Nick Mulcahy

January 23, 2013

A new diagnostic classification system categorizes colorectal cancers into 3 "completely different subtypes" on the basis of tumor gene-expression patterns, according to a  researcher who helped develop the tool.

The tumor subtypes are associated with different prognoses and responses to adjuvant chemotherapy, said study coauthor Josep Tabernero, MD, director of clinical research at Vall d'Hebron Institute of Oncology in Barcelona, Spain.

He spoke at a presscast in advance of the  American Society of Clinical Oncology (ASCO) 2013 Gastrointestinal Cancers Symposium, being held January 24 to 26 in San Francisco, California.

"Although several treatments exist, we do not have a good way to select treatments for individual patients," Dr. Tabernero told reporters. Only KRAS status has been established as a predictor of response to anti-EGFR therapy, he explained.

For colorectal cancer, a broad molecular classification is "still missing," the authors note in their study abstract.

This is in contrast to breast cancer, for which "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," they write.

The hope for the colorectal cancer classification system is that it will eventually aid in treatment decisions, including those related to chemotherapy and targeted therapies, according to ASCO press materials.

In their study, Dr. Tabernero and his fellow European researchers used gene-expression data from 188 patients with stage I to IV colorectal cancer to develop their molecular subtype classification system.

They found 3 major intrinsic subtypes of colorectal cancer (A, B, and C).

The classification system was subsequently validated in tumor samples from 543 patients with stage II or III disease. Of those, 21.5% were subtype A, 62.0% were subtype B, and 16.5% were subtype C.

The heterogeneity of the subtypes is "largely based" on 3 biologic hallmarks of the tumors, the authors report: an epithelial-to-mesenchymal transition; a deficiency in mismatch repair genes that results in a high frequency of mutation associated with microsatellite instability; and cellular proliferation. These features are known to independently affect outcomes in patients with cancer, they state.

Ten-year follow-up data show that patients with subtype C tumors have the worst outcome, a mesenchymal gene-expression phenotype, and receive no benefit from adjuvant chemotherapy treatment with fluorouracil (5-FU).

Patients with subtype A or B tumors have a better clinical outcome, a more proliferative and epithelial phenotype, and benefit from adjuvant 5-FU chemotherapy.

Subtype B tumors have a low overall kinome mutation frequency (1.6%), whereas subtype A and C tumors have a higher mutation frequency (4.2% and 6.2%, respectively), "in agreement with their mismatch repair deficiency," the authors report.

Compared with subtype B tumors, subtype A and C tumors have higher rates of gene alterations, including genes that play a role in the development and growth of colorectal cancer, such as KRAS, BRAF, and PI3KCA, according to ASCO press materials.

"These subtypes are potentially clinically relevant, as they differ in their underlying biology and clinical outcome and, consequently, require different treatment strategies," the authors write in their abstract.

As a next step, the researchers are validating the system in patients with stage IV disease.

This study reflects the direction that diagnostic medicine is headed, said Neal J. Meropol, MD, who moderated the presscast. "Tumors that all look the the level of their molecular make-up may actually fit into several different categories," said Dr. Meropol, who is chief of the division of hematology and oncology at the Case Western Reserve University School of Medicine in Cleveland, Ohio.

The study was funded by Agendia. Dr. Tabernero reports receiving research funding from Agendia. Some of his coauthors are employees of Agendia. Dr. Meropol reports being a consultant for Precision Therapeutics

2013 Gastrointestinal Cancers Symposium (GICS): Abstract 333. To be presented January 26, 2013.