Another Fine Mess

 

Did you guess from the title that this short piece is about the seeming inability of the British Government to run well, most things but especially IT programmes? Of course you did! Provoked by the latest National Health Service furore. In case you’ve been away with the fairies for a bit, a major cock-up in its computer system has just come to light whereby, between 2009 and 2018, it failed to invite 450,000 women between the ages of 68 and 71 for breast screening. Secretary of State for Health, Jeremy Hunt (our man usually on hand with a can of gasoline when there’s a fire), told Parliament that “there may be between 135 and 270 women who had their lives shortened”. Cue: uproar, headlines: HUNDREDS of British women have died of breast cancer (Daily Express), etc.

Logo credit: Breast Cancer Action

I’ve been reluctant to join in because I’ve said all I think is worth saying about breast cancer screening in two earlier pieces (Risk Assessment and Behind the Screen). Reading them again I thought they were a reasonable summary and I don’t think there’s anything new to add. However, this is  a cancer blog and it’s a story that’s made big headlines so I feel honour-bound to offer a brief comment — in addition to sympathizing with the women and families who have been caused much distress.

My reaction was that Hunt was misguided in mentioning specific numbers — not only because he was asking for trouble from the press but mainly because the evidence that screening itself saves lives is highly questionable. For an expert view on this my Cambridge colleague David Spiegelhalter, who is Professor for the Public Understanding of Risk, has analysed the facts behind breast screening with characteristic clarity in the New Scientist.

Anything to add?

I was relieved on re-reading Risk Assessment to see that I’d given considerable coverage to the report that had just come out (2014) from The Swiss Medical Board.  They’d reviewed the history of mammography screening, concluded that systematic screening might prevent about one breast cancer death for every 1000 women screened, noted that there was no evidence that overall mortality was affected and pointed out that false positive test results presented the risk of overdiagnosis.

In the USA, for example, over a 10-year course of annual screening beginning at 50 years of age, one breast-cancer death would have been prevented whilst between 490 and 670 women would have had a false positive mammogram calling for a repeat examination, 70 to 100 an unnecessary biopsy and between 3 and 14 would have been diagnosed with a cancer that would never have become a problem.

Needless to say, this landed the Swiss Big Cheeses in very hot water because there’s an awful lot of vested interests in screening and it’s sort of instinctive that it must be a good thing. But what’s great about science is that you can do experiments — here actually analysing the results of screening programmes — and quite often the results turn to be completely unexpected, as it did in this case where the bottom line was that mammography does more harm than good.

This has led to the recommendation that the current programmes in Switzerland should be phased out and not replaced.

So we’re all agreed then?

Of course not. In England the NHS recommendation remains that women aged 50 to 70 are offered mammography every three years — which is just as well or we’d have Hunt explaining the recent debacle as new initiative. The American Cancer Society “strongly” recommends regular screening mammography starting at age 45 and the National Cancer Institute refers to “experts” that recommend mammography every year starting at age 25 for women with mutations in their BRCA1 or BRCA2 genes.

The latter is really incredible because a study published in the British Medical Journal in 2012 found that these mutations made the carriers much more vulnerable to radiation-induced cancer. Specifically, women with BRCA 1/2 mutations who were exposed to diagnostic radiation (i.e. mammography) before the age of 30 were twice as likely to develop breast cancer, compared to those with normal BRCA genes.

They are susceptible to radiation that would not normally be considered dangerous because the two BRCA genes encode proteins involved in the repair of damaged DNA — and if that is defective you have a recipe for cancer.

Extraordinary.

So it’s probably true that the only undisputed fact is that we need much better ways for detecting cancers at an early stage of development. The best hope at the moment seems to be the liquid biopsy approach we described in Seeing the Invisible: A Cancer Early Warning System? but that’s still a long way from solving a general cancer problem, well illustrated by breast mammography.

Advertisements

No It Isn’t!

