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.

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Please … Not Another Helping

 

You may have seen the headlines of the: “Processed food, sugary cereals and sliced bread may contribute to cancer risk” ilk, as this recently published study (February 2018) was extensively covered in the media — the Times of London had a front page spread no less.

So I feel obliged to follow suit — albeit with a heavy heart: it’s one of those depressing exercises in which you’re sure you know the answer before you start.

Who dunnit?

It’s a mainly French study (well, it is about food) led by Thibault Fiolet, Mathilde Touvier and colleagues from the Sorbonne in Paris. It’s what’s called a prospective cohort study, meaning that a group of individuals, who in this case differed in what they ate, were followed over time to see if diet affected their risk of getting cancers and in particular whether it had any impact on breast, prostate or colorectal cancer. They started acquiring participants about 20 years ago and their report in the British Medical Journal summarized how nearly 105 thousand French adults got on consuming 3,300 (!) different food items between them, based on each person keeping 24 hour dietary records designed to record their usual consumption.

Foods were grouped according to degree of processing. The stuff under the spotlight is ‘ultra-processed’ — meaning that it has been chemically tinkered with to get rid of bugs, give it a long shelf-life, make it convenient to use, look good and taste palatable.

What makes a food ‘ultra-processed’ is worked out by something called the NOVA classification. I’ve included their categories at the end.

Relative contribution of each food group to ultra-processed food consumption in diet (from Fiolet et al. 2018).

And the result?

The first thing to be said is that this study is a massive labour of love. You need the huge number of over 100,000 cases even to begin to squeeze out statistically significant effects — so the team has put in a terrific amount of work.

After all the squeezing there emerged a marginal increase in risk of getting cancer in the ultra-processed food eaters and a similar slight increase specifically for breast cancer (the hazard ratios were 1.12 and 1.11 respectively). There was no significant link to prostate and colorectal cancers.

Which may mean something. But it’s hard to get excited, not merely because the effects described are small but more so because such studies are desperately fraught and the upshot familiar.

One problem is that they rely on individuals keeping accurate records. Another problem here is that the classification of ‘ultra-processed’ is somewhat arbitrary — and it’s also very broad — leaving one asking what the underlying cause might be: ‘is it sugar, fat or what?’ Furthermore, although the authors tried manfully to allow for factors like smoking and obesity, it’s impossible to do this with complete certainty. The authors themselves noted that, for example, they couldn’t allow for the effects of oral contraception.

The authors are quite right to point out that it is important to disentangle the facets of food processing that bear on our long-term health and that further studies are needed.

I would only add ‘rather you than me.’

Perforce in these pages we have gone on about diets good and bad so there is no need to regurgitate. Suffice to say that my advice on what to eat is the same as that of any other sane person and summarized in Dennis’s Pet Menace — and it’s not been remotely affected by this new research which, in effect, says ‘junk food is probably bad for you in the long run.’ But let’s leave the last word to Tom Sanders of King’s College London: “What people eat is an expression of their life-style in general, and may not be causatively linked to the risk of cancer.” 

Reference

Fiolet, T. et al. (2018). Consumption of ultra-processed foods and cancer risk: results from NutriNet-Santé prospective cohort. BMJ 2018;360:k322 http://dx.doi.org/10.1136/bmj.k322

NOVA classification:

The ultra-processed food group is defined by opposition to the other NOVA groups: “unprocessed or minimally processed foods” (fresh, dried, ground, chilled, frozen, pasteurised, or fermented staple foods such as fruits, vegetables, pulses, rice, pasta, eggs, meat, fish, or milk), “processed culinary ingredients” (salt, vegetable oils, butter, sugar, and other substances extracted from foods and used in kitchens to transform unprocessed or minimally processed foods into culinary preparations), and “processed foods” (canned vegetables with added salt, sugar coated dried fruits, meat products preserved only by salting, cheeses, freshly made unpackaged breads, and other products manufactured with the addition of salt, sugar, or other substances of the “processed culinary ingredients” group).

Much Ado About … Some Things

Given that the ‘festive season’ is approaching, maybe we should try to find something joyous to say about cancer. It’s not difficult. Over the last 60 years (1950-2013) the 5-year Relative Survival Rates for white Americans for breast and prostate cancers have gone from about 50% to over 90% (99.6% in fact for prostate). A number of other types (e.g., testicular cancer) are now largely curable, if treated early enough. Similar trends have occurred in most developed countries – all this through advances in surgery and radiotherapy but, most of all, because of new drugs.

Big Pharma

It’s big business. According to the Financial Times, annual spending on cancer drugs hit $100 billion worldwide in 2014 and is projected to exceed $150 billion by 2020. As you would hope, this expenditure on drug development and production has resulted in a gradual rise in available cancer drugs, represented below by the number of new cancer drugs approved each year by the American Food and Drug Administration (FDA).

Number of new cancer drugs approved each year by the American Food and Drug Administration from 1949 to 2016 (from Hope Cristol, The American Cancer Society, 2016).

Data compiled from drugs@fda.gov, National Cancer Institute, FDA Orange Book, FDA.gov, and centerwatch.com. Reporting and analysis by Sabrina Singleton, ACS research historian.

We should note that the FDA equivalent on this side of the Atlantic is the European Medicines Agency (EMA) and they tend to follow similar licensing patterns. Thus in 2016 a total of 74 new drug approvals were granted by the FDA and the EMA — 19 by the EMA only, 19 by only the FDA, with 36 approved by both. Of the drugs approved by the EMA in 2016, 17 had received prior FDA approval (i.e. in 2015 or earlier). However, only six drugs registered in the US in 2016 had prior EMA approval, indicating that drug companies tend to apply for approval in the US first before registering their products in the EU.

So rejoice and be merry — and drink to the triumph of science!!

