Breast cancer answers, short and long

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.

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.

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.”

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.”

Dr. Cobleigh says it’s a smart move for pathologists to turn to the ASCO/CAP guidelines for HER2 and ER/PgR testing. “They’ve gone a long way toward making testing better, not just in terms of the stains themselves but the preanalytic and postanalytic issues that they’ve identified,” she says. “And now you see path reports that have that synoptic reporting on them and say what antibody they used, how long the tissue was fixed, what it was fixed in, etc., etc. I think it has been a real service to women with breast cancer.”

Medical oncologists are highly attuned to new therapies, like sailors watching for favorable winds. Innovative ways of looking at ER and HER2 results could help them set a new course.
Call them emerging tests, which have a proven record in the literature but lack well-defined clinical value. Nevertheless, says Dr. Pusztai, they’ll likely become important in the next several years. This includes tests for predicting late recurrence, particularly in ER-positive cancer, a scenario that’s creeping into medical oncologists’ awareness. “These tests are about to break,” says Dr. Pusztai.

Until recently oncologists focused on early recurrences, assuming that if a cancer hadn’t reappeared in a patient within the first five years of diagnosis, the patient had the all-clear sign. “But unfortunately that’s not the case,” Dr. Pusztai says.

At the same time, it’s becoming clear that some patients with ER-positive tumors benefit from extended hormonal therapy—10 years instead of the five years typically recommended now. That’s created the need for, and the appearance of, a new generation of tests that will identify those who are cancer-free at five years but remain at risk for recurrence in the next five years, and thus would benefit from extended adjuvant therapy. “That’s going to be the next growth area of prognostic prediction in breast oncology,” Dr. Pusztai predicts.

Estrogen receptor mutations appear to be relatively common in the endocrine therapy refractory group, says Dr. Ellis. The mutations, naturally, will also be eligibility criteria for clinical trials of drugs that inhibit ER despite the presence of mutation or perhaps inhibit the functions of ER downstream from the receptor. These studies aren’t in a dreamed-of future; they’re set to begin this year, says Dr. Ellis.

HER2 is also disproving the idea that there are no second acts in life.

Dr. Hicks foresees a time in the not-too-distant future when new drugs will become FDA approved on an accelerated basis. Case in point: pertuzumab (Perjeta; Genentech), a HER2-targeted therapy that was rapidly approved last fall based on a neoadjuvant study. “We now know that a complete pathologic response is a great surrogate for a good outcome and a good prognosis,” he says.

That can only up the ante for HER2 testing, as oncologists look to other promising HER2-targeted drugs, such as T-DM1, also known as trastuzumab emtansine, a conjugate of Herceptin and a chemotherapeutic agent that appears to be remarkably effective in patients whose tumors are HER2 positive and who have become resistant to Herceptin. Dr. Ellis is involved in a phase two clinical trial of a HER2-directed kinase inhibitor in HER2-mutant breast cancer, as some HER2 nonamplified tumors rarely have activating mutations that can be targeted with a tyrosine kinase inhibitor. Even further down the road, medical oncologists look to combine HER2-targeted biologic agents and dodge the troubling toxicities of chemotherapy. In fact, medical oncologists appear to spend as much time trying to avoid inappropriate treatments as they do finding the right ones.

Dr. Ellis and his colleagues are also wrestling with the issue of rebiopsying metastatic disease. For most oncologists, he says, the practice still is to treat patients on the basis of the original pathology report. “But our work and many other people’s work have clearly shown that metastatic disease has a different molecular profile.” One study, from the Karolinska Institute, near Stockholm, has shown that at relapse, about 15 percent of patients switch from being ER positive to ER negative; a smaller number shift in the opposite direction. HER2 status also appears to be unstable, and in about five percent of cases, says Dr. Ellis, patients with HER-negative primary tumors who relapse have HER-positive metastases. That one in 20 incidence is definitely worth testing for, he adds, because of the dramatic benefits of HER2-directed therapy in the advanced disease setting.

