr. Hsieh says he needed to correct pathologists’ misperception that it’s preferable to work with a larger, resection specimen, which meant some pathologists didn’t bother sending biopsy material. “But the patient might not even get a resection. They might wait until they die of the disease. And we know from the original studies that biopsies are good, and biopsies do not decrease the rate of detection of HER2 positivity,” Dr. Hsieh says. Even if a resection is done, it may be months later—again, time that most gastric cancer patients can’t afford to squander.

Dr. Streutker notes that the advent of GI HER2 testing is also calling long-held lab logistics into question. “People obsess about breast,” she says, noting concern about ischemic time and the need to cut breast specimens quickly. “And then the stomach sits there marinating in its own acid.” If biopsies were always available, the issue might be moot. But that’s not the case, and both she and Dr. Hsieh suggest that as personalized testing expands, pathologists will need to more carefully consider how all specimens, not just breast, are fixed.

Not everything boils down to a difference. In breast cancer, Herceptin was first shown to benefit those with metastatic disease; when clinical trials moved to an earlier stage, it became evident that Herceptin was beneficial in the adjuvant setting. “I think we’re going to see a similar evolution in gastric cancer,” Dr. Hicks says.

Most obviously, oncologists with GI patients want the same thing breast experts do when it comes to results: a clear, yes-no answer that will help them decide the next step in the patient’s care, says Dr. Hezel. “Most medical oncologists who are not molecular characterization gurus simply want to know if there’s enough strong evidence to act.”

Despite their long history of interpreting HER2 testing, breast pathologists are unlikely to take over GI cases completely. But given GI cancer’s relatively low numbers (some 21,000 new cases are diagnosed each year in the United States), it won’t be easy for every lab to develop GI HER2 expertise.

Cancer Care Ontario’s recommendations include a statement that those who interpret gastric HER2 need a “fair amount” of GI knowledge, says Dr. Hsieh. “Not necessarily be a specific GI pathologist, but have spent sufficient time training specifically in GI HER2 interpretation.” It’s a commonsense approach, he adds. “But that’s not something that always happens at all institutions.”

GI HER2 is not as easy as it looks, says Dr. Streutker. “It’s a fussy enough test that people should only do it if they do it quite a bit. People should be looking at at least 100 cases a year—even if you’re not signing out 100 cases—to stay good at it.”

Alternatively, Dr. Hsieh suggests that an institution have a “good three-digit number,” with frequent internal consultations within the department. “We’ve been telling our colleagues at other institutions to think of it as a new test. Don’t think of it as HER2; think of it as gastric HER2, which is a separate test,” he says.

But not every institution has its own GI specialists. CCO made a conscious decision to limit the number of sites where GI HER2 testing would be done; given the lower number of cases, the intent was to make sure those reading it would be able to maintain their expertise.

GI and breast pathologists are working more closely together at Rochester, a fact Dr. Hezel appreciates. “It’s helpful to have both groups provide reference and be open to help with interpretation,” he says.

Dr. Hicks says that while GI pathology is not part of his practice, it’s become part of his career. “I will still be brought a slide [by a GI colleague] and asked, ‘What do you think of this?’” And while the GI pathologists do the IHC and then decide if FISH is needed, the FISH itself is done by the breast experts. So even the technical staff, who are more familiar with breast cancer, have had to adapt to doing gastric samples. “The techs all say gastric’s a lot tougher to read and score than breast is,” he says. Challenges include finding the right area to examine and distinguishing inflammatory infiltrate from tumor cells. One approach advocated by both Drs. Hsieh and Hicks is to use the light microscope to look at the morphology before ISH is done.

At Sunnybrook, notes Dr. Hsieh, the ISH for GI cases is read by a GI pathologist. His lab also does SISH (silver ISH), which is used for the majority of cases. FISH (also read by the pathologist) is used as a backup. At St. Michael’s, DISH (dual color ISH) is used.

Each method has its own peculiarities, he says. With FISH, “It’s hard to know where you are on the slide, in my opinion. So if you use FISH, it’s often quite helpful to have a good idea in your mind what the regular histology slide looks like in advance to help orient you.” With SISH and DISH, which are both brightfield methods, it’s easier to recognize the structures, he says.

Like a mini-lesson in relativity, GI HER2 testing also challenges notions of time.

On the one hand, though it may be a hoary saying, time is of the essence.
For patients whose life expectancy is a mere six months, “Spending three or four weeks mucking about to get the [HER2] test is unfair,” says Dr. Streutker. She sees oncologists who are frustrated by having to wait for the test. “If we’re going to do this test, we need to have it ready for the oncologists. It needs to be a reflex.”

Indeed, says Dr. Hsieh, medical oncologists, who’ve been at the vanguard of this testing, express virtually no questions or confusion about the testing, other than, How can we get labs to do the testing as early as possible?

On the other hand, despite that enthusiasm, labs should be cautious about rushing into GI HER2 testing, says Dr. Hsieh. Move too fast, he says, and labs could easily run into some of the same problems they ran into during the early days of breast HER2 testing, including so-called scoring drift. Labs need to think hard about whether it makes sense for them to offer testing.

For those who decide to offer it, Drs. Streutker and Hsieh have one final piece of advice, which will no doubt resonate with fans of the old TV police drama “Hill Street Blues.”

Says Dr. Streutker: “Be careful out there.”

Adds Dr. Hsieh with a laugh: “Yes. That’s the best way to put it—be careful.”

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