It’s not unbounded joy, of course, because global cancer incidence continues to rise and a number of cancers (e.g., lung, liver and pancreas) remain refractive to all approaches thus far with survival rates stuck below 20%.

A Winter’s Tale

But what’s this? A further, wintry blast of reality from The British Medical Journal no less. It comes from Courtney Davis and her friends at King’s College London and the London School of Economics and Political Science (LSE) who looked at the track record of cancer drugs approved by the EMA between 2009 and 2013. Over this period the EMA approved the use of 48 new cancer drugs.

Charge your glass

It might be a good idea to sit down with a stiff drink at this point and remind ourselves that there are only two aims for cancer drugs: they must either extend the life of the patient or improve their quality of life.

What Dr. D & chums found was — and here, to be absolutely clear, we should quote exactly what they said — “… that most drugs entered the market without evidence of benefit on survival or quality of life. At a minimum of 3.3 years after market entry, there was still no conclusive evidence that these drugs either extended or improved life for most cancer indications. When there were survival gains over existing treatment options or placebo, they were often marginal.”

To be precise, it was 57% (39 of the 68 drugs) that entered the market with no evidence that they improved survival or quality of life.

Cripes!

What does this mean – and how can it be?

Well, first up, clearly a lot of money has been spent by drug companies and health services for absolutely no benefit to patients. Unsurprisingly the authors of the study called on the EMA to “increase the evidence bar for the market authorisation of new cancer drugs.” Which I take to mean ‘get some meaningful data before you stick stuff out there.’ But here’s where things get tricky. If your aim is to extend life, how can you prove a drug works other than by giving it to a significant number of patients and waiting a long time to see what happens?

The way round this has been for clinical trials to use indirect or “surrogate” measures of drug efficacy. The idea is that these endpoints show whether a drug has biological activity and thus might be of clinical use. However, they are not reliable measures of improved quality of life or survival.

So this report leaves us with a long-standing problem. On the one hand there is the understandable drive to get new drugs to patients asap but, on the other, there is the fact that only human beings can model how well a drug works in us. However good your in vitro systems may be and however closely mice may resemble men, they’re not the real thing.

One thing we could do that the report suggests, is to integrate the development and commercialization of cancer drugs at least across the two biggest markets of America and Europe so that the FDA and the EMA don’t appear to be operating in parallel worlds.

All told then, perhaps we should supplant our earlier merriment with the chilling thought that, even after so many years of perspiration and inspiration, cancers still present an immense challenge.

References

Davis, C. et al. (2017). Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13. BMJ 2017;359:j4530 doi: 10.1136/bmj.j4530 (Published 2017 October 03).

SEER Cancer Statistics Review (CSR) 1975-2014, updated June 28, 2017.

Cristol, H. (2016). Evolution and Future of Cancer Treatments, The American Cancer Society.

 

Cancer GPS?

The thing that pretty well everyone knows about cancers is that most are furtive little blighters. They kill one in three of us but usually we don’t they’re there until they are big enough to make something go wrong in the body or to show up in our seriously inadequate screening methods. In that sense they resemble heart problems of one sort or another, where often the first indication of trouble is unexpectedly finding yourself lying on the floor.

Meanwhile, out on the highways and byways you are about 75 times less likely to be killed in an accident than you are to succumb to either cancers or circulation failure. Which is a way of saying that in the UK about 2000 of us perish on the roads each year. That it’s ‘only’ 2000 is presumably because here your assailant is anything but furtive. All you’ve got to do is side-step the juggernaut and you’ll probably live to be – well, old enough to get cancer.

Did you know, by the way, that ‘juggernaut’ is said to come from the chariots of the Jagannath Temple in Puri on the east coast of India. These are vast contraptions used to carry representations of Hindu gods on annual festival days that look as though walking pace would be too much for them. So, replace the monsters on our roads with real juggernauts! Problem largely solved!!

Flagging cancer

But to get back to cancer or, more precisely, the difficulty of seeing it. After centuries of failing to make any inroads, recent dramatic advances give hope that all is about to change. These rely on the fact that tissues shed cells – and with them DNA – into the circulation. Tumours do this too – so in effect they are scattering clues to their existence into blood. By using short stretches of artificial DNA as bait, it’s possible to fish out tumour cell DNA from a few drops of blood. That’s a pretty neat trick in itself, given we’re talking about fewer than 100 tumour cells in a sea of several billion other cells in every cubic millimeter of blood.

There are two big attractions in this ‘microfluidics’ approach. First it’s almost ‘non-invasive’ in needing only a small blood sample and, second, it is possible that indicators may be picked up long before a tumour would otherwise show up. In effect it’s taking a biochemical magnifying glass to our body to ask if there’s anything there that wouldn’t normally be present. Detect a marker and you know there’s a tumour somewhere in the body, and if the marker changes in concentration in response to a treatment, you have a monitor for how well that treatment is doing. So far, so good.

And the problem?

These ‘liquid biopsy’ methods that use just a teaspoonful of blood have been under development for several years but there has been one big cloud hanging over them. They appear to be exquisitely sensitive in detecting the presence of a cancer – by sequencing the DNA picked up – but they have not been able to pinpoint the tissue of origin. Until now.

Step forward epigenetics

Shuli Kang and colleagues at the University of California at Los Angeles and the University of Southern California have broken this impasse by turning to epigenetics. We noted in Twenty More Winks that an epigenetic modification is any change in DNA, other than in the sequence of bases (i.e. mutation), that affects how an organism develops or functions. They’re brought about by tacking small chemical groups (commonly methyl (CH3) groups) either on to some of the bases in DNA itself or on to the proteins (histones) that act like cotton reels around which DNA wraps itself. The upshot is small changes in the structure of DNA that affect gene expression. You can think of DNA methylation as a series of flags dotted along the DNA strand, decorating it in a seemingly random pattern. It isn’t random, of course, and the target for methylation is a cytosine nucleotide (C) followed by a guanine (G) in the linear DNA sequence – called a CpG site because G and C are separated by one phosphate (p). Phosphate links nucleosides together in the backbone of DNA.

