Determination of test performance of two contemporary screening tests for Lynch syndrome in endometrial cancer: A clinical trial.

Published data on the performance of the immunohistochemistry (IHC) test for mismatch repair (MMR) protein expression to detect Lynch syndrome (LS) index cases suggests it is highly variable; its performance in our system was unknown. Moreover, a brief family history questionnaire (bFHQ) developed by Eiriksson and colleagues in Canada demonstrated 100% sensitivity for LS case identification thus was of interest to us, but its performance outside of its original setting was unknown. Determination of the performance of these tests requires complete LS case identification in the testing population. Two hundred women were recruited during routine care for endometrial cancer (EC) to administer the bFHQ and perform genetic testing for the LS genes. Independently, the IHC test was performed to screen for presumptive LS cases. We determined the sensitivity, specificity, and positive and negative predictive values of the bFHQ and IHC test as well as simulating outcomes of the complete protocols. Genetic testing all participants identified 8 cases of LS out of 200 (4% prevalence), the bFHQ identified 5 of 8 of these cases (62.5%, CI: 31.5%-87.6%), and the IHC test identified 6 or 7 of 8 cases (mean of 75% or 87.5%) depending on interpretation of test results. The specificities of the bFHQ and IHC test were 56.8% (CI: 49.8%-63.7%) and 79.8% (CI: 73.6%-85.1%), respectively. This study is the first, to our knowledge, to test the effectiveness of the bFHQ in an EC population since its original reporting; our results are consistent with many reports of the challenges of collecting family health history. The performance of the IHC test as a screen falls within ranges reported in the literature but do not provide the confidence to drive a decision for or against continued use of this test as a LS screen.

Gudgeon JM ，Wallentine JC ，Bonham EM ，McLaughlin HD ，Dodson MK ... -  《-》

Performance characteristics of a brief Family History Questionnaire to screen for Lynch syndrome in women with newly diagnosed endometrial cancer.

The brief Family History Questionnaire (bFHQ) was developed to identify endometrial cancer patients whose family histories suggest Lynch syndrome (LS). We compared the bFHQ, extended Family History Questionnaire (eFHQ) and dictated medical records (DMRs) to determine which family history screening strategy is superior in identifying LS in unselected women with newly diagnosed endometrial cancer that have undergone universal germline testing. Prospective cohort study recruited women with newly diagnosed endometrial cancer to evaluate screening strategies to identify LS. Participants completed bFHQ and eFHQ, had tumor assessed with immunohistochemistry (IHC) for mismatch repair proteins (MMR) and micro-satellite instability testing and underwent universal germline testing for LS. The sensitivity, specificity, positive and negative predictive values (PPV, NPV) were compared between the family history screening strategies as well as IHC. 118 of 182 eligible patients (65%) consented; 87 patients (74%) were evaluable with both family history and germline mutation status. Median age was 61years (range 26-91). All 7 patients with confirmed LS were correctly identified by bFHQ, compared to 5 and 4 by eFHQ and DMR, respectively. The sensitivity, specificity, PPV and NPV values of bFHQ were 100%, 76.5%, 25.9% and 100%, respectively, performing similar to IHC testing. While eFHQ was more specific than bFHQ (86.7% vs. 76.5%, P=0.007), 2 cases of LS were missed. The patient-administered bFHQ effectively identified women with confirmed LS and is a good screening tool to triage women with endometrial cancer for further genetic assessment.

Eiriksson L ，Aronson M ，Clarke B ，Mojtahedi G ，Massey C ，Oza AM ，Gallinger S ，Pollett A ，Mackay H ，Bernardini MQ ，Ferguson SE ... -  《-》

Performance characteristics of screening strategies for Lynch syndrome in unselected women with newly diagnosed endometrial cancer who have undergone universal germline mutation testing.

Immunohistochemistry (IHC) for mismatch repair protein expression, microsatellite instability (MSI) testing, tumor morphology, and family history were compared to determine which screening strategy is superior in identifying Lynch syndrome (LS) in unselected women with newly diagnosed endometrial cancer (EC) who have undergone universal germline mutation testing. A prospective cohort study was performed that recruited women with newly diagnosed EC. Participants completed a family history assessment with molecular characterization of EC with IHC and MSI testing and EC assessment for LS-associated morphologic features and underwent universal germline mutation testing for mutations in the mismatch repair pathway. The sensitivity, specificity, and positive and negative predictive values were compared between the screening strategies. A total of 118 (65%) of 182 consecutive women with EC participated. Of these, 34 women (29%) had tumors that were IHC deficient and 27 women (23%; N = 117) had tumors that were positive for MSI. Twenty women (17%) met IHC criteria and 16 women (15.2%, N = 105) met family history criteria based on Ontario Ministry of Health Criteria for the genetic assessment for LS. Seven women (5.9%) had a germline mutation: 4 had MLH1 (mutL homolog 1), 2 had MSH6 (mutS homolog 6), and 1 had MSH2 (mutS homolog 2). IHC in women aged <60 years had the best performance characteristics, with a sensitivity of 100%, a specificity of 86.1%, a positive predictive value of 58.3%, and a negative predictive value of 100%. Family history and tumor morphology both had the lowest sensitivity at 71.4%. Overall tumor morphology had the poorest performance, with a specificity of 42.1%. The mutation rate of 5.9% was higher than expected in this unselected cohort of women with EC. The superior screening strategy to identify women presenting with EC is universal IHC screening in women aged <60 years.

Ferguson SE ，Aronson M ，Pollett A ，Eiriksson LR ，Oza AM ，Gallinger S ，Lerner-Ellis J ，Alvandi Z ，Bernardini MQ ，MacKay HJ ，Mojtahedi G ，Tone AA ，Massey C ，Clarke BA ... -  《-》

The proportion of endometrial tumours associated with Lynch syndrome (PETALS): A prospective cross-sectional study.

Ryan NAJ ，McMahon R ，Tobi S ，Snowsill T ，Esquibel S ，Wallace AJ ，Bunstone S ，Bowers N ，Mosneag IE ，Kitson SJ ，O'Flynn H ，Ramchander NC ，Sivalingam VN ，Frayling IM ，Bolton J ，McVey RJ ，Evans DG ，Crosbie EJ ... -  《-》

Comparison of screening strategies for Lynch syndrome in patients with newly diagnosed endometrial cancer: a prospective cohort study in China.

Chao X ，Li L ，Wu M ，Ma S ，Tan X ，Zhong S ，Bi Y ，Lang J ... -  《Cancer Communications》