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

2021 ◽  
Vol 13 ◽  
pp. 175883592110359
Author(s):  
Amy Jamieson ◽  
Tjalling Bosse ◽  
Jessica N. McAlpine
Keyword(s):  
Endometrial Cancer ◽  
Molecular Subtypes ◽  
Treatment Decision ◽  
Molecular Classification ◽  
The Cancer Genome Atlas ◽  
Molecular Profile ◽  
Therapeutic Implications ◽  
Treatment Decision Making ◽  
Exciting Time ◽  
Classification Tool

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.

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

2020 ◽  
Vol 38 (29) ◽  
pp. 3388-3397 ◽  
Author(s):  
Alicia León-Castillo ◽  
Stephanie M. de Boer ◽  
Melanie E. Powell ◽  
Linda R. Mileshkin ◽  
Helen J. Mackay ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
High Risk ◽  
Prognostic Value ◽  
Cox Model ◽  
Molecular Classification ◽  
The Cancer Genome Atlas ◽  
Adjuvant Chemoradiotherapy ◽  
Molecular Profile ◽  
Rank Test ◽  
Radiotherapy Alone

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.

scholarly journals Mismatch Repair Deficiency as a Predictive and Prognostic Biomarker in Molecularly Classified Endometrial Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3124
Author(s):  
Mikko Loukovaara ◽  
Annukka Pasanen ◽  
Ralf Bützow
Keyword(s):  
Risk Factors ◽  
Mismatch Repair ◽  
Molecular Classification ◽  
The Cancer Genome Atlas ◽  
Molecular Profile ◽  
New Therapeutic Approaches ◽  
Increased Risk ◽  
Mmr Deficiency ◽  
Endometrial Carcinomas ◽  
Risk Of Cancer

The aggressiveness of mismatch repair (MMR) deficient endometrial carcinomas was examined in a single institution retrospective study. Outcomes were similar for MMR proficient (n = 508) and deficient (n = 287) carcinomas, identified by immunohistochemistry. In accordance with molecular classification based on The Cancer Genome Atlas (TCGA), tumors with abnormal p53 staining or polymerase-ϵ exonuclease domain mutation were excluded from the MMR proficient subgroup, termed as “no specific molecular profile” (NSMP). Compared with NSMP (n = 218), MMR deficiency (n = 191) was associated with poor disease-specific survival (p = 0.001). MMR deficiency was associated with an increased risk of cancer-related death when controlling for confounders (hazard ratio 2.0). In the absence of established clinicopathologic risk factors, MMR deficiency was invariably associated with an increased risk of cancer-related death in univariable analyses (hazard ratios ≥ 2.0). In contrast, outcomes for MMR deficient and NSMP subgroups did not differ when risk factors were present. Lymphatic dissemination was more common (p = 0.008) and the proportion of pelvic relapses was higher (p = 0.029) in the MMR deficient subgroup. Our findings emphasize the need for improved triage to adjuvant therapy and new therapeutic approaches in MMR deficient endometrial carcinomas.

scholarly journals Recurrent hormone-binding domain truncated ESR1 amplifications in primary endometrial cancers suggest their implication in hormone independent growth

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Frederik Holst ◽  
Erling A. Hoivik ◽  
William J. Gibson ◽  
Amaro Taylor-Weiner ◽  
Steven E. Schumacher ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endometrial Cancer ◽  
Acquired Resistance ◽  
Estrogen Therapy ◽  
Binding Domain ◽  
The Cancer Genome Atlas ◽  
Breast Cancers ◽  
Hormone Binding ◽  
Therapeutic Implications ◽  
Hormone Binding Domain

Abstract The estrogen receptor alpha (ERα) is highly expressed in both endometrial and breast cancers, and represents the most prevalent therapeutic target in breast cancer. However, anti-estrogen therapy has not been shown to be effective in endometrial cancer. Recently it has been shown that hormone-binding domain alterations of ERα in breast cancer contribute to acquired resistance to anti-estrogen therapy. In analyses of genomic data from The Cancer Genome Atlas (TCGA), we observe that endometrial carcinomas manifest recurrent ESR1 gene amplifications that truncate the hormone-binding domain encoding region of ESR1 and are associated with reduced mRNA expression of exons encoding the hormone-binding domain. These findings support a role for hormone-binding alterations of ERα in primary endometrial cancer, with potentially important therapeutic implications.

scholarly journals Treatment preferences and involvement in treatment decision making of patients with endometrial cancer and clinicians

2014 ◽  
Vol 111 (4) ◽  
pp. 674-679 ◽  
Author(s):  
M Kunneman ◽  
A H Pieterse ◽  
A M Stiggelbout ◽  
R A Nout ◽  
M Kamps ◽  
...  
Keyword(s):  
Decision Making ◽  
Endometrial Cancer ◽  
Treatment Decision ◽  
Treatment Preferences ◽  
Treatment Decision Making

Diagnostic utility and prognostic performance of a 92-gene cancer classifier to molecularly profile periampullary adenocarcinomas.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 197-197 ◽  
Author(s):  
Michael J. Overman ◽  
Huamin Wang ◽  
Catherine A. Schnabel ◽  
Jeff Anderson ◽  
Mark G. Erlander ◽  
...  
Keyword(s):  
Molecular Classification ◽  
Good Prognosis ◽  
Molecular Profile ◽  
Molecular Testing ◽  
Diagnostic Utility ◽  
Prognostic Performance ◽  
Therapeutic Implications ◽  
Rna Profiling ◽  
Gene Assay

197 Background: Due to the small anatomic size, multiplicity of epitheliums, and suboptimal diagnostics determining the site of origin of periampullary adenocarcinomas (PAA) is a challenge. We investigated the ability of a 92-gene RT-PCR assay (CancerTYPE ID) to categorize PAA and to prognostically stratify ampullary adenocarcinomas. Methods: 45 PAA patients who underwent pancreaticoduodenectomies were included; samples were histopathologically verified for tumor subtype determination (pancreatic, extrahepatic biliary, ampullary, or duodenal). Blinded FFPE tumor sections underwent molecular testing and were compared for concordance to histopathological tumor types and prognostic performance. 28 of these samples had previously undergone whole-genome RNA profiling (Overman et al. GI ASCO 2011 a161). Results: Molecular classification of 43 (96%) evaluable samples (13 ampullary, 10 pancreatic, 10 biliary, 10 duodenal) showed 91% concordance: ampullary [5 intestinal (int), 7 pancreaticobiliary (pb)], pancreatic [10 pb], duodenal [3 int, 7 gastroesophageal (ge)], biliary [7 pb]. The 92-gene assay was prognostic with a median OS of 70 m for ge/int cases vs. 32 m for pb cases, P=0.05. Discordant classifications were ge for 1 ampullary and 2 biliary samples, and ovary for 1 biliary case. Previous unsupervised RNA hierarchical clustering of all 13 ampullary cases had identified two prognostic groups (a good-prognosis int-like and a poor-prognosis pb-like), which were identical to the 92-gene classification for 12 cases (5 int and 7 pb). These two ampullary subgroups were prognostic with median OS of 63 vs. 24 m, P=0.07, respectively. Conclusions: The 92-gene assay demonstrated diagnostic utility for molecular site-of-origin classification of PAA. These results support exploration of this approach for the management of metastatic PAA (in which pathologic review of a primary resection specimen is not an option). Molecular classification of ampullary adenocarcinomas into intestinal and pancreaticobiliary subgroups is prognostically relevant; these and the gastric-like molecular profile of duodenal adenocarcinomas may have therapeutic implications.

scholarly journals RNA-seq Reveals the Overexpression of IGSF9 in Endometrial Cancer

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Zonggao Shi ◽  
Chunyan Li ◽  
Laura Tarwater ◽  
Jun Li ◽  
Yang Li ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
The Cancer Genome Atlas ◽  
Rna Seq ◽  
Illumina Platform ◽  
Tissue Samples ◽  
Significance Level ◽  
Glandular Cells ◽  
Cancer Genome Atlas ◽  
Classification Tool ◽  
Gene Functional Classification

We performed RNA-seq on an Illumina platform for 7 patients with endometrioid endometrial carcinoma for which both tumor tissue and adjacent noncancer tissue were available. A total of 66 genes were differentially expressed with significance level at adjusted p value < 0.01. Using the gene functional classification tool in the NIH DAVID bioinformatics resource, 5 genes were found to be the only enriched group out of that list of genes. The gene IGSF9 was chosen for further characterization with immunohistochemical staining of a larger cohort of human endometrioid carcinoma tissues. The expression level of IGSF9 in cancer cells was significantly higher than that in control glandular cells in paired tissue samples from the same patients (p=0.008) or in overall comparison between cancer and the control (p=0.003). IGSF9 expression is higher in patients with myometrium invasion relative to those without invasion (p=0.015). Reanalysis of RNA-seq dataset from The Cancer Genome Atlas shows higher expression of IGSF9 in endometrial cancer versus normal control and expression was associated with poor prognosis. These results suggest IGSF9 as a new biomarker in endometrial cancer and warrant further studies on its function, mechanism of action, and potential clinical utility.

scholarly journals Mismatch repair deficiency: a step forward personalized medicine in endometrial cancer?

