Contemplating Breast Cancer, Beyond October 2012

It’s foggy today, October 3, ten years since the last mammogram I had and will ever need. I’ve been remiss in updating the blog. The reasons include family concerns and other projects. Meanwhile, I’ve been thinking about the big picture – what’s most important for progress against breast cancer in the decade ahead.

So here’s what I see, now – in terms of three priority areas: improving treatment, prevention, and education to inform treatment decisions.

Pumpkins, organized by subtype (WikiCommons image)

As an oncologist, I perceive huge strides in understanding BC since the time of my diagnosis. But these advances are largely invisible to patients because they’re in the realm of pathology and classification of different subtypes. What was essentially a 3-type malignancy with a handful of treatment options has expanded under the molecular microscope to a spectrum of 4, 10 or – what’s probably most accurate – hundreds or thousands of patient-particular conditions, depending on the level of precision by which you define a disease. I’m optimistic, because it looks as though, in my lifetime, BC treatment will be tailored to each patient. There’ll be less surgery and better drugs.

The hitch, now, is not so much with science as with funding– funding to analyze each patient’s tumor at the genetic and protein levels, funding to pay for treatments selected by patients (which might include less treatment and/or palliative care in advanced cases), and funding to educate doctors about BC subtypes and medical progress, so they might offer “modern” advice to each patient in ordinary clinics, apart from clinical trials and academic centers. Newer is not always better in medical care. Same goes for more treatment (especially when it comes to higher doses). Still, the lag between advances in BC science and application of distinct, targeted and better treatments is frustrating at best.

Some of my colleagues call for patience – emphasizing that studies need be confirmed, drugs tested in mice, etc. Their point is that we can’t jump from pathology research and new BC classifications to new therapy. But one lesson I take from progress against AIDS is that maybe we shouldn’t be so patient. At least not for young people with poor-prognosis BC subtypes or stage. We could do studies and studies of particular BC treatments, and studies of studies (those would be meta-analyses) and debate 8 or 10 years from now whether a particular drug or combination of drugs worked in clinical trials that selected for patients with an antiquated subtype of the disease. Or we could move toward “n=1” trials, with smart, well-trained physicians assessing each patient by a combination of old-fashioned physical exams and the most modern of molecular studies of the tumors, considering the options, and moving forward with individual, mini-experimental treatment plans.

I vote for the latter. If the drug works in a patient with advanced BC and the patient feels better, why not?

For people with early-stage BC, prescribing or taking new and essentially untested drugs makes less sense at first glance. That’s because standard treatments are “successful” – leading to long-term remissions and possible cures in over 80 percent of those affected. But these relatively good results may have, paradoxically, hampered development of better drugs that could obviate the need for breast-deforming surgeries and radiation in many women. The possible application of BC drug cocktails, in lieu of surgery for early-stage patients, is a huge question for the future, and one for which trials would be necessary. Just getting those projects going – applying BC science to treatment of early-stage cases – would be a step in the right direction.

As for BC prevention, of course that would be infinitely better than detecting or treating the disease. Unfortunately, I think we’re farther away from preventing the disease than we are from having effective and less brutal treatments for most patients. The problem with lifestyle modification – like staying active and not obese – is that it’s far from full-proof: You can be seemingly fit as a fiddle and get a lethal case of BC. Still, there are plenty of other health-related reasons for women to exercise and eat sensibly. As for avoiding carcinogens or, first, just knowing what chemicals contribute to BC formation and growth, the science isn’t there yet.  It’ll be a long haul before anyone can prove that a particular chemical causes this disease. That said, I advocate research in the slow-growing field of environmental oncology and wish there’d be more enthusiasm for regulating our exposure to likely-toxic chemicals.

The third priority is for improving education in math and science, starting at the elementary school level. Doctors need to understand statistics, but many don’t. They need to know about genomics and basic science in medicine. Patients need this kind of knowledge if they want to have a clue, if they want to engage meaningfully in decisions about which antibody to take, or pill, or whether they want to participate in a clinical trial of pills instead of surgery for a Stage II tumor with high levels of Her2, for example. That’d be a tough decision for an oncologist. I only wish that we could reach the point where we could have those kinds of truly informed conversations about clinical treatment of breast cancer, which happen every day.

We’ve got a lot of information in hand, but we need to learn how to apply that to more patients, faster and more openly.

All for a while. I’m open to ideas on this. Happy October!

ES

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10 Newly-Defined Molecular Types of Breast Cancer in Nature, and a Dream

Breast cancer is not one disease. We’ve understood this for decades. Still, and with few exceptions, knowledge of BC genetics – information on tumor-driving DNA mutations within the malignant cells – has been lacking. Most patients today get essentially primitive treatments like surgical hacking, or carving, traditional chemotherapy and radiation. Some doctors consider hormone therapy as targeted, and thereby modern and less toxic. I don’t.

Until there’s a way to prevent BC, we need better ways to treat it. Which is why, upon reading the new paper in Nature on genetic patterns in breast cancer, I stayed up late, genuinely excited. As in thrilled, optimistic..The research defined 10 molecular BC subgroups. The distinct mutations and gene expression patterns confirm and suggest new targets for future, better therapy.

The work is an exquisite application of science in medicine. Nature lists 31 individuals and one multinational research group, METABRIC (Molecular Taxonomy of Breast Cancer International Consortium), as authors. The two correspondents, Drs. Carlos Caldas and Samuel Aparicio, are based at the University of Cambridge, in England, and the University of British Columbia in Vancouver, Canada. Given the vastness of the supporting data, such a roster seems appropriate, needed. The paper, strangely and for all its worth, didn’t get much press –

Just to keep this in perspective – we’re talking about human breast cancer. No mice.

The researchers examined nearly 2000 BC specimens for genetic aberrations, in 2 parts. First, they looked at inherited and acquired mutations in DNA extracted from tumors and, when available, from nearby, normal cells, in 997 cancer specimens – the “discovery set.” They checked to see how the genetic changes (SNPs, CNAs and/or CNVs) correlated with gene expression “landscapes” by probing for nearly 29,000 RNAs. They found that both inherited and acquired mutations can influence BC gene expression. Some effects of “driver” mutations take place on distant chromosomal elements, in what’s called a trans effect; others happen nearby (cis).

Next, they honed in on 45 regions of DNA associated with outlying gene expression. This led the investigators to discover putative cancer-causing mutations (accessible in supplementary Tables 22-24, available here). The list includes genes that someone like me, who’s been out of the research field for 10 years, might recall – PTEN, MYC, CDK3 and -4, and others. They discovered that 3 genes, PPP2R2A, MTAP and MAP2K4 are deleted in some BC cases and may be causative. In particular, they suggest that loss of PPP2R2A may contribute to luminal B breast cancer pathology. They find deletion of MAP2K4 in ER positive tumors, indicative of a possible tumor suppressor function for this gene in BC.

Curtis, et al. in "Nature": April 2012

The investigators looked for genetic “hotspots.” They show these in Manhattan plots, among other cool graphs and hard figures, on abnormal gene copy numbers (CNAs) linked to big changes in gene expression. Of interest to tumor immunologists (and everyone else, surely!), they located two regions in the T-cell receptor genes that might relate to immune responses in BC. They delineated a part of chromosome 5, where deletions in basal-like tumors marked for changes in cell cycle, DNA repair and cell death-related genes. And more –

Cluster Analysis (abstracted), Wikipedia

Heading toward the clinic, almost there…

They performed integrative cluster analyses and defined 10 distinct molecular BC subtypes. The new categories of the disease, memorably labeled “IntClust 1-10,” cross older pathology classifications (open-access: Supplementary Figure 31) and, it turns out, offer prognostic information based on long-term Kaplan-Meier analyses (Figure 5A in the paper: Supplementary Fig 34 and 35). Of note, here, and a bit scary for readers like me, is identification of an ER-positive group, “IntClust 2” with 11q13/14 mutations. This BC genotype appears to carry a much lesser prognosis than most ER-positive cases.

Finally, in what’s tantamount to a 2nd report, the researchers probed a “validation set” of 995 additional BC specimens. In a partially-shortened method, they checked to see if the same 10 molecular subtypes would emerge upon a clustering analysis of paired DNA mutations with expression profiles. What’s more, the prognostic (survival) information held up in the confirmatory evaluation. Based on the mutations and gene expression patterns in each subgroup, there are implications for therapy. Wow!

I won’t review the features of each type here for several reasons. These are preliminary findings, in the sense that it’s a new report, albeit a model of what’s a non-incremental published set of observations and analysis; it’s early for patients – but not for investigators – to act on these findings. (Hopefully, this will not be the case in 2015, or sooner, preferably, for testing some pertinent drugs in at least a subset of the subgroups identified.) Also, some of the methods these authors used came out in the past decade, after I stopped doing research. It would be hard for most doctors to fully appreciate the nuances, strengths and weaknesses of the study.

Most readers can’t know how skeptical I was in the 1990s, when grant reviewers at the NCI seemed to believe that genetic info would be the cure-all for most and possibly all cancers. I don’t think that’s true, nor due most people involved with the Human Genome Project, anymore. The Cancer Genome Atlas and Project should help in this regard, but they’re young projects, larger in scope than this work, and don’t necessarily integrate DNA changes with gene expression as do the investigators in this report. What’s clear, now, is that some cancers do respond, dramatically, to drugs that target specific mutations. Recently-incurable malignancies, like advanced melanoma and GI stromal tumors, can be treated now with pills, often with terrific responses.

Last night I wondered if, in a few years, some breast cancers might be treated without surgery. If we could do a biopsy, check for the molecular subtype, and give patients the right BC tablets. Maybe we’d just give just a tad of chemo, later, to “mop up” any few remaining or residual or resistant cells. The primary chemotherapy might be a cocktail of drugs, by mouth. It might be like treating hepatitis C, or tuberculosis or AIDS. (Not that any of those are so easy.) But there’d be no lost breasts, no reconstruction, no lymphedema. Can you imagine?

Even if just 1 or 2 of these investigators’ subgroups pans out and leads to effective, Gleevec-like drugs for breast cancer, that would be a dream. This can’t happen soon enough.

With innovative trial strategies like I-SPY, it’s possible that for patients with particular molecular subgroups could be directed to trials of small drugs targeting some of the pathways implicated already. The pace of clinical trials has been impossibly slow in this disease. We (and by this I mean pharmaceutical companies, and oncologists who run clinical trials, and maybe some of the BC agencies with funds to spend) should be thinking fast, way ahead of this post –

And given that this is a blog, and not an ordinary medical publication or newspaper, I might say this: thank you, authors, for your work.

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Study Finds Wide Variation in Reoperation Rates after Lumpectomy for Breast Cancer

The Feb 1 issue of JAMA includes a major report on the practice of lumpectomy in the U.S. The study examined what happened to 2,206 women at four medical centers who opted for breast-conserving surgery at the time of breast cancer diagnosis. The main finding was that after lumpectomy, nearly one in four women had another operation to remove cancerous cells in the breast. Among all the breast cancer patients who began with a lumpectomy, 8.5% wound up with a mastectomy.

These are staggeringly high rates of re-operation in women who opted for small procedures to begin with. Many of the women who had additional procedures did so for concern over having “clean margins” – that upon removal of a tumor, the edges of the specimen don’t reveal malignant cells. Re-excision for patients with negative margins varied by hospital; at one medical center the re-excision rate was 1.7%, at another it was 20.9%. Analysis by surgeon revealed huge variation, with re-excision rates ranging between 0 and 70%. The incidence of positive margins was 14%.

What further clouds the story is that among women who did have positive margins, meaning that cancerous cells were evident along the edge of the lump removed, nearly 15% didn’t have a second procedure. The big picture is that there was little pattern – or reason evident, at least at the collective level – for the surgeries and decisions to re-operate after lumpectomy for breast cancer.

The study, funded by the NIH, was sufficiently large to merit concern. It involved careful chart and pathology review of the specimens through a consortium of four medical centers around the country: the University of Vermont, Kaiser Permanente Colorado, Group Health in Washington State and the Marshfield Clinic in Wisconsin. And it reflects current practice; the surgeries took place between 2003 and 2008.

Lumpectomy is a very common procedure – and a significant issue, in terms of costs, and risks, and decisions women make every day upon receiving a new BC diagnosis. An estimated 60-70% of newly-diagnosed breast cancer patients choose breast-conserving surgery. So we’re talking about 160,000 or so lumpectomies per year in the U.S. (very approximate, ES: 2/3 of 240,000 new BC cases).  The variable results affect cosmetic outcome – the very reason many women choose lumpectomy to begin with and, potentially, the rate of BC recurrence.

The authors discuss: “Our finding…suggests that patients under similar clinical conditions are likely to undergo reexcision based on the treating surgeon and not just the clinical characteristics.” They offer possible explanations, including differences in surgical training, surgeons’ confidence in their operative techniques, how tumors are assessed in the operating room, and variation in how pathologists review specimens and “call” the margins positive or negative.

All of this meshes with my experience – knowing women who’ve had breast-conserving surgery and then got mixed information about the results and what to do next. You’d think lumpectomy would be a standard procedure by now, and that decisions about what to do after the procedure, surgically speaking (let alone decisions about chemo, hormonal treatments and radiation) would be straightforward in most cases.

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More on DCIS

More, a magazine “for women of style & substance,” has an unusually thorough, now-available article by Nancy F. Smith in its September issue on A Breast Cancer You May Not Need to Treat.

Ductal Carcinoma in Situ (DCIS) in the breast, histopathology w/ hematoxylin & eosin stain, Wiki-Commons image

The article’s subject is DCIS (Ductal Carcinoma in Situ). This non-invasive, “Stage O” malignancy of the breast has shot up in reported incidence over the past two decades. It’s one of the so-called slow-growing tumors detected by mammography; a woman can have DCIS without a mass or invasive breast cancer.

While some people with this diagnosis choose to have surgery, radiation or hormonal treatments, others opt for a watchful waiting strategy. The article quotes several physicians, including oncologists, who consider the surveillance approach favorably and otherwise.

In 2009 the NCI sponsored a conference on diagnosis and management of DCIS. The participants issued a helpful, albeit technical, consensus statement.

The bottom line is that optimal treatment for DCIS remains uncertain because doctors don’t yet know the natural course of this early-stage breast malignancy. The ClinicalTrials.gov website lists active and ongoing studies.

 

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FDA Approves New Assay for Her2 in Breast Cancer

This week the FDA approved a new assay for Her2 expression in breast cancer biopsies. The technology, Inform Dual ISH, is manufactured by Ventana Medical Systems, a Roche subsidiary.

From Ventana Medical: the HER2 and Chromosome 17 probes are detected using two color chromogenic in situ hybridization (ISH)

Inform Dual ISH works like this: technicians, typically working under the supervision of a pathologist, expose a tiny bit of a breast biopsy specimen, fixed on a microscope slide, to probes for Her2. This gene, normally found on human chromosome 17, is amplified in some breast cancer cells. The assay exploits an enzyme, linked to the genetic probe, which creates a color (in this case, red) upon exposure to a chemical. The system allows a pathologist, using a microscope, to “see” and measure the gene’s presence on chromosomes in cells of an ordinary biopsy sample.

What’s interesting about this in situ hybridization (ISH) kit is that it doesn’t require a fluorescent microscope for imaging. The Ventana probe generates a simpler, ordinary color signal that can be detected by a light microscope. Most commercial assays for Her2 use a method called immunohistochemistry (IHC); that technique relies on antibodies that bind Her2, a cell surface receptor that’s implicated in cancer cell signaling and growth. This and other ISH assays measure genes directly on the chromosomes; by contrast, IHC usually tests for protein.

Her2 is the molecular target for Herceptin, and there’s been considered discussion about how and where it might be accurately assessed. So the “readout” from this diagnostic test might inform a woman and her doctor in deciding whether or not she should receive treatment with Herceptin.

How pathologists evaluate breast biopsy specimens matters a lot, especially when you’re on the receiving end of a diagnosis and you’re choosing among treatments. In 2007, ASCO and the College of American Pathologists published guidelines on Her2 testing in the Journal of Clinical Oncology. These groups recently updated the recommendations. How this new assay will be received by these societies, I’m not sure.

