Sticky Cancer Genes

 

In the previous blog I talked about Breath Biopsy — a new method that aims to detect cancers from breath samples. I noted that it could end up complementing liquid biopsies — samples of tumour cell DNA pulled out of a teaspoon of blood — both being, as near as makes no difference, non-invasive tests. Just to show that there’s no limit to the ingenuity of scientists, yet another approach to the detection problem has just been published — this from Matt Trau and his wonderful team at The University of Queensland.

This new method, like the liquid biopsy, detects DNA but, rather than the sequence of bases, it identifies an epigenetic profile — that is, the pattern of chemical tags (methyl groups) attached to bases. As we noted in Cancer GPS? cancer cells often have abnormal DNA methylation patterns — excess methylation (hypermethylation) in some regions, reduced methylation in others. Methylation acts as a kind of ‘fine tuner’, regulating whether genes are switched on or off. In the methylation landscape of cancer cells there is an overall loss of methylation but there’s an increase in regions that regulate the expression of critical genes. This shows up as clusters of methylated cytosine bases.

Rather helpfully, a little while ago in Desperately SEEKing … we talked about epigenetics and included a scheme showing how differences in methylation clusters can identify normal cells and a variety of cancers and how these were analysed in the computer program CancerLocator.

The Trau paper has an even better scheme showing how the patterns of DNA decoration differ between normal and cancer cells and how this ‘methylscape’ (methylation landscape) affects the physical behaviour of DNA.

How epigenetic changes affect DNA. Scheme shows methylation (left: addition of a methyl group to a cytosine base in DNA) in the process of epigenetic reprogramming in cancer cells. This change in the methylation landscape affects the solubility of DNA and its adsorption by gold (from Sina et al. 2018).

Critically, normal and cancer epigenomes differ in stickiness — affinity — for metal surfaces, in particular for gold. In a clever ploy this work incorporated a colour change as indicator. We don’t need to bother with the details — and the result is easy to describe. DNA, extracted from a small blood sample, is added to water containing tiny gold nanoparticles. The colour indicator makes the water pink. If the DNA is from cancer cells the water retains its original colour. If it’s normal DNA from healthy cells the different binding properties turns the water blue.

By this test the Brisbane group have been able to identify DNA from breast, prostate and colorectal cancers as well as from lymphomas.

So effective is this method that it can detect circulating free DNA from tumour cells within 10 minutes of taking a blood sample.

The aim of the game — and the reason why so much effort is being expended — is to detect cancers much earlier than current methods (mammography, etc.) can manage. The idea is that if we can do this not weeks or months but perhaps years earlier, at that stage cancers may be much more susceptible to drug treatments. Trau’s paper notes that their test is sensitive enough to detect very low levels of cancer DNA — not the same thing as early detection but suggestive none the less.

So there are now at least three non-invasive tests for cancer: liquid biopsy, Breath Biopsy and the Queensland group’s Methylscape, and in the context of epigenetics we should also bear in mind the CancerLocator analysis programme.

Matt Trau acknowledges, speaking of Methylscape, that “We certainly don’t know yet whether it’s the holy grail for all cancer diagnostics, but it looks really interesting as an incredibly simple universal marker for cancer …” We know already that liquid biopsies can give useful information about patient response to treatment but it will be a while before we can determine how far back any of these methods can push the detection frontier. In the meantime it would be surprising if these tests were not being applied to age-grouped sets of normal individuals — because one would expect the frequency of cancer indication to be lower in younger people.

From a scientific point of view it would be exciting if a significant proportion of ‘positives’ was detected in, say, 20 to 30 year olds. Such a result would, however, raise some very tricky questions in terms of what, at the moment, should be done with those findings.

Reference

Abu Ali Ibn Sina, Laura G. Carrascosa, Ziyu Liang, Yadveer S. Grewal, Andri Wardiana, Muhammad J. A. Shiddiky, Robert A. Gardiner, Hemamali Samaratunga, Maher K. Gandhi, Rodney J. Scott, Darren Korbie & Matt Trau (2018). Epigenetically reprogrammed methylation landscape drives the DNA self-assembly and serves as a universal cancer biomarker. Nature Communications 9, Article number: 4915.

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.

