A study of overdiagnosis due to mammography reported during Breast Cancer Awareness Month

I knew it. I just knew it. I knew I couldn’t get through October, a.k.a. Breast Cancer Awareness Month, without a controversial mammography study to sink my teeth into. And I didn’t. I suppose I should just be used to this now. I’m referring to the latest opus from H. Gilbert Welch and colleagues that appeared in the New England Journal of Medicine last night, Breast-Cancer Tumor Size, Overdiagnosis, and Mammography Screening Effectiveness. Yes, it’s about overdiagnosis, something I’ve blogged about more times than I can remember now, but it’s actually a rather interesting take on the issue.

Before 2008 or so, I never gave that much thought to the utility of mammographic screening as a means of early detection of breast cancer and—more or less—accepted the paradigm that early detection was always a good thing. Don’t get me wrong. I knew that the story was more complicated than that, but not so much more complicated that I had any significant doubts about the overall paradigm. Then, in 2009, the United States Preventative Services Task Force (USPSTF) dropped a bombshell with its recommendation that mammographic screening beginning at age 50 rather than age 40 for women at average risk of breast cancer. Ever since then, there have been a number of studies that have lead to a major rethinking of screening, in particular screening mammography and PSA testing for prostate cancer. It’s a rethinking that affects discussions even up to today. After all, it was only six days ago that I pointed out how Ben Stiller almost certainly gave too much credit to PSA testing for having saved his life from prostate cancer. Basically, screening is not the panacea that we had once hoped for, and the main reason is the phenomenon of overdiagnosis. Before I go on, though, remember that we are talking about screening asymptomatic populations. If a woman has symptoms or a palpable lump, none of this discussion applies. That woman should undergo mammography.

Basically, overdiagnosis is a phenomenon that can confound any screening program in which large populations of asymptomatic patients are subjected to a diagnostic test to screen for a disease. The basic concept is that there can be preclinical disease that either does not progress or progresses so slowly that it would never threaten the life of the patient within that patient’s lifetime. yet the test picks it up. Because we don’t have tests that can predict which lesions picked up by such a screening test will or will not progress to endanger the patient, physicians are left with little choice but to treat each screen-detected lesion as though it will progress, resulting in overtreatment. This situation is very much the case for mammography and breast cancer, for example, for which there is evidence that as many as one in five to one in three screen-detected (as opposed to cancers detected by symptoms or a mass) breast cancers are overdiagnosed. As a result, physicians are much less confident in traditional recommendations for screening mammography than we once were. Add to that the phenomenon of lead time bias, in which earlier detection doesn’t actually impact survival but only gives the appearance of prolonged survival, as I described recently in more detail. Similarly, due to the phenomenon of length bias (also described by yours truly recently), mammography also tends to preferentially detect slower growing tumors.

With that background in mind, let’s take a look at Welch’s latest. The basic idea behind the study is rooted in the key assumption behind mammography, which is that the detection of small tumors that have not yet become palpable, will prevent progression and, over time, lead to fewer large or more advanced tumors being diagnosed. Welch et al also note the difference between efficacy (how well a treatment or screening test works in randomized clinical trials) and effectiveness (how well an intervention works when “unleashed” in the community):

Although it may be possible to show the efficacy of screening mammography in reducing cancer-specific mortality in the relatively controlled setting of randomized trials, those trials may not accurately reflect the actual effectiveness of screening when it is used in clinical practice. Differences between efficacy and effectiveness with respect to the benefit of screening may be particularly stark when the treatments administered in practice have markedly changed from those administered in the trials that led to the implementation of widespread screening. Furthermore, although trial data may provide an assessment of some negative consequences of screening, such as false positive results and associated diagnostic procedures, such assessments may understate what actually occurs when screening is implemented in the general community. The collection of data regarding other harms, such as overdiagnosis (i.e., tumors detected on screening that never would have led to clinical symptoms), requires additional long-term follow-up of trial participants, and those data are often either not available or they reflect patient follow-up and testing practices from decades earlier.

This actually reflects a key controversy in breast cancer treatment. We know that breast cancer mortality has been steadily declining since 1990 or so, roughly 30% since then. The controversy is not over whether breast cancer mortality is declining. It is. The controversy is over what’s the cause: screening, better treatment, or some combination of the two. Indeed, Welch et al even note that in models used by the Cancer Intervention and Surveillance Modeling Network the estimates of the contribution of screening to the observed reduction in breast-cancer mortality range from as little as 28% to as much as 65%. To approach this question, Welch et al decided to take a very simple approach. At least, the question is simple. They decided to look at a metric that’s been measured for many years: The size of breast cancer tumors at the time of diagnosis. The hypothesis, of course, is that mammography should produce a shift towards smaller tumors. So Welch looked at breast cancer diagnoses in the SEER Database from 1975 to 2012, which encompasses the time period before the advent of mass mammographic screening in the US, the period during which screening programs were implemented, and the period after. Size at diagnosis was recorded and divided into the following groups:

  • Less than 1 cm
  • 1 - 1.9 cm
  • 2 - 2.9 cm
  • 3 - 3.9 cm
  • 5+ cm

There were a fair number of complexities, the main one having to correct for missing tumor sizes in the database, which were common decades ago but became less common as time went on. Without going into the details, I can point out that the results were as follows:

Figure 1 Size distribution

At first glance, this looks as though mammography is doing exactly what it’s supposed to be doing. Notice how, beginning in the early 1980s, there was a shift in the distribution of tumor size at diagnosis from larger tumors to smaller tumors. For example, the combination of in situ and tumors less than 1 cm increased from 11% to 40%, while the percentage over 3 cm in size decreased from 38% to 18%. So far, so good, right?

Not exactly:

Figure 2: Tumor size frequency

The observation here is that the increase in the number of small tumors was considerably greater than the decrease in the number of large tumors. Indeed, the results look very much like the results of Welch’s last study, which compared the incidence of advanced versus early cancers and found basically the same thing: The introduction of mammographic screening was associated with a greater increase in the incidence of early cancers than there was a decrease in the incidence of more advanced cancers. Thus, we have fairly consistent results showing in two different studies that, while the introduction of mammographic screening appears to have resulted in a decrease in the incidence of larger/more advanced tumors, it resulted in a far larger increase in the diagnosis of smaller/less advanced tumors. In the last study, Welch estimated the rate of overdiagnosis to be around 30%. What about in this study?

