Identification of Three Molecular Subtypes of Colorectal Tumors Might Improve Treatment Planning

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(ChemotherapyAdvisor) – A new molecular diagnostic classification system for colorectal cancers based on patterns of tumor gene expression might help identify patients who are likely to benefit from adjuvant chemotherapy, according to study findings presented at the 10th annual Gastrointestinal Cancers Symposium being held January 24-26 in San Francisco, CA.

“Unbiased genome-wide analyses of gene expression patterns have been successfully used for the molecular classification of breast cancer into subtypes that have clear relevance for prognosis and development of treatment plans” reported study co-author Josep Tabernero, MD, Vall d'Hebron University Hospital, Barcelona, Spain.

But for colorectal cancers, such a molecular classification system has been missing—until now.

“We have developed a diagnostic single sample predictor that allows the classification of colorectal tumors of different intrinsic molecular types,” Dr. Tabernero reported. “These subtypes are potentially clinically relevant, as they differ in their underlying biology and clinical outcomes, and consequently require different treatment strategies.”

The study of tumor gene expression from 188 patients with stage I-IV colorectal cancers identified three molecular subtypes of colorectal tumor: Type A (mismatch repair-deficient epithelial); B (proliferative epithelial); and C (mismatch repair-deficient mesenchymal), and which represent 35%, 50%, and 15% of patients, respectively.

“The heterogeneity of the intrinsic subtypes is largely based on three biological hallmarks of the tumor: an epithelial-to-mesenchymal transition, deficiency in mismatch repair genes that result in a high mutation frequency associated with MSI, and cellular proliferation,” Dr. Tabernero explained.

BRAF mutations were present in 39% of Type A, 2% of Type B, and 16% of Type C tumors, Dr. Tabernero noted.

“C-type patients have the worst outcome, a mesenchymal gene expression phenotype, and show no benefit from adjuvant chemotherapy treatment,” he reported. “Patients having A-type or B-type tumors have a better clinical outcome, a more proliferative and epithelial phenotype, and benefit from adjuvant chemotherapy. B-type tumors showed low overall kinome mutation frequency (1.6%) while both A-type and C-type patients harbor a higher mutation frequency (4.2 and 6.2%), in agreement with their mismatch repair deficiency.”

The study “really highlights where the field of oncology is going both in terms of research and practice; tumors that look the same under the microscope may actually, in terms of molecular makeup, fit into several different categories,” commented Neal Meropol, MD, Division Chief of Hematology and Oncology at Case Western Reserve University in Cleveland, OH.

“We're starting to use these molecular profiles of what genes are turned on and off to make treatment decisions about what drugs to use,” Dr. Meropol said.

The 2013 Gastrointestinal Cancers Symposium is co-sponsored by the American Gastroenterological Association (AGA) Institute, the American Society of Clinical Oncology (ASCO), the American Society for Radiation Oncology (ASTRO) and the Society of Surgical Oncology (SSO).

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