Screening for mismatch repair deficiency in colorectal cancer: data from three academic medical centers

Abstract

Reflex immunohistochemistry (rIHC) for mismatch repair (MMR) protein expression can be used as a screening tool to detect Lynch Syndrome (LS). Increasingly the mismatch repair‐deficient (dMMR) phenotype has therapeutic implications. We investigated the pattern and consequence of testing for dMMR in three Irish Cancer Centres (CCs). CRC databases were analyzed from January 2005–December 2013. CC1 performs IHC upon physician request, CC2 implemented rIHC in November 2008, and CC3 has been performing rIHC since 2004. The number of eligible patients referred to clinical genetic services (CGS), and the number of LS patients per center was determined. 3906 patients were included over a 9‐year period. dMMR CRCs were found in 32/153 (21%) of patients at CC1 and 55/536 (10%) at CC2, accounting for 3% and 5% of the CRC population, respectively. At CC3, 182/1737 patients (10%) had dMMR CRCs (P < 0.001). Additional testing for the BRAF V600E mutation, was performed in 49 patients at CC3 prior to CGS referral, of which 29 were positive and considered sporadic CRC. Referrals to CGS were made in 66%, 33%, and 30% of eligible patients at CC1, CC2, and CC3, respectively. LS accounted for CRC in eight patients (0.8%) at CC1, eight patients (0.7%) at CC2, and 20 patients (1.2%) at CC3. Cascade testing of patients with dMMR CRC was not completed in 56%. Universal screening increases the detection of dMMR tumors and LS kindreds. Successful implementation of this approach requires adequate resources for appropriate downstream management of these patients.

Next-Generation Service Delivery: A Scoping Review of Patient Outcomes Associated with Alternative Models of Genetic Counseling and Genetic Testing for Hereditary Cancer

“…In tumor-first GC models, genetic screening is first performed on a sample of tumor tissue, often as part of a pathology workflow, with GC offered based on the tumor results. A total of 26 publications from six countries that reviewed patient outcomes of tumor testing were identified ( Table 7 ) [ 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 ]. In total, 23 publications [ 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 ], including four abstracts [ 90 , ...…”

“…In a study assessing the role of ethnicity, Kupfer et al reported high rates of GC referral and GT in Caucasian patients [ 92 ]. A total of 14 studies reported the uptake of GC among patients who screened positive for Lynch syndrome [ 79 , 80 , 81 , 82 , 83 , 85 , 86 , 88 , 89 , 90 , 95 , 96 , 99 , 100 ]. The majority of patients who were referred for GC attended an appointment.…”

“…Additionally, patients receiving negative GT results may be less likely to attend post-test GC recommended based on family history [ 76 ]. Most studies assessing GC referral, GC attendance, and the uptake of germline GT after tumor testing to screen for Lynch syndrome reported high uptake of these services; however, low rates have also been reported [ 82 , 89 , 92 , 95 , 99 ]. The data from this review demonstrates that facilitation by a genetic counselor or navigator results in a higher uptake of GC and germline GT, suggesting that some central oversight may be required when implementing tumor-first GT models.…”

Evaluating the impact of universal Lynch syndrome screening in a publicly funded healthcare system

“…Other studies have shown that specialist referral is a challenge. 22,23 Increasing knowledge of LS by referring healthcare providers may help alleviate patient confusion and worry in the context of an initial positive LS screen. Further research could include reviewing the number of referrals per specialist group and ensuring that all specialists are aware of criteria for Lynch assessments.…”

Colorectal cancer in adolescents and young adults: Defining a growing threat

“…Universal screening of all incident CRC is increasingly being recommended using immunohistochemical staining for markers of DNA mismatch repair (MMR) deficiency. This strategy has been adopted widely in many jurisdictions and is recommended as an important element of the synoptic reporting for incident CRC . Increasingly, tumor sequencing has been utilized for patients with advanced or metastatic CRC, and appears to be an extremely sensitive method of detecting LS .…”