Mismatch Repair Deficiency an Ideal Marker to Initiate Precision Care in CRC

Research from The University of Texas MD Anderson Cancer Center has tried to fill the knowledge gaps that exist in the treatment of colorectal cancers (CRCs) that harbor mutations in genes involved in DNA mismatch repair (dMMR). The authors establish that dMMR rectal cancer (which makes up about 15% of CRCs) has excellent prognosis and pathologic response with the current multimodality treatment options.

Despite progress across the entire spectrum of cancers, CRC remains a hard one to treat—the third most common cancer in the United States, irrespective of gender (excluding skin cancers), CRC is the second leading cause of cancer-related deaths in the population. Nearly 50,000 deaths due to CRC have been projected for 2016.

However, things have been improving, especially with studies that have tried to uncover the genomic basis of this disease. Speaking at the National Comprehensive Cancer Network’s 21st Annual Conference, Alan P. Venook, MD, from the University of California, San Francisco, said that complexity with CRC treatment guidelines arises from patient subsets. “The challenge is to identify patients that belong in these subsets as early as possible, so their treatment path can be clearly delineated early on.”

For their current paper in the Journal of Clinical Oncology, researchers conducted a retrospective analysis of data from 62 patients with dMMR rectal cancer who were treated over a 20-year period between 1992 and 2012. Genetic make-up of the tumors, the treatment that patients received, and the subsequent clinical outcomes were all included in the analysis.

Most common mutations were observed in the MSH2 (53%) and MSH6 (23%) genes. With a median follow-up of 6.8 years, the 5-year rectal cancer—specific survival was marked at 100% for stage I and II patients, 85.1% for stage III patients, and 60% for stage IV patients. Neoadjuvant chemoradiation, which was fluoropyrimidine-based, yielded a complete pathologic response of 27.6%.

“Our paper provides a perfect illustration of how the power of precision medicine can be realized,” said Y. Nancy You, MD, associate professor of Surgical Oncology at MD Anderson, in a statement. “This new genetic understanding of dMMR provides immediate implications for telling patients how well they will do long term and for choosing the best surgical and chemotherapy options.” The now known hereditary nature of the MSH2 and MSH6 mutations offer the option for early surveillance in individuals who have a family history of CRC.

“If we know a patient carries this mutation, then we can enroll them in our Familial High-Risk GI Cancer Clinic, where we follow them and their at-risk family members and conduct cancer surveillance tests to detect pre-cancerous lesions and remove them as early as we can,” You added.

Reference

de Rosa N, Rodriguez-Bigas MA, Chang GJ, et al. DNA mismatch repair deficiency in rectal cancer: benchmarking its impact on prognosis, neoadjuvant response prediction, and clinical cancer genetics [published online July 18, 2016]. J Clin Oncol. doi:10.1200/JCO.2016.66.6826.