The third day began with two very inspiring plenary lectures.
Integrative Sequencing for Improved Precision Medicine: the tale of MiOnco Seq.
The first talk delivered by Arul Chinnaiyan from Michigan, USA, introduced the concept of integrative genomic sequencing for improved precision medicine. The MiOnco Seq: platform set up in the state of Michigan, was the first comprehensive approach to allow the simultaneous sequencing of RNA and DNA to direct treatment plans in patients.
The overall aim of the platform is to improve therapy selection and enrich clinical trails in a more intelligent and informed way, which is hoped will translate into better patient outcomes. It is interesting to see that such platforms require the support of multi-disciplinary precision medicine tumour boards, which incorporate specialists in bioinformatics, geneticists, patient advocates and bioethicists. As precision medicine continues to push its way into mainstream clinical practice in the UK, will we see the composition of MDT’s in this country change in a way not previously anticipated.
Most of the exciting results generated by the platform have come from the analysis of prostate cancers and various metastatic tumours. A key finding to emerge from the prostate cohort, in which 150 patients had the mutational landscape of their tumours sequenced, was the unexpected high prevalence of defects found in molecules associated with DNA repair pathways (~25%). Strikingly, around 12% of patients with metastatic castrate resistant prostate cancer also harboured germ-line alterations in the same pathways. This raises the possibility that a certain, but not an insignificant subset of prostate cancer patients, may benefit from treatment with a new class of therapies called PARP inhibitors. These drugs specifically target defective DNA repair pathways in cancer cells.
The reach of the MiOnco Seq platform has recently been extended to include 500 patients with metastatic patients, covering over 30 different cancer types. It is greatly encouraging to hear that this precision medicine approach has resulted in a clinically meaningful response in around 50% of patients determined to have an actionable drug target using this methodology.
Professor Chinnaiyan concluded his excellent talk by presenting some of the challenges that need to be overcome before the technology can be used more widely. These include, tumour heterogeneity, cost of sequencing, cost of suggested therapies, ability to act on findings, lack of drugs against many cancer drivers and difficulty in combining agents against targets. Although this may seem daunting at first glance, the research and clinical communities, and also the policy makers, can’t afford to bury their heads in the sand. These difficulties need to be tackled head-on, but in a smarter more intelligent way – just like MiOnco Seq itself.
T Cell Recognition and Scheduling of Immune Checkpoint Inhibitors in Cancer
The second plenary talk of the morning saw Tom Schumacher from the Netherlands Cancer Institute discuss some of the parameters that affect the efficacy of immune checkpoint inhibitors in cancer, above and beyond mutational load. Other factors found to influence outcome in patients treated with agents such as anti-PD1 include; general immune status; immune cell infiltration; tumour metabolism; absence of checkpoints and soluble inhibitory immune mediators.
It was the work that Professor Schumacher presented regarding the use of immune checkpoint inhibitors in metastatic melanoma that was the most fascinating. Ever since the introduction of immunotherapies nearly a decade ago, knowing exactly when to use them in the often complex multi treatment plan of cancer patients, has caused much debate. Traditionally, these class of agents have been administered during end stage disease, but the question often asked, is whether this represents the most ideal time. Professor Schumacher presented compelling evidence for the use of anti-PD1 immune checkpoint inhibitors prior to surgery in advanced melanoma. Patient outcomes were far superior when they received anti-P1 therapies before surgery, as opposed to after. Although the reported patient number was small, the study certainly represents a significant step in the right direction.
Is the Future Proton Beam Therapy?
With two NHS proton centres planned to come on line in 2018, and several other private centres being built across Britain, the country stands on the cusp of a proton therapy wave. Therefore, it was very timely that several of today’s sessions were dedicated to the very topic.
The first talk of the mornings parallel session dedicated to proton beam therapy, was given by Cai Grau. He began by laying down some of the challenges that proton beam therapy faces in this country. What really resonated in his talk, and the other related presentations throughout the day – is the evidence void that currently exists to support the use of proton therapy, above other already existing, and continually improving, radiotherapy treatments. A major part of this problem appears to be the lack of randomised comparative trials.
Cai Grau, while not dismissing the need for randomised trials, stated the nature of proton beam therapy, and the type and number of specialised patients that tend to be treated with this modality, make the recruitment of patients to randomised trials a challenge. Professor Grau went onto describe the Model Based Approach for patient selection that is currently being adopted in The Netherlands and Denmark as an alternative to classical randomised trials.
The first argument for using proton beam therapy is to limit serious long term complications, it was stressed, this must always be the first consideration. Only then, can we begin to speak about dose escalation and better disease control. The perceived ability of protons to limit serious side effects is what makes this therapy very attractive for use in paediatric oncology. Children are very sensitive to the effects of radiation and run an increased risk of developing secondary tumours following standard radiotherapy as well as other associated developmental problems. Therefore, it was rather surprising to hear that in reality there is limited evidence to actually show proton therapy can limit such complications in this setting.
