Universal endometrial cancer tumor typing: How much has immunohistochemistry, microsatellite instability, and MLH1 methylation improved the diagnosis of Lynch syndrome across the population?

Kahn, Richard L.; Gordhandas, Sushmita; Maddy, Brandon Paul; Nelson, Becky Baltich; Askin, Gülce; Christos, Paul J.; Caputo, Thomas A.; Chapman‐Davis, Eloise; Holcomb, Kevin; Frey, M.K.

doi:10.1200/jco.2019.37.15_suppl.e17119

Cited by 6 publications

(9 citation statements)

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“…MSH2 expression in one cervical precursor lesion and in one urothelial carcinoma of the urinary bladder could be explained by the oncogenic role of human papillomavirus and tobacco as potent carcinogens in the cervix and urothelial epithelium [ 20 , 21 ]. In the two endometrial MSH2-positive cancers, the remaining MMR proteins were also expressed, although the PCR microsatellite instability analysis results were unstable (data not shown), consistent with results previously reported [ 22 , 23 ]. In the two breast lesions, other carcinogenetic pathways different from the MMR system may be activated [ 24 ].…”

Section: Discussionsupporting

confidence: 91%

Complete Loss of EPCAM Immunoexpression Identifies EPCAM Deletion Carriers in MSH2-Negative Colorectal Neoplasia

Cuatrecasas

Gorostiaga

Riera

et al. 2020

Cancers

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The use of epithelial cell adhesion molecule (EPCAM) immunohistochemistry (IHC) is not included in the colorectal cancer (CRC) screening algorithm to detect Lynch syndrome (LS) patients. The aim of the present study was to demonstrate that EPCAM IHC is a useful tool to guide the LS germ-line analysis when a loss of MSH2 expression was present. We retrospectively studied MSH2 and EPCAM IHC in a large series of 190 lesions composed of malignant neoplasms (102), precursor lesions of gastrointestinal (71) and extra-gastrointestinal origin (9), and benign neoplasms (8) from different organs of 71 patients suspicious of being LS due to MSH2 alterations. LS was confirmed in 68 patients, 53 with MSH2 mutations and 15 with EPCAM 3′-end deletions. Tissue microarrays were constructed with human normal tissues and their malignant counterparts to assist in the evaluation of EPCAM staining. Among 154 MSH2-negative lesions, 17 were EPCAM-negative, including 10 CRC and 7 colorectal polyps, and 5 of them showed only isolated negative glands. All lesions showing a lack of EPCAM expression belonged to patients with EPCAM 3′-end deletions. EPCAM IHC is a useful screening tool, with 100% specificity to identify LS patients due to EPCAM 3′-end deletions in MSH2-negative CRC and MSH2-negative colorectal polyps.

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Section: Discussionsupporting

confidence: 91%

Complete Loss of EPCAM Immunoexpression Identifies EPCAM Deletion Carriers in MSH2-Negative Colorectal Neoplasia

Cuatrecasas

Gorostiaga

Riera

et al. 2020

Cancers

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“…Over a quarter of our study patients (28%) had tumor mismatch repair deficiency which is similar to rates reported in the literature (6). While none were found to have a pathogenic mutation in MMR proteins associated with Lynch syndrome, several VUS were discovered in MMR proteins.…”

Section: Methodssupporting

confidence: 88%

“…Information about mismatch repair deficiency even in the absence of a germline mutation has clinical implications including eligibility for targeted therapy for recurrent mismatch repair-deficient tumors. While mismatch repair status was initially found to predict clinical benefit of a PD-1 blockade in patients with colorectal cancer, subsequent studies then demonstrated response in other solid tumors as well, including endometrial cancer, where mismatch repair deficiency is found in up to 30% of tumors (6,17,18). Since the Food and Drug Administration (FDA) approval in 2017, PD-1 blockade with pembrolizumab has been used in the treatment of mismatch repair-deficient recurrent endometrial cancer.…”

Section: Methodsmentioning

confidence: 99%

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Retroactive assessment for DNA mismatch repair deficiency in women with a history of endometrial cancer

Chen

Gordhandas

Musselman

et al. 2021

MRAJ

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Objectives. Beginning in 2014, the Society of Gynecologic Oncology and the American College of Obstetricians and Gynecologists have recommended universal tumor testing for mismatch repair deficiency in endometrial cancer. Mismatch repair testing can triage patients who may benefit from genetic testing for Lynch syndrome. Many women previously diagnosed with endometrial cancer have not undergone mismatch repair tumor testing. We sought to determine the feasibility of retroactive assessment for mismatch repair deficiency among women with diagnosed with endometrial cancer prior to 2014. Methods. Between 2016 and 2018, we identified 36 patients presenting for gynecologic oncology follow-up visits who were previously diagnosed with endometrial cancer. The endometrial pathology underwent tumor assessment for loss of expression of mismatch repair proteins by immunohistochemistry. Patients with abnormal mismatch repair testing were referred to genetic counseling and, if indicated, for germline genetic testing. Results. Thirty-six patients underwent retroactive tumor immunohistochemistry, yielding 10 (28%) abnormal results, including nine (25%) with loss of one or more mismatch repair proteins and one with inconclusive staining (2.8%). All ten patients with abnormal immunohistochemistry were referred to genetic counseling; 9 (90%) accepted the referral and proceeded with genetic testing. One pathogenic mutation was identified in CHEK2 (11%). Five patients (56%) were found to have a variant of unknown significance. Conclusions. Implementation of universal retroactive tumor testing for mismatch repair deficiency in patients previously diagnosed with endometrial cancer is feasible. With the growing use of new molecular classification protocols for endometrial tumors, identification of mismatch repair deficiency may have significant clinicopathologic implications.

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“…Molecular subtyping of two models with serous histology revealed one was p53wt tumor (PDX23) and another was MMRd (PDX53), which was consistent with a germline MSH6 mutation (p.Tyr214*) in the latter patient and the finding that 13% of patients with germline MMR mutations have a mixed serous histology (32). Somatic mutations detected in other genes were consistent with TCGA findings.…”

Section: Genomics Of Ec Pdx Modelssupporting

confidence: 74%

Genomic analysis of patient-derived xenograft models reveals intra-tumor heterogeneity in endometrial cancer and can predict tumor growth inhibition with talazoparib

Bonazzi

Kondrashova

Smith

et al. 2021

Preprint

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Background: Endometrial cancer (EC) is a major gynecological cancer with increasing incidence. It comprised of four molecular subtypes with differing etiology, prognoses, and response to chemotherapy. In the future, clinical trials testing new single agents or combination therapies will be targeted to the molecular subtype most likely to respond. Pre-clinical models that faithfully represent the molecular subtypes of EC are urgently needed, we sought to develop and characterize a panel of novel EC patient-derived xenograft (PDX) models. Methods: Here, we report whole exome or whole genome sequencing of 11 PDX models and the matched primary tumor. Analysis of multiple PDX lineages and passages was performed to study tumor heterogeneity across lineages and/or passages. Based on recent reports of frequent defects in the homologous recombination (HR) pathway in EC, we assessed mutational signatures and HR deficiency scores and correlated these with in vivo responses to the PARP inhibitor (PARPi) talazoparib in six PDXs representing the different molecular subtypes of EC. Results: PDX models were successfully generated from all four molecular subtypes of EC and uterine carcinosarcomas, and they recapitulated morphology and the molecular landscape of primary tumors without major genomic drift. We also observed a wide range of inter-tumor and intra-tumor heterogeneity, well captured by different PDX lineages, which could lead to different treatment responses. An in vivo response to talazoparib was detected in two p53mut models consistent with stable disease, however both lacked the HR deficiency genomic signature. Conclusions: EC PDX models represent the four molecular subtypes of disease and can capture intra-tumoral heterogeneity of the original primary tumor. PDXs of the p53mut molecular subtype showed sensitivity to PARPi, however, deeper and more durable responses will likely require combination of PARPi with other agents.

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Universal endometrial cancer tumor typing: How much has immunohistochemistry, microsatellite instability, and MLH1 methylation improved the diagnosis of Lynch syndrome across the population?

Cited by 6 publications

References 0 publications

Complete Loss of EPCAM Immunoexpression Identifies EPCAM Deletion Carriers in MSH2-Negative Colorectal Neoplasia

Complete Loss of EPCAM Immunoexpression Identifies EPCAM Deletion Carriers in MSH2-Negative Colorectal Neoplasia

Retroactive assessment for DNA mismatch repair deficiency in women with a history of endometrial cancer

Genomic analysis of patient-derived xenograft models reveals intra-tumor heterogeneity in endometrial cancer and can predict tumor growth inhibition with talazoparib

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