Molecular Classification to Prognosticate Response in Medically Managed Endometrial Cancers and Endometrial Intraepithelial Neoplasia.
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ABSTRACT: Background
The aim of this study was to evaluate whether molecular classification prognosticates treatment response in women with endometrial cancers and endometrial intraepithelial neoplasia (EIN) treated with levonorgestrel intrauterine system (LNG-IUS).Methods
Patients treated with LNG-IUS for endometrial cancer or EIN from 2013 to 2018 were evaluated. Using immunohistochemistry and single gene sequencing of POLE, patients were classified into four groups as per the Proactive Molecular Risk Classifier for Endometrial cancer (ProMisE): POLE-mutated, mismatch repair-deficient (MMRd), p53 wild type (p53wt), and p53-abnormal (p53abn). Groups were assessed relative to the primary outcome of progression or receipt of definitive treatment.Results
Fifty-eight subjects with endometrioid endometrial cancer or EIN treated with LNG-IUS were included. Of these, 22 subjects (37.9%) had endometrial cancer and 36 subjects (62.1%) had EIN. Per the ProMisE algorithm, 44 patients (75.9%) were classified as p53wt, 6 (10.3%) as MMRd, 4 (6.9%) as p53abn, and 4 (6.9%) as POLE-mutated. Of the 58 patients, 11 (19.0%) progressed or opted for definitive therapy. Median time to progression or definitive therapy was 7.5 months, with p53abn tumors having the shortest time to progression or definitive therapy.Conclusions
Molecular classification of endometrial cancer and EIN prior to management with LNG-IUS is feasible and may predict patients at risk of progression.
SUBMITTER: Puechl AM
PROVIDER: S-EPMC8201008 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:The aim was to estimate the risk of subsequent extra-cervical Human Papillomavirus (HPV) related cancer in patients surgically treated for high grade cervical intraepithelial neoplasia (CIN 2-3). This is the first study in Italy investigating the occurrence of extra-cervical tumors in this cohort of patients. METHODS:3184 patients surgically treated for CIN2-3 since 1992 at the Department of Surgical Sciences of University of Torino were considered. The risk of HPV-related cancer was calculated as Standardized Incidence Ratio (SIR), using as expected values tumour age specific incidence of resident population. RESULTS:173?second primary cancer (SCPs) were identified. SIR to develop cancer after treatment for CIN2-3 was 2.2 (CI 95% 1.89-2.50). Among these occurrences, 10 are in HPV related sites: 1 anus (SIR?=?1.8; 0.04-10.0), 3 vagina (SIR?=?12.4; 2.56-36.3), 1 vulva (SIR?=?1.7; 0.04-9.59), 5 oropharynx (SIR?=?8.5; 2.76-19.8). Significant risk has been also recorded for pulmonary (SIR?=?3.1; 0.70-5.27) and bladder (SIR?=?4.05; 1.10-10.56), with smoking as possible cofactor. We also found increased risk for breast (SIR?=?2.4; 2.07-2.84) and ovarian cancers (SIR?=?2.1; 1.13-3.49), probably due to an higher adherence to spontaneous and programmed screening programs. CONCLUSIONS:Our study supports the hypothesis of an increased risk of HPV-related tumours for CIN treated patients, mostly for CIN3. It is conceivable the need of early diagnosis for these cancers in this higher-risk populations.
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Project description:The mortality associated with cervical cancer can be reduced if detected at the precancer stage, but current methods are limited in terms of subjectivity, cost and time. Optical spectroscopic methods such as Raman spectroscopy can provide a rapid, label-free and nondestructive measurement of the biochemical fingerprint of a cell, tissue or biofluid. Previous studies have shown the potential of Raman spectroscopy for cervical cancer diagnosis, but most were pilot studies with small sample sizes. The aim of this study is to show the clinical utility of Raman spectroscopy for identifying cervical precancer in a large sample set with validation in an independent test set. Liquid-based cervical cytology samples (n = 662) (326 negative, 200 cervical intraepithelial neoplasia (CIN)1 and 136 CIN2+) were obtained as a training set. Raman spectra were recorded from single-cell nuclei and subjected to a partial least squares discriminant analysis (PLSDA). In addition, the PLSDA classification model was validated using a blinded independent test set (n = 69). A classification accuracy of 91.3% was achieved with only six of the blinded samples misclassified. This study showed the potential clinical utility of Raman spectroscopy with a good classification of negative, CIN1 and CIN2+ achieved in an independent test set.
