A cell among trillions: Understanding cancer’s unruly origins helps early diagnosis

Share this page on:

DIANE MILLEY, a teacher, remembers getting the small, dry cough just before school broke up for the summer in 2013. She wasn’t worried: she considered herself generally healthy—she ran three times a week and went to the gym. Her doctor in Bradford, Massachusetts, put her on a course of antibiotics. When they didn’t work she had an X-ray. It showed nodules across her lungs. A bronchoscopy was ordered to retrieve a tissue sample from her lung. As she came round from the anaesthetic she remembers overhearing two medical staff talking. One said “It’s malignant.” She had late-stage lung cancer.

Ms Milley’s body, like all human bodies, contained tens of trillions of copies of her genome. In theory, all those copies should be more or less the same. In practice, over the years, they all get knocked around in different ways. The oxygen that powers cell metabolism damages the DNA on which the genes are stored as a matter of course; so do background radiation and exposure to the many low-level carcinogens; so do sunlight and infection with viruses; so do choices about diet and recreational drugs, notably alcohol and tobacco (from which Ms Milley abstained).

The vast bulk of this damage is quickly fixed by DNA-repair enzymes; fewer than one mutation in a thousand persists. But wear and tear builds up. Many such changes make little or no difference. A few will be of consequence to the cell concerned, reducing or eliminating its capacity to do its job. But the loss of a single cell’s contribution matters not a jot.

There are some genes, though, where uncorrected damage can matter a lot. Foremost are the genes which control cell growth, such as HER2, which tells the cell how to make a protein called human epidermal-growth-factor receptor type 2. This is a protein that, when it sees a particular hormone, tells the cell it is in to divide. Mutations in the HER2 gene can make cells proliferate when there is no need. When they do so their daughter cells, which will share that HER2 mutation, will go on to do the same.

Among some 20,000 genes in the genome there are dozens which, like HER2, can cause unwanted cell division when they go wrong. To forestall such problems there are various tumour-suppressor genes whose job is to make sure that cells damaged in this way shut themselves down. The best known is the gene for a protein called p53, which stops cells from reproducing if their DNA is damaged. But these tumour-suppressor genes, too, are subject to mutation.

The numbers game

Thus over time, as genetic damage accumulates, the likelihood rises that somewhere in the body’s trillions of cells there is one that has, through five or six mutations in key genes, developed the ability to grow without check. This likelihood is not the same for everyone. Some people start off with quirks in their genome which make them more susceptible. Take the genes BRCA1 and BRCA2, which describe proteins that repair DNA; people who inherit a damaged version of one or the other face a higher risk of cancer (in particular, breast and ovarian cancer) because, with one crucial function already compromised, it takes fewer mutations for a tumour to get going.

Once a cancer has begun its unruly growth it will pick up more and more mutations: the cancer genome project at the Sanger Institute, outside Cambridge in England, has found that cancers can have as few as ten mutations or as many as a few hundred. Though all the cells in the cancer are descended from one parent cell, they become increasingly diverse over time. Some cells come loose and start new tumours of their own elsewhere. The body’s immune system will often recognise that something is amiss and try to fight the cancer and slow its spread. Sometimes it wins, stopping the cancer or killing it. Sometimes it doesn’t.

When Ms Milley’s cancer was diagnosed all the things that could go wrong already had; the tumour was well developed and had spread through the lung and beyond. It would have been far better for her if it had been diagnosed earlier (see chart). But with lung cancer, as with many other forms of the disease, there are often few symptoms until the disease is already at an advanced stage. If cancer could be reliably detected earlier, many lives might be saved.

In some wealthy countries, some cancers—for example, those of the breast, prostate and cervix—are regularly sought out before they start to cause symptoms. Now researchers are trying to improve diagnostic tools even further, so that more types of cancer can be found early on (and with greater reliability). For some it is a terribly personal hunt. Billy Boyle, the president of a small biotech company, Owlstone Medical, based in Cambridge, in England, is one of them. He lost his wife Kate, mother to their two young boys, on Christmas morning in 2014. She died of colon cancer that had been picked up too late. Mr Boyle says that if colorectal cancer is detected early, 95% of sufferers survive. Only 6% survive if the cancer reaches stage four. For many cancers, early detection is “our greatest opportunity to improve survival,” says Mr Boyle.

