Vol. 25 • Issue 9 • Page 14
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 5-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 for3-5 years post resection using computed tomography (CT) scans complemented by carcinoembryonic antigen (CEA) blood testing2-4 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 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-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, non-malignant 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), as well as breast and colorectal cancers.5-7
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 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 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 represents a new analyte. 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 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 patent anxiety. The question of how to translate sensitive and specific ctDNA tests to clinically actionable data to improve patient outcomes must be explored.
We now find ourselves16 years after the completion of the Human Genome Project at the beginning of the genomic testing era as human genome biomarkers become routine for patient care. The promise of ctDNA diagnostic tests is to identify and treat cancer at its most deadly stage, metastasis.
- Lowy DR, Collins FS. Aiming High. N Engl J Med. 2016;374(20):1901-4.
- O’Connell MJ, Campbell ME, Goldberg RM, et al. Survival Following Recurrence in Stage II and II Colon Cancer: Findings From the ACCENT Data Set. J Clin Oncology, 2008;26(14):2236-41.
- André T, Quinaux E, Louvet C, et al. Phase III Study Comparing a Semimonthly With a Monthly Regimen of Fluorouracil and Leucovorin as Adjuvant Treatment for Stage II and III Colon Cancer Patients: Final Results of GERCOR C96.1
- Fakih MG, Padmanabhan A. CEA monitoring in colorectal cancer. What you should know. Oncology (Williston Park, NY). 2006;20(6):579-87.
- Garcia-Murillas I, Schiavon G, Weigelt B, et al. Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer. Sci Transl Med. 2015;7(302):302ra133.
- Jamal-Hanjani M, Wilson GA, Horswell S, et al. Detection of ubiquitous and heterogeneous mutations in cell-free DNA from patients with early-stage non-small-cell lung cancer. Ann Oncol. 2016;27(5):862-7.
- Tie J, Wang Y, Tomasetti C, et al. Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer. Sci Transl Med. 2016;8(346):346ra92.
- Li Y, Fu XH, Yuan JQ, et al. Colorectal cancer: using blood samples and tumor tissue to detect K-ras mutations. Expert Rev Anticancer Ther. 2015;15(6):715-25.
- Thierry AR, Mouliere F, El messaoudi S, et al. Clinical validation of the detection of KRAS and BRAF mutations from circulating tumor DNA. Nat Med. 2014;20(4):430-5.
- Lawrence MS, Stojanov P, Polak P, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499(7457):214-8.
- Potter N et. al. Validation of a real-time PCR-based qualitative assay for the detection of methylated SEPT9 DNA in human plasma. Clin Chem. 60(9):1183-1191.
- deVos T et al. Blood-based tests for colorectal cancer screening. Clin Lab Int. Oct. 2014:18-20
- Pedersen SK, Symonds EL, Baker RT, et al. Evaluation of an assay for methylated BCAT1 and IKZF1 in plasma for detection of colorectal neoplasia. BMC Cancer. 2015;15:654.
- Symonds EL et al. A Blood Test for Methylated BCAT1 and IKZF1 vs. a Fecal Immunochemical Test for Detection of Colorectal Neoplasia. Clin Trans Gastro. 2016; 7, e137.
- Pedersen SK et al. A Two-Gene Blood Test for Methylated DNA Sensitive for Colorectal Cancer. PLoS One2015;10(4):e0125041
- Pedersen SK et al. A novel 2-gene blood test for colorectal cancer recurrence. J Clin Oncol 34, 2016 (suppl 4S; abstr 495)