Feasibility of two-antibody vs four-antibody mismatch repair protein immunohistochemistry as initial screening for Lynch syndrome in patients with endometrial adenocarcinoma

Crim, Aleia; Perkins, Victoria; Husain, Sanam; Ding, Kai; Holman, Laura L.

doi:10.1016/j.ygyno.2017.03.112

Cited by 3 publications

(5 citation statements)

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“…Furthermore, two studies did not indicate if loss was isolated or in a dimeric pair 39,60 . Of note Zhu et al 53 reported isolated loss of MLH1 and MSH2 which is unusual given the literature on the ability to use a two‐antibody screen in MMRd using PMS2 and MSH6 77,78 . In addition, Xue et al reported isolated MLH1 loss, however it was not described as absent but as “low expression.” 34 Therefore 19 studies had sufficient information to describe MMR protein expression in OC 23,24,26,31‐34,36,42,45,49,53,54,58,61,64,66,75,76 .…”

Section: Resultsmentioning

confidence: 99%

The prevalence of mismatch repair deficiency in ovarian cancer: A systematic review and meta‐analysis

Atwal

Snowsill

Dandy

et al. 2022

Intl Journal of Cancer

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Ovarian cancer (OC) is the least survivable gynecological malignancy and presents late. Five-year survival for OC is around 45% increasing the need for innovative treatments. Checkpoint inhibitors have shown significant clinical efficacy in mismatch repair deficient (MMRd) cancers and could be a powerful treatment in OC. However, their application in OC is limited due to the lack of data on the prevalence of MMRd.The aim of our study was to conduct a systematic review of the literature and metaanalysis to provide an accurate estimate of the prevalence of MMRd in OC. We followed PRISMA guidelines throughout. Studies were identified by electronic searches of Medline, Embase, Cochrane CENTRAL and Web of Science followed by citation searching. Studies not written in English were excluded. All studies were reviewed by at least two independent reviewers. Proportions of test positivity were calculated by random and fixed-effects meta-analysis models. I 2 score was used to assess heterogeneity across studies. In total 54 studies were included with 17 532 analyzed for MMRd. The overall proportions of MMRd by immunohistochemistry and microsatellite instability analysis were 6.7% and 10.4%, respectively. MMRd was reported in all histotypes of epithelial OC but was most common in endometrioid OC. We estimate that on average 46.7% (95% CI: 28.8-65.4) of ovarian carcinomas showing MMRd by IHC had a germline path_MMR variant identified. OC in those with Lynch syndrome seems to present at an earlier age and stage. Studies however were generally of low quality and there was a high degree of heterogeneity. A significant minority (up to 16%) of OC displays MMRd and, therefore, could be amenable to checkpoint inhibition therapy. However, the current literature base is of limited quality and therefore high-quality prospective studies exploring MMRd in OC with the use of multimodal testing are required. In addition, trials researching efficacy of checkpoint inhibition in MMRd OC are needed.

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Section: Resultsmentioning

confidence: 99%

The prevalence of mismatch repair deficiency in ovarian cancer: A systematic review and meta‐analysis

Atwal

Snowsill

Dandy

et al. 2022

Intl Journal of Cancer

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“…Our study suggests that the Manchester approach is cost-effective compared to no testing and compared to other reflex testing strategies, costing around £5500 per QALY gained, and further that universal testing (without restricting by age or predicting risk of Lynch syndrome using PREMM₅) is cost-effective. We found that restricting IHC testing to a two-antibody (MSH6 and PMS2) panel would improve cost-effectiveness, but this finding was based on no Lynch syndrome cases failing to display deficient expression for one of these proteins within PETALS, whereas other studies have shown that a two-antibody panel is inferior to a four-antibody panel [ 35 ]. We found that including MSI-L as a “test positive” result was not sufficient to make MSI-based testing cost-effective compared to the Manchester approach.…”

Section: Discussionmentioning

confidence: 99%

Cost-Effectiveness of the Manchester Approach to Identifying Lynch Syndrome in Women with Endometrial Cancer

Snowsill

Ryan

Crosbie

2020

JCM

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Lynch syndrome (LS) is a hereditary cancer syndrome responsible for 3% of all endometrial cancer and 5% in those aged under 70 years. It is unclear whether universal testing for LS in endometrial cancer patients would be cost-effective. The Manchester approach to identifying LS in endometrial cancer patients uses immunohistochemistry (IHC) to detect mismatch repair (MMR) deficiency, incorporates testing for MLH1 promoter hypermethylation, and incorporates genetic testing for pathogenic MMR variants. We aimed to assess the cost-effectiveness of the Manchester approach on the basis of primary research data from clinical practice in Manchester. The Proportion of Endometrial Tumours Associated with Lynch Syndrome (PETALS) study informed estimates of diagnostic performances for a number of different strategies. A recent microcosting study was adapted and was used to estimate diagnostic costs. A Markov model was used to predict long-term costs and health outcomes (measured in quality-adjusted life years, QALYs) for individuals and their relatives. Bootstrapping and probabilistic sensitivity analysis were used to estimate the uncertainty in cost-effectiveness. The Manchester approach dominated other reflex testing strategies when considering diagnostic costs and Lynch syndrome cases identified. When considering long-term costs and QALYs the Manchester approach was the optimal strategy, costing £5459 per QALY gained (compared to thresholds of £20,000 to £30,000 per QALY commonly used in the National Health Service (NHS)). Cost-effectiveness is not an argument for restricting testing to younger patients or those with a strong family history. Universal testing for Lynch syndrome in endometrial cancer patients is expected to be cost-effective in the U.K. (NHS), and the Manchester approach is expected to be the optimal testing strategy.

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“…20 Meanwhile, a study by Crim el al reported one case of isolate MLH1 loss which is impossible in the 2-antibody method, however, there was no associated germline mutation. 18 *cases in which the 2-antibody method could not detect defects compared to the 4-antibody method and 11 had convincing MSH6 expression. Germline testing of these cases revealed MSH2 mutations in 7/8 cases with ambiguous MSH6 expression and 9/11 cases with convincing MSH6 expression.…”

Section: Discussionmentioning

confidence: 97%

“…Rates of MMR deficiency in endometrial cancer range from 19.8%-35%. 4,7,10,12,17,18,20,21 Recently, Puangsricharoen et al reported MMR deficiency in 34.9% of 166 endometrial cancer cases in Thailand. 22 The rate of MMR deficiency in this study is 25.12% which is lower than a previous Thai study.…”

Section: Discussionmentioning

confidence: 99%

“…3,4 In addition, MSI is less sensitive to the MSH6 germline mutation. 1,2 Many studies claim that IHC for only PMS2 and MSH6 is sufficient for initial screening [15][16][17][18] due to the binding properties of MMR heterodimer complexes; MSH2 binds with MSH6 and MLH1 binds with PMS2. With a 2-antibody approach, universal LS screening in endometrial cancers is easier to achieve, especially in places with limited resources.…”

Section: Original Article Smjmentioning

confidence: 99%

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Two-Antibody Staining Method, A Cost-Saving Strategy for Universal Lynch Syndrome Screening in Endometrial Cancers

Anansitthikorn

Hanamornroongruang

2022

Siriraj Med J

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Objective: Lynch syndrome is an autosomal dominant disorder that increases the risk of cancers in many sites. In women, endometrial cancer is often a sentinel tumor and thus immunohistochemistry for mismatch repair (MMR) proteins MLH1, MSH2, MSH6 and PMS2 is encouraged as a screening test. To reduce cost, staining for only 2 MMR proteins PMS2 and MSH6 has been proposed. This study aimed to determine whether a 2-antibody staining test is enough to screen for Lynch syndrome in endometrial cancer patients.Materials and Methods: Cases of endometrial carcinoma with immunohistochemistry for 4 MMR proteins were reviewed. Results of immunohistochemistry screening were compared between all four antibodies and only two (PMS2 and MSH6) antibodies.Results: Loss of expression of any MMR proteins was detected in 51 out of 203 cases (25.12%). Twenty-three cases (45%) showed loss of MLH1 and PMS2; 13 cases (25%) showed loss of MSH2 and MSH6; five cases (10%) showed loss of MSH6; seven cases (14%) showed loss of PMS2 and three cases (6%) showed loss of MSH2. The 2-antibody method detected 48 cases (94%) with a MMR deficiency but failed to detect three cases (6%) with an isolate loss of MSH2. The screening results from the 2-antibody method are 98.5% (200/203) in accordance with the original 4-antibody method.Conclusion: The 2-antibody method is a quite effective option to screen for Lynch syndrome in endometrial cancers. However, MSH2 mutations may be missed in a few cases.

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Feasibility of two-antibody vs four-antibody mismatch repair protein immunohistochemistry as initial screening for Lynch syndrome in patients with endometrial adenocarcinoma

Cited by 3 publications

References 0 publications

The prevalence of mismatch repair deficiency in ovarian cancer: A systematic review and meta‐analysis

The prevalence of mismatch repair deficiency in ovarian cancer: A systematic review and meta‐analysis

Cost-Effectiveness of the Manchester Approach to Identifying Lynch Syndrome in Women with Endometrial Cancer

Two-Antibody Staining Method, A Cost-Saving Strategy for Universal Lynch Syndrome Screening in Endometrial Cancers

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