Considering Evidence for a New Drug for Immune Thrombocytopenia Purpura

I’ve been wondering, lately, why so many of the medical blogs cover the same topics, like last week’s lung cancer detection trial, which are often the exact same studies as are reported by conventional news outlets. I’ve been trying, here, to sometimes consider new published articles that seem important to me but, for whatever reasons, don’t get so much attention.

Here’s one:

Yesterday’s NEJM includes an article Romiplostim or Standard of Care in Patients with Immune Thrombocytopenia.* It’s about a drug, manufactured and sold by Amgen as NPlate, that received FDA approval for treatment of chronic immune thrombocytopenia purpura (ITP) in August, 2008. Some consider ITP a rare disease, and I suppose it is; my perception is skewed by the fact that as a practicing hematologist I saw patients with ITP almost constantly in the clinic and hospital. In patients with this autoimmune condition, the body produces pathologic antibodies that bind and lead the tiny, clot-forming blood cells to destruction. Sometimes patients with chronic ITP need treatment, such as steroids, surgical removal of the spleen (splenectomy) or other drugs that raise the platelet count and reduce their risk of bleeding.

The new-ish drug, romiplostim, is effective in raising the platelet count in most patients who are said to have chronic ITP. It’s similar to another platelet-stimulating agent, eltrombopag, that’s manufactured and sold by GlaxoSmithKline under the brand name Promacta. Eltrombopag received FDA approval for the same condition in November, 2008.

So long before reading the thoughtful editorial* by Dr. James George, this hematologist was impressed by the availability of two agents that work by stimulating platelet production in the bone marrow. Dr. George considers the possibility that these new drugs alter the usual but debatable algorithms that most hematologists use in caring for patients for ITP. He acknowledges having consulted to the study’s sponsor, Amgen, on this drug and serving as an investigator in clinical trials, and considers:

…In this randomized study, 85 investigational sites in 14 countries enrolled 234 patients…The conclusions are clear. The outcomes were better in patients receiving romiplostim than in patients receiving standard care (short of splenectomy): romiplostim was associated with a greater incidence of a sustained platelet response, less bleeding and fewer transfusions, a decreased requirement for other treatments (including splenectomy), and greater improvement in quality of life. The side effects of romiplostim therapy were minimal, but …confidence about the safety of the drug requires that more patients be observed for a longer time. Because patients treated with romiplostim had better outcomes, does the work of Kuter and colleagues establish romiplostim as the new standard of care?

As I read the original study results, this issue – of possibly changing the standard of care in this disease – became evident. His question is on-point.

The problem is this: In the study, the authors treat a total of 234 patients who are said to have chronic ITP. But, if you look closely at the eligibility for enrollment, besides having a low platelet count (defined for the study as less than 50,000 platelets per microliter of blood, which in itself is a questionable criterion), examination of a bone marrow-biopsy specimen was required to confirm the diagnosis of immune thrombocytopenia in patients older than 60 years. According to Table 1 in the paper, the median age for study participants was 57 years. This means that more than half of the participants were under 60 years and, as far as we know, they did not have a diagnostic pathology test for ITP. They might instead have a myelodysplastic syndrome or other bone marrow disorder that was missed.

Why this matters, besides to patients who have low platelets and their hematologists, is that it’s really a problem in the practice of evidence-based medicine. If data are derived and published from fundamentally flawed studies, in which the patient groups who respond or don’t to a particular intervention are not well-defined by careful diagnostic parameters, the conclusions we draw from those studies may be incorrect.

I am definitely in favor of evidence based medicine, but we need to be careful in how we evaluate the results of published studies, even in the best of journals, and how we incorporate those findings into recommendations for care.

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*subscription required

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Five Ways to Improve the Quality and Success of Breast Cancer Screening by Mammography

Here are some ideas on how we might reduce the incidence of metastatic breast cancer, by making high-quality mammography available to all women:

1. Modernize all breast imaging facilities. All should comply with the Mammography Quality Standards Act and Program (MQSAP) of 1992.

2. Ensure that radiologists, technicians and other BC screening workers are up to date: requirements for continuing medical education in an academic, unbiased (non-pharma or biotech setting), should be strict. We depend on practitioners’ current knowledge of breast imaging methods, breast biopsy techniques, hygiene, information technology (IT) and patient privacy laws.

3. Implement digital mammography in all screening facilities; Digital images allow radiologists to adjust the contrast, magnify or otherwise highlight areas of concern, to better analyze potential lesions without subjecting patients to extra x-rays.

4. Supplement mammograms with sonograms of the breasts. These inexpensive tests can help radiologists discern cysts and other benign lesions from malignant tumors. In some situations, a radiologist inspecting a sonogram can spot a small solid abnormality that’s missed in a mammogram. In principle, this low-rad combo – of digital mammography and breast sonography – would increase sensitivity and specificity of breast cancer screening.

(5.) Consider transmitting digital images to breast screening centers, so that expert radiologists can review every woman’s films.

As Sue, a woman who’s had breast cancer told me last month: “You don’t want a radiologist who’s just looked at someone’s broken foot examining your mammogram.” She’s right: Expertise can make a huge difference in clinical outcomes.

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A Lead Poisoning Outbreak in Nigeria, Plumbism and Anemia

Over 400 Nigerian children have died from lead poisoning this year, the Times reported yesterday. The outbreak is centered in five villages in the northwestern state of Zamfara.

Small-scale gold mining in the region leads to lead toxicity, as follows: “In an attempt to extract gold from ore rich with lead, miners crush and dry the ore, often inside their own homes. The soil and in some cases the groundwater get contaminated,” according to an Oct 5 field report from Doctors Without Borders/Médecins Sans Frontières (MSF).

I learned long ago that lead poisoning is sometimes called plumbism, stemming from plumbum, the Latin term for lead (Pb, atomic number 82), a metal used by plumbers. A rarer term is Saturnism, based on the metal’s association with the planet and ancient Roman god.

