DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Guiding Therapeutic Decisions for Patients Using microRNA Biomarkers

Posted March 24, 2016
Curtis Harris, M.D., Center for Cancer Research, National Cancer Institute

Curtis Harris, M.D. Lung and colon cancer are the leading causes of cancer-related deaths in the United States, and the American Cancer Society estimates there will be approximately 95,000 and 220,000 new cases of colon and lung cancer, respectively, in 2016. Current standards of care for these diseases have improved survival of some patients; however, there is still a great need for Precision Medicine, the term given to a more personalized method to guide therapeutic decisions. Patients with pre-metastatic lung or colon cancer can often be cured by surgery alone, but a significant portion of patients will have undetectable micrometastases that progress after surgery. Prognostic biomarkers are needed that can identify high-risk patients who would benefit from adjuvant treatments and minimize unnecessary harm in patients that can be cured by surgery alone.

Dr. Curtis Harris, of the National Cancer Institute's Center for Cancer Research, discovered that the presence of certain inflammatory gene biomarkers and microRNA expression patterns in a patient could predict cancer-specific mortality for lung and colon cancer. With a fiscal year 2010 Investigator-Initiated Research Award from the Peer Reviewed Medical Research Program, Dr. Harris has validated the association of increased miR-21 expression - a microRNA identified with a wide variety of cancers - with worse prognosis in both early stage colon cancer and early stage lung cancer. Additionally, Dr. Harris has developed and validated a prognostic, four-gene classifier of stage I lung cancer.

For the validation studies in lung cancer, Dr. Harris measured the expression of microRNA in primary lung tumors and noncancerous tissue samples from three patient cohorts. Results from these studies showed that high miR-21 expression was associated with poor survival in all three cohorts. Using global mRNA expression profiling, Dr. Harris discovered four genes (BRCA1, HIF1A, DLC1, and XPO1) associated with survival in stage I lung cancer. Further studies showed that this four-gene classifier could predict prognosis in 12 independent cohorts. Additional analysis led him to conclude that when the four-gene classifier is paired with the miR-21 expression data, prediction of lung cancer prognosis is superior to either method alone. The validation of the four-gene classifier will impact therapeutic decisions as it can aid in identifying high-risk, early stage lung adenocarcinoma and guide clinicians to a more aggressive treatment plan for those individuals.

Similarly, Dr. Harris conducted validation studies on miR-21 expression and its association with survival in colon cancer in primary colon tumors and paired noncancerous tissue. Results showed that higher than median miR-21 expression in tumors was associated with poor survival in two cohorts, indicating that patients with high miR-21 expression are at an increased risk for disease recurrence. The studies also examined the efficacy of adjuvant chemotherapy in low- and high-miR-21 expressing patients. The results show that while the adjuvant chemotherapy (5-fluorouracil) was not beneficial in patients with high miR-21 expression, it was beneficial in those with low miR-21 expression. This suggests that miR-21 expression can be used to identify patients who may benefit from adjuvant chemotherapy and provides insight that patients with miR-21-high colon cancer may require alternative or combination adjuvant treatments to 5-fluorouracil chemotherapy alone.

The results of Dr. Harris's validation studies support the development of clinical tests to guide treatment decisions. These results have the potential to refine the standard of care to a more precise approach and aid in reducing the burden of lung and colon cancer. Dr. Harris continues to work on validating new biomarkers and microRNA expression patterns in hopes of identifying further associations with prognosis of lung and colon cancer.

Publications:

Hiyoshi Y, Schetter AJ, Okayama H, et al. 2015. Increased microRNA-34b and -34c predominantly expressed in stromal tissues is associated with poor prognosis in human colon cancer. PLoS One 10(4):e0124899.

Obles AI, Arai E, Mathé EA, et al. 2015. An integrated prognostic classifier for stage I lung adenocarcinoma based on mRNA, microRNA, and DNA methylation biomarkers. J Thoracic Oncol 10(7):1037-1048.

Okayama H, Schetter AJ, Ishigame T, et al. 2014. The expression of four genes as a prognostic classifier for stage I lung adenocarcinoma in 12 independent cohorts. Cancer Epidemiol Biomarkers Prev 23(12):2884-2894.

Oue N, Anami K, Schetter AJ, et al. 2014. High miR-21 expression from FFPE tissues is associated with poor survival and response to adjuvant chemotherapy in colon cancer. Int J Cancer 134(8):1926-1934.

Akagi I, Okayama H, Schetter AJ, et al. 2013. Combination of protein coding and noncoding gene expression as a robust prognostic classifier in stage I lung adenocarcinoma. Cancer Res 73(13):3821-3832.

Saito M, Schetter AJ, Mollerup S, et al. 2011. The association of microRNA expression with prognosis and progression in early-stage, non-small cell lung adenocarcinoma; a retrospective analysis of three cohorts. Clin Cancer Res 17(7):1875-1882.

Links:

Public and Technical Abstracts: Validation of microRNA and Inflammatory Gene Biomarkers that Predict Prognosis and Therapeutic Outcome in Lung and Colon Adenocarcinoma

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Last updated Thursday, March 24, 2016