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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Sad Stats for Science Knowledge in U.S. Schools

Today’s Times reports on our nation’s students’ poor science test results. The results are bleak: only 34% of fourth graders scored at a “proficient” level or higher; just 30% of eight graders scored at a proficient level or higher; 21% of twelfth graders scored at a proficient or higher level in science.

The mega-analysis, prepared by the National Center for Education Statistics, derives from 2009 testing of 156,500 fourth-graders and 151,100 eighth-graders, with state-by-state and nationwide metrics of those, and of 11,100 twelfth-graders. Student scores were ranked at one of three science knowledge levels for each peer group: advanced, proficient and basic, as defined by the Department of Education. Only a tiny fraction – as few as 1 or 2% of students – attained “advanced” scores on the science exams.

The complete report card analyzes the data by race, sex, urban vs. rural districts, private vs. public schools and other factors, and includes interactive state maps.

These numbers don’t bode well for our future-docs, or for empowered patients. With 70-80% of high school seniors lacking proficiency in science, informed consent and meaningful participation in health decisions are just theoretical concepts for most U.S. citizens.

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Informed Consent on Paper, but Not in Reality

Over the long weekend I caught up on some reading. One article* stands out. It’s on informed consent, and the stunning disconnect between physicians’ and patients’ understanding of a procedure’s value.

The study, published in the Sept 7 Annals of Internal Medicine, used survey methods to evaluate 153 cardiology patients’ understanding of the potential benefit of percutaneous coronary intervention (PCI, or angioplasty). The investigators, at Baystate Medical Center in Massachusetts, compared patients’ responses to those of cardiologists who obtained consent and who performed the procedure. As outlined in the article’s introduction, PCI reduces heart attacks in patients with acute coronary syndrome – a more unstable situation than is chronic stable angina, in which case PCI relieves pain and improves quality of life but has no benefit in terms of recurrent myocardial infarction (MI) or survival.

The main result was that, after discussing the procedure with a cardiologist and signing the form, 88% of the patients, who almost all had chronic stable angina, believed that PCI would reduce their personal risk for having a heart attack. Only 17% of the cardiologists, who completed surveys about these particular patients and the potential benefit of PCI for patients facing similar scenarios, indicated that PCI would reduce the likelihood of MI.

This striking difference in patients’ and doctors’ perceptions is all the more significant because 96% of the patients “felt that they knew why they might undergo PCI, and more than half stated that they were actively involved in the decision-making.”

What we have, here, is a study of informed consent, set up in a way that the doctors knew the study was ongoing – because they and their patients were participating, all in one division of one hospital – and, presumably, spent if anything more time and not less than usual talking with patients and answering questions about the procedure. (Note: this particular point is an assumption on my part, supported by the reported fact that 83% of the patients reported that their questions had been answered.)

The central finding is a failure of communication between doctors and patients about the potential benefit of the procedure: 88% of the patients, who’d signed consent, thought that PCI would prevent heart attacks and only 17% of the cardiologists at the same medical center thought the same. This matters, first, because over a million people in the U.S. undergo angioplasty each year and, more broadly, because it represents an everyday outgrowth of the  phenomenon of therapeutic misconception – when patients think a procedure has a greater potential benefit than it does.

The concept of therapeutic misconception, as was initially defined narrowly in the context of clinical trials, applies to all areas of medicine. In cancer treatment it’s a big deal but, in my experience, under-addressed. A common misconception among breast cancer patients, for example, concerns the benefit of adjuvant chemotherapy, which generally reduces the odds of recurrence by about a third. So if you have a stage II tumor with good molecular features and the odds of recurrence are somewhere around 15%, that comes down to around 10% with the treatment, which does bear significant side effects and risks. Another fairly common misunderstanding in oncology is in the area of Phase I clinical trials, in which the drugs are tested for toxic effects in humans, and to see how much people can withstand, and not for therapeutic effect.

This topic is worthy of lots more discussion than I can afford here. I do recommend reading the full article, including the methods about how the survey was done, and the editorial* in the Annals, which accompanied the paper, which like so many other provocative and significant reports in the medical literature, didn’t get much attention in the lay press.

One point the editorial considers is that, perhaps, the PCI consent form used by the study authors and said to be at a 12th grade reading level, should instead be provided at an 8th grade level, as some institutions recommend and require. I’m not so sure about this, because I think a lot of medical ideas and decisions simply cannot be communicated at a lower level without loss of content, i.e. nuanced information.

I’m eager for readers’ views on this – how often is it that doctors effectively convey why a procedure should be done or a treatment be given, and what might be done to improve the process?

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First Take On the Big C

Laura Linney as Cathy in The Big C

Last night I stayed up to watch the first episode of Laura Linney portraying a middle-aged woman in a new series called The Big C. The story is that she’s got a teenage son and a recently estranged, overweight husband who loves her. She lives in a suburban house that could use some work.  She teaches in a high school. She has a brother who’s deliberately homeless.

Her name’s Cathy – how ordinary can you get? Well, Cathy recently found out she has a terminal case of melanoma. In a change of pace, she expresses herself freely and does pretty much whatever she feels like doing.

For me, this TV situation has some big draws:

Laura Linney‘s a fine, not uninteresting actress. A few years ago she played a charming Abigail Adams in a history-minded miniseries. But I couldn’t bear to watch her miscast counterpart, Paul Giamatti, pretending to be President John Adams, so I didn’t. As in the storyline of the Big C, here’s an opportunity for Linney to shine.

Gabourey Sidibe, a young obese woman who stars in the movie Precious, may or may not be a fantastic figure on film or TV. She’s yet to be established beyond her debut and after watching last night’s episode I’m concerned already that she’s being “used” as an object for the protagonist’s preterminal beneficence. Still, she’s a definite plus.

The Big C‘s plot includes at least two “atypical” and potentially complex features. First, Cathy chooses not to take chemotherapy or other treatment. This intrigues me, and may be the show’s most essential component – that she doesn’t just follow her doctor’s advice. Second, she doesn’t go ahead and inform her husband, brother or son about the condition, at least not so far.

We’ve seen this non-communication before in movies (Susan Sarandon in Stepmom, for instance) and in real life, for most of human history. It’s too-easy for a blogger-patient-oncologist to forget that not long before our Facebook era, most people didn’t talk much about having cancer and even today, many patients prefer not to do so. Norms change.

If the point of the Big C is to broaden the dialog on cancer and talking about cancer, that’s worth a lot, still.

What’s wrong with the program? I think the doctor has some brushing-up to do about his image. He’s 31 and Cathy’s his first “case” – all of which is credible, but with the exception of an x-ray briefly revealed on the wall-mounted light-box, it’s not clear if he’s an oncologist or a dermatologist somehow offering her chemotherapy and pamphlets. His white coat is too short, in the style of a medical student’s. He uses few polysyllabic words. He looks well-rested and neat. In one strange scene, the patient and doctor meet for lunch at a pleasant outdoor restaurant. That’s not how oncology’s practiced, at least as I know it.

But I’m learning, too. And I’m wondering about the informational content of the doctor’s slick handouts, about which the protagonist, Cathy, has a vision.

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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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A Small Study Offers Insight On Breast Cancer Patients’ Capacity and Eagerness to Participate in Medical Decisions

Last week the journal Cancer published a small but noteworthy report on women’s experiences with a relatively new breast cancer decision tool called Oncotype DX. This lab-based technology, which has not received FDA approval, takes a piece of a woman’s tumor and, by measuring expression of 21 genes within, estimates the likelihood, or risk, that her tumor will recur.

As things stand, women who receive a breast cancer diagnosis face difficult decisions regarding the extent of surgery they should undergo (see the New York Timesarticle of last week, with over 200 people weighing in on this ultra-sensitive matter). Once the surgeon has removed the tumor, choices about chemotherapy, hormone modifiers, radiation and other possible treatments challenge even the most informed patients among us.

Oncotype DX and similar techniques, like the FDA-approved Mammaprint, provide a more detailed molecular profile of a malignancy than what’s provided by conventional pathology labs. For women who have early-stage (non-metastatic), estrogen-receptor positive (ER+) breast cancer, this test provides risk-assessment that’s personalized, based on gene expression in the individual’s tumor.

Oncotype DX has been commercially available since 2004. The test “reads” three levels of risk for breast cancer recurrence at 10 years: “low” if the predicted recurrence rate is 11% or less, “intermediate” if the estimated rate falls between 12% and 21%, and high if the risk for recurrence is greater than 21%.

The investigators, based at the University of North Carolina, Chapel Hill, identified women eligible for the study who had an ER+, Stage I or II breast cancer removed and tested with the Oncotype Dx tool between 2004 and 2009. The researchers sent surveys to 104 women, of whom 78 completed the questionnaires and 77 could be evaluated for the study. They distributed the surveys between December, 2008 and May, 2009.

Several factors limit the study results including the small number of participants and  that the women were treated at just one medical center (where the oncologists were, presumably, familiar with Oncotype Dx). The patients were predominantly Caucasian, the majority had a college degree and most were financially secure (over 60% had a household income of greater than $60,000). Nonetheless, the report is interesting and, if confirmed by additional and larger studies involving other complex test results  in cancer treatment decisions, has potentially broad implications for communication between cancer patients and their oncologists.

Some highlights of the findings:

1. The overwhelming majority of women (97% of the survey respondents) recalled receiving information about the Oncotype Dx test from their oncologists. Two-thirds (67%) of those women reported they “understood a large amount or all” of what the doctors told them about their recurrence risk based on the test results.

2. Nearly all of the respondents (96%) said they would undergo the test if they had to decide again, and 95% would recommend the test to other women in the same situation.

3. Over three-quarters, 76% “found the test useful” because it determined whether there was a high chance their cancer would come back.

4. The majority of respondents (71%) accurately recalled their recurrence risk, indicating a number within 4% of that indicated by their personal test results.

Taken together, these findings support that a majority of women with breast cancer whose oncologists shared with them these genomic testing results, and who filled out the surveys, had good or excellent recall of the Oncotype Dx reports and felt that the test was helpful.

As an aside, the women were asked to rate their preferences regarding their personal input in medical decisions. Among the 77 respondents, 38% indicated they prefer to have an active role in medical decisions (meaning that they prefer to make their own decisions regardless of the doctor’s opinion or after “seriously considering” the doctor’s opinion) and 49% indicated they like a shared role, together with their doctors, in medical decisions. Only 13% of the women said they “prefer to leave the decision to <the> doctor.”

What’s striking is that among these women with early-stage breast cancer, 85% said they like to be involved in medical decisions. And 96% said they’d undergo the test again. Most of the women, despite imperfect if not frankly limited numeracy and literacy (as detailed in the publication) felt they understood the gist of what their doctors had told them, and indeed correctly answered questions about the likelihood of their tumor’s recurrence.

The results are encouraging, overall, about women’s eagerness to participate in medical decisions, and their capacity to benefit from information derived from complex, molecular tests.

*The capacity of Oncotype Dx to accurately assess the risk of breast cancer recurrence has been evaluated in previous, published studies including a 2004 publication in The New England Journal of Medicine and a 2006 paper in the Journal of Clinical Oncology. The test is manufactured, run and marketed by Genomic Health, based in Redwood City, California.

The National Cancer Institute lists an ongoing trial for women with hormone receptor-positive, node-positive breast cancer that includes evaluation with the Oncotype Dx tool.

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Health Care Costs, Communication and Informed Choices

For those of you who’ve been asleep for the past year: the health care costs conundrum remains unsolved. Our annual medical bills run in the neighborhood of $2.4 trillion and that number’s heading up. Reform, even in its watered-down, reddened form, has stalled.

Despite so much unending review of medical expenses – attributed variously to an unfit, aging population, expensive new cancer drugs, innovative procedures, insurance companies and big Pharma – there’s been surprisingly little consideration for patients’ preferences. What’s missing is a solid discussion of the type and extent of treatments people would want if they were sufficiently informed of their medical options and circumstances.

Maybe, if doctors would ask their adult patients how much care they really want, the price of health care would go down. That’s because many patients would choose less, at least in the way of technology, than their doctors prescribe. And more care.

What I’m talking about is the opposite of rationing. It’s about choosing.

Several recent stories have considered the problem of physicians not talking with their patients about treatment limits. Last month the journal Cancer published a study, based on canvassing over 4000 doctors who care for cancer patients in California, North Carolina, Iowa and Alabama, revealing that only a minority of physicians would raise the subject of a DNR order or hospice care for patients with metastatic cancer and a short life expectancy.

When it comes to recommending palliative care, aimed at patients’ nutrition and comfort, rather than cure, some doctors remain tight-lipped. Many good physicians, including cancer specialists, are reluctant to stop prescribing chemotherapy and aggressive treatments. The reasons vary. Based on my experience as a practicing oncologist, I’ll list a few:

Some doctors think it’s better for their patients if they are upbeat, and this may indeed be true. Conversely, many patients choose doctors who are optimistic: if you tell patients there are no treatment options, they’ll go elsewhere. Most patients, of course, do want treatment; more than a few are desperate enough to try anything a doctor says might work.

Another, unfortunate factor is financial pressure; giving treatment and doing procedures is far more lucrative than simple exam and discussion-based visits. I’m afraid, too, that many physicians don’t recognize the extent they’re influenced by effective marketing, usually blatant but sometimes subtle.

For others it’s an ego thing – doctors try to “outsmart” a disease, even when it’s not feasible, trying one therapy and the next, to no avail.

Harder to assess, still, is doctors’ internal unwillingness to give up on some patients because they care about them so much. Some excellent doctors may become so invested in a case that they, themselves, cannot be objective.

Besides, “throwing in the towel” is not something most good doctors like to do. And it’s not something most patients want to hear about.

Yet, maybe some dying patients would appreciate a doctor’s honesty –

These issues relate directly to the practice of oncology, the area of medicine I know best. But similar hesitations and conflicts of interest arise among doctors in most fields – cardiologists caring for people with severe heart disease, neurologists caring for people with end-stage Parkinson’s, and infectious disease experts caring for people with late-stage HIV, to name a few.

If doctors could somehow find the time, and take the trouble, to talk with their patients in a meaningful way, and then heed their patients’ wishes, they might find that many patients would, of their own volition, put a brake on health care spending.

For this reason, among the changes in health care I most favor is greater support for primary care and non-procedural services. If  were paid more for thinking and communicating, rather than ordering tests and performing treatments in a perfunctory manner, they and their patients might opt for less expensive, more humane remedies.

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Henrietta’s Cells Speak

“One of the ways that I gained the trust of the family is that I gave them information.”

(R. Skloot, a journalist, speaking about her interactions with Henrietta Lacks’ family, Columbia University, Feb 2, 2010)

This week I had the opportunity to hear a terrific talk by Rebecca Skloot, author of a new, flying-off-the-shelves book –The Immortal Life of Henrietta Lacks.

Mrs. Henrietta Lacks died of metastatic cervical cancer in the colored ward at Johns Hopkins Hospital in Baltimore, MD in September 1951. She lived no more than 31 years and left behind a husband, five children and an infinite supply of self-replicating cancer cells for research scientists to study in years to come.

HeLa cells with fluorescent nuclear stain (Wikimedia Commons)

Like many doctors, I first encountered HeLa cells in a research laboratory. Investigators use these famous cells to study how cancer cells grow, divide and respond to treatments. I learned about Mrs. Lacks, patient and mother, just the other day.

Skloot chronicles her short life in fascinating detail. She contrasts the long-lasting fate and productivity of her cells with that of the woman who bore them. She connects those, and her human descendants’ unfortunate financial disposition, to current controversies in bioethics.

In the years following their mother’s death, scientists repeatedly approached her husband and asked her young children for blood samples to check the genetic material, to see if their DNA matched that of cell batches, or clones, growing in research labs.

The issue is this: her husband had but a third-grade education. The children didn’t know what is a “cell,” “HLA-testing” or “clone.”

The family had essentially no idea what the doctors who’d taken, manipulated and cloned their mothers’ cells were talking about, Skloot recounts. They thought the doctors were testing them for cancer.

Years later, when they learned that their mother’s cells were bought, sold and used at research institutions throughout the world, they became angry and distrustful. The problem was essentially one of poor communication, she considered.

“Even a basic education in science would have helped,” Skloot said. “Patients, they want to be asked, and they want to be told what’s going on.”

Well said!

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