American Gastroenterological Association Institute and College of American Pathologists Quality Measure Development for Detection of Mismatch Repair Deficiency and Lynch Syndrome Management

Abstract

This document presents the official recommendations of the American Gastroenterological Association (AGA) and the College of American Pathologists (CAP) regarding quality measures and quality payment measures related to the diagnosis and management of Lynch syndrome (LS).1Rubenstein J.H. Enns R. Heidelbaugh J. et al.American Gastroenterological Association Institute guideline on the diagnosis and management of Lynch syndrome.Gastroenterology. 2015; 149: 777-782Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar The current report outlines the process by which the Quality Committee (QC) evaluates guidance statements published by the AGA’s Clinical Guidelines Committee (CGC) and the CAP’s Pathology and Laboratory Quality Center for Evidence-Based Guidelines to inform quality measure development, including for submission in a quality payment program (QPP) such as the Centers for Medicare & Medicaid Services (CMS) Merit-Based Incentive Payment System.2Bocsi G.T. Kang J. Kennedy A. et al.Developing pathology measures for the Quality Payment Program—Part I: a quest for meaningful measures.Arch Pathol Lab Med. 2020; 144: 686-696Crossref PubMed Scopus (2) Google Scholar The following recommendations were developed by the QC in consultation with the CGC as well as the CAP Measure and Performance Assessment Subcommittee through a measure harmonization process. Their development was funded by the AGA Institute with no additional outside funding. As the most common hereditary colorectal cancer (CRC) syndrome, LS accounts for up to 3%–5% of all CRCs and also raises the risk of numerous other malignancies such as gastric, small intestinal, pancreaticobiliary, endometrial, ovarian, genitourinary (kidney, renal pelvis, ureter, bladder, and prostate), and brain cancers, as well as sebaceous neoplasms of the skin.3Yurgelun M.B. Hampel H. Recent advances in Lynch syndrome: diagnosis, treatment, and cancer prevention.Am Soc Clin Oncol Educ Book. 2018; 38: 101-109Crossref PubMed Scopus (35) Google Scholar,4Duraturo F. Liccardo R. De Rosa M. et al.Genetics, diagnosis and treatment of Lynch syndrome: old lessons and current challenges.Oncol Lett. 2019; 17: 3048-3054PubMed Google Scholar The current prevalence of LS is estimated at 1 in 279.5Win A.K. Jenkins M.A. Dowty J.G. et al.Prevalence and penetrance of major genes and polygenes for colorectal cancer.Cancer Epidemiol Biomarkers Prev. 2017; 26: 404-412Crossref PubMed Scopus (180) Google Scholar Identification of individuals with LS is important because of their own elevated risk of CRCs and extracolonic cancers as well as to identify relatives with an increased risk of earlier-onset cancer compared to the general population. Adherence to regular colonoscopy guidelines for LS has been shown to reduce mortality from CRC.6Järvinen H.J. Aarnio M. Mustonen H. et al.Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer.Gastroenterology. 2000; 118: 829-834Abstract Full Text Full Text PDF PubMed Scopus (1083) Google Scholar Furthermore, a diagnosis of LS can affect surgical and chemotherapeutic management decisions. Indeed, histologic and laboratory screening for LS, through immunohistochemistry (IHC), polymerase chain reaction (PCR), or next-generation sequencing can be accomplished by reflexively testing all resected colon adenocarcinomas and pretreated rectal adenocarcinomas for mismatch repair (MMR) deficiency via universal testing. This approach, when combined with somatic germline testing panels to confirm a diagnosis, has been found to be cost-effective.7Ladabaum U. Wang G. Terdiman J. et al.Strategies to identify the Lynch syndrome among patients with colorectal cancer: a cost-effectiveness analysis.Ann Intern Med. 2011; 155: 69-79Crossref PubMed Scopus (276) Google Scholar Finally, tumor screening for LS in the context of noncolorectal malignancies also leads to improved detection with the associated benefit of long-term risk stratification.8Latham A. Srinivasan P. Kemel Y. et al.Microsatellite instability is associated with the presence of Lynch syndrome pan-cancer.J Clin Oncol. 2019; 37: 286-295Crossref PubMed Scopus (207) Google Scholar,9Adar T. Rodgers L.H. Shannon K.M. et al.Universal screening of both endometrial and colon cancers increases the detection of Lynch syndrome.Cancer. 2018; 124: 3145-3153Crossref PubMed Scopus (50) Google Scholar A universal testing approach has been endorsed by a number of professional organizations, including the AGA, National Comprehensive Cancer Network, US Multi-Society Task Force on Colorectal Cancer, and others.10Giardiello F.M. Allen J.I. Axilbund J.E. et al.Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on colorectal cancer.Gastroenterology. 2014; 147: 502-526Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar, 11Bruegl A.S. Ring K.L. Daniels M. et al.Clinical challenges associated with universal screening for Lynch syndrome-associated endometrial cancer.Cancer Prev Res (Phila). 2017; 10: 108-115Crossref PubMed Scopus (33) Google Scholar, 12Salvador M.U. Truelson M.R.F. Mason C. et al.Comprehensive paired tumor/germline testing for Lynch syndrome: bringing resolution to the diagnostic process.J Clin Oncol. 2019; 37: 647-657Crossref PubMed Scopus (20) Google Scholar Acknowledging these best practices, the current commentary focuses on the creation, and opportunities for implementation, of a measure to track the performance of universal testing for LS. The resulting quality measure is distinct from, but based on, guideline recommendations. This accountability measure provides clinicians across specialties, such as gastroenterology and pathology, as well as health systems an opportunity to monitor and report their performance within this important clinical context. It also provides the basis for quality improvement. Moreover, the development process used and described herein creates a framework for future collaborative measure development across disciplines. The AGA published its guidance documents to assist in the diagnosis and management of LS in 2015, and CAP published recommendations for the use of molecular biomarkers for the evaluation of CRC in 2017.1Rubenstein J.H. Enns R. Heidelbaugh J. et al.American Gastroenterological Association Institute guideline on the diagnosis and management of Lynch syndrome.Gastroenterology. 2015; 149: 777-782Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar,13Sepulveda A.R. Hamilton S.R. Allegra C.J. et al.Molecular biomarkers for the evaluation of colorectal cancer: guideline from the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology.Arch Pathol Lab Med. 2017; 141: 625-657Crossref PubMed Scopus (40) Google Scholar The aggregate recommendation statements from these documents were evaluated for development as potential quality measures. A standardized process first implemented by the AGA in 2016 and outlined elsewhere was used for measure development.14Adams M.A. Allen J.I. Saini S.D. Translating best practices to meaningful quality measures: from measure conceptualization to implementation.Clin Gastroenterol Hepatol. 2019; 17: 805-808Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar,15Leiman D.A. Maratt J.K. Ketwaroo G.A. et al.AGA Institute quality measure development for the diagnosis and management of COVID-19.Gastroenterology. 2020; 160: 985-992Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar The AGA’s quality measures for acute pancreatitis were developed using the same process.16Mosko J.D. Leiman D.A. Ketwaroo G.A. et al.Development of quality measures for acute pancreatitis: a model for hospital-based measures in gastroenterology.Clin Gastroenterol Hepatol. 2020; 18: 272-275Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Optimal understanding of this measure evaluation process will be enhanced by reading the applicable portions of the topic guideline. Briefly, the AGA QC follows a guidelines-to-measures protocol that is based on best practices outlined by the American Thoracic Society.17Kahn J.M. Gould M.K. Krishnan J.A. et al.An official American Thoracic Society workshop report: developing performance measures from clinical practice guidelines.Ann Am Thorac Soc. 2014; 11: S186-S195Crossref PubMed Scopus (28) Google Scholar Guideline recommendation statements are evaluated as potential measure concepts along several axes, including the strength of the recommendation and quality of the evidence, as specified using Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Only those statements with strong recommendations based on high- or moderate-quality evidence are considered for further measure development, which includes an assessment of their potential utility for practicing gastroenterologists. This level of rigor in development is vital, especially when a recent analysis of a sample of 271 measures within a QPP rated 30 as “not valid,” of which 19 were judged to be insufficiently supported by evidence.18MacLean C.H. Kerr E.A. Qaseem A. Time out—charting a path for improving performance measurement.N Engl J Med. 2018; 378: 1757-1761Crossref PubMed Scopus (81) Google Scholar The assessment also involves QC subcommittee analysis of measure importance, including rating topics on their meaningfulness, potential magnitude of effect, quality gaps, feasibility, and applicability to gastroenterologists. High-priority measure concepts subsequently undergo review and voting by the entire QC ahead of a 30-day public comment period before testing and formal adoption. Finally, measures that receive 60% or more of the full QC vote are recommended for national implementation. By adhering to these standards, trust in the validity and confidence in the utility of quality measures is increased, which is particularly important to reduce the lingering sense that quality measurement is rote rather than intimately aligned with clinicians’ professional duty. The initial LS quality measure was developed in 2017 and stated the following: “testing of all patients with colorectal adenocarcinoma diagnosed by colonoscopy for potential cases of Lynch Syndrome using immunohistochemistry (IHC) or microsatellite instability (MSI) by polymerase chain reaction (PCR).” This was then subject to public comment in 2018. Several themes arose from this feedback, which included questions related to primary measure ownership (“Would caution that any quality measures need to be under the control of the gastroenterologist” and “This is likely a marker more reflective of the quality of a hospital’s surgical pathology department or their oncologist rather than their GI [gastrointestinal]”), measure scope (“Many institutions prefer to do MMR testing on surgically resected CRC specimens so colonoscopic biopsies are not routinely tested” and “Recommend that the metric include testing of biopsy and noncolonic tissue (ie, metastatic tissue) in addition to resected colon tumors”), specificity to identify the appropriate patient population (“Concerned that the CPT [Current Procedural Terminology] codes for IHC will not capture the data you want—these codes are generic, and would include people who have IHC for BRAF, KRAS, etc” and “Differentiate the MMR IHC from other IHCs that may be performed by pathology”), methodology used for testing (“Recommend that the metric include tumor sequencing as a modality for assessment of deficient mismatch repair status” and “Consider measure satisfied if patient has germline genetic testing”), and responsibility of clinical follow-up (“Recommend that the metric explicitly state that follow-up of abnormal universal tumor test results is critical to ensure proper diagnosis of Lynch syndrome” and “Identifying patients at risk for Lynch syndrome is the first step, but that needs to be communicated to the patient and follow-up steps (such as germline testing) should be recommended”). Concurrently, the CAP was developing a related quality measure for Lynch testing applicable to pathologists, which read as follows: “the percentage of all primary or metastatic colorectal carcinoma surgical pathology reports that address the status of biomarker evaluation for mismatch repair (MMR) by immunohistochemistry (biomarkers MLH1, MSH2, MSH6, and PMS2), or microsatellite instability (MSI) by DNA-based testing status, or both.” Based on the opportunity to resolve the issues outlined during the public comment feedback, the AGA and CAP undertook a process of measure harmonization.19Guidance for measure harmonization: a consensus report. National Quality Forum, Washington, DC2010Google Scholar The AGA has previously used the harmonization process to develop quality measures for age-appropriate screening colonoscopy, which are co-owned with the American Society of Gastrointestinal Endoscopists and American College of Gastroenterology. Measure harmonization may improve quality measurement and tracking20Anema A. Fielden S.J. Castleman T. et al.Food security in the context of HIV: towards harmonized definitions and indicators.AIDS Behav. 2014; 18: S476-S489Crossref PubMed Scopus (23) Google Scholar and is appropriate when separate measures are intended to address the same focus (eg, LS screening testing) or target population (eg, patients with CRC).19Guidance for measure harmonization: a consensus report. National Quality Forum, Washington, DC2010Google Scholar The current harmonization process for an LS screening measure began in 2019 and was completed in 2020. The resulting measure and collaborative development addressed the previous concerns outlined during the initial feedback. Namely, there was an invested partner who would co-own and steward the measure (CAP), which included screening on either biopsy or surgical resection specimens; patients were identified by pathology specimen and diagnostic test (not via claims codes); the testing methodology was not prespecified; and the intent of the measure and responsibility of follow-up were more clearly defined to account for “communicating the information for care coordination” in a pathology report. In anticipation of forthcoming CAP guideline recommendations that encompass screening for LS and its implications for guiding checkpoint inhibitor therapy and in consultation with CMS, the scope of the measure was expanded to include extracolonic tumors as well, which is reflected in the measure workflow detailed in Figure 1. The resulting measure subsequently underwent additional alpha, or feasibility, testing. During this process, gastroenterology, pathology, and genetic counseling practices were invited to provide comments via a scorecard regarding the practicality of extracting the necessary information for measure reporting from their existing clinical workflow or data. This encompasses an assessment of whether the data elements needed to report on a measure are regularly collected and how such data are structured to facilitate reporting. A total of 29 practices (14 GI, 4 pathology, 7 genetic counseling, and 4 multispecialty medical center representatives) reported. The average feasibility, as measured by data availability, was 72.9% among gastroenterologists, genetic counselors, and multispecialty medical centers compared to 70.3% for pathologists. These results indicated practices have an average 72.6% overall chance of having the data elements already available in their electronic health record before starting to report on this measure. Identifying individuals with LS is paramount to provide appropriate guidance for cancer screening and surveillance intervals, both for patients and their relatives. An approach using universal screening of tumor specimens is evidence based and supported by multiple society guidelines, including those of the AGA. Recognizing the broad impact of testing for LS beyond CRC and the shared accountability in performing, interpreting, and reporting these results is particularly important for generating a meaningful LS quality measure. Within this context, the QC recommended and developed a harmonized inclusive quality measure with the CAP. This measure expanded the initial recommendation for universal tumor testing of CRCs, based on the strong recommendation and moderate quality of evidence, to include non-CRCs as well. Additional recommendation statements from