Cancer cells often display abnormal DNA methylation patterns – excess methylation (hypermethylation) in some regions, reduced methylation in others – that contributes to their peculiar behavior. It’s possible to determine the methylation profile of a DNA sample (by a method called bisulfite sequencing).

Kang & Co. developed a computer program to analyse methylation profiles from solid tumours and healthy samples in public databases and compare them to patient DNA of unknown tissue origin.

The peaks represent CpG clusters that characterize normal cells (top) and a variety of cancers. The key point is that the different patterns identify the tissue of origin (from Kang, S. et al., 2017).

The program’s called CancerLocator and in this initial study it was used to test samples from patients with lung, liver or breast cancer. In the modest words of the authors, CancerLocator ‘vastly outperforms’ previous methods – mind you, they struggle to even to distinguish most cancer samples from non-cancer samples. Nevertheless, CancerLocator’s a big step forward, not least because it can detect early stage cancers with 80% accuracy.

It’s also reasonable to expect major improvements as methylation sequencing becomes more extensive and higher resolution reveals more subtle signatures. What’s more, in principle, it should be able to detect all types of cancers – meaning that, after all so many centuries we may at last have a way of side-stepping the juggernaut.

References

Kang, S. et al. (2017). CancerLocator: non-invasive cancer diagnosis and tissue-of-origin prediction using methylation profiles of cell-free DNA. Genome Biology DOI 10.1186/s13059-017-1191-5.

A Taxing Inheritance

The centenary of the beginning of the First World War prompted me, as perhaps many others, to reflect on how successive generations have done since then in terms of what they’ve bequeathed to their offspring. I didn’t need to think for too long though, to find myself muttering ‘Thank heavens for science’—because most of the rest is a pretty dismal chronicle. I know, not all technological advances in the past one hundred years have been a cause of unrestrained joy but many of them transformed life in the most wonderful ways. Would that we could point to such success in other fields.

Our best defence may be to aver: “Man cannot control the current of events. He can only float with them and steer”, a saying attributed to Otto von Bismarck. If the ‘Iron Chancellor’ actually did utter those words it seems to me he was being coy beyond belief. He is, after all, generally credited with unifying Germany, seeing off the last French monarch (Napoleon III) and establishing the peaceful domination of Europe by the German Empire that lasted until long after his death—and setting up the first welfare state along the way. “The main thing is to make history, not to write it” sounds much more like Bismarck in full and frank mode.

Nature and Nurture

One form of history that we do write but indeed we cannot control comes in the form of the genetic material that we pass to the next generation. We’re all familiar with some of this legacy because we literally see it in physical resemblances and other attributes between parents and children (“He’s got his Mum’s eyes”) or shared by siblings (“Jack and Jill are wonderful musicians”). They’re shared because large chunks of the genetic code (i.e. DNA) are identical between the individuals concerned. But if conserved DNA makes for similarities, what of the differences—the fact that our parents and brothers look different to all the seven thousand million other people on the planet? Our unique features come from variations in the genetic code—odd changes in the units (bases) of DNA scattered through our genome. Called SNPs (pronounced ‘snips’ for single nucleotide polymorphisms), they’re what make the differences between us. In other words, a SNP is a difference in a single nucleotide—A, T, C or G—within a stretch of DNA sequence that is otherwise identical between two individuals. For example, you have AAGCCTA whereas I have AAGCTTA. These genetic variations that make individuals different are the basis of DNA fingerprinting.

There’s about three million SNPs scattered throughout the human genome (so, on average, you’d come across one in every 1,000 bases if you scanned your DNA from beginning to end) and they’re what makes each of us unique. Within ethnic groups common patterns of such variants confer characteristics (dark skin/light skin, tall/short, etc) and, with that in mind, you might guess that there will also be variants that make such groups more (or less) susceptible to diseases.

Of course, there’s an endless debate about the border between our genetic inheritance and how the world we experience makes us what we are—how much of Jack and Jill’s precocious talent is because Mum and Dad made them practice twelve hours a day from age five? Fortunately we can ignore nurture here and stick to genes because we’re trying to pin down the good and the bad of our genetic legacy.

What’s all this got to do with cancer?

A good bit is that we’re distinct from everyone else but still share family features. However, our genetic baggage may also contain some unwanted freebies—the most potent of which can give a helping hand to a variety of diseases, including cancers. Cancers are caused by damage to DNA—a build-up of changes, i.e. mutations, that affect the activity of proteins critically involved in controlling cell growth. For most cancers (90%) these mutations accumulate over the lifetime of the individual—they’re called “somatic mutations”—so you can’t blame anyone but yourself and Lady Luck. But about 10% get a kind of head start when someone is born with a key mutation. That is, the mutated gene came from either egg or sperm (so it’s a germline mutation). This effect gives rise to cancers that “run in families”: a critical mutation is passed from generation to generation so that children who inherit it have a greatly increased risk of developing cancer. Two of the most common cancers that can come in hereditary form are those of the breast and bowel.

Steeplechase

A mutational steeplechase leads to cancer. Of the tens of thousands of mutations that accumulate over time in a cancer cell, a small number of distinct “drivers” make the cancer develop (four are shown as Xs). Almost all mutations arise after birth, but about one in every ten cancers start because a person is unfortunate enough to be born with a mutation: they are already one jump ahead and are much more likely to get cancer than those born with a normal set of genes. The rate at which mutations arise is increased by exposure to carcinogens, e.g., in tobacco smoke.