 

It’s great that newspapers carry the number of science items they do but, as regular readers will know, there’s nothing like the typical cancer headline to get me squawking ‘No it isn’t!” Step forward The Independent with the latest: “Major breakthrough in cancer care … groundbreaking international collaboration …”

Let’s be clear: the subject usually is interesting. In this case it certainly is and it deserves better headlines.

So what has happened?

A big flurry of research papers has just emerged from a joint project of the National Cancer Institute and the National Human Genome Research Institute to make something called The Cancer Genome Atlas (TCGA). This massive initiative is, of course, an offspring of the Human Genome Project, the first full sequencing of the 3,000 million base-pairs of human DNA, completed in 2003. The intervening 15 years have seen a technical revolution, perhaps unparalled in the history of science, such that now genomes can be sequenced in an hour or two for a few hundred dollars. TCGA began in 2006 with the aim of providing a genetic data-base for three cancer types: lung, ovarian, and glioblastoma. Such was its success that it soon expanded to a vast, comprehensive dataset of more than 11,000 cases across 33 tumor types, describing the variety of molecular changes that drive the cancers. The upshot is now being called the Pan-Cancer Atlas — PanCan Atlas, for short.

What do we need to know?

Fortunately not much of the humungous amounts of detail but the scheme below gives an inkling of the scale of this wonderful endeavour — it’s from a short, very readable summary by Carolyn Hutter and Jean Claude Zenklusen.

TCGA by numbers. The scale of the effort and output from The Cancer Genome Atlas. From Hutter and Zenklusen, 2018.

The first point is obvious: sequencing 11,000 paired tumour and normal tissue samples produced mind-boggling masses of data. 2.5 petabytes, in fact. If you have to think twice about your gigas and teras, 1 PB = 1,000,000,000,000,000 B, i.e. 1015 B or 1000 terabytes. A PB is sometimes called, apparently, a quadrillion — and, as the scheme helpfully notes, you’d need over 200,000 DVDs to store it.

The 33 different tumour types included all the common cancers (breast, bowel, lung, prostate, etc.) and 10 rare types.

The figure of seven data types refers to the variety of information accumulated in these studies (e.g., mutations that affect genes, epigenetic changes (DNA methylation), RNA and protein expression, duplication or deletion of stretches of DNA (copy number variation), etc.

After which it’s worth pausing for a moment to contemplate the effort and organization involved in collecting 11,000 paired samples, sequencing them and analyzing the output. It’s true that sequencing itself is now fairly routine, but that’s still an awful lot of experiments. But think for even longer about what’s gone into making some kind of sense of the monstrous amount of data generated.

And it’s important because?

The findings confirm a trend that has begun to emerge over the last few years, namely that the classification of cancers is being redefined. Traditionally they have been grouped on the basis of the tissue of origin (breast, bowel, etc.) but this will gradually be replaced by genetic grouping, reflecting the fact that seemingly unrelated cancers can be driven by common pathways.

The most encouraging thing to come out of the genetic changes driving these tumours is that for about half of them potential treatments are already available. That’s quite a surprise but it doesn’t mean that hitting those targets will actually work as anti-cancer strategies. Nevertheless, it’s a cheering point that the output of this phenomenal project may, as one of the papers noted, serve as a launching pad for real benefit in the not too distant future.

What should science journalists do to stop upsetting me?

Read the papers they comment on rather than simply relying on press releases, never use the words ‘breakthrough’ or ‘groundbreaking’ and grasp the point that science proceeds in very small steps, not always forward, governed by available methods. This work is quite staggering for it is on a scale that is close to unimaginable and, in the end, it will lead to treatments that will affect the lives of almost everyone — but it is just another example of science doing what science does.

References

Hutter, C. and Zenklusen, J.C. (2018). The Cancer Genome Atlas: Creating Lasting Value beyond Its Data. Cell 173, 283–285.

Hoadley, K.A. et al. (2018). Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer. Cell 173, 291–304.

Hoadley, K.A. et al. (2014). Multiplatform Analysis of 12 Cancer Types Reveals Molecular Classification within and across Tissues of Origin. Cell 158, 929–944.