the AGA Guideline on the Diagnosis and Management of LS were independently evaluated, and an assessment was made, as outlined in Table 1.Table 1Summary of Recommendations and Rationale for Quality Measure Development: Guideline on the Diagnosis and Management of Lynch SyndromeStatementGRADEDecisionRationaleIn patients without a personal history of colorectal or another cancer but with a family history suggestive of Lynch syndrome, the AGA suggests that risk prediction models be offered rather than doing nothing.Conditional recommendation, very low quality of evidenceNo measure concept to developInsufficient quality of evidence and strength of recommendationIn patients without a personal history of colorectal or another cancer but with a family history suggestive of Lynch syndrome, the AGA suggests that risk prediction models be offered rather than proceeding directly with germline genetic testing.Conditional recommendation, very low quality of evidenceNo measure concept to developInsufficient quality of evidence and strength of recommendationThe AGA recommends testing the tumors of all patients with colorectal cancer with either IHC or for microsatellite instability to identify potential cases of Lynch syndrome vs doing no testing for Lynch syndrome.Strong recommendation, moderate quality of evidenceMeasure concept approved for developmentStrength of recommendation and quality of evidence support measure development. Existing quality gaps are recognized. Collaborative and inclusive design widens the impact of the measure.The AGA suggests that in patients with colorectal cancer with IHC absent for MLH1, second-stage tumor testing for a BRAF mutation or for hypermethylation of the MLH1 promoter should be performed rather than proceeding directly to germline genetic testing.Conditional recommendation, very low quality of evidenceNo measure concept to developInsufficient quality of evidence and strength of recommendationThe AGA recommends surveillance colonoscopy (vs doing nothing) in persons with Lynch syndrome.Strong recommendation, moderate quality of evidenceNo measure concept to developLack of demonstrated or suspected quality gapThe AGA suggests that surveillance colonoscopy should be performed every 1 to 2 years vs at less frequent intervals in persons with Lynch syndrome.Conditional recommendation, low quality of evidenceNo measure concept to developInsufficient strength of recommendation and certainty of evidenceThe AGA suggests that aspirin be offered for cancer prevention in patients with Lynch syndrome.Conditional recommendation, low quality of evidenceNo measure concept to developInsufficient strength of recommendation and certainty of evidence Open table in a new tab The most frequently identified limitation for further quality measure concept development was related to insufficient quality of the available evidence and, relatedly, the strength of recommendations. For example, for recommendations regarding the use of risk prediction models to identify patients with LS, the recommendations were weak and based on very low quality of evidence. In other cases, the interval for surveillance colonoscopy and offering of aspirin as a chemopreventive agent were conditional recommendations based on a low quality of evidence. Finally, the recommendation to perform surveillance colonoscopy in persons with LS vs doing nothing, despite a strong recommendation and moderate quality of evidence, was lacking a demonstrated quality gap. Indeed, it is unlikely that clinicians would recommend no CRC surveillance for patients with LS, and the resulting minimal gap would be insufficient for inclusion in future reporting programs. Given the burden of LS as a proportion of CRCs as well as the value of identifying and performing surveillance on affected patients, universal screening of tumors followed by confirmation testing is a widely accepted and cost-effective practice. However, it is not broadly used.21Beamer L.C. Grant M.L. Espenschied C.R. et al.Reflex immunohistochemistry and microsatellite instability testing of colorectal tumors for Lynch syndrome among US cancer programs and follow-up of abnormal results.J Clin Oncol. 2012; 30: 1058-1063Crossref PubMed Scopus (165) Google Scholar,22Hissong E. Crowe E.P. Yantiss R.K. et al.Assessing colorectal cancer mismatch repair status in the modern era: a survey of current practices and re-evaluation of the role of microsatellite instability testing.Mod Pathol. 2018; 31: 1756-1766Crossref PubMed Scopus (19) Google Scholar Studies have shown that preoperative testing of specimens to help guide therapy may be as low as 17%, and among adults with CRC in a national database, only 28% had MMR testing performed.23Karlitz J.J. Hsieh M.C. Liu Y. et al.Population-based Lynch syndrome screening by microsatellite instability in patients ≤50: prevalence, testing determinants, and result availability prior to colon surgery.Am J Gastroenterol. 2015; 110: 948-955Crossref PubMed Scopus (36) Google Scholar,24Shaikh T. Handorf E.A. Meyer J.E. et al.Mismatch repair deficiency testing in patients with colorectal cancer and nonadherence to testing guidelines in young adults.JAMA Oncol. 