In which Orac co-authors a paper in the New England Journal of Medicine

Unfortunately, this happens to be a day when I didn't really have much time to blog, as I had to go to an evening meeting last night related to my work. Fortunately, this corresponds with a most excellent day, a first in my life. Basically, I'm coauthor on a Perspective article published in today's New England Journal of Medicine on trends in metastatic disease in breast cancer and prostate cancer. Even better, it's not behind a paywall (at least for now); so you—yes, you!—can read it. It's also written at a level that I think a lot of our readers will enjoy it, although the strict word limits for NEJM Perspective articles guarantee that it isn't as long as a typical Orac reading experience.

So, go and read it. I don't know how long it'll be available for free. Then tell me what you think.

Until tomorrow...


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Congratulations on this achievement!

Fascinating article! I appreciate what you write here and your NSSOB. This, while shorter than the usual Oracian postings, was very well written and quite interesting. I had never heard of the 2 other paradigms (besides Halsted). Thanks for letting us know about it.


By James Lind (not verified) on 29 Oct 2015 #permalink

Thanks for the pointer. I have downloaded a copy.

Congratulations on the publication.

By Richard Abbott (not verified) on 29 Oct 2015 #permalink

Best wishes, Orac.

By Denice Walter (not verified) on 29 Oct 2015 #permalink


Achievement Unlocked!


By Chadwick Jones (not verified) on 29 Oct 2015 #permalink

Thoroughly enjoyed this and appreciated it much more because of your previous posts on this topic. BTW, the second comment on the NEJM site is worthy of your attention: quantum healing woo!

Three cheers for Orac!

Well written, understandable for an educated layperson, gets right to the point and a fascinating topic. The distinction between progressive disease and systemic disease was particularly interesting especially in light of what we've learned recently about genetic factors and cancer development.

Unfortunately, the second commenter in NEJM is a sad figure who infests Italian medical blogs with some phantasy techniques to detect cancer, such as with a stethoscope.
see @

By perodatrent (not verified) on 29 Oct 2015 #permalink

Once this gets out into the wider media (I think I saw an article about it in the paper this morning but I didn't have time to read it) and combined with the recent changes in the mammography recommendations, I predict a lot of very emotionally charged discussions of cancer screening.

As for the "quantum" guy in the comments on the NEJM page, well, I guess it shows that if there is a comment section anywhere on the internet, there will be weirdos.

Oh, and our friend Daniel comments about X-rays and mutations in DNA repair genes.

By JustaTech (not verified) on 29 Oct 2015 #permalink

"quantum healing woo!"

You definitely don't want sick quanta. They stumble around and get entangled.

Reminds me to think, given the status of the New England Journal, does anybody know why the British Medical Journal is so ashamed of its name?

Years ago, they changed the name to BMJ, recently they've started calling themselves The BMJ, and I always wonder when they will get it that the world is not going to accept either of those, no matter what they say about it. As such, it's a failed brand.

It's either low self-esteem in thinking that the international community has a problem with "British", or its excessive self-esteem in thinking BMJ, or now The BMJ, will become recognised like BBC. But it won't...

Anyhow, the New England Journal of Medicine is #1, and nobody seems to think its only read in Boston.

By Brian Deer (not verified) on 29 Oct 2015 #permalink

Congratulations, Orac. We minions and sheeple bow to your greatness.

No, really. Great work. :)

Where's the "like" button on this thing?

By Johanna Mead (not verified) on 29 Oct 2015 #permalink

@Brian Deer

Hardly anyone in the US knows that BP gas stations are a descendant of British Petroleum. I believe the airline is now known only as BA as well. It's a sad trend.
Nice job Orac! It was very readable and seems to tie in with posts here and at the other blog. The comments were interesting too except as noted above. Will you reply?

By darwinslapdog (not verified) on 29 Oct 2015 #permalink

Congratulations! Even if you do tend to bring out the woomeisters....

Way to go, Orac!

Congratulations Orac on such an accomplishment.

Congratulations indeed - very well done!


Thanks for the alternative to races, ribbons and shirts.
When are we getting a better screening tool?
(Half in jest. I was hoping for better news.)

@ darwinslapdog

The difference, I guess, is that BP would naturally occur in a sentence such as "I went to the BP gas station", or similar. Or, more likely, "I went to the gas station".

But with "BMJ", you end up having to say "the British Medical Journal", or at least "the British medical journal", otherwise not .1% of people would know what you were talking about.