Now, in the U.S., lead poisoning most commonly comes from environmental toxins like lead-based paint. It affects children, who may eat flakes of peeling, lead-based paint or accidentally ingest lead by licking or eating toys or jewelry that contain this toxic metal. The problem occurs in adults, too, typically from unknown sources.

The EPA provides some helpful information on its website. Lead poisoning can be subtle; common symptoms are fatigue and poor concentration. Doctors may detect anemia, and upon inspection of a patient’s red blood cells might find characteristic basophilic stippling. The National Institute of Environmental Health Sciences (NIEHS) reports that lead toxicity declined dramatically from 1980 to 2000 in the U.S.

lead poisoning; arrows point to characteristic basophilic stippling (attr: Herbert L. Fred, MD and Hendrik A. van Dijk, Wikimedia Commons)

In northwest Nigeria, MSF workers are treating some of the affected children and nursing mothers with chelating agents; these metal-binding compounds clear lead from the bloodstream and, to some extent, remove it from body organs where it’s already deposited. The World Health Organization (WHO) issued a bulletin on lead poisoning from gold-mining in Nigeria in June, 2010.

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Why It’s So Hard to Assess False Positives, and How We Might Reduce Them

It’s been nearly a year since we “learned” about the false positives issue, and still there’s hardly any data published on this much-maligned cost of breast cancer screening by mammography.

From the U.S. Preventive Services Task Force November 2009 paper in the Annals, on the lack of information on the incidence of  FP’s:

“Published data on false-positive and false-negative mammography results, additional imaging, and biopsies that reflect current practices in the United States are limited. The probability of a false-positive screening mammography result was estimated at 0.9% to 6.5% in a meta-analysis of studies of sensitivity and specificity of mammography published 10 years ago <ref. 38>. The cumulative risk for false-positive mammography results has been reported as 21% to 49% after 10 mammography examinations for women in general <39–41>, and up to 56% for women aged 40 to 49 years (41)

False positives happen in mammography when a woman has an abnormal result that looks like it might be breast cancer, but upon a further workup – which might involve another, more expert radiologist taking a look, or a sonogram, or an MRI, or even a breast biopsy, but in the end the problem turns out not to be breast cancer.

Why is it so hard to ascertain how often false positives occur?

1. The rate of false positive mammograms is, most likely, declining (i.e. the number is in flux).

Reduced errors would result from two factors: improved methods, such as by adaptation of digital mammography, and by more careful application of extant technology due to progressive compliance with the FDA’s Mammography Quality Standards Act and Program.

2. There’s no precise definition of what constitutes a false positive in mammography, and what isn’t. As I’ve suggested previously, finding a pre-malignant condition like LCIS or an early-stage malignancy like DCIS should not be “counted” as a false positive. If over-treatment occurs, that reflects an error in clinical decision-making rather than in mammography, per se.

3. The false positive rate varies among radiologists and medical centers. That’s because a radiologist who spends her days doing nothing but reading mammograms and breast sonograms will, overall, have a lower FP rate than a general radiologist who also handles hip fracture films and MRIs of the brain.

What are financial costs of false positives? I’m not aware of any new data on this.

How can we reduce the costs of false positives in mammography? My suggestions:

1. Radiologists should be well-trained and carefully-credentialed. As in surgery and other fields in medicine, the physician’s skills and experience affects the probable outcome.

2. Avoid doing breast biopsies in an operating room whenever possible. A fine needle aspirate or core needle biopsy, performed under local anesthesia, is almost always sufficient for diagnosis and less costly.

3. Thinking for the future: Maybe, one good application of Telemedicine would be in sharing digital mammography images, so that no matter where a woman lives, her test could be checked by a radiologist working in a central cancer center and who specializes in breast imaging.

4. Do the procedure every other year for women of average risk for breast cancer (rather than annually). Quite a few theoretical calculations of mammography costs “stack” the purported costs by assuming the procedure is done every year, but there’s no data to support such frequency.

In sum, there’s every reason to think the rate of false positives in screening mammography is falling and that costs from errors will diminish in the future.

Many, if not all, of the costs attributed to false positives will be reduced by advances in technology, better training of radiologists, and education of physicians (oncologists, surgeons, primary care physicians) who recommend the procedure and make decisions based on the results.

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What’s Missing in the Recent Mammography Value Study

This week’s New England Journal of Medicine includes an article*on the potential benefit of breast cancer (BC) screening by mammography. The paper, authored by a group of epidemiologists and biostatisticians from the Cancer Registry of Norway, Harvard University, the Dana Farber Cancer Institute and Stockholm’s Karolinska Institutet, suggests that mammography has a relatively small influence on survival.

The work, along with an accompanying editorial* by H. Gilbert Welch, M.D., M.P.H., got front-page attention in the Times and elsewhere. My friends want to know why this particular research study was featured and, really, what it showed.

So here’s my take –

The analysis:

The researchers studied chronological trends in BC diagnosis and mortality in Norway. To see if mammography had an effect, they divided the country into two groups, “screening” and “non-screening,” based on when a state-sponsored mammography screening program was implemented in each of 19 counties there. The national plan, which required that each region establish a centralized, multidisciplinary BC care team before participation, began in 4 counties in 1996 and gradually expanded to include all of Norway by 2005. According to the authors, all Norwegian women between the ages of 50 and 69 years have been asked to participate in screening mammography since 2005; 77% have done so; Norway’s nationwide cancer registry is nearly 100% complete.

They evaluated a total of 40,075 women (“subjects”) who received a diagnosis of BC between 1986 and 2005.

Major findings:

For women between the ages of 50 and 69, BC-associated mortality** fell from 25.3 to 18.1 in counties where a government-sponsored mammography program was implemented early on, and from 26.0 to 21.2 in counties where mammography was not covered, over a similar time frame. Because BC-associated mortality declined in all regions of Norway, regardless of whether mammography was offered, the authors conclude that screening can’t account for all the reduction in mortality.

By their calculations, mammography accounts for roughly 10 percent of the enhanced survival. (This finding was not statistically significant.)

