Cancer is the second leading cause of death in the United States and will kill nearly 600,000 Americans in 2016.1 Of these, 50,000 will succumb to colorectal cancer.
Even when detected and removed, the recurrence rate of colorectal cancer (CRC) is estimated to be 30-40%, with approximately 80% of those recurrences expected to occur within two years of initial surgical resection. Recent studies in Stage II and Stage III recurrences suggest a five-year survival rate of approximately 20-30%.2,3 Early detection of CRC recurrence is thus important to provide clinicians with the widest window for intervention.
Current clinical guidelines include annual investigation and follow-up for three to five years post resection using computed tomography (CT) scans complemented by carcinoembryonic antigen (CEA) blood testing two to four times a year. While CEA testing is included in surveillance guidelines issued by the American Society of Clinical Oncology (ASCO), the National Comprehensive Cancer Network (NCCN) and others, the test has well known deficiencies. Approximately 74% of resectable cancers are missed.4 Furthermore, CEA testing may yield high false-positive rates caused by inflammatory diseases, smoking and infection. CEA testing-while a valuable tool-is not viewed with high confidence among clinicians and may lead to excessive referrals for expensive and unnecessary diagnostic imaging.
To reduce the mortality rate of colorectal cancer, we must improve the early detection of cancer relapse and better understand the nature of minimal residual disease leading to metastasis.
We have known for decades that cancer is a disease of the genes. The most widely accepted conceptual model suggests oncogene promotion that pushes cells down pathological pathways or else a breakdown in tumor suppressor gene networks that fail to contain the cell within the normal, nonmalignant state. Building on greatly improved molecular biology tools (e.g., modern PCR, high speed DNA extraction, etc.) and a better understanding of cancer genetics, there is an inexorable shift toward detecting and tracking cancer at the genomic level using modern pathology methods.
In particular, diagnostic testing based on DNA leaking from tumors into the bloodstream, the circulating tumor DNA (ctDNA) fraction, is advancing rapidly. Unlike tissue-based biopsies, obtaining blood is a minimally invasive, low-cost sampling method, and several proof-of-concept studies have demonstrated that ctDNA can detect organ specific disease types, including non-small cell lung cancer (NSCLC), breast and colorectal cancers.5,6,7
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For colorectal cancer, there are a growing number of ctDNA-based solutions being advanced for clinical testing. Many are based on the recognition of known hot-spot mutations implicated in the cancer gene pathway.5,8,9,10 Other tests are aimed at detecting epigenetic changes (e.g., gene silencing by hypermethylation). Epigenetic-based biomarkers may have advantages over mutation-based tests if epigenetic biomarkers prove to be more stable as the cancer evolves over time and becomes more heterogeneous with respect to mutation profile. Perhaps unsurprisingly, the first FDA approved ctDNA test for colon cancer screening is based on methylation detection.11,12
Our own work to introduce a commercial ctDNA test is supported by almost a decade of research and provides encouraging proof of concept that ctDNA can reliably inform colorectal cancer recurrence.13,14,15 Studies measuring the level of methylated BCAT1 and IKZF1-two genes closely linked to CRC-in DNA extracted from plasma show two-fold better sensitivity than CEA testing without significant loss of specificity.16
While the field has progressed significantly, the integration of ctDNA testing into routine clinical care will require ongoing clinical evaluation and important questions will need to be addressed.
From a clinical chemistry perspective, circulating DNA (whether of cancer or benign origin) represents a new analyte. Passionate cancer researchers have invested heavily to discover and publish the next “breakthrough” cancer biomarkers to detect cancer. Yet, there is poor understanding of the normal range of free circulating DNA in healthy controls. Does the detection of circulating “tumor” DNA always mean there is a tumor to worry about? What is the optimum sample volume for detecting these rare circulating molecules? How often should we draw blood to look for ctDNA?
We will also need to evolve the monitoring pathway given the potential that ctDNA-based recurrence detection is able to pick up minimal residual disease earlier, sometimes much earlier, than current radiology imaging modalities are able to localize secondary lesions.5 Early detection in this circumstance may leave surgeons and oncologists with no obvious treatment pathway, and may result in patient anxiety. The question of how to translate sensitive and specific ctDNA tests to clinically actionable data- in order to improve patient outcomes-must be explored.
Sixteen years after the completion of the Human Genome Project, however, we now find ourselves at the beginning of the genomic testing era as human genome biomarkers become routine for patient care. The promise of ctDNA diagnostic tests, such as those developed for detecting colorectal cancer recurrence, creates profound opportunities to identify and treat cancer at its most deadly stage, metastasis.
Lawrence LaPointe is president and CEO, Clinical Genomics.
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