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Article ; Online: A tale of two pathways: Review of immune checkpoint inhibitors in DNA mismatch repair-deficient and microsatellite instability-high endometrial cancers.

Liu, Ying L / Weigelt, Britta

2024

Abstract: The DNA mismatch repair (MMR) pathway is critical for correcting DNA mismatches generated during DNA replication. MMR-deficiency (MMR-D) leads to microsatellite instability (MSI) associated with an increased mutation rate, driving cancer development. ... ...

Abstract	The DNA mismatch repair (MMR) pathway is critical for correcting DNA mismatches generated during DNA replication. MMR-deficiency (MMR-D) leads to microsatellite instability (MSI) associated with an increased mutation rate, driving cancer development. This is particularly relevant in endometrial cancer (EC) as 25%-30% of tumors are of MMR-D/MSI-high (MSI-H) phenotype. Comprehensive assessment using immunohistochemistry (IHC) and sequencing-based techniques are necessary to fully evaluate ECs given the importance of molecular subtyping in staging and prognosis. This also influences treatment selection as clinical trials have demonstrated survival benefits for immune checkpoint inhibitors (ICIs) alone and in combination with chemotherapy for MMR-D/MSI-H EC patients in various treatment settings. As a portion of MMR-D/MSI-H ECs are driven by Lynch syndrome, an inherited cancer predisposition syndrome that is also associated with colorectal cancer, this molecular subtype also prompts germline assessment that can affect at-risk family members. Additionally, heterogeneity in the tumor immune microenvironment and tumor mutation burden (TMB) have been described by MMR mechanism, meaning MLH1 promoter hypermethylation versus germline/somatic MMR gene mutation, and this may affect response to ICI therapies. Variations by ancestry in prevalence and mechanism of MMR-D/MSI-H tumors have also been reported and may influence health disparities given observed differences in tumors of Black compared to White patients which may affect ICI eligibility. These observations highlight the need for additional prospective studies to evaluate the nuances regarding MMR-D heterogeneity as well as markers of resistance to inform future trials of combination therapies to further improve outcomes for patients with EC.
Language	English
Publishing date	2024-02-29
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1429-1
ISSN	1097-0142 ; 0008-543X ; 1934-662X
ISSN (online)	1097-0142
ISSN	0008-543X ; 1934-662X
DOI	10.1002/cncr.35267
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Article ; Online: High-Risk Human Papillomavirus-Associated Mixed Intestinal-Type Mucinous Adenocarcinoma and Low-grade Neuroendocrine Tumor of the Uterine Cervix: Report of a Case Harboring Shared ARID1A and SMAD4 Mutations Between Morphologically Distinct Components.

Alwaqfi, Rofieda / Gill, Kaitlyn / Brown, David N / Weigelt, Britta / Park, Kay J / Chui, M Herman

International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists

2024

Language	English
Publishing date	2024-01-31
Publishing country	United States
Document type	Journal Article
ZDB-ID	604859-6
ISSN	1538-7151 ; 0277-1691
ISSN (online)	1538-7151
ISSN	0277-1691
DOI	10.1097/PGP.0000000000001011
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Article: Tumor lenvatinib addiction and withdrawal rebound response in patients with advanced endometrial cancer.

Lam, Clarissa / Sarasohn, Debra / Weigelt, Britta / Zamarin, Dmitriy

Gynecologic oncology reports

2023 Volume 49, Page(s) 101258

Abstract: Combination therapy of lenvatinib, a multitargeted tyrosine kinase inhibitor (TKI), plus pembrolizumab, a monoclonal antibody targeting programmed death receptor 1 (PD-1), was recently approved by the Food and Drug Administration for therapy of advanced ... ...

Abstract	Combination therapy of lenvatinib, a multitargeted tyrosine kinase inhibitor (TKI), plus pembrolizumab, a monoclonal antibody targeting programmed death receptor 1 (PD-1), was recently approved by the Food and Drug Administration for therapy of advanced endometrial cancer. This case series highlights three patients with endometrial serous carcinoma who experienced disease stabilization or slow progression on lenvatinib plus pembrolizumab followed by rapid symptomatic growth of disease after lenvatinib discontinuation, and subsequent repeated response and symptom resolution after lenvatinib re-initiation. All patients died of disease complications 3 to 10 months after retreatment with lenvatinib. These observations highlight an important phenomenon of lenvatinib withdrawal rebound, likely driven by oncogenic signaling pathways upregulated in response to lenvatinib therapy. The findings of this case series represent a potential area for further research into the underlying mechanism for rebound and repeated response to lenvatinib, as well as strategies to mitigate disease flare related to lenvatinib withdrawal.
Language	English
Publishing date	2023-08-11
Publishing country	Netherlands
Document type	Case Reports
ZDB-ID	2818505-5
ISSN	2352-5789
ISSN	2352-5789
DOI	10.1016/j.gore.2023.101258
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Article ; Online: Response to Letter to the Editor, Gilks et al.