Mr Boyle wants to detect cancer on the breath using an ion-mobility spectrometer—a gadget that weighs chemicals by passing them through an oscillating electric field. The breath contains a wide range of organic molecules that reflect what is going on in the body’s metabolism. Cancers, which affect the metabolism, should in so doing change the pattern of molecules on the breath. Although Owlstone’s system is very small—it fits on a chip the size of a coin—it is sensitive, identifying molecules at a level of a few parts per billion. The firm hopes that when it has identified molecular “fingerprints” associated with particular cancers it will be able to detect the disease earlier than other tests do.

Improved diagnostics reveal cancer’s weaknesses

Improved diagnostics can do more than pick up cancers sooner. They can also reveal the cancers’ weaknesses. Because cancer drugs work in different ways, some will do well against a tumour with one set of mutations but leave unscathed one that has become cancerous by some other pathway. Troy Cox, head of Foundation Medicine, a diagnostics company based in Cambridge, Massachusetts, says that in America 14 cancer drugs now have “companion diagnostics”—tests that show whether a cancer is likely to be susceptible to them or not. Ms Milley’s lung cancer, for example, turned out to harbour a mutation which meant she could be treated with a drug that targets that specific protein (see article).

So far, such genetic tests are used when planning therapy for 50% to 60% of solid tumours, according to Foundation. New drugs, new understanding of cancer mechanisms and new technologies that can scan many genes for mutations at once mean such testing will be more informative in the near future. Many, including England’s chief medical officer, Sally Davies, want cancer patients to be routinely offered genetic screening of their tumours. Foundation and ThermoFisher, a diagnostics firm in Waltham, Massachusetts, are hoping to encourage this by offering every gene of interest on a mass-produced chip. Some of these mutations will help doctors pick the best drugs for that particular cancer, others may indicate how it is likely to develop. The tests would also identify mutations for which there is not yet an approved therapy—but for which there is one in clinical trials.

David Hyman, at the Memorial Sloan Kettering Cancer Centre in New York, worked on a trial of an experimental drug, larotrectinib, that was expected to work in cancers where a gene called NTRK1 had undergone a specific mutation. Because that mutation is found in less than 1% of all cancer patients, recruiting people to the trial was a “Herculean effort”, he says. It was worth it, though. The drug was tested on 50 patients with 17 different types of tumour. In results published in June, 78% of patients with 12 different tumour types responded to the drug.

Aside from picking the right drugs, genetic tests are also starting to reveal more about the outcome and risks of any individual cancer—something that is useful for deciding whether a cancer needs to be treated at all. The MammaPrint test, made by Agendia, based in Amsterdam, analyses the activity of genes in early-stage breast cancer. If women with early-stage breast cancer were routinely tested in this way, those who will not need chemotherapy after surgery could be picked out (a recent study of patients found 58% to be in this category). A similar test is available for prostate cancer from the firm Myriad Genetics, based in Salt Lake City, Utah. A recent study suggests that people who have inherited a mutation in the P53 tumour-suppressor gene might be well advised to have whole-body MRI scans to screen for cancers, since their unsafeguarded cells are at particular risk.

Identifying genes from tumours normally means retrieving cancer cells via biopsies. This is invasive and often done only once in the course of the disease. But cancers are both heterogeneous and labile; elsewhere in a tumour, and later in a tumour’s progression, things may look different.

These challenges are now being tackled with blood tests, a technique termed “liquid biopsy”. Tumours shed DNA into the blood, and these circulating fragments of DNA can be tested for mutations. Regularly testing this DNA could be a way of keeping track of a tumour’s mutations. The Institute for Cancer Research, based in London, recently showed that it could use a liquid biopsy to pick out whether a patient was likely to benefit from a new type of drug called a PARP inhibitor. Using liquid biopsies the researchers were able to find out if the drug was doing any good in just four to eight weeks. Liquid biopsies are also a promising technology for the routine monitoring of patients who have been successfully treated for cancer, lest their disease return. Mark Roschewski, a researcher with America’s National Cancer Institute, the NCI, thinks the technology could be “orders of magnitude more sensitive than radiographic imaging”.

