Challenges Prevent Cancer Cure

“The BACR Conference on The Challenges Preventing Cancer Cure was absolutely fantastic; it was an amazing experience to be completely immersed in the key oncology topics for the three days. To be surrounded by such brilliant minds, and listening to the debates and experiences was a real privilege. A real positive for me was seeing lots of people from all backgrounds and countries coming together under one roof to learn from each other; I have never experienced something like this as I feel normally different industries can be quite siloed.  I think I left the conference with more questions than answers given the amount of information absorbed in a short time period; which is a good thing!!!”
 

Dominic Carver, Close Brothers Asset Management

 

The recent BACR conference brought together speakers and delegates from diverse backgrounds and affiliations to discuss various challenges preventing cure, and to propose potential solutions. The conference was a great succcess and below are two commentaries written by PhD students who attend the event from the Francis Crick Institute:

 

Perspective on BACR conference on “The Challenges Preventing Cancer Cure”, March 2019
Jesse Boumelha, Graduate Student at the Francis Crick Institute

As a 2nd year PhD student at the Crick studying mechanisms of immune evasion in KRAS-mutant lung cancer, it was a privilege to attend the BACR conference on ‘The Challenges Preventing Cancer Cure’. A variety of different speakers, each with their own perspectives, gave me a striking insight into the current real-world impact of cancer research.

What almost everyone agreed on was that the current paradigm for drug discovery and cancer treatment is not working and things need to change. The era of targeted therapies has failed to live up to the hype with increasingly expensive drugs providing survival benefits, on average, of a couple of months. This is of course, in part, due to a failure to take into account the complexity of cancer biology, as highlighted by Charles Swanton.
As someone who works in cancer research this is not a novel issue and there was quite rightly a call for better pre-clinical models - something we are trying to develop in our own lab. Importantly, there was also an acknowledgment that we are underinvesting in high-risk curiosity-driven basic research.

However, as Paul Workman suggested, it would be naïve to assume that just carrying out more and better basic research will deliver better treatments. We also need to address the agendas of pharmaceutical companies and the remit of regulatory bodies. We need to ask whether the treatments being tested in clinical trials are designed to overcome the barriers to progress. For example, Vinay Prasad spoke about the growing number of ongoing clinical trials that are combining anti-PD-1 blockade with all manner of drugs, often without scientific rationale. As a scientist carrying out basic research in cancer biology, I want to see the best use of research coming from my field. There needs to be more effective collaboration between academia and industry to design trials based on solid biological rationale. The academic community, both basic and clinical researchers, have a collective responsibility to be involved in shaping the trials agenda. We need to assert ourselves in front of regulators and industry, working with patients, to change the incentives for developing new drugs towards using fundamental scientific knowledge to try to tackle the biological barriers to a cure. This will be the only way we can hope to transform the next decade of basic research into meaningful benefits for patients.

The challenges preventing cancer cure are not all about drugs. Richard Sullivan reminded us that only 11% of cancer patients are cured by systemic therapy. The era of molecular biology narrowed the scope of research to the molecular pathways that drive tumour progression. However, the focus has been on drug targets and there has been huge underinvestment in basic research into the underlying biological mechanisms of chemotherapy and radiotherapy. Especially in the context of immunotherapy, we need to learn how to most effectively combine these treatment modalities with systemic therapies to maximise benefit to patients. It is also not all about treatment – many people raised the point that there is little investment or focus on prevention and early diagnosis, where the scope for saving lives is greatest. We heard from Nick Papadopoulos, of CancerSEEK, about how the recent advancements in liquid biopsies could help. However, it is still relatively unclear whether they can ever be used as a diagnostic tool due to mutational noise especially in older people. Perhaps they will be best used to monitor responses and inform on-off treatment cycles to exploit cancer evolution and prevent the emergence of resistant clones.

We also had the privilege of hearing from Emma Robertson, who is living with incurable breast cancer and talked about her struggles to get access to treatments that could help her, because the cost of new drugs compared with their benefit is unaffordable for the NHS.
It is very easy to lose ourselves in the day-to-day affairs of our job in the lab and forget about all the people for whom curing or controlling cancer is a matter of life or death. It was eye-opening to hear from someone who has benefited from drugs stemming from basic research, but who urgently needs something more and better. It was a reminder of the privilege and responsibility entailed in our job, and why we need to make our research count.

Perspective on BACR conference on “The Challenges Preventing Cancer Cure”, March 2019
Amit Samani, Graduate Student at the Francis Crick Institute

The ideal outcome of an anti-cancer therapy is to eradicate the cancer. Unfortunately, approximately half of cancers in the UK are not cured in this way, and the proportion is lower in developing countries. The recent BACR conference brought together speakers and delegates from diverse backgrounds and affiliations to discuss various challenges preventing cure, and to propose potential solutions.
 
It was refreshing to partake in such open, candid and at times controversial debate. As clinical trainees, we are often exposed to stereotyped narratives heard repeatedly via different outlets. Therefore, it felt liberating to hear evidence and opinions that explored and challenged current thinking on cancer biology, trial design, the economics of cancer care and the policies which shape this.
 
As clinicians, it is tempting to perceive our primary role as attempting to heal patients who are already sick. The patients I remember most vividly are those who were significantly debilitated by their disease. It is natural, therefore, that our instinct when conceptualising research is to focus on treating these patients. However, we now know that cancer is far more heterogeneous than ever imagined. The problem of curing a patient’s “cancer” should instead read “cancers” reflecting diverse subclones generating inevitable treatment resistance. A pervading theme of the conference was that, in order to cure, we need to also focus on tumours much earlier in their natural history, before insurmountable diversity emerges. One example is the use of circulating tumour DNA detection both for adjuvant patients and to predict evolution in those with advanced disease. As oncology clinicians, perhaps we will have to rebrand ourselves as ‘preventers’ or at least ‘early detectors’ rather than ‘healers’.
 
Conversely, we heard that despite almost inordinate biological complexity, constraints to evolution exist that may enable prediction of tumour escape strategies. Clinically, we wait for resistance before deciding to act. We need to embrace evolutionary biology to combine clonal targets with potential escape strategies upfront/earlier or use on-off cycling to exploit the dynamics of subclonal competition. We should become proactive rather than reactive.
 
Clinical trials were also widely discussed. One of the most controversial opinions claimed that clinical trial conception is not always in the interest of patients. The FDA recently estimated the median phase III trial cost at $19 million, money that could go a long way in basic science. However, this cost pales in comparison to what a company could make should the drug reach the market. One speaker joked that he could trial all 20 spices in his mother’s cupboard, find one positive result by chance, and make back more than the money spent in the other 19 trials! In essence, we may be discouraging innovation by distracting funds away from basic science research towards testing drugs with marginal benefit.
 
For a drug to generate profit however, it needs to pass regulatory approval and then be embraced by clinicians. Therefore, are we guilty of celebrating drugs with marginal benefit often using only surrogate endpoints? This is a matter of opinion but there was a common feeling that the value:benefit ratio of modern oncology drugs is unacceptable. One delegate coined the term ‘neophilia’ to describe clinicians’ eagerness to adopt new drugs despite this. In my most recent job, I looked after patients with hepatocellular carcinoma where there was only one first-line treatment for advanced disease. This drug had a 2% response rate and provided 3 months median survival benefit. Shortly after, another drug was approved for exactly the same indication. By design, the trial showed ‘non-inferiority’ compared to the first drug. The obvious question is whether the funds could have been better spent on innovation elsewhere.
 
Various other clinically relevant issues discussed included the disproportionate amount of research on systemic therapy versus radiotherapy/surgery (which are responsible for almost 90% of cancer cures), the inequality of cancer care globally (set to be exacerbated by the value:benefit problem) and the disconnect between patients’ expectations and physicians’, often fuelled by sensationalist media headlines. The problem and solution was well summed-up by one speaker who described the cancer ‘ecosystem’. This is the concept that academia, industry, clinicians, regulators and patients need to align agendas and work co-ordinately. It is telling that as clinicians we are invited to many market research studies about drugs where regulatory approval is imminent but are never consulted en masse about pipelines or early phase output.
 
We have made important strides over the past few decades but the next phase is going to be much harder. Perhaps improved dialogue such as that at the conference, and novel relationships within the ecosystem, most critically between academic drug discovery centres and commercial partners, will help achieve our aim of discovering genuinely transformative therapies and delivering them at affordable prices.