Molecular Biomarkers Support Screening, Diagnosis, and Treatment of Cancer

Frontiers in cancer diagnostics: what’s around the corner?

Biomarkers play a critical role in screening and diagnosis of cancer with increasing powers of early detection, as well as in tumour characterisation, treatment selection, and prognosis. What are the latest advances and what’s next for cutting edge cancer biomarkers?

Diagnostics Journey

Prevention of tumorigenesis (and onset of other chronic diseases) involves understanding environmental and inherited genetic risk factors, and not a little bit of luck. Combining prevention and early detection to effectively reduce the rates of both cancer morbidity and mortality is the holy grail of public health initiatives.

Early detection – do I have cancer now?

One of the most significant breakthroughs in cancer diagnostics in the past decade is the development of liquid biopsies for early detection and monitoring. Unlike traditional tissue biopsies, which can be invasive and limited by tumour accessibility, liquid biopsies analyse biomarkers present in bodily fluids such as blood, urine, or saliva [1]. These biomarkers include circulating tumour DNA (ctDNA) like Grail’s multi-cancer Galleri test that uses DNA methylation, circulating tumour cells (CTCs) like Datar Genetics’ multi-cancer Trucheck test, and exosomes or extracellular vesicles like ExoDx Prostate IntelliScore for early prostate cancer detection from urine. 

Liquid biopsies claim to offer a less invasive and real-time approach to cancer detection and monitoring, allowing for earlier intervention and personalised treatment strategies, and valuable insights into the presence of cancer, its tissue of origin and sub type, and its response to treatment. The early detection space has garnered a huge amount of excitement, however results from large clinical trials and real world evidence show a mixed story. High costs of around $1000 for an annual screen are prohibitive to many in the private health space, and challenges remain even if adopted by health systems like the NHS. Grail’s test has adopted the bold endpoint of all cause mortality reduction in its ongoing clinical trial, the effect of which may be limited by Galleri’s reported low sensitivity to early stage cancers, and offset by the negative impact of excess follow up procedures from false positives when unable to specify cancer type and origin [2]. 

While liquid biopsy platforms are leveraging complex multi-omic approaches including epigenomics, transcriptomics, metabolomics, and proteomics for multi-cancer detection, near term gains in accessibility and accuracy may be found in single cancer diagnostics. Well established screening tests like faecal immunochemical testing (FIT) and prostate specific antigen (PSA) reach millions of people, yet have well known gaps in accuracy and reliability. Guardant’s Shield liquid biopsy test looks at ctDNAin blood to detect colorectal cancer as a novel intermediate step after a positive or uncertain FIT test, prior to getting an expensive and invasive colonoscopy [3]. And Proclaryx from Proteomedix is a reflex test on the same sample as an uncertain PSA result that combines two novel protein markers thrombospondin 1 (THBS 1) and cathepsin D (CTSD) with age and free / total PSA to give a more accurate risk score for presence of clinically significant prostate cancer, and therefore who should proceed to an invasive biopsy [4].

Classification – ok I have cancer, which therapies are tailor made for that sub-type?

Next-generation sequencing (NGS) techniques allow researchers to sequence entire cancer genomes. This information is critical for cancer sub-typing or stratification, as it helps identify distinct molecular subtypes of cancer with unique clinical features and treatment responses. Comprehensive genomic profiling (CGP) has been in use for many years, with providers adding more and more genes of interest to panels, including other genomic markers such as copy number variants (CNV), splice variants, indels, gene fusions, tumour mutational burden (TMB), and microsatellite instability (MSI). By understanding the genetic makeup of tumours, clinicians can tailor treatment regimens to target specific molecular vulnerabilities, maximising efficacy and minimising toxicity. 

Today, advances in sequencing technology and reductions in cost means that many health systems are beginning to adopt whole genome sequencing or exome sequencing as standard practice. In addition, DNA methylation classifiers are emerging as a powerful new method of assigning sub-types to tumours, in some cases expanding the diversity of detectable variants by an order of magnitude. This has proved particularly valuable to classify previously unclassifiable tumours and direct doctors to the optimal treatment pathway [5]. 

In addition to early detection and sub-typing, innovations in cancer diagnostics are also improving our ability to predict prognosis and monitor treatment response. Biomarkers such as microRNAs, circulating tumour cells, and tumour-derived exosomes can provide valuable information about disease progression and treatment effectiveness. By monitoring these biomarkers over time, clinicians can assess a patient’s risk of recurrence, predict response to therapy, and adjust treatment strategies accordingly. These advancements in cancer diagnostics not only improve patient outcomes but also empower patients and healthcare providers with valuable information to make informed decisions about treatment and care.