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Breast cancer answers, short and long

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Karen Titus

February 2014—When it comes to breast cancer, medical oncologists have two “wish lists” for their pathologist colleagues.

Here’s the short list of test results they need when they sit down with a patient, courtesy of Melody Cobleigh, MD. “ER, PR, HER2,” says Dr. Cobleigh, professor of medicine and the Brian Piccolo Chair for Cancer Research, Rush University Medical Center, Chicago.

It’s a direct, unassailable answer. But so, too, is saying that the assassination of the Archduke Ferdinand caused World War I.

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Dr. Matthew Ellis at Washington University’s Siteman Cancer Center: “Breast oncology is going in the direction of hematopathology, where the practitioner is an expert in pathology and molecular testing.”

And thus oncologists have a longer, more absorbing list. Not only do they want ER, PR, and HER2 results (some might be willing to trim even this lineup), but in many cases they would like guidance in how to use those results. They want new tests, such as those for Ki-67, a nuclear protein associated with cellular proliferation; PI3K (phosphatidylinositol 3-kinase) mutations; and tumor-infiltrating lymphocytes. They badly want risk stratification assays, particularly those that will guide therapies for ER-positive disease. They could use fresh input on BRCA1 and BRCA2 testing. They want to know if, when, and how to use next-generation sequencing panels.

If anyone ever thought breast cancer was a simple disease, now would be the time to abandon that ship. “Breast cancer, of all the common solid tumors, is the one that’s closest in complexity to the hematopoietic malignancies,” Matthew J. Ellis, MB, BChir, PhD, says, with good reason—it’s a stem cell disorder, just like leukemia, he notes.

That complexity expands as researchers unravel the biological mysteries of the disease, medical oncologists identify promising therapies, and pathologists respond with new assays. Along the way, medical oncologists are even seeing their roles being refashioned. “Breast oncology is going in the direction of hematopathology, where the practitioner is an expert in pathology and molecular testing,” says Dr. Ellis, director of oncology, Siteman Cancer Center, Washington University School of Medicine, St. Louis.

Amid all these changes, the goal for pathologists and medical oncologists holds steady: Pursue what looks hopeful, but not at the expense of reason.

Dr. Pusztai

Dr. Pusztai

Reason rests most comfortably with the stalwarts of cancer testing. ER, PR, and HER2 have established clinical value and “are used with very little controversy,” says Lajos Pusztai, MD, DPhil, professor of medicine, chief of breast medical oncology, and codirector, Yale Cancer Center Genetics and Genomics Program, Yale School of Medicine, New Haven, Conn.

“Very little controversy” isn’t the same as “no need to ask questions,” however. In fact, the motif of pathologist-oncologist communication is tightly woven into the recently revised ASCO/CAP HER2 testing guideline.

That might be true especially for community-based medical oncologists, who see every kind of cancer and do not have the luxury to specialize, says Dr. Pusztai. “They probably wouldn’t be able to make a living. Breast cancer is common, but it’s not that common.”

Furthermore, the amount of new information that’s been generated in the past decade on all cancers, not just breast, continues to race ahead like wildfire. “It’s practically impossible to maintain up-to-date knowledge in all the cancers that general oncologists are involved with in the community,” Dr. Pusztai says.

In academic settings, oncologists have the luxury of seeing only one type of cancer and typically meet with patients only once or twice a week, he says. “The rest of the time we give interviews,” he jokes, “and also do research, teach, and read—not counting administrative work. So to us it can seem naive when they [community oncologists] ask questions about tests and treatments, but if I put myself in their shoes, then surely I’d have the exact same problem of how to keep up with the latest and greatest.”

That makes community physicians vulnerable to two things, Dr. Pusztai says: being oversold tests that are on the market but lack solid evidence supporting their use (“They only hear upbeat stories, from people who are promoting the test,” he says), and missing out on important progress. It’s a little like adjusting a hearing aid. In one sense, they’re getting too much noise; at the same time, they might be hearing too little. How do you pick up what’s important and tune out what’s not? “I don’t know how my community colleagues solve it,” Dr. Pusztai admits.

That’s where the conversations come in, both with pathologists and fellow medical oncologists. Oftentimes a second opinion is the spur.

At Siteman Cancer Center, about half of the practice comes from community referrals, Dr. Ellis estimates. Little wonder—along with Barnes-Jewish Hospital in St. Louis, it serves a population of approximately 8 million people spread over Missouri, southern Illinois, and parts of Arkansas and Indiana. That means he and his colleagues see plenty of cases for second opinions, particularly those with equivocal HER2 results.

“In all molecular testing, we have to accept that there’s going to be gray cases,” Dr. Ellis says. Many are likely due to intratumor heterogeneity, which has triggered new thinking among oncologists about how to treat those patients, he says. Pathologists and oncologists need to look at such cases very carefully for a smattering of amplified cells, “even though when you average out the number of gene copies across 30 or 40 cells, it may be close to be labeled HER2 negative. If I have a patient with a whiff of positivity for HER2, I treat them with Herceptin,” he says. “You want to treat the HER2-positive clones, because they’re the ones that, if left untreated, are likely to drive a poor outcome.”