Breast cancer is about twice as common in first-degree relatives of women with the disease as it is in the general population (you’re a first degree relative if you’re someone’s parent, offspring, or sibling). About 5% of all female breast cancers (men get the disease too but very rarely—about 1% of all breast cancers) arise from inherited mutations. In the 1990s two genes were identified that can carry such mutations. These are BRCA1 and BRCA2 and their abnormal versions can increase the lifetime risk of the disease to over 50%, compared with an average of about 10%. Since then heritable mutations in some other genes have also been shown to increase the risk.

Angelina Jolie

Angelina Jolie

A star turn

Breast cancer genetics came under the spotlight with the much-publicised saga of Angelina Jolie, the American film actress. Jolie’s mother and maternal grandmother had died of ovarian cancer and her maternal aunt from breast cancer—a family history that persuaded Jolie to opt for genetic testing that indeed revealed she was carrying a mutation in BRCA1 (BRCA1 and BRCA2 mutations account for about 10% of breast cancers and 15% of ovarian cancers). For Jolie the associated lifetime risk of breast cancer was estimated as 87%, prompting her to have a preventative double mastectomy, thereby reducing her risk to less than 5%. The months after she revealed her story saw the “Angelina effect”, a doubling in the number of women being referred for genetic testing for breast cancer mutations.

What’s all this got to do with SNPs?

The story so far is of the one in ten cancers that get kicked off by a powerful, inherited mutation that changes the action of the affected protein—the BRCAs being the best-known examples. However, the BRCAs and other known mutated genes account for only about 25% of familial breast cancers, meaning that for three quarters of cases the genetic cause remains unknown. And yet we know there is an inherited (genetic) cause simply because of the generational thread. Which brings us back to those other, more subtle tweaks to DNA that we mentioned—SNPs—alterations that don’t directly affect proteins, so they’re often called variants to distinguish them from mutations.

It seems very likely that the missing culprits are indeed SNPs—lots of them. These DNA variants each make a contribution so small that on its own would have no detectable effect on the chances that the carrier will get cancer. Their impact comes from a cumulative effect. They’re like pieces of straw, individually easily bent or broken but put a dozen of them together and you have a rope. Thus combinations of individually insignificant SNPs can raise the risk of cancer by, say, 10%—not a massive increase but not negligible either. Twins who are genetically identical have similar risks of developing breast cancer, consistent with the idea that many variants, each having a very small effect, can combine to give a substantial increase in risk. Very slowly, by sequencing lots of genomes, these rare variants are being identified. Given that clusters of appropriate variants confer risk, people with the “other” variant have, in effect, a degree of protection against cancer.

And in our more distant relatives?

All this comes from the huge effort that has gone into finding genetic variants linked to one of the most common cancers but, unsurprisingly, almost all the attention has focused on European women. Not before time, someone has got round to looking for breast cancer variants in East Asians who, after all, make up over one fifth of all the people in the world. Cai Qiuyin and his colleagues at the Vanderbilt University School of Medicine compared the genomes of over 20,000 cancer cases from China, Japan and South Korea with a similar number of disease-free controls. After much selecting and comparing of sequences, three particular DNA variants consistently associated with significant cancer risk. The variants were much less common in European women, suggesting that as the DNA keyboard has been strummed by evolution, distinct patterns associated with breast cancer have emerged in diverse populations.

Just two problems then. First it’s a huge task to assemble the lists of runners (and as the Asian results show, they will differ between ethnic groups). But the real challenge is yet to come. Almost all of these variants (99.9%) don’t change the sequence of proteins (i.e. how the proteins work). What they do is exert subtle effects on, for example, how much RNA or protein is made from a DNA gene at any time. At the moment we have little understanding of how this works, yet alone ideas on how to intervene to change the outcome.

Although identifying the BRCA genes that help to drive breast and ovarian cancers was a giant breakthrough, we still have no effective therapy for countering their malign influences. The intervening twenty-five years of effort have brought us to a new era of revealing the more subtle effects of variants. But the price we pay for unveiling the complete picture is perceiving just how tough is the therapeutic challenge.

Reference

Qiuyin Cai, et al. (2014). Genome-wide association analysis in East Asians identifies breast cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1. Nature Genetics 46, 886–890. doi:10.1038/ng.3041.

Risk Assessment

For UK readers a title that instantly raises the spectre of the ’Elf & Safety police and the annoyance, irritation and amusement generated by the seemingly ubiquitous injunctions of their minions. Even my department is not spared, the harbinger of warm weather invariably being an email reminding us that this is no reason for abandoning the rule that at all times we should wear a lab coat – though, to be fair, our local enforcer usually includes the cheeky inference that we retain the option of going naked underneath. Ah, The Joy of Science! ’E & S’s reputation comes, of course, from periodically making the headlines by banning a centuries-old tradition in some rustic backwater involving such fun activities as rolling cheeses down a hill.

Stuart Kettell and sprout

Stuart Kettell and sprout

Mind you, they’ve slipped up recently by allowing Stuart Kettell to push a Brussels sprout up Mount Snowdon with his nose. As that’s 3,560ft (vertically) he probably did lasting damage to his knees, to say nothing of his hooter, as well as inflicting grievous bodily harm on 22 sprouts (they wear out on the basalt, obviously). By his own admission, he’s probably mad – but he did at least raise some money for Macmillan Cancer Support.

 

But why are we bothered about assessing risk?

