World Cancer Day: Mainstreaming cancer genetics

To mark World Cancer Day, Oncology Central spoke with Nazneen Rahman (The Institute of Cancer Research, London, UK). Rahman leads research directed at identifying, characterizing and clinically implementing genes that predispose to cancer and developing foundational resources for genetic medicine. She is currently Head of the Division of Genetics and Epidemiology at The Institute of Cancer Research and Head of the Cancer Genetics Clinical Unit at The Royal Marsden NHS Foundation Trust. She was awarded a CBE in the Queen’s 2016 Birthday Honours in recognition of her contribution to medicine.

Can you tell us about your career to date and your work at the Institute of Cancer Research?

I first trained as doctor specializing in Medical Genetics. I am now Head of the Cancer Genetics Unit at the Royal Marsden NHS Foundation trust. Nearly 20 years ago I did a PhD at The Institute of Cancer Research with Sir Mike Stratton, who is now Director of the Wellcome Trust Sanger Institute. It was just at the time he was discovering the BRCA2 gene. I instantly became captivated by genetics and I spent the first decade of my career discovering genes that predispose to human disease, particularly in breast and ovarian cancer. More recently I have been leading two innovative translational research programmes. The Mainstreaming cancer genetics (MCG) programme is undertaking the technological, scientific and translational work required to make cancer predisposition gene testing part of routine cancer care. The Transforming Genetic Medicine Initiative (TGMI) is building the knowledge base, tools and processes required to deliver the promise of genetic medicine.

What would you say has been your greatest achievement of your career to date?

I don’t think there is one single achievement that is more important than others. I have dedicated my career to discovering genetic causes of disease and using that knowledge to improve the lives of cancer patients and their families. It’s a 20 year body of work. And it’s made difference, in science and medicine. I feel happy and privileged to have had that opportunity.

You are currently leading the MCG programme, the aim of which is to make genetic testing available to more patients as part of their routine cancer care.Could you tell us more about this programme?

The MCG Program has pioneered a new “oncogenetic” pathway for testing the BRCA1 and BRCA2 genes which brings gene testing to patients through their existing oncology appointments.

Previously, patients could only have a gene test after referral to genetics departments, which adds significant time and cost to the testing process. In the mainstreaming pathway members of the cancer team can order gene tests for eligible patients directly, though the flexibility to refer to genetics for testing is retained. Any patient found to have a gene mutation is automatically also seen by a geneticist. Those with normal results can be referred for further discussions, but generally this not required.

This model offers more streamlined, flexible, patient-centred and efficient testing for cancer patients. It is much faster and cheaper than the traditional model and the patient and clinician feedback has been overwhelmingly positive. It’s a win-win for everyone.

What barriers are there to incorporating genetic testing into routine cancer care? (economically/logistically)

The video on the first page of the MCG Programme website explains this well.

Historically, the cost and time of gene sequencing meant that access to testing had to be severely restricted, and was only useful for people that had time to wait for the results.

New sequencing technologies are much cheaper and much faster (there is a short video on the MCG Programme website that explains why) which provides the opportunity to help many more people and particularly to help cancer patients – who need to get the information quickly.

However, there have also been logistical barriers for patients to access testing. The referral criteria were complex and patients often had to go to another appointment, often in another hospital. The mainstream cancer genetics pathway, removes the logistical barriers.

There are still some testing challenges – many providers of gene tests find the interpretation of genetic data difficult, and there needs to be better standardisation in this area. There remain logistical barriers – particularly in terms commissioning and paying for tests. And naturally if there was more money available one could do more testing, but with the improved technology and testing access, we can do lot more with the existing money available.

What strategies do you believe are vital for integrating this care into oncology clinics?

The cancer team have to feel confident in offering the test to their patients, and supported by the genetics team and the genetic test providers.

The model that we have proposed and implemented is a partnership between these. The cancer team consent for the test and send the blood sample to the lab. The gene testing lab, TGLclinical provides clear reports that are sent to the patient, cancer team and genetics team. The cancer team use the information to optimize the cancer management. The genetics team quickly see any individual with a mutation and take on cascading the information to relatives.

We provide short online videos that explain the process and what cancer team members have to say to consent patients. And at any stage they can refer to genetics, if that feels more appropriate.

What are the clinical advantages to uncovering cancer predisposition genes?

It is currently estimated that, overall, approximately 3% of cancers are the result of germline mutations in cancer predisposition genes (CPGs). Identifying a pathogenic mutation in a CPG provides important information that can help in the diagnosis and management of a cancer patient and have significant impact on future cancer screening and prevention for both the patient and, potentially, their relatives.

Knowledge of a pathogenic mutation in a CPG may alter the care of a cancer patient in several ways. For example more radical surgery might be more appropriate as there is an increased risk of further cancer. Radiation treatment might be modified or excluded because some CPGs are associated with increased radiation sensitivity. Chemotherapy might be changed because some treatments are more effective and others less effective in CPG mutation carriers. Newer, personalized therapies that either target the CPG mutation directly or pathways that become vulnerable because of the CPG mutation, are increasingly being developed. For example, some gastrointestinal tumors result from germline gain-of-function mutations in KIT or PDGFRA that could be inhibited by imantinib.

Identifying an underlying CPG mutation can also provide prognostic information. For instance, survival is significantly better for patients with BRCA2 mutation-positive ovarian cancer, but significantly worse for patients with BRCA2 mutation-positive prostate cancer.

CPGs are unusual because they can serve as a biomarker of future disease. Identifying a CPG mutation in either a cancer patient or their relatives allows the implementation of surveillance and risk-reducing measures that may mitigate or prevent future cancer.

Ultimately this knowledge helps us to provide the best possible treatment for cancer patients and reduce the incidence of cancer in the future.

Can you tell us about some of the emerging concepts in cancer genetics?

We will increasingly see tailored therapies targeting genetic mutations in the cancer tissue itself. These are sometimes called precision medicine. Also using deep-sequencing in blood to monitor cancer is progressing fast, and will lead to better ways of early detection of relapse or treatment resistance. In time these so-called ‘liquid biopsies’ may also be useful in diagnosing cancer in the first place, but we will need to be careful that we don’t detect and treat things that would have never become symptomatic.

What are you excited about working on over the next year or so?

We are launching MCG-International, which is building a global community of team implementing mainstream BRCA gene testing across the world, to share good practice and to help centers that want to make the change to mainstream testing. In particular we want to increase the number of ovarian cancer patients that are offered BRCA testing. 15% of ovarian cancer is due to BRCA mutations but only a minority of these are getting testing in most countries. As well as providing important information for the management of ovarian cancer, testing will allow more unaffected women with BRCA mutations to access preventative options. We know that the majority of women at increased risk of ovarian cancer choose to have their ovaries removed by keyhole surgery after they have completed their families, and we also know this is a very effective cancer prevention strategy. In theory virtually all BRCA-related ovarian cancer is preventable.