Weigelt, Britta / Mueller, Jennifer J / Ellenson, Lora H / Abu-Rustum, Nadeem R / Aghajanian, Carol

Gynecologic oncology

2023 Volume 176, Page(s) 181–182

Language	English
Publishing date	2023-07-10
Publishing country	United States
Document type	Letter
ZDB-ID	801461-9
ISSN	1095-6859 ; 0090-8258
ISSN (online)	1095-6859
ISSN	0090-8258
DOI	10.1016/j.ygyno.2023.07.001
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Article ; Online: Moving into the modern era of molecular classification for endometrial cancer.

Dagher, Christian / Liu, Ying L / Mueller, Jennifer J / Weigelt, Britta

Journal of surgical oncology

2023 Volume 129, Issue 1, Page(s) 120–125

Abstract: The molecular subtypes of endometrial carcinoma (EC) were first described by The Cancer Genome Atlas (TCGA) a decade ago. Using surrogate approaches, the molecular classification has been demonstrated to be prognostic across EC patients and to have ... ...

Abstract	The molecular subtypes of endometrial carcinoma (EC) were first described by The Cancer Genome Atlas (TCGA) a decade ago. Using surrogate approaches, the molecular classification has been demonstrated to be prognostic across EC patients and to have predictive implications. Starting in 2020, the molecular classification has been incorporated into multiple guidelines as part of the risk assessment and most recently into the International Federation of Gynecology and Obstetrics (FIGO) staging. This review article discusses the implementation of the EC molecular classification into clinical practice, the therapeutic implications, and the molecular and clinical heterogeneity of the EC molecular subtypes.
MeSH term(s)	Female ; Humans ; Neoplasm Staging ; Endometrial Neoplasms/genetics ; Endometrial Neoplasms/therapy ; Endometrial Neoplasms/pathology ; Prognosis
Language	English
Publishing date	2023-12-28
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	82063-5
ISSN	1096-9098 ; 0022-4790
ISSN (online)	1096-9098
ISSN	0022-4790
DOI	10.1002/jso.27552
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Zs.A 706: Show issues

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Article: Molecular profiling of primary endometrioid endometrial cancer and matched lung metastases:

Gordhandas, Sushmita / Da Cruz Paula, Arnaud / Kertowidjojo, Elizabeth C / Pareja, Fresia / Dessources, Kimberly / da Silva, Edaise M / Derakhshan, Fatemeh / Mueller, Jennifer J / Abu-Rustum, Nadeem R / Herman Chui, M / Weigelt, Britta

Gynecologic oncology reports

2024 Volume 53, Page(s) 101391

Abstract: Both primary endometrial cancers (ECs) and matched lung metastases shared a common ancestor with independent evolution at each site.•The two endometrioid ECs studied acquired additional mutations during the distant metastatic process.• ... ...

Abstract	•Both primary endometrial cancers (ECs) and matched lung metastases shared a common ancestor with independent evolution at each site.•The two endometrioid ECs studied acquired additional mutations during the distant metastatic process.•Subclonal
Language	English
Publishing date	2024-04-10
Publishing country	Netherlands
Document type	Case Reports
ZDB-ID	2818505-5
ISSN	2352-5789
ISSN	2352-5789
DOI	10.1016/j.gore.2024.101391
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Article ; Online: Histologic and genomic characterization of a primary mucinous carcinoma of the skin.

Papanastasiou, Anastasios D / De Filippo, Maria R / Sirinian, Chaido / Selenica, Pier / Repanti, Maria / Reis-Filho, Jorge S / Weigelt, Britta

EJC skin cancer

2023 Volume 1

Abstract: Aims: Primary skin mucinous carcinoma is a rare sweat gland neoplasm with a high local recurrence rate after conventional excision but a low distant-metastasis rate. The genetic underpinning of skin mucinous carcinoma is presently unknown. Here, we ... ...