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Project description:BackgroundMost endometrial cancer cases are preceded by abnormal uterine bleeding, offering a potential opportunity for early detection and cure of endometrial cancer. Although clinical guidelines exist for diagnostic workup of abnormal uterine bleeding, consensus is lacking regarding optimal management for women with abnormal bleeding to diagnose endometrial cancer.ObjectiveWe report the baseline data from a prospective clinical cohort study of women referred for endometrial evaluation at the Mayo Clinic, designed to evaluate risk stratification in women at increased risk for endometrial cancer. Here, we introduce a risk-based approach to evaluate diagnostic tests and clinical management algorithms in a population of women with abnormal bleeding undergoing endometrial evaluation at the Mayo Clinic.Study designA total of 1163 women aged ≥45 years were enrolled from February 2013 to May 2019. We evaluated baseline absolute risks and 95% confidence intervals of endometrial cancer and endometrial intraepithelial neoplasia according to clinical algorithms for diagnostic workup of women with postmenopausal bleeding (assessment of initial vs recurrent bleeding episode and endometrial thickness measured through transvaginal ultrasound). We also evaluated risks among women with postmenopausal bleeding according to baseline age (<60 vs 60+ years) as an alternative example. For this approach, biopsy would be conducted for all women aged 60+ years and those aged <60 years with an endometrial thickness of >4 mm. We assessed the clinical efficiency of each strategy by estimating the percentage of women who would be referred for endometrial biopsy, the percentage of cases detected and missed, and the ratio of biopsies per case detected.ResultsAmong the 593 women with postmenopausal bleeding, 18 (3.0%) had endometrial intraepithelial neoplasia, and 47 (7.9%) had endometrial cancer, and among the 570 premenopausal women with abnormal bleeding, 8 (1.4%) had endometrial intraepithelial neoplasia, and 7 (1.2%) had endometrial cancer. Maximum risk was noted in women aged 60+ years (17.7%; 13.0%-22.3%), followed by those with recurrent bleeding (14.7%; 11.0%-18.3%). Among women with an initial bleeding episode for whom transvaginal ultrasound was recommended, endometrial thickness did not provide meaningful risk stratification: risks of endometrial cancer and endometrial intraepithelial neoplasia were nearly identical in women with an endometrial thickness of >4 mm (5.8%; 1.3%-10.3%) and ≤4 mm (3.6%; 0.9%-8.6%). In contrast, among those aged <60 years with an endometrial thickness of >4 mm, the risk of endometrial cancer and endometrial intraepithelial neoplasia was 8.4% (4.3%-12.5%), and in those with an endometrial thickness of ≤4 mm, the risk was 0% (0.0%-3.0%; P=.01). The most efficient strategy was to perform biopsy in all women aged 60+ years and among those aged <60 years with an endometrial thickness of >4 mm, with the lowest percentage referred to biopsy while still detecting all cases.ConclusionExisting clinical recommendations for endometrial cancer detection in women with abnormal bleeding are not consistent with the underlying risk. Endometrial cancer risk factors such as age can provide important risk stratification compared with the assessment of recurrent bleeding. Future research will include a formal assessment of clinical and epidemiologic risk prediction models in our study population as well as validation of our findings in other populations.
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Project description:ObjectiveTo study the long term risk of cervical and other cancers after treatment for cervical intraepithelial neoplasia.DesignRetrospective cohort study.SettingUniversity Hospital, Helsinki, Finland.Participants7564 women treated for cervical intraepithelial neoplasia during 1974 and 2001 and followed up through the Finnish cancer registry until 2003.Main outcome measuresStandardised incidence ratio for cervical cancer and other cancers.ResultsDuring follow-up 22 cases of invasive cervical cancer occurred in women treated for cervical intraepithelial neoplasia (standardised incidence ratio 2.8, 95% confidence interval 1.7 to 4.2). The highest risk was during the second decade (10 cases observed: 3.1, 1.5 to 5.7). The standardised incidence ratio for cervical intraepithelial cancer type 1 was 3.1 (1.4 to 6.2) and for type 2 was 3.7 (0.9 to 10.7).ConclusionsThe risk of cervical cancer in the first 20 years after treatment for cervical intraepithelial neoplasia is higher than in the average population. The risk of smoking related cancers is also increased.
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Project description:BackgroundMultiplatform molecular subtyping has been put into clinical practice as an alternative for The Cancer Genome Atlas (TCGA)-based classification for endometrial cancer (EC), which proved a tool for predicting prognosis and guiding treatment. The traditional methods for the molecular classification of EC only based on pathological indicators are not accurate. The present study aimed to classify EC on a molecular level and explored the possibility of a one-time solution to guide clinical treatment and prognosis determination by utilizing data from a next-generation sequencing (NGS) panel. The ultimate aim was to utilize multiplatform testing to overcome disadvantages of long detection periods and limitations in the information regarding genetic variation.MethodsAn NGS-panel was produced using FFPE samples isolated from 86 patients pathologically diagnosed with EC, and molecular subtyping was performed according to the recommended criteria. In addition, 45 matched samples from 86 patients were randomly selected for immunohistochemical (IHC) staining of P53, MLH1, MSH2, PMS2, and MSH6. Another 41 samples were not analyzed due to incomplete IHC staining results. SPSS (V26.0; IