Evaluation of a nationwide Dutch guideline to detect Lynch syndrome in patients with endometrial cancer

Tjalsma, AS; Wagner, Anja; Dinjens, Winand N.M.; Ewing-Graham, PC; L, Alcala; Groot, M.E.R. de; Hamoen, Karen E; Hof, Arjan C. van; Hofhuis, Ward; Hofman, Laura; Hoogduin, Klaas J.; Kaijser, Jeroen; Makkus, L.; Mol, Suzanne; Plaisier, G.M.; Schelfhout, K.; Smedts, H.P.M.; Smit, R.A.; Timmers, Petra; Vencken, P.M.L.H.; Visschers, B.A.J.T.; Wurff, A.A.M. van der; Doorn, Helena C. van

doi:10.1016/j.ygyno.2020.12.028

Cited by 9 publications

(13 citation statements)

References 36 publications

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“…We identified 57 articles analyzing MLH1 promoter methylation [ 19 , 26 , 32 , 33 , 34 , 36 , 40 , 42 , 46 , 47 , 52 , 55 , 57 , 58 , 59 , 69 , 71 , 75 , 79 , 81 , 82 , 83 , 84 , 85 , 86 , 90 , 91 , 94 , 95 , 96 , 99 , 100 , 112 , 113 , 116 , 122 , 124 , 125 , 127 , 128 , 129 , 136 , 137 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 ,…”

Section: Resultsunclassified

The Role of Immunohistochemistry Markers in Endometrial Cancer with Mismatch Repair Deficiency: A Systematic Review

Favier

Varinot

Uzan

et al. 2022

Cancers

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The objective of this systematic review was to summarize our current knowledge of the role of immunohistochemistry (IHC) markers for identifying mismatch repair-deficient (MMRd) tumors in endometrial cancer (EC). Identification of MMRd tumors, which occur in 13% to 30% of all ECs, has become critical for patients with colorectal and endometrial cancer for therapeutic management, clinical decision making, and prognosis. This review was conducted by two authors applying the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using the following terms: “immunohistochemistry and microsatellite instability endometrial cancer” or “immunohistochemistry and mismatch repair endometrial cancer” or “immunohistochemistry and mismatch repair deficient endometrial cancer”. Among 596 retrieved studies, 161 fulfilled the inclusion criteria. Articles were classified and presented according to their interest for the diagnosis, prognosis, and theragnostics for patients with MMRd EC. We identified 10, 18, and 96 articles using IHC expression of two, three, or four proteins of the MMR system (MLH1, MSH2, MHS6, and PMS2), respectively. MLH1 promoter methylation was analyzed in 57 articles. Thirty-four articles classified MMRd tumors with IHC markers according to their prognosis in terms of recurrence-free survival (RFS), overall survival (OS), stage, grade, and lymph node invasion. Theragnostics were studied in eight articles underlying the important concentration of PD-L1 in MMRd EC. Even though the role of IHC has been challenged, it represents the most common, robust, and cheapest method for diagnosing MMRd tumors in EC and is a valuable tool for exploring novel biotherapies and treatment modalities.

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Section: Resultsunclassified

The Role of Immunohistochemistry Markers in Endometrial Cancer with Mismatch Repair Deficiency: A Systematic Review

Favier

Varinot

Uzan

et al. 2022

Cancers

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“…5,10 There is evidence of significant drop-off between finding an abnormal IHC result and completion of genetic testing. 10,11 A recent countrywide initiative in Canada found that despite universal tumor testing, LS was underdiagnosed. 12 Mutations in cancer susceptibility genes (CSGs) other than those associated with LS are thought to play a smaller role in EC risk.…”

Section: Introductionmentioning

confidence: 99%

Up-Front Multigene Panel Testing for Cancer Susceptibility in Patients With Newly Diagnosed Endometrial Cancer: A Multicenter Prospective Study

Levine

Pearlman

Hampel

et al. 2021

JCO Precision Oncology

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PURPOSE Clinical utility of up-front multigene panel testing (MGPT) is directly related to the frequency of pathogenic variants (PVs) in the population screened and how genetic findings can be used to guide treatment decision making and cancer prevention efforts. The benefit of MGPT for many common malignancies remains to be determined. In this study, we evaluated up-front MGPT in unselected patients with endometrial cancer (EC) to determine the frequency of PVs in cancer susceptibility genes. METHODS Patients with EC were prospectively enrolled at nine Ohio institutions from October 1, 2017, to December 31, 2020. Nine hundred and sixty-one patients with newly diagnosed EC underwent clinical germline MGPT for 47 cancer susceptibility genes. In addition to estimating the prevalence of germline PVs, the number of individuals identified with Lynch syndrome (LS) was compared between MGPT and tumor-based screening. RESULTS Likely pathogenic variants or PVs were identified in 97 of 961 women (10.1%). LS was diagnosed in 29 of 961 patients (3%; 95% CI, 2.1 to 4.3), with PVs in PMS2 most frequent. MGPT revealed nine patients with LS in addition to the 20 identified through routine tumor-based screening. BRCA1 and BRCA2 PVs were found in 1% (10 of 961; 95% CI, 0.6 to 1.9) of patients and that group was significantly enriched for type II ECs. CONCLUSION This prospective, multicenter study revealed potentially actionable germline variants in 10% of unselected women with newly diagnosed EC, supporting the use of up-front MGPT for all EC patients. The discovery that BRCA1 or BRCA2 heterozygotes frequently had type II cancers points to therapeutic opportunities for women with aggressive histologic EC subtypes.

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“…In a study from the Netherlands, Tjalsma et al showed that of 15 patients with tumor testing suggestive of LS, three (20%) were not informed of the tumor testing results and were not referred for germline genetic testing. Of the remaining 12 patients referred for genetic counseling, only nine completed testing leaving only 9/15 (60%) patients with likely LS having completed genetic testing [8]. Lee et al describe that at their institution (NY, US), 10/583 (1.7%) patients with EC had germline genetic testing confirming the diagnosis of LS.…”

Section: Discussionmentioning

confidence: 99%

“…A large, multi-institution study that prospectively tested newly diagnosed EC patients with tumor and germline testing found that the most common causes of LS in EC were PMS2 and MSH6 PVs and identified numerous challenges with IHC screening that ultimately could have resulted in missed diagnoses of LS [2]. It is important to note that even in those instances in which tumor screening identifies possible LS, the diagnosis is not confirmed until germline genetic testing is completed, with several studies demonstrating a significant drop off between an abnormal IHC result and completion of genetic testing [6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Implementing universal upfront multi-gene panel testing in endometrial cancer: From cost to practical considerations

Levine

Barrington

Hampel

et al. 2022

Gynecologic Oncology

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Evaluation of a nationwide Dutch guideline to detect Lynch syndrome in patients with endometrial cancer

Cited by 9 publications

References 36 publications

The Role of Immunohistochemistry Markers in Endometrial Cancer with Mismatch Repair Deficiency: A Systematic Review

The Role of Immunohistochemistry Markers in Endometrial Cancer with Mismatch Repair Deficiency: A Systematic Review

Up-Front Multigene Panel Testing for Cancer Susceptibility in Patients With Newly Diagnosed Endometrial Cancer: A Multicenter Prospective Study

Implementing universal upfront multi-gene panel testing in endometrial cancer: From cost to practical considerations

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