Performance characteristics of screening strategies to identify Lynch syndrome in women with ovarian cancer - PubMed

Performance characteristics of screening strategies to identify Lynch syndrome in women with ovarian cancer - PubMed

Performance characteristics of screening strategies to identify Lynch syndrome in women with ovarian cancer

Soyoun Rachel Kim 1 2, Alicia Tone 1, Raymond H Kim 3 4 5, Matthew Cesari 6, Blaise A Clarke 6, Lua Eiriksson 7, Tae Hart 4 8, Melyssa Aronson 4, Spring Holter 4, Alice Lytwyn 9, Manjula Maganti 10, Leslie Oldfield 11, Steven Gallinger 12, Marcus Q Bernardini 1 2, Amit M Oza 5, Bojana Djordjevic 6, Jordan Lerner-Ellis 6, Emily Van de Laar 1, Danielle Vicus 2 13, Trevor J Pugh 11 14 15, Aaron Pollett 6 16, Sarah E Ferguson 1 2 4

Affiliations 

• PMID: 32809219
 
• DOI: 10.1002/cncr.33144

Abstract

Background: For women with ovarian cancer (OC), the optimal screening strategy to identify Lynch syndrome (LS) has not been determined. In the current study, the authors compared the performance characteristics of various strategies combining mismatch repair (MMR) immunohistochemistry (IHC), microsatellite instability testing (MSI), and family history for the detection of LS.

Methods: Women with nonserous and/or nonmucinous ovarian cancer were recruited prospectively from 3 cancer centers in Ontario, Canada. All underwent germline testing for LS and completed a family history assessment. Tumors were assessed using MMR IHC and MSI. The sensitivity, specificity, and positive and negative predictive values of screening strategies were compared with the gold standard of a germline result.

Results: Of 215 women, germline data were available for 189 (88%); 13 women (7%) had pathogenic germline variants with 7 women with mutS homolog 6 (MSH6); 3 women with mutL homolog 1 (MLH1); 2 women with PMS1 homolog 2, mismatch repair system component (PMS2); and 1 woman with mutS homolog 2 (MSH2). A total of 28 women had MMR-deficient tumors (13%); of these, 11 had pathogenic variants (39%). Sequential IHC (with MLH1 promoter methylation analysis on MLH1-deficient tumors) followed by MSI for nonmethylated and/or MMR-intact patients was the most sensitive (92.3%; 95% confidence interval, 64%-99.8%) and specific (97.7%; 95% confidence interval, 94.2%-99.4%) approach, missing 1 case of LS. IHC with MLH1 promoter methylation analysis missed 2 patients of LS. Family history was found to have the lowest sensitivity at 55%.

Conclusions: Sequential IHC (with MLH1 promoter methylation analysis) followed by MSI was found to be most sensitive. However, IHC with MLH1 promoter methylation analysis also performed well and is likely more cost-effective and efficient in the clinical setting. The pretest probability of LS is high in patients with MMR deficiency and warrants universal screening for LS.

Keywords: Lynch syndrome; ovarian cancer; screening; tumor testing.

© 2020 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.

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