Setting the above entertainment to one side, estimating risk can be a really serious business and never more so than when it comes to cancer. It’s an especially contentious, long-running issue for breast cancer and both in Betrayed by Nature and more recently in Behind the Screen I tried to crystallize some clear guidelines from the vast amount of available info. In short these were: ignore commercial plugs for thermography – the only test to go for is mammography – i.e. X-ray imaging to find breast cancer before a lump can be felt. And the simple message you were relieved to read in BbN was that, whilst the matter is controversial, if you are offered screening, accept – but be aware that the method is not perfect. There’s a small risk that a cancer may be missed and a bigger chance that something abnormal but harmless will be picked up – a signal for intervention (by surgery and drugs) and that, in those cases, would be unnecessary.

And we’re revisiting this question?

Because there have been some recent contributions to the debate that might well have increased confusion and concern in equal measure for women who are desperately trying to make sense of it all. The most controversial of these comes from a panel of experts (The Swiss Medical Board) who reviewed the history of mammography screening – and recommended that the current programmes in Switzerland should be phased out and not replaced.

Needless to say, their report caused a furore, not only in Switzerland, with experts damning its conclusions as ‘unethical’ – mainly because they ran counter to the consensus that screening has to be a good thing.

So what did the Swiss Big Cheeses point out to get into such hot water? Their view after considering the cumulative evidence was that systematic mammography might prevent about one breast cancer death for every 1,000 women screened. However, two other things struck them. First, it was not clear that this result outweighed the disadvantages of screening – what are inelegantly referred to as the ‘harms’ – the detection and treatment of something ‘abnormal but harmless’ mentioned earlier. Second that, on the basis of a survey by American group, women had a grossly optimistic idea of the benefits of mammography.

Good versus bad

Two of the weightiest bits of evidence that led them to conclude that screening does more harm than good were studies that had combined several independent investigations – what’s called a meta-analysis – which is a way of increasing your sample size and hence getting a more meaningful answer. One of these (The Independent United Kingdom Panel on Breast Cancer Screening) pulled together 11 trials from which it emerged that women invited to screening had a reduction of about 20% in their risk of dying from breast cancer compared with controls who were not offered screening. So far so good. However, inevitably there were differences in methods between the trials, which made the UK Panel very cagey about drawing more specific conclusions but their best estimate was that, for every 10,000 UK women aged 50 years invited to screening for the next 20 years, 43 deaths from breast cancer would be prevented and 129 cases would be over-diagnosed. Over-diagnosis means detection of cancers that would never have been emerged during the lifetime of the individuals and these healthy women will be needlessly subjected to some combination of surgical interventions, radiotherapy and chemotherapy.

The second combined study is from The Cochrane Collaboration, the trials involving more than 600,000 women. Their review also emphasized the variation in quality between different studies and noted that the most reliable showed that screening did not reduce breast cancer mortality. However, less rigorous methods introduced bias towards showing that screening did reduced breast cancer mortality. In this sort of trial “less rigorous” relates particularly to the problem of ensuring that the two groups of subjects are truly randomized – i.e. that nothing influences whether a woman is assigned to receive screening mammograms or not. This is much harder than it sounds, mainly because human beings do the assigning so there is always a chance of either a genuine mistake or a flaw in the design of a particular study. One simple example of how the best laid plans … The consent form for a study specifically states that women are assigned, at random, to either the mammography or no mammography group. Women are then examined by a specially trained nurse. However, if these two steps are reversed, assignment may be biased by the findings of the examination. Precisely such a failure to adhere to a protocol has been revealed in at least one study.

Making the liberal assumption that screening reduces mortality by 15% and that over-diagnosis occurs at a rate of 30%, they estimated that for every 2000 women invited for screening over 10 years, one will avoid dying of breast cancer and 10 will be treated unnecessarily. In addition, false alarms will subject 200 women to prolonged distress and anxiety.

All of which explains why, taking everything into consideration, the Big Cheeses recommended that the Swiss abandon mammography screening.

MammogramWhat does the NHS say?

Actions speak louder than words and in the UK women aged 50 to 70 are invited for mammography screening every three years. By way of explanation, the NHS document (NHS breast screening: Helping you decide) says that for every 200 screened about one life is saved from breast cancer. The American Cancer Society recommends screening annually from age 40 – so it’s clear that Britain and the USA are firmly in favour.

You will have noted that the NHS figure of one saved for every 200 screened is seriously at odds with the findings summarized above and they don’t say where it comes from. However, they are clear about the critical point in saying “for every 1 woman who has her life saved from breast cancer, about three women are diagnosed with a cancer that would never have become life-threatening.”

Misplaced optimism

It will be obvious by now that attaching precise numbers to the effects of screening is next to impossible but the overall message is clear. At best screening yields a small reduction in breast cancer deaths but this comes with a substantially greater number of women who are treated unnecessarily – hence the Swiss position that it is ethically difficult to justify a public health program that does more harm than good.

It’s a bit difficult to assess just how knowledgeable women are about the benefits of mammography screening but one study that tried came up with some positively alarming pointers. A telephone survey of more than 4000 randomly chosen females over 15 years of age in the USA, the UK, Italy and Switzerland revealed that a substantial majority believed that (i) screening prevents or reduces the risk of getting breast cancer, (ii) screening at least halves breast cancer mortality, and (iii) 10 years of regular screening prevents 10 or more breast cancer deaths per 1000 women.

A clear conclusion?

Rates of breast cancer mortality are declining. Hooray! And the five-year survival rate in developed countries is now about 90%. Hooray again! It seems probable that this trend is more though improved treatments and greater awareness – leading to early detection – than because of screening. Nevertheless, all that doesn’t alter the fact that where women are offered the choice they need to be as well informed as possible. The weaknesses of the telephone survey are obvious but the implication that misconceptions are widespread indicates that we need to do much better at explaining the facts of mammography screening.

References

Biller-Andorno N. and Jüni P. (2014). Abolishing mammography screening programs? A view from the Swiss Medical Board. New England Journal of Medicine 370:1965-7.

