Today we talk to Ranjit Manchanda, Professor of gynaecological oncology, Queen Mary University of London and Barts Health NHS Trust about how genetic testing could help identify those who are most at risk and how to manage that risk. Recently the hard work and successes of the research led by Ranjit and his team has been recognised via publication of their NICE guidelines for ovarian cancer.
(Ranjit’s full biography is at the end of the article)
Can you explain what a NICE guideline is and why they are important.
NICE guidelines are in place to ensure excellent standard of care. Guidelines are built on evidence, ensuring all factors are considered so that ultimately more lives are saved by providing high-quality care to patients.
Could you tell us a bit about the purpose of the guideline and why we need it.
Around 7,500 women are diagnosed with ovarian cancer annually and about 20% or 1 in 5 of these are caused by high-risk genes. People may not know that they are at high risk and carry an alteration of one of these high-risk genes which puts them at increased risk of ovarian cancer. So, the guideline is for these people who are increased risk of ovarian cancer usually due to carrying an inherited alteration called a pathogenic variant in one of these ovarian cancer genes. This may be women, men, trans and non -binary people who can carry a gene linked to ovarian cancer and can pass it onto their children. It is not just for women and people born with reproductive organs. The guideline aims to raise greater awareness on the availability of gene testing allowing people to take preventive measures such as surgery this would mean that fewer people go on to develop ovarian cancer.
Do they have similar guidelines in other countries?
The National Comprehensive Cancer Network (NCCN) in the USA have guidelines for management of high-risk breast and ovarian cancer. There is nothing else that is comprehensive that I am aware of. Some societies have published guidelines related to different aspects of management of women at increased risk, but these are not as broad covering the full spectrum of care like the NICE guideline.
It must be so rewarding for a clinical scientist to see their research leading to a NICE guideline. How did it feel?
It felt extremely satisfying. It took a lot of work to get this far. Us researchers are most comfortable when we are doing our research, influencing policy makers is a whole new learning curve and is outside of my comfort zone. Luckily, earlier in my career, I had a role as an NHS Innovation Accelerator Fellow which really helped me meet with policy makers, and also understand what is involved in influencing people and decision makers implementing policy. There is also quite a lot of marketing and networking type work involved. Prior to this I never knew what a 2-minute elevator pitch was!
Ok next I’ve a few technical questions so people reading blog can understand the guideline:
The guideline talks about “familial and genetic risk”. What is the difference?
Genetic risk is the proportion of risk contributed to by genetic factors. This may include the presence of ‘faulty’ genes. Familial refers to the fact that some cancers run in families. It may include factors beyond just presence of faulty genes (known and unknown).
It also uses the phrase “pathogenic variant”. What is a pathogenic variant?
A change in the DNA sequence of a gene that causes a person to have or be at risk of developing a certain genetic disorder or disease, such as cancer. Pathogenic variants can be inherited from a parent or occur during a person’s lifetime.
Can you explain “cascade testing”
Cascade testing is the process of informing family members of a genetic condition discovered within the family, along-with offering family members genetic testing for the condition.
It seems that identifying people at very high risk of ovarian cancer is a great idea because you can intervene to greatly reduce that risk. From what I know there are two main options
1) Primary preventative medicines and;
2) Risk reducing surgery or preventative surgery, can you tell us a bit about both?
The most effective intervention for reducing risk without doubt is preventative surgery. This involves removal of the fallopian tube and ovaries and is usually feasible through keyhole surgery. It also includes taking peritoneal washings and from the abdomen and the pelvis at the same time and sending that for examination. Patients usually go home the same day. The guideline provides recommendation on the age of when surgery should be offered, and this is recommended from the age of 35 – 45, depending on the variant a person is carrying. The guidelines offer personalised risk management for individuals who carry one of these variants.