Biopsies optimised

The big question for the firms developing these liquid biopsies is whether the technology will also be suitable for the early-detection market that Mr Boyle is chasing with his breath tests. Guardant Health, a firm based in Redwood City, California, currently offers a liquid biopsy that allows patients to obtain a genetic profile of their tumour. It is using the data it gathers to look at the feasibility of early detection. Helmy Eltoukhy of Guardant says the firm is “agnostic” about the markers it seeks in the blood, meaning that its researchers will not look just for DNA from tumours—if the data suggest that RNA (a relative of DNA) or proteins provide the telltale fingerprint, then that is what they will look at.

All diagnostic tests have to overcome two hurdles. They have to be sensitive enough to identify those who have the disease correctly and also specific enough that they do not see signs of the disease when it isn’t actually present. The more widely they are used, the more important that second requirement gets; false positives are a pervasive problem with existing tests such as mammograms and PSA, a test for prostate cancer. (This is why PSA screening, while common in America, is much less prevalent in Europe.)

In liquid biopsies the challenge will be to detect cancer-specific signals against a noisy and confusing background. Barry Kramer, director of the division of cancer prevention at the NCI, warns that the same marker can have different functions in different organs. He notes that a programme screening infants for neuroblastoma was halted after it started to pick up too many growths that did not merit clinical concern and didn’t reduce the death rate. Specificity, says Mr Eltoukhy, is early detection’s Achilles’ heel. Others warn that liquid biopsies aimed at DNA will never be sensitive enough for early detection, because early tumours may shed very little DNA, or shed it only occasionally; other molecules might prove more telling.

Nonetheless, biotech is gung-ho about the idea. Grail, a liquid-biopsy startup in Silicon Valley spun out of Illumina, a sequencing firm, recently raised $900m. Earlier this year Guardant raised $360m, and Alphabet invested $65m in Freenome, a San Francisco startup with similar plans. Grail has begun a trial of its technology which will enroll 120,000 women who are receiving mammograms to see if its technology really does offer early detection.

Whether it will make sense to adapt liquid biopsies to population screening will depend on their costs—currently still too high for widespread use—their sensitivity and, crucially, their false-positive rates. Unnecessary investigations after false positives are both worrying and debilitating for patients and costly for the health-care system. But some, such as Luis Diaz, an oncologist at Memorial Sloan Kettering, argue that initial overdiagnosis is a necessary part of moving ahead: “One never learns to ride a bike without falling off.”

The costs and difficulties of blood screening are one of the things that tiny Owlstone has going for it. Testing the breath for metabolites doesn’t require the tumours to have started shedding DNA. Britain’s NHS is running a £1.1m trial of the technology in patients suspected of having lung cancer who are also being examined by other means. If this finds the technology to be reliable it might be expanded for use in population screening. In July Owlstone said it would collaborate with academic partners to see if breath biopsies could be expanded to pick up bladder, breast, kidney, pancreatic, prostate, brain, and head and neck cancers.

There is no question that blood biopsies will be at the heart of the future of tracking and profiling tumours. But for early detection other options might yet win out; success will not hinge on which company starts with the most money but which offers the biggest bang for the buck. Health-care systems will seek to adopt technologies that work at scale. The benefit will be that more cancers can be cured with the most basic, oldest and most effective methods of cancer treatment.

Would you like to share your opinion?
  • I entirely agree (0.00%)
  • I entirely disagree (0.00%)
  • I somehow agree (0.00%)
  • I somehow disagree (0.00%)
  • I have no opinion (0.00%)
  • I don´t care (0.00%)
  • This is bullshit! (0.00%)
Follow mr

Julio Marchi ©

Publisher / Editor at BS News & Media Services
A free thinker, not labelled as anything, not associated with any party, not part of any group or engaged with any religion... A simple guy tired of the nowadays bullshit who decided to promote more serious debates about what is really happening hoping to bring back intelligence to the superficial and shallow news & headlines that unfortunately took over the existing media scene.
Follow mr

Leave a Reply

%d bloggers like this: