The second day always sees the NCRI conference in full flow, with most of the delegates having now arrived from across the UK and many other parts of the world.
Update of the ProtecT Prostate Cancer Trial
The morning started with the two traditional plenary talks. The first saw Freddie Hamdy, a urological surgeon from Oxford, give an update on the important ProtecT trial for prostate cancer. This trial was designed to determine the effectiveness of the three most commonly used approaches for the treatment and management of prostate cancer, which are surgery (radical prostatectomy), radiotherapy or active monitoring or surveillance.
Freddie Hamdy set the scene with two very astute, interconnected statements. The first – “that you can never over diagnose cancer, only over detect and over treat it”. The second – “it is the great genomic diversity seen, in and between prostate cancer patients, that is acting as an Achilles heel, serving to promote the over detection and over treatment of prostate cancer”. It is against this backdrop that the results of ProtecT look set to define the future of prostate cancer diagnosis and treatment.
The initial findings show the risk of death from prostate cancer in those patients recruited to the trial was very low ~ 1%. This probably reflects the presence of slow growing and low grade tumours so often detected by PSA testing. Surgery and radiotherapy were also found to reduce the risk of cancer progression (but not necessarily cancer related deaths), however, these modalities were associated with troublesome longterm side effects such as urinary incontinence, erectile dysfunction and bowel problems. Interestingly, Professor Hamdy commented that the new robotic surgical interventions for prostate cancer have not reduced related side-effects.
Perhaps one of the most important findings to emerge from the trial is the benefit that active monitoring seems to have for the detection and prompt treatment of prostate cancers that have progressed. Active monitoring is a surveillance programme with the intention of preventing over-treatment and side effects, while still being able to capture cancers that have progressed, yet remain within the window of curability. By Professor Hamdys own admission – very much a tricky balancing act!
The ProtecT trial has made a huge impact since the first results were published last year and has quickly become one of the most highly cited clinical trials in recent times. The trial has also highlighted some of things that need to be implemented moving forward. Perhaps some of the most important of these are the need to undertake pre-biopsy imaging and develop better non-invasive tests to eventually replace PSA. It is likely these new tests will be multi-parametric in nature, measuring many different markers simultaneously which could include circulating tumour DNA released from tumours.
As risk stratification of prostate cancer patients at biopsy is inaccurate, any breakthroughs that enable clinicians to distinguish lethal from non-lethal cancers is very welcomed and is the Holy Grail of prostate cancer diagnostics.
Cancer Immunology, Immunoscore and Risk Stratification
The second plenary lecture of the morning, given by Jerome Galon, was an impressive and inspiring whistle stop tour of cancer immunology and the development of Immunoscore. The latter is a new approach that incorporates the use of immune profiles in tumours as part of its classification to determine the prognosis of disease.
The initial work really set the field alight when it was first published in 2006. In this study, bowel cancer patients whose tumours harboured an increased density of T cells (highly specialised cells of the immune system) at the point of biopsy or surgery, were found to have a much more favourable outcome than patients whose tumours had limited evidence of T cell infiltration. Ten years on, Immunoscore is readily becoming accepted as a much improved and more accurate system for predicting disease progression than conventional prognostic models that rely on standard pathological parameters, such as tumour grade and stage.
Jerome Galon and his team at INSERM in France, have recently extended the work by assessing the validity of Immunoscore in the metastatic setting. Secondary brain, liver and lung tumours deemed to have a ‘High’ Immunoscore have a tendency to progress more slowly and these patients live significantly longer. However, it was noted that not all secondary tumours are the same and multiple metastatic tumours in a single patient may have different immunoscores. Unfortunately, more often than not, it is the least immune controlled secondary tumours that leads to death.
As discussed a number of opportunities exist which include the identification of novel treatments that may increase the Immunoscore of both primary and secondary tumours. Looking back at the news from last week, where we learnt that the gut microbiome has an impact on the outcome of patients treated with immunotherapy, it is now plausible to ask if a change in diet in the pretreatment setting may lead to an improved Immunoscore in some tumour settings.
There is no doubt that Immunoscore is here to stay and its importance in prognosis and prediction of treatment response looks set to increase, particularly as immunotherapy becomes a viable treatment option for an increasing number of cancer types. The simplicity of the assay that uses standard laboratory techniques and the universal nature of the immune system, which doesn’t discriminate against cancer type, will help Immunoscore to establish itself as a fundamental part of any future prognostic and treatment decision making tool for cancer.
Tumour Metabolism in the Spotlight
Tumour metabolism is one of the more recently identified hallmarks of cancer as first laid out in the seminal papers of Douglas Hanahan and Robert Weinberg. In a series of complimentary talks we were informed how cancers may need to constantly rewire their metabolism as cancer cells and tumours continually evolve. Therefore, metabolic evolution has to parallel genomic evolution if cancer cells are to survive the harsh environments that are created within tumours.
Newly developed bioinformatics platforms have now made it possible to interrogate the vast amounts of published and readily assessable datasets in an effort to discover the master regulators of cancer metabolism. One such platform known as Cancerplot has led to the identification of an enzyme, PGC1 alpha, involved in polyamine synthesis. This allows prostate cancer cells to grow in stressed conditions and facilitates their metastasis.
Other talks in this session discussed how pancreatic tumours are professional foragers and efficiently make use of the limited nutrients in the tumour environment. Metabolic crosstalk with other biochemical pathways in pancreatic cancer cells serve to promote chemotherapy resistance. To add to this complexity, infiltrating macrophages (a type of immune cell which digest alien matter in the body) are also shown to rescue stressed cancer cells by generating and releasing pyrimidines. These essential building blocks of DNA are vital for cancer cells to multiply. Therefore, it is no wonder pancreatic cancers are so difficult to treat as they appear stubbornly hard wired for survival. However, it is hoped these important new insights will provide an avenue for the development of much needed novel treatment strategies for this disease.
What’s Hot in Basic Cancer Research
In this current era, basic cancer research can be easily overlooked as the research community pursues the more fashionable topics and the rich grant awards that come with these. However, it is basic cancer research that underpins most, if not everything. Without basic research most of the recent discoveries and breakthroughs in cancer research and treatment would not have occurred.
Therefore, it was fitting that one of the last sessions of the day was dedicated to the current hot topics in basic cancer research. Valerie Weaver has spent most of her career trying to understand how the stiffness of cancers contribute to their aggressive nature. According to Professor Weaver, cancer was first described as a crab due to the remarkable stiffness observed in cancerous tissue.
It transpires that it is the stiffening of the extracellular matrix (ECM) and basement membrane, which act as a foundation upon which cancer cells sit, that determines how aggressive tumours become. Professor Weaver demonstrated that when this fibrosis response is eliminated or reduced in the experimental setting, many different cancer types fail to spread.
The strong correlation between ECM stiffness and tumour aggression is profound in the often lethal form of brain tumour known as glioblastoma. In these cancers a bulky ECM also serves to protect brain tumours from immune attack, as immune cells can no longer easily recognise and gain access to cancer cells. Importantly, future treatments aimed at softening the ECM are under evaluation. One such approach is looking to utilise Galectin sponges inserted at the time of surgery, in order to mop up some of the stiffening agents present in the ECM that surround glioblastomas.
Lifetime Achievement Award
Elsewhere, it was great to see Professor Jack Cuzick receive the Cancer Research UK Lifetime Achievement Award for his work on cancer prevention. Professor Cuzick’s research is greatly varied and far reaching, and is well known for his early work on the use of Tamoxifen and aromatase inhibitors for the prevention of breast cancer. A very talented statistician, he has also made important contributions to the areas of HPV testing for cervical cancer, sigmoidoscopy for early bowel cancer detection and the use of aspirin as a cancer preventative.