2016 ◽  
Vol 4 (2) ◽  
pp. 34-41
Author(s):  
Chiara Della Pepa ◽  
Susana Banerjee ◽  
Angela George
Keyword(s):  
Endometrial Cancer ◽  
Copy Number ◽  
Current Knowledge ◽  
Prognostic Significance ◽  
Good Prognosis ◽  
The Cancer Genome Atlas ◽  
Therapeutic Implications ◽  
Repair Deficiency ◽  
Cancer Genome Atlas

Endometrial cancer (EC) is the most common female malignancy in the world, it has traditionally been classified into two subgroups based on histopathological features, however this dualistic classification does not take into consideration subtypes such as high-grade endometrioid EC. Recently, work performed as part of The Cancer Genome Atlas study has focused on molecular genomic classification of EC, with four distinct molecular subtypes described: 1. POLE ultramutated, associated with a good prognosis; 2. Microsatellite instability (MSI) hypermutated; 3. Copy number low and microsatellite stable; 4. Copy number high, serous like, associated with a poor prognosis. The subgroup of patients with MSI is of particular interest for a number of reasons, including the use of tumour screening to identify patients with Lynch syndrome, the prognostic significance of MSI, and the potential therapeutic implications. This review will focus on the current knowledge in these areas and potential future directions.

Genomic characteristics of endometrial cancer in China.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e17569-e17569
Author(s):  
Hong Zheng ◽  
Lina Cui ◽  
Bei Zhang ◽  
Xiaochen Zhao
Keyword(s):  
Endometrial Cancer ◽  
Large Scale ◽  
White Blood Cells ◽  
Molecular Classification ◽  
The Cancer Genome Atlas ◽  
Nucleotide Polymorphisms ◽  
Coding Region ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Genomic Studies

e17569 Background: Molecular classification of endometrial cancer has been applied in patient stratification and treatment strategy. Although the Cancer Genome Atlas project and other genomic studies have established comprehensive molecular classification, its genomic characteristics in Chinese endometrial cancer remain unclear. Methods: Tumor tissue and matched white blood cells from 316 patients with endometrial cancer underwent next-generation sequencing (NGS), which targeted the whole coding region of 733 or 381 genes. Endometrial cancer was classified into four subtypes according to genomic characteristics: polymerase (POLE) ultramutated, microsatellite instability (MSI), TP53 wild type (TP53wt), and TP53 mutant (TP53mut). Tumor mutation burden (TMB) was calculated based on the number of somatic single nucleotide variants and indels in examined coding regions. Deleterious or suspected deleterious genes were included for analysis. Genomic instability was also evaluated with Homologous Recombination Deficiency (HRD) score by over 10, 000 single-nucleotide polymorphisms distributed across human genome. HRD algorithm combined loss of heterozygosity score (LOH), telomeric allelic imbalance score (TAI) and large-scale state transition score (LST). Results: The 316 endometrial cancer patients were divided into four subtypes: POLE ultramutated (16, 5.06%), MSI tumors (70, 22.2%), TP53wt (131, 41.5%), and TP53mut (99, 31.3%). Median TMB was 26.5 mut/Mb in overall cohort and POLE ultramutated subtype possessed the highest TMB (181 mut/Mb), followed by MSI (54.1 mut/Mb), TP53mut (7.11 mut/Mb) and TP53wt (6.61 mut/Mb) subtypes. POLE, PTEN, LRP1B, BRCA2 and ATRX were the top frequently mutated genes in POLE ultramutated subtype, which mutation rate are more that 80%. The most frequent mutations were detected in ARID1A, PTEN, PIK3CA in MSI subtype, TP53, PIK3CA, PTEN in TP53mut subtype, and PTEN, PIK3CA, ARID1A in TP53wt subtype. HRD score was significantly higher in TP53mut subtype, followed by TP53wt, MSI and POLE ultramutated subtype (median HRD score, 21.7, 6.15, 3.65 and 0; P < 0.001). Conclusions: Our study revealed the heterogeneous genomic characteristics of four molecular subtypes in Chinese endometrial cancer. POLE ultramutated and MSI subtypes display higher TMB. TP53mut subtype showed genome features of HRD and would likely benefit from HRD-targeted therapy.

