May 2010
Feature Story

Karen Titus

How hard does David Krag, MD, look for micrometastases in his patients with breast cancer?

Dr. Krag, the S.D. Ireland professor of surgical oncology, University of Vermont, Burlington, does a quick backflip to the lab. Says Dr. Krag: “I can’t look any harder than Don Weaver looks.” That would be Donald Weaver, MD, his pathologist colleague in Vermont.

Pathologists are the ones charged with detecting micrometastases, but that’s only a first step. Surgeons and oncologists must then make their own decisions, often after drawn-out discussions with their patients, about what to do with the information.

For Regina Rosenthal, MD, a breast surgeon in private practice in Salt Lake City, those conversations have become more complex over the years. “They get longer and longer,” she says. Finding micrometastases in sentinel lymph nodes has gotten easier, thanks to improved detection methods and surgical techniques, but deciding on the next steps has not. Each and every case is a challenge and a diagnostic quandary.

So what do clinicians do?

That’s not an idle question. “It’s a real dilemma,” says Dr. Rosenthal. “We ask our pathologists to look at lymph node, recognizing the harder you ask them to look, the more you’ll find. And we don’t always know what to do with that information.”

It’s apt that these complex discussions often stem from somewhat tangled pathologic roots. Each decision pathologists make has its trade-offs. Should they use H&E? Immunohistochemistry? Both? How many cuts should they make? Are they achieving the 2-mm sections that are the accepted standard? (See “Micrometastases still a waiting game,” CAP TODAY, March 2010.)

These are largely questions for pathologists, though surgeons and oncologists are hardly disinterested bystanders.

R. Dirk Noyes, MD, a surgical oncologist who works at Intermountain Healthcare and the University of Utah, Salt Lake City, has elected not to use IHC routinely, a decision he says was largely influenced by discussions he had with pathologist Elizabeth H. Hammond, MD, who also holds joint appointments at Intermountain Healthcare and the University of Utah.

Beyond that, in the operating room, Dr. Noyes adapts to whatever his pathology colleagues prefer. “If I’m working with a pathologist who’s boarded in cytology, they much prefer to do cytologic preps on the node,” says Dr. Noyes, clinical professor of surgery. “If I’m working with a pathologist who’s not as comfortable with cytology, they prefer to do a frozen section.” And some pathologists, he notes, do both. Does he have a preference? “I don’t. I leave that up to the pa­thologists.”

At the hospitals where Dr. Rosenthal practices (several Intermountain Healthcare locations as well as St. Mark’s Hospital, Salt Lake City), pathologists routinely do serial step sectioning using H&E. The surgeons do not request immunohistochemical stains, she says, though pathologists will occasionally perform IHC if they feel it’s needed for clarification—for lobular cancers, say, where it’s harder to distinguish malignant cells from normal lymph node.

“I’m one of the surgeons who requests intraoperative analysis of the lymph node—I guess not everybody does,” Dr. Rosenthal says; she prefers this approach because it lessens the chance of making patients return for “yet another operation.” On the other hand, there are times when a pathologist will prefer to do a frozen section; occasionally, at the pathologist’s discretion, the pathologist will do a touch prep analysis. “It’s case-dependent,” Dr. Rosenthal says.

At Memorial Sloan-Kettering Cancer Center, New York, pathologists use both H&E and IHC, says Clifford Hudis, MD, chief of the breast cancer medicine service. What does he think about this approach? “Well, I’m used to what we do,” he says. “I understand the rationale for it. But it is possible to be a very strict and conservative reader and declare that nobody should do IHC.”

That sort of High Church approach is, in fact, widely supported in theory if not in actual practice. IHC, though commonly used, does not have the formal blessing of any official guidelines or recommendations. The resulting disparity has created something of a pseudo-crisis, says Dr. Hudis. “And I understand the concern.”

On the other hand, this is a train that may have left the station. Practices, once begun, are hard to undo. This leaves surgeons and oncologists to hash out micrometastases and SLN biopsies from other angles.

From clinicians’ perspectives, a breast cancer diagnosis functions as a question, not an answer. While that may be true in other areas of medicine as well, it’s heightened in breast cancer because patients (and, often, active partners) frequently voice strong opinions about their treatments. That means two groups—clinicians and patients—are struggling to make sense of information that is often conflicting, incomplete, or unknowable. And, as Dr. Rosenthal points out, patients (as well as some clinicians) don’t always appreciate the nuances of lab testing. “They accept that tissue will be sent to ‘the lab’ for analysis,” she says, but they may also think cancer diagnostics is on par with an automated blood test.

