Performance of a HER2 testing algorithm specific for p53‐abnormal endometrial cancer

Vermij, Lisa; Singh, Naveena; León‐Castillo, Alicia; Horeweg, Nanda; Oosting, Jan; Carlson, Joseph W.; Smit, Vincent T.H.B.M.; Gilks, C Blake; Bosse, Tjalling

doi:10.1111/his.14381

Cited by 13 publications

(7 citation statements)

References 30 publications

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“…10,13 Notably, HER2 amplification has not only been reported in SEC but also in "serous-like" carcinomas with aberrant p53 expression. 14 Given the significant clinicopathologic and molecular overlap between SEC and UCS, it is plausible that similar rates of HER2 overexpression and amplification exist across both entities. We herein evaluate the rates of HER2 overexpression and amplification in a cohort of UCSs and additionally determine whether any correlation between HER2 positivity and programmed cell death-ligand 1 (PD-L1) expression and mismatch repair (MMR) status exists.…”

mentioning

confidence: 99%

“…In addition, most UCSs have TP53 mutations and fall into the copy-number high (serous-like) molecular subclassification of endometrial carcinomas 10,13. Notably, HER2 amplification has not only been reported in SEC but also in “serous-like” carcinomas with aberrant p53 expression 14. Given the significant clinicopathologic and molecular overlap between SEC and UCS, it is plausible that similar rates of HER2 overexpression and amplification exist across both entities.…”

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confidence: 99%

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HER2 Overexpression and Amplification in Uterine Carcinosarcomas With Serous Morphology

Jenkins¹,

Cantrell

Stoler³

et al. 2022

American Journal of Surgical Pathology

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Uterine carcinosarcoma (UCS) is an aggressive malignancy with few treatment options. A recent clinical trial has shown an increase in progression-free survival in patients with human epidermal growth factor receptor 2 (HER2)-positive serous endometrial carcinomas treated with anti-HER2-targeted therapies. Few studies have evaluated HER2 expression/amplification in UCS. Similar to serous endometrial carcinoma, the majority of UCS have TP53 mutations and a serous epithelial component, suggesting that UCS may show similar rates of HER2 positivity and therapeutic response. Therefore, we evaluated HER2 expression/amplification in a cohort of UCS over a 5-year period. HER2 immunohistochemistry (IHC) and chromogenic in situ hybridization were performed on tissue microarray and whole tissue sections and scored according to the most recent clinical trial recommendations. Three of 48 UCS (6%) had strong (3+) HER2 IHC expression, and 3 cases (6%) were equivocal (2+). Seven cases (15%) had HER2 amplification by chromogenic in situ hybridization, including all 3 with overexpression and 2 that were equivocal by IHC. Mismatch repair (MMR) protein, p53, and programmed cell death-ligand 1 (PD-L1) expression status was obtained from prior whole section analyses. All HER2-positive cases had a serous morphology and aberrant p53 expression. Only minimal PD-L1 expression was seen in the HER2-positive cases, and none had MMR loss. A subset of UCS with serous morphology have overexpression and/ or amplification of HER2, which may predict response to HER2-targeted therapies. HER2-positive UCS may be less susceptible to immune checkpoint inhibition as they uncommonly show MMR deficiency and/or strong PD-L1 expression. Thus, HER2-targeted therapies could be of clinical utility in a subset of UCS without other adjuvant treatment options.

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confidence: 99%

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confidence: 99%

HER2 Overexpression and Amplification in Uterine Carcinosarcomas With Serous Morphology

Jenkins¹,

Cantrell

Stoler³

et al. 2022

American Journal of Surgical Pathology

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“…53 Vermij et al also recently evaluated a HER2 IHC scoring system on 78 p53abn ECs of all histotypes, in order to establish an optimal diagnostic HER2 testing algorithm for p53abn EC. 54 They also found substantial interobserver agreement with this molecular subtype directed HER2 scoring. This work provides an important step towards refining inclusion criteria for anti-HER2 therapy EC clinical trials.…”

Section: P53abn Endometrial Cancermentioning

confidence: 86%

The emerging role of molecular pathology in directing the systemic treatment of endometrial cancer

2021

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Following the discovery of the four molecular subtypes of endometrial cancer (EC) by The Cancer Genome Atlas (TCGA) in 2013, subsequent studies used surrogate markers to develop and validate a clinically relevant EC classification tool to recapitulate TCGA subtypes. Molecular classification combines focused sequencing ( POLE) and immunohistochemistry (mismatch repair and p53 proteins) to assign patients with EC to one of four molecular subtypes: POLEmut, MMRd, p53abn and NSMP (no specific molecular profile). Unlike histopathological evaluation, the molecular subtyping of EC offers an objective and reproducible classification system that has been shown to have prognostic value and therapeutic implications. It is an exciting time in EC care where we have moved beyond treatment based on histomorphology alone, and molecular classification will now finally allow assessment of treatment efficacy within biologically similar tumours. It is now recommended that molecular classification should be considered for all ECs, and should be performed routinely in all high grade tumours. It is also recommended to incorporate molecular classification into standard pathology reporting and treatment decision-making algorithms. In this review, we will discuss how the molecular classification of EC can be used to guide both conventional and targeted therapy in this new molecular era.

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“…Beyond the supported role for chemotherapy in p53abn ECs, 20,25 p53 status may also be considered as a stratification feature for antiangiogenic agents 31 1 chemotherapy, ICB 1 chemotherapy, or combinations, with appreciation that the subset of patients with MMRp tumors most likely to benefit from combined pembrolizumab/lenvatinib may be those with p53abn ECs. 45 Subsets of p53abn high-risk tumors are recognized to have targetable features, including 20% to 25% with HER2 overexpression, 46 20% to 40% with homologous recombination deficiencies, [47][48][49] and 30% to 50% with CCNE1 amplification. 7,48 Molecular subtype-specific trials (examples listed previously) with substratification within p53abn ECs may offer an opportunity to finally improve outcomes for patients with these aggressive tumors.…”

Section: P53abn Endometrial Cancermentioning

confidence: 99%

Molecular Profiling of Endometrial Cancer From TCGA to Clinical Practice

Jamieson

McAlpine

2023

Journal of the National Comprehensive Cancer Network

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Molecular classification provides an objective, reproducible framework for categorization of endometrial cancers (ECs), informing prognosis and selection of therapy. Currently, the uptake of molecular classification, integration in to EC management algorithms, and enrollment in molecular subtype-specific clinical trials lags behind what it could be. Access to molecular testing is not uniform, and subsequent management (surgical, adjuvant therapy) is unacceptably variable. We are in the midst of a critical landscape change in this disease site, with increasing emphasis on the integration of molecular features in EC care that can potentially improve standard of care globally. This article summarizes the rationale for molecular classification of ECs, strategies for implementation in low and high resource settings, and actionable opportunities based on this information.

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Performance of a HER2 testing algorithm specific for p53‐abnormal endometrial cancer

Abstract: specificity of 100%. Conclusions: Our EC-specific HER2 IHC scoring method is reproducible. A screening strategy based on IHC scoring on all cases with subsequent DISH testing on IHC-2+/-3+ cases has perfect test accuracy for identifying HER2-positive EC.

Cited by 13 publications

References 30 publications

HER2 Overexpression and Amplification in Uterine Carcinosarcomas With Serous Morphology

HER2 Overexpression and Amplification in Uterine Carcinosarcomas With Serous Morphology

The emerging role of molecular pathology in directing the systemic treatment of endometrial cancer

Molecular Profiling of Endometrial Cancer From TCGA to Clinical Practice

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