Tumors are constantly evolving, a fact dramatically shown in recent work Dr. Ellis and colleagues have done on HER2 mutation, translocation, and amplification. “A hormone-receptor–positive tumor will evade endocrine therapy by mutating the estrogen receptor to generate constitutively active mutants,” he says. “We’re trying to figure out what that means therapeutically.”

Long term, work such as this suggests to Dr. Ellis that patients will be tested not only at diagnosis, but once or even more upon relapse, to guide medical oncologists in the best therapeutic approach.

Medical oncologists aren’t content to stick only with ER, PR, and HER2.

Dr. Pusztai, for example, champions Ki-67. High Ki-67 is linked with high risk of recurrence in ER-positive cancers and is associated with greater responsiveness to chemotherapy.
Dr. Ellis is also a fan of Ki-67 to help determine a tumor’s aggressiveness, an area that has traditionally been most useful in the hormone-receptor–positive, HER2-negative subset of tumors, which have a broad range of cell growth rates. “There’s no question Ki-67 assessment is high in prognostic value,” he says.

But Ki-67 test results are as fickle as an undergrad’s major. “What is high varies from lab to lab and person to person,” says Dr. Pusztai, a point he says was reinforced by a presentation at the San Antonio Breast Cancer Symposium in December, which showed large discordance in how labs assign Ki-67 results. He sounds almost desperate for pathologists (specifically the CAP) to standardize Ki-67 tests, “the same way they have made very good progress in standardizing progesterone, estrogen, and HER2 measurements.” If Ki-67 immunohistochemistry could safely be added to ER/PR/HER2 testing, turning the trio into a quartet, physicians would have good, accurate risk predictors for ER-positive disease. “It would present a very powerful competition, or alternative, to the fancy molecular tests,” he says.

Commercially available tests such as Prosigna (NanoString Technologies), Breast Cancer Index (bioTheranostics), Oncotype DX (Genomic Health), and Mamma­Print (Agendia) already provide prognostic information, but medical oncologists want to know whether the next-generation tests can help them make the right decisions about which drug or specific therapy to choose.

It’s an intoxicating idea. But will it work?

Antonio Wolff, MD, professor of oncology, Johns Hopkins University, Baltimore, falls in the skeptics’ camp. “A lot of commercial labs are describing their panels or gene profiling assays as a tool to identify actionable mutations that would allow me to then make a decision about giving treatment—drug X versus drug Y,” he says. If only. Identifying a genetic mutation doesn’t necessarily signify that a patient’s tumor is driven by the abnormality, he says, no matter how much the marketing material suggests otherwise.

Adopting these assays universally, without critical thinking, is risky, Dr. Wolff continues. Driven by anecdotes rather than data, physicians and patients will be anxious to use therapies that may not work. “This is going to become a major issue,” he says. “We’re going to have a lot of, as I call it, N=1 trials.”

Dr. Ellis says multigene prognostic tests may be useful in circumstances in which the clinical management is unclear, such as low node-positive/node-negative, ER-positive, HER2-negative disease. “Many practitioners will be using these,” he says, specifically mentioning the Prosigna and Oncotype DX tests. (He discloses that he helped develop the PAM50 gene signature used in the Prosigna test and retains patent and commercial interests in the test.) Yet he too urges caution, noting that it remains controversial whether Oncotype DX can be used to predict response to Herceptin, or whether Oncotype DX or Prosigna or any similar tests are useful in predicting response to chemotherapy. Answers won’t be forthcoming until the results of the TAILORx Breast Cancer Trial and the SWOG RxPonder Trial become available.

To be sure, Dr. Ellis says, these tests have been shown to be highly prognostic, and for medical oncologists, “prognosis does drive a lot of clinical decision making in the ER-positive, HER2-negative subset. Because if the prognosis of the patient is determined to be excellent, then chemotherapy would be of limited or low benefit, just based on prognosis alone and not worrying about whether there’s prediction.”

