Comparison to Traditional Assessments
Compared with traditional clinicopathological assessment, the results of the study showed that incorporation of the RS result into clinical decision making changed treatment recommendations for 45% of T3 MMR-P Stage II colon cancer patients in this prospective multicenter study. Use of the RS assay, the investigators concluded, may lead to overall reduction in adjuvant chemotherapy use in this subgroup of Stage II colon cancer patients.
ColoPrint was validated in several independent cohorts of Stage II CRC patients at multiple institutions, with the aim being to enroll 785 eligible patients to validate the performance of ColoPrint in estimating three-year relapse rate. In a pooled data set from 416 patients in a study comparing Coloprint assessments with those obtained through clinical risk factors described in the National Comprehensive Cancer Network (NCCN) 2013 Guidelines for Colon Cancer, ColoPrint could distinguish between patients at high and low risk for relapse.
Clinicians say that although information is emerging about use of GEP assays to inform the decision about use of adjuvant chemotherapy in patients with Stage II colon cancer, studies to date have not provided the type of information needed to address major uncertainties.
Insurance companies consider these tests investigational. “It seems unlikely that the 12-gene expression test for predicting colon cancer recurrence risk in individual patients could guide clinical decision making,” says one major medical insurance company. “The differences between recurrence risk categories established in the validation study were not sufficiently discriminative, and the associated confidence intervals overlapped considerably.”
For example, an insurer might say, an RS of 33 corresponds to a recurrence risk of 16%, which could be low risk, intermediate risk, or high risk when confidence intervals of the category mean estimates are considered. To help guide interpretation, Genomic Health has established RS category ranges for low (<30), intermediate (30–40) and high (≥41) risk categories.
Insurance companies also point out that the validation study lacks information on how the test adds to current methods of predicting risk, and on how extensively and accurately patients are reclassified by RS. Relevant issues concern quality of classification by current predictors and comparisons to known recurrence outcomes.
Other researchers investigated whether four well-documented gene expression risk scores could improve patient stratification compared the TNM staging system from the American Joint Committee on Cancer.
Microarray-based versions of risk scores were applied to an independent cohort of 688 Stage II/III tumors from the Pan-European Trials in Alimentary Tract Cancers trial, a Phase III randomized trial that yielded pathologic samples evaluable for immunohistochemistry and molecular testing from 1,404 patients with Stage II/III cancer. Prognostic value assessments were made for relapse-free survival (RFS), survival after relapse (SAR), and overall survival (OS).
All four risk scores showed a statistically significant association (single test, P < .0167) with OS or RFS in univariate models, but with hazard ratios below 1.38 per interquartile range. Three scores were predictors of shorter RFS, one of shorter SAR. Each risk score could, the authors said, only “marginally improve” an RFS or OS model with the known factor’s T stage, N stage, and microsatellite instability status. A combination of the risk scores, they said, might provide more robust information, but they added that RFS and SAR predictors might need to be different.
Identification of patients with Stage II and III colon cancer who will benefit from adjuvant treatment remains a major clinical challenge. Many patients treated with surgery alone experiences relapse; some patients receiving chemotherapy would be cured with surgery alone.
The use of GEP testing in conjunction with clinicopathological parameters has clear potential for improved treatment decisions based on risk assessment, but physicians have concluded that their clinical implementation awaits prospective validation.