Consensus group calls for routine use of cancer biomarkers and molecular profiling to guide precision medicine 

8th August 2022

All patients’ cancers should be genetically profiled to improve care, say leading health experts

The NHS should offer all cancer patients genetic profiling of their cancers at diagnosis and during treatment to shape care and track how the disease evolves, a consensus group of leading experts has concluded.

Group members said action was needed to ensure use of cancer treatments was routinely guided by information about a patient’s individual cancer.

They called for barriers preventing patients from gaining access to ‘biomarker’ tests to be removed – so genetic information and other tests could routinely be used to select the most suitable precision medicine for each patient.

The consensus group was convened by The Institute of Cancer Research, London, and included nine leading institutions, charities, stakeholder groups and life-science companies, including Cancer Research UK, AbbVie, the Association of British HealthTech Industries, AstraZeneca, Bioclavis, Bristol Myers Squibb, Leukaemia UK and Precision Life and the Association of the British Pharmaceutical Industry.

Biomarker tests look for genetic, protein or imaging ‘markers’ to identify which patients are most likely to respond to treatment. 

It is crucial for clinicians to be able to assess biomarkers so they can select patients with particular weaknesses in their cancers and match treatment accordingly. But the consensus group warned that testing is not always done because regulatory processes and resources have not kept pace with the science.

The statements are calling for a series of changes in the way biomarker tests are developed, made available and routinely used in the UK:

• All people with cancer should have their cancers molecularly profiled as standard within the NHS to identify mutations and guide their treatment – helping them access more personalised and effective treatments, both as part of standard care and by taking part in clinical trials.
• The NHS should be using panel tests to assess many different biomarkers at once – not only at a patient’s diagnosis, but also at intervals afterwards so treatment can be adjusted in line with changes in the cancer.
• Biomarker tests should be routinely developed alongside new cancer drugs to ensure that the right patients are treated, and the cancers are targeted more effectively. Regulations should be reformed to make it much easier to assess biomarkers in trials and get them approved for use.
• The UK’s health technology assessment bodies, such as NICE, should take a more positive view of companion biomarker tests for new drugs – the UK could explore the possibility of offering incentives for companies that bring forward biomarker tests alongside new treatments. 
• The NHS should develop a broader and more transparent directory of biomarker tests, including all the non-genomic biomarker tests that the NHS will provide alongside gene tests.
• Patients and clinicians should be better informed and more aware of the biomarker tests available to them and their benefits. There is currently wide variation in access to biomarker tests in different parts of the UK.

Regulatory barriers to biomarker testing and development have a direct impact on patients – potentially denying them more personalised treatment.

Biomarker testing and development is expensive – currently, the costs of developing biomarker tests often outweigh the financial benefits of doing so, discouraging industry and academia from investing in biomarker research. 

But targeting therapies to those who are most likely to respond would be more cost-effective for the NHS. And clinical trials that use biomarkers to select patients are much more likely to succeed and result in marketing approval.

The ICR and the rest of the consensus group members hope that the calls to action in the new 13-point set of consensus statements will help speed up development of biomarker tests and widen access to them – so that the best treatments can reach the right patients as quickly as possible.

Professor Kristian Helin, Chief Executive of The Institute of Cancer Research, London, said: “We believe every cancer patient should have the opportunity for their cancer to be molecularly profiled to assess biomarkers that can give vital clues about how their disease should best be treated. Biomarker tests can direct treatment precisely to the patients who will most benefit, which can both improve the lives of patients and increase the cost-effectiveness of treatment for the NHS.

“It’s essential that the regulations that govern clinical trials and the approval of new tests and treatments keep pace with the rapidly moving science. At the moment, it can be hard to get new biomarker tests developed, approved and made available for patients. That can in turn act as a disincentive for companies and academics to develop new biomarkers to guide treatment in the future.”

Cancer clinical trial recruitment dropped by 60% during COVID

9th December 2021

Calls for urgent investment in COVID-19 recovery for cancer clinical trials, as well as streamlined regulation and redesigned treatment pathways 

Cancer experts set out a series of findings on 9 December 2021 on the barriers to carrying out clinical trials in the UK, and proposals for boosting participation by enhancing information, changing treatment pathways and streamlining regulations.