Desperately SEEKing …

These days few can be unaware that cancers kill one in three of us. That proportion has crept up over time as life expectancy has gone up — cancers are (mainly) diseases of old age. Even so, they plagued the ancients as Egyptian scrolls dating from 1600 BC record and as their mummified bodies bear witness. Understandably, progress in getting to grips with the problem was slow. It took until the nineteenth century before two great French physicians, Laënnec and Récamier, first noted that tumours could spread from their initial site to other locations where they could grow as ‘secondary tumours’. Munich-born Karl Thiersch showed that ‘metastasis’ occurs when cells leave the primary site and spread through the body. That was in 1865 and it gradually led to the realisation that metastasis was a key problem: many tumours could be dealt with by surgery, if carried out before secondary tumours had formed, but once metastasis had taken hold … With this in mind the gifted American surgeon William Halsted applied ever more radical surgery to breast cancers, removing tissues to which these tumors often spread, with the aim of preventing secondary tumour formation.

Early warning systems

Photos of Halsted’s handiwork are too grim to show here but his logic could not be faulted for metastasis remains the cause of over 90% of cancer deaths. Mercifully, rather than removing more and more tissue targets, the emphasis today has shifted to tumour detection. How can they be picked up before they have spread?

To this end several methods have become familiar — X-rays, PET (positron emission tomography, etc) — but, useful though these are in clinical practice, they suffer from being unable to ‘see’ small tumours (less that 1 cm diameter). For early detection something completely different was needed.

The New World

The first full sequence of human DNA (the genome), completed in 2003, opened a new era and, arguably, the burgeoning science of genomics has already made a greater impact on biology than any previous advance.

Tumour detection is a brilliant example for it is now possible to pull tumour cell DNA out of the gemisch that is circulating blood. All you need is a teaspoonful (of blood) and the right bit of kit (silicon chip technology and short bits of artificial DNA as bait) to get your hands on the DNA which can then be sequenced. We described how this ‘liquid biopsy’ can be used to track responses to cancer treatment in a quick and non–invasive way in Seeing the Invisible: A Cancer Early Warning System?

If it’s brilliant why the question mark?

Two problems really: (1) Some cancers have proved difficult to pick up in liquid biopsies and (2) the method didn’t tell you where the tumour was (i.e. in which tissue).

The next step, in 2017, added epigenetics to DNA sequencing. That is, a programme called CancerLocator profiled the chemical tags (methyl groups) attached to DNA in a set of lung, liver and breast tumours. In Cancer GPS? we described this as a big step forward, not least because it detected 80% of early stage cancers.

There’s still a pesky question mark?

Rather than shrugging their shoulders and saying “that’s science for you” Joshua Cohen and colleagues at Johns Hopkins University School of Medicine in Baltimore and a host of others rolled their sleeves up and made another step forward in the shape of CancerSEEK, described in the January 18 (2018) issue of Science.

This added two new tweaks: (1) for DNA sequencing they selected a panel of 16 known ‘cancer genes’ and screened just those for specific mutations and (2) they included proteins in their analysis by measuring the circulating levels of 10 established biomarkers. Of these perhaps the most familiar is cancer antigen 125 (CA-125) which has been used as an indicator of ovarian cancer.

Sensitivity of CancerSEEK by tumour type. Error bars represent 95% confidence intervals (from Cohen et al., 2018).

The figure shows a detection rate of about 70% for eight cancer types in 1005 patients whose tumours had not spread. CancerSEEK performed best for five types (ovary, liver, stomach, pancreas and esophagus) that are difficult to detect early.

Is there still a question mark?

Of course there is! It’s biology — and cancer biology at that. The sensitivity is quite low for some of the cancers and it remains to be seen how high the false positive rate goes in larger populations than 1005 of this preliminary study.

So let’s leave the last cautious word to my colleague Paul Pharoah: “I do not think that this new test has really moved the field of early detection very far forward … It remains a promising, but yet to be proven technology.”

Reference

D. Cohen et al. (2018). Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science 10.1126/science.aar3247.

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.

The Hay Festival

According to the Hay Festival  a recording of my talk ‘Demystifying Cancer’ on Wednesday 28th May should be available on their web site shortly and it can also be heard on the university site. However, I thought it might be helpful to post a version, not least for the for the rather breathless lady who arrived at the book signing session apologising for missing the lecture because she’d got stuck in mud. So for her and perhaps for many others I had the privilege of chatting to afterwards, read on …

 The Amazing World of Cells, Molecules … and CancerOpening pic

One of the biggest influences on my early years was the composer and conductor Antony Hopkins, who died a few days ago. Most of what I knew about music by the time I was 15 came from his wonderfully clear dissections of compositions in the series Talking About Music broadcast by the BBC Third Programme. When he was axed by the Beeb in 1992 for being ‘too elitist’ – yes, they talked that sort of drivel even then – Hopkins might have wished he’d been a biologist. After all, biology must be the easiest subject in the world to talk about. Your audience is hooked from the outset because they know it’s about them – if not directly then because all living things on the planet are interlinked – so even the BBC would struggle to make an ‘elitism’ charge stick. They know too that it’s beautiful, astonishing and often funny – both from what they see around them and also, of course, courtesy of David Attenborough. So it’s not a surprise when you show them that the micro-world of cells and molecules is every bit as wonderful.