By Brian Deer (not verified) on 30 Oct 2015 #permalink

@Brian Deer

Agreed. I only meant that there is a trend to obscure the British(ness) of these companies.

By darwinslapdog (not verified) on 30 Oct 2015 #permalink

That graphic is a REALLY clear way to explain that screening mammography hasn't worked out as well as people initially thought it would. The picture is worth at least a thousand words.

By Young CC Prof (not verified) on 30 Oct 2015 #permalink

Congratulations! May this thread reach epic lengths from those of us who appreciate your work.

Congratulations Orac. Well-played! And in the publish-or-perish game, it is very smart to have omitted the incidence of primary invasive breast cancers during the same period, otherwise you would have led to conclude, in the same line of thinking as in the paper, that x-ray screening increases the incidence of invasive breast cancers.
And this, as JustaTech suggests, is the idea of a crank.

By Daniel Corcos (not verified) on 30 Oct 2015 #permalink

So, rather than differing individual paradigms, meatastasis conforms to a spectrum

Congratulations Orac!

On a different topic, my autistic son (age 25) was recently diagnosed with an egg allergy. Yes, he gets the flu shot annually.

Flu vaccines that contain egg proteins are scary and can be horrible.

Happy Halloween and vaccine happy to all of Orac's minions.

By Michael J. Dochniak (not verified) on 31 Oct 2015 #permalink

@MJD: Not all flu vaccines contain egg proteins. And it is not always contraindicated in egg allergic persons. However, that is best determined by his own physician.

Yes, I got my flu vaccine. So have my children. Annually.

@dingo99: "So, rather than differing individual paradigms, meatastasis conforms to a spectrum."

It's all about meat with you, isn't it?

By N. S. Alito (not verified) on 01 Nov 2015 #permalink

The trends in the article are very interesting. But since it is about incidence of metastasis at diagnosis, it is subject to biases:
(1) Lead time bias-- just because % metastatic at diagnosis decreases with implementation of PSA doesn't mean that PSA saves lives.
(2) Changing methods and trends on testing for metastasis in new diagnoses of cancer. Newer techniques are more sensitive, so it may be easier to detect metastatic disease at diagnosis today, artificially elevating incidence of metastatic at diagnosis.
(3) The issue of change in baseline incidence was pointed out, but giving % of diagnoses rather than cases per 100,000 population would introduce another bias (e.g. adding all the DCIS and early stage cases to the denominator will make % metastatic seem low today).

Also, a small point, it is not clear if the graphs are age adjusted.

The interpretations in the article are measured and careful to draw a distinction from mortality benefit--so I don't think they are affected by the bias above. Perhaps a very minor interpretation that is overlooked is that rapid Halstedian progression could elude annual mammographic screening.

By MadisonMD (not verified) on 01 Nov 2015 #permalink

@ MadisonMD
Actually, high PSA levels are correlated with metastasis. It is therefore likely that many of the cases detected at the end of the eighties were also metastatic. Obviously, as for breast cancer, the incidence of metastatic prostate cancer BEFORE implementation of widespread screening should have been included in the curve, but the results might have shown a peak at implementation, consistent with lead time bias. Again, well-played!

By Daniel Corcos (not verified) on 01 Nov 2015 #permalink

I am always glad when a professional backs up what I've been saying. :). Great job, shared with thousands.

One of the issues for us in metastatic breast cancer-land is how few of us are counted. The number being bantered around is that only about 10% of us who are living with metastatic cancer started out that way-the vast majority ended up progressing after a number of years with cancer remaining dormant. My mets didn't show up for 18 months after a Stage 2 diagnosis and many become metastatic years later. We are not counted statistically. Perhaps if we were, there would be a bit more clarity in the mechanics of metastatic disease.

Thanks for an interesting article.

By ButDoctorIHatePink (not verified) on 02 Nov 2015 #permalink

Without depreciating the achievement of publishing a paper in NEJM, and having given my word about the data (biases in the two curves), I would like to comment on the nonsensical conclusion that prostate and breast cancers follows different paradigm. If micro-metastases were always present at the time a breast cancer is detected, then there would be no need to do any surgery. But lumpectomy prevents metastasis and breast cancers with lymph node involvement can be detected by self-examination. In the case of prostate cancer, there is no such situation. Well, I would not recommend self-examination for prostate cancer prevention.

