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Matt Ridley is the author of provocative books on evolution, genetics and society. His books have sold over a million copies, been translated into thirty languages, and have won several awards.

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Curing cancer is harder than preventing it

Genomics helps head off cancer, but cures remain elusive

My column in The Times:

Preventing cancer is proving a lot easier than curing it. The announcement that the NHS will fund five-year courses of the drugs tamoxifen or raloxifene for healthy women who are genetically predisposed to get breast and ovarian cancer is overdue. The US has been doing “chemo-prevention” for some time and clinical trials have confirmed that the benefits comfortably outweigh the side-effects. Tens of thousands of deaths a year could be averted.

This is another incremental advance in the prevention of cancer that began with the gradual recognition (resisted, ironically, by some of those fighting pesticides in the late 1950s) that tobacco smoke was a chief cause of lung cancer. Mainly thanks to such prevention, along with early diagnosis, surgery and some treatments, deaths from cancer, adjusted for age, are falling.

According to Cancer Research UK, age-adjusted cancer death rates in Britain are down by 20 per cent over 30 years and 10 per cent over 10 years. Stomach cancer deaths are down a third since 2001. Even with cancers whose incidence is increasing, such as prostate cancer, there are falls in mortality: early diagnosis improves cure rates.

None the less, the fall in cancer mortality is slow compared with the steep collapse in age-adjusted mortality from heart disease or strokes(down by 75 per cent over 30 years) and infectious disease (bumping along the bottom of the graph since falling rapidly earlier in the last century).

Most of the success has been early in a cancer’s life, before it spreads “metastatically” to other organs. With some exceptions, curing metastatic cancer remains as difficult as ever, more than 40 years after Richard Nixon declared a “war on cancer”. In particular, most carcinomas and sarcomas remain effectively incurable once they have spread beyond the reach of surgery or radiotherapy.

It is ten years since the Human Genome Project completed its first high-quality read-out of the recipe for a person. Given the optimism that attended that event, not least among cancer researchers, this relative lack of progress is disappointing. Genomics has arguably done at least as much for forensic science and ancestor-seeking as it has for cancer cures.

Prevention is a different matter. Knowledge of genetic mutations that predispose people to cancer, especially the BRCA1 and BRCA2 genes linked with breast cancer, have already helped to save lives through prophylactic surgery of the kind that Angelina Jolie underwent. But more mutations turn up all the time. This month, a study in the US and Japan found two mutations (ZNF423 and CTSO) that enhance the effectiveness of chemo-prevention with tamoxifen and raloxifene by nearly six times.

Conversely, a recent study at Manchester University has identified mutations in a third of women resulting in low levels of a protein known as pERK, making tamoxifen much less effective. Plainly, taking tamoxifen preventively makes much more sense for some individuals than others and thanks to genetic knowledge you can know which you are.

Vast amounts of genetic and molecular knowledge about how cancer works have accumulated since the Genome Project began, much of it penetratingly significant, but surprisingly little of it has led to effective cures. America’s huge project known as the Cancer Genome Atlas, for example, is telling us in great depth what genetic and molecular steps lead to different cancers, but not enough about where the vulnerabilities lie.

Moreover, we are up against Darwin. Cancer evolves rapidly within the body by deploying genetic trial and error on a huge scale, accompanied by fierce competition between the cells within the tumour. This evolution means that a “successful” cancer outwits the body’s attempts to kill it, and it does the same to drug treatments. So, for example, drugs that prevent the growth of blood vessels seemed to show promise by starving tumours of new blood supply, but the victory proved fleeting as cells emerged with mutations to reverse the effect, and these soon dominated the tumour.

Reflecting this helter-skelter evolutionary change, the chromosomes of cancer cells are notoriously messy — rearranged in lots of ways and duplicated en masse. The consequence is that there are lots of different ways a tumour can escape the body’s surveillance, and drugs that work against one way will often not work against another. Hence the devastating experience of so many sufferers and their families when hope that a treatment has begun to work turns to despair when it stops working.

The key to metastasis is when a cell accidentally acquires the genetic capacity to defy the order to kill itself. We now know that often this comes with the disabling of the gene p53, the queen of the tumour-suppressor genes, but we still have almost no idea how to design drugs that prevent the breakdown of p53. A new insight causing some surprise is that cells use “reactive oxygen species” to trigger cell suicide. If so, there is a suspicion that anti-oxidants, far from preventing cancer by preventing genetic mutations, might conceivably make it slightly more likely by preventing cell death. That this is still unsettled shows the depth of the ignorance we still have about this disease.

James Watson, whose career after the discovery of the structure of DNA in 1953 was largely devoted to studying cancer, is severely critical of “the inherently conservative nature of today’s cancer research establishments”, saying that they pursue wrong approaches and show too much interest in cancer rather than cures for cancer.

This may be harsh, but Lord Saatchi is making a similar point about therapy in his Bill asking for doctors to have much more freedom from legal liability when treating cancer so they can try more high-risk strategies. “Innovation is deviation” is how he summarises the problem for doctors.

Cancer is such a diverse disease that there will never be a single pill that cures all cancers. Nor can cancer ever be prevented altogether, if only because its incidence increases sharply with age. The more we stop people dying from pneumonia, tuberculosis, heart disease, stroke and car accidents, the more we condemn people to an eventual diagnosis of cancer. None the less, inch by inch, cancer by cancer, we can look forward to delaying the diagnosis, averting the metastasis and then maybe treating cancer more like a chronic disease that our children and grandchildren die with, rather than an acute one that they die from.