Factor in real, if not quantifiable, patient worries, along with a bias toward aggressive treatment by patients as well as clinicians, and even solid data can bend in rather astonishing ways. Women in recent years have increasingly been requesting contralateral prophylactic mastectomies, a handful of recent studies report, even when their cancer is in its earliest stages or confined to one breast. Evidence-based medicine is one thing; fear is another. In breast cancer, the two often run neck and neck.

Little wonder clinicians have come to value the art of conversation. Not every case needs to be narrated with a “My Dinner with Andre” thoroughness, but a brief e-mail isn’t going to cut it, either.

Dr. Rosenthal considers herself to be in a particularly lucky situation where she practices, with surgeons and pathologists typically talking to one another about each case. This has been crucial not only for sorting out how to handle information about SLN biopsies, micrometastases, and isolated tumor cell clusters, but for understanding the constraints pathologists face in their own practices. Even in the best of circumstances, Dr. Rosenthal notes, “There’s still an awful lot of lymph node that doesn’t get looked at, even though you think you’re looking at it very thoroughly.” She speaks with her pathologist colleagues while she’s in the OR, either in person or over the phone.

Dr. Noyes flat-out insists on meeting with his pathologists. “Not only in breast, but in all cancer cases, I have a face-to-face talk with the pathologist. The pathologist comes into my room on every case I do, and we talk about the case as I’m handing the specimens to him, so that he hears what my concerns are, and I hear what his concerns are.”

“I can tell you in my practice, there are very few pathologic errors. Just because we have that communication,” he adds.

Dr. Noyes admits his approach is unusual. He credits a pathology rotation he did during his fellowship and training at the University of Texas M.D. Anderson Cancer Center, Houston, for his hyperconversational approach. Even those brief few months working in the lab allowed him to see what pathologists were up against—and vice versa. “It’s helpful to know that even if you have the best pathologists in the world at your institution, there are limitations to any of the techniques that we ask of them,” says Dr. Noyes.

The more surgeons ask pathologists to do to the lymph node during surgery, the more possibility that the architecture of the lymph node is destroyed in a way that could reduce the accuracy of a permanent evaluation. “So we’re always walking a fine line,” Dr. Rosenthal says.

Pathologists can make that walk easier if they’re willing to explain their processes to their clinicians. “I’ve learned a lot from our pathology colleagues,” Dr. Rosenthal says. SLN analysis is only one example, she says; they’ve also helped her sort through the complexities of assessing margins around tumors. “Perhaps pathologists elsewhere can educate their clinical colleagues about what they do,” she suggests.

Surgeons contend with their own limitations, though training and experience have improved their methods over the past decade.

Preliminary data from the NSABP’s B-32 protocol (a randomized, phase III trial to compare SLN biopsy to axillary dissection) have driven home an important point, says Dr. Noyes: “Surgeons should not be doing sentinel lymph node staging in breast cancer if they haven’t got experience.” Early on, breast surgeons began by doing SLN procedures along with the axillary dissection, he explains, enabling them to identify their personal false-positive and false-negative rates. “So I think it’s important to know that if they [patients] go to a surgeon who’s only done two of these, it’s not going to be very accurate. And that’s not fair to patients. Surgeons need to police themselves. And even though they learn the technology, they shouldn’t go out and practice it on women without knowing what their own false-positive and false-negative rates are,” says Dr. Noyes, who helped train surgeons in SLN techniques for B-32, and whose institution was the highest-accruing site for that trial.

Surgeons can have false-negatives for several reasons, says Kambiz Dowlatshahi, MD, professor of surgery, Rush University Medical Center, Chicago.

They may not pick up a signal from the radioisotope or blue dye, although that’s relatively rare, he says. Other false-negatives occur when a surgeon fails to identify the sentinel node; still others when the surgeon picks the wrong node, and the pathologist reports negative findings. This can happen—though, again, it’s relatively rare—when the sentinel node is filled with cancer and diverts the dye to the next node, which might be cancer-free. In such cases, however, surgeons should be able to identify the cancer-filled node by careful visual examination and palpation.

Dr. Dowlatshahi has been a weather vane of sorts as micrometastases/SLN discussions blow one way, then the other.

He was an early advocate of intense scrutiny for micrometastases. Using an approach developed with his former pathologist colleague at Rush, Kenneth Bloom, MD, he and his colleagues did detailed screening and staining of sentinel nodes from one end to the other.

