The over-hyping of precision medicine

The rapidly decreasing cost of sequencing a person’s genome is one of the factors driving the hype of precision medicine. Photo: AFP

Precision medicine might not be as well-known a term as personalised medicine, but they both mean essentially the same thing.

According to the United States National Institutes of Health, precision medicine is “an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person”.

In other words, every patient receives a truly individual healthcare approach that is tailored specifically for their medical condition and needs.

The difference in terminology represents the perception that personalised medicine might imply the creation of medicines or treatments that are unique to the individual patient, while the truth is that that is not (currently) a viable technique.

Doctors have also argued that all patients receive personalised treatment anyway, hence, rendering the term “personalised medicine” redundant.

Precision medicine has received much hype in recent years, especially with the rapidly decreasing cost of sequencing a person’s genome – genomic medicine and targeted therapy are essential components of this model.

But does the reality of the current state and future potential of precision medicine hold up to the hype?

I think if I have a message, it is to move away from magic bullet therapy, to move away from thinking there is one drug, one treatment that will cure it all, said Prof McKenna. Photo: Sunway University
I think if I have a message, it is to move away from magic bullet therapy, to move away from thinking there is one drug, one treatment that will cure it all, said Prof McKenna. Photo: Sunway University

More downs than ups

Cancer is one of the areas where precision medicine has probably being hyped the most.

Said University of Oxford, United Kingdom, Department of Oncology head Prof Dr Gillies McKenna: “We’ve been saying for the last 30 years – for cancer at least – that personalised cancer therapy, or precision cancer therapy, is the way forward.

“And by that, we largely meant, in some sense, molecularly-targeted therapies – using biologically-targeted drugs, trials driven by biomarkers, using genomic sequencing to reveal new targets for therapy.”

He was speaking on the topic of Personalised Healthcare and Precision Treatment at the Interna-tional Symposium on Precision Medicine: The Future of Population Health held recently at Sunway University, Bandar Sunway, Selangor.

He also noted that the idea that cancer is a genetic disease is not new, citing the discovery of the Philadelphia chromosome in chronic myelogenous leukaemia in 1960, and the subsequent development and success of one of the first targeted drugs – the tyrosine kinase inhibitor imatinib – in treating it in the 1990s.

“At that time, this seemed to many of us, myself included, that this was the revolutionary treatment we had all been waiting for,” said Prof McKenna.

“However, as time went on, we realised that there were indeed many, many more mutations in cancer than we had anticipated.

“And they were not all evenly distributed throughout all cancers.”

Some cancers like Ewing’s sarcoma and neuroblastoma, have only a few mutations, while some like melanoma, stomach cancer and colorectal cancer, have several hundred mutations.

But, Prof McKenna added, the comforting thing is that these mutations tend to form clusters that cause certain signs and symptoms that form the hallmarks of the cancer.

“And for each hallmark, there will indeed be a drug of some kind that will emerge,” he said.

“So then, the idea of multi-targeted therapy simply means deciding which cluster or hallmark you need to target for each individual tumour.

“And there would be clonally-dominant mutations (cells with the same mutation that contribute the most towards the tumour’s malignant effects) that would determine the outcome of treatment.”

He added: “And certainly, no one bought into that hypothesis more than the pharmaceutical industry; every time a new mutation was identified, the pharmaceutical industry rushed to produce new drugs against it.”

However, according to a 2014 study in The Journal of the American Medical Association, the median improvement in overall survival rate from the 71 cancer drugs approved by the US Food and Drug Administration from 2002 to 2014 was only 2.1 months.

In addition, with only around five percent of molecularly-targeted drugs making it from the laboratory to the hospital, the prices of such novel drugs are skyrocketing to hundreds of thousands of US dollars.

“Those that do reach the clinic purchase ever smaller increments of survival at heavily increasing cost, because the pharmaceutical industry passes the cost of failure onto the relatively small number of successes,” said Prof McKenna.

Too many mutations

The cause of this is likely to be the extremely complicated mass of mutations that make up malignant tumours.

In a 2012 study published in The New England Journal of Medicine, researchers took multiple biopsies from a single tumour and genetically sequenced each biopsy.

The results, said Prof McKenna, showed that while some mutations were found in all the samples, these were usually tumour-suppressor genes, which are not amenable to drug therapy.

A small number of mutations were found in some, but not all, of the samples, while most mutations were unique to the specific biopsy sample, even though they were all from the same tumour.

“What is happening is that as the tumour is growing and evolving, new mutations are continuously arising at the ends of this pattern of growth and mutation,” he explain-ed.

What this means is that the main mutation(s) driving the abnormal behaviour of a tumour does not remain the same, and is likely to change as time passes.

“And so, what you are doing, in a sense, when you give a molecular therapy is you are simply trimming off some of the branches of this tree, but some of them will remain and the tree will inevitably grow back,” he said.

The current precision medicine model is failing, Prof McKenna concluded, and it is still being pursued only because “you are selling hope in a bottle, and you cannot refuse people who are dying”.

Changing the model

However, according to him, the chances of someone surviving cancer has doubled over the last 30 years, with the chances of being cured more than 50%.

Presenting a 2011 pie chart from then-United Kingdom National Cancer Director Prof Sri Mike Richards, Prof McKenna pointed out that nearly 90% of cancer cures come from surgery and radiotherapy, indicating that curable cases come from early-stage cancer patients.

Surgeons have moved increasingly to minimally-invasive techniques, including robotic surgery, while radiotherapy has become more and more precise, and at the same time, less toxic.

“So, to my mind, when we talk about this concept of precision cancer medicine, we really need to start from the idea that the therapies that are most effective are the physically-targeted therapies.

“We need to start thinking about what we do in early stages, using techniques such as robotic therapy (and) modern advances in radiotherapy such as proton therapy or HIFU (high intensity focused ultrasound) or radioablation or other minimally-invasive therapies,” he said.

“So, the strategy that I would propose for developing precision cancer medicine is to try to transform the model by focusing on early-stage cancer; minimising the effect of genetic diversity; looking for combinations of both molecular and interventional therapies that would be effective in that setting; and to look for therapies, therefore, that would optimise the chance that we can cure the patient.

“We have to embrace the complexity of cancer treatment if we are going to take this concept of precision medicine forward,” he said.

According to Prof McKenna, the components necessary for this concept include molecular diagnostics, molecular imaging, window of opportunity trials (where potential therapeutic drugs are tested in patients in the period between diagnosis and commencement of treatment), proton therapy and minimally-invasive interventions.

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