COMMENTARY

Top 6 Cancer Highlights of 2019

Prof Karol Sikora

Disclosures

December 27, 2019

This transcript has been edited for clarity.

Hello, it's Professor Karol Sikora here, with my Christmas edition on Medscape - a summary of the key directions to the future during 2019. As we come to the end of the year, let's look back and see what developments there've been.

You know, I'm an old oncologist. I've been a consultant here in the UK for 40 years, and you don't see progress very easily, you don't see where progress is coming. And yet there have been huge changes right across the whole cancer space. And there are going to be many more changes. So let's look at 2019 and what I think have been the most significant six discoveries if you like.

The summaries are all referred to here so you can look them up easily.

1. TRACERx

I think the first is the TRACERx study. This is a Cancer Research UK sponsored survey of evolution: TRAcking Cancer Evolution through therapy (Rx) – TRACERx.

The key first paper came out in Nature earlier this year: Neoantigen-directed immune escape in lung cancer evolution. The problem with cancer as we know is it evolves. It's under selective pressure, Darwinian evolution, natural selection, and mutation. The two go hand-in-hand - just as in the classical evolution of the species ascribed to Darwin, so within the micro-environment of cancer, there's continual evolution there.

This paper from Charles Swanton's group at University College London is a very elegant analysis of how the immune system and non-small cell lung cancer in humans actually operates. A large number of biopsies were taken, a large number of samples from different sites examined for immune response, tumour infiltrating lymphocytes, and examining the mutational change in the face of selective pressure by the immune system.

So to survive, the cancer cells had to get rid of the antigenic load that they had, and they did so by mutation by shedding HLA, by doing all sorts of other processes. A fascinating paper. There'll be many more to come along this line, and why stop at the interaction of the immune system and cancer in this project? You can look at drugs, you can look at changes in tumours, conversion from ER-positive to ER-negative breast cancer, all these things. That's going to be the future for that. So the TRACERx study is guaranteed to have a fantastic future.

2. TAILORx      

The second is called TAILORx. Everyone's using the Rx designation this year. So TAILORx - Trial Assigning IndividuaLised Options for Treatment (Rx). The paper is called Clinical and Genomic Risk to Guide the Use of Adjuvant Therapy for Breast Cancer . You know, 80% of people we give adjuvant therapy to, it's wasted, wasted on them, wasted for the whole healthcare system, and costs a lot of money. How can we predict who to give it to and who not? The definitive analysis of a 21 gene expression analysis, called Oncotype DX came out in the New England Journal of Medicine earlier this year. This clearly shows the logic of trying to reduce the use of chemotherapy in those women that have good risk breast cancer and concentrate on making sure that those with poor risk cancer, a much higher chance of recurrence, even though they have no nodes involved, even though they're oestrogen receptor positive, actually still get chemotherapy because they're at high-risk, and that's about 25% of all women. So this complex genetic analysis, expression analysis, is showing its worth and the definitive paper has come out this year. It's one of many, can we get the same for all cancers? Can we get the same for lung cancer, prostate cancer? If it works for breast cancer, there's no reason that, not necessarily with the same genes, but similar processes can work.

I visited the Oncotype DX genomic health factory. It's just south of San Francisco airport, a fantastic experience, – roboticised, modern, simple – a sample comes in, gets processed, put onto a conveyor belt, data come out. Fantastic. How much data we need and how much data mining we're going to have to do remains to be seen.

3. Immunotherapy Response Signatures

The third paper is from an ASCO educational book entitled Patterns of Response and Progression to Immunotherapy . It reflects very well on the whole problem of pseudoprogression and aggressive progression in patients given immunotherapy. We've known for some time that you can predict, to a certain extent, who's more likely and who's less likely to respond by looking at PD-L1 both receptor and ligand levels by immunohistochemistry.

But we also have this problem that the response to immunotherapy is different in timing and you do get infiltration, swelling, and pseudoprogression on radiological images. So it looks as though the disease is actually progressing when it's not.

Obviously these drugs are very expensive, £120-140,000 a year for some of them, and sometimes they're given together. So this is pretty important health economic information. This is a very good summary of the definition of pseudoprogression and true progression.

4. Tissue Agnosticism

The fourth study in Clinical Cancer Research is all about tissue agnosticism - a great name, religious or sort of religious anyway: Agnostic-Histology Approval of New Drugs in Oncology: Are We Already There? Of course we're there.

If we look at pembrolizumab, the PD-L1 is a marker which is tissue agnostic, it can be done for anything. And indeed, 'pembro' does work in a whole range of cancers that even 2 years ago, we didn't know it would.

Anything that gives us a better molecular signature of response will improve the use of a drug. Is this of an advantage to the drug companies making the drug? Maybe it should be. Biomarkers are clearly the key tools to the future of selling drugs, and drugs without a suitable biomarker of response are just not going to get through the legislation. Not just 'pembro' but also larotrectinib, which is very interesting – the neurotrophic tyrosine receptor kinase inhibitor actually got the first FDA tissue agnostic approval for a range of cancers that have a specific gene fusion product.

So this is clearly going to be the way forward for the future for new drugs. And this is an excellent review explaining the situation and how it's likely to become the framework for future drug discovery and development.

5. Precision Radiotherapy and Artificial Intelligence (AI)

I'm a radiotherapist by training and this fifth paper is about artificial intelligence in radiotherapy. It's written by physicists, and it's a little bit geeky, but it is pretty frightening, because this is the way it's definitely going to go. And this is the key to the future of radiotherapy.

It talks about big data analysis. Radiotherapists, in the old days, were seeing 500-600 new patients a year. They'd build up a personal experience, they'd understand how tumours behave, they’d understand how to do the contouring to discriminate between cancer and organs at risk around the cancer. But the future has got to be to let the mathematical data on the scans, both MRI and CT, do the same for you with big analysis.

It talks about the four big Vs of artificial intelligence, the volume of data, the variety of data, the velocity of data is accumulating way beyond human capacity to analyse, and the veracity of the data. Not all data is accurate, there will be some that's clearly wrong, the wrong data from the wrong patient gets put in. We've seen those errors, the wrong-sided treatment of cancer for example. But at the end of the day, the computer will sort it out. This is a great prediction for the future, a futuristic look of what AI will do in radiotherapy.

6. Exercise as Cancer Therapy

The final paper, on exercise as cancer therapy, in CA: A Cancer Journal for Clinicians , with a very good review here on Medscape . It's an ignored area. There's no doubt exercise is as good as many drugs in the adjuvant situation. It's simple, and yet it's not used. A large study of about 13,000 people, both in the US and here in the UK, showed that the majority, two thirds of people with cancer, give up on exercise. They become overweight, they do less, and this is not good.

Now the cardiac community have recognised this in cardiac patients and cardiac rehabilitation is big business everywhere. The NHS has a fabulous programme of networked cardiac rehabilitation, post stenting, post valve replacement, and so on. We don't have the same for cancer. Cardiac patients even get gym vouchers paid for by the NHS to encourage their activity, and they’re monitored, phone calls and so on. This is what we should be doing for cancer - encouraging activity. And I think Macmillan Cancer Support has made significant inroads in this area. And I'd like to see a network of cancer exercise programmes, tailored to need, tailored to the age, and so on.

Looking Ahead

Well, these are my six pointers to the future for 2019. Let's see what 2020 brings. Meanwhile, it's party time and here we are - Happy Christmas to everybody at Medscape from me, Professor Sikora. I shall be enjoying a nice well-earned glass of champagne. I hope you have a wonderful time and see you again in the New Year. Thank you.

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