Dr. Dowlatshahi and his colleagues subsequently reviewed 209 cases of patients with T1/T2 invasive breast cancer, treated with lumpectomy and SLN biopsy, between December 1997 and May 2002. Fifty-two of the patients showed micrometastases ranging in number from a few cells to hundreds or thousands.

In their followup five-plus years later, they found a “big surprise,” says Dr. Dowlatshahi: Incidence of recurrence was the same among patients with a few isolated tumor cells and those with big colonies. (Their findings were presented in an abstract at the San Antonio Breast Cancer Symposium in December 2008.)

Dr. Dowlatshahi still laughs when he recalls his first thoughts about the finding. “I thought I had broken a big sound barrier,” he jokes, “and discovered that there were a whole bunch of the metastases that were not detected by routine examination.” This would have led him to advocate for more careful examination, from stem-to-stern, using 0.25-mm sectioning and IHC.

But when he tried that himself, the results were the same. There was no uptick to explain why some patients developed a recurrence.

Late last year, the Annals of Surgical Oncology (Langer I, et al. 2009;16:3366–3374; editorial by Damle S, et al. 3215–3216) published a similar paper from a Swiss group, who pooled results from five different hospitals. The conclusion, says Dr. Dowlatshahi, was the same—presence or absence of micrometastases makes no difference in overall survival and recurrence of disease.

“So, we are in a bit of a quandary right now as to worth of sentinel node in determining recurrence of cancer,” he says. “I am puzzled,” though he suspects the answer lies in the genetic makeup of tumors.

Dr. Dowlatshahi declined to participate in the B-32 trial. At the time, he says, he was intent on that thorough pathologic examination of SLNs, an approach that, frankly, would have been impractical for a large trial. (In fact, he and his pathologist colleagues at Rush have abandoned this approach in favor of the more standard 2-mm cuts, for an average of three or four sections per lymph node.) Dr. Dow­latshahi, with Dr. Bloom, decided to seek answers for himself. “Which I did. And I think Ken and I looked at about 80,000 sections over the course of three, four years. And then we did that followup [of the 209 cases].

“And now,” he says, laughing heartily, “now I have this baby on my hands, and I don’t know what to do with it!” Knowing what he knows now, however, he says he would still decline to participate in B-32. Given the heterogeneous nature of breast cancer, he says, he questions the current methods of most clinical trials. Large trials (B-32 has 4,000 patients) run the danger of comparing apples and oranges, he says. “Your baseline is impure.” Smaller trials would involve more homogeneous groups of patients (at least to Dr. Dowlatshahi’s way of thinking), enabling resear­chers to ask more precise questions and, presumably, obtain more precise answers.

He plans further followup of his own patient group this year, which should give him answers 10-plus years out. In the meantime, amid the current chaos, how does he make his decisions? He runs down the usual clues: clinical expression, poor differentiation of tumor, HER2 status, ER and PR receptors, BRCA mutations, other gene expression, patient age. “I’m not giving you a very clean answer,” he says, “but I’m giving you a complex response”—and one that reflects how he talks with his patients.

Dr. Dowlatshahi does not do intraoperative frozen sections. He uses positive SLN findings to decide whether patients should receive chemotherapy, and permanent sections are fine for this purpose, he says. “So ahead of time, when I am discussing it with patients, I tell them that if the sentinel node comes back positive on permanent section, I am not going to take them to the operating room and do the complete axillary dissection. Why? I think the benefits gained from finding one other lymph node, or two other lymph nodes, does not outweigh the added harm to the patient by taking her back into the operating room,” he says. “One, it’s more painful. Two, they get the side effects of axillary node dissection.”

During surgery, “I make a thorough search of the axilla to ensure there are no other suspicious lymph nodes to the eye or to the fingers. When I close that axilla, I am fairly sure that I have not left anything gross behind. I may be wrong. There may be microscopic cells in the next lymph node. I concede that. But, my argument is that if there are some microscopic cells, we will pick it up on permanent sections of the sentinel nodes identified initially.” That patient will receive additional treatment to the axilla, extended to the lower axilla, as well as chemotherapy. He does this unless there is gross disease, in which case, Dr. Dowlatshahi says, “I’ll remove whatever is there to be seen or felt.”

This approach has proved satisfactory with his patients, he says, who greatly fear sensory loss to the skin and arm and, worse, the risk of edema. Moreover, he says, “I have not had a single case of local recurrence in easily 10 years, if not longer.”

In some ways, micrometastases in SNL biopsies are findings in search of a meaning. Biologically, it’s far from clear what, if any, their significance might be.

Dr. Noyes says, “A fairly large amount of data out there show patients have these cells in their bone marrow, too,” even if the nodes are negative. “And what does that mean?” (He notes that this is being investigated through the NSABP trial.)

Anyone who’d hoped they might have prognostic significance has been disappointed. “It’s not as if the sentinel lymph-node positive patient is definitely going to have a worse prognosis. They may; they may not,” Dr. Rosenthal says. At best, micrometastases would only serve as a surrogate for a tumor’s biological behavior. “We can try to make appropriate recommendations based on size of the tumor burden, but recognizing that may not be the most important thing,” Dr. Rosenthal says. “And five years from now we may not be using it at all.”

That leaves clinicians and their patients in a difficult position—how aggressively should they respond when pathologists find these cancer cells?

“The default, always, with breast cancer, is that more is better: more treatment, more surgery, more chemotherapy. But that’s not always borne out by the data,” says Dr. Rosenthal. Ten years ago, for example, women with breast cancer were urged to have bone marrow transplants. When the data were looked at, this drastic approach didn’t necessarily improve outcomes compared with an aggressive but more standard chemotherapy.

The discussion is, slowly, becoming more nuanced, Dr. Rosenthal says. “Five years ago, we would have routinely said, ‘Standard treatment is to complete an axillary dissection.’ And often we may still recommend it.” But now, “I think that’s getting less important,” Dr. Rosenthal says. “It’s more important that if there’s micrometastatic disease, they’re targeted for more systemic treatment.”

Conveying those messages to patients can be difficult. “In the immediate period of diagnosis, people are upset and very emotional and often say to their clinicians, ‘Be as aggressive as you can—I just want to live to see my kids grow up,’ or something like that,” Dr. Rosenthal says. It’s understandable, if not always scientifically supportable.

Dr. Rosenthal says she finds it “very distressing that we’ve spent 25 years showing that performing mastectomy will not improve survival versus a breast preservation approach. We have very good data supporting that. And yet with all the extra scrutiny that women with breast cancer are being subjected to these days, including sentinel node biopsy, we’re finding more disease, which might have been perfectly adequately treated with lumpectomy and radiation if we didn’t know someone had a second, tiny abnormal focus.” As a result of this extra scrutiny, more women are either being urged to have or choosing to have mastectomy. “I think it’s a step backwards,” says Dr. Rosenthal. “Women with breast cancer are under an awful lot of pressure to do more, whether it’s more chemotherapy or more surgery. And I think it’s a shame.”

It’s not as if patients are demanding it and physicians are acquiescing. “Every week, in our weekly tumor conference, you realize that amount of anxiety a cancer patient faces as they’re followed long-term,” she says. Thus the typical response from surgeons: Do a bigger operation.

Scaling back has not been an easy sell. “There are many surgeons to whom it’s anathema to say, ‘Less surgery is more,’” Dr. Rosenthal says.

The same is true of systemic chemotherapy. In Europe, the tide seems to be shifting, with awareness that hormonal manipulation—whether tamoxifen or aromatase inhibitors—may be just as effective as chemotherapy in some patients. “Clinicians here are just starting to catch up to the idea that maybe chemotherapy is overkill in a lot of patients,” Dr. Rosen­thal says.

This jibes with her current inclinations. “I’m more and more finding myself in the situation of finding a patient with a micrometastatic lymph node and actually saying to them, ‘We could take you back for more surgery, but I’m really not sure it’s in your interest.’”

“What I say to patients is, of course we want to be aggressive—as long as being aggressive translates into better outcome,” she continues. “If patients can actually hear you say that, they can either make more informed choices, or at least understand what the dilemmas are. There are almost too many choices.”

Thanks to pathologists, “We can scrutinize patients within an inch of their lives,” says Dr. Rosenthal. “We get more information. But we may not know what to do with it.”

Dr. Rosenthal doesn’t necessarily want less from her pathologists. The size of a lymph node metastasis is important, even if it is controversial. So is other SLN-related information, such as extracapsular extension. “Let me deal with that information,” she says.

