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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

None the less, the fall in cancer mortality is slow compared with
the steep collapse in age-adjusted mortality from heart disease or
(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

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

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

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.

By Matt Ridley | Tagged:  rational-optimist  the-times