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MMR Deficiency Screening is Under-utilised in Young Adult Patients with Colorectal Cancer

Non-adherence to guidelines recommendations for MMR deficiency testing for all patients with colorectal cancer younger than age 50 due to an increased incidence of Lynch syndrome and MSI-H tumours
11 Dec 2017
Cancer in Adolescents and Young Adults (AYA)
Gastrointestinal Cancers

Despite established guidelines that advocate testing for mismatch repair (MMR) deficiency in colorectal cancer, less than a third of adult patients with colorectal cancer received this screening. Furthermore, less than half of younger adult patients under the age of 50 who are at higher risk of Lynch syndrome and of having microsatellite instability-high (MSI-H) tumours underwent MMR deficiency testing. 

This non-adherence to MMR deficiency testing was reported in a recent article in the Journal of the American Medical Association (JAMA) Oncology by lead author Dr. Talha Shaikh of the Department of Radiation Oncology, Fox Chase Cancer Center, in Philadelphia, Pennsylvania. 

MMR deficiency stems from germline mutations in genes coding for proteins involved in DNA MMR, including MLH1, MSH2, MSH6, and PMS2, or from somatic epigenetic silencing of MLH1. These alterations have the end result of unrepaired repetitive, altered DNA sequences, which increase the risk of many cancers but are most commonly associated with colorectal cancer. 

Importantly, MMR deficiency of DNA has been observed in up to 15% of sporadic colorectal cancers and is a characteristic feature of Lynch syndrome, which has a higher incidence in younger adults, aged less than 50 years with colorectal cancer. 

The analysis aimed to identify patients receiving MMR deficiency testing and to determine risk factors for non-adherence 

Dr. Shaikh and colleagues assessed patient socio-demographic factors, the treatment facility, the tumour type, and treatment characteristics in adult patients aged <30 to 70 years and in a subset of younger adult patients aged <18 to 49 years who were diagnosed with invasive colorectal adenocarcinoma from 16 March 2016 to 1 March, 2017. The investigators used the National Cancer Database to identify patients, determine their age, confirm the diagnosis of colorectal cancer, and to find out whether the patients underwent MMR deficiency testing. 

Using multivariable logistic regression, they identified the patient characteristics that emerged as independent predictors of MMR deficiency testing in the patients and determined the risk factors for non-adherence to the universal testing guidelines. 

The primary outcome of this analysis was the receipt of MMR deficiency testing in the overall population of patients with colorectal cancer and in the cohort of patients aged younger than 50 years. 

Receipt of MMR deficiency testing is increasing but in majority of cases non-adherence to guideline recommendations has been reported 

The study included 152 993 adults with colorectal cancer; of these, 78579 (51.4%) patients were men and the mean (standard deviation) age was 66.9 (13.9) years. 

In the overall population of adult patients with colorectal cancer, just 43143 (28.2%) underwent MMR deficiency testing. However, a higher proportion of patients received MMR deficiency testing in more recent years, with the proportion of patients tested increasing from 22.3% in 2010 to 33.1% by 2012 (p < 0.001). 

Although adherence to testing guidelines was improved in the cohort of 17218 younger adult patients with colorectal cancer, only 7422 (43.1%) patients aged less than 50 years underwent MMR deficiency testing, with the proportion of patients being tested increasing from 36.1% in 2010 to 48% in 2012 (p < 0.001). 

Patient age was not a factor in the proportion of patients that received MMR deficiency testing. Factors that independently associated with receipt of MMR deficiency testing included having a higher educational level (odds ratio [OR] 1.38; 95% confidence interval [CI] 1.15, 1.66), being diagnosed in a later year (OR 1.81; 95% CI 1.65, 1.98), having early stage disease (OR 1.24; 95% CI 1.18,1.30), and the number of regional lymph nodes examined (OR 1.44; 95% CI 1.34,1.55). 

Factors that were associated with the underuse of MMR deficiency testing and guideline non-adherence included older age (OR 0.31; 95%CI 0.26, 0.37) and receiving government funded healthcare, such as Medicare (OR 0.89; 95%CI 0.84, 0.95), or Medicaid (OR 0.83; 95%CI 0.73, 0.93), or being uninsured (OR 0.78; 95%CI 0.66, 0.92).  Treatment or tumour-related factors that associated with underutilization of testing included being treated in a non-academic as compared to an academic or research facility (OR 0.44; 95%CI 0.34, 0.56), having a tumour with rectosigmoid or rectal location (OR, 0.76; 95%CI 0.68, 0.86), having a tumour of unknown grade (OR 0.61; 95%CI 0.53, 0.69), and not receiving definitive surgery for the tumour (OR 0.33; 95%CI 0.30, 0.37). 

MMR deficiency testing identifies patients that may respond to specific treatments 

MMR deficiency results in unrepaired repetitive DNA sequences, which increases the risk of multiple malignant tumours, thus affecting disease prognosis. MMR deficiency may also affect the response to systemic therapy. 

Identification of patients with MSI-High or Low tumours may alter the treatment choices. While patients with MSI-H tumours generally have a better prognosis compared to patients with MSI-L or stable tumours, it has been reported that they may not benefit from standard single-agent, fluorouracil-based adjuvant chemotherapy. 

However, findings from recent studies suggest that immunotherapeutic agents targeting the programmed death-1 (PD-1) pathway may deliver a profound benefit in patients with MMR deficient tumours. 

FDA approval of pembrolizumab in patients with colorectal cancer and MMR-deficient tumours 

In May 2017, the United States Food and Drug Administration granted an accelerated approval to pembrolizumab for the treatment of adult and paediatric patients with unresectable or metastatic, MSI-H or MMR deficient solid tumours who progressed after prior treatment and who had no satisfactory alternative treatment options. This approval was also extended to include patients having colorectal cancer and MSI-H or MMR deficient tumours who progressed on a regimen of fluoropyrimidine, oxaliplatin, and irinotecan. 


The authors underscored the importance of enhancing awareness and knowledge of Lynch syndrome among patients with colorectal cancer and health care professionals. They called for more referrals for genetic testing, and increased adherence to both MMR deficiency testing guidelines and cancer screening recommendations.

 They also pointed out that, since several trials of pembrolizumab in the adjuvant setting are planned or ongoing, MMR deficiency testing is likely to play an increasingly important role in the care of patients with colorectal cancer.


This work was supported by NIH grant P30CA006927.  


Shaikh T, Handorf EA, Meyer JE, et al. Mismatch Repair Deficiency Testing in Patients With Colorectal Cancer and Nonadherence to Testing Guidelines in Young Adults. JAMA Oncology; Published online 9 November 2017. doi:10.1001/jamaoncol.2017.3580

Last update: 11 Dec 2017

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