In Conversation with Rosalind Eeles

Disease prevention is a holy grail of medicine. This is particularly true for cancer, where protracted treatment such as surgery, chemotherapy, and radiation can profoundly impact physical and mental quality of life.

Genetic testing is increasingly being added to the armamentarium of preventive tools, helping to identify inherited susceptibility before signs of a tumor appear. Plummeting sequencing costs and technological advances make it both increasingly feasible and cost effective, to the point where whole genome sequencing may soon become part of routine primary care.

Yet spotting the genetic mutations and sequences that cause cancer remains a major stumbling block. This is where Rosalind Eeles, oncogenetics professor at the Institute of Cancer Research (ICR), comes in.

As an Honorary Consultant in Clinical Oncology and Cancer Genetics at the Royal Marsden NHS Foundation Trust, she is regularly involved in the frontline treatment of prostate and bladder cancer and genetic testing of adults for their predisposition to all cancer types. She is a driving force behind studies on genetic predisposition to prostate cancer, discovering three-quarters of the known genetic variants that can increase a man’s risk of prostate cancer, authoring at least 400 scientific papers, and editing major textbooks in the field.

Her path began with medical training at the University of Cambridge, after which she attended St Thomas’s Hospital Medical School in London. Higher medical training followed, and she is a fellow of both the Royal College of Physicians and the Royal College of Radiologists.

Eeles now leads an ICR program on genetic predisposition to prostate cancer and the management of BRCA mutation carriers. In addition, she has helped set up international consortia to enable researchers to access hundreds of thousands of genetic samples from prostate cancer patients and has been a part of the team that recently launched a prostate cancer risk prediction tool.

Eeles spoke to Anita Chakraverty at Inside Precision Medicine about her inspirations, the challenges she faces, and what inspires her in the world of cancer genetics.

Q: How did your interest in cancer genetics take off?

It was while I was doing a PhD at the ICR in multicentric breast cancer. At that time, Professor Bruce Ponder—he’s like the grandfather of genetics in this country—was at the ICR, and he was spearheading a research clinic at that time in cancer genetics, working mainly with breast cancer families.

I went to sit in his clinic, and I just got completely immersed in the subject. So, the PhD turned into one chapter on multicentric breast cancer and the other chapters were all about cancer genetics and families.

Q: What are you working on now?

My research now is trying to find new genes that predispose to prostate cancer. BRCA alterations increase the risk of prostate cancer in men, and really that’s led to the next sort of career development. We’ve tried to push the field forward in how groups work together internationally, across borders with data sharing agreements, and have three main very large initiatives.

One of these is the PRACTICAL Consortium, with 133 groups worldwide, which is designed to find genetic variants that affect prostate cancer risk using over 200,000 samples from diverse populations. So hopefully from this we’ll get a gene test using saliva looking at common variants across the genome that would enable us to stratify populations by risk.

Q: How important will genetics be to cancer treatment in future?

It really is the new medicine, using the power of genetics in both risk prediction but also in cancer care. The tests are faster, they come back in a matter of weeks rather than years, and they’re cheaper. For example, in the private sector, BRCA tests used to cost about £3,000 in the United States—that was for analysis of two genes. Now you can do 84 genes for nearer [to] £400, 30 genes for about £300. The costs are coming down really very rapidly.

And the bioinformatics has also really helped the field. For my PhD, sequencing one gene in 57 families took three years running radioactive gels. Now machines can sequence the whole genome very rapidly. If you send off a whole genome to be sequenced, it might come back in 12 weeks with a report.

Q: Should we be doing mass genetic testing then?

I think it’s an unanswered question at the moment. There are some early studies that have been done. One of my colleagues in London, Ranjit Manchanda, has done studies in the Jewish community of Askenazi origin, where he’s shown they have a 1 in 40 chance of having certain variants in the BRCA genes. And now NHS England has a new exciting initiative, and they’re going to offer testing of BRCA1 and BRCA2 to the Ashkenazi population.

Q: What challenges remain in translating screening into treatment?

We are now starting to have genetic tests that could potentially be offered more widely to stratify risk so that people would know if they need earlier screening. There are some areas where we would know what your risk was, but we might not  know what the screening algorithm should be. So, for example, we have assessed that you have a higher prostate cancer risk: should we do an MRI of your prostate, should we biopsy it, should we do more frequent [tests for] PSAs [prostate-specific antigens]? And that often is an unknown area, so we can get the risk assessments right now, but what we do about the screening still needs to be refined.

Q: How can genetics tailor cancer treatment?

Some of these gene variants, particularly the single gene variants like BRCA, for example, may be important for treatment. We have some early data that we’re trying to validate: they’re in less than a hundred individuals with BRCA gene mutations, and we show that if you have surgery for your prostate cancer and you’ve got a BRCA mutation, you do equally well if you’ve got the mutation or not.

But if you have radiotherapy, everybody has relapsed by year five if you’ve got the mutation. We don’t really know if that’s because they get a new tumor or whether maybe for some reason the radiotherapy doesn’t work so well. We are strongly suspicious it’s a new tumor, which means then maybe you would err towards surgery, rather than radiotherapy, in men with a BRCA mutation, but this needs to be proven. So, it can alter the treatment pathway, but then also it might actually open up the avenue potentially to targeted medicines.

Q: Should all cancer patients be tested for inherited mutations then?

I think as the costs go down, it will eventually become standard of care, and then it will become part of our MDTs [multidisciplinary team meetings to assess optimal treatments of cancer patients]. And in some centers in the United States, it’s almost becoming standard of care in many cases. In the U.K. for example, in leukemias and lung cancer, sequencing of the tumor cells is regularly undertaken to find targets for certain medicines.

Q: What is most exciting area you are currently working on?

I think the exciting area is the polygenic risk score. For prostate cancer, we have the rare variants like those in BRCA1 and BRCA2 and other DNA repair gene mutations, and they’re relatively rare; they form about seven percent of the genetic component. But in prostate cancer, quite a lot of the genetic component—which is why we couldn’t find it for years—is common variants. I often say to patients, it’s like having a hand of cards in a bridge game, and you’ve got a set of points and they’re specific to each individual. This forms your polygenic risk score. So, I can line up a hundred men in a field for example, and I can tell if you are European and the man on the right of the field (i.e., in the top one percent of the cancer risk distribution) that you’ve nearly 11-fold times the risk of the average of the field—it’s huge. We hope to shortly also have a polygenic risk score that will be applicable to diverse populations.

The thing about these common variants is that they’re little subtle gene changes across the genome……you could test many, many individuals, the tests are quite cheap to do. You can do a saliva test, say for a couple of hundred variants, and that might cost the actual consumer less than £100. It’s the same as doing the PSA, for example, and you can tell somebody what risk level they’re at.

So, I think that’s going to be the really exciting area. In theory, large numbers of people could have risk assessment testing and policymakers could determine if it is helpful to concentrate screening in higher-risk groups. I think this will probably start to sit in primary care, as they are experts in risk assessment of their patients.

Anita Chakraverty is a UK-based journalist who has been writing about medicine and health across several international publications for more than 20 years. In her spare time, she enjoys reading, films and walks in the countryside.

The post In Conversation with Rosalind Eeles appeared first on Inside Precision Medicine.

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