Independent UK Panel on Breast Cancer Screening. (2012). The benefits and harms of breast cancer screening: an independent review. Lancet 380:1778-86.

Gøtzsche, P.C. and Jørgensen, K.J. (2013). Screening for breast cancer with mammography. Cochrane Database Syst Rev; 6:CD001877.

Domenighetti G, D’Avanzo B, Egger M, et al. (2003). Women’s perception of the benefits of mammography screening: population-based survey in four countries. Int J Epidemiol., 32:816-21.

Keeping Cancer Catatonic

Over a century ago there lived in London an astute physician by the name of Stephen Paget. He was one of those who may or may not be envied in being part of a super-talented family. His Dad, Sir James Paget, was pals with Charles Darwin and, together with Rudolph Virchow, laid the foundations of modern pathology, though today medical students usually encounter his infinitesimal immortality through several diseases that bear his name. These include a rare condition, Paget’s disease of the breast, in which malignant cells form in the skin of the nipple creating an itchy rash, usually treatable by surgery. His Uncle George had been Regius Professor of Physic at Cambridge and he had several brothers, two of whom became bishops. Fortunately Stephen continued the medical thread of the family and Paget’s passion became breast cancer.

A Key Question

Paget had that invaluable scientific gift of being able to pinpoint a key question – in his case ‘What is it that allows tumour cells to spread around the body?’ – and it was such a good question that to this day we don’t have a complete answer. That it happens had been known long before the appearance of Paget Junior. René-Théophile-Hyacinthe Laënnec, French of course, in the early years of the 19th century described how skin cancer could spread to the lungs before he went on to invent the stethoscope in 1816. The mother of this invention was a young lady whom he described as having a ‘great degree of fatness’ that made her heartbeat inaudible by the then conventional method of placing ear to chest. Using a piece of paper rolled into a tube as a bridge, Laënnec was somewhat taken aback that the beat was more distinct than he’d ever heard before. Needless to say, medicine being a somewhat reactionary profession, not all its practitioners had ears tuned to receive this advance with glee but in the end, of course, it caught on and we can therefore award Laënnec first prize in reducing human cumulative embarrassment. It was another French surgeon, Joseph Récamier, who subsequently coined the term metastasis, (to be precise ‘métastase’) to describe the formation of secondary growths derived from a primary tumour.

Early Ideas about Metastasis

The notion that primary tumours could give rise to a diaspora gradually took root but it was not until 1840 that the Munich-born surgeon Karl Thiersch showed that it was actually cells – malignant cells – that wandered off and found new homes. Rudolf Virchow had come up with the idea that spreading was via a ‘juice’ released by primaries that somehow converted normal cells at other sites into tumours. As Virchow was jolly famous, having not only made the study of disease into a science but also discovered leukemia, it took a while for Thiersch to triumph, notwithstanding the evidence of Laënnec and others. Funnily enough, and as quite often happens in scientific arguments, it now looks as though both were right if for ‘juice’ you substitute ‘messengers’ – that is, chemicals dispatched by tumour cells – as we shall see.

Paget’s attention had been drawn to this subject through his observations on breast cancer, and he’d taking as a starting point the most obvious question: ‘How do tumour cells know where to stick?’ Or, as he elegantly phrased it in a landmark paper of 1889: ‘What is it that decides what organs shall suffer in a case of disseminated cancer?’ The simplest answer would be that it just depends on anatomy: when cells leave a tumour and get into the circulation they stick to the first tissue they meet. But in looking at over 700 cases he’d found this just didn’t happen and that secondary growths often appeared in the lungs, kidneys, spleen and bone. Paget acknowledged the uncommonly prescient suggestion a few years earlier by Ernst Fuchs that certain organs may be ‘predisposed’ for secondary cancer and concluded that ‘the distribution of secondary growths was not a matter of chance.’ This led him to a botanical analogy for tumour metastasis: ‘When a plant goes to seed, its seeds are carried in all directions; but they can only live and grow if they fall on congenial soil.’ From this, then, emerged the ‘seed and soil’ theory of metastasis, its great strength being the image of interplay between tumour cells and normal cells, their actions collectively determining the outcome. Rather charmingly, Paget concluded his paper with: ‘The best work in the pathology of cancer is now done by those who are studying the nature of the seed. They are like scientific botanists; and he who turns over the records of cases of cancer is only a ploughman, but his observation of the properties of the soil may also be useful.’

BOOKMARKING

Bookmarking cancer: Primary tumours mark sites around the body to which they will spread (metastasize) by sending out chemical signals that create sticky ‘landing sites’ (red protein A) on target cells. Cells released from the bone marrow carry proteins B and C. B attaches to A and tumour cells ‘land’ on C. Cells may remain quiescent in a new site for years or decades, their growth suppressed by signals (e.g., TSP-1) released from nearby blood vessels. Only when appropriate activating signals dominate (e.g., TGFbeta) is secondary tumour growth switched on.

Finding a Landing Strip

For well over a century Paget’s aphorism of  ‘seed and soil’ pretty well summed up our knowledge of metastasis. It’s obvious that before any rational therapy can be designed we need to unravel the molecular detail but we’ve had to wait until the twenty-first century for any further significant insight into the process. As so often in science, the hold-up has been largely due to waiting for the appropriate combination of methods to be developed – in this case fluorescently tagged antibodies to detect specific proteins in cells and tissues and genetically modified mice.

