Population-Based Universal Screening for Lynch Syndrome: Ready, Set… How?
Authors: Joanne Ngeow, Charis Eng
Journal: Journal of Clinical Oncology (2013)

Although the fields of health care and public health have many evidence-based innovations, the failure to implement health interventions that have been rigorously demonstrated to be cost effective hampers health care delivery. The identification of individuals who are at increased risk of hereditary cancer allows for the possibility of heightened surveillance and early cancer detection, resulting in decreased disease-specific mortality. Such data-driven identification and risk stratification to guide management is one of the foundations of value-based health care delivery. However, it is not always easy to identify those in the general population who may be at increased risk. As clinicians, we rely on our collective observations and clinical acumen to identify patients with observed clinical red flags that signal heritable cancers. However, clinical criteria may not be optimal, either because it is not sufficiently sensitive or because of a lack of clinical utility in a public health setting. Indeed, one of the most common hereditary cancer syndromes, Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer, has served as a platform for raging debate in recent years. It is in this context that the article that accompanies this editorial, by Ward et al, adds significant new insights to the ongoing discussion of population-based universal LS screening for all patients with colorectal cancer (CRC). As the third most common cancer in men and women, CRC is a significant public health problem. It accounts for approximately 50,000 deaths each year in the United States and is largely preventable with recommended population screening. It is estimated that approximately 3% of CRCs are attributable to LS. This autosomal dominant genetic disorder is associated with greatly increased risks of developing colorectal, endometrial, and other cancers. Despite the increased risk of cancers seen in patients with LS, these patients show no increase in cancer-related mortality when compared with mutation-negative family members undergoing long-term follow-up, in part as a result of high compliance with current surveillance. However, we already know that unless there is a strong clinical suspicion, many cases of LS are missed. Moreover, standard population-wide CRC screening guidelines fail to provide early detection or prevention for most LS colon cancers, given that they tend to occur at young ages. Therefore, there is a clear rationale for exploring universal LS screening protocols at the population level. Universal screening is feasible, given that the diagnosis of LS is primarily based on the presence of a germline mutation in a mismatch repair (MMR) gene, resulting in tumors that demonstrate MMR deficiency, defined as the presence of microsatellite instability (MSI) or loss of MMR protein expression (detected via immunohistochemistry [IHC]), which are the cellular hallmarks of this disorder. Ward et al explored a population-based approach by including all incident CRCs that were identified within their catchment area of 1.2 million residents in New South Wales, Australia. The study consisted of two phases. In the first phase, without obtaining patient consent, they identified all MMR-deficient cancers by IHC and assigned an a priori likelihood for LS as either low (both MLH1 loss and BRAF mutation) or high (all other cancers). Recommendations were sent to the treating surgeon suggesting that all patients with “high-likelihood cancers” undergo formal genetic risk assessment and testing; referral was not recommended for low-likelihood cases. In the second phase of the study, patient consent to participate was obtained along with blood or saliva samples for research testing. Consent for germline testing was received from 79% of participants; of the 143 consenting patients who provided samples for germline analysis, 12 (8%) were found to have germline mutations in MMR genes. Of the 102 patients who neither consented nor provided biologic samples for testing, 5% were estimated, by the authors, to carry germline mutations and were therefore missed. The authors should be congratulated for conducting a study that evaluates real-world limitations of population-based screening. This study demonstrates that population-based universal screening for LS in all incident CRCs is feasible and could detect a significant number of patients with germline MMR mutations among eligible incident CRC cases. Equally emphatically, the study underlines significant barriers to successful clinical implementation. Less than half (41 of 91; 45%) of the patients with a high a priori likelihood of LS elected to undergo germline testing. Thirteen percent of participants declined to receive test information despite being fully informed of the implications of the test. As highlighted by the authors, these findings have significant implications for centers and state public health departments considering such population-based screening. Opponents of implementation of universal LS screening have long contended that many patient-level and social implications of adopting testing of all newly diagnosed patients with CRC have not been adequately addressed. The current study does seem to lend support to the notion that significant numbers of patients perhaps might not wish to be informed of screening results. Population screening without previous patient knowledge and consent could meet with a similar rate of low follow-through to clinical implementation. It is unfortunate that the JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 20 JULY 1