“Seeing those results for the first time made my whole career seem worthwhile” – Peter Sasieni wins Don Listwin Award

You were the lead author of the study showing a dramatic reduction in cervical cancer incidence following HPV vaccination – tell us about that… it must have been incredibly satisfying to see the data that finally confirmed the effectiveness of the approach?

Yes, that was a highlight of my career. I had worked on cervical cancer control since my post-doc at the Imperial Cancer Research Fund. First looking at optimising the cervical screening programme in the UK, then studying the potential for HPV testing to improve cervical screening, and finally studying HPV vaccines. When HPV vaccination was first introduced in England, we modelled the likely impact over time.

I had also written articles suggesting that as we understood the aetiology of cervical cancer so well, and because we knew from randomised controlled trials that vaccination prevents HPV infection, there was no doubt that vaccination would also prevent cervical cancer. But there is a difference between having complete scientific confidence and generating empirical evidence. Seeing those results for the first time made my whole career seem worthwhile. As a friend said to me: “In the 90s you were trying to prevent cervical cancer, now you’ve done it.”

It was a huge collaborative effort by scientists all over the world, but knowing that science and health service implementation can virtually eliminate a cancer that had once been one of the most common causes of death of women worldwide was incredibly uplifting.

We reasoned, that if we could get access to data on cancer incidence up to 2018 or 2019, we should be able to show an impact of vaccination on cervical cancer incidence. But we would need access to individual level patient data and that was generally not possible. Cancer rates in 5-year age-groups would not be good enough. We needed to be able to look by school year because the vaccine was offered in schools so someone born on 31 August would probably not have been offered the vaccine, but someone born just a day later probably would have.

We did a deal with the cancer registry. They would not send us the data, but if we wrote code to analyse the data they would run it for us. The COVID-19 pandemic delayed things by several months, but when the analyses were run the results exceeded our expectations. Cancer rates in the cohorts offered HPV vaccination aged 12-14 were down by over 80%.

The first HPV vaccination was available in 2006 – so that is over a decade before your work showing its effectiveness. As someone so focussed on the epidemiology of prevention, I guess such long timescales are part of the gig?

When I was young, I went to an event at the Royal Society at which Sir Richard Doll presented the results of 50 years of follow-up of the British Doctors’ Study. It was quite special – not just hearing from the legendary Professor Doll in person, but also because even though cancer epidemiology is a slow process, there can’t be many scientists who have set up a study and continued to work on the same study for 50 years!

I’ve been working with Professor Fitzgerld on her Cytosponge for the prevention of oesophageal adenocarcinoma since 2010. We recently received funding for a the BEST4 platform study that will include a randomised controlled trial of the use of the Cytosponge in targeted screening. That trial is aiming to see whether screening can reduce mortality from oesophageal adenocarcinoma. The follow-up will continue until 2035. Rebecca first had the idea for a Cytosponge in 2000. So, it could be a 35-year journey. That presents a challenge for cancer prevention and screening research. Today we are trying to accelerate the evaluation timeline. But it is controversial… some colleagues think I am cutting corners.

But epidemiologists have always tried to come up with novel designs to save time. Case-control studies, for example, start with disease diagnosis and look backwards at what preceded it. Using such a design we were able to study the association between treatment for cervical cancer and subsequent pre-term births in a couple of years even though there was often many years between the treatment and the pregnancy. We showed that there was very little additional risk associated with excision of average depth, but deep excision did increase the risk of a preterm birth.

What advice do you have for researchers interested in making meaningful contributions to the field of cancer prevention and early detection?

Dream big. Collaborate with people you like. Be happy with making small advances. Don’t lose sight of the big picture. Have fun.

Whilst early detection research has yielded some incredible advances, there is still a long way to go to rule out late diagnosis of cancer… what areas of research give you the most encouragement that we will get there?

Visiting colleagues in low- and middle-income countries, you realise how far we have come. There it is common for cancers not to be diagnosed until they and fungating.

The low-hanging fruit is to educate the public regarding the symptoms of cancer and to empower them to seek help early from their GP. But that will only achieve so much. New technologies enable liquid biopsies (from blood and urine) and breath biopsies to detect signals from cancers. With advances, these non-invasive biopsies will be able to detect smaller and smaller cancers. The potential for screening programmes that will enable most cancers to be detected before they cause symptoms and whilst they can be easily and effectively treated is great. I really hope that such screening will be routine in 30 years’ time.

However, people are rightly concerned about screening leading to overdiagnosis of indolent cancers. My vision is that as we improve technologies to detect more microscopic cancers, so too will we expand our treatment options. Wouldn’t it be great if anyone screening positive could be given a well-tolerated therapeutic vaccine that would help clear any small foci of cancer including those that are too small to see on routine scans?

Are there specific populations that stand to benefit the most from advancements in cancer prevention, and how do you think we can ensure equitable access to these interventions?

There are a small number of people who have a strong genetic predisposition that makes it extremely likely they’ll develop certain types of cancer. We already consider prophylactic surgery for women with BRCA1 and BRCA2 mutations, and biennial screening colonoscopy from a young age in people with Lynch Syndrome. But, as we showed, approximately half of the population born since 1960 will get cancer. So, we would all benefit from prevention.

Society and politicians need to do more to create an environment in which it is easier for people not to smoke, eat healthily, exercise, and avoid air pollution. There are drugs that reduce the risk of some cancers. But they all have some side effects, so the benefits only clearly outweigh the risks in people who are at high risk of cancer.  Perhaps the best way to prevent cancer is though detection and treatment of pre-cancer. This has been highly effective for prevention of cervical cancer and could be used to prevent many bowel cancer cases. But unfortunately, most cancers don’t have a clear pre-cancerous state.

Equitable access is a real issue. Even in the UK where screening is free at the point use, there are substantial inequalities in screening coverage associated with deprivation and ethnicity. On the other hand, introduction of breast screening led to greater equity in the treatment of breast cancer and it’s often those who are the most health deprived who have the most to gain from cancer screening. So screening is not all bad.

You asked before about HPV vaccination in the UK. That is the poster boy for equitable access. Prior to the pandemic, coverage in the routine HPV vaccination programme was uniformly high in every borough.

As for MCED tests, for some the jury is still out on if we could ever get a workable solution. However, the GRAIL Galleri test is well into the trial phase here in the UK, which is very exciting, but is it too ambitious to hope for a one-test approach to screen for all major cancers?

Having a leading role in the NHS-Galleri trial I want the Galleri test to work. It would be wonderful to have worked on a trial that results in a substantial reduction in advanced stage cancers with their associated aggressive treatments and high fatality. But I don’t think the Galleri test will do away with the need for other types of cancer screening.

Data from other studies suggests that one would still want to do HPV testing for cervical screening and mammography for breast screening. And in countries where the threshold for colonoscopy in bowel screening is low, existing screening programmes could prevent colorectal cancer by detecting and removing advanced adenomas, whereas the GRAIL test will only detect early cancers.

But I’m optimistic. Future MCED tests should have improved sensitivity to cancers at more sites. Maybe it won’t be a one-test approach, but I could see a blood test, a urine test and a breath test being sufficient to eliminate the need for any other types of screening. The trick always will be to ensure that, despite having three different tests, only a very small proportion of people without cancer have a positive result.

Maybe I’m a dreamer, but I do hope that my children will be able to have a single health check every three years to screen for all cancers.

The Don Listwin Award recognises a sustained contribution to, or singular achievement in, the cancer early detection field. The award, established in 2019, is named in honour of Don Listwin, founder and chairman of The Canary Foundation.

Peter is a world leading biostatistician and epidemiologist who has had significant impact on the design and execution of clinical trials in cancer early detection and prevention. Peter led the clinical trial showing the impact of HPV vaccination on reducing cervical cancer rates in England. He set up, and directs, the Cancer Prevention Trials Unit, which has run practice changing research including breast cancer and e-cigarette trials, early detection of Barrett’s oesophagus and the prevention of oesophageal cancer.