By Daniel Corcos (not verified) on 02 Nov 2015 #permalink

Oops! I should have written folloW different paradigmS.

By Daniel Corcos (not verified) on 02 Nov 2015 #permalink

Without depreciating high-impact journals (I have a great respect for The Sun's readers), I am waiting for the day when one of these journals (NEJM, Science or Nature) publishes a study showing a dramatic difference in mortality rates in hospitals as compared to home. The paper would include, as usual, a huge number of patients (NEJM), would be backed by high throughput sequencing and system biology analysis (Nature and Science), ignorance of previous scientific literature and alteration of reasoning, and would be accompanied by a press release
suggesting that we should find new high-tech alternatives to hospitals.

By Daniel Corcos (not verified) on 02 Nov 2015 #permalink

Having followed your link, I have not found any data showing that lumpectomy has no preventive value against metastasis. However, I found this: "there was a larger relative reduction in mortality among women who were not exposed to screening mammography than among those who were exposed", which is consistent with the hypothesis that x-rays enhances cancer rates in a subset of patients.

By Daniel Corcos (not verified) on 02 Nov 2015 #permalink

Again, I do not see in the article any evidence showing that lumpectomy does not prevent metastasis. All the paper is about screening, i.e. x-rays.

By Daniel Corcos (not verified) on 03 Nov 2015 #permalink

Oh, bloody hell. What does screening inevitably lead to? Why do we even bother with it in the first place? It's so that we can do surgery to remove detected cancers at a smaller size. So we can do lumpectomies and mastectomies to treat the cancer. If we treat cancers at an earlier stage, the thinking goes, then we prevent progression to locally advanced and then to metastatic. The NEJM paper shows that there has been some decrease in advanced disease, but much less than we would expect, consistent with the hypothesis that lumpectomy often doesn't prevent metastasis, that metastasis has already occurred at the time of diagnosis and happens very early in many cancers.

Screening by x-rays leads to surgery, preventing metastasis in some cases, and triggers primary cancers in predisposed individuals, as shown by the increase in primary cancers. Is that clear enough?

By Daniel Corcos (not verified) on 03 Nov 2015 #permalink

Kudos for the paper, it doesn't get much better than the NEJM. I have some thoughts, but wanted to finish reading 'Emperor of All Maladies' before commenting, which I just did.

It takes more than one mutation to create an invasive, malignant tumor, so it must make a difference in what order they occur. EoAM suggests we think of some genes as accelerators of cell replication (oncogenes) and others as brakes (tumor suppressors). It takes a failure of both to create a malignant (invasive, metastatic)tumor, with cells proliferating and uncontrolled.

If an oncogene (accelerator) mutates first, there are still the brakes (tumor suppressors) to stop wild proliferation so we get a benign tumor that could be detected by mammography and successfully treated with surgery. If a tumor suppressor (brake) mutates too, before this tumor is detected, we may still get a malignant metastatic tumor.

If the tumor suppressor mutates first (or a mutation is inherited as in BRCA) then there will be no tumor unless or until an oncogene mutates too, but if or when it does a malignant metastatic tumor may be the immediate result - you notice your brake failure as soon as your accelerator pedal gets stuck down, as it were . In this case mammography will be of little use as a breast tumor that is large enough to be detected may already have metastasized having started life malignant.

Obviously this is over-simplistic, as there are many more than two genes involved (an average of ten or more IIRC), and tumor conditions lead to increased mutations, heterogeneity, angiogenesis etc. etc., but is this a useful way of thinking about this? I'm probably flogging a dead horse and someone has already constructed some computer models of this sort of thing. If so, I wonder how it might fit with what we see in reality with mammography.

By Krebiozen (not verified) on 03 Nov 2015 #permalink

Daniel Corcos,

I have not read “Emperor of all maladies”, but if it says that tumor suppressor mutations distinguish between benign and malignant tumors, I would not read it.

That would be a shame as it's an excellent book. However, I don't understand your point. Are you suggesting that a tumor suppressor mutation is not required for breast cancer malignancy?

By Krebiozen (not verified) on 03 Nov 2015 #permalink

@ Krebiozen
No, what I am saying is that you can find tumor suppressor mutations in benign tumors, and that it is not possible to distinguish benign and malignant tumors on the tumor suppressor mutation criteria.

By Daniel Corcos (not verified) on 03 Nov 2015 #permalink