An international research team has developed a new diagnostic classification system that categorises colorectal cancers into subtypes based on tumour gene expression patterns.

The investigators found that these tumour subtypes are associated with different prognoses and responses to adjuvant chemotherapy.

“This study clearly shows that there are different subtypes in colorectal cancer with completely different biological and clinical characteristics,” said study co-author Josep Tabernero, director of clinical research at Vall d’Hebron Institute of Oncology in Barcelona, Spain.

“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 help us to predict which patients will respond to specific chemotherapy drugs and targeted agents, regardless of cancer stage.”

It’s not always clear which patients would benefit from additional therapy to prevent relapse after surgery, especially in stage II, because the clinical and pathological poor-prognosis factors do not always identify the patients that will relapse.

The availability of recent genomic classifiers, like Oncotype® or ColoPrint®, can improve the identification of high-risk patients with stage II disease who have a higher risk for relapse and eventually could benefit from such additional treatment, but clear recommendations for administration of postoperative chemotherapy in this stage are still lacking.

Additionally, these tests are not useful in patients with later-stage disease who have already undergone treatment, nor can they help determine which therapy might be best for the individual patient– which is part of the researchers’ ultimate goal with the new classification system.

In this study, investigators developed a molecular subtype classification system using gene expression data from188 patients with colorectal cancer.

The classification system was subsequently validated in tumour samples from 543 stage II and III patients and it was determined that 21.5% of samples belonged to subtype A, 62% to subtype B, and 16.5% to subtype C.

The three subtypes differed in three biological hallmarks of the tumour – epithelial-tomesenchymal 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.

A 10-year patient follow-up revealed that patients with subytpe C had the worst outcome and showed no benefit from adjuvant chemotherapy. Patients with subtypes A and B had better outcomes and they benefited from adjuvant chemotherapy.

Subtype C tumors had signatures that reflect mesenchymal tissue characteristics, whereas subtypes A and B have gene signatures consistent with epithelial tissue characteristics. The study also found that, compared to subtype B, subtypes A and C had higher rates of alterations in many genes including those that play an important role in colorectal cancer development and growth, such as KRAS, BRAF, and PI3KCA.

Researchers are currently validating this molecular subtype classification system in stage IV colorectal cancer. “I predict that in the next two or three years we and other research teams will have several gene expression signatures developed, informed by ours and other studies planned,” said Tabernero.

Source: ASCO