A key question, in this author’s mind, is where the Her2 measurements take place, and whether women should rely on local labs’ assays – by whatever method – to determine the Her2-ness of their breast tumors.

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More News On Lymph Nodes and Breast Cancer Surgery

Last week the New England Journal of Medicine (NEJM) printed a major research article on lymph node dissection in breast cancer surgery. When I first saw the Times’ recent headline, I thought it would cover this paper: Effect of Occult Metastases on Survival in Node-Negative Breast Cancer.*

It turns out there were separate articles on axillary node dissection after sentinel node biopsy in breast cancer – one in JAMA and one in the NEJM – published a week apart. For some reason, the NEJM paper got little attention in the media.

In the work reported in the NEJM, investigators based at the Univ. of Vermont evaluated if the presence of occult metastases – cancer cells found upon further examination of dissected lymph node specimens after the sentinel nodes were deemed negative – affects survival in women with early-stage breast cancer. What they found was that yes, it does: there’s a small but significant reduction in overall survival and disease-free survival at 5 years in women who have “negative” sentinel nodes but turn out, upon more detailed path inspection, to have some malignant BC cells in the armpit.

Kinda scary for someone like me, who had a negative sentinel node. The Vermont investigators determined that 16% of us have occult mets. Of those, 11.1% would be isolated tumor-cell clusters (less than 0.2 millimeters in greatest dimension), 4.4% micrometastases (between 0.2 and 2 millimeters) and 0.4% macrometastases (larger than 2 millimeters), all as classified by the American Joint Committee on Cancer.

On the other hand, the results were generally favorable all-around:

“The 5-year Kaplan-Meier survival estimates for patients in whom occult metastases were detected were 94.6% for overall survival, 86.4% for disease-free survival, and 89.7% for distant-disease–free interval; the survival estimates for patients in whom occult metastases were not detected were 95.8%, 89.2%, and 92.5%, respectively.”

Some details on the well-done study I feel compelled to insert here, a vestige of my thrice-weekly-journal-clubs-in-academic-medicine days:

The Vermont study is strong from a statistical standpoint: The researchers examined stored pathology samples from 5611 women with operable, clinically node-negative BC who were already registered in a large multicenter clinical trial (NSABP B-32). The study participants were randomized to receive either sentinel node dissection or sentinel node dissection followed by full axillary lymph node dissection.

It was a prospective analysis, and the median time on study was just under 8 years. Of the 5611 women enrolled, 3887 (~70%) had negative sentinel nodes and sufficient pathology material available for evaluation. Oncologists treating the patients were “blinded” to the data regarding occult mets, so that they wouldn’t be influenced in their treatment decisions. Among the women with negative sentinel nodes, 1927 underwent sentinel node dissection followed by axillary node removal and 1960 got sentinel node dissection only (based on the earlier randomization).

One result not emphasized in the paper was that removing additional nodes, after the sentinel lymph node exam, didn’t affect the clinical outcome in women with or without occult mets. This finding ties in with this week’s JAMA report, covered separately.

It’s a long article, probably of more interest to pathologists and BC oncologists than to the average reader here. There’s a lot interesting detail, including subtle results of planned subgroup analyses, on the prognostic significance of different kinds (sizes) of occult mets.

I know from my experiences – mainly lately as a friend of people with BC who, in the past few years since sentinel node studies have become the norm – that these issues regarding the significance of occult mets bear on everyday decisions patients make together with their oncologists: how much chemo to take?; should I get radiation to the axilla if there’s a tiny cluster of cells found?; should we add Taxol to the regimen? etc.

These are very real, every-day questions in oncology, and the answers aren’t obvious. But I do think the carefully-established findings reported in this paper will shed light, in an incremental sort of way, on how to best treat BC in women who have negative sentinel nodes at surgery.

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An Oncologist Considers Rare Lymphomas in Women With Breast Implants

I have to admit that when I first read about the FDA’s report tying rare cases of anaplastic large cell lymphoma to breast implants, my mind raced with a strange blend of excitement, intense interest and concern. My thoughts shifted from “wow, that’s really interesting” to “exactly what did the FDA find” to “should I be worried?”

So I’ve decided to write this morning’s post from my perspective as an oncologist who spent roughly 15 years of her life studying the causes of lymphomas and related blood malignancies. Some readers of this blog, who fortunately at this point in ML’s slow-but-steady growth are mainly strangers, may be unaware that understanding rare lymphomas was what I lived for in my research work, which occupied the bulk of my time and thought, which I loved very much (as strange as that may seem to some) and which I miss intensely, still, today.

The reality, as very-carefully documented by the FDA in its excellent analysis (which, in my opinion, far surpasses that of most case series reported in the medical literature; I’d give the agency an A+ for detail, thoroughness, clarity and openness about the limitations of the findings thus far), is that these cases of ALCL are few and far between: a total of 60 cases, worldwide, as I reviewed in yesterday’s post. Sometimes just a few cases are indicative of a problem, and I think that is exactly what’s going on with these rare lymphomas.

The pathology is interesting: Essentially all of the ALCL cases are T-cell derived and express CD30. Anaplastic lymphoma kinase (ALK) was negative in each of 26 cases examined for that receptor. The findings are plausible in the context of an aberrant immune response – which can occasionally become malignant – to a foreign body or particular antigen associated with the implants. These oddly uniform characteristics among these rare lymphoma cases support that the FDA’s findings are not random.

Most of the ALCL tumors were limited to the area of the implant capsules, and could – as best I can tell from the few reports – be treated by removal of the implants and affected, adjacent breast tissue. These don’t appear to be aggressive lymphomas, as are some ALCL’s. I would go as far as to speculate that these might indeed be antigen-driven tumors; in this light, it would make sense in principle and in practice to treat these by removal of the implants, at least as a first-line approach.

So if I had a patient with this condition, I’d tell her that these lymphomas are very rare and, when they do arise, can usually be treated by removal of the implant. But I wouldn’t down-play the risk, which is tiny but real.

As an oncologist, I found most of the coverage of the FDA’s alert disappointing, the discussion dominated by plastic surgeons’ reassurances and device makers’ dismissals. Statements like “a woman is more likely to be struck by lightning than get this condition” – proffered by an Allergan spokeswoman as quoted and emphasized in the WSJ Health Blog, Bloomberg News, LA Times and elsewhere – are not helpful to women with implants who are genuinely concerned about their health.

Because I understand that once a woman has had one form of cancer, her risk of developing another tumor is elevated – from whatever genetic, environmental or other disposition she has for malignancy, and from treatment toxicity. Most of the women I’ve seen with implants after mastectomies have some problems considered minor – like thickening of the capsule and dimpling in peri-implant tissue. But these are the exact sort of abnormalities as described in the FDA’s alert, for which there is now a recommendation: evaluate and report cases to the FDA.

Ultimately this is an issue about informed consent – and I don’t mean by this the paperwork, but the reality of women with choosing, or not, to get breast implants. Doctors need more information about these rare lymphomas: how often these arise, why they occur, and how they should be managed so as to cause the least harm when and if treatment is necessary.

The FDA provides a helpful list of sources, from which I’ve selected those that seem most relevant (see reference page). Of historic interest, also, is a NEJM perspective from 15 years ago on the debate about rheumatologic illness, the public’s perception and risks associated with breast implants.

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Suggestions to Reduce Errors in Breast Cancer Pathology

A prominent article in yesterday’s New York Times considers some troubling problems regarding inaccuracy in breast cancer diagnosis and pathology. The main point is that some women get needless, disfiguring and toxic treatments after being told they have breast cancer when, it turns out, their condition was benign.

My main take on this situation – which doesn’t just apply to breast cancer – is that, whenever possible, patients should get a second opinion on biopsy results before undergoing major treatment. The costs of a second pathology review is sometimes covered by insurance, but sometimes it’s not; either way, that’s money well-spent, especially if the opinion is rendered by an appropriately-credentialed, expert pathologist who works in a state-of-the-art facility.

From the doctor’s perspective there’s responsibility, too. Surgeons shouldn’t lop off a woman’s breast without knowing that the pathology is real. Well-trained oncologists know they’re supposed to review the pathology, to make sure the diagnosis is true, before giving chemo. The Times story indicates that the Cancer Treatment Centers of America has a specific policy in this regard, that doctors there must review the pathology for patients who are new to their system. This wise policy, common in some hospitals and tumor boards such as where I practiced, makes it less likely that oncologists or other doctors will give inappropriate treatment.

From an administrative standpoint, there could be better regulation to assure quality. Pathologists who are employed, busy evaluating tumor specimens without supervision, should be board-certified and required to be up-to-date in the specialized fields of their practice. And laboratories (as opposed to pathologists who work there) should be closely monitored because pathology errors can arise from faulty stains, use of poor-quality or old reagents, incorrect calibration of a machine, lack of appropriate “controls” for each batch of cases evaluated, etc.

A related story appeared earlier this year, also in the Times, on the variability of pathology reports. That article reported on how different pathology labs provide disparate results on whether a breast tumor has estrogen and progesterone receptors in the malignant cells, and whether the malignant cells express Her2 – the target of Herceptin – or not. The lack of agreement among pathologists renders treatment decisions difficult. The piece focused on a physician who couldn’t decide if she should take Herceptin or not, because she received conflicting reports about her tumor.

Getting the diagnosis right underlies many cancer care problems and undue costs. If I were an insurance company executive, I’d recommend that my firm cover the costs of a second pathology opinion in all cases. It’s far less costly to find out that a “tumor” is not really malignant than to pay for surgery, chemotherapy and radiation that’s not needed.

Better still, I’d insist that biopsy specimens be evaluated by pathologists who are trained in current methods and who work in trust-worthy laboratories.

Such a policy would reduce false positives in cancer diagnosis, and would thereby reduce the toxicity and costs of unwarranted cancer treatments. With better diagnostic facilities, those patients who do have cancer would not be so afraid to undergo the treatments they really need, because they’d be confident that they and their doctors were making decisions based on reliable information.

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Why Blog on OncotypeDx and BC Pathology?

A few days ago I wrote on a relatively new pathology tool called OncotypeDx. This device measures expression of 21 genes in tumor cells to establish the likelihood a cancer will recur. For women with early-stage, ER+ tumors that haven’t yet spread to the lymph nodes, the OncotypeDx results stratify patients into three groups – those having a low, intermediate or high risk for recurrence at 10 years.

As things stand, chemotherapy is routinely prescribed for most women with early-stage BC after initial treatment by mastectomy or lumpectomy and radiation. But the overall relapse rate is fairly low (around 15% at 5 years, higher over time depending on other factors) for women who take an anti-estrogen pill like tamoxifen. Chemo reduces the recurrence rate by approximately one third. The problem is that women and their doctors don’t know in advance who’s likely to benefit.

Here’s why this is important:

What happens now is that most women choose to undergo treatment even though it’s unlikely their cancer will come back. This – the problem of overtreatment – was one of the main concerns to emerge from the mammography screening debate.

