Cancer is the second-leading cause of death in the United States, after heart disease. Major advances have been made in diagnosis using solid tumor biopsies that have fundamentally changed how we target and treat various types of cancer. The completion of mapping the human genome and subsequent technological advances in genomic medicine have led to the development of solid tumor diagnostics that use individualized tumor information to personalize treatments which can ultimately prolong life and sometimes even cure patients with cancer. Molecular testing of tumors using high-throughput genomic technologies, such as next generation sequencing (NGS), has further expanded our knowledge of oncogenic pathways. Access to NGS enables the genomic profiling of tumors and facilitates individualized approaches to cancer treatment by sub-classifying cancer types based on genomics. Physicians can use an in-depth understanding of cancer at a molecular level to optimize therapy by selecting the most appropriate drugs based on known targets.
Numerous genomic alterations have been transformed into diagnostic markers for treatment with targeted therapeutics, and several anti-cancer drug labels require that pharmacogenomic information is obtained. Examples of oncology diagnostic tests that comprise the new standard of care include ER and HER2 in breast cancer, bcr-abl in chronic myeloid leukemia, c-Kit in gastrointestinal stromal tumors, BRAF in melanoma, and EGFR and ALK in lung cancers. With increasing development of targeted biological therapeutic agents in oncology comes a corresponding need for personalized treatment strategies. These strategies will facilitate the selection of patients who are most likely to benefit from a particular therapy, while simultaneously avoiding the cost and morbidity of futile interventions.
Despite the availability of these new technologies, a key limitation found in solid tumor oncology is the lack of tissue biopsy material necessary to run the battery of tests needed at the time of initial diagnosis as well as throughout the course of disease treatment. As an alternative, in many cases, medical professionals are opting for a non-invasive diagnostic method known as a liquid biopsy. Rather than staging and monitoring cancer using tumor tissue, the liquid biopsy enables a serum testing to identify specific biomarkers that can help direct the course of treatment.
A major advantage of a liquid biopsy over solid tumor testing is that physicians can monitor changes in tumor genetics over time to modify treatment accordingly, to achieve better patient outcomes. Until recently, the availability, robustness, and validation of methods for analyzing key biomarkers for solid tumors using patient blood have been limited, but the sensitivity of blood-based diagnostics is improving.
A liquid biopsy provides an alternative sample type when solid tumor sampling is unavailable or difficult to obtain. In some cases a patient may have had a biopsy, but it has been exhausted, not allowing further diagnostic tests to be performed. In other instances, it may be quite difficult to obtain a biopsy from a patient due to tumor location. For example, tumors in bone, brain, lung, pancreas, or other organs may be hard to access, or could put the patient at risk due to the invasive nature of the procedure. Ultra-sensitive methods to capture circulating tumor cells (CTCs) or methods that permit the sensitive analysis of cell-free circulating tumor DNA (ctDNA) provide physicians with the resources to test for important biomarkers that inform therapeutic decisions.
New clinical offerings from a number of cancer diagnostic companies are beginning to demonstrate that the technology and timing of blood-based biomarker testing for solid tumor indications have reached a key inflection point that may have poised the technology for mass adoption. Well-validated studies continue to demonstrate that blood-based biomarker testing using CTCs and ctDNA are able to identify predictive biomarkers with high correlation to those same markers found in the tumors.
Technical advances that have been achieved in recent years have significant implications for clinicians and medical laboratories. Medical professionals now have the ability to interrogate a hard-to-access tumor using a liquid biopsy. Previously this was only possible using invasive procedures that posed significant adverse risks to patients. Innovations in liquid biopsy have also made it possible to profile tumor cells on a continual or on-demand basis—at the time of initial diagnosis and repeatedly thereafter. This monitoring capability enables clinicians and doctors to track ongoing changes in a patient’s disease state through a repeatable, non-invasive procedure and modify a patient’s treatment plan as needed.
In order to achieve these potential treatment monitoring benefits without solid tumor tissue, highly sensitive analysis from blood-based CTCs or ctDNA is crucial. Although relatively abundant in late-stage diseases, the amount of tumor burden found in the blood is not close to the number of cells obtainable via tissue biopsy. Most key predictive biomarker tests would need sensitivities at the single-cell level in order to successfully be detected in blood. In a best-case scenario, detection of expression, amplification, and mutation changes requires sensitivities of one tumor cell in 100,000 nucleated blood cells. However, tumor cells are more likely to occur at only 1:1,000,000, or even down to 1:100,000,000 in the total nucleated cell population.
Today, for a tissue biopsy, sensitivity rates reach approximately 1:20–1:1,000 at best. Therefore, the shift in sensitivity from tissue biopsy to a liquid biopsy requires significant advances in lab-based technological platforms. This reality does not address the various informatics hurdles that come from managing the wealth of data that is produced from a single biopsy sample. Cutting-edge platforms to extrapolate tumor information from blood-based samples must also be implemented in a manner that proves to be scalable, cost-effective, and reproducible.
Liquid biopsy, combined with personalized therapies, has the potential to transform cancer from a deadly disease to a chronic but manageable one. As newer and more effective therapies reach the market, the need to monitor patients’ cancer-associated molecular profiles on a regular basis is essential. A liquid biopsy enables physicians to appropriately monitor and modify the course of treatment for patients based on their response to therapy. Physicians have the ability to save and extend lives without solid tumor tissue now that diagnostics assessing genetic biomarkers have advanced to a point where meaningful information can be gleaned from a blood-based sample. As the future of cancer treatment becomes increasingly personalized, clinicians will need to carefully consider how liquid biopsies fit into their diagnostic and treatment decisions.
Lyle Arnold serves as Senior Vice President and Chief Scientific Officer for Biocept, Inc. Raaj Trivedi serves as Vice President, Commercial Operations for Biocept.