2018; 4e173580Crossref PubMed Scopus (46) Google Scholar In the context of this demonstrable benefit but observed gap in care, the current quality measure is poised to be useful in tracking health care delivery over time. Importantly, collecting data necessary to report on the developed measure is feasible based on testing conducted during measure development. Although it is expected—and desired—that improvement will occur, the apparent gap helps ensure that the measure will be meaningful going forward. Furthermore, this measure would provide a pathway for reporting on the proportion of patients with CRC who undergo screening for LS at the time of their diagnosis, which is an aim for the US Department of Health and Human Service’s Healthy People 2030 goals, which set data-driven national objectives to improve health and well-being over the next decade. Moreover, the cross-cutting nature of the measure and applicability to multiple clinician types provides additional rationale for development and use. Implicit in the measure is the shared accountability that all members of the health care team have in delivering high-quality care. The harmonization of Lynch testing measures with the CAP is an important collaboration that provides a pathway toward more inclusive measures in the future, which is an opportunity to increase relevance to subspecialists. Previous studies25Noll A. Parekh P.J. Zhou M. et al.Barriers to Lynch syndrome testing and preoperative result availability in early-onset colorectal cancer: a national physician survey study.Clin Transl Gastroenterol. 2018; 9: e185Crossref PubMed Scopus (20) Google Scholar and feedback received during the public comment period suggested that a gastroenterology-only measure would not address the opinion that tumor screening for LS was a responsibility shared by multiple providers. The current measure resolves this tension. In addition, although specialty practices have identified quality reporting through government programs such as the Merit-Based Incentive Payment System as costly and less relevant to their performance than to primary care providers,26Khullar D. Bond A.M. Qian Y. et al.Physician practice leaders’ perceptions of Medicare’s Merit-Based Incentive Payment System (MIPS).J Gen Intern Med. 2021; 36: 3752-3758Crossref PubMed Scopus (2) Google Scholar the inclusion of additional specialty-specific measures may combat this perception. The AGA’s CGC has provided guidance regarding the diagnosis and treatment of patients with LS. Although several recommendations were not proposed for quality measure development, it is acknowledged that with future guideline updates, new data may strengthen the recommendation or increase the quality of evidence on which a best practice statement is generated, and the QC will re-evaluate these recommendations for measure development. The current measure for universal testing, meanwhile, was submitted to CMS for inclusion in the QPP. Preliminary feedback from CMS was favorable; current indications are that the measure will be included in the list of measures under consideration later this year. Regardless of the outcome of this submission, we believe the measure will remain relevant and should be tracked for quality improvement purposes across health systems and could serve to reinforce interdisciplinary collaboration in an environment where balancing and sharing risk will be increasingly relevant. The CAP has existing infrastructure and data registries through which pathologists can report on measures, and future steps may include developing an architecture for gastroenterologists to document measure adherence. It is also acknowledged that tumor screening is a necessary, though not sufficient, first step. Systems are needed to follow up on testing results and perform germline confirmation as well as cascade testing among family members appropriately, which can occur less frequently among some populations.27Muller C. Lee S.M. Barge W. et al.Low referral rate for genetic testing in racially and ethnically diverse patients despite universal colorectal cancer screening.Clin Gastroenterol Hepatol. 2018; 16: 1911-1918Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar However, the importance of including issues of equity and health systems improvement into quality measures are not challenges unique to LS and should be the focus of future improvements. In conclusion, the current best practices, guidelines, and recommendation statements from the AGA represent an important framework for the diagnosis and treatment of patients with LS. The quality of the evidence, strength of recommendations, and lack of known quality gaps currently preclude the development of some statements into quality measures at this time. The QC nonetheless encourages practitioners to adhere to these recommendations when appropriate and feasible and track their impact through active engagement in quality improvement. Overall, the harmonized universal testing quality measure now defined is an opportunity to quantify and improve the care of patients with LS and helps develop a framework for future collaborative measure development. We would like to particularly acknowledge the work of David Godzina and Drs Jennifer Maratt, Miriam Naveed, Ellen Stein, Chioma Anjou, and Won Kyoo Cho, who participated in generating and evaluating this measure while members of the American Gastroenterological Association Quality Committee. Within the College of American Pathologists, we would also like to acknowledge Colleen Skau and Drs Sarah Eakin, Jennifer Laudadio, Jason Kang, Leilani Valdes, and James Kelley as contributing members in the creation and submission of this measure while members of the CAP Measure and Performance Assessment Subcommittee.