Current preventative medicine includes the contraceptive pill. Taken for five years, it can half your risk of ovarian cancer, but it does potentially increase your risk of breast cancer. So, there is trade off there. People might consider taking the pill at a young age when risk of breast cancer is very low and then it would provide the benefit for ovarian cancer risk reduction. The other thing is if you are going to have your ovaries and tubes removed later (due to genetic / familial risk), then you’re not going to get much benefit from the pill in terms of reducing ovarian cancer risk, because the surgical prevention is going to provide you all that benefit and more. So you need to not only look at the short term taking of the pill but the long-term decision making. There is some emerging data about Aspirin, but the committee did not feel the data was strong enough at the moment to warrant any change in practice.
Could you tell us a little the downsides of these interventions?
The downside of preventative surgery is that women can go into early menopause. Early menopause is in turn associated with health consequences such as osteoporosis, increased risk of heart disease, sexual dysfunction. But all of these things are alleviated by HRT (Hormone Replacement Therapy) so this is advised where not contraindicated. That said HRT is not the same as having your own ovaries. Most of these cancers come from the tubes, not the ovaries. We are currently running a trial where we are offering women to have their tubes removed, followed by the ovaries at a later time point nearer or at menopause, as a 2-step procedure. So the idea is to offer some protection while delaying the early onset of menopause and it’s consequences.
Deciding what route to take is a complicated decision. One must consider the issues of the level of benefit of ovary risk reduction, the desire to have surgical prevention, future fertility, the implication on breast cancer risk, the impact of unwanted pregnancy, the possibility of taking alternate methods of contraception.
Looking at the guidelines it seems quite complicated. They seem to involve clinical genetics, counselling, primary care, and gynaecology oncology. Can the NHS cope with these new guidelines or might it create too much work?
Yes, the NHS has proved to be a resilient organisation and has coped with much more! But it does require some amount of restructuring, ensuring teams are in place that are responsible for delivering the guidelines. Ultimately it is going to save more lives and provide high quality care for high-risk women and support them through their journey. Changes in healthcare delivery and structure tends to follow guidance. You don’t change the health system and then produce a guideline. I’m not aware of that happening, because nobody’s willing to change in anticipation of what’s going to come!
Many of these patients will be at elevated risks of other cancers too. Are they as easy to manage or do you simply advise these women to be vigilante about symptoms of these other types of cancer?
Yes, some are at an increased risk of breast cancer or the Lynch syndrome patients of bowel cancer and womb cancer. We manage womb cancer risk with gynaecologists/ gynae-oncologists, we manage bowel cancer risk in collaboration with our bowel cancer colleagues. For example, they get referred on for high-risk bowel cancer screening and they get aspirin, which does work. For breast cancer there is a high-risk breast cancer screening programme that is well established to manage women with increased risk of breast cancer. Guidance on breast cancer has been in place for the last 15 years. We have a well-established infrastructure and network for managing breast cancer patients and now we are trying to build one from the ovary perspective.
Can you tell us a little bit about some of the research you have done that has informed these guidelines? What study are you most proud of?
A lot of our research has informed the guidelines. For example, our work shows that everyone over 18 years in the Jewish population should have BRCA testing, independent of family history. is backed by our research.
We now have a new NHS BRCA program running and was launched formally at the end of January this year in the House of Lords, chaired by the cancer programme director Prof Peter Johnson, and delivered by NHS. QMUL are involved in evaluating the outcomes of that programme. We are also part of the expert advisory team supporting the programme.
Setting the threshold for surgical prevention of ovarian cancer and personalising the cancer susceptibility gene-based approach, is also based on our research. We have also been involved in ovarian cancer surveillance studies which has also produced data for these NICE guidelines. We have also done modelling work to show that panel germline testing is better that BRCA testing alone in women with ovarian cancer.
What are you working on now?
Currently we are working on a number of projects including: (a) PROTECT-C: population testing implementation study using a digitised pathway for a panel of cancer genes and personalised breast and ovarian cancer risk prediction in the general population. (b) PROTECTOR-2: extension of the PROTECTOR early salpingectomy and delayed oophorectomy study to address the level of ovarian cancer risk reduction. (c) PRESCORES- study on quality of life following preventive hysterectomy in women at increased risk of endometrial cancer; (d) DETECT-2: A RCT evaluating a new scalable direct to patient approach for genetic testing at cancer diagnosis in women undergoing mainstreaming for ovarian, bowel and womb cancer. (e) OVACATCH: A programme of work to improve ovarian cancer screening in high risk women using a multimarker longitudinal modelling approach. (f) evaluation of the NHS Jewish BRCA testing programme.
What advice would you give to a young doctor thinking of specialising in gynaecological oncology?
I love gynae oncology. I’ve built a career in it. There’s a lot you can do to help people and save lives. It will challenge you, but also provide huge satisfaction. It’s a surgical discipline which involves a lot of complex high-end operating. If you enjoy surgery then and you enjoy taking care of patients then it’s definitely something to consider. I would encourage people to join gynae oncology and challenge themselves. I have found it extremely satisfying, gratifying and I wouldn’t go back and do anything else if you turn the clock back.
Biography
Ranjit trained at the All India Institute of Medical Sciences (AIIMS), Delhi, India and then the East of England Deanery (Cambridge), UK. He completed his PhD and NIHR Academic Clinical Lectureship at University College London (UCL) along with subspecialty training in gynaecological oncology at UCLH & Barts Health. He has a keen interest in ultra-radical cyto-reductive surgery for ovarian cancer as well as management of women at increased risk of gynaecological cancer.
Ranjit’s main research interests are focused on Targeted Precision Prevention. This includes population-based genetic testing, mainstreaming genetic testing and precision medicine approaches for risk prediction, stratification, targeted screening and targeted cancer prevention, along with health economic issues related to these areas of research. He is the Chief Investigator on the PROTECTOR, PROTECT-C, DETECT-2, GCaPPS, PROMISE Pilot trials, and OVACATCH, SECRETS, SIGNPOST, JHCR, UKCOGS, PRESCORES, RRESDO studies. He has published and lectured widely on areas related to his research interest.
Ranjit has served as the Integrated Academic Training Programme Director, London Specialty School of Obstetrics & Gynaecology, Health Education England, UK (2019-2023).
Ranjit was awarded the Distinguished Infosys Chair in Oncology at AIIMS, Delhi, India (2022-2023), the Ovacure Innovation Challenge Award (Copenhagen) in Sep 2022, an NHS Innovation Accelerator (NIA) Fellowship for Population Genetic Testing in 2019, RCOG Blair Bell award (2018) for research in population testing, and the Dr Shyam Agarwal Memorial Oration award (2019) for contribution to cancer genetics. He has also received the Helen Harris Memorial Trust travelling Fellowship, NIHR Clinical Lecturer Fellowship, and ICMR Fellowship awards.
He chairs the London Cancer High risk Gynaecological Cancer MDT. He has been the Topic Advisor (Clinical Lead) for the NICE guideline on Ovarian cancer: identifying and managing familial and genetic risk; and member of the National Standards Quality Advisory Board on Ovarian Cancer. He Chairs the UK GTG (Gynae-oncology Trials Group (formerly NCRI)) Gynaecological Cancer Early Diagnosis Working Group. He is the Specialty Research Lead for Gynaecological Cancer, NIHR North Thames Clinical Research Network (CRN). He is a member of a number of other advisory bodies and oversight committees.
He is a member of number of committees related to research and training, and led a number of training initiatives in Gynaecological Oncology across Europe. He has served as President of the European Network of Young Gynaecological Oncologists (ENYGO) and member of the European Society of Gynaecological Oncology (ESGO) Council from 2011-2013.
The views expressed are those of the author. Posting of the blog does not signify that the Cancer Prevention Group endorses those views or opinions.
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