Mismatch Repair Deficiency Testing in Patients With Colorectal Cancer and Nonadherence to Testing Guidelines in Young Adults

Shaikh, Talha; Handorf, Elizabeth A.; Meyer, Joshua E.; Hall, Michael J.; Esnaola, Nestor F.

doi:10.1001/jamaoncol.2017.3580

Cited by 69 publications

(49 citation statements)

References 38 publications

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“…Recent publications have highlighted MSI testing as relatively underused in the early stages of disease. In an analysis of 152,993 adults including 17,218 younger adult patients with CRC, only 28.2% and 43.1% underwent MMR testing, respectively (62). Older age, uninsured, recto-sigmoid, and nonsurgical cases were those associated with no receipt of testing.…”

Section: Discussionmentioning

confidence: 99%

Microsatellite Instability and Survival in Stage II Colorectal Cancer: A Systematic Review and Meta-analysis

et al. 2019

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Background/Aim: About 15-20% of colorectal cancers (CRCs) have deficiency in a mismatch repair (MMR) protein. MMR has a high level of microsatellite instability (MSI-H). We have conducted this review and meta-analysis to determine the prognostic role of MSI-H status in stage II CRC. Materials and Methods: We searched PubMed, EMBASE, The Cochrane Library, Web of Science, and SCOPUS for studies reporting data on overall survival (OS) and disease-free or relapse-free survival (DFS or RFS) for MSI-H compared to microsatellite stable (MSS) CRC. Results: A total of 39 studies were analysed, including 12,110 patients. MSI-H status was associated with a significantly reduced risk of death (HR=0.64, 95%CI=0.52-0.8, p<0.01) and relapse (HR=0.59, 95%CI=0.45-0.77, p<0.01) in stage II CRC. Conclusion: MSI-H represents an important prognostic determinant in stage II CRC and may be considered when estimating the risk of recurrence in stage II CRC. Stage II colorectal cancer (CRC) is usually associated with a good prognosis; five-year overall survival (OS) rates range from 75 to 87.5% (1). However, the administration of postoperative 5-fluorouracil (5-FU)-based chemotherapy in this group of patients remains controversial, since it has been shown that survival gain generally does not exceed 5% (2). Several prognostic factors have been evaluated in order to identify a high-risk stage II CRC subgroup, for which adjuvant chemotherapy would have a better indication. High-risk features include an inadequate sampling of lymph nodes (less than 12), extension of primary tumor (pT4), poor differentiation (grade 3), acute onset of the disease with obstruction or perforation, lymph-vascular and perineural invasion, and close, indeterminate or positive resection margins (3). Recently, microsatellite instability status (MSI) has been identified as a reliable prognostic indicator in stage II CRC, with an additional role in predicting the lack of benefit of 5-FU-based adjuvant chemotherapy (4-6). These data have been replicated in the large randomized phase III Quick and Simple and Reliable (QUASAR) trial, where 2,291 patients with stage II CRC were randomized to receive adjuvant chemotherapy with 5-FU and folinic acid or to undergo observation. An analysis performed on these patients found a prognostic role for MMR status, even if it was not shown to be predictive of any benefit from adjuvant chemotherapy (6). Although a number of molecular markers of outcome in CRC has been proposed (BRAF/KRAS), there has been no clear consensus about their role in early stage CRC. Despite that a series of studies have investigated the relationship between MSI status and survival in CRC patients, they often included mixed populations of early (stage II-III) and advanced CRCs (stages IV). The aim of our study was to evaluate the prognostic significance of MMR status in stage II CRC by analyzing all the available data coming from prospective and retrospective studies.

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Section: Discussionmentioning

confidence: 99%

Microsatellite Instability and Survival in Stage II Colorectal Cancer: A Systematic Review and Meta-analysis

et al. 2019

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“…The panel recognized several future opportunities for research that might help inform and optimize future recommendations. Although the goal of universal tumor screening is to identify individuals at risk for Lynch syndrome, implementation of this practice has been slow, and risk assessment and referral for hereditary CRC syndromes is not widely used [55][56][57][58] ; strategies to improve implementation are needed. It is also unclear whether all patients with a personal history of cancer should be offered multigene testing to screen for both Lynch syndrome and other potential hereditary causes.…”

Section: Conclusion and Future Considerationsmentioning

confidence: 99%

NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 2.2019

Gupta

Provenzale

Llor

et al. 2019

Journal of the National Comprehensive Cancer Network

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218

177

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Identifying individuals with hereditary syndromes allows for improved cancer surveillance, risk reduction, and optimized management. Establishing criteria for assessment allows for the identification of individuals who are carriers of pathogenic genetic variants. The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal provide recommendations for the assessment and management of patients with high-risk colorectal cancer syndromes. These NCCN Guidelines Insights focus on criteria for the evaluation of Lynch syndrome and considerations for use of multigene testing in the assessment of hereditary colorectal cancer syndromes.

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“…Both are also considered to be relatively cheap and cost‐effective for LS screening (Snowsill et al, ). However, the uptake of MMR deficiency testing has been poor; only 28% of 152,993 CRC cases were analyzed during 2010–2012 in the USA (Shaikh, Handorf, Meyer, Hall, & Esnaola, ), with a similar proportion being analyzed in the UK This is despite guidelines recommending testing and estimates that only 1.2% of LS gene carriers were known to clinical services in the US in 2011 (Hampel & de la Chapelle, ). We estimate that only 5% of carriers are currently known in the UK.…”

Section: Introductionmentioning

confidence: 99%

Sequencing‐based microsatellite instability testing using as few as six markers for high‐throughput clinical diagnostics

et al. 2019

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Microsatellite instability (MSI) testing of colorectal cancers (CRCs) is used to screen for Lynch syndrome (LS), a hereditary cancer‐predisposition, and can be used to predict response to immunotherapy. Here, we present a single‐molecule molecular inversion probe and sequencing‐based MSI assay and demonstrate its clinical validity according to existing guidelines. We amplified 24 microsatellites in multiplex and trained a classifier using 98 CRCs, which accommodates marker specific sensitivities to MSI. Sample classification achieved 100% concordance with the MSI Analysis System v1.2 (Promega) in three independent cohorts, totaling 220 CRCs. Backward–forward stepwise selection was used to identify a 6‐marker subset of equal accuracy to the 24‐marker panel. Assessment of assay detection limits showed that the 24‐marker panel is marginally more robust to sample variables than the 6‐marker subset, detecting as little as 3% high levels of MSI DNA in sample mixtures, and requiring a minimum of 10 template molecules to be sequenced per marker for >95% accuracy. BRAF c.1799 mutation analysis was also included to streamline LS testing, with all c.1799T>A variants being correctly identified. The assay, therefore, provides a cheap, robust, automatable, and scalable MSI test with internal quality controls, suitable for clinical cancer diagnostics.

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Mismatch Repair Deficiency Testing in Patients With Colorectal Cancer and Nonadherence to Testing Guidelines in Young Adults

Cited by 69 publications

References 38 publications

Microsatellite Instability and Survival in Stage II Colorectal Cancer: A Systematic Review and Meta-analysis

Microsatellite Instability and Survival in Stage II Colorectal Cancer: A Systematic Review and Meta-analysis

NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 2.2019

Sequencing‐based microsatellite instability testing using as few as six markers for high‐throughput clinical diagnostics

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