The original OncotypeDx data, which have been considered here and elsewhere, support that most women with low recurrence scores are unlikely to benefit from chemo. So if women and their doctors could access the kind of information provided by OncotypeDx, at a cost of ~$3800 each, tens of thousands of women with BC and low risk scores might opt out of chemo treatments each year.

For example, if a woman’s recurrence score is less than 18, the likelihood of a relapse within 10 years is only 7%. Such a patient might happily and rationally choose not to take adjuvant chemotherapy.

I can’t even begin to think of how much money this might save, besides sparing so many women from the messy business of infusions, temporary or semi-permanent IV catheters, prophylactic or sometimes urgent antibiotics, Neulasta injections, anti-nausea drugs, cardiac tests and then some occasional deaths in treatment from infection, bleeding or, later on, from late effects on the heart or not-so-rare secondary malignancies like leukemia. And hairpieces; we could see a dramatic decline in women with scarves and wigs.

So why doesn’t every woman with eligible (ER+, node-negative) BC get an OncotypeDx readout, or some other modern pathology report, such as Mammaprint, that’s available and already FDA-approved? (OncotypeDx is just an example, really, of an advance in science that’s moving at a snail’s pace into the clinic.)

One issue, perhaps, is that it’s challenging for some doctors to learn about this test sufficiently that they’re comfortable with it. Quantitative RT-PCR, the method by which RNA is measured in the assay, wasn’t invented until around 1990, long after many practicing oncologists completed school. And as for the particular 21 genes measured – they’re unfamiliar to most physicians I know. Now, you might say that it doesn’t matter – if the device works, the doctor doesn’t have to understand the underlying technology. But a black box-like approach to clinical cancer decisions is far from ideal.

From the physician’s perspective, it may be easier, and perhaps legally safer, simply to prescribe the chemo – which she knows well and uses all the time – than to engage in a decision-making process using new methods and terms she doesn’t fully command.

Besides, there’s a conflict of interest: many oncologists, hospitals and infusion centers make money by giving infusions of chemotherapy. Identifying a large subset of patients who wouldn’t benefit from chemo may not be a priority for some clinicians. In a recent JCO paper, half of the oncologists’ initial recommendations for a combination of chemotherapy and hormonal treatments changed to hormonal treatment (without chemo) upon seeing the patients’ OncotypeDx scores.

An ongoing large, NIH-sponsored TailorRx trial involving 10,000 patients aims to clarify the potential benefit of this test. I’m concerned that by the time those results are available, with relapse rates and survival curves at 5 and 10-years, the technology in science and availability of new treatments may persuade doctors, then, to question the trial’s relevance. Meanwhile, hundreds of thousands of women will be treated off protocol, many without this sort of information, in a sort of blinded guessing game about the chances of recurrence and whether or not they should take chemo.

For now I hope that all women with newly-diagnosed BC, and their physicians, know about OncotypeDx and other tools, and their potential to inform decisions regarding chemotherapy.

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More News, and Considerations, on OncotypeDx

This week I’ve been reading about new developments in breast cancer (BC) pathology.

At one level, progress is remarkable. In the 20 years since I began my oncology fellowship, BC science has advanced to the point that doctors can distinguish among cancer subtypes and, in principle, stratify cases according to patterns of genes expressed within tumors. This sort of information – cancer cell profiling – might inform prognosis and influence treatment decisions that BC patients and their doctors, usually oncologists, make every day.

What disappoints is the slow pace by which this knowledge infiltrates the clinic. In practice, women and their physicians rarely have much more information on BC pathology than what was available two decades ago – the tumor size in its largest dimension (crudely measured in centimeters), whether it’s spread to the lymph nodes (and if so, how many nodes), the type of cancer (based on the cells’ appearance under a light microscope: infiltrating ductal, lobular carcinoma and other BC forms) and whether the cells express a few key molecules including estrogen receptors (ER).

In the past five years, more laboratories are offering data on Her2 in BC samples. This complex molecule, an epidermal growth factor receptor, normally transmits signals from a cell’s surface to the interior. Her2 expression dictates the BC subtype in some newer classifications of the disease and usually determines the cells’ responsiveness to Herceptin, a monoclonal antibody treatment. Still, there’s been some controversy, in part due to variation among lab facilities in the reproducibility of Her2 testing results.

The problem is this: if pathologists don’t provide accurate, valid results on Her2 expression in BC cells – which can be measured by various methods – it’s hard for women and their physicians to make sound decisions based on the molecule’s expression. And Her2 is just one of dozens of molecules that can be measured in BC. The reason it’s tested, for the most part, is to foster decisions on Herceptin treatment and also, perhaps to a lesser extent, to provide prognostic information.

What puzzles me is why so few use better, modern pathology and other decision tools. Technologies like Mammaprint, Adjuvant! and OncotypeDx have been available for years but aren’t used routinely in most clinical settings. So I thought I’d do some more research and, in future posts, will consider each of these and other, relevant technologies.

For today I’ll focus on OncotypeDx.  This test, manufactured by the Redwood City, California-based Genomics Health, assesses BC recurrence risk in cases that are ER+, node negative (see below). As cancer gene testing panels go, OncotypeDx is a baby, based on expression of just 21 genes by a two-decade old method called quantitative RT-PCR. The test intrigues me; I’ve posted on it once before.

No doubt, my interest in OncotypeDx is intensified by my personal history of BC. My case was exactly the sort of ER+, node-negative tumor for which OncotypeDx is intended; often I’ve wondered what would have been my tumor’s recurrence score (RS) and if knowing that would have affected my decision to undergo treatment with adjuvant chemotherapy.

Some background terms –

ER+ means that the cells express hormone receptors, for estrogen, at the surface;

Node negative means that the breast cancer has not spread to the lymph nodes, or glands, of the armpit. (Axilla is the medical term for armpit. Axillary lymph nodes are normal immune organs that drain fluid including potentially foreign particles from the breast, chests and nearby arm. The nodes can swell if there’s an infection to which the body reacts, if malignant cells infiltrate the gland and sometimes due to autoimmune diseases like lupus.)

So an ER+, node negative breast tumor is one in which the cancer cells are sufficiently differentiated, or mature, to produce and bear hormone receptors at their surfaces and in which the tumor cells haven’t yet migrated to the armpit (or at least haven’t done so at a level that can be detected by a pathologist).

Real-Time, Reverse Transcriptase (RT) – Polymerase Chain Reaction (PCR) is a standard method for amplifying tiny amounts of nucleic acids such that they can be measured and sequenced. Standard PCR usually amplifies DNA whereas in RT-PCR, RNA transcripts are converted to DNA before amplification in a machine. This method can assess the amount of RNA, or message for a particular gene, that’s expressed in a pathology sample.

Adjuvant therapy refers to additional, or extra, treatment that’s given after initial cancer surgery to reduce the chances of the tumor’s recurrence.

Back to OncotypeDx –

This pathology tool predicts the likelihood that ER+, node-negative BC tumors will come back within 10 years of a woman’s primary treatment (mastectomy, or lumpectomy with radiation) usually followed by tamoxifen. The assay measures each of 21 genes in a panel and, using those results, calculates a “recurrence score” (RS) between 1 and 100. The higher the RS, the more likely the cancer will re-emerge after treatment.

According to the Genomics Health website, the test measures RNA in BC tumor specimens for the following transcripts:

Groups of genes measured in OncotypeDx assay, according to the manufacturer
cell proliferation tumor invasiveness growth factor receptors hormone responsiveness other genes of interest reference** genes
Ki-67

STK15

Survivin*

Cyclin B1

MybL2

Stromelysin 3

Cathepsin L2

Grb7

Her2

ER

PR (progesterone receptor)

Bcl-2*

Scube2

GSTM1

CD68

BAG1

Beta actin

GAPDH

RPLPO

GUS

TFRC

*In my opinion, survivin and bcl-2 might be better classified distinctly; the products of these genes inhibit apoptosis (programmed cell death).

**These “housekeeping” genes are not of known significance in BC pathology. Rather, they serve as controls in the assay for the quality of the RNA sample, and for comparison to other measured genes.

The OncotypeDx results are reported by risk group, as follows:

Low risk (RS <18, the 10-year recurrence rate was 7% in NSABP study – see below)

Intermediate (RS 18 – 30, the 10-year recurrence rate was 14%, in same);

Higher risk (RS >31, the 10-year recurrence rate was 30%, in same).

The tool has been tested in multiple clinical trials for its capacity to predict BC recurrence after surgery and tamoxifen in women with ER+, node-negative tumors. The study most-cited, and from which the above statistics are drawn, was published in the New England Journal of Medicine in 2004, based on a retrospective analysis of 668 cases by Genomics Health in collaboration with investigators of the National Surgical Adjuvant Breast and Bowel Project (NSABP, a large, NIH-sponsored, multicenter cancer research effort).

OncotypeDx has been on the market since 2004. The cost of one assay runs near $3800, and most U.S. insurance plans including Medicare will cover it. Tumor samples, set in fixative, are sent to a single lab – a Genomic facility – that’s regulated according to the Clinical Laboratory Improvement Amendments of 1988 (CLIA). The whole process takes 10-14 days. Still, the FDA has not approved the test for use as a decision-making tool.

Meanwhile, an NCI-sponsored trial called TAILORx will recruit and evaluate 10,000 women with ER+, node negative disease. Those investigators will determine, prospectively, if decisions based on OncotypeDx results can safely spare women with low RS the side effects and toxicity of chemotherapy without compromising their survival.

Why Oncotype and other new BC pathology tools matter –

In the U.S., the number of women who learn they have an ER+, node-negative BC approximates 100,000 per year. The question of adjuvant therapy – whether a woman should take tamoxifen or another hormonal agent and/or chemotherapy after surgery to reduce the risk of recurrent disease – is crucial.

If patients and their doctors could access more detailed molecular information about each case, they’d have a better sense of whether adjuvant treatment is likely to help in their particular situation. This approach would, potentially, spare many individuals with early-stage BC the costs, toxicity and hassle of unneeded chemotherapy. At the same time, it would help patients with small but riskier tumors by informing them that they have a high RS and thereby would more likely benefit from added therapy. Fewer women would receive chemotherapy, driving down costs, and the risks of additional treatment would be assumed only by those with a high likelihood of recurrence.

Some numbers here might help:

Overall, for women with ER+, node-negative tumors the chances of cancer recurring five years after primary treatment (mastectomy, or lumpectomy and radiation) followed by tamoxifen are around 15%. Over time that risk rises – BC can strike back after 10, 15 years or even later; the recurrence rate is said to approach 30% over time. In general, a basic chemotherapy regimen – something like CMF – cyclophosphamide (Cytoxan), methotrexate and 5-fluorouracil (5FU) reduces the probability of recurrence by about a third.

