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Multi-mRNA Signature May Predict Chemo Sensitivity in Colorectal Cancer Patients

NEW YORK – Researchers at the Sun Yat-Sen University in China have identified a 15-messenger RNA signature to assess colorectal cancer patients' prognosis and response to adjuvant chemotherapy.

The researchers hope this signature, published Monday in Cancer Management and Research, may aid in the selection of early-stage colorectal cancer patients who are most likely to benefit from adjuvant chemotherapy following surgery.

To develop the signature, the researchers, led jointly by Jianxia Li and Jianwei Zhang, first analyzed microarray data from fresh frozen tissue samples from 32 patients with colorectal cancer. These patients had undergone surgery to remove stage III colorectal cancer, after which they received treatment with adjuvant chemotherapy (either FOLFOX6 or CapeOx).

Within this group, patients who experienced disease recurrence or metastasis at a 1.5-year follow-up were identified as "non-responders" to adjuvant chemo and patients who remained disease-free for at least three years were identified as "responders." The group contained 16 responders and 16 non-responders.

The researchers assessed the association between gene expression and patients' disease-free survival, relapse-free survival, or overall survival as assessed by univariate Cox regression analysis. They identified three unique pathways — CXCR chemokine receptor, negative regulation of anoikis (a type of programmed cell death), and regulation of synapse assembly — that played a role in either promotion or inhibition of cancer cells or in drug resistance. They then narrowed down the 15 genes involved in these key pathways and created a prognostic model using messenger RNA from these genes.

Within the signature, higher expression of six genes including SIX4, PIK3CA, ITGB1, ITGA5, DKK1, and CXCL5 were associated with shorter survival, and higher expression of nine genes including WANT5A, PTRH2, NLN3, LRTM1, EPHB3, EPHB2, CXCL2, CXCL1, and CBLN1 were associated with improved survival.

The researchers then went on to validate the signature in two microarray cohorts, which together included 332 patients — 293 with early-stage disease and 39 with metastatic cancer. Through this validation process, they determined that the predictive accuracy of this signature applied to both patients with early-stage and metastatic disease.

To assess the signature's ability to predict response to adjuvant chemotherapy, the researchers then considered data on nearly 700 patients across three cohorts where patients received such treatment. The researchers reported that overall survival after adjuvant chemotherapy was significantly longer for the group that the signature deemed low risk. In the high-risk group, on the other hand, the researchers found that the overall survival "was not remarkable" after adjuvant chemotherapy.

Following this, the researchers performed an additional analysis between the high- and low-risk groups in a cohort of 417 patients in whom there was information on age, sex, adjuvant chemotherapy, T stage, N stage, location of primary tumor, and mutation status of KRAS and BRAF genes as covariates. According to the authors, this additional analysis further validated that "the risk score of 15-mRNA remained as an independent prognostic factor for predicting overall survival."

Taken together, the study showed that patients who receive a low-risk score based on this signature are likely to have a favorable response to adjuvant chemo, while those with a high-risk score are likely not to derive much benefit from such treatment.  "These results indicated that the proposed classifier may be clinically applicable for the selection of CRC patients in the early stages to undergo adjuvant chemotherapy," the authors wrote. "Patients in the low-risk group are encouraged to undergo 5-Fu-based adjuvant chemotherapy to prolong overall survival, while patients in the high-risk group may require an enhanced chemotherapy regimen or other alternative chemotherapy regimens."

Going forward, the researchers noted that it will be important for the signature to be validated in prospective studies, and to home in on not only the biological behaviors of the pathways at play in their signature but also the "cross-talk" between these interconnected pathways.

"Future research should concentrate on the validation of our findings in planned clinical trials and present the role of these genes in biological behavior of tumors and drug resistance," they wrote.