Biomarkers in cancer

The importance of biomarkers is unquestionable. They enable the objective measurement of physiological processes, pathogenic progression and pharmacologic response to therapeutic intervention. In simple terms, they allow one to measure the state of human health. Biomarkers can take the form of proteins, DNA, RNA , metabolites, or even cells present in blood, urine, semen, saliva, biopsies, or any extractable human sample. They can take the form of electrical activity such as in electrocardiogram or electroencephalogy readouts from the heart and brain respectively. They can take the form of body temperature, blood pressure, genetic and epigenetic modifications, and images obtained by shooting radioactive or magnetic waves through our bodies. They may even encompass behavioral changes or changes in how we perceive our environment although these may prove more challenging to measure objectively.

The use of biomarkers, specifically predictive biomarkers, are closely tied to the dawn of personalized medicine. Predictive biomarkers offer information on the likelihood of response to a given therapy and have been increasingly used in the field of cancer to decide first-line treatments. It seems obvious that people are a heterogenous lot and a standardized treatment may not work for everyone. Patients suffering from chronic myeloid leukemia (CML) experience a chromosomal translocation from chromosome 9 to 22 (forming the Philadelphia chromosome) which produces a fusion protein called BCR-ABL. BCR-ABL acts as a constitutively active tyrosine kinase that results in unregulated cell division. Imatinib (Gleevec) was developed in the late 1990s by Novartis (then known as Ciba Geigy) and inhibits the tyrosine kinase activity of BCR-ABL, reducing proliferation of BCR-ABL-expressing cells and significantly improving survival. Resistance to imatinib however occurs in 10-15% of patients and is influenced by mutations in the catalytic domain of BCR-ABL (30-50% of patients with this mutation develop resistance). Catalytic domain mutation screening in BCR-ABL is used as a predictive biomarker for identifying patients to be treated with other recently developed tyrosine kinase inhibitors for imatinib-resistant CML, namely nilotinib and dasatinib. Similarly, activating mutations in epidermal growth factor receptor (EGFR) correlate with higher response rates in non-small cell lung carcinoma (NSCLC) patients to gefinitab while patients without these mutations respond better to carboplatin-paclitaxel treatment. EGFR testing is therefore now recommended to NSCLC patients to decide first-line treatment.

Another form of biomarkers, prognostic biomarkers, reveal if a therapeutic intervention is working by offering insight into disease progression. The current gold standard of monitoring clinical benefit in a cancer trial is overall survival, but this is increasingly being replaced by progression-free survival. Still, these are often supplemented with other biomarkers known as surrogate end-points of efficiency and usually involve measuring tumour size or function by imaging techniques like magnetic resonance imaging, computed tomography and positron emission tomography. These latter surrogate measures cannot be used in isolation however due to issues in reproducibility of assessment, inability to assess certain disease sites (e.g. bone) and the inability to distinguish between tumour and necrotic/fibrotic masses. Furthermore, they may not work in therapies that utilize the immune system to target cancer cells which tend to increase tumour size presumably due to infiltration of immune cells.

Blood biomarkers offer the advantage of being easily accessible and are assayed more objectively with machines rather than human interpretation. Currently in the field of cancer, protein biomarkers such as antigens (e.g. cancer antigen 125 in ovarian cancer) are most commonly used to monitor therapeutic response. However their ability to derive from non-tumour origins and fluctuations with concomitant illness limit their use as reliable and robust surrogate biomarkers in advanced-stage solid tumours. Circulating tumour cells have some prognostic value but experience limited dynamic range and difficulties in measurement. Circulating cell-free DNA (cfDNA) perhaps provide the most promise as surrogate end points in clinical trials, providing a wide dynamic range, high sensitivity, and apparent correlation with tumour burden. They are DNA fragments usually ~170 base pairs in length released from apoptotic/necrotic cells and harbor mutations in cancer patients. Techniques involved in their assay include targeted DNA-capture methods and next-generation sequencing.

Pharmacodynamic biomarkers or biomarkers that measure the effect of a drug on its target are perhaps the most desired type of biomarker in a clinical trial as they provide proof-of-concept that the drug is working through a specified pathway to provide clinical benefit. They usually involve tissue biopsies to examine the status of target activation (e.g. phosphorylation if the drug is a kinase inhibitor).

Technology is advancing at a rapid pace leading to the identification of many novel biomarkers yet challenges remain with regard to implementing their use in the clinic. Hospitals often rely on practices that have withstood the test of time and healthcare staff often experience an inertia or fear of implementing changes. Furthermore, the assay of some of these biomarkers require advanced equipment and expertise that may not be readily available or implemented in a hospital setting. The multicenter nature of clinical trials also make it difficult to standardize assays, a key aspect to producing reliable and reproducible measurements.

So it appears we have our work cut out for us.

(Sources: “Developing biomarker-specific end points in lung cancer clinical trials” Joel W. Neal, Justin F. Gainor & Alice T. Shaw. Nature Reviews Clinical Oncology 2014, doi:10.1038/nrclinonc.2014.222)

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  1. Pingback: Big data technology – where are we heading? | Science on a daily basis

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