Dr. Krag also evinces a bring-it-on attitude—with a twist. He’s helped create a Web site (www.treeofmedicine.com, now in beta testing) cataloguing published medical research. The first module, handily enough, lists the complete literature on sentinel node and breast cancer. As of late April, that tallied 3,000 articles and counting. The category for “Overall incidence of metastases to SNs” listed 316 articles. “It’s no wonder there’s a fair amount of controversy about this,” says Dr. Krag.

Dr. Krag, the protocol PI for the B-32 trial, has watched with fascination as the micrometastases/SLN biopsy discussions have swung one way, then the other. The Z-11 sentinel node trial, which would have addressed whether axillary dissection was necessary in patients with positive SLNs, sputtered out due to lack of patient accrual. “Surgeons were too concerned about leaving unresected node behind that had cancer,” says Dr. Krag. “Now the pendulum has swung dramatically the other way.” Faced with a negative sentinel node, surgeons are unlikely to do a further dissection. Even if the node contains small amounts of cancer, the odds are low that the cancer has metastasized to other nodes. “So people are trying to second-guess the sentinel node, in terms of whether they should do a completion axillary dissection.”

Dr. Krag finds the shift almost transfixing. “What’s going on between these two time points?” he asks. His answer: “Opinions.”

He rues that the Z-11 study wasn’t done. “We lost a big opportunity,” he says. “We’d know for sure what the regional recurrences were; we’d know what the survival issues were.” You can practically hear him shaking his head over the phone as he says this.

All of which leaves him with those aforementioned opinions. “I just find it incredibly interesting that something could go so far, in such an extreme direction, with no real meaningful intervening data.”

Dr. Hudis, of Memorial Sloan-Kettering, sees another shift. “We’re starting to ask the right question,” he says. “Not just about the academic value, but the clinical and practical value of the things we do.” Prognosis in a vacuum is not useful. “Telling someone that they have a higher risk or lower risk, in isolation, doesn’t do very much but scare them a little more or a little less, right?” he says.

SLN micrometastases rarely tip the scales when oncologists make their decisions about systemic adjuvant therapy.

“There are lots of examples of breast cancer presentations where knowledge of micrometastases won’t change our approach to treatment,” Dr. Hudis says. “The therapeutic decisions are slam-dunk already for other reasons. An older person with a small, 100 percent ER-positive breast cancer—two micromets are not going to persuade me or most people to give chemo.” At the extreme is the young person with a large tumor that’s ER- and PR-negative. “They’re getting chemo,” he says flatly.

Only in rare situations will micrometastases status alone shape treatment. As Dr. Hudis notes, however, there is no evidence-based patient population where that applies.

Dr. Krag hopes the B-32 trial will provide some evidence-based answers to his questions. In the interim, he faces the same struggles as his fellow surgeons.

In essence, says Dr. Krag, every institution is doing its own risk analysis. “If they’re doing their job right, they’re giving accurate risk assessments, and then they’re also having a frank discussion with the patients and trying to put it all in perspective.”

Dr. Krag says his basic strategy is to lay out the issues and determine which one is paramount for a particular patient. In some cases, the most important issue is whether to do a completion axillary lymphadenectomy. In others, it’s making decisions about chemotherapy. “That’s really what it boils down to,” he says. “You just bracket them out and pause.”

Then it gets messy. If, for example, the primary decision concerns axillary dissection, the surgeon’s best medical judgment might be to complete the dissection. But telling the patient is another matter. “You’ve got a patient in their first postoperative visit,” Dr. Krag says. “They’re hurting, they’ve got a drain, they’re not feeling good, they just had a bunch of surgery—and now there’s a proposal to go back and do this all over again. That’s not very appealing. And a lot of people say, ‘I don’t want to. Is there any other way to deal with this?’ Well, there is—radiation.”

Although clinicians are often accused of looking at lab testing as if it were a black box, it would be foolish to pin that charge on breast cancer clinicians. They see, daily, that context is king. “You have to take them one by one,” says Dr. Krag. “Right now it’s a discussion with each one of these cases.”

Dr. Krag notes that decisions about systemic adjuvant therapy have, until now, been population- and risk-based. What makes the sentinel node story interesting, however, is that it allows physicians to map individual status in individual patients. Though he’s cautious of overusing the phrase “personalized medicine,” he sees this as a material step in that direction.

Though personalized medicine has been greeted with hope and hosannas in recent years, these clinicians are getting a vivid look at how it performs in real time, in real life, with real patients. As it turns out, personalized medicine can be one big gabfest, with the “personal” component just as important as the medical one.