Universal Tumor Screening For Lynch Syndrome Research Articles

EE513 Economic Evaluation of Universal Lynch Syndrome Screening Protocols Among Newly Diagnosed Patients with Endometrial Cancer

Between 2%-6% of endometrial cancer (EC) cases are attributable to Lynch syndrome (LS). Although universal tumor screening for LS among patients with EC is recommended by professional societies, implementation remains suboptimal. Our objective is to compare the relative performance, costs, and efficiency of different LS screening protocols among newly diagnosed EC patients from a U.S. healthcare system perspective.

Histology of colorectal adenocarcinoma with double somatic mismatch-repair mutations is indistinguishable from those caused by Lynch syndrome

Lynch syndrome (LS) is the most common form of hereditary colon cancer. Germline mutations in the mismatch-repair (MMR) genes MLH1, MSH2 (EPCAM), MSH6, and PMS2, followed by a second hit to the remaining allele, lead to cancer development. Universal tumor screening for LS is routinely performed on colon cancer, and screening has identified patients with unexplained MMR deficiency that lack MLH1 methylation and a germline mutation. Tumor sequencing has since identified double somatic (DS) mutations in the MMR gene corresponding with the absent protein in 69% of these patients. We assessed whether histomorphology could distinguish patients with DS mutations from those with LS. Colorectal cancer patients with DS mutations were identified from population-based cohorts from Iceland (2000-2009); Columbus, Ohio (1999-2005); and the state of Ohio (2013-2016). Next-generation sequencing was performed on tumors with unexplained MMR deficiency. Patients with LS from Ohio cohorts were the comparison group. The histologic features associated with MMR deficiency (tumor-infiltrating lymphocytes, Crohn-like reaction, histologic subtype, necrosis) were evaluated. We identified 43 tumors with DS mutations and 48 from patients with LS. There was no significant difference in histologic features between tumors in LS patients and tumors with DS mutations. Because histology of tumors with DS mutations is indistinguishable from those caused by LS, tumor sequencing for evaluation of DS mutations should be considered to help clarify sporadic versus hereditary causes of unexplained MMR deficiency.

Assessment of Tumor Sequencing as a Replacement for Lynch Syndrome Screening and Current Molecular Tests for Patients With Colorectal Cancer

Universal tumor screening for Lynch syndrome (LS) in colorectal cancer (CRC) is recommended and involves up to 6 sequential tests. Somatic gene testing is performed on stage IV CRCs for treatment determination. The diagnostic workup for patients with CRC could be simplified and improved using a single up-front tumor next-generation sequencing test if it has higher sensitivity and specificity than the current screening protocol. To determine whether up-front tumor sequencing (TS) could replace the current multiple sequential test approach for universal tumor screening for LS. Tumor DNA from 419 consecutive CRC cases undergoing standard universal tumor screening and germline genetic testing when indicated as part of the multicenter, population-based Ohio Colorectal Cancer Prevention Initiative from October 2015 through February 2016 (the prospective cohort) and 46 patients with CRC known to have LS due to a germline mutation in a mismatch repair gene from January 2013 through September 2015 (the validation cohort) underwent blinded TS. Sensitivity of TS compared with microsatellite instability (MSI) testing and immunohistochemical (IHC) staining for the detection of LS. In the 465 patients, mean age at diagnosis was 59.9 years (range, 20-96 years), and 241 (51.8%) were female. Tumor sequencing identified all 46 known LS cases from the validation cohort and an additional 12 LS cases from the 419-member prospective cohort. Testing with MSI or IHC, followed by BRAF p.V600E testing missed 5 and 6 cases of LS, respectively. Tumor sequencing alone had better sensitivity (100%; 95% CI, 93.8%-100%) than IHC plus BRAF (89.7%; 95% CI, 78.8%-96.1%; P = .04) and MSI plus BRAF (91.4%; 95% CI, 81.0%-97.1%; P = .07). Tumor sequencing had equal specificity (95.3%; 95% CI, 92.6%-97.2%) to IHC plus BRAF (94.6%; 95% CI, 91.9%-96.6%; P > .99) and MSI plus BRAF (94.8%; 95% CI, 92.2%-96.8%; P = .88). Tumor sequencing identified 284 cases with KRAS, NRAS, or BRAF mutations that could affect therapy for stage IV CRC, avoiding another test. Finally, TS identified 8 patients with germline DPYD mutations that confer toxicity to fluorouracil chemotherapy, which could also be useful for treatment selection. Up-front TS in CRC is simpler and has superior sensitivity to current multitest approaches to LS screening, while simultaneously providing critical information for treatment selection.

Abstract C06: Implementation of Universal Colorectal Cancer Screening for Lynch Syndrome: A Population-Based Study

Abstract Introduction: Colorectal cancer (CRC) is the leading cause of cancer death in Puerto Rico and the third one among US Hispanics. Up to 2-4% of colorectal cancer cases are caused by germline mutation in at least one of these four DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6, and PMS2. Mutations in these genes cause Lynch Syndrome (LS), the most common hereditary form of CRC. Immunohistochemistry (IHC) tests for the presence of MMR proteins and microsatellite instability (MSI) analysis is often performed on the tumor of CRC cases to screen for LS and as markers for prognosis. Universal screening of CRC for LS has been recommended by the National Comprehensive Cancer Network (NCCN) since 2014. Objective: The purpose of this study was to determine the prevalence of positive LS-screening test as determined by absence of MMR proteins in CRC since the implementation of universal tumor screening for LS in the largest private pathology laboratory in Puerto Rico. Methods: We collected the data from all CRC cases performed at Hato Rey Pathology Laboratories from September 2014 to December 2015. Pathologies performed where collected from 11 hospitals that cover the island of Puerto Rico. The data collected included results of IHC and MSI analysis as well as tumor location, gender, age, date reported and hospital. Results: A total of 317 CRC tumors were evaluated for LS-screening; with a mean age of 66 years, and 54.3% were males. IHC analysis was performed in 288 cases and of these, 11.1% demonstrated absence of one or more of the MMR proteins, compatible with a positive screening test for LS. There were 21 cases that had only MSI analysis performed and they were all reported as microsatellite stable. Conclusion: This is the first evaluation of a systematic program for Universal CRC screening for LS in Puerto Rico. Our data is consistent with results from other studies of US-Hispanics where approximately 10% of individuals of Hispanic origin with CRC have MSI. The observed prevalence of absence of MMR-proteins in our study supports universal screening of LS among Hispanics in accordance with NCCN guidelines. Citation Format: Isabel Sierra, Yaritza Diaz-Algorri, Valerie Maldonado, Kimberly Alicea, Kathia Rosado, Marcia Cruz-Correa. Implementation of Universal Colorectal Cancer Screening for Lynch Syndrome: A Population-Based Study. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr C06.

Stakeholder perspectives on implementing a universal Lynch syndrome screening program: a qualitative study of early barriers and facilitators.

BackgroundEvidence-based guidelines recommend that all newly diagnosed colon cancers be screened for Lynch syndrome (LS). Best practices for implementing universal tumor screening have not been extensively studied.PurposeWe interviewed a range of stakeholders in an integrated health care system to identify initial factors that might promote or hinder the successful implementation of a universal (LS) screening program.MethodsWe conducted interviews with health plan leaders, managers, and staff. Interviews were audio recorded and transcribed. Thematic analysis began with a grounded approach and was also guided by the Practical Robust Implementation and Sustainability Model (PRISM).ResultsWe completed 14 interviews with leaders/managers and staff representing involved clinical and health plan departments. While in general stakeholders supported the concept of universal screening, they identified several internal (organizational) and external (environment) factors that promote/hinder implementation. Facilitating factors included: 1) perceived benefits of screening for patients and organization; 2) collaboration between departments; and 3) availability of organizational resources. Barriers were also found, including: 1) lack of awareness of guidelines; 2) lack of guideline clarity; 3) staffing and program “ownership” concerns; and 4) cost uncertainties. Analysis also revealed nine important infrastructure-type considerations for successful implementation.ConclusionWe found that clinical, laboratory, and administrative departments supported universal tumor screening for LS. Requirements for successful implementation may include interdepartmental collaboration and communication; patient and provider/staff education; and significant infrastructure and resource support related to laboratory processing and systems for electronic ordering and tracking.

Colorectal Cancer Survivors' Interest in Genetic Testing for Hereditary Cancer: Implications for Universal Tumor Screening

Benefits of universal tumor screening for Lynch syndrome (LS), the most common form of hereditary colorectal cancer (CRC), will be realized only if patients are interested in genetic counseling and testing. This study explores interest in genetic testing for hereditary CRC among CRC patients who have never received genetic counseling or testing. Using results from a cross-sectional survey of CRC patients (n=91) at varying categories of risk for hereditary CRC, bivariate and multivariable analyses were conducted to compare positive and negative attitudinal beliefs regarding genetic testing, risk perceptions, demographics, and tumor stage of those who were interested in genetic testing (n=61) and those who were not interested or were not sure (n=30). Although significant at the bivariate level, gender, perceived relative risk of hereditary cancer, employment status, and belief that genetic testing would help in preparing for the future were not significantly related to interest in genetic testing when controlling for all other variables in a logistic regression model. The two factors that remained significant include a single-item question measuring the belief that genetic testing is warranted based on personal/family history and a positive attitudinal scale regarding the utility of genetic testing in medical decision making and cancer prevention. Results have potential implications for policies regarding universal tumor screening for LS.