This was the magnitude of the shift:

However, this shift in size distribution was less the result of a substantial decrease in the incidence of large tumors and more the result of substantial increases in the detection of small tumors(Figure 2B). Nevertheless, modest decreases were seen in the incidence of large tumors. The changes in size-specific incidence of breast cancer after the introduction of screening mammography are shown in Table 1. The incidence of large tumors decreased by 30 cases of cancer per 100,000 women (from 145 to 115 cases of cancer per 100,000 women), and the incidence of small tumors increased by 162 cases of cancer per 100,000 women (from 82 to 244 cases of cancer per 100,000 women). Assuming that the underlying burden of clinically meaningful breast cancer was unchanged, these data suggest that 30 cases of cancer per 100,000 women were destined to become large but were detected earlier, and the remaining 132 cases of cancer per 100,000 women were overdiagnosed (i.e., 30 subtracted from 162).

This is an estimate of overdiagnosis even greater what previous studies have found, roughly 80% or 132/162 additionally detected tumors were overdiagnosed, and the estimated decrease in mortality attributable to mammography was 12 per 100,000 women in the earlier time period after mammographic screening was introduced. In more recent years, with better treatment, the estimated reduction in mortality was smaller, around 8 per 100,000. In comparison, the estimated reduction in mortality due to better treatment was 17 per 100,000. Thus, overall, better treatment has reduced mortality from breast cancer more than screening has. However, that’s not to say that mammography doesn’t save lives. It does. It’s just that the effect is more modest than previously believed.

Here’s a video video in which Welch explains his results:

Given the randomized controlled clinical trials that show a much larger reduction in breast cancer mortality due to screening mammography, why is it that more recent studies like this one show a much more modest effect of screening? Well, it’s frequently the case that “real world” effectiveness is less than what is found in clinical trials; so this observation should not come as a surprise. It should also not be a surprise that breast cancer treatment has been getting better and that that might make mammography less useful than it was 30 years ago. It’s also very complicated, as Welch points out:

There is no perfectly precise method to assess the population effects of cancer screening. Screening mammography performed in an asymptomatic population that has an average risk of cancer can, at best, have only a small absolute effect on cancer-specific mortality because the vast majority of women are not destined to die from the target cancer. Because the mortality effect is necessarily delayed in time, the availability of improving cancer treatment over time further complicates the assessment of the contribution of screening. Inferences regarding overdiagnosis are equally imprecise since overdiagnosis cannot be measured directly.

One notes that this study is also imprecise. As Joann G. Elmore, MD, MPH notes in an accompanying editorial, Welch et al rely on data with extensive missing values, forcing them to make assumptions about underlying disease burden that cannot be verified, which is why they acknowledge that their estimates are imprecise. She also notes:

We are using archaic disease-classification systems with inadequate vetting and defective nosologic boundaries. Diagnostic thresholds for “abnormality” need to be revised because the middle and lower boundaries of these classification systems have expanded without a clear benefit to patients. Disease-classification systems are often developed by experts on the basis of a small number of ideal cases and are then adopted broadly into clinical practice — a system that is antithetical to the scientific process. The National Academies of Sciences, Engineering, and Medicine recently deemed improvement of the diagnostic process “a moral, professional, and public health imperative.”10 Rigorous analytic methods are required for the development of disease nosologies, and physicians need more sophisticated tools to improve diagnostic precision and accuracy. At the patient level, we need better methods of distinguishing biologically self-limited tumors from harmful tumors that progress.

In cancer, I consider that last need to be the most critical of all. We require biological markers that tell us which of these tumors detected by mammography are safe to keep an eye on through “watchful waiting” and which are dangerous. Until we have those tools, overdiagnosis will remain a problem.

Here’s the thing. People will see what they want to see in this study. Those who believe screening saves lives will argue that the small benefit observed is worth the cost of overdiagnosis or will try to argue that Welch greatly overestimates how much overdiagnosis there is. Even so, there is a broad consensus that overdiagnosis is a problem. Indeed, new suggested mammography guidelines that have been recommended in the last few years have come about because of a desire to decrease overdiagnosis and overtreatment while maintaining early detection of potentially dangerous In contrast, the mammography “nihilists,” as I like to call them, will point to this study as saying that screening mammography is useless. However, science can never really fully answer whether a woman should undergo mammography or whether mass screening programs are worthwhile. The reason is that it boils down to a value judgment: Is a small decrease in one’s chance of dying of breast cancer worth the risk of overdiagnosis and harm from overtreatment? Many women will answer yes. Different women will make different choices, and different people will have different opinions.cancers.

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We are getting large numbers of requests for genetic panels such as OncotypeDx. How much do you think that they are really contributing to the care of patients with smaller tumors? Are they really capable of identifying the patients with more indolent cancers, or are we spending a lot of money on something that is not that helpful?

My sense is that we do not yet have a reliable way of identifying those patients who do not need to be treated.

I also think we have a cultural problem with cancer in general. I suspect that many patients who we will be able to identify as not needing treatment will insist upon having it anyway just to be sure. There are advocacy groups who are contributing to the problem as well.

By Michae Finfer, MD (not verified) on 13 Oct 2016 #permalink

OncoType DX is actually pretty darned good at differentiating between patients with ER(+)/PR(+)/HER2(-) node-negative tumors who will won't benefit from chemotherapy. Patients with a low score definitely don't benefit and, in general, shouldn't get chemotherapy. Patients with a high score should. We're still waiting for the results of the TAILORx study to narrow down the too-large "intermediate" range of scores, where benefits of chemotherapy are unclear. Better, studies have consistently shown that use of OncoType DX is associated with decreased use of chemotherapy in these patients, with no change in survival. In fact, I'm co-author on a paper just accepted that examines the uptake of OncoType DX in our state and looks at the use of chemotherapy. It's also likely that OncoType DX is useful in patients with low volume node positivity (one to three positive lymph nodes) in identifying patients who will not benefit from chemotherapy. That's not standard of care yet, but there's enough evidence that it's in the NCCN guidelines to "consider" OncoType in these patients.

Possibly a silly question. Is the size of the tumor always an indicator of it's danger / advancement? I ask this as my understanding of the stages of cancer involve metastasis to adjoining systems, and not necessarily tumor size. So does the danger of the cancer to life hinge on the size of the tumors or the spread of the tumors? A single 3cm tumor is more of a hazard then three 1cm tumors?

In regards to this study, do they consider finding a number of >1cm tumors as a single tumor equal to the total size, or do they consider it finding X number of cancers.

By Anonymous Pseudonym (not verified) on 13 Oct 2016 #permalink

That's kind of the point. In the past, size was all we had to go on. However, it's become clear that there are large tumors that are indolent and unlikely to metastasize and there are small tumors that have already metastasized when they are discovered. Mammography, however, looks pretty much only at size, shape, and associated calcifications. Clearly, that is very imperfect.

People will see what they want to see in this study:
For myself, I see that Welch assumes that breast cancer incidence has been stable after the advent of screening mammography, although he finds 132 more cases of BC a year per 100,000 women. When you begin to enter this kind of logic, you may conclude that cancer is not cancer after all and that you could treat it with homeopathy.

By Daniel Corcos (not verified) on 13 Oct 2016 #permalink

Don't start obsessing about your hobby horse yet again. Seriously, don't. I will not allow you to derail another comment thread with it. I was nice enough to take you out of automatic moderation purgatory. Please don't force me to rethink that decision, because I will if you persist.

If you have problems with the study, I suggest that you take it up with Prof. Welch or post in the comments of the NEJM article, which is open access. We've dealt with your claims about mammography more times than I can remember, and I don't have the patience for it any more.

It's not bullshit. And my comment cannot be more on topic.

By Daniel Corcos (not verified) on 13 Oct 2016 #permalink

By the way, the paper is not in open access, and I could enjoy it through my institutional library.

By Daniel Corcos (not verified) on 13 Oct 2016 #permalink

@ Anonymous Pseudonym
If you follow Welch's logic, small cancers are either very bad, metastasizing as soon as thet are detected or not harmful at all. And there is no way (and IMHO, there will be no way, never) to make the distinction.

By Daniel Corcos (not verified) on 13 Oct 2016 #permalink

Definitely a conundrum. I am a layman, and I want to survive as long as I can. Therefore, my instinctive reactions are:

-Find any possible cancers as early as you can.
-Blast the cancer to oblivion!

This, in spite of knowing that overdiagnosis/treatment can indeed be harmful. I hear the word "cancer," and I get scared.

By Heidi_storage (not verified) on 13 Oct 2016 #permalink

"We are using archaic disease-classification systems with inadequate vetting and defective nosologic boundaries."

I love this sentence, even though I'm not quite sure what the hell it means.

I was also struck by how heavily this latest study relies on breast cancer size in determining the value of screening and whether tumors are being "overtreated". Size Matters is problematic for reasons already mentioned, and not just in breast cancer detection/treatment. For instance, there is a seemingly magic cutoff for thyroid nodules, in that ones under a centimeter in size are usually just watched, but once they hit 1 cm, look out - better stick a needle in them and do a biopsy, just to make sure. I am unaware of good evidence that says papillary thyroid cancers under 1 cm are harmless but 1 cm or greater puts them in the Danger category. These tumors are often indolent despite size considerations, and once again we lack good molecular markers to predict which ones will progress and threaten the patient's life. And since it's common to pick up thyroid nodules incidentally when doing ultrasound or CT of the neck/chest for other reasons, harmless thyroid nodules are often surgically removed when there's no good reason to do so.

Ultimate solution: better lab tests to stratify risk!

By Dangerous Bacon (not verified) on 13 Oct 2016 #permalink

Orac says (#6),

I was nice enough to take you out of automatic moderation purgatory.

MJD says,

Sh*t what about me? I've been in said purgatory for about 2 years now.

Release me so I can have my opinions displayed at a reasonable time in the comments.

What say you?

By Michael J. Dochniak (not verified) on 13 Oct 2016 #permalink

My wife's tumor was discovered by ultra sound. She had had annual mammograms since from 2001 to 2010 reporting all clear. Still, her doctor ordered the ultra sound upon reviewing family history (mother, grandmother, two aunts- fatal for all except her mother). By the time it was discovered, the tumor was 6+ cm with auxiliary lymph involvement. She had the standard course of treatment- double mastectormy (her choice), chemo and radiation. Follow up, in my opinion, was wholly inadequate, consisting of basically a social hour followed followed by tactile examination. She never had any type of scan after her one and only PET in 2010. She died in 2014 of liver failure exactly 28 days after her three mets (liver, lung and spine) were diagnosed.

To me, after this experience, leads me believe her health provider took a cookie cutter approach. Mams, mams, oh, we finally found it. She should have had her family history considered, which I was constantly telling them every year, and ordered the ultrasound. Early detection would have at least given her better odds. I mean, 6 cm! Ten mams missed it.

As far as "guessing" whether or not to treat what may be an indolent tumor...would you leave an IDE in the street on the assumption that it won't explode? I would rather see overdiagnosis and overtreatment than death.

Been there.

@ DB
Ultimate solution: knowledge and logic!
It is known for more than a century that in the absence of surgery, BC patients face a mortality rate of 100%.
Now, thanks to Welch, we must conclude that some small cancers will kill the patients by producing metastasis before growing, and that many others, which nobody can distinguish, will grow so slowly that they will never kill the patients.
Thus, the protective effect of mastectomy could only be seen with big tumors. So, if we follow Welch's logic, big tumors have never been small.
Or, alternatively, there has been a large increase in BC incidence after mammography screening implementation.

By Daniel Corcos (not verified) on 13 Oct 2016 #permalink

Thank you for a timely, well-balanced article explaining the conundrum of breast cancer over-diagnosis. As a former breast cancer patient, I have to admit that I. HATE. OCTOBER. For thirty-one excruciating days, I just want to hide under the bed because of all the nonsense that goes on (do I need to mention, also, that I. HATE. PINK?) in the guise of "awareness". However, this was a welcome analysis of a complex problem that has interested me deeply.

By Selena Wolf (not verified) on 13 Oct 2016 #permalink

Some months back, I had a diagnostic mammogram, with follow on ultrasound, due to a painful mass in one breast.
Considering the family medical history includes breast cancer, I was a tad concerned and immediately consulted with doctor, who scheduled the testing quickly.
Fortunately, in my case, it was gynecomastia, secondary to hyperthyroidism, but I can see how many could let fear drive them towards wanting less evidence based approaches. Growth ceased once my thyroid hormone levels approached normal.

Of course, doing a bit of research in Google resulted in high noise to signal levels, but as usual, Google Scholar produced excellent results, informing me that gynecomastia would be the most probable finding. That helped when I was at doctor's office and we could converse intelligently about a differential.
It also helped me keep my wife calm, as she lost her mother to breast cancer (no clue the precise variety) and hence, she was looking for zebras upon hearing the first hoof beat.
Of course, her prognosis wasn't exceptionally good, as she ignored a mass, ignored expressing blood (she literally said, "I didn't want to bother the doctor about that") and only paid attention and sought treatment once the tumor eroded through a rib.
Sadly, that is indeed a true story.

@ Michael J. Dochniak:

I hate to be the one to inform you but there's a REASON Orac keeps you in automatic moderation.

Read CAREFULLY what he says to Daniel ( #6) and make appropriate adjustments relevant to your own situation.

By Denice Walter (not verified) on 13 Oct 2016 #permalink

I had Stage 1 Grade 1 breast cancer in 2014 and the Oncotype DX came back as an annoying 23 which is the lower end of intermediate; I'm one of those people where you have to make a judgement call about chemo. My oncologist and I agreed that chemo would be more dangerous than beneficial and honestly, I figured a grade 1 tumour didn't really need it.

What I find aggravating now though is that I have mammograms galore because they found something strange in the other breast which the radiologist thinks is most likely a node and not a tumour. But this means I have had a mammogram every 6 months in which I panic. I almost wish they'd just biopsy the darn thing & be done with it!

By Diana MacPherson (not verified) on 13 Oct 2016 #permalink

Count me up in the "I hate pink October" camp! Especially since I'm closer and closer in age to fifty. It's hard not to let the pressure build up. I'm lucky in that there's zero breast cancer in my family history, so it's easier to politely brush off the well-intentioned inquiries of "when was your latest mammography" from friends and health providers alike.

I did have a cancer scare once, when I was barely 25. My regular MD felt a lump on my thyroid gland during a routine exam for a sore throat. Of course he sent me in for sonogram, blood works, then a scintigraphy. It was actually the beginning of a goitre! Replacement thyroid hormones fix that. But I still feel the elation of having dodged as bullet, even though there was nothing to dodge.

By irenedelse (not verified) on 13 Oct 2016 #permalink

Wonderful analysis of a timely and interesting article. Yet the concern about overtreatment / overdiagnosis is confounded by Pinktober's exclamation that "early detection saves lives!!" How do we reconcile those two distinct messages, when both are equally important? The word "cancer" scares the crap out of all of us - how do we balance the need to be aware of our bodies, with the fear that "doing nothing" will most certainly kill us? For years I've been a part of the conversation that is deeply rooted in the belief that the earlier breast cancer is detected, the better our chances for a "cure" (please let's not get started on that today, which is Metastatic Breast Cancer Awareness Day).

My first go-round with breast cancer five years ago came after several years of clear mammograms. My small(ish) lump, on the inner edge of my left breast was only found on CBE; Onctoype DX score was 42 so a clinical trial and chemo was my reward for not falling in that awful intermediate "grey area". Four years later a small(ish) local recurrence (but now triple negative) has bought me another dance with chemo. Incidentalomas on my spine and hip have advanced me to the next round of this "overdiagnosis / overtreatment" party - how do we appropriately screen for metastases without raising fear levels and further exposing us to radiation and unnecessary testing, which (according to much of the literature) does nothing to increase overall survival?

The message imparted during Pinktober is clear - Be Aware!! Schedule your Mammogram!! Save your Boobies!! And because of this incorrect and inaccurate messaging, we're now afraid and want All The Tests to calm and soothe and reassure us. But until we can accurately determine and screen for which *thing* will go on to become Big-C Cancer, we will continue to overdiagnose and overtreat, because those are, sadly, our current best options.

@ Nancy B
"Yet the concern about overtreatment / overdiagnosis is confounded by Pinktober’s exclamation that “early detection saves lives!!”
How do we reconcile those two distinct messages, when both are equally important?"
- Because there is no overdiagnosis. Only x-ray induced cancers.

By Daniel Corcos (not verified) on 13 Oct 2016 #permalink

It's a shame that Daniel won't join us in the 21st century. Diagnostic imagery uses a *lot* less radiation than back in the mid-20th century, indeed, it seems almost like the x-ray exposure decreases nearly every year as detectors become even more sensitive than before.
For crying out loud, I received far more radiation exposure flying across the country than any diagnostic imagery will ever use today!
He's about as bad as the maniac who warned all who was near about the dangers of those radioactive granite countertops (I countered by reporting my superior radiation exposure endured while walking to work, courtesy of Sol).

By Wzrd1 (not verified) on 14 Oct 2016 #permalink

In reply to by Daniel Corcos (not verified)

Michael J. Dochniak , Daniel Corcos

Many lurkers and almost-lurkers appreciate Orac's thoughtful and detailed posts. And many (most!) of the commenters have something useful to say. And this post has brought out some of the poignant voices of those who have to bear the consequences of these difficult choices. That has to flow into the equation as well.

What people who come here don't want is to find the thread polluted, possibly derailed, by your monomaniacal ravings about your pet theories. You've abused Orac's hospitality many times already: he's shown the patience of Job - your theories remain for anyone to peruse in other threads, and when the time comes and your theory becomes mainstream, you will enjoy priority and have your genius finally acknowledged.

In the meantime, couldn't you just show enough courtesy to allow the discussion to continue on topic Orac started?

By Peter Dugdale (not verified) on 13 Oct 2016 #permalink

Peter Dugdale
In the case you didn't notice, Orac's topic was on mammography, breast cancer and overdiagnosis.

By Daniel Corcos (not verified) on 13 Oct 2016 #permalink

@Daniel: You're playing with with words. Again. Talking about overdiagnosis in mammograms is not an invitation to blurt out any and every conspiracy theory on mammograms available. Stick to science of you can, or if not, read the posts of those who do have an experience w/ breast cancer.

By irenedelse (not verified) on 13 Oct 2016 #permalink

Because there is no overdiagnosis. Only x-ray induced cancers.

You just couldn't restrain yourself, could you? Back to automatic moderation with you!

Oh Daniel....... We do what we can with what we have. What we have, however, is imperfect for a myriad reasons. My point is that the rallying cry of "early detection" feeds into the societal fear-mongering that we *must* detect - through mamms or MRIs or biopsies or surgeries or otherwise - in order to survive. Not every lump, bump, dimple, rash or pain is breast cancer - but our fear of this beast and the constant buzz of the early-detection buzz leads us to demand testing that may be (MAY be) otherwise unnecessary. We've created this overdiagnosis epidemic.

Even then, "early detection" doesn't necessarily "save" some of us with aggressive cancers where the horse is already out of the barn (and romping around the meadow nibbling flowers). Cancer - particularly breast cancer - can be hard to detect, and doesn't necessarily behave well. While we need better screening to catch it early (when it is easier to treat and, yes, can potentially be "curable" or at least allow us to achieve NED), more importantly we need a cure. With that, perhaps the whole "early detection" and overdiagnosis and treatment conversation becomes moot.

Assuming that the underlying burden of clinically meaningful breast cancer was unchanged

Is that a good assumption? I mean, presumably the avg age, weight, carcinogen exposture, and whatnot was changing at the same time.

By Andreas Johansson (not verified) on 14 Oct 2016 #permalink

It's a reasonable assumption because by far the major determinants of breast cancer risk are unalterable, compared to which alterable risk factors like diet, exercise, and environmental exposures are much less important. Basically, if the underlying burden of breast cancer has changed over the last 40 years (which is a short period of time, epidemiologically speaking, for cancer), there is no good evidence to suggest that it has changed sufficiently to account for the data.

My apologies.....I derailed and devolved. No more posting without the aid of caffeine.

@3 & 8: I see what you mean and understand that there is a conundrum.

I assume that it would be unethical to perform a study where women who undergo normal screening (at 40 or 50) and are found to have a small tumor or a number of tumors to be monitored over either 5 years or until the cancer becomes a hazard to life. This would allow doctors to have the beginning of a solid base of knowledge to work from. If doctors could discover a method to the madness of malignancy and size variability of the types of breast cancers, dispassionate science could indicate treatment. It would be light-years better than the immediate panic setting in to people's brains from being diagnosed with Cancer, it could be relegated to merely another diagnosable and treatable disease.

I assume that a study like this has already occurred on non-human analogs. I also assume, possibly incorrectly, that it bears little resemblance to the reality of cancer in humans.

Orac, what do you think would be a reasonable and ethical method to discover why some cells become malignant while others are indolent.

By Anonymous Pseudonym (not verified) on 14 Oct 2016 #permalink

As a woman, I'd be much happier not doing yearly mammograms. Kinda like pap smears...if you have X number of years of normal, then you can do them every Y number of years instead of annually. They are uncomfortable, if not painful, for most women and I honestly think there would be better compliance with screening (based on family history, woman's age, and other variables that increase risk, of course!) if they weren't annually for all women.

As for the OncoTypeDX test - I'm happy to say my insurance company covers it for certain medically indicated uses. I'll keep my eyes open for your article, Orac, and alert our medical people to see if expanding the medically necessary indications is supported.

@#26 Orac:

Thanks. You don't mention what I thought might be the most significant variable, the age distribution of American women, but I take it that, too, hasn't changed enough to affect the conclusions. (Would it, incidentally, count as an alterable or unalterable factor? Clearly it's alterable in that it changes over time, but it's not something that can be done anything about on the individual level.)

By Andreas Johansson (not verified) on 14 Oct 2016 #permalink

Incidence rates in SEER are age-adjusted because many cancers increase in incidence with age; so the aging of the population is not a factor.

@ Irene
Overdiagnosed cancers are cancers that are found in excess after mammography screening, that's how they are defined. X-ray-induced cancers are cancers that are found in excess after mammography screening, which makes sense. If screening does not have the protective effect that is expected, it cannot be due to overdiagnosis, but to x-ray induced carcinogenesis.

By Daniel Corcos (not verified) on 14 Oct 2016 #permalink

@ Andreas
The age-adjusted increase is only observed in women in age of screening. The only significant variable before and after implementation of screening is administration of x-rays, a known carcinogen.

By Daniel Corcos (not verified) on 14 Oct 2016 #permalink

You write: "It’s a reasonable assumption because by far the major determinants of breast cancer risk are unalterable, compared to which alterable risk factors like diet, exercise, and environmental exposures are much less important. Basically, if the underlying burden of breast cancer has changed over the last 40 years (which is a short period of time, epidemiologically speaking, for cancer), there is no good evidence to suggest that it has changed sufficiently to account for the data."

Perhaps you have seen that Medscape gave considerable space to Dr. Daniel Kopan$ to denounce the study on the grounds that in the 1960s and 1970s, the rate of advanced breast cancer had increased about 1% per year, and therefore we must all assume that the underlying rate has continued to increase 1% per year from then right up until now, and presumably will keep on doing so forever until every female fetus comes out of the womb with breast cancer. He has pulled that shtick before. What he fails to note, of course, is that during the time period with that rapid increase in breast cancer, the vast majority of American women were being coerced to use HRT, which increases risk of breast cancer about 50%. And that since the 1980s more women have gotten savvy enough to tell profit- and power-minded fellows like Kopans where to shove their little pills.

"Only x-ray induced cancers"

Thank you, orac. I was ready to reach through the screen and junk-punch him.

By Selena Wolf (not verified) on 14 Oct 2016 #permalink

@ Wzrd1
There is evidence that the effect of radiation is not linear:
https://www.ncbi.nlm.nih.gov/pubmed/12679524
with low doses causing damage that are not repaired and do not lead to cell death, i.e. are more susceptible to give rise to cancer.
The linear relationship is mere extrapolation from a very small number of cancers from atomic bomb survivors. The debate has been altered by political issues bearing on the nuclear risk.

By Daniel Corcos (not verified) on 14 Oct 2016 #permalink

@Daniel, actually, the non-linear risk was found not from atomic bomb survivors only. There was an entire era of above ground nuclear testing, where fallout spewed across the US.
Oh, we'll ignore that, as it confounds your x-ray hypothesis badly.

Or more to the point, I'm still fairly radioactive (directly measured not so long ago, during thyroid screening), courtesy of growing up in the early 1960's.
That said, crossing the Atlantic, my full body burden of radiation exposure was three to four times greater than whatever Strontium-90 is inside of my bones. I'll not even go into being in a basement of a house on granite bedrock and the Radon there...
You've a lot of noise to signal in your hypothesis, way too much noise.

By Wzrd1 (not verified) on 15 Oct 2016 #permalink

In reply to by Daniel Corcos (not verified)

@ Selena Wolf
I have more convincing data that I cannot put in this forum, because I must publish them. If you are interested, give me your e-mail address, I'll send them to you and you'll see whether you still want to junk-punch me, or other people that lied to you instead.

By Daniel Corcos (not verified) on 14 Oct 2016 #permalink

Selena - you said it! Gah, if his inane 'reasoning' were correct we should all have mouth cancer from all those dental x-rays. *eyeroll*

I've been coming at this topic from a new direction recently: I found a lump on my cat and the vet had some concern that it might be a mammary tumor. In cats the only treatment for that is to remove the mammary tissue, which is basically all of their underside.
The bioposy came back "probably nothing but a cyst", but even if it hadn't I thought to myself "there is no way I am going to put my cat through two surgeries to have all of her teats removed!"

By JustaTech (not verified) on 14 Oct 2016 #permalink

I had always assumed the thrust of the BC Awareness month was to increase funding for more research and better treatments. I mean, it's kind of impossible to save your breasts by getting a breast cancer diagnosis, they almost always get cut off (or cut out of) after diagnosis. It's your life you're saving, not your breasts. BUT, the more people who get diagnosed, the more research gets done, and the better the outcomes in the future, more or less.

Near and dear to my heart just now, my 26 year old sister is about to start radiation after chemo and a double mastectomy. And after feeling her lump of about 6cm before her diagnosis, I am wondering how on earth Jeff M's (#13) wife's mammogram missed that size of a tumor, or how she didn't feel it herself- I know it happens, I'm just trying to wrap my head around it. Anyway, I apparently don't have the BRCA2 gene she does, so back to not screening until age 50 for me, but I do expect that by the time I start to have higher risk of diagnosis due to age that there will be even more and better treatment options,

@ Wzrd1
Not everyone agreed on the interpretation of the nuclear testing results (see John Gofman, for instance), but opponents were under attack of the nuclear lobby. Gofman, I don't know how, found estimates that are in agreement with my measurements (yes, it's measurements, not hypothesis).
Concerning the effect of radiation, we still don't have biologic information on cancer genesis after continuous exposure as compared to one shot or several shots, so it is possible that continuous exposure results in DNA repair adaptation.
As I told Orac, if you want to go against my data, present me yours. I am in the process of submitting mine for publication and I cannot put them on the Internet. If you have published or unpublished data, I would be happy to see them.

By Daniel Corcos (not verified) on 15 Oct 2016 #permalink

One shot, many shots, natural sources...
If our diagnostic imagery were causing cancers, thunderstorms would also be causing cancers (you do realize that lightning strikes are x-ray emitters and strong strikes can emit gamma radiation?). Wow, we should be extinct!
http://phys.org/news/2009-12-lightning-produced-potential-health-air.ht…

Not soft x-rays either.
https://www.scientificamerican.com/article/x-rays-abound-when-lightn/
Tens of megaelectron volts from storms vs mammography using 15 - 30 keV.
Yeah, all life on the planet must be extinct, largely from cancer.

By Wzrd1 (not verified) on 16 Oct 2016 #permalink

In reply to by Daniel Corcos (not verified)

@ Wzrd1
And I would be happy to send you my data by mail.

By Daniel Corcos (not verified) on 15 Oct 2016 #permalink

Yet more evidence that mass mammographic screening is marginally helpful but comes at great cost. Follow up of abnormals is expensive, anxiety producing, and often leads to overtreatment with chemo or RadRx with serious consequences.
The response to the NEJM article is quite predictable. As a community GYN I will receive letters from the Chairs of Diagnostic Imaging at the regional Universities, assuring me that they are still saving women's lives right and left. They will point out this study is deeply flawed and manage to add that the skills, experience, and equipment of their competitors may reasonably by questioned. There was that Canadian study that didn't show a mortality benefit, but of course we all know those Canadians aren't much good with this sort of thing.
Next, I will receive abundant marketing materials from device makers. They will point out in a variety of subtle and not so subtle ways that any practitioner sending their patients for mammogram must be sure the new "WonderMamm Mark 7 " is used, or forever be guilty of implied malpractice.
Of course it turns out that our early detection programs only make sense when histologic exam correctly predicts behavior. In this and other cancers it does not.

I have several questions that the more involved might have some insight.

1. How do oncologists deal with or treat clearly rising cancer markers that don't have visible targets yet.

2. Is any one aware of breast cancer candidates on the Redo list - old, generic drugs that may have additive or adjuvant value. I know most people think surely if there was any value, it would already be generally known. However, there appear tp be some significant unfollowed leads in the generic pharmacopia across many cancer lines with often mild drugs. In the colorectal world, cimetidine and celecoxib have molecular targets that can totally change the disease progression with 5FU but are little known or applied by MSM oncologists.

3. How ways do researchers measure the immune dysfunctions on an extended workup for research?

Thanks in advance for any insights.

Another comment mentions societal/cultural views of and responses to cancer. Just the word "cancer" elicits fear from most people - and those people generally also have cancer at the top of their list of things "I hope I never get," vs diabetes or heart disease, for example, that they likely have a much higher chance of getting.

I think it was the same comment that also mentioned the issue/problem with the plethora of advocacy groups; and I'd like to add the seemingly non-stop, 24/7 media hype about runs, jumps, walks, row your boats, grow your hair, shave your hair, wear ribbons "raising awareness" industry that sees hundreds of millions of dollars being thrown at "beating," "fighting," or "curing" cancer. Add in a seemingly overwhelming societal lack of even basic scientific knowledge and a very limited understanding of cancers (e.g., that cancer isn't a single thing/disease), and it is all going to make for a very hard sell, I think, of what will likely be the path that cancer treatment is going to take in the coming decades: I don't foresee there being much in the way of "cures" for certain cancers/patients, but more that they will become chronic manageable conditions such as HIV has now become.

By Robert Riley (not verified) on 16 Oct 2016 #permalink

@ GynDoc
I think too that the response to the NEJM is quite predictable, but not in your sense. Women with mammography detected cancers will wait three months for another mammogram showing that the cancer has grown before undergoing surgery. As a delay of one month before surgery results in an increase of 10% in mortality, you can easily imagine the outcome, since every cancer will grow in the interval.

By Daniel Corcos (not verified) on 16 Oct 2016 #permalink

In light of Orac's early exchange (#6) on this thread about tumor size, I would like to see him post about how thinking has changed over time about metastasis risks of large v. small tumors in the public's mind. Public perception is probably still somewhat "big tumor bad/small tumor not bad." That is certainly the attitude among three female relatives who all had ductal in situ. No amount of updated knowledge will convince them that treating a 1.5cm in situ abnormality very aggressively made less sense than treating a very different 1cm mass--not ductal in situ--less aggressively that eventually spread quickly (her decision contrary to medical advice). All outcomes were ultimately positive and remain so after more than ten years, thank goodness.

@ Sara
I too would like to know what he will do when he will see a tumor less than 1 cm on a mammogram. Active surveillance?
Or will he make this decision when the epidemic of overdiagnosis will be even greater.

By Daniel Corcos (not verified) on 16 Oct 2016 #permalink

Public perception is probably still somewhat “big tumor bad/small tumor not bad.”

I'm part of the public, and my perception is that if it might be cancer, I want it dead and gone. Big cancer, little cancer, any cancer, I want to kill it with fire. Or anything else that will make cancer go away.

Science doesn't really matter, but emotions do,

Maybe cancer lite needs a better name. But I don't want cancer-anything, or anything-cancer, living in or around me or anyone I love. 'Pre-cancer', well, that doesn't really help.

Yeah, sometime science doesn't back me up. So sue me.

@ Johnny
Science matters, but here it is politics, bad publishing and stupidity. And you are right, breast cancer is cancer.

By Daniel Corcos (not verified) on 16 Oct 2016 #permalink

I am not challenging Orac's opinions about this. One of our grad students is doing a basic cancer biology postdoc at his institution, and my disciplinary focus is in basic, not clinical work. I am only interested in encouraging him to expand on the old idea that small tumors=OK/big tumors= bad. That has unfortunately been given a pass in popular understanding and needs someone to persistently dismiss it.

As for previous fear-driven posts that cancer anywhere must be eradicated immediately, I think many researchers and clinicians here will provide ample evidence that the human body is fighting abnormal and potentially cancerous cells all the time. Many people live with cancers that will never cause big problems.

There is never a reason to be automatically hysterical upon hearing the "C" word. It alarms me that people are posting here who reflect an obsolescent (I hope) view that any cancer is cause for "Get It Now!!." No....There are hundreds of types of cancers. This has become an urgent educational problem because the fears of the 50s and 60s about the big C are often unrealistic. Much progress has been made in effective treatment--esp. in breast cancer--and there is no reason to perpetuate old--very old--hysterias about any cancers.

Trolls, please go somewhere else. You are irritating and interfere with the exchange of useful information here. I am not as subtle as long-time posters about this, but honestly I am really getting tired of this. It clutters this wonderful site.

By Sara (not verified) on 17 Oct 2016 #permalink

In reply to by Daniel Corcos (not verified)

I'm a former SF medic, as such, I had to perform a clinical rotation or so.
My first, a VA hospital oncology unit.

So, CA isn't a uber big deal ender in life, some can be beat, others are a battle, still a few are unbeatable.

Here today, I'm in my mid-50's. My health is somewhat off, but nowhere near lethal, now that my hyperthyroidism is under control. The latter damned near killed me.
So, I learn that my PSA is elevated, my first question is, "why did you measure it?", then, what do you plan to do about it.
Both questions are those about retention of a physician, long before this news. Now, a greater elevation on some points.
Wrong answer, doctor is "fired".
I've never been shy about replacing a primary care physician who wasn't competent.

I've worked in quite a number of fields in my life, I've come to know subject matter experts and those posing as such.
I'm not shy about dismissing the incompetent or idiots.
But, when a consensus evolves, I pay attention, then use that same fine reason to explore my initial opinion.
Google Scholar is an excellent resource. I have a few others as well, some professional.
Alas, John Q Public lacks that resource. :(

By Wzrd1 (not verified) on 17 Oct 2016 #permalink

In reply to by Sara (not verified)

You make two good points. The culture of mediocrity among primary care physicians needs to be examined and frankly fixed. I am frequently frustrated by the medical profession's failure to police people who are neither trained nor inclined to refer problems out to specialists and insist on treating complex problems themselves. I saw it just this week with a friend who has Parkinson's and needs to see a movement disorder neurologist--urgently.

Second issue is the fantasy that patients are partners in their care and that primary care people and other clinicians welcome a challenge to their opinions. This is utter nonsense. In my own life any scientifically valid challenge to an opinion results in either being dismissed by the physician outright or some kind of hostility in the form of passive-aggressive nonsense.

I do basic research and have spent thirty years in academic medicine, and I am really tired of this shibboleth that you are a partner in your care. Uh, no. That has never been my experience. As wzrd1 has said, I affirm that asserting my informed opinion has never resulted in anything except petulant hostility and being dumped as a patient.

Back to the point of this post. My mother's breast cancer surgeon cautioned that screening is not exactly the panacea that it has been claimed to be. This wise surgeon told me that he had a hard time making that case to his patients because of decades of marketing breast cancer hysteria and the craven involvement of the pinkwashing corporations. I wonder how many experienced breast cancer surgeons believe likewise and are reluctant to stand up to all the pinkness of commercial interests about this.

By Sara (not verified) on 17 Oct 2016 #permalink

In reply to by Wzrd1 (not verified)

@wzrd1
You are overestimating the role of cancer in evolution. Most cancers occur late in life. Even the BRCA1/2 mutations, which represent a high cancer burden, may bring a selective advantage.
There is clear evidence that x-rays are carcinogenic. The question is how much? The answer is not simple, because it depends on the cell type, the age, the presence of other factors and obviously the dose, but the response is non linear. I don't think there is a way to answer the question of mammography-induced cancer risk other than to follow the curve of cancer incidence as a function of the number of mammograms per woman, which is what I did.
I think I will stop to make comments on this thread because , due to the moderator, my comments appear after several hours.

By Daniel Corcos (not verified) on 17 Oct 2016 #permalink

I don’t think there is a way to answer the question of mammography-induced cancer risk other than to follow the curve of cancer incidence as a function of the number of mammograms per woman, which is what I did.

No, I showed where we receive, on a very regular basis, a much *higher* dosage of ionizing radiation. The dose and the energy, in the case of ionizing radiation makes the poison.
Age does add to it, where in the genome was impacted also comes into play, how the damage plays out (crosslink, deletion, etc) also. It's a *lot* more complex, but the simple reality is, Earth exposes us to a hell of a lot more radiation than a mammogram. Or 50.
Especially in parts of Florida!
I'll not even go into one place in Columbia, where there's a perpetual thunderstorm...

So, with no due respect, you're totally full of schmidt.

By Wzrd1 (not verified) on 17 Oct 2016 #permalink

In reply to by Daniel Corcos (not verified)

Just to know how fair is Orac for letting his minions insulting me while blocking me I give you my last answer:
Have you ever heard of the adaptive response to radiation?

By Daniel Corcos (not verified) on 17 Oct 2016 #permalink

Ah, adaptive response to radiation, Incredible Hulk syndrome.

You had the right of it earlier on, DNA repair mechanisms kick in.

As for mediation purgatory, you earned it, fair and square. I never did have much tolerance for complaining over the pain from a self-inflicted injury.

By Wzrd1 (not verified) on 17 Oct 2016 #permalink

In reply to by Daniel Corcos (not verified)

Dear G-d, Mr. ResearchGate Revolution is hormesis-flouncing?

@ #57 "Second issue is the fantasy that patients are partners in their care and that primary care people and other clinicians welcome a challenge to their opinions..."

There is another side to this problem of making the patient a partner in their own care. After my own diagnosis of cancer, within a whirlwind of days of that involved diagnostic tests, biopsies, staging tests, etc., I was sat down at a conference table with my treatment team and the results were discussed. A number of scenarios were discussed and various treatment options were offered, then everyone looked at me expectantly, obviously waiting for my input. While I appreciated the effort to solicit my opinion in my own treatment, frankly - at that point - I was shell-shocked and overwhelmed, and didn't have the foggiest idea what to do. Some guidance would have been welcome, but no one would offer an opinion of what - in their clinical experience - would be suitable for my particular case. However, when I asked, I was told that it was entirely up to me.

Thankfully, I had two friends that were nurses and an old classmate that was a radiologist who walked me through the various scenarios and were more helpful in guiding me to the right decision.

By Selena Wolf (not verified) on 18 Oct 2016 #permalink

@Selena Wolf, I hear you.
Maybe I'm a bit different, dealing with events as a military medic, maybe it's due to losing so many people in my life, I don't know.
When this man went for a mammogram, he was expecting bad news, only to learn after, it was simple breast growth, due to thyroid dysfunction.
I was honestly expecting to hear the big C.
Then, to have to, yet again, follow a steep learning curve in a specific topic. I've done that a number of times in my life, the number being well past two hands now and we're running out of toes.
Some, equally learned under conditions of sheer terror.

But, over the decades, I've also learned the great value of subject matter experts. Experts in their field, it's what they do for a living.
I'm a subject matter expert in a number of fields today, ranging from electronic circuit repair through advanced hand to hand combat. Where the advances in career took me, I became an expert. I also have an odd affinity to learn quickly and encyclopedic in nature, such things.
That left me with trust in my subject matter experts and second opinions.

I'm no biochemist. I'm not a microbiologist. I'm far from being an oncologist. I'm nowhere near being a physician.
But, I can spot a BS artist a mile away.
Promising unicorn farts and rainbows, BS artist. Not promising anything, but a chance or even a great chance, likely not a BS artist is a first hint.

Learning how to think through things fully when crapping one's pants, that's pretty much the hardest lesson to ever try to teach. If anyone had a good idea, I'm still all ears. :/
So is every medical school on the planet.

By Wzrd1 (not verified) on 18 Oct 2016 #permalink

In reply to by Selena Wolf (not verified)

Second issue is the fantasy that patients are partners in their care and that primary care people and other clinicians welcome a challenge to their opinions. This is utter nonsense. In my own life any scientifically valid challenge to an opinion results in either being dismissed by the physician outright or some kind of hostility in the form of passive-aggressive nonsense.

I do basic research and have spent thirty years in academic medicine, and I am really tired of this shibboleth that you are a partner in your care. Uh, no. That has never been my experience. As wzrd1 has said, I affirm that asserting my informed opinion has never resulted in anything except petulant hostility and being dumped as a patient.

Thanks. I've encountered these behaviors a number of times now, sometimes with disastrous effects. The worst and best responses have been with the nurses. In the worst situations, at some level I expected reason, law or professionalism to finally prevail.

The most gracious have been the alternative doctors, who recognize that there are different options and modalities and that it is my informed choice.

Some conventional doctors have been helpful. One instantly recognized how much work and research I had have to put in to achieve good results and gave me support with extra leeway. These are the doctors that we return to.

I think you have missed my point. My point was that I needed MORE guidance from my conventional treatment team. I needed their advice and their opinion, but they had swallowed the whole let's-involve-the-patient in their treatment decisions because it will give them more power. I didn't want power, I wanted their expertise and their knowledge. I didn't want MY treatment team to embrace the whole kumbaya nonsense of alternative practitioners in catering to the patients' emotional distress; I wanted facts, science, statistics, outcomes. The problem wasn't with my head, it was with the cancer growing in my body. Graciousness was the last thing I wanted and, while appreciated (with hindsight), I feel quite strongly that the CAM approach a very unfortunate outcome of conventional treatment centres trying appeal to alternative treatment nonsense.

By Selena Wolf (not verified) on 19 Oct 2016 #permalink