Abstract	Aims: Primary skin mucinous carcinoma is a rare sweat gland neoplasm with a high local recurrence rate after conventional excision but a low distant-metastasis rate. The genetic underpinning of skin mucinous carcinoma is presently unknown. Here, we sought to define whether the repertoire of somatic mutations of a primary mucinous carcinoma of the skin would be similar to that of mucinous breast carcinomas, given the histologic similarities between these tumor types. Methods and results: The tumor was situated in the dermis and partially involved the subcutaneous fat. Tumor cells were suspended in periodic acid-Schiff diastaseresistant- positive mucin lakes and expressed cytokeratin 7, synaptophysin and estrogen receptor. DNA samples extracted from microdissected tumor and matched normal tissue were subjected to massively parallel sequencing targeting 410 cancer-related genes. The skin mucinous tumor was found to have a low tumor mutation burden, but to harbor a clonal Conclusions: In this primary skin mucinous carcinoma,
Language	English
Publishing date	2023-11-22
Publishing country	England
Document type	Journal Article
ISSN	2772-6118
ISSN (online)	2772-6118
DOI	10.1016/j.ejcskn.2023.100011
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Article ; Online: Ovarian RASoma With Mesonephric-like Adenocarcinoma and Mixed Mullerian Components: A Case Report With Molecular Analysis Demonstrating Multidirectional Mullerian Differentiation.

Stolnicu, Simona / Bartalis, Rolland-Jozsef / Ye, Qiqi / Da Cruz Paula, Arnaud / Weigelt, Britta / Soslow, Robert A

International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists

2023 Volume 42, Issue 6, Page(s) 620–626

Abstract: Gynecologic carcinomas with RAS mutations may show a wide spectrum of histologic types, including mixed types. We present the case of a 63-yr-old patient diagnosed with an ovarian tumor harboring a mesonephric-like adenocarcinoma in a background of mixed ...

Abstract	Gynecologic carcinomas with RAS mutations may show a wide spectrum of histologic types, including mixed types. We present the case of a 63-yr-old patient diagnosed with an ovarian tumor harboring a mesonephric-like adenocarcinoma in a background of mixed mesonephric-like, mucinous, and endometrioid components. Molecular analysis revealed that all 3 components shared the same clonal KRAS mutation (p.G12A) and chromosome 1q gain. Based on shifts in clonality, copy number gains, and acquisition of an additional mutation, our data suggest that the mucinous component likely constituted the substrate from which the mesonephric-like and endometrioid components arose.
MeSH term(s)	Female ; Humans ; Adenocarcinoma/diagnosis ; Adenocarcinoma/genetics ; Adenocarcinoma/pathology ; Endometrium/pathology ; Mutation ; Ovarian Neoplasms/diagnosis ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/pathology ; Middle Aged
Language	English
Publishing date	2023-01-09
Publishing country	United States
Document type	Case Reports ; Journal Article
ZDB-ID	604859-6
ISSN	1538-7151 ; 0277-1691
ISSN (online)	1538-7151
ISSN	0277-1691
DOI	10.1097/PGP.0000000000000935
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Zs.A 1814: Show issues

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Article ; Online: Molecular and pathologic data to guide selection of patients with endometrioid endometrial cancer for ovarian preservation.

Manning-Geist, Beryl L / Rios-Doria, Eric / Liu, Ying L / Ellenson, Lora H / Zhou, Qin C / Iasonos, Alexia / Leitao, Mario M / Abu-Rustum, Nadeem R / Weigelt, Britta / Mueller, Jennifer J

International journal of gynecological cancer : official journal of the International Gynecological Cancer Society

2024

Abstract: Objectives: To investigate the association of molecular and pathologic factors with concurrent or recurrent ovarian disease to guide ovarian preservation in endometrioid endometrial cancer.: Methods: Patients with endometrial cancer ≤50 years of age ... ...

Abstract	Objectives: To investigate the association of molecular and pathologic factors with concurrent or recurrent ovarian disease to guide ovarian preservation in endometrioid endometrial cancer. Methods: Patients with endometrial cancer ≤50 years of age at diagnosis were grouped by elective oophorectomy versus ovarian preservation at staging (January 2010 to June 2021). Tumors were stratified by molecular sub-type and Results: Among 317 patients with endometrial cancer who underwent bilateral oophorectomy, 27 (9%) had malignant ovarian tumors, of whom 11 (41%) had no gross ovarian involvement on intra-operative survey. For patients with sequencing, concurrent malignant ovarian tumors were diagnosed in 0/14 (0%) Conclusions: The integration of molecular and pathologic data may improve risk stratification of pre-menopausal patients with endometrial cancer and enhance candidate selection for ovarian preservation.
Language	English
Publishing date	2024-04-11
Publishing country	England
Document type	Journal Article
ZDB-ID	1070385-8
ISSN	1525-1438 ; 1048-891X
ISSN (online)	1525-1438
ISSN	1048-891X
DOI	10.1136/ijgc-2023-005194
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Zs.A 3198: Show issues

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Article ; Online: Problematic breast tumors reassessed in light of novel molecular data.

Pareja, Fresia / Weigelt, Britta / Reis-Filho, Jorge S

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc

2020 Volume 34, Issue Suppl 1, Page(s) 38–47

Abstract: Breast cancer is a vastly heterogeneous disease encompassing a panoply of special histological subtypes. Although rare breast tumors have largely not been investigated systematically in large scale genomics series, recent studies have shed light on the ... ...

Abstract	Breast cancer is a vastly heterogeneous disease encompassing a panoply of special histological subtypes. Although rare breast tumors have largely not been investigated systematically in large scale genomics series, recent studies have shed light on the genetic underpinnings of special histologic subtypes of breast cancer. Genomic analyses of estrogen receptor-positive special histologic types of breast cancer have not resulted in the identification of novel pathognomonic genetic alterations in addition to the confirmation of the presence of CDH1 loss-of-function mutations in invasive lobular carcinomas. By contrast, the analyses of triple-negative breast cancers have demonstrated that low-grade triple-negative breast cancers categorically differ from the common forms of high-grade triple-negative disease biologically and phenotypically and are underpinned by specific fusion genes or hotspot mutations. A subset of low-grade triple-negative disease has been shown to harbor highly recurrent if not pathognomonic genetic alterations, such as ETV6-NTRK3 fusion gene in secretory carcinomas, the MYB-NFIB fusion gene, MYBL1 rearrangements or MYB gene amplification in adenoid cystic carcinomas, and HRAS Q61 hotspot mutations coupled with mutations in PI3K pathway genes in estrogen receptor-negative adenomyoepitheliomas. A subset of these pathognomonic genetic alterations (e.g., NTRK1/2/3 fusion genes) now constitute an FDA approved indication for the use of TRK inhibitors in the advanced/metastatic setting. These studies have also corroborated that salivary gland-like tumors of the breast, other than acinic cell carcinomas, harbor the repertoire of somatic genetic alterations detected in their salivary gland counterparts. Reassuringly, the systematic study of special histologic types of breast cancer utilizing state-of-the-art sequencing approaches, rather than rendering pathology obsolete, has actually strengthened the importance of breast cancer histologic typing and is providing additional ancillary markers for the diagnosis of these rare but fascinating entities.
MeSH term(s)	Adenomyoepithelioma/diagnosis ; Adenomyoepithelioma/genetics ; Adenomyoepithelioma/pathology ; Antigens, CD/analysis ; Antigens, CD/genetics ; Biomarkers, Tumor/analysis ; Biomarkers, Tumor/genetics ; Breast/pathology ; Breast Neoplasms/diagnosis ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Cadherins/analysis ; Cadherins/genetics ; Carcinoma/diagnosis ; Carcinoma/genetics ; Carcinoma/pathology ; Carcinoma, Acinar Cell/diagnosis ; Carcinoma, Acinar Cell/genetics ; Carcinoma, Acinar Cell/pathology ; Carcinoma, Lobular/diagnosis ; Carcinoma, Lobular/genetics ; Carcinoma, Lobular/pathology ; Diagnosis, Differential ; Female ; Genomics/methods ; Humans ; Mutation ; Neoplasm Grading ; Oncogene Proteins, Fusion/analysis ; Oncogene Proteins, Fusion/genetics ; Pathology, Molecular ; Triple Negative Breast Neoplasms/diagnosis ; Triple Negative Breast Neoplasms/genetics ; Triple Negative Breast Neoplasms/pathology
Chemical Substances	Antigens, CD ; Biomarkers, Tumor ; CDH1 protein, human ; Cadherins ; Oncogene Proteins, Fusion
Language	English
Publishing date	2020-10-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	645073-8
ISSN	1530-0285 ; 0893-3952
ISSN (online)	1530-0285
ISSN	0893-3952
DOI	10.1038/s41379-020-00693-7
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