Given that proven prognostic value, medical oncologists are unlikely to drift away from these tests. But as Dr. Pusztai already suggested, the information doesn’t have to come from a “fancy molecular test.”

Pathologists may already have that information at their fingertips, in fact, in the form of traditional IHC results. But to compete with multigene assays, they’ll need to deliver it differently, an effort that’s already well underway, according to Dr. Hicks.

When the multigene assays first came out, “Medical oncologists thought, Great! Finally, a test that will tell us what to do,” Dr. Hicks says, particularly in sorting through the ER-positive, HER2-negative patients.

Cost and questions about the necessity of ordering such tests in every patient have caused some pathologists and oncologists to think differently. “After you get experience with these tests, you can almost predict which ones will come back low risk and which ones will come back high risk,” Dr. Hicks says. Generally speaking, the information comes from what oncologists are already asking for: ER results, HER2 results, and results for a proliferation group, which, as noted, is associated with Ki-67.

“So the question becomes, can we take the IHC we already do and calculate risk?” Dr. Hicks asks.

Yes, quite possibly. The four IHC markers are referred to as IHC4, an index of risk of distant recurrence that was largely developed, says Dr. Hicks, by Mitch Dowsett, PhD, of the Institute of Cancer Research, London. It’s now being offered commercially, including by Genoptix Medical Laboratory, which offers the test on its Aqua technology.

But IHC4 might be done more locally, Dr. Hicks says. He cites a study published in Modern Pathology (Klein ME, et al. 2013;26:658–664) that favorably compared a recurrence score predicted by combining the four IHC markers and other standard pathologic variables like tumor grade and size—named the Magee equation, after Magee-Womens Hospital in Pittsburgh, where it was developed—with Oncotype DX. “It turns out, it works great,” says Dr. Hicks.

In his own lab, Dr. Hicks and colleagues have also compared their experience with Oncotype DX results with those derived from the Magee equation. They, too, found that the two methods provide similar information. “It worked beautifully,” he says. (They presented their findings in an abstract at the San Antonio meeting.) The lab now prospectively calculates these scores. “Our oncologists find it useful,” Dr. Hicks says.

“I don’t want to make it sound like I want to put Genomic Health out of business,” he hastens to add. If there were no other way for his lab to provide that information to oncologists, he says, he’d be more in favor of ordering a commercial test. “But it measures things we already measure. Now we have a tool that allows us to do it.”

Dr. Dowsett cautions, in his publications, that the work in his lab has been done by experienced pathologists who have been doing this a long time—and that it may not necessarily work in other labs. That’s a caveat Dr. Pusztai picks up on as well. “We know that the concept works, but we don’t know whether this works in every single laboratory. It needs to be standardized,” he says. Laboratories are unlikely to succeed in validating their own multivariate assays, he adds, unless they have multiple independent, large data sets.

Beyond the stalwarts and the emerging tests, medical oncologists are keeping an eye on the large category of promising tests. Unlike parents, “We all have our favorites,” Dr. Pusztai says.

One possibility would be to measure response to trastuzumab or other, similar drugs. So far there’s no consistent, supporting evidence for any particular drug sensitivity marker. “But in this research category there are a lot of interesting things,” Dr. Pusztai says. PI3K is one possibility, although the data on this are still conflicting. “But it probably will settle down in a couple of years.” The hope is that evidence will eventually support detecting PI3-kinase mutations as a way of identifying patients whose tumors are less sensitive to Herceptin therapy or those who might benefit from PI3-kinase pathway inhibitors.