Dr. Ellis doesn’t blame the tests for the confusion. And while he’s a fan of guidelines in general, “There’s some complexity related to tumor biology and somatogenetics that’s going to be hard to address in a guideline.” That’s why, he says, “in the end there’s no substitute for working with a pathologist in borderline cases, and looking at the individual cells, and trying to work out what the basis of the borderline status is. Are they all cells with borderline amplification and some expression of HER2? Or is it a case where there are mostly negative cells but nests of clearly positive cells? I address each one of these cases with my pathologists, asking those very questions.”

“In the end, there’s no substitute for working with a pathologist,” he adds.
As another example of the type of case where medical oncologists could use guidance, Dr. Cobleigh points to a strongly ER-positive, classical lobular carcinoma that’s also HER2 positive. “You’d wonder about that,” she says. “Oftentimes when you look into it it turns out to be true, because the tumor didn’t read the textbook.”

Dr. Hicks

Dr. Hicks

David Hicks, MD, also feels the pain of the community oncologist. “With merger mania and accountable care networks, I’m dealing more and more with community oncologists who see multiple areas [of cancer]. For the most part, they are extremely grateful if a pathologist is willing to get on the phone and talk to them and clarify things,” he says, recounting a recent 20-minute conversation with an oncologist faced with a complex case. “At the end of it, I ended up sending him a PDF of the [HER2] guideline.”

Even the breast specialists where he practices need input and interpretation, says Dr. Hicks, professor of pathology and laboratory medicine, and director of surgical pathology, University of Rochester (NY) Medical Center. And though Dr. Hicks says his department chair is fond of reminding him these discussions aren’t reimbursable, he calls them “the best part of my job.”
Tumor boards can be an excellent way for pathologists to have those conversations, though Dr. Hicks concedes it can be intimidating for general pathologists to speak with confidence on every case. “Some of these breast-related issues get complicated quickly.” He points to the CAP’s

Multidisciplinary Breast Pathology AP3 program as one source of helpful information; the live workshops (there’s an online component too) might be especially useful, he says. Likewise, the College is developing PowerPoint presentations that would enable pathologists to present the ASCO/CAP HER2 guideline at tumor boards.

R and HER2 appear to be the divas here, with PR a mere supernumerary.
That’s not quite the case, says Dr. Pusztai, who calls PR a “minor” good prognostic marker. If a tumor is ER or PR positive (both are referred to under the umbrella term “hormone receptor positive cancers”), it should be treated with antiestrogen therapy. Tumors that are ER and PR positive do better than those that are ER positive/PR negative, but PR alone may be sufficient to confer some sensitivity to antiestrogen therapy, he says. And the very few cases that are PR positive but ER negative remain candidates for endocrine antiestrogen therapy. Moreover, oncologists find it helpful to know percent positivity when PR (and ER) results are reported.

Recent data suggest that PR status may be even more prognostic than ER and is independently associated with clinical outcome, says Dr. Hicks, though the two receptors are linked biologically. Expression of the PR gene is regulated by ER and usually is detected in tumor cells with an activated ER signaling pathway, he explains. The loss of PR expression in ER-positive tumors, on the other hand, “correlates with an increased likelihood of having a high recurrence score” on the Oncotype DX breast cancer assay.

Clinical trial data haven’t shown whether ER-positive/PR-negative tumors should be treated differently, in terms of endocrine therapy, compared with ER- and PR-positive tumors, he continues. “While both groups appear to benefit from some form of endocrine therapy, some medical oncologists will be more likely to include chemotherapy in the adjuvant treatment regimen for the ER-positive/PR-negative subset of patients, given the influence of this phenotype on prognosis,” he says. Current recommendations continue to call for PR analysis alongside ER analysis, he adds.

Not everyone is equally sold on the value of PR testing. Dr. Ellis, for one, is not a huge fan. “I don’t find PR testing is all that helpful,” he says. “It adds quite a lot of confusion in the field.”

PR testing, he says, hasn’t kept pace with the advances in ER testing, suggesting that the antibodies aren’t as good as those used for ER. “I think one of the more complex areas is, what does PR positivity mean in the setting of an ER-negative tumor?” Dr. Ellis says. He also notes that some basal-like breast cancers will express low levels of PR—“in the order of Allred score three, four, five range. I don’t think that that means those tumors should be treated with endocrine therapy. But the persistence of PR testing might lead to some degree of endocrine therapy overtreatment,” he suggests.

He holds no such reservations about ER testing, though he notes that recent efforts to increase the sensitivity of ER tests have created some controversy as well—what percent of cells staining positive for ER should be considered a positive result? “One percent sounds crazy, and maybe it is,” says Dr. Ellis. Nonetheless, he continues, several retrospective studies have shown that such low positivity can predict benefits from endocrine therapy, and he joins Dr. Pusztai in calling on pathologists to report on percent positivity.

Dr. Ellis has a few other thoughts about what oncologists don’t want. “Obviously I read a lot of path reports, and most breast oncologists think they’re unnecessarily complex, with a lot of descriptive terms which are not helpful for clinical practice,” he says. “Essentially what we’re looking for is the histological type and grade.” Specialists also find it helpful to know what grading system was used and the components of the grade, not just the overall grade itself.

If it’s a primary breast cancer, “obviously we want the size of the tumor and involvement of the lymph nodes,” he continues. At this point, there is no recommendation to do special staining on lymph nodes, so oncologists are looking for H&E-evident lymph node metastases. But this can be controversial, Dr. Ellis says, “because some labs persist in using cytokeratin staining on lymph nodes, when it’s been shown not to be helpful in clinical practice.”

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