In the forefront of this pursuit has been David Lyden and his colleagues at Weill Cornell Medical College and other centers and their most extraordinary finding is that cells in the primary tumour release proteins into the circulation and these, in effect, tag what will become landing points for wandering cells. Extraordinary because it means that these sites are determined before any tumour cells actually set foot outside the confines of the primary tumour. These are chemical messengers rather equivalent to Virchow’s ‘juice’: they don’t change normal cells into tumour cells but they do direct operations. However, it’s a bit more complicated because, in addition to sending out a target marker, tumours also release proteins that signal to the bone marrow. This is the place where the cells that circulate in our bodies (red cells, white cells, etc.) are made from stem cells. The arrival of signals from the tumour causes some cells to be released into the circulation; these carry two protein markers on their surface: one sticks to the pre-marked landing site, the other to tumour cells once they appear in the circulation. It’s a double-tagging process: the first messenger makes a sticky patch for bone marrow cells that appear courtesy of another messenger, and they become the tumour cell target. It’s molecular Velcro: David Lyden calls it ‘cellular bookmarking.’

Controlling Metastatic Takeoff

Tumour cells that find a new home in this way, after they’ve burrowed out of the circulation, could in principle then take off, growing and expanding as a ‘secondary.’ However, and perhaps surprisingly, generally they do the exact opposite: they go into a state of hibernation, remaining dormant for months or years until some trigger finally sets them off. The same group has now modeled this ‘pre-metastatic niche’ for human breast cancer cells, showing that the switch between dormancy and take-off is controlled by proteins released by nearby blood vessels. The critical protein that locks tumour cells into hibernation appears to be TSP-1 (thrombospondin-1). As long as TSP-1 is made by the blood vessel cells metastatic growth is suppressed. This effect is overridden by stimuli that turn on new vessel growth and in so doing switch secretion from TSP-1 to TGFB (transforming growth factor beta). Now proliferation of the disseminated tumour cells is activated and the micro-metastasis becomes fully malignant. It should be said that this is a model system and may possibly bear little relation to what goes on in real tumours. However, the fact that specific proteins that are, moreover, highly plausible candidates, can control such a switch strongly suggests its relevance and also highlights potential targets for therapeutic manipulation.

Stranger Than Fiction

The system for directing tumour cells to a target seems extraordinarily elaborate. Given that tumour cells cannot evolve in the sense of getting better at being metastatic – they just have to go with what they’ve got – how on earth might it have come about? We don’t know, but the most likely explanation is that they are taking advantage of natural defense mechanisms. Although tumours start from normal cells, the first reaction of the body is to see them as ‘foreign’ – much as it does bugs that get into a cut – and the response is to switch on inflammation and an immune response to eliminate the ‘invader.’

Perhaps what is happening in these mouse models is that the proteins released by the tumour cells are just a by-product of the genetic disruption in cancer cells. Nevertheless, they may signal ‘damage somewhere in the body’. That at least would explain why the bone marrow decides to release cells that are, in effect, a response to the tumour. The second question is trickier: Why should tumours release proteins that mark specific sites? We’ve known since Dr. P’s studies that cells from different tumours do indeed head for different places and it may just be that the messengers arising in the genetic mayhem happen to reflect the tissue of origin. The mouse models, encouragingly, show that the target changes with tumour type (e.g., swap from breast to skin and the cells go somewhere else). In other words, tumours send out their own protein messengers that set up sticky landing strips in different places around the circulation.

As for take-off, it may be that newly arrived tumour cells simply adapt to the style of their neighborhood. By and large, the blood vessels are pretty static structures: they don’t go in for cell proliferation unless told to do so by specific signals, as happens when you get injured and need to repair the damage. TSP-1 appears to be a ‘quiescence’ signal, telling cells to sit tight. The switch to proliferation comes when that signal is overcome by TGFB, activating both blood vessels and tumour. All of which would delight Paget: not only is our expanding picture consistent with ‘seed and soil’ but the control by local signals over what happens next makes his rider that ‘observation of the properties of the soil may also be useful’ spot on.

References

Kaplan, R.N., Riba, R.D., Zacharoulis, S., Bramley, A.H., Vincent, L., Costa, C., MacDonald, D.D., Jin, D.K., Shido, K., Kerns, S.A., Zhu, Z., Hicklin, D., Wu, Y., Port, J.L., Altork, N., Port, E.R., Ruggero, D., Shmelkov, S.V., Jensen, K.K., Rafii, S. and Lyden, D. (2005). VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820-827.

http://www.ncbi.nlm.nih.gov/pubmed/16341007

Ghajar, C.M. et al. (2013). The perivascular niche regulates breast tumour dormancy. Nature Cell Biology 15, 807–817.

http://www.readcube.com/articles/10.1038/ncb2767

 

 

Signs of Resistance

In Beware of Greeks … we noted that in one sort of leukemia at least, tumour cells have come up with an extraordinary way of escaping from the bone marrow where they start life into the circulation where they cause trouble – by releasing pieces of their own DNA that then break down the retaining barrier.

Keeping track of tumors

Curious behaviour though it may be, there’s nothing new about the idea of cells shedding bits of their genetic code – that was first shown to happen over 60 years ago. What is novel is the evidence that not only does this happen in a variety of cancer cells but that modern methods enable those fragments to be isolated from just a teaspoonful of blood: the sequence of the DNA can then be determined – which gives the mutational signature of the original tumour. A remarkable development has now shown that repeating these steps over a period of time can reveal the response of secondary tumours (metastases) to drug treatment (chemotherapy).

Untitled

One great advantage of this blood sampling method is that it is as near as makes no difference ‘non-invasive’. That is, it uses only a (small) blood sample and there’s no need for painful excavations to dig out tumour samples. The study, largely funded by Cancer Research UK, looked at three major cancers (breast, ovarian and lung) and identified specific mutations caused by drugs over a period of one to two years. For good measure they also took tumour samples to show that the mutation patterns found in circulating DNA did indeed represent what had gone on in the tumour itself. In other words, they had established what scientists like to call ‘proof of principle’ – i.e. we can do it!