So if 100 women with node-negative tumors have to decide whether to take chemotherapy after surgery +/- radiation, or not, without a tool like OncotypeDx or another modern pathology test, they’re making those decisions based on very crude approximations of their odds. Because they don’t know whose tumors will recur, most if not all of their oncologists will recommend chemotherapy. And most women do choose to undergo the extra treatment because they’re afraid that, otherwise, there’s a greater chance the cancer will come back.

This is exactly the situation I faced in November, 2002, when I had an ER+, node negative, 1.5 cm tumor. Then, I reasoned that BC tends to be more aggressive in younger women. With hopefully more decades ahead in my life – more time, in effect, for the disease to recur – an 85% disease-free rate at 5 years wasn’t good enough. So I went for the chemo and upped my chances to the 90% range. Not a big difference in the stats, but I wanted to position myself on the upper branch of that Kaplan-Meier curve. Now, had I known my recurrence score based on the pattern of gene expression in the tumor cells, that information would have been useful. But it wasn’t an option then and, unfortunately, it’s still rarely available to most women who are undergoing treatment for BC in 2010.

The slow pace of progress, science in hand, is kind-of shocking.

So what’s new with OncotypeDx?

Two months ago, I reviewed a small study published in the ACS Cancer journal on the experiences of most of 100 women with newly-diagnosed breast cancer whose oncologists used the OncotypeDx assay to evaluate their cases. In that, two-thirds of the women reported they “understood a large amount or all” of what the doctors told them about the results and nearly all said they would undergo the test if they had to decide again.

In its April 1 issue the Journal of Clinical Oncology (JCO) published two relevant reports and an editorial. These papers support that OncotypeDx offers useful information to women with early-stage breast cancer and that it can assist patients and doctors in care decisions, in some cases providing support for them to choose a chemotherapy-free treatment regimen.

One study, a “Prospective Multicenter Study of the Impact of the 21-Gene Recurrence Score Assay on Medical Oncologist and Patient Adjuvant Breast Cancer Treatment Selection” by Dr. Shelly Lo and colleagues, followed the analysis and prescribing patterns of 17 medical oncologists at 3 diverse academic medical centers and one community hospital. Genomic Health, provided free OncotypeDx kits and testing at their central lab for all 93 patients with ER+, node-negative BC who enrolled in the trial.

The mean age of the women was 55 years (range 35 – 77). The oncologists were asked to state their treatment preferences (hormonal treatment with or without chemo) before and after receiving the OncotypeDx results for their patients. What happened was this:

Before seeing the OncotypeDx results, the oncologists recommended chemo and hormonal therapy (CHT) to 42 of the 89 women for whom the study was completed. In 20 of those 42 cases (22% of the total, and nearly half of those women who were to receive chemo) the doctors changed their recommendation from CHT to HT (hormones only) upon reviewing the OncotypeDx report. In 8 cases, the oncologists switched their recommendation to include chemotherapy. In total, the OncotypeDx results influenced the oncologists’ preferences in 31% of the cases – nearly a third.

As for the patients – 74 of the 89 (83%) said the OncotypeDx results influenced their treatment decision. The assay report persuaded 9 patients in the group to opt for a less aggressive (chemo-free) approach. The majority (78 women, 95% of those responding) said they were glad they used the OncotypeDx assay. According to the paper, many patients felt reassured by the assay findings and benefited from a diminished perceived risk of recurrence (less worry, in effect).

The upshot is that the OncotypeDx assay – which costs around $3800 per evaluation – led to significantly fewer women with early-stage breast tumors getting chemotherapy in this trial of 89 patients. The doctors were more confident in their decisions to not give chemotherapy in cases with low RS and, overwhelmingly, the women felt glad about the decision-making process.

In the second JCO study in the April 1 issue, the number of patients evaluated was much greater – over a thousand. But this was a more complicated analysis in which the investigators applied OncotypeDx to old tumor samples and then, upon reviewing those cases in some well-documented randomized trials, examined how the cases fared in relation to the RS. What they found was that OncotypeDx score predicted the likelihood of loco-regional recurrence (LRR) in women who had node-negative, ER+ disease.

Bottom line –

The OncotypeDx tool has been on the market for 6 years. It has, in multiple and well-done studies, identified patterns of BC gene expression that accurately predict the likelihood of recurrence in women with early-stage, ER+, node-negative tumors. This should, in principle, reduce administration of chemotherapy – along with its attendant risks, costs and side effects – to women whose tumors are unlikely to relapse. Recent trials show that doctors find the results useful and that patients find it helpful in their decisions.

I can’t know for sure why the tool’s not used more often. But I have some concerns:

1. It takes time for doctors – even knowledgeable oncologists – to learn about this device, to know how it differs from other BC pathology tests like Mammaprint and decision tools (like Adjuvant!) and then it takes even more time for those physicians to discuss the results with their patients.

From the perspective of a physician sitting behind her desk or at a table with a newly-diagnosed BC patient, saying “this is what I think, you need treatment X” may be a lot easier than “well, let’s go over these OncotypeDx results…”

2. If the OncotypeDx report does indeed identify large subgroups of early-stage breast cancer patients who don’t need chemotherapy, the use of this test would reduce the number of patients who get chemotherapy. Oncologists, infusion centers and others generate income by prescribing chemotherapy. So there’s a potential conflict of interest.

3. Perhaps some physicians fear lawsuits for not giving chemotherapy to women who, without the OncotypeDx results, would receive it.

4. Some doctors might not recommend OncotypeDx because they don’t really understand the test, its merits and limitations.

5. Maybe OncotypeDx isn’t the best of the new BC adjuvant therapy decision tools. For this reason, among others, I will consider some of the other methods available in future posts.

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