Several gene expression profile (GEP) tests have been developed for use to identify those individuals with stage 2 colon cancer who are considered to be at high risk for recurrence after surgery and therefore most likely to benefit from additional treatment such as chemotherapy.
A review of several trials comparing adjuvant therapy versus surgery alone in individuals with stage 2 colon cancer showed that there was a very small benefit of chemotherapy for disease-free survival, but not for overall survival.
Colon cancer is classified as stage 2 when it has spread outside the colon and/or rectum to nearby tissue but has not spread to the lymph nodes or metastasized to distant sites. Surgical resection of the primary cancer and colonic anastomosis is the primary treatment for stage 2 colon cancer. The survival rate following surgery is 75 percent to 80 percent at 5 years. Those individuals who are most likely to benefit from chemotherapy are difficult to identify by standard clinical and pathological risk factors. The current system for determining individuals at risk depends upon a variety of factors, including tumor sub-stage 2B (T4A tumors that invade the muscularis propria and extend into pericolorectal tissues) or 2C (T4B tumors that invade or are adherent to other organs or structures); obstruction or bowel perforation at initial diagnosis; inadequately low number of sampled lymph nodes at surgery (12 or less); histological features of aggressiveness; a high preoperative carcinoembryonic antigen level; and the presence of indeterminate or positive resection margins.
Several assays are available in the United States: ColonPRS®, Signal Genetics, New York, NY; Coloprint® Agendia NV, Amsterdam, Netherlands; Genefx Colon®, Precision Therapeutics, Pittsburgh, PA; OncoDefender-CRC (colon and rectal cancer), Everist Genomics, Ann Arbor, MI; and Oncotype DX® colon cancer test, Genomic Health, Inc., Redwood City, CA.
No studies of GEP for determining prognosis of patients with stage 2 or stage 3 colon cancer have been published demonstrating the effect of testing on overall reclassification of patients when compared with existing methods of risk analysis. Cartwright et al (2014) and Srivastava et al (2014) published studies showing the effect of Oncotype DX® results on treatment recommendations made according to traditional risk classifiers in patients with stage 2 colon cancer. However, this study did not assess survival or recurrence outcomes. Currently, there is no published information on the impact of use of GEP results on patient outcomes. Absent information showing a direct effect on outcomes or establishing a strong chain of evidence that testing has a positive net effect on outcomes, the clinical utility of testing remains unclear.
A Technical Brief, published by the Agency for Healthcare Research and Quality in December 2012, reviewed the clinical evidence for GEP for predicting outcomes, including benefit from adjuvant chemotherapy, in patients with stage 2 colon cancer. The 4 assays reviewed earlier that are commercially available for clinical use were included in the brief. No prospective studies were identified that assessed change in net health outcome with use of a GEP assay, and no studies were identified that used a net reclassification analysis and subsequently evaluated the impact of the reclassification on net health outcome. Additionally, evidence was limited on the reproducibility of test findings, indications for GEP testing in stage 2 patients, and whether results of GEP assays can stratify patients into groups defined by clinically meaningful differences in recurrence risk.
Current clinical practice guidelines from the National Comprehensive Cancer Network on colon cancer state that data are insufficient “to recommend the use of multigene assays to determine adjuvant therapy” in patients with stage 2 or 3 colon cancer.
The evidence for the use of gene expression profiling (GEP) tests in patients who have stage 2 or stage 3 colon cancer includes development and validation studies. Relevant outcomes are disease-specific survival, test accuracy, test validity, and change in disease status. The available evidence indicates that GEP tests for colon cancer can improve risk prediction, particularly the risk of recurrence in patients with stage 2 or stage 3 colon cancer. However, evidence to date is insufficient to permit conclusions on how GEP classification compares with other approaches for identifying recurrence risk in stage 2 or stage 3 patients, or on how GEP classification impacts patient outcomes (clinical utility). There is even less evidence to permit conclusions about how GEP classification compares with other approaches for management of other stages of colon cancer. The evidence is insufficient to determine the effects of the technology on health outcomes.