The authors suggest that recent progress in BC survival – which in their study improved significantly in all regions of Norway – comes, for the most part, from better care and treatments.

What’s wrong with the paper? I see several key flaws:

1.  The average follow-up is only 2.2 years after diagnosis, with a maximum follow-up of 8.9 years (“Results,” p. 1206). This is far too short a follow-up interval to measure the benefit of mammography or any sort of intervention in women with breast cancer. When BC recurs it’s often after several years and, occasionally, decades later.

2. Among women under the age of 50 there was a slight increase in BC-mortality noted: A non-significant relative increase in mortality, of 4%, after the introduction of the screening program for older women (p. 1207, Table 1). This worrisome finding is not adequately addressed by the authors; one might wonder – did fewer women in their forties go for mammograms after 1996, since they were only recommended and covered for older women? (My concern is that reduced screening, now, in younger women might lead to an increase in BC mortality.)

3. Digital mammography was not evaluated in this study.

4. The authors detected the greatest benefit of screening among women with Stage II BC; there was a “marked” 29% reduction in mortality relative to the historical counterparts for that group who were screened, as compared to only a 7% reduction in mortality for women with Stage II tumors in counties where screening was not available over the same historical interval (p. 1207). This observation suggests that mammography screening is most life-saving for women with Stage II tumors. As an oncologist, I find this highly-plausible; the purpose of mammography is to identify tumors in early stage and spare women morbidity and mortality associated from advanced disease.

5. There’s no mention of the absolute number of lives saved by the procedure according to the authors’ calculations, but I think this is an important number to keep in mind when we assess the procedure’s value. If the paper’s conclusion is true – that mammography reduces BC-associated deaths by just 10 percent – then in Norway, with a total population of 4.8 million and where some 4,791 women in the study died (p. 1206), these results support that mammography spared approximately 480 lives in those 20 years.

My spin:

Mortality in the U.S. from breast cancer has declined by roughly a third since the implementation of wide-spread mammography screening. Here, where some 45,000 women die each year of BC, we’d save 4500 lives per year if the added value of mammography is just 10 percent, as suggested by the new study. If the benefit of screening mammography is higher – in the range of 45 percent, as was supported by a 2007 paper, also published in the NEJM – then the value would exceed 20,000 women’s lives per year. If the benefit is only 25 percent in terms of reduced mortality, that would result in over 11,000 lives saved, per year in the U.S.

As for the editorial, first I’ll say that the opening statement – that “no screening test has ever been more carefully studied than screening mammography,” is misleading. While this was, indeed a well-organized and careful study, among other issues it was far too short in patients’ follow-up to measure the impact of mammography on BC survival. The Annals papers, which caused so much controversy last year, relied heavily on old data and did not at attempt to examine the efficacy of digital mammograms.

What’s needed, still, for public health policy in the U.S. is evidence regarding the long-term outcomes after digital mammography performed in FDA-regulated, modern facilities by skilled, board-certified radiologists applied every other year in women who are over the age of 40 in the context of modern, adjuvant treatments and current pathology methods.

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As for the analysis by G. Kolata in the Times, where she wrote:

“…it indicates that improved treatments with hormonal therapy and other targeted drugs may have, in a way, washed out most of mammography’s benefits by making it less important to find cancers when they are too small to feel.”

I’d say the opposite is true:

It’s precisely because there are effective treatments for early-stage disease that it’s worth finding breast cancer by mammography. Otherwise, what would be the point?

Metastatic breast cancer is quite costly to treat and, even with some available targeted therapies, remains incurable.  Despite so many advances in treating early-stage BC, the survival rate at 5 years is under 25 percent for women with Stage IV disease.

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*abstract available, otherwise by subscription

**mortality rates: per 100,000 person-years

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Perspective on Screening for Sickle Cell Trait in Student Athletes

Today I watched a video, The Student-Athlete with the Sickle Cell Trait, sponsored by the National Collegiate Athletic Association (NCAA) on its website. The 12-minute presentation provides some helpful background on what it means to have sickle cell trait and how awareness of that condition might influence a student’s (or coach’s?) behavior during rigorous conditioning and competitive sports.

“The more medical information we know about our student athletes, the better equipped we are to help keep them safe,” says Mark Richt, Head Coach at the University of Georgia, at around 3 minutes into the clip.

A new NCAA policy mandates screening all Division I college sports participants for sickle cell trait. Not coincidentally, the Sept 9 issue of the New England Journal of Medicine opens with a noteworthy perspective* on this topic. The screening recommendation, effective at the start of this academic year (i.e. now) directly affects more than a few young adults in the U.S.: among nearly 170,000 athletes who’ll be tested this year, it’s expected that several hundred “carriers” will be identified.

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The Physical Exam’s Value is Not Just Emotional

Lately there’s been some talk about the value of the physical examination. It’s my sense that this discussion was sparked by a lovely piece by Danielle Ofri published two weeks ago in the New York Times. In that, Dr. Ofri describes a patient’s visit in which, toward the end and almost as an afterthought, she pulled out her stethoscope and performed a physical exam in a perhaps cursory but essential, thoughtful manner.

Or is it so cursory? There’s little scientific evidence to support the physical exam in practicing medicine but, as she writes:

…Touch is inherently humanizing, and for a doctor-patient relationship to have meaning beyond that of a business interaction, there needs to be trust — on both ends. As has been proved in newborn nurseries, and intuited by most doctors, nurses and patients, one of the most basic ways to establish trust is to touch…

KevinMD picked up on the story, essentially echoing the idea in a post called “Touch Humanizes the Doctor-Patient Relationship.” In that, he considers that some doctors (including him, previously) dismiss the physical exam obsolete – “like staying with a horse and buggy when cars are rapidly becoming available.”

It happens I know something about physical exams. Early in my years as a junior faculty member at Cornell’s medical school, around 1994, I was assigned to teach physical examination to second-year students during each of two consecutive spring semesters. To prepare for teaching, I carefully reread my copy of Bates’ Guide to Physical Examination.

my old copy of Bates’ Guide to Physical Examination, on my desk now

Together, my students and I listened to normal and abnormal heart sounds. We looked in each others eyes with ophthalmoscopes. We visited some of my patients with lymphadenopathy (swollen glands), big livers and palpable spleens who were willing to let us learn from their pathological physical findings. We listened and described course and fine rales on some pneumatics’ lung exams, and checked arthritic joints for swan-like deformities characteristic of rheumatoid arthritis. We examined patients’ petechiae, purpura, ecchymoses and more, and discussed the differences among those findings and what they might signify. All of this we did without CT scans or echos.

I know also, as a patient, that physical examination can be life-saving. Once, when I was in the hospital as a child and had unexplained fevers after surgery, it seemed for a while that no one could figure out what was wrong. I was terrified. The surgical team consulted with an infectious disease specialist, who as I recall ordered a whole bunch of unpleasant tests, and then my dad – a physician – noticed that one of my legs was more swollen than the other. He realized, based on my physical exam, that I might have a blood clot. It turned out that he was right.

So I agree that the physical exam is humanizing. So much so that, later in my career when I routinely donned space suit-like gowns and masks on rounds for the leukemia and bone marrow transplant services, I became frustrated by those barriers, and by the very lack of touch which, I think, can help patients heal.

But what’s also true, in a practical and bottom-line sort of way, is that a good physical exam can help doctors figure out what’s wrong with patients. If physicians were more confident – better trained, and practiced – in their capacity to make diagnoses by physical exam, we could skip the costs and toxicity of countless x-rays, CT scans and other tests.

Recently I wrote a piece on medical education and going back to basics. The physical exam should be included, for sure.

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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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DNA Comes Home, or Maybe Not

Earlier this month employees at most of 7500 Walgreens pharmacies geared up to stock a new item on their shelves: a saliva sampler for personal genetic testing. On May 11, officials at Pathway Genomics, a San Diego-based biotech firm, announced they’d sell over-the-counter spit kits for around $25 through an arrangement with the retailer. A curious consumer could follow the simple package instructions and send their stuff in a plastic tube, provided in a handy box with pre-paid postage, for DNA analysis.

DNA helix structure (Wikimedia Commons)

Once the sample’s in the lab, the cost of genomics testing depends on what, and how much, you want to know. Pathway offers a variety of options. A pre-pregnancy planning report would check to see if you carry mutations for each of 37 inherited diseases – conditions as varied as beta thalassemia, cystic fibrosis and familial Mediterranean fever – for $179. A profile of tests for genes involved in metabolizing specific drugs, such as Plavix and Coumadin, goes for $79. A vaguer, health conditions panel suggests a propensity to develop particular diseases including Type II diabetes and melanoma. This series runs $179 if purchased separately, but might be had for less through a discounted package rate. A genetics ancestry evaluation lists for $249.

Within two days, after some controversy and a receipt of a letter from the FDA Office of In Vitro Diagnostic Device Evaluation and Safety addressed to James Plante, Founder and CEO of Pathway (dated May 10), Walgreens nixed the plan. Now, Congress wants to know more about direct-to-consumer personal genomics testing. On May 19, the House Committee on Energy and Commerce sent letters to Plante and the CEOs of two major competitors – Navigenics and 23andMe. House Committee Chairman Henry Waxman and colleagues have some questions about how samples are processed and the accuracy of the results:

“The Committee is requesting information from the companies on several aspects of the tests:  How the companies analyze test results to determine consumers’ risk for any conditions, diseases, drug responses, and adverse reactions; the ability of the companies’ genetic testing products to accurately identify any genetic risks; and the companies’ policies for the collection, storage, and processing of individual genetic samples collected from consumers.

The Federal Trade Commission has cautioned consumers about genetic testing kits since 2006.  Still, personal genomics tests are readily through available on-line sales. You can get the 23andMe “DNA Test for Health and Ancestry Information” from the manufacturer or at Amazon.com for $499. Navigenics takes a distinct approach by marketing its genetic tests strictly as a laboratory service for medical practitioners and so, thus far, avoids some rules regarding in vitro diagnostic tools.

New York State, my home, is one region where Walgreens wouldn’t have sold the kits in stores. That’s because of stricter state laws regarding genetic testing.

Dan Vorhaus, writing for the Genomics Law Blog, provides a considered analysis:

At present, whether a genetic test is subject to FDA regulation largely depends on how it is developed and marketed. The literature, as well as current FDA regulatory policy, divides genetic tests into two primary categories:

(i) in vitro diagnostic test kits (also sometimes referred to as IVD kits or, simply, as genetic test kits), which may be sold by their manufacturers directly to consumers, testing laboratories, clinicians or other approved recipients, depending on the device; and

(ii) laboratory developed tests (or LDTs, also sometimes referred to as “home brew” assays), which are not sold directly to the general public or to physicians; rather, a testing service (as opposed to the actual test itself) is marketed, and samples (e.g., of saliva) are collected and submitted to the laboratory for evaluation.

The FDA regulates IVD kits as medical devices…

Up until now personal genomics testing companies have had few constraints, and little profit. What’s clear from the recent news is that we’ll be hearing more about these kits – their manufacture, distribution, accuracy and interpreting results. And that doctors, for our part, have some serious studying to do. Whether the test results go directly to patients, or not, they’re sure to raise many legitimate questions. We’ll need some solid answers about the testing process in itself, besides meaningful responses about what’s found in our DNA.

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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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Uncertainty Rules (on Eyjafjallajokull, volatility and a patient’s prognosis)

(on Eyjafjallajokull, volatility and a patient’s prognosis)

Eyjafjallajökull, April 2010 (Wikimedia Commons, attr: David Karnå)

As pretty much anyone traveling in Europe this week can tell you, it’s sometimes hard to know what happens after an unusual, disruptive event. Volcanologists – the people most expert in this sort of matter – can’t say for sure what the spitfire at Eyjafjallajokull will do next.

It comes down to this: the volcano’s eruption could get better or it could get worse. Or it might fluctuate for a while. If the situation persists, there’s no telling if its course will stutter, like seizures of varying intensity in a person with untreated epilepsy, or if it will flare sporadically like disease exacerbations in patients with MS and then, with some luck, peter out.

Some wonder if the ash might spread westward over the ocean, affecting distant cities like New York and Chicago. Unlikely, it seems to me, but this is far afield from my area of expertise.

What I do know is oncology, and so how I’m thinking about Eyjafjallajokull in medical terms – I want to know the prognosis: how bad and extensive will be the damage, how much will it cost, and in a few weeks or (please, volcanologist, don’t say it could be months) from now, how we can know for sure when the situation has cleared.

Aside from a few pulmonologists who rushed in to say there’s not much to worry about the silica-laden aerosolized dust particles, most scientists who’ve been interviewed have been cautious. I admire their candidness about what they don’t know.

For example, yesterday NPR’s All Things Considered offered this assessment:

“The volcanic eruption that has grounded planes and closed airports throughout Europe appears to be slowing down. But before travelers start rejoicing, Icelandic scientists have a warning: The eruption could start up again any time.

The website of the American Geophysical Union offers some explanations provided by Dr. John Eichelberger, Volcano Hazards Program Coordinator at the U.S. Geological Survey who, it happens, was grounded in Europe after attending a scientific conference:

“Although we’re pretty good at saying when an eruption will start, we’re not so good at saying when it’s going to end. You go mainly on the basis of history, what the volcano has done before. In the case of this volcano, the last time it erupted it was active for over a year. The other factor is how the wind is blowing…

Today, the BBC published several scientists’ opinions including these differing views:

Dr John Murray, an Earth scientist from the Open University in Milton Keynes, said that the ash had “significantly diminished” and the ice over the crater itself had melted…”This is the stage we have been waiting for: the steam explosions due to water being trapped within the erupting lava will have virtually ceased, and the activity has changed to lava outpouring,” he said. …Ash may resume at any time, but it is likely to be less pronounced and prolonged than before.”

But Dr Sue Loughlin from the British Geological Survey pointed out that a decrease in the volcano’s activity might not mean the end of the eruption all together. “There’s seismic activity ongoing, which means the eruption is ongoing…

You get the idea, a volcano in Iceland exploded for the second time in two months, putting much of Europe at a stand-still. Business travelers, vacationers, and companies had to stop and make new arrangements and even compromises. Disappointment and frustration ensued, besides some anger toward those whose job it is to decide if it’s safe to fly.

Going back to medicine – I’m thinking of a patient I once cared for with a non-Hodgkin’s lymphoma. When her disease struck, she was a young mother like me who led a complicated life with lots of responsibilities.

The type of lymphoma she had was uncommon; she sought multiple expert opinions regarding her exact diagnosis and treatment. My colleagues and I didn’t all agree about chemotherapy and radiation, and she was uncertain of how to proceed. Ultimately she opted for surgery and six months of chemotherapy. At the end of all that, she wanted to know if the lymphoma would come back.

“We can never be sure,” I told her. There’s really no choice but to watch and wait.

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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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Skyping Medicine

Yesterday, Dr. Pauline Chen reported in the New York Times on virtual visits, a little-used approach for providing care to patients hundreds or thousands of miles apart from their physicians.

Telemedicine depends on satellite technology and data transfer. It’s a theoretical and possibly real health benefit of the World Wide Web, that giant, not-new-anymore health resource that’s transforming medicine in more ways than we know.  Chen writes:

Telemedicine has the potential to improve quality of care by allowing clinicians in one “control center” to monitor, consult and even care for and perform procedures on patients in multiple locations. A rural primary care practitioner who sees a patient with a rare skin lesion, for example, can get expert consultation from a dermatologist at a center hundreds of miles away. A hospital unable to staff its intensive care unit with a single critical care specialist can have several experts monitoring their patients remotely 24 hours a day.

I’m reminded of three things:

First, my recent visit to my internist’s office on East 72nd Street, a short walk from my home. When I see my doctor she smiles warmly, shakes my hand firmly and examines me from head to toe. She takes my blood pressure with an old-fashioned sphygmomanometer, looks at my eyes and into my throat, applies a stethoscope to my scarred chest as she listens to my heart and lungs, and palpates – “feels” in doctorspeak – my lymph nodes, liver and spleen. All that along with a neurological exam; she sees how I stand, walk and balance my head over my torso.

Second, my husband’s conversation with his mom yesterday evening, via Skype, transmitted between his laptop in our living room and her computer in a Buenos Aires apartment.

Third, some history from the 1950s – on how early computer scientists envisioned the future of medicine. From my master’s thesis at Columbia University’s Graduate School of Journalism, on how the “How the Internet is Changing the Practice of Oncology”:

When Vladimir Kozmich Zworykin addressed the 1956 assembly on “Electrical Techniques in Medicine and Biology,” he marveled at the technological feats of computers, and envisioned how these new instruments might be applied in health care. Zworykin, an inventor of television …was privy to the newest developments in applied science.

…He’d seen closed-circuit “Telecolor Clinics” that transmitted the latest cancer research news to physicians in cities along the eastern Seaboard and Great Lakes Region. A color, television microscope linking monitors in Philadelphia, Washington and Baltimore enabled doctors in one city to identify cancer in another…

We’re back in the future! My take on telemedicine includes three components; each corresponds to one association above.

1. Telemedicine is not the same as real medicine. I like seeing my doctor in real life and am reassured by her true presence in the room.

Besides, a hands-on exam has some tangible benefits. A good doctor, who knows how breathing sounds should sound, confident in her examination skills, might skip an x-ray she’d otherwise order. A competent hematologist, skilled in palpating her patients’ lymph nodes, liver and spleen, could spare us the costs and risks of some CT scans and MRIs.

Of course, the doctor’s hands should be clean… (a topic unto itself)

2. Virtual visits might help. The reality of medicine requires innovation and compromise – making the best of a sometimes difficult situation.

As Pauline Chen points out in her column, there’s a shortage of doctors affecting some, particularly rural, parts of the U.S. Policy experts anticipate the problem won’t go away with current health care reform measures, and some business reports warn the situation will get worse. Telemedicine, while not ideal, might ameliorate this effect and make a positive difference in the health of people living far from major medical centers. The technology could, indeed, connect patients with specialists who would otherwise be out of reach.

3. The future of medicine will embrace some elements of telemedicine. We just need to fine-tune the process.

As I see it, Internet or satellite-directed medical examinations are most promising for image and data-centric fields like radiology and pathology. It’s telling that Pauline Chen’s first example pertains to dermatology (skin diseases). Sure, I think a far-away expert’s view of a skin lesion could be helpful – it might reassure some that a mole or a rash is nothing to worry about, or inform them that indeed, they should hop on a train to Memphis. For patients with benign-appearing lesions, telemedicine could save costs and time in travel and unnecessary appointments, besides biopsies.

But I’m wary of implementing this tool in primary care areas and interventional fields like surgery and obstetrics. The prospect of delivering babies upon real-time instruction by doctors in cities far away is not what I’m hoping for, at least not for my kids’ kids.

I guess we’ll have to wait and see.

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Looking Ahead on Breast Cancer Screening

My plan is to move on after this post – too much is happening in medicine to dwell on the mammography issue longer, or at least for the time being.

So I’ll close on the 2009 screening controversy with a few comments and considerations for the future.

Breast cancer, along with lymphoma and a few other tumors, is one of the few malignancies that oncologists can treat effectively in the majority of cases – well enough that most women with the disease now live for an essentially normal lifespan. About the risks and costs of breast cancer screening, I think they’re exaggerated and misrepresented in the recent news.

My concerns are chiefly three – as outlined elsewhere and previously here:

1. The Task Force analyzed data that are decades old;

2. The updated recommendations don’t apply to digital mammography (a fact rarely mentioned in the press coverage);

3. Radiologists vary in training and skill.

My conclusion is that rather than ditching a life-saving procedure that’s imperfect, we should make sure that all doctors and radiology facilities are up to snuff.
——–
On the reputed risks of mammography, harms and costs stemming false positive test results –

The risks of mammography should be minimal if the FDA does its job regulating the procedure. Among women in their forties and fifties, the number of false positives in Category I (as outlined in my proposed classification) can be reduced by digital technology supplemented with sonograms, an inexpensive and safe procedure.

Clerical-type errors shouldn’t happen, as in all of healthcare. Put simply, the system needs be scrupulous.

False positives due to misunderstanding of results, as in Category 2, can be resolved by better education and more effective communication.

Regarding the costs of follow-up testing by sonograms, MRIs, and biopsies – the medical risks and financial costs can be minimized through more careful, besides current, evaluation of each method. Just this month, an article in the Annals of Internal Medicine described the value of core needle biopsy (by any of several methods) in evaluating breast lesions. This technology, in widespread use over the ten years, renders open biopsy – a procedure done in an operating room – obsolete; there’s no reason to consider operating room costs in assessing breast biopsies in 2010.

As for the risk of over-treatment, I think doctors and patients have a lot learn and discuss, carefully. My take on the news of the past season is that somehow there’s been a blurring of facts for different cancer types.

For decades, oncologists including me have recommended a “watchful waiting” approach for some elderly men who have prostate cancer. This sort of treatment, while often appropriate for a 75 or 85-year old man with a small prostate tumor, is irrelevant to the decisions facing a 45 year old woman with breast cancer, another disease entirely.

Going back to my definition of a false positive in mammography screening –

We need to distinguish between errors in the measurement (cancer or not) and errors in decisions that we – patients and doctors – make after upon detecting a premalignant or early-stage malignancy in a woman’s breast.

A finding of either DCIS or LCIS upon biopsy does not constitute a false positive result. Rather, it’s good medicine to identify these conditions, especially for a middle-aged woman who anticipates a meaningful half-life ahead. What goes wrong after the diagnosis, such as a rushed or ill-informed decision to treat only subtle pathology, is not a mistake from mammography.

Errors in over-treating small tumors, and all the physical and financial costs associated, should be attributed instead to a lack of knowledge regarding DCIS and LCIS. Our understanding of these conditions – the molecular and cellular pathology, the course over time if left untreated, and the effects of medication, surgery and other therapies – lags far behind what we know about most forms of breast cancer.

What I hope we can learn, through clinical trials over the next decade, is how best to treat low-grade conditions such as DCIS and LCIS. That way, the costs of over-treating those will not, come 2020, cloud what should be straightforward decisions on the diagnosis and treatment of breast cancer in relatively young women.

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Proposed Model for Evaluating False Positives in Screening Mammography

First, a definition* –

False positives happen in screening mammography when the images suggest the presence of a malignancy in a woman who doesn’t have cancer in her breast.

Here’s my proposed model –

Categories of False Positives in Screening Mammograms

False positives can arise during any of three conceptual segments of the testing process:

1. False positives occur during the test itself.

This happens when a radiologist inspects a film or digital image and labels the result as abnormal, but no cancer is present. This sort of problem is interpretive.

A common scenario goes like this – a spot in a mammography image suggests the presence of a possible tumor and the radiologist correctly notes that abnormality; later on, a doctor determines by sonogram, biopsy or another method that there is no malignancy in the breast.

(Other, uncommon problems in this category would include faulty equipment that reduce image quality, mislabeling or accidental switching of films; in principle, these kinds of errors should be non-events.)

2. False positives stem from miscommunication or misunderstanding of test results.

If a clerk accidentally phones the wrong patient and tells her she needs another procedure because the results of her mammogram are abnormal, that call might instigate an untoward, false positive result. If the error is corrected early on, so that affected woman worries only for a period of hours and has difficulty sleeping for one night, she might experience some psychological and/or small financial cost from the matter. But if the mistake isn’t caught until after she’s had a sonogram or MRI, and consulted with a surgeon or another physician, the costs grow.

False positives also arise if a patient misunderstands a test result. An essentially normal mammography report, for example, might mention the appearance of benign calcifications. Upon reading that result, a woman or her husband might become upset, somehow thinking that “benign” means “malignant.” This type of false positive error, based in poor communication and lack of knowledge, can indeed generate extra doctors’ visits, additional imaging tests and, rarely, biopsies to relieve misguided fears.

3. False positives derive from errors or misinterpretation of results upon follow-up testing.

This category of false positives in screening mammography is by far the biggest, hardest to define and most difficult to assess. It includes a range of errors and confusion that can arise after breast sonograms, MRIs and breast biopsies.

3a. false positives in subsequent breast imaging studies such as sonograms and MRIs:

Many women in their forties and early fifties are premenopausal; their estrogen-stimulated breasts tend to be denser than those of older women. Reading their mammograms may be less accurate than for postmenopausal women. For this reason, a doctor may recommend a sonogram or MRI to further evaluate or supplement the mammography images.

These two radiology procedures – sonograms and MRIs – differ and, for the most part, are beyond the scope of this discussion except that they, too, can generate false positive results. A sonogram, for instance, may reveal a worrisome lump that warrants biopsy. MRIs are more expensive and sensitive; these tend to pick up subtle breast irregularities including a relatively high proportion of benign breast lesions.

3b. false positives in breast biopsy:

A breast biopsy is an invasive procedure by which a piece of the gland is removed for examination under the microscope. Sometimes pathologists use newer instruments to evaluate the genetic, protein and other molecular features of cells in the biopsy specimen. Years ago, surgeons did the majority of breast biopsies. Now, skilled radiologists routinely do a smaller procedure, a core needle biopsy, using a local anesthetic and a small albeit sharp instrument that’s inserted through the skin into the breast. Some doctors do a simpler procedure, fine-needle aspiration, by which they remove cells or fluid from the breast using a small needle attached to a syringe.

In principle, a false positive biopsy result would occur only when a pathologist, a physician trained to examine tumors at the cellular and molecular levels, misreads a case, meaning that he or she reports that the cells appear cancerous when they’re not. Fortunately, this is not a frequent issue in breast cancer diagnosis and management.

The real issue about false positives – and what may be the heart of the issue in mammography screening – has to do with how pathologists describe and define some premalignant conditions and low-grade breast tumors. This concern extends well beyond the scope of this tentative outline, but a few key terms should facilitate future discussion:

Lobular Carcinoma in Situ (LCIS) is not considered a malignancy by most oncologists, but rather an abnormality of breast glands that can develop into breast cancer.

Ductal Carcinoma in Situ (DCIS) is a Stage 0 breast tumor – a tiny cancer of breast cells that have not penetrated through the cells lining the ducts of the breast gland.

Indolent or “slow” tumors – The idea is that some breast cancers grow so slowly there’s no need to find or treat these.**

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*This definition warrants some discussion, to follow in a separate post.

**As a physician and trained oncologist, I am uncomfortable with the published notion of some breast tumors being “so slow” that they needn’t be found or evaluated. I include these tumors only for the sake of completeness regarding theoretical types of false positive results upon screening mammography, as there’s been considerable discussion of these indolent tumors in recent news.

Slow-growing breast tumors are quite rare in young women. In my view, their consideration has no bearing on the screening controversy at it pertains to women in their forties and fifties.

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As outlined above, the first two categories of false positives seem relatively minor, in that they should be amenable to improvements in quality of mammography facilities and technology; the third category is huge and where lies the money, so to speak.

Clearly there’s more work ahead –

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Legitimate Concerns and Unfortunate Timing on Radiation from C.T. Scanning

This week’s cancer news features a study in the current issue of the Archives of Internal Medicine, first reported by Reuters:

CHICAGO (Reuters) – Radiation from CT scans done in 2007 will cause 29,000 cancers and kill nearly 15,000 Americans, researchers said on Monday:

…The findings, published in the Archives of Internal Medicine, add to mounting evidence that Americans are overexposed to radiation from diagnostic tests, especially from a specialized kind of X-ray called a computed tomography, or CT, scan.

The risks of radiation from CT scanning will almost certainly add to the current confusion and concerns about the risks of breast cancer screening.

Mammography differs from CT scanning in several important ways:

1. Mammograms involve much less radiation exposure than CT scans.

According to the American Cancer Society, a typical mammogram uses between 0.1 to 0.2 mSV per image. So even if multiple images are taken of each breast, the total dose remains under 1 mSV.

Another source, the Health Physics Society, estimates a dose of 0.7 mSV per mammogram. So if a woman were to have a screening mammogram every other year between the ages of 40 and 49, she’d receive approximately 3.5 mSV in total from those procedures.

By contrast, a single CT scan involves over a 10-fold greater amount of radiation (such as 8 mSV for a CT of the chest, 10 mSV for a CT of the abdomen) according to the Health Physics Society fact sheet.

2. Mammography is well-regulated by the Food and Drug Administration (FDA) and other agencies.

The Mammography Quality Standards Act (MQSA) requires mammography facilities across the nation to meet uniform quality standards. The law, first passed in October, 1992, requires all mammography facilities to 1) be accredited by an FDA-approved accreditation body, 2) be certified by FDA, or its State, as meeting the standards, 3) undergo an annual MQSA inspection, and 4) prominently display the certificate issued by the agency.

3. Women who undergo screening mammograms can control when and where they get this procedure.

Screening mammograms are elective by nature; a woman can choose an accredited screening facility and, in advance, learn something about its reputation and screening methods. Most women between the ages of 40 and 50 are capable of tracking their mammograms, whether they choose to have those annually, biennially, or less often.

Many CT scans are ordered for patients who are in the hospital – a very different sort of circumstance. Many hospitalized patients don’t feel well, don’t understand what’s happening to them and/or lack the needed assertiveness or language skills to ask about a scan before it’s done.

Summary:

Mammography is a relatively safe and highly-regulated procedure in the U.S.  The recent news on risks from radiation in CT scanning should not confound the discussion of breast cancer screening.

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On Juno and Screening Test Stats

——–
“Well, well” says the convenience store clerk. “Back for another test?”

“I think the first one was defective. The plus sign looks more like a division symbol, so I remain unconvinced,” states Juno the pregnant teenager.

“Third test today, mama-bear,” notes the clerk.

Juno recluses herself and uses a do-it-yourself pregnancy test in the restroom, on film.

“What’s the prognosis … minus or plus?” asks the clerk.

…”There it is. The little pink plus sign is so unholy,” Juno responds.

She’s pregnant, clearly, and she knows she is.

(from Juno the movie*)
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Juno\’s pregnancy test
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Think of how a statistician might consider Juno’s predicament – when a testing device is useful but sometimes gives an unclear or wrong signal.

Scientists use two terms – sensitivity and specificity – among others, to assess the accuracy of diagnostic tests. In general, these terms work best for tests that provide binary sorts of outcomes – “yes” or “no” type situations. Sensitivity refers to how well a screening tool detects a condition that’s really present (pregnancy, in the teenager’s case). Specificity, by contrast, measures how well a test reports results that are truly negative.**

Juno’s readout is relatively straightforward – a pink plus sign or, not; the possibilities regarding her true condition are few.

Still, even the simplest of diagnostic tests can go wrong. Errors can arise from mistakes in the procedure (a cluttered, dirty store is hardly an ideal lab environment), from flawed reagents (the package might be old, with paper that doesn’t turn vividly pink in case of pregnancy) or from misreading results (perhaps Juno needs glasses).

Why does this matter, now?

The medical and political news are dense with statistics on mammograms; getting a handle on the costs of cancer screening requires more information than most of us have at our disposal.

Of course, breast cancer is not like pregnancy. Among other distinguishing features, it’s not a binary condition; you can’t be a little bit pregnant.  (Both are complicated, I know.)

To get to the bottom of the screening issue, we’ll have to delve deeper, still.

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*Thanks Juno, Dwight and everyone else involved in the 2007 film; details listed on IMBD.

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**I was surprised to find few accessible on-line resources on stats. For those who’d like to understand more on the matter of sensitivity and specificity, I recommend starting with a 2003 article by Tze-Wey Loong in the British Medical Journal. This journal, with a stated mission to “help doctors to make better decisions” provides open, free access to anyone who registers on-line.

I’ll offer an example here, too:

To measure the accuracy of Juno’s kit, a statistician might visit a community of 100 possibly pregnant women who used the same type of device. If 20 of the women are indeed pregnant (as confirmed by another test, like a sonogram), but only 16 of those see the pink plus sign, the sensitivity of the test would be 16/20, or 80 percent. And if, among the 80 women who aren’t due, 76 get negative results, the specificity would be 76/80, or 95 percent.

False negatives: among the 20 pregnant women 4 find negative results; the false negative rate (FN) is 4/20, or 20 percent.

False positives: among the 80 women who aren’t pregnant 4 see misleading traces of pink; the false positive (FP) rate is 4/80, or 5 percent.

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Stats in the News!

False positives have hit the headlines.

Check the New York Times, Wall Street Journal, CNN – they’re everywhere. Even the Ladies’ Home Journal skirts the subject.

The discussion on mammography runs something like this: studies show that cancer screening save few lives. Among women younger than 50 years, there’s a high rate of false positive results. Those misleading tests lead to more imaging procedures such as sonograms and MRIs, additional biopsies and, necessarily, higher screening costs.

Women are ignoring the numbers, choosing reassurance over hard facts. Some say members of the pro-mammogram camp are irrational, even addicted.

The best response is to look carefully at the research findings.

Two recent publications sparked the current controversy: one, a single paper in the Journal of the American Medical Association and the other, a cluster of articles in the most recent Annals of Internal Medicine. Using a variety of research tools, the authors in both journals examine the effectiveness of cancer screening. Here, the investigators consider the risks and benefits of mammography from a medical perspective; they don’t focus on monetary aspects of the issue.

The problem of false positives in mammography is most-fully addressed in the AnnalsScreening for Breast Cancer: An Update for the U.S. Preventive Services Task Force. The authors assess, among other newsworthy subjects (such as the value of breast self-examination) the potential risks and benefits of mammography. In the Results section, they delineate five sorts of mammography-associated harms (see “key question 2a”):

1. Radiation exposure – not a big deal, the exposure level’s low;

2. Pain during procedures – women don’t mind this, at least not too much;

3. Anxiety, distress and other psychological responses – the patronizing terms tell all;

4. False-positive and false-negative mammography results, additional imaging, and biopsies – the subject of this and tomorrow’s posts;

5. Over-diagnosis – this interesting and, in my view, exaggerated issue warrants further discussion.

For now, let’s approach the problem of false positives in mammography (as in #4, above).

What is a false positive?

False positives happen in mammography when the images suggest the presence of a malignancy in a woman who doesn’t have cancer in her breast.

How often do these occur?

To their credit, the Annals authors state clearly: “published data on false-positive and false-negative mammography results, additional imaging, and biopsies that reflect current practices in the United States are limited…”

Before we can establish or even estimate the costs of false positives in screening mammography, medical or economic, we need to better define those and, then, establish the frequency with which they occur.

Turns out, the calculation’s not so simple as you might think.

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Another Take on Mammography

In my latest piece, Mammography: a Not-So-Fatalistic View, I outline reasons why the recent task force findings on mammography don’t hold.

Three key issues have escaped the headlines:

1. The expert panel carried out a careful analysis using data that are, necessarily, old;

2. The recommendations don’t apply to digital mammography;

3. Mammograms are not all the same – the quality varies by the methods used and skills of the radiologists who read them.

We need to set the bar higher for mammography. If everyone could have a state-of-the-art mammogram, as I did some years ago, followed by a sonogram to better analyze the tiny abnormalities the radiologist noted (before rushing to biopsy), the stats on cancer screening would be incontrovertible; there would be no debate.

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