Circulating Colon Cancer DNA Mutations May Predict Metastases

Dr. Jeanne Tie Medical Oncologist | Royal Melbourne and Western Hospital Research Fellow Walter and Eliza Hall Institute of Medical Research Parkville, VICMedicalResearch.com Interview with:
Dr. Jeanne Tie
Medical Oncologist | Royal Melbourne and Western Hospital
Research Fellow
Walter and Eliza Hall Institute of Medical Research
Parkville, VIC

Medical Research: What is the background for this study?

Dr. Tie: The increasing number of active agents available to treat metastatic colorectal cancer has resulted in an ever-improving life expectancy in this group of patients. However, the ability to expose patients with metastatic colorectal cancer to all effective anti-cancer treatment, particularly 3rd line treatment and beyond, is increasingly challenging in routine practice as some patients’ condition deteriorate too rapidly and do not live long enough to enjoy the benefit of these additional therapies. This is partly due to the current imaged-based method of assessing treatment response with the Response Evaluation Criteria in Solid Tumors (RECIST), which is usually performed every 8-12 weeks during the course of treatment. This means that for non-responders to treatment, several weeks to months will elapse before a switch to alternative therapy will be made. Conceptually, if a patient’s response to treatment could be made earlier, such as with a blood test,  then an earlier switch to an alternative treatment can be made, minimizing the side-effects of the ineffective therapy and providing the opportunity for a more effective one. Currently, blood biomarkers add little to imaging-based assessment, with CEA lacking sensitivity and specificity.

Colorectal cancer is characterised by several recurrently mutated genes and advances in genomics and molecular technologies have now enabled rapid detection and quantification of these cancer-specific mutations in patient’s circulation (circulating tumor DNA – ctDNA). Previous studies have demonstrated that ctDNA can be detected in a high proportion of patients with advanced cancer. In this study, we describe the potential role of ctDNA as an early predictor of treatment response in patients with treatment naïve metastatic colorectal cancer (mCRC) undergoing chemotherapy and as a marker of disease bulk that could complement RECIST measurement.

Medical Research: What are the main findings?

Dr. Tie: Our study showed that ctDNA can be detected in a very high proportion (92%) of patients with untreated metastatic colorectal cancer and ctDNA levels correlated more strongly with tumor burden when compared to serum CEA.  Importantly, there is a significant drop in ctDNA levels as early as 2 weeks after starting chemotherapy (median 5.7-fold decrease in levels) whilst no significant change in CEA level was observed. This early drop in ctDNA appeared to correlate with treatment response as measured on CT scan 8-10 weeks later. A greater proportion of patients with a ≥10-fold drop in ctDNA levels 2 weeks after starting chemotherapy experienced treatment response compared to patients with <10-fold drop in ctDNA (74% vs 35%)

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Tie: Though the study results are encouraging, they need to be further validated in a larger cohort of patients. If serial ctDNA changes is proven to be a robust early marker of treatment response, this non-invasive biomarker should be incorporated into future clinical trials  to complement imaging-based method for assessment of treatment efficacy.

Citation:

Tie, I. Kinde, Y. Wang, H.L. Wong, J. Roebert, M. Christie, M. Tacey, R. Wong, M. Singh, C. S. Karapetis, J. Desai, B. Tran, R. Strausberg, L. A. Diaz, Jr, N. Papadopoulos,K.W. Kinzler, B. Vogelstein, and P. Gibbs

Circulating Tumor DNA as an Early Marker of Therapeutic Response in Patients with Metastatic Colorectal Cancer Ann Oncol first published online April 7, 2015 doi:10.1093/annonc/mdv177

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MedicalResearch.com Interview with: Dr. Jeanne Tie, Medical Oncologist | Royal Melbourne and Western Hospital, Research Fellow, Walter and Eliza Hall Institute of Medical Research, & Parkville, VIC (2015). Circulating Colon Cancer DNA Mutations May Predict Metastases MedicalResearch.com