The secret of life

What does come as a bit of a shock to most non-scientists is when you explain the secret of life. No, that’s not handing round pots of an immortalization elixir – much better, it’s outlining what’s sometimes rather ponderously called the central dogma of molecular biology – the fact that our genetic material (aka DNA) is made from only four basic units (most easily remembered by their initials: A, C, G and T – humans have over three thousand million of these stuck together). This is our ‘genome’ and the ‘genetic code’ enshrined in the DNA sequence makes us what we are – with small variations giving rise to the differences between individuals. The genetic code carries instructions for glueing together another set of small chemicals to make proteins. There are 20 of these (amino acids) and they can be assembled in any order to make proteins that can be thousands or even tens of thousands of amino acids long. These assemblies fold up into 3D shapes that give them specific activities. Proteins make living things what they are – they’re ‘the machines of life’ – and their infinite variety is responsible for all the different species to have appeared on earth. Can the basis of life really be so simple?

The paradox of cancer

Turning to cancer, a three word definition of ‘cells behaving badly’ would do fine. A more scientific version would be ‘cells proliferating abnormally.’ That is, cells reproducing either when they shouldn’t, or more rapidly than normal, or doing so in the wrong place. The cause of this unfriendly behavior is damaged DNA, that is, alteration in the genetic code – any such change being a ‘mutation’. If a mutation affects a protein so that it becomes, say, hyperactive at making cells proliferate (i.e. dividing to make more cells), you have a potential cancer ‘driver’. So at heart cancer’s very simple: it’s driven by mutations in DNA that affect proteins controlling proliferation. That’s true even of the 20% or so of cancers caused by chronic infection – because that provokes inflammation, which in turn leads to DNA damage.

The complexity of cancer arises because, in contrast to several thousand other genetic diseases in which just a single gene is abnormal (e.g., cystic fibrosis), tumour cells accumulate lots of mutations. Within this genetic mayhem, relatively small groups of potent mutations (half a dozen or so) emerge that do the ‘driving’. Though only a few ‘driver mutations’ are required, an almost limitless number of combinations can arise.

Accumulating mutations takes time, which is why cancers are predominantly diseases of old age. Even so, we should be aware that life is a game of genetic roulette in which each individual has to deal with the dice thrown by their parents. The genetic cards we’re dealt at birth may combine with mutations that we pick up all the time (due to radiation from the sun and the ground, from some foods and as a result of chemical reactions going on inside us) to cause cancers and, albeit rarely, in unlucky individuals these can arise at an early age. However, aside from what Mother Nature endows, humans are prone to giving things a helping hand through self-destructive life-style choices – the major culprits, of course, being tobacco, alcohol and poor diets, the latter being linked to becoming overweight and obese. Despite these appalling habits we’re living longer (twice as long as at the beginning of the twentieth century) which means that cancer incidence will inevitably rise as we have more time to pick up the necessary mutations. Nevertheless, if we could ban cigarettes, drastically reduce alcohol consumption and eat sensibly we could reduce the incidence of cancers by well over a half.

How are we doing?

Some readers may recall that forty-odd years ago in 1971 President Nixon famously committed the intellectual and technological might of the USA to a ‘War on Cancer’ saying, in effect, let’s give the boffins pots of money to sort it out pronto. Amazing discoveries and improved treatments have emerged in the wake of that dramatic challenge (not all from Uncle Sam, by the way!) but, had we used the first grant money to make a time machine from which we were able to report back that in 2013 nearly six hundred thousand Americans died from cancer, that the global death toll was over eight million people a year and will rise to more than 13 million by 2030 (according to the Union for International Cancer Control), rather less cash might subsequently have been doled out. Don’t get me wrong: Tricky Dicky was spot on to do what he did and scientists are wonderful – clever, dedicated, incredibly hard-working, totally uninterested in personal gain and almost always handsome and charming. But the point here is that, well, sometimes scientific questions are a little bit more difficult than they look.