At the San Antonio meeting, presentations showed the value of measuring tumor-infiltrating lymphocytes, says Dr. Pusztai. Such information would be relatively easy to incorporate into pathology reports, he says, and might be worth doing, since they carry some degree of prognostic and predictive value, even in triple-negative disease. Tumors with a lot of lymphocytes tend to do better, even without systemic therapy, and also respond better to chemotherapy. But, like Ki-67, such tests will need to be standardized before they can steer their way into clinical practice. “These are all experimental tests, which have a fascinating biological rationale behind them, but there is little consistent data to prove their clinical value”—at least for now, says Dr. Pusztai. But this is where much research in academic centers is focused.

Medical oncologists would also like help with that most challenging of breast cancers, the triple-negative tumor. With other types of tumors, says Dr. Pusztai, “We’re doing reasonably well.” With triple-negative tumors, however, there are few new treatment options or diagnostic or prognostic tests, Dr. Pusztai says. “There are no molecular tests, unfortunately, that could identify low-risk versus high-risk triple-negative breast cancer that’s highly sensitive to chemotherapy, or less sensitive, or would not benefit. It seems that this is a very heterogeneous group of cancers. So it’s difficult to come up with a variable that would carry the same prognostic or predictive value across all triple-negative tumors.”

Dr. Wolff sees a time when a new class of drugs—for many cancers, not just breast—becomes available that would be based on markers of antibodies that modulate regulatory T cells. The markers can be expressed in tumors and might identify patients more likely to benefit from these drugs.

Dr. Ellis occasionally sees labs reporting results on markers that have not entered the standard lexicon, including p53 and CK5/6. Until new markers have shown clinical utility, however, he’d like labs to pull the plug on reporting results of lab-derived tests of uncertain utility.

Sequencing-based tests will likely be most useful in cases involving patients with metastatic disease, Dr. Ellis says, where oncologists need to find therapeutic targets beyond ER and PR. “This, in my mind, remains a research area,” he says, even though these tests are available commercially. Test panels are large, with 30, 40, or more genes. “Most of the data you get, if not all of the data you get, from those sequencing-based panels, is of extremely uncertain value from the clinical management perspective,” he says. “Even if you find a mutation, it’s not clear how predictive that mutation is of drug benefit.”

Even if a sequencing panel reveals a gene mutation for which a targeted therapeutic is available, medical oncologists can still face a tough decision. What, for example, should be done with a breast cancer patient who has a BRAF mutation? Should that patient be given vemurafenib, a B-Raf enzyme inhibitor approved for treating late-stage melanoma? Apart from clinical trials, where patients aren’t billed for the sequencing, Dr. Ellis says he’s unenthusiastic about efforts to sell these tests that lack clear clinical utility.

He also complains that sequencing tests are too expensive to use to screen patients for most rare mutations. HER2 mutations, while rare, are worth finding because the denominator is so large, he says—the two to three percent of breast cancer cases it accounts for is about the same number of patients diagnosed with chronic myeloid leukemia annually. Making these diagnoses is important. “But if the screening process is $4,000 or more per patient because you’ve front-loaded the test with a bunch of genes of uncertain or no clinical utility, that’s not sustainable,” Dr. Ellis says.

Rather than run many genes on one patient, he suggests, it might be better to run many patients on one or a handful of genes. This would drive down the screening cost substantially, he says. “It could be a couple hundred dollars to screen a patient for a HER2 mutation or an ER mutation or perhaps a very small handful of other mutations that might be druggable for the metastatic patient.”

BRCA offers its old-but-new conundrums. Last summer’s Supreme Court ruling opened the door for laboratories other than Myriad Genetics to start offering BRCA testing. At the same time, new therapies are emerging that target tumors with BRCA1 and BRCA2 mutations.

At Johns Hopkins, BRCA testing involves a lengthy genetic counseling process. Dr. Wolff says this will need to be streamlined, because in some cases he’ll need to make a decision about drawing a blood sample at the time he first sits down with a new patient. A new class of drugs called PARP inhibitors could be effective against BRCA-related cancers; knowing a patient’s BRCA status initially could help medical oncologists direct treatment in clinical trials, and eventually, perhaps, in clinical practice. “So the information that the oncologist will need to have in hand at the start will be quite significant, both in terms of the clinical implication, and about the test itself, if the lab chooses to do it in-house or send it to a new reference lab.”

“You’re going to see more and more oncologists ordering these tests without waiting for a genetic counseling session,” Dr. Wolff continues. That could put the onus on labs to help educate patients about what the test means, not only for the individual patient but also potentially affected family members.

BRCA testing is expanding in another sense: The genetic panels themselves have expanded beyond BRCA mutations to include some 20 other related genes that are associated with breast cancer but at a lower penetrance, such as CHEK2, PALB2, and p53. “It’s a bit like the multigene sequencing panels for therapeutic targets: You know patients and their doctors are suddenly getting much more complicated sequencing panels, with genes where the clinical scenarios are not well developed,” says Dr. Ellis.

“There’s still a lot of mystery out there,” he continues. “It’s leading us to tread carefully,” guided by evidence-based clinical standards. “Because patients will do almost anything to escape breast cancer, or even the risk of breast cancer. Just because we have the ability to do these panels now, whether it’s the somatic mutations or the germline mutations, we shouldn’t lose our heads ordering tests.”

Nor do medical oncologists want to let patients lose their heads. Dr. Wolff exhales sharply and says, “Oh my God, yes,” when asked if patients come to him demanding that certain tests be done on their tumors. He recalls one patient who handed him (and her surgeon) a list of assays she wanted ordered on her tumor. “She requested that we do biopsies exclusively to order assays, some of them quite expensive—an invasive procedure to submit tissue to a commercial lab. The patient wants it because the Web site appears to be talking about very exciting things, [such as] individualized treatment and profiling treatment.”

Physicians need to figure out how to handle these requests carefully. Otherwise, any well-intentioned effort to gather more test results becomes a misguided move at best, like handing a Father of the Year award to Rigoletto. “We risk preying on the fears and anxieties of our patients, ordering tests just because they’re available,” Dr. Wolff says.

Dr. Ellis says he sees these demands on the high end of the private health care market, particularly among patients with advanced disease. “They’ve bought a bunch of tests, and they’re looking at this long sheet of paper and wondering what it means. There’s a whole industry evolving on the interpretation of test results for individual patients,” says Dr. Ellis—and he doesn’t mean traditional pathologists at work. But again, more information doesn’t necessarily bring clarity. “You’re still left with uncertainty and confusion in most cases.”

Weighs in Dr. Hicks: “I think the most common scenario is where the patient goes on the Internet, and they come in and say to the oncologist, ‘I need an Oncotype, I need a MammaPrint.’ Some of these companies have invested quite a bit in marketing these tests to the general public and to medical oncologists.”

What gets lost in that transaction, says Dr. Wolff, is the difference between data and information. Profiling a tumor with next-generation sequencing will produce the former. “The question is whether these data will be useful information that helps me make decisions.”

Ideally, he says, pathologists will be able to discuss with their medical oncologist colleagues whether adding a test will be feasible and useful. At Johns Hopkins, he says, his pathologists don’t adopt every new test—and he, for one, is grateful they’re not spreading out a buffet of test options. “They can tell us about a test, and we can decide together. Rather than simply saying, I’m a pathologist; give me the tissue, I can order this test. The real question is, do we, as end users, need that information?”

Dr. Ellis piles on even more questions. “There’s a lot of controversy out there. What’s a prognostic test? What’s a predictive test? What’s the evidence for a claim of prediction? What’s an approved test? What’s an experimental test? When should oncologists order an experimental test? How should they order them? When they do, are they prepared for the complexity of results? Are they trained to order germline testing beyond BRCA1 and BRCA2?”

To answer these questions, he says, “We need to work tirelessly to not only identify all this complex biology but translate it into useful tests. That’s a role that pathologists and the CAP can fill, particularly the educational role. Not just targeted at pathologists, but at medical oncologists and pathologists as teams to get the individual diagnoses right.”

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