Molecular classification of neuroendocrine tumors: Clinical experience with the 92-gene assay in >24,000 cases.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15700-e15700
Author(s):  
Andrew Eugene Hendifar ◽  
Harris S Soifer ◽  
Mason Israel ◽  
Catherine A. Schnabel
Keyword(s):  
Islet Cell ◽  
Treatment Decision ◽  
Large Cell ◽  
Molecular Classification ◽  
Tumor Type ◽  
Clinical Testing ◽  
Age And Gender ◽  
Treatment Decision Making ◽  
Gene Assay ◽  
And Gender

e15700 Background: Histological diagnosis of metastatic neuroendocrine tumors (NET) can be straightforward, but identification of the specific NET tumor type/subtype is often challenging based on morphology alone. Accurate identification of tumor type/subtype in NETs of unknown primary has implications for grading, staging, and treatment decision-making as availability of targeted therapies increases. The 92-gene assay (CancerTYPE ID) is a validated gene expression classifier of 50 tumor type/subtypes (including 7 NET subtypes) for patients with unknown/uncertain diagnoses. In this study, 92-gene assay results from cases submitted for clinical testing with molecular diagnoses of NET were evaluated. Methods: A de-identified database was created under an IRB approved protocol that contains clinical and molecular information from consecutive cases submitted for clinical testing with the 92-gene assay with sufficient tissue for testing. In this analysis, patient demographics and distribution of molecular diagnoses were analyzed based on biopsy site, age, and gender. Chi-squared tests were used to compare between subgroups. Results: Analysis included 24,484 patients. Median age was 65y (51% female). The 92-gene assay rendered a molecular diagnosis of NET in 6.3% of cases (n = 1551). Small/large cell lung carcinoma (50%) was the most common NET molecular diagnosis, followed by GI carcinoid (14%), islet cell (14%), Merkel cell (10%), and lung carcinoid (9%). In liver biopsies (39% of cases), all 7 NET subtypes were identified by the 92-gene assay. The proportion of molecular diagnoses classified as small/large cell lung NET increased with age, from 25% in < 40y to 45% in 40-65y and 55% in > 65y, and the proportion of islet cell NET decreased with age (p < 0.0001). Men had a higher proportion of molecular diagnoses that were small/large cell lung NET (53%) vs women (46%; p < 0.0001). Conclusions: These findings highlight the utility of molecular classification to identify distinct NET tumor types/subtypes to improve diagnostic precision and treatment decision-making. In addition, significant differences in the distribution of molecular diagnoses of NET subtype by age and gender were identified.

scholarly journals The TCGA Molecular Classification of Endometrial Cancer and Its Possible Impact on Adjuvant Treatment Decisions

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1478
Author(s):  
Matthias Alexa ◽  
Annette Hasenburg ◽  
Marco Johannes Battista
Keyword(s):  
Endometrial Cancer ◽  
Adjuvant Treatment ◽  
Copy Number ◽  
Histological Grade ◽  
Treatment Decision ◽  
Risk Groups ◽  
Molecular Classification ◽  
Treatment Decisions ◽  
P53 Expression

Adjuvant treatment decisions for endometrial cancer (EC) are based on stage, the histological grade of differentiation, histological subtype, and few histopathological markers. The Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) identified four risk groups of EC patients using a combination of immunohistochemistry and mutation analysis: Polymerase Epsilon exonuclease domain mutated (POLE EDM), mismatch repair deficient (MMRd), p53 wild-type/copy-number-low (p53 wt), and p53-mutated/copy-number-high (p53 abn). Patients allocated to the POLE or abnormal p53 expression subtype are faced with a significantly altered outcome possibly requiring a modified adjuvant treatment decision. Within this review, we summarize the development of ProMisE, characterize the four molecular subtypes, and finally discuss its value in terms of a patient-tailored therapy in order to prevent significant under or overtreatment.

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