There’s another more subtle advantage of this approach in that it gets round a problem we described in Molecular Mosaics: tumours are a mixture and the mutational signature differs depending on which bit you sample and sequence. The cell-free DNA fragments collected from blood are a gemisch – an averaged signature if you like – that may therefore give a better picture of the target for drug cocktails at any given time during tumour evolution.

Why is this so important?

There are two main reasons why it’s difficult to exaggerate the potential important of this step. The first is that metastasis accounts for over 90% of cancer deaths, the second that the fiendish ingenuity with which tumours negate chemotherapy, i.e. develop drug resistance, is one of the biggest challenges to successful treatment. So, the sooner changes that enable tumours to become insensitive to drugs can be detected the better in terms of adjusting the treatment regime. Even more exciting, however, is that notion that the DNA shed by cancers into the circulation may permit detection years or even decades earlier than is possible with any of the current methods (e.g., mammography) – with screening being carried put routinely from blood samples. Being even more optimistic, very early stage tumours may be particularly susceptible to appropriate drug combos, so that we might look forward to the day when chemotherapy replaces surgery as the first line of treatment for most cancers.

Reference

Murtaza, M. et al., (2013). Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 497, 108–112.

Wake up at the back

Living with someone of the opposite sex, or getting married as it used to be known, is an interesting experience. One of the things you rapidly discover that your Mum never warned you about is that women are a distinct species.  You missed that revelation in your biology classes? Serves you right for snoozing on the back row but, as a recap of the evidence, consider the following. Species often show major differences in sensory perception – thus our cat is much better than I am at seeing in the dark, though he misses out a bit in daylight as cats don’t have colour vision. When it comes to hearing it’s a bit the other way round: most of the time you can shout at him til you’re hoarse with absolutely no effect – but one faint clink of a food bowl at the back door and, yet again, he’ll set a new Feline Fifty metres Steeplechase record from the front garden. And dogs, as is well known, hear frequencies way beyond what we can pick up.

Not in my lectures!!

The gentle sex has similarly evolved beyond what mere man can manage. Take colour, for example, at which men are, as we’ve noted, quite good – compared to cats. But, as you discover the first time you are taken ‘clothes shopping’ by your wife, other half, inamorata, partner, mistress or whatever, women have evolved far beyond merely spotting that blue is different from red and being able to recite Richard Of York (to remind themselves of the rainbow sequence). They see ‘combinations’ – so you are curtly informed that what has taken your fancy ‘just doesn’t go together’ in the sort of voice that adds ‘any nitwit can see that’ without the need to expend breath on the last seven syllables.

They’re at a similarly lofty level of evolution when it comes to sound. My lady wife avers that I snore – all the time (when asleep, that is) and very loudly. So much so that she tends to use a bed at the opposite end of the house for sleeping and only ventures within sonar range for other purposes. I’d always explained this behaviour as a manifestation of the amazing imagination possessed of the female that us boys are, of course, completely lacking. However, I’ve now come to appreciate that, like Fido (who sleeps in the kitchen), she simply has exquisitely sensitive aural apparatus. So maybe I do snore – but only very quietly or at ultra high frequency, so that I would be undetectable at rest to my own species and only my beloved and the dog would know what was going on (oh, and the cat because he can see the heaving chest).

Which is very reassuring since some fellows at the Universities of Wisconsin and Barcelona have got together to discover that snoring makes you nearly five times more likely to develop cancer. Strictly the problem is sleep disordered breathing (SDB) – which happens when there’s some kind of blockage of the upper airway and, apart from disrupting sleep, it can make you snore. Of course, there’s evidence that sleep disruption can contribute to all sorts of problems from heart disease to car crashes but this is the first study making a link to cancer.

No problem for me (discounting the wife’s super sonar) but should real, habitual snorers panic? Please don’t for most of the usual reservations to this type of study apply – relatively small numbers (1522) for example. The volunteers came from an alluringly named body of men and women called the Wisconsin Sleep Cohort, set up in 1988 for prospective studies of sleep disorders. In fact the interesting ones here are what we might call the Winsomniacs – the 365 of the Cohort who can’t do it rather than the majority of Badger State dreamers. Split in this case into sub-groups of SDB severity – the strongest association being with the most severe SDB. Although the authors did their best to allow for other factors (obesity – a common cause of SDB – diabetes, smoking, etc.) it’s almost impossible in this type of study to eliminate everything bar the one factor you’re focussing on.

The most frequent linked cancer was of the lung, followed by bowel, ovary, endometrial, brain, breast, bladder, and liver. And the cancer risk was up to four-fold greater for the worst afflicted.

Do the boffins have any helpful suggestions? Not really. Those unlucky enough to be severely affected can try a gadget called a continuous positive airway pressure device but, for the rest, console yourselves that the risk is small and the data so far are very preliminary. Put another way, you have more important things to think about – like finding a partner (preferably with sub-standard sonar detection capability) who loves you so much they’re willing to poke you in the ribs whenever you become aurally intrusive.

References

http://www.telegraph.co.uk/health/healthnews/9278214/Snoring-can-raise-cancer-risk-five-fold.html

Javier Nieto, F.J. et al. (2012). Sleep-disordered Breathing and Cancer Mortality: Results from the Wisconsin Sleep Cohort Study. American Journal of Respiratory and Critical Care Medicine 186, Iss. 2, pp 190–194.

And Now For Something …

It’s not often that science and rugby collide (though to be fair they do a couple of times in BbN) but when it happens we should enjoy the spectacle. This item therefore comprises the cover page of my referees’ society newsletter (which goes by the name of Contact) for November. It is the work of the editor, Mr. Michael Dimambro, who has given immeasurable service to the game but is quite cheeky and has an inimitable style. Read on: