Interobserver Agreement for Mismatch Repair Protein Immunohistochemistry in Endometrial and Nonserous, Nonmucinous Ovarian Carcinomas

Sarı, Ayşegül; Pollett, Aaron; Eiriksson, Lua; Lumsden-Johanson, Brenda; Laar, Emily Van de; Kazerouni, Hamid; Salehi, Amir Mohammad; Sur, Monalisa; Lytwyn, Alice; Ferguson, Sarah E.

doi:10.1097/pas.0000000000001220

Cited by 23 publications

(21 citation statements)

References 24 publications

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“…The assessment of MMR proteins and p53 immunohistochemistry are highly concordant with MSI and TP53 mutational status, respectively, 16 , 17 and the interobserver agreement is > 95%. 17 , 18 Authors of a recent study proposed pragmatic guidelines for the interpretation of nonhotspot POLE -EDM in EC, 13 ensuring uniform interpretation. Furthermore, multiple-classifier EC can now be assigned to the appropriate molecular subgroup.…”

Section: Discussionmentioning

confidence: 99%

Molecular Classification of the PORTEC-3 Trial for High-Risk Endometrial Cancer: Impact on Prognosis and Benefit From Adjuvant Therapy

León‐Castillo

Boer

Powell

et al. 2020

JCO

438

443

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PURPOSE The randomized Adjuvant Chemoradiotherapy Versus Radiotherapy Alone in Women With High-Risk Endometrial Cancer (PORTEC-3) trial investigated the benefit of combined adjuvant chemotherapy and radiotherapy (CTRT) versus radiotherapy alone (RT) for women with high-risk endometrial cancer (EC). Because The Cancer Genome Atlas defined an EC molecular classification with strong prognostic value, we investigated prognosis and impact of chemotherapy for each molecular subgroup using tissue samples from PORTEC-3 trial participants. METHODS Paraffin-embedded tissues of 423 consenting patients were collected. Immunohistochemistry for p53 and mismatch repair (MMR) proteins, and DNA sequencing for POLE exonuclease domain were done to classify tumors as p53 abnormal (p53abn), POLE-ultramutated ( POLEmut), MMR-deficient (MMRd), or no specific molecular profile (NSMP). The primary end point was recurrence-free survival (RFS). Kaplan-Meier method, log-rank test, and Cox model were used for analysis. RESULTS Molecular analysis was successful in 410 high-risk EC (97%), identifying the 4 subgroups: p53abn EC (n = 93; 23%), POLEmut (n = 51; 12%), MMRd (n = 137; 33%), and NSMP (n = 129; 32%). Five-year RFS was 48% for patients with p53abn EC, 98% for POLEmut EC, 72% for MMRd EC, and 74% for NSMP EC ( P < .001). The 5-year RFS with CTRT versus RT for p53abn EC was 59% versus 36% ( P = .019); 100% versus 97% for patients with POLEmut EC ( P = .637); 68% versus 76% ( P = .428) for MMRd EC; and 80% versus 68% ( P = .243) for NSMP EC. CONCLUSION Molecular classification has strong prognostic value in high-risk EC, with significantly improved RFS with adjuvant CTRT for p53abn tumors, regardless of histologic type. Patients with POLEmut EC had an excellent RFS in both trial arms. EC molecular classification should be incorporated in the risk stratification of these patients as well as in future trials to target specific subgroups of patients.

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Section: Discussionmentioning

confidence: 99%

Molecular Classification of the PORTEC-3 Trial for High-Risk Endometrial Cancer: Impact on Prognosis and Benefit From Adjuvant Therapy

León‐Castillo

Boer

Powell

et al. 2020

JCO

438

443

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“…This reclassification was partly due to the improvement in IHC assay performance over the past 10 years, but mainly to the application of the new rules for MMR immunostaining interpretation when reviewing. We applied the decision tool recently validated to interpret MMR immunostaining of endometrial and ovarian carcinomas 25 , 26 . This is a very useful tool in the analysis of faint or equivocal staining.…”

Section: Discussionmentioning

confidence: 99%

An unusual phenotype occurs in 15% of mismatch repair-deficient tumors and is associated with non-colorectal cancers and genetic syndromes

et al. 2022

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Immunohistochemistry (IHC) and/or MSI-PCR (microsatellite instability-polymerase chain reaction) tests are performed routinely to detect mismatch repair deficiency (MMR-D). Classical MMR-D tumors present a loss of MLH1/PMS2 or MSH2/MSH6 with MSI-High. Other profiles of MMR-D tumors have been described but have been rarely studied. In this study, we established a classification of unusual MMR-D tumors and determined their frequency and clinical impact. All MMR-D tumors identified between 2007 and 2017 were selected. Any profile besides the classical MMR-D phenotype was defined as unusual. For patients with unusual MMR-D tumors, IHC, and PCR data were reviewed, the tumor mutation burden (TMB) was evaluated and clinical and genetic features were collected. Of the 4948 cases of MMR testing, 3800 had both the available IHC and MSI-PCR results and 585 of these had MMR-D. After reviewing the IHC and PCR, 21% of the cases initially identified as unusual MMR-D were reclassified, which resulted in a final identification of 89 unusual MMR-D tumors (15%). Unusual MMR-D tumors were more often associated with non-CRC than classical MMR-D tumors. Unusual MMR-D tumors were classified into four sub-groups: i) isolated loss of PMS2 or MSH6, ii) classical loss of MLH1/PMS2 or MSH2/MSH6 without MSI, iii) four MMR proteins retained with MSI and, iv) complex loss of MMR proteins, with clinical characteristics for each sub-group. TMB-high or -intermediate was shown in 96% of the cancers studied (24/25), which confirmed MMR deficiency. Genetic syndromes were identified in 44.9% (40/89) and 21.4% (106/496) of patients with unusual and classical MMR-D tumors, respectively (P < 0.001). Five patients treated with an immune checkpoint inhibitor (ICI) had a prolonged clinical benefit. Our classification of unusual MMR-D phenotype helps to identify MMR deficiency. Unusual MMR-D phenotype occurs in 15% of MMR-D tumors. A high frequency of genetic syndromes was noted in these patients who could benefit from ICI.

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“…Lynch syndrome (LS), also known as Hereditary Nonpolyposis Colorectal Carcinoma (HNPCC) is an autosomal dominant inherited cancer predisposition syndrome caused by germline mutations in MMR genes. It is associated with an increased risk of colorectal cancer (CRC), EC as well as adenocarcinomas of ovary, stomach, pancreas, and urinary tract 3 . Female relatives inheriting this mutation have a high risk of developing endometrial carcinoma, about 43% by age 75 4 .…”

Section: Introductionmentioning

confidence: 99%

The utility of evaluating mismatch repair proteins in endometrial carcinoma: an experience from a tertiary referral centre in North India

Jain¹,

Prasad²,

Dhar³

et al. 2021

Pathologica

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Summary Background Endometrial cancer (EC) is a common gynecological malignancy. Around 25-30% patients have mismatch repair deficiency (MMRd). Lynch syndrome is caused by germline mutations in MMR genes. Lynch-associated tumours have better prognosis, however implications for prognosis and survival is less known. Microsatellite insufficiency (MSI) is associated with high neoantigen loads and number of tumor infiltrating lymphocytes, which overexpresses PD-1 and PD-L1 and are excellent candidates for PD-1-targeted immunotherapies. In this study, we aim to evaluate the utility of MMR in patients with EC and its clinico-pathological correlation. Methods Eighty-two cases of EC which underwent MMR evaluation over a period of five years at our centre were included. Demographics, clinical details including family history, histopathological and immunohistochemical (IHC) parameters were recorded. Tumors with loss-of at least one protein were considered MMR deficient (MMRd) and those with intact expression were MMR proficient (MMRp). Results Of 82 cases tested, 27 (33%) were MMRd. Frequencies of IHC MMR loss of expression were: MLH1/PMS2: 17 (21%), MSH6 loss only: 3 (4%), MSH2/MSH6 loss: 3 (4%), PMS2 loss: 2 (2%). In MMRd cases, most common histologic tumor type was endometrioid adenocarcinoma (70%). Loss of expression was significantly (p < 0.001) more frequent in lower uterine segment involvement and positive family history. Conclusions MSI plays an important role in the progression of endometrial cancer. Lower uterine segment involvement and positive family history are significant predictor of MMR loss. Routine testing of MMR proteins in endometrial cancer can contribute to screening of Lynch syndrome families and make immunotherapy available as a treatment option.

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Interobserver Agreement for Mismatch Repair Protein Immunohistochemistry in Endometrial and Nonserous, Nonmucinous Ovarian Carcinomas

Cited by 23 publications

References 24 publications

Molecular Classification of the PORTEC-3 Trial for High-Risk Endometrial Cancer: Impact on Prognosis and Benefit From Adjuvant Therapy

Molecular Classification of the PORTEC-3 Trial for High-Risk Endometrial Cancer: Impact on Prognosis and Benefit From Adjuvant Therapy

An unusual phenotype occurs in 15% of mismatch repair-deficient tumors and is associated with non-colorectal cancers and genetic syndromes

The utility of evaluating mismatch repair proteins in endometrial carcinoma: an experience from a tertiary referral centre in North India

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