Notwithstanding, there have been fantastic advances. The five year survival rates for breast and prostate cancers have gone from below 50% to around 90% – improvements to which many factors have contributed including greater public awareness (increasing the take-up of screening services), improved surgical and radiology methods and, of course, new drugs. But for all the inspiration, perspiration and fiscal lubrication, cancer still kills over one third of all people in what we like to refer to as the “developed” world, globally breast cancer killed over half a million in 2012 and for many types of cancer almost no impact has been made on the survival figures. In the light of that rather gloomy summary we might ask whether there is any light at the end of the tunnel.

The Greatest Revolution

From one perspective it’s surprising we’ve made much progress at all because until just a few years ago we had little idea about the molecular events that drive cancers and most of the advances in drug treatment have come about empirically, as the scientists say – in plain language by trial and error. But in 2003 there occurred one of the great moments in science – arguably the most influential event in the entire history of medical science – the unveiling of the first complete DNA sequence of a human genome. This was the product of a miraculous feat of international collaboration called The Human Genome Project that determined the order of the four units (A, C, G and T) that make up human DNA (i.e. the sequence). Set up in 1990, the project was completed by 2003, two years ahead of schedule and under budget.

If the human genome project was one of the most sensational triumphs in the history of science what has happened in the ensuing 10 years is perhaps even more dazzling. Quite breathtaking technical advances now mean that DNA can be sequenced on a truly industrial scale and it is possible to obtain the complete sequence of a human genome in a day or so at a cost of about $1,000.

These developments represent the greatest revolution because they are already having an impact on every facet of biological science: food production, microbiology and pesticides, biofuels – and medicine. But no field has been more dramatically affected by this technological broadside than cancer and already thousands of genomes have been sequenced from a wide range of tumours. The most striking result has been to reveal the full detail of the astonishing genetic mayhem that characterizes cancer cells. Tens of thousands or even hundreds of thousands of mutations featuring every kind of molecular gymnastics imaginable occur in a typical tumour cell, creating a landscape of stunning complexity. At first sight this makes the therapeutic challenge seem daunting, but all may not be lost because the vast majority of this genetic damage plays no role in cancer development (they’re ‘passenger’ mutations) and the power of sequencing now means they can be sifted from the much smaller hand of ‘driver’ mutations. From this distillation have emerged sets of ‘mutational signatures’ for most of the major types of cancers. This is a seismic shift from the traditional method of assessing tumours – looking directly at the cells after treating them with markers to highlight particular features – and this genetic approach, providing for the first time a rigorous molecular basis for classifying tumours, is already affecting clinical practice through its prognostic potential and informing decisions about treatment.

A new era

One of the first applications of genomics to cancer, was undertaken by a group at The Wellcome Trust Sanger Institute near Cambridge (where the UK part of the Human Genome Project had been carried out), who screened samples of the skin cancer known as malignant melanoma. This is now the fifth most common UK cancer – in young people (aged 15 to 34) it’s the second most common – and it killed over 2,200 in 2012. Remarkably, about half the tumours were found to have a hyperactivating mutation in a gene called BRAF, the effect being to switch on a signal pathway so that it drives cell proliferation continuously. It was a remarkable finding because up until then virtually nothing was known about the molecular biology of this cancer. Even more amazingly, within a few years it had lead to the development of drugs that caused substantial regression of melanomas that had spread to secondary sites (metastasized).

This was an early example of what has become known as personalized medicine – the concept that molecular analysis will permit treatment regimens to be tailored to the stage of development of an individual’s cancer. And maybe, at some distant time, the era of personalized medicine will truly come about. At the moment, however, we have very few drugs that are specific for cancer cells – and even when drugs work initially, patients almost invariably relapse as tumours become resistant and the cancer returns – one of the major challenges for cancer biology.

It behoves us therefore to think laterally, of impersonal medicine if you like, and one alternative approach to trying to hit the almost limitless range of targets revealed by genomics is to ask: do tumour cells have a molecular jugular – a master regulator through which all the signals telling it to proliferate have to pass. There’s an obvious candidate – a protein called MYC that is essential for cells to proliferate. The problem with stopping MYC working is that humans make about one million new cells a second, just to maintain the status quo – so informed opinion says that blocking MYC will kill so many cells the animal will die – which would certainly fix cancer but not quite in the way we’re aiming for. Astoundingly, it turns out in mice at least it doesn’t work like that. Normal cells tolerate attenuation of MYC activity pretty well but the tumour cells die. What a result!! We should, of course, bear in mind that the highway of cancer therapy is littered with successful mouse treatments that simply didn’t work in us – but maybe this time we’ll get lucky.

An Achilles’ heel?

In defining cancers we noted the possibility that tumour cells might proliferate in the wrong place. So important is this capacity that most cancer patients die as a result of tumour cells spreading around the body and founding secondary colonies at new sites – a phenomenon called metastasis. Well over 100 years ago a clever London physician by the name of Stephen Paget drew a parallel between the growth of tumours and plants: ‘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 emerged the “seed and soil” theory as at least a step to explaining metastasis. Thus have things languished until very recent findings have begun to lift the metastatic veil. Quite unexpectedly, in mouse models, primary tumours dispatch chemical messengers into the blood stream long before any of their cells set sail. These protein news-bearers essentially tag a landing site within the circulatory system on which the tumour cells touch down. Which sites are tagged depends on the type of tumour – consistent with the fact that human cancers show different preferences in metastatic targets.

These revelations have been matched by stunning new video methods that permit tumour cells to be tracked inside live mice. For the first time this has shone a light on the mystery of how tumour cells get into the circulation – the first step in metastasis. Astonishingly tumour cells attach themselves to a type of normal cell, macrophages, whose usual job is to engulf and digest cellular debris and bugs. The upshot of this embrace is that the macrophages cause the cells that line blood vessels to lose contact with each other, creating gaps in the vessel wall through which tumour cells squeeze to make their escape. This extraordinary hijacking has prognostic value and is being used to develop a test for the risk of metastasis in breast cancers.

The very fact that cancers manifest their most devastating effects by spreading to other sites may lay bare an Achilles’ heel. Other remarkable technical developments mean that it’s now possible to fish out cancer cells (or DNA they’ve released) from a teaspoonful of circulating 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 cells for every cubic millimeter of blood). Coupling this to genome sequencing has already permitted the response of patients to drug therapy to be monitored but an even more exciting prospect is that through these methods we may be moving towards cancer detection perhaps years earlier than is possible by current techniques.

As we’ve seen, practically every aspect of cancer biology is now dominated by genomics. Last picIt’s so trendy that anyone can join in. Songs have been written about DNA and you can even make a musical of your own genetic code, French physicist Joel Sternheimer having come up with a new genre – protein music – in which sequence information is converted to musical notes. Antony Hopkins, ever receptive to new ideas, would have been enthralled and, with characteristic enthusiasm, been only too happy to devote an episode of Talking About Music to making tunes from nature.

Spinning Out In Control

In Signs of Resistance and Seeing the Invisible we emphasized two things well known to the interested, namely that most cancer deaths occur because cells spread from the original (primary) to secondary sites (metastases) where they are very difficult to treat, and that this places massive importance on early detection. Many will also be familiar with the currently used methods for tumor detection – X-ray based imaging (as in mammography and CT scans) and PET that detects injected radioactive tracers. The problem is that these are not sensitive enough to detect growths smaller than about 1 cm in diameter – and by that point there are several hundred million cells in the tumor and some may already have metastasized.

Tumor cells spread around the body by detaching from the primary and getting into the circulatory system and it’s beginning to look as though quite literally tapping into the circulation may revolutionize cancer detection. Seeing the Invisible showed how silicon chip technology can be used to retrieve circulating tumor cells (CTCs) by getting them to stick to targets anchored in a flow cell. Although this is hugely promising, another very recent advance may be even more effective. This uses centrifugal force to separate cells in blood on the basis of their size – that’s the one that pushes outwards on objects rotating about an axis. Because force is proportional to mass and tumor cells are larger than red blood cells and most white cells, this effect can be used to extract CTCs from fluid being pumped around a spiral microchannel. The spirals are made from a silicon-based polymer (the same stuff that’s used for contact lenses) stuck on glass slides and they have two outlet channels. Their shape creates two-counter rotating vortices in the fluid that exert a drag force on the cells so that bigger (heavier) tumor cells can be selectively directed to one of the outlets. Typically red blood cells are about 6 microns (one-millionth of a metre), white cells 8-14 microns and CTCs 16-25 microns in diameter.

The vortices are named after a Cambridge chappie, William Dean, who worked on flow patterns in curved pipes and channels and you can look up Dean vortices on the internet for images of these in action.

MCF7s right, rest left

In this picture of the two exits from a spiral microchannel breast cancer cells are carried to the right (yellow arrows) whilst all the other types of blood cell funnel left.

This method appears to be remarkably efficient in that over 90% of tumor cells (10-100 cells per ml of blood) can be separated from 99.99% of red cells (5,000,000 per ml) and 99.6% of white cells (10,000 per ml).

References

Hou, H.W., Warkiani, M. E., Khoo, B.L., Li, Z.R., Soo, R.A., Tan, D.S.-W., Lim, W.-T., Bhagat, A.A.S., and Lim, C.T. (2013). Isolation and retrieval of circulating tumor cells using centrifugal forces. Scientific Reports 3, Article Number: 1259. DOI: 10.1038/srep01259.

Bhagat, A.A.S. et al., 15th International Conference on Miniaturized Systems for Chemistry and Life Sciences October 2-6, 2011, Seattle, Washington, USA

Spray Painting Cancer

I’m pretty certain that anyone reading this will be fully aware that one of the biggest problems in cancer is spotting the blighters. We have, of course, X-ray detection (as in mammography), CTs and MRI scans, all so familiar we need not bother to define them, and there’s also a variety of sampling methods for specific cancers (e.g., the Pap test for cervical cancer). But, useful though all these are, the plain fact of the matter is that none are ideal and in particular the pictures created by imaging methods are very limited in sensitivity. Put another way, they won’t pick something up until it is quite large – a centimeter in diameter – meaning that the abnormal growth is already quite advanced.

Cunning Chemistry

Needless to say, much inspiration and perspiration is being applied to this matter and what has been really exciting over the last ten years or so is the way very smart chemists are collaborating with clinicians to come up with new ways of looking at the problem. One of these clever tactics is being developed in the University of Tokyo using a different type of imaging ‘reporter’ that signals its presence by fluorescing. Fluorescence occurs when a molecule absorbs light and becomes ‘excited’ before relaxing back to its ‘ground state’ by giving off a photon. Fluorescent molecules (fluorophores) are much used in biology because the background signal is often very low so the high signal-to-noise ratio gives excellent sensitivity.

Spray Paint scheme

The cell-surface enzyme GGT converts the small molecule  gGlu-HMRG to a fluorescent form (HMRG) that is then taken up by the cell. GGT is only found on tumor cells so they light up and normal cells do not

Fortunately we don’t need to know how the chemists did it – merely to say that Yasuteru Urano and his colleagues came up with a small molecule (called gGlu-HMRG for short) that does not give off light until a small fragment is chopped off its end, whereupon it changes shape: this flips the switch that turns on fluorescence. The cutting step needs an enzyme that is found on the surface of various cancer cells but not in normal tissue (GGT for short).

Joining Forces

To show that there was real mileage in their idea they followed the time-honored blue-print of cancer research, showing first that it works on tumor cells grown in the lab (and, equally important, that it doesn’t highlight normal cells), before moving to mouse models of ovarian tumors. The later is where chemists meet clinicians because an endoscope is required (quite a small one) – a flexible tube for looking inside the body – devices now so sophisticated that they can incorporate a fluorescence camera.

In the final synthetic step the cunning chemists formulated a spray-on version of their probe molecule so that it can be dispensed during endoscopy or surgery – a bit like an underarm deodorant. Now it’s easy: find suspect tissue, give it a squirt of gGlu-HMRG, wait a few minutes and see if it lights up. The answer is, of course, that in their ovarian cancer model the spray-on graffiti lights up within 10 minutes of sticking to a tumor cell and can detect clumps of cells as small as 1 millimeter in diameter – a terrific advance in terms of sensitivity. The brief time taken for the signal to be visible after the probe has been applied means that within the same procedure it could be used to guide surgeons in removing small tumor masses.

The Tokyo system is not the only one under development. My colleague Andre Neves at the Cambridge Cancer Centre, another of these fiendishly clever chemists, is working on a parallel line using different fluorophores that can be topically applied to the lining of the intestine. The goal here is, of course, the early detection of colon tumors. Yet other approaches use molecules that accumulate preferentially in tumor cells and respond to light in the near-infrared region of the spectrum (800 nm to 2500 nm wavelength, compared to just under 500 nm for gGlu-HMRG), giving an even better signal-to-noise ratio.

This is, as Mr. Churchill might have pointed out, not even the beginning of the end of this story. But it is one more small and innovative step forward. Not all cancers even of the same type will be detectable by a given probe because they vary so much in the genes they express but the ingenuity of the chemists gives hope that a substantial panel of ever more sensitive reporters will emerge. It is also true that endoscopy is unlikely to gain widespread popularity as a routine screening method. However, these advances, moving us to detection at ever earlier stages may become very powerful as a follow-up test, combined with the capacity for simultaneous treatment, when tumor cells have been detected in more comfortable screens, for example as circulating cells in small blood samples, an immensely exciting prospect to which we will return in a later episode.

 References

Urano, Y., Masayo Sakabe, Nobuyuki Kosaka, Mikako Ogawa, Makoto Mitsunaga, Daisuke Asanuma, Mako Kamiya, Matthew R. Young, Tetsuo Nagano, Peter L. Choyke, and Kobayashi, H. (2011). Rapid Cancer Detection by Topically Spraying a γ-Glutamyltranspeptidase–Activated Fluorescent Probe. Science Translational Medicine 3, 110ra119.

http://www.ncbi.nlm.nih.gov/pubmed/22116934

Shi, C. (2012). Comment on “Rapid Cancer Detection by Topically Spraying a γ-Glutamyltranspeptidase–Activated Fluorescent Probe. Science Translational Medicine 4, 121le1.

http://stm.sciencemag.org/content/4/121/121le1.long

A Radiant Visitor

In an historic first, Cancer For All welcomes a guest, Stacey McGowan, who is a physicist just starting a Ph.D. on something called Proton Therapy. She is a member of the Department of Oncology in Cambridge and you can find out more about her in her blog www.planningforprotons.com but today she is going to take us into her world with a simple guide to radiotherapy in the treatment of cancer.

As undergraduate there was a lot of pressure to know what you wanted to do after graduation. I knew I wanted to stay in physics as it was what I loved; I also knew I wanted a job that meant something to me. I did not want to work in finance or for a defence company. At the time I also didn’t think I wanted to go into research! This seemed to have left me with two options, to work in the energy industry, or in medicine.

A lot of people, including my undergrad self, are unaware of medical physicists and their role in the hospital and in treating patients. After an inspiring talk at a careers event from a medical physicist working in the NHS I knew that this was what I wanted to do after graduation: I wanted to be a medical physicist.

There are three main methods for treating cancer; surgery, chemotherapy and radiotherapy. A patient will usually receive one or more of these methods as part of their treatment. Of the cures achieved about 49% of them involve surgery, 11% involve chemotherapy and 40% involve radiotherapy. However of the NHS’s cancer budget surgery costs around 22%, chemotherapy 18% and radiotherapy just 5%. This makes radiotherapy both a successful treatment option, sometimes on its own but usually in combination with surgery or chemotherapy, and it is extremely cost effective. Despite this many people don’t really know what radiotherapy is and the prospect of it as a treatment often makes patients apprehensive. As much as radiation sounds scary, we are exposed to it all the time in nature from the sun and soil and nowadays in our homes from electrical devices including Wi-Fi and mobile phones. In addition, we use it in many diagnostic applications including X-rays, CT scanners and nuclear medicine.

The difference between the radiation used for cancer treatment and that received from other sources is in the amount of radiation, or dose, delivered. When I talk about dose, think of it in the same way you would any other type of medicine. An oncology doctor will prescribe a course of radiotherapy with a specific dose to be delivered to the patient every weekday for between 4 and 6 weeks. The radiation is delivered in the form of X-rays – highly energetic particles of light – delivered at higher energies and doses than those used to image a broken bone (Editor’s enlightenment: physicists tend to use the word ‘light’ to mean electromagnetic radiation of any wavelength – not just what the eye sees). To create such highly energetic light we need a powerful machine that can also precisely deliver the X-rays to the part of the patient where the cancer lies. This machine is known to the medical community as a linac, and to the scientific community as a linear accelerator!

The linacs used in the hospital differ from those used in physics research as medical linacs have a very different role and it is the medical physicists’ job to ensure they work as intended. The X-rays delivered to the patient will harm cells in their body, both cancerous and healthy, by damaging their DNA. It is extremely important that the cancer cells receive the dose necessary to kill them so that they cannot continue to grow, resulting in a cure. It is also a priority that healthy tissue receives the smallest possible radiation dose to ensure a low chance of long term side effects. To accomplish these goals linacs are designed to rotate about the patient so that the tumour can be targeted from more than one direction. Treatment is usually delivered in daily doses (known as fractions) over a period of a few weeks because healthy cells are better at repairing damage to their DNA than cancer cells, so they can recover from each dose, whereas damage will accumulate in the tumour cells. Cumulative DNA damage leads to cell death, stopping the cancer in its tracks.

Linacs can also shape the beam so that it will match the shape of the tumour, shielding the adjacent healthy tissue from the highest radiation doses. To produce such patient-specific and intricate treatments powerful computer programs are used to design the treatment based on images of the patient (usually CT scans). Oncologists and physicists will work together, distinguishing cancer tissue from healthy, choosing beam directions and designing beam shapes to ensure that the patient receives the optimal treatment.

Many types of cancers respond to radiotherapy including those of the lung, breast, prostate, brain and spine and the method can be used to treat both adults and children. The short term side effects from radiotherapy vary depending on the region being treated. For example, radiation of the abdominal area may cause digestive and bowel discomfort or if the head and neck is the target, the patient may experience difficulty swallowing and develop a dry mouth. Generally radiotherapy can lead to tiredness, nausea and skin irritation in the targeted areas. Long term side effects can include secondary cancer, more probably in young patients, and growth problems in children.

The future of radiotherapy in the NHS is to use of protons and not X-rays to deliver radiation for specific types of cancer. The nature of protons makes the aim of cure without complication more achievable and is the topic of my PhD research.

Unlike X-rays, protons have a finite range (we can choose where they stop) which reduces the amount of radiation exposure to the patient, making this form of therapy especially beneficial for spine and brain tumours in adults and for most cancers in children. Proton therapy is particularly attractive for treating childhood cancers because it is less likely than conventional radiotherapy to cause growth defects and other health complications, including the development of cancers in later life.

Despite the UK lacking the facilities necessary to treat cancer using proton radiotherapy, a limited number of NHS patients are currently offered this option abroad as part of the NHS Proton Overseas Programme. The Government also announced in April 2012 that two proton centres will be established in England, in Manchester and in London. It is hoped that these will start to treat patients by early 2017.

Stacey McGowan

Department of Oncology, University of Cambridge

http://www.planningforprotons.com

Behind the Screen

Anyone who’s romped through to the closing pages of Betrayed by Nature will (we hope) be grateful to have come upon a succinct summary of the pros and cons of screening, particularly for breast cancer. In the UK screening (i.e. mammography: see Breast Cancer – Seeing Red, Jan 2012 for explanation) is offered to women aged 50-70 every three years – so clearly ‘we’ think it’s a Good Thing. However, the waters are less than crystal clear because several studies have concluded that as many as one in three cancers identified by mammography would not cause any symptoms during the lifetime of the patient  – and suggested that countries should spend the money on other things. The simple message you were relieved to read in BbN was that, whilst the matter is controversial, if you are offered screening, accept – whilst being aware that a ‘positive’ is not always a signal for intervention (by surgery and drugs) and that in deciding on a course of action you should be guided by the best advice your clinicians can give.

Photo: Alamy

Trying to bring resolution to this complicated and important matter, yet another ‘official review’ has just appeared in The Lancet – predictably accompanied by some absurdly inflammatory press headlines. So, ignoring them and your groans – and because it is important – can we recap the key points and reassess the clear BbN message? Of course we can – that’s what we do in “Cancer for All.”

Any type of screen for signs of cancer has two problems for those on the receiving end. First it will miss some and second it will sometimes pick up things that, although abnormal, will never become life-threatening. This latest report estimates that screening reduces the relative risk by 20%, i.e. prevents one breast cancer death for every 235 women invited for screening, equivalent to 43 preventions per 10,000 women aged 50 who are screened over the next 20 years. The downside is that about 130 women in every 10,000 are what is called ‘overdiagnosed’: they receive treatment for something that could simply be left alone. Of course that’s highly undesirable as well as stressful and unpleasant for the patient. However, it is rarely fatal – and at least carries an element of reassurance that they won’t develop breast cancer.

So, in the light of the newest info, is BbN’s take in need of modification? No, it’s just fine. What a relief!! But just bear a couple of other points in mind: the sensitivity of screening is gradually improving and dramatic improvements in analysing tumours at the molecular level mean that ‘overdiagnosing’ will decline. As we’ve pointed out, the system isn’t perfect – then neither are we or we wouldn’t get cancers – but it’s heading in the right direction.

References

Independent UK Panel on Breast Cancer Screening. The benefits and harms of breast cancer screening: an independent review. The Lancet October 2012.

http://www.telegraph.co.uk/health/healthnews/9641609/Breast-cancer-screening-harming-thousands.html