Molecular Pathology Laboratory Network

Colorectal cancer (CRC), a combination of colon and rectal cancers, is the second leading cause of cancer-related death for men and women in the United States. To raise awareness about this disease, March is recognized as Colorectal Cancer Awareness Month.

For patients diagnosed with CRC there are several new and novel molecular and cellular diagnostic assays offered by MPLN to assist clinicians with patient management decisions, including treatment selection and clinical course monitoring.

Studies show that the KRAS gene is mutated in approximately 35 to 45% of colorectal carcinomas and that the determination of KRAS mutation status in CRC patients can better define those who will benefit from treatment with anti-EGFR monoclonal antibody therapies such as Erbitux® (cetuximab) and Vectibix® (panitumumab). 

In 2010, the National Comprehensive Cancer Network (NCCN) updated practice guidelines for colon and rectal cancer to include testing for the BRAF mutation, which occurs in approximately 10-15% of CRC cases. The guidelines recommend that patients with metastatic colorectal disease have BRAF gene status determined when the KRAS gene is not mutated. BRAF mutation analysis also supports the exclusion of a diagnosis of hereditary non-polyposis colon cancer (HNPCC) in colorectal carcinomas that exhibit microsatellite instability (MSI) or loss of MLH1 protein expression.

MSI is commonly detected in approximately 90% of patients with HNPCC and 15% of sporadic CRC. Targeted MSI testing can be performed utilizing immunohistochemistry (IHC) for the expression of MLH1, MSH2, MSH6 and PMS2. A subset of HNPCC patients and some CRC patients are predisposed to cancer caused by germline mutations in the DNA mismatch repair (MMR) genes, and identification of these inherited MMR mutations can enable familial predictive testing. For instance, individuals with mutations in one of the MMR genes are defined as having Lynch Syndrome, a genetic condition that greatly increases risk of colon cancer. It is generally recommended that these patients undergo pre-screening with MSI analysis by IHC.

For patients with metastatic carcinoma of the colon or rectum (primary or recurring) or EGFR positive metastatic disease, The Invader® UGT1A1 Molecular Assay (Hologic®) can be performed to identify patients who may be at risk for therapy related toxicity if treated with irinotecan (Camptosar^TM). The assay detects molecular (DNA) variations in the UGT1A1 gene that influences a patient's ability to effectively metabolize the drug.

To monitor treatment effectiveness for individual patients on chemotherapy, the CellSearch^TM Circulating Tumor Cell Test (Veridex, LLC) is available. CellSearch identifies and counts circulating tumor cells (CTCs) in a blood sample.  In metastatic colorectal cancer, a CTC count of three or more per 7.5 mL of blood at any time during clinical course monitoring is associated with a poor prognosis and is predictive of shorter progression-free survival and overall survival.

It is recommended that physicians order a CellSearch test before initiating a new therapy, again at the patient's first follow-up visit, and thereafter at monthly intervals and in conjunction with computed tomography (CT scans). If CTC levels are elevated from baseline to routine follow-up visits, a physician may choose to evaluate the appropriateness of alternative treatments.

Health management of patients with CRC may require an integrated approach to minimize treatment cost and maximize treatment efficacy. For more information about the advanced laboratory tests available at MPLN, contact a service specialist at 800-932-2943.