Recent Position Papers from the Institute for Cancer Research Advocate an Extended Role for Biomarker Testing on the NHS. Professor Noel Clarke Evaluates the Statements, and Considers Important Obstacles to be Overcome
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Increased understanding of the molecular and genetic landscape of cancer has driven important advances in precision medicine, opening up new avenues for treatment, and leading to the development of innovative targeted therapies and immunotherapies.1 A spectrum of biomarker tests—including genetic typing/gene profiling of tissue and body fluids, and protein expression using complex immune and fluorescent histochemistry—are now available, allowing clinicians to fingerprint the genetic and molecular makeup of a patient’s tumour and thereby select the most appropriate treatment.1 Cancer biomarkers are the map that enables oncologists to follow the path of precision medicine.
In recognition of its increasing importance in optimising modern cancer care, the Institute of Cancer Research (ICR) issued two position statements on cancer biomarkers in January 2023.2,3 These highlight the need for greater availability of tests on the NHS, and call for increased collaboration between industry and regulatory bodies to drive the development of new diagnostic and prognostic methods.2,3 The statements emphasise the collective and synergistic endeavour that is required from clinicians, academic science, industry, and patients if this targeted approach to cancer treatment is to become routine practice.
Impact and Applicability of Cancer Biomarkers
Cancer biomarkers can be specific or multifaceted, and involve molecular, cellular, physiological, or imaging-based aspects, either alone or in combination. The ICR applies a catch-all definition to cancer biomarkers as: ‘measurable indicators that could help us to detect early signs of cancer in patients who have not been diagnosed yet, identify the type of cancer a patient has and how aggressive it is likely to be, or make judgements about how a patient is responding or likely to respond to treatment.’3
Broadly speaking, testing for molecular cancer biomarkers involves profiling a patient’s genetic predisposition to develop a malignancy (a germline defect) by sampling body fluid or a cell sample (for example, saliva or a buccal smear), or by sampling the tumour itself, using a tissue or liquid biopsy to detect actionable changes in DNA, RNA, proteins, or other biomolecules.4 DNA-based cancer biomarkers include gene mutations, fusions, deletions or insertions, circulating DNA, and epigenetic modifications. RNA biomarkers provide information on gene expression signatures. Protein biomarkers encompass cancer-associated changes in protein structure and function within the cell and on the cell surface, or in circulation, and can be used to detect specific tumour neoantigens.4
The potential application of cancer biomarkers is wide-ranging, and encompasses risk assessment and prognostication, screening and early detection, diagnosis, treatment selection, prediction of response, and cancer surveillance and monitoring.4 Traditionally, the site of origin, tumour histology, and image/marker-based risk stratification determined the management strategy. But nowadays, sophisticated biomarkers are routinely used in the diagnosis and treatment of a variety of malignancies, including common cancers such as breast, colorectal, and prostate cancer. Advances in molecular technology have made it possible to map the unique genetic, molecular, and immune profiles of an increasing range of rare and common tumours, which are used to inform and direct personalised decisions about management of an individual patient, including whether to de-escalate treatment to minimise the risk of toxicity in cancers with an indolent natural history, or to intensify specific treatments/therapeutic combinations in cancers that pursue a more aggressive course.5
The Role of Biomarkers in Mapping and Treating Cancer
Checkpoint inhibitor therapies that target immune-oncology biomarkers such as programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) have significantly improved outcomes in many cancers, changing therapeutic approaches globally—for example, survival outcomes in metastatic renal cell carcinoma (RCC).6,7 Biomarkers are key to predicting treatment response to PD-1/PD-L1 blockers in RCC, notably quantification of PD-L1 expression, but also of tumour mutational burden and other molecular signatures, such as alterations in DNA mismatch repair (MMR) genes.4,6,7 Immunotherapy is also a mainline therapeutic approach within genitourinary medicine for bladder cancer, requiring differentiation of specific tissue subtypes.8
In addition, the identification of an alteration in the fibroblast growth factor receptor 3 (FGFR3) gene as a potent oncogenic driver of muscle invasive bladder cancer has provided a new avenue of treatment for patients with this aggressive malignancy.9 Its presence is predictive for response to targeted treatment with novel and selective FGFR3 inhibitors, allowing a directed, translational science-based approach to therapy.9
In prostate cancer, the premier biomarker for diagnosis and treatment response is prostate specific antigen (PSA), an extremely good cancer biomarker that has revolutionised the management of this disease. However, it has limitations, including issues with sensitivity and specificity, and the potential for overdiagnosis.10
Testing for genetic and other abnormalities in cellular metabolism can have a profound impact. One approach is to identify homologous recombinant repair (HRR) defects in patients with familial (germline) cancers or those who have HRR defects arising in their tumours (somatic defects). This is due to a better understanding of the risk of developing cancer associated with germline defects (particularly BRCA2), and the knowledge that targeted DNA repair inhibition can yield highly effective responses in tumours with somatic HRR defects. Poly adenosine diphosphate-ribose polymerase (PARP) inhibitors are a useful treatment in this scenario, with the first drug in this class—olaparib—recently approved by NICE as monotherapy in patients with advanced BRCA1/BRCA2 mutated prostate cancer.11 Understanding of their efficacy when used in combination with standard anti-androgens in earlier stage metastatic disease is improving, with evidence of synergy when PARP inhibitors are used together with more powerful anti-androgenic drugs.12,13 Homologous recombination deficiency variants, such as BRCA1/BRCA2, are also key biomarkers across a range of other cancers, including breast, ovarian, and pancreatic cancer, and are predictive of response to PARP inhibition.14–16
In recent years, the first therapies for tumour agnostic indications have been approved. Treatment is biomarker driven, and the type of primary cancer is no longer the sole arbiter of the treatment pathway.17 An example is the use of the tyrosine kinase inhibitors larotrectinib and entrectinib in neurotrophic tyrosine kinase gene fusions, with therapy predicated on gene-specific aberrations rather than the specific cancer type.17,18
Investigations into genes that are potentially predictive of sensitivity and response to conventional cancer treatment approaches, such as radiotherapy, are ongoing,3 and could help to spare patients from associated drug toxicity if they are unlikely to benefit from a particular treatment.19 The National Comprehensive Cancer Network biomarkers compendium provides an up-to-date list of cancer biomarkers currently being used for this.20
Furthermore, clinical trials have highlighted the importance of genomic disruption in relation to outcome, such as that by Grist and colleagues in patients with high-risk localised and metastatic prostate cancer which used genomic copy number alterations as a measure of genetic instability. This study found a non-linear association between the alterations and an increased risk of disease progression and death in patients with advanced prostate cancer. Grist et al conclude that copy number burden can aid in prognosis and risk stratification, with a limited number of alterations associated with most of the increase in relative risk.21
Biomarkers can also be used in combination with imaging modalities to guide treatment. High expression of prostate-specific membrane antigen (PSMA) is an independent biomarker of poor prognosis for prostate cancer, and is associated with reduced survival.22 PSMA–positron emission tomography (PET) can be used to stage prostate cancer and determine which patients would benefit from metastasis-directed therapy—for example, surgery, stereotactic body radiotherapy, or a combination of the two. PSMA–PET may identify recurrence in high-risk patients early enough to delay disease progression and improve survival outcomes, but there are also concerns that the use of potentially toxic therapies at an earlier stage and over a longer period of time can lead to overtreatment and a decline in quality of life.23–26
Widening Access and Availability
A wide range of techniques are employed in the detection of molecular cancer biomarkers—Table 1 summarises some mainstream testing approaches.4 The technology is constantly evolving, with a focus on new high sensitivity- and specificity-testing approaches that can detect low concentrations of biomarkers in body fluids. Testing for the presence of an accurate and reproducible biomarker is obviously essential if results are to inform clinical decision making. However, significant barriers exist, including the difficulty of obtaining fresh samples representative of the malignant element of the tumour, access to reimbursement for testing, fragmented testing protocols/guidelines, and a low awareness of actionable biomarkers.27 The uptake and rates of testing for cancer biomarkers vary markedly across different tumour types.27
Table 1: Testing for Cancer Biomarkers4
| Test Approach | Application |
|---|---|
| Fluorescence in situ hybridisation | Identification of chromosomal abnormalities |
| Polymerase chain reaction (digital or real-time) | Detection of gene/DNA alterations (including targeted sequence mutations, gene fusions, and DNA methylation) |
| Next generation sequencing | High throughput detection of somatic or germline gene changes |
| Flow cytometry | Quantification of DNA and cell counting and identification |
| Gene expression microarrays | Analysis of differential gene expression levels |
| Immunohistochemistry | Protein expression analysis |
| © Sarhadi V, Armengol G. Molecular biomarkers in cancer. Biomolecules 2022; 12: 1021 | |
| Box 1: Accessing Biomarker Tests on the NHS: the ICR Vision2 |
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The ICR has also stressed the need to expand testing for inherited mutations that may confer an increased risk of developing cancer.2 NHS England recently introduced a change in genetic screening for prostate cancer, with constitutional (germline) genomic testing of markers for BRCA1, BRCA2, partner and localiser of BRCA2 (PALB2), MutL homolog 1, MutS homolog 2, MutS Homolog 6, ataxia telangiectasia mutated (ATM), and checkpoint kinase 2 (CHEK2) now available for individuals with prostate cancer in the following circumstances:
- Prostate cancer diagnosed at age <50 years
- Prostate cancer in an individual with Ashkenazi Jewish ancestry
- Metastatic prostate cancer diagnosed at age <60 years.
If a pathogenic variant is also identified during tumour testing in a gene that is known to be associated with prostate cancer predisposition (for example, BRCA1/BRCA2), germline testing for the same variant is also appropriate.
The relevance of MMR defects in prostate cancer has also been recognised recently in the NHS genetic testing programme for lynch syndrome, which is to be offered to all patients diagnosed with endometrial or bowel cancer. A positive result opens the door to targeted immunotherapy with pembrolizumab, and enables family members to undergo testing.29
Maintain Demand at Manageable Levels
Increased access to biomarker testing aligns with the ambitious NHS Long Term Plan target to detect 75% of cancers at an early stage by 2028.29,30 However, more testing will inevitably lead to more incidental diagnoses, so it is important to retain an element of targeting to limit the additional burden that could result from large numbers of ‘worried well’ seeking tests, or from over-diagnosis of incidental cancers, particularly in elderly patients with multiple comorbidities.31
In prostate cancer, targeting diagnostic effects and expanding biomarker testing should focus on populations for whom early cancer diagnosis rates are poor, and in areas of the country with high levels of socioeconomic deprivation where the incidence of primary presenting metastatic disease is high.32,33 There should also be a greater spotlight on rare—so-called ‘Cinderella’—cancers, such as penile cancer. This devastating disease commonly affects men aged less than 50 years, and is often associated with human papillomavirus infection, but receives little research funding and virtually no sophisticated biomarker coverage.
Compared to counterpart nations, the UK’s current performance in the field of cancer biomarkers is inadequate, and needs to improve. Access to genetic testing is more widely available in the US, where sophisticated techniques are routinely employed. Certain European countries, notably Germany, France, and the Scandinavian nations, benefit from greater access to genetic tests than that at clinicians’ disposal in the UK.34 For example, current guidance from the European Association of Urology states that germline testing be considered for men who have:
- metastatic prostate cancer
- high-risk prostate cancer and a family member diagnosed with prostate cancer at age <60 years
- multiple family members diagnosed with prostate cancer at age <60 years, or a family member who died from prostate cancer
- a family history of high-risk germline mutations, or a family history of multiple cancers on the same side of the family.34
The ICR has highlighted the ongoing need to ‘keep track of how the UK is doing’ by carrying out regular benchmarking against international comparators to gauge performance in uptake of, and access to, national biomarker testing.1
Take Care of Resource Needs
In the UK, some obvious workflow challenges must be addressed, including workforce shortages. Furthermore, seven regional genomic laboratory hubs are shouldering the burden of delivering the national genomic testing strategy in all disease areas across the UK.2 It is therefore imperative that individual subspecialities, for example, urological oncologists or lung oncologists, receive targeted and practical genetics training in the recognition of patterns associated with specific disease areas. UK cancer specialists need to be upskilled in biomarker testing, and adequate funding supplied for facilities and education to support this.
The ICR has flagged the need to rethink how cancer biomarker testing is delivered and paid for in the UK. The National Genomic Test Directory lays out the specific genomic tests for cancer, patient eligibility criteria, the medical specialties able to order particular tests, and the funding routes. But, only those tests covered by the directory can be commissioned and funded by the NHS; the ICR describes the directory as ‘too limited’, and is calling for more regular updates, as well as the inclusion of a broader range of tests, with the aim of establishing a clear route to non-genomic tests for the NHS.2
Developing New Biomarker Tests to Direct Cancer Therapy
Looking to the future, cancer biomarkers carry important implications for research into new targeted treatments and the continued acceleration of precision medicine in oncology. According to the ICR, biomarkers have the potential to make clinical trials ‘smaller, smarter, and cheaper’, thus expediting the process whereby a new treatment receives approval for NHS use (Box 2).3 Companion diagnostics, in particular, can help to secure the vital NICE endorsement of cost effectiveness, by precisely targeting treatment at those individuals most likely to benefit.3 The European Medicines Agency agrees that biomarker investigations, either for exploratory or confirmatory purposes, now constitute a central pillar of anticancer drug development.39 Expanding whole genome sequencing is also one of the key targets set out in the NHS Long Term Plan.30,40
| Box 2: Creating New Biomarker Tests to Guide Cancer Treatment: The ICR Vision3 |
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The pace of technological advancements in biomarker testing is continuing to accelerate. Next generation sequencing is advancing the study of genes, and artificial intelligence (AI) techniques such as machine learning are increasingly being applied to the widely available genomic data it generates. AI use in oncology biomarker research has benefited from the availability of high dimensionality datasets, advanced computing, and novel deep learning architectures.42 Its potential applications appear boundless—improved identification and classification of cancer, precise molecular characterisation of tumours and their microenvironment, drug discovery, and prediction of clinical outcomes—all powered by the engine of cancer biomarkers.42
Conclusion
Cancer biomarkers can optimise outcomes for both individual patients and the healthcare system, bringing important benefits across many areas of care, including diagnosis, treatment selection, and response prediction, but optimal adoption of testing is critical to achieving these aims. The ICR position statements highlight the need to increase the biomarker tests available on the NHS and expand their accessibility to cancer patients. These are vital steps to ensure that biomarker testing and molecular and genetic profiling of all tumours become routine in UK oncology care.
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ICR=Institute of Cancer Research |