At this juncture, various commercially available assays for colon cancer may be of little added value, and accelerated biomarker development with clinical validation is desperately needed.
Colon cancer is a common disease that has been the subject of decades of clinical research, yet it is a cancer that appears to be stubborn in its paucity of predictive biomarkers. Commercially available molecular diagnostic assays are ubiquitous and applied to colon cancer patients in the clinical setting with remarkable frequency, often in the absence of supporting data. As clinicians, we are routinely engaged in complicated and lengthy discussions with patients regarding the role of biomarkers, although usually it is to explain why these elegant tests are not helpful and should be ignored.
In their article in this issue of ONCOLOGY, Mettu et al provide a meticulous and comprehensive review of candidate molecular markers that we would aspire to use in managing colon cancer patients. Just the length of the article should raise eyebrows, though, considering that most of these biomarkers are currently not relevant to clinical practice. This reflects the fact that the market for predictive biomarkers in colon cancer has transcended our capacity to provide rigorous technical and clinical validation. Similarly, biomarker discovery has been out of sync with companion drug discovery. As a result, promises of clinical benefits remain unfulfilled, leaving us to grapple with the premature implementation of these assays in the clinical setting. As we enter into an era of clinical practice that will likely be defined by molecular profiling technologies, we face associated challenges of how to assimilate these technological advances into clinical practice.
Microsatellite instability (MSI) status, nodal sampling for accurate staging, molecular markers, and genetic signatures are all topics of ongoing investigation to inform the question of which stage II patients benefit from adjuvant therapy. Development of novel diagnostic methods such as guanylyl cyclase C to identify tumor cells in lymph nodes may improve prognostication in patients who, according to current standards, are falsely diagnosed with pN0 disease; however, this technique still requires validation in a clinical trial. Loss of heterozygosity at 18q has been implicated as having prognostic value in the setting of colorectal cancer, but this has been called into question by the heterogeneity of allelic loss within a colorectal tumor. As the result of a negative phase III trial that randomized 2,070 KRAS wild-type patients with stage III colon cancer to receive modified FOLFOX6 (mFOLFOX6; leucovorin/fluorouracil [5-FU]/oxaliplatin) with or without cetuximab, it was determined that KRAS status does not impact therapeutic management in the adjuvant setting.
As discussed by Mettu et al, two genetic signatures derived from microarray-based gene expression profiles have been validated and are commercially available: the Oncotype DX Colon Cancer Assay and ColoPrint. Although each test was developed with unique methods for selection of component genes, neither predicts for benefit from adjuvant therapy. The Oncotype DX Colon Cancer Assay can be performed on paraffin slides and has been previously validated as a prognostic index in three cohorts of patients with stage II or III disease.[7-9] Market research has shown that results of testing with the Oncotype DX Colon Cancer Assay may impact treatment recommendations for stage II colon cancer patients approximately 30% of the time; however, the assay’s relatively narrow range of recurrence scores and the absence of predictive value have undermined its incorporation into National Comprehensive Cancer Network (NCCN) guidelines and standard practice. At the time of this publication, use of ColoPrint is still limited by a requirement for fresh tissue. These and other gene signatures in development require further refinement and validation as tools for predicting which stage II patients derive benefit from adjuvant chemotherapy. Intratumor heterogeneity presents a major challenge to assay development and may foreshadow that results based upon single tumor biopsy samples will never be applicable for individualization of care.
Experts might disagree as to whether the data are sufficient to support use of multigene assays to inform clinical decisions regarding selection of adjuvant therapy. However, the same criticism applies to the traditional features that are used to designate high risk of recurrence in stage II disease (eg, advanced tumor stage, tumor perforation, lymphovascular invasion, post-surgical analysis of fewer than 12 nodes, and poorly differentiated histology). These tumor features are similarly prognostic but not predictive.[12,13] Moreover, tumor grade and lymphovascular invasion are poorly reproducible and have not been substantiated as prognostic factors in some studies. In fact, the Oncotype DX recurrence score provides independent value beyond tumor stage, lymphovascular invasion, number of nodes examined, and tumor grade. The magnitude of the value is modest at best, but it is reasonable to consider the use of this recurrence score on a case-by-case basis for patients with normal-risk stage II colon cancer in which all other factors are equal.
In the current climate of increasing molecular testing capabilities, clinicians are urged to approach commercially available biomarker tests with a healthy level of scrutiny of their clinical application and validation. At this juncture, various commercially available assays may be of little added value, and accelerated biomarker development with clinical validation is desperately needed.
Financial Disclosure:Dr. Van Loon has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article. Dr. Venook has received research funding from Genomic Health, Inc.
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