The Institute of Cancer Research (ICR), London, is publishing a report collating data on cancer trials, and the views of patients and clinicians on how barriers to making trials more widely available can be overcome. It is warning that without urgent action to open up clinical trials to patients more widely and earlier in treatment, huge opportunities could be missed to drive improvements in outcomes.

Figures obtained from the National Institute for Health Research show that the number of patients recruited onto clinical trials for cancer in England fell to 27,734 in 2020/21, down from an average of 67,057 over the three years previously. The number of patients recruited onto trials fell for almost every type of cancer analysed.

The ICR also published findings showing that issues with making clinical trials available to patients are longstanding and go far beyond the COVID-19 pandemic.

An interview-based study of 12 leading clinical trial researchers from across the UK commissioned from health charity Picker found strong agreement that more needed to be done to widen access to clinical trials for cancer patients. The study, carried out from April to July 2020 during the early part of the pandemic, identified the following issues:

• There is an excessive administrative burden in setting up clinical trials, especially for innovative trial designs such as biomarker-driven studies for precision medicine.
• The NHS does not have systems in place for rapid genetic testing of patients to select them for precision medicine trials.
• Patients face a postcode lottery in access to the latest trials. Funding for doctors to carry out clinical research varies between hospitals – meaning some patients miss out on the latest treatments.
• Information about clinical trials for patients and doctors is inadequate – existing information is spread across multiple platforms, not kept up to date and often in a format that is difficult for patients to understand.

The ICR also commissioned a YouGov survey of 500 people who had been treated for cancer, which was carried out in March 2020. It found that 95% of respondents thought it was important that cancer patients were offered access to treatment in clinical trials. But only 37% had had a conversation about clinical trials during their own treatment, and just 11% participated in a trial. There was also a difference in ability to access trials in different parts of the country, with some patients in rural areas reporting travelling more than 100 miles for treatment on a clinical trial. In light of the barriers identified, the ICR is calling for the following:

• Urgent investment in cancer clinical trial recovery post pandemic – to build patient recruitment back up and ensure new trials can enter the pipeline.
• Learning from COVID-19 to streamline regulations – making it easier and faster to set up innovative study designs including biomarker-driven trials for precision medicine, and virtually monitoring patients.
• Making trials available earlier in treatment – by having conversations about trials and offering genetic testing shortly after diagnosis, and ensuring trials are no longer seen as a last resort, but a viable alternative to some existing treatments.
• Making trial information accessible – through funding to ensure information is up to date, understandable for patients and doctors, and accessible through a single point of
• Addressing the postcode lottery in access – ensuring hospitals across the UK have trained staff in specialisms such as R&D, pathology and radiology, and that oncologists are properly supported to devote time to research.
• Tackling barriers to reaching underserved communities – since there is evidence that poorer patients and those from ethnic minorities are less likely to gain access to trials.

Professor Udai Banerji, Deputy Director of the Drug Development Unit at The Institute of Cancer Research, London said: “Cancer medicine has changed hugely over the last two decades, with patients increasingly treated with precision drugs targeted against particular genetic faults within tumours. It’s essential that our clinical trial systems keep pace with the science.

“We need streamlined and accelerated approval of promising drugs using novel trial designs. Clinical trials of drugs should be embedded into all aspects of cancer medicine from prevention, curative or non-curative therapy to palliative care. The pandemic has caused us to pause and identify areas we can do better. It’s time to make up for lost time.” 

Professor Kristian Helin, Chief Executive of The Institute of Cancer Research, London, said: “Clinical trials have huge benefits for patients, both by providing access to the latest drugs and technologies, and by demonstrating the effectiveness of the next generation of treatments for use on the NHS. We would like to see a clinical trial being made available for every cancer patient who would like to participate in one. That requires both investment in recovery of clinical research post Covid-19, to get us back to where we were before the pandemic, and broader measures to widen access to trials by reshaping funding, regulation, information and treatment pathways.”

New drug class could treat range of cancers with faulty BRCA genes

18th June 2021

Scientists have identified a class of targeted cancer drugs that offer the potential to treat patients whose tumours have faulty copies of the BRCA genes.

The drugs, known as POLQ inhibitors, specifically kill cancer cells with mutations in the BRCA genes while leaving healthy cells unharmed.
 
And crucially, they can kill cancer cells that have become resistant to PARP inhibitors – an existing treatment for patients with BRCA mutations. 
 
Researchers are already planning to test the new drug class in upcoming clinical trials. If the trials are successful, POLQ inhibitors could enter the clinic as a new approach to treating a range of cancers with BRCA mutations, such as breast, ovarian, pancreatic and prostate cancer.
 
Scientists at The Institute of Cancer Research, London, and the pharmaceutical company Artios, explored the potential of using POLQ inhibitors in treating cancer cells with defects in the BRCA genes. 
 
Their study, published in Nature Communications, was funded by Artios, Cancer Research UK and Breast Cancer Now.
 
For some time now, scientists have known that genetically removing a protein known as POLQ killed cells with BRCA gene defects, although drugs that prevent POLQ from working had not been identified. In this new work, the researchers identified prototype drugs that not only stop POLQ from working, but which also kill cancer cells with BRCA gene mutations. 
 
Both BRCA genes and POLQ are involved in repairing DNA. Cancer cells can survive without one or other of them, but if both are blocked or their genes switched off, cancer cells can no longer repair their DNA and they die. 
 
Researchers found that when cells were treated with POLQ inhibitors, cancer cells with BRCA gene mutations were stripped of their ability to repair their DNA and died, but normal cells did not. By killing cancer cells with BRCA gene mutations, while leaving normal cells unharmed, POLQ inhibitors could offer a treatment for cancer with relatively few side effects.
 
Researchers also found that POLQ inhibitors work very well when used together in combination with PARP inhibitors. 
 
The addition of POLQ inhibitors meant that PARP inhibitors were effective when used at a lower dose. And in laboratory tests in rats and in organoids – three-dimensional mini-tumours grown in the lab – POLQ inhibitors were able to shrink BRCA-mutant cancers that had stopped responding to PARP inhibitors because of a defect in a set of genes known as the ‘Shieldins’. 
 
This suggests that POLQ inhibitors could offer an alternative treatment where PARP inhibitors are no longer working. Researchers believe that using a POLQ inhibitor in combination with a PARP inhibitor in patients with cancers that have faulty BRCA genes could prevent resistance from emerging in the first place. 
 
Scientists at The Institute of Cancer Research (ICR), funded by Breast Cancer Now and Cancer Research UK, discovered how to genetically target PARP inhibitors against BRCA-mutant cancers and, with colleagues at The Royal Marsden NHS Foundation Trust, helped run clinical trials leading to the first PARP inhibitor being approved for use.
 
The next step will now be to test POLQ inhibitors in clinical trials led by Artios.
 
Study co-leader, Professor Chris Lord, Professor of Cancer Genomics at The Institute of Cancer Research, London, and Deputy Director of the Breast Cancer Now Toby Robins Research Centre at the ICR, said: “All cells have to be able to repair damage to their DNA to stay healthy – otherwise mutations build up and eventually kill them. We have identified a new class of precision medicine that strips cancers of their ability to repair their DNA. This new type of treatment has the potential to be effective against cancers which already have weaknesses in their ability to repair their DNA, through defects in their BRCA genes. And excitingly, the new drugs also seem to work against cancer cells that have stopped responding to an existing treatment called PARP inhibitors – potentially opening up a new way of overcoming drug resistance. I’m very keen to see how they perform in clinical trials.”
 
Professor Paul Workman, Chief Executive of The Institute of Cancer Research, London, said: “It’s exciting that the new POLQ inhibitors should provide a different approach to treating cancers with BRCA gene defects – and particularly that this class of drugs should retain their activity in cancers that have developed resistance to PARP inhibitors. Most exciting of all is the potential of combining POLQ and PARP inhibitor drugs to prevent the evolution of BRCA-mutant cancers into more aggressive, drug-resistant forms – a major challenge that we see in the clinic.”
 
Study Co-Leader, Dr Graeme Smith, Chief Scientific Officer at Artios Pharma, Cambridge, said: “These exciting preclinical results provide a clear rationale for future clinical studies with a POLQ inhibitor. At Artios, we are on track to initiate our POLQ clinical programme before the year end to explore POLQ inhibition in the sensitive cancer types that this study has uncovered. Our planned POLQ inhibitor clinical studies will leverage these results, exploring combination treatment with PARP inhibitors and different types of DNA damaging agents.” 

Citation
Zatreanu D et al. Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance. Nat Commun 2021;12:3636