The second talk addressed some of the uncertainties that surround the use of proton beam therapy, and considerations were given to the added capacity needed to support this new treatment modality. It was suggested that conventional radiotherapy treatment planning systems may not be suitable for proton therapy, and motion correction during treatment more difficult to manage. Therefore, this type of therapy will require more frequent and robust imaging, perhaps on a daily basis.
The third and final talk of the parallel session was given by Adrian Crellin, who is the appointed clinical lead for proton beam therapy for NHS England. One of the first challenges will be to manage patients expectations as currently an unbalanced view exists in the public’s mind that protons are a lot safer and more effective than standard photon radiotherapy. As Professor Crellin rightly stated, this view will put patients in harms way.
While it is easy to see some issues that surround the use of proton therapy, it certainly does have its niche, but this needs to be fully defined. This is where the UK has an enormous opportunity to make great strides in the field of proton therapy, learning from the mistakes made in the USA, so eloquently described by Anthony Zietman in his often humorous afternoon plenary talk on the same subject. Professor Crellin stressed the need for scientists and clinicians to be extremely careful how they accumulate the evidence base if proton therapy is going to succeed in the UK.
What will be critical is the establishment of a proper research platform that overlays and supports the use of proton therapy. In addition to the considerations given to the physics of the treatment, fully integrated biological research will also be needed, as it is likely proton beams will invoke different biological responses to the photons used in conventional radiotherapy. Equally important will be the embedding of proton partners within the larger radiation oncology community.
To reiterate the closing statement of Professor Anthony Zietman, one of the world leading proponents on the use of proton beam therapy, “The USA and the rest of the world are looking to Britain to produce the kind of randomised trials that this country does so well”. While these will certainly add to the evidence base, will it be the evidence we are expecting to see? Only time will tell, but what does seems certain, is that there are some exciting times ahead for proton beam therapy research and treatment in the UK.
Let’s Talk About Cancer Prevention
Lifestyle and Cancer – who really cares? was the challenging title of Professor Annie Anderson afternoon plenary lecture. It left many of us wishing we had chosen the healthy eating option at lunchtime or taken a brisk walk instead. We often hear the reason behind the increased incidence of cancer, is an ageing population. While this maybe a factor, it doesn’t paint the whole picture. Oncologists are seeing more younger people attend their clinics than they did twenty years ago.
Professor Anderson was quick to remind us that the correct lifestyle choices can reduce the risk of cancer by 25%. As she stated – if we had a drug that could achieve this, would we be quiet? Unlikely, we would be shouting from the rooftops. But this is exactly what can be achieved if the right choices are adopted.
Although smoking rates are dropping, especially in men, around 19% of the population still smoke. However, it is perhaps obesity that sets the biggest challenge we face today. Research undertaken by the World Cancer Research Fund has determined up to 45% of bowel cancers; 38% of breast cancers; 34% of oesophageal cancer; and strikingly 67% of common head and neck cancer can be avoided through appropriate food, nutrition and physical exercise. Whilst not advocating the use of Bariatric surgery as a preventative for cancer, Professor Anderson did share some interesting data from USA that supports the above statistics. Used as a last resort for extreme obesity, Bariatric surgery aims to restrict the capacity of the stomach with dramatic reductions in weight often observed. Follow up of American patients who have undergone this procedure show their risk of developing some common obesity related cancers to be reduced by up to 50%.
While the evidence is overwhelming – are we listening? Professor Anderson was quick to point out that some communities are harder to reach, often those associated with increased deprivation. It is these that see some of the highest rates of preventable cancers and the ones we need to engage with.
Professor Anderson went on to describe some of the innovative research programmes that she has led in Scotland, such as ActWELL for breast cancer, and BeWEL for bowel cancer. Other programmes have seen Scottish Premier League clubs link up with communities, with men encouraged to participate in football based physical activities. Men are more likely to talk about football than healthy body weight and cancer prevention. These studies have also shown that preventative interventions not only increase well being, but also improve the symptoms of other co-morbitities.
Given the forecast burden of cancer on our society over the next 10-15 years, we will no longer be able to simply treat our way out of it, as recently stated by a eminent advocate in the field. While we do need to diagnose cancer earlier, it is more important we prevent cancer in the first place, where we can. The familiar statement “prevention is better than cure” is never more true when it comes to cancer. Cancer prevention is poorly funded when compared to other areas of cancer research such as cancer biology and treatment. Currently, only 3% of the NCRI partners total budgets are spent on prevention. I have a feeling this is about to change over the next few years.