Colorectal Cancer Prognosis and Response to Chemotherapy Vary by Molecular Subtype

Josep Tabernero, MD

Using a new classification system that categorizes colorectal cancers (CRC) by tumor gene expression patterns, researchers have determined that tumor prognosis and response to adjuvant chemotherapy in CRC vary according to molecular subtype. The research was presented at a press conference prior to the 10th annual Gastrointestinal Cancers Symposium.

Researchers developed the molecular classification system based on gene expression data from 188 patients with CRC, and then validated the system in tumor samples from 543 patients with stage II and III disease. Subtypes were analyzed for correlation to clinical information, mutations in the kinome (protein kinases in the genome), known molecular marker status, and chemotherapy response.

The analysis found that CRC consists of at least three major intrinsic subtypes, A, B, and C, based on three biological hallmarks of the tumor: epithelial-to-mesenchymal transition (a biologic change associated with more aggressive tumors), deficiency in mismatch repair genes (a tumor characteristic that leads to high rates of genetic alterations), and the rate of cell proliferation. These features are known to independently affect outcomes in patients with cancer.

Of the samples analyzed, 21.5% belonged to subtype A, 62% to subtype B, and 16.5% to subtype C.

A 10-year follow-up found that patients with subtype C had the worst outcomes, showed no benefit from adjuvant chemotherapy, and had a mesenchymal gene expression phenotype. Patients with subtypes A and B had better outcomes, benefited from adjuvant chemotherapy, and had a more proliferative and epithelial phenotype.

In addition, compared with subtype B, subtypes A and C had higher rates of mutation frequency in many genes, including those that play an important role in CRC development and growth, such as KRAS, BRAF, and PI3KCA.

The classification system could be used to determine disease prognosis and individualized treatment plans. For instance, in stage II disease, clinical and pathological factors do not always accurately identify patients who face a high risk of relapse after surgery and might therefore benefit from additional therapy. Furthermore, currently available genomic classifiers such as Oncotype and ColoPrint are not linked to clear recommendations for postoperative chemotherapy. Finally, in patients with later-stage disease who have undergone treatment, currently available tests cannot help individualize therapy—the researchers’ goal in developing the classification system.

“There’s no way to select treatment for individual patients. Currently, only KRAS has been established as a predictor of anti-EGFR treatment activity,” said study co-author Josep Tabernero, MD, at the press conference. Tabernero is director of Clinical Research at Vall d’Hebron Institute of Oncology in Barcelona, Spain.

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“This study clearly shows that there are different subtypes in colorectal cancer with completely different biological and clinical characteristics,” Tabernero said. “We hope that with continued research, we’ll be able to develop new molecular tests based on this classification system, not only to identify patients needing more aggressive adjuvant treatment, but also to help us to predict which patients will respond to specific chemotherapy drugs and targeted agents, regardless of cancer stage.”

Researchers are currently validating the classification system in stage IV CRC. “I predict that in the next 2 or 3 years we and other research teams will have several gene expression signatures developed, informed by ours and other studies,” Tabernero said.

Simon I, Roepman P, Schlicker A, et al. Association of colorectal cancer intrinsic subtypes with prognosis, chemotherapy response, deficient mismatch repair, and epithelial to mesenchymal transition (EMT). Presented at the 10th annual Gastrointestinal Cancers Symposium; January 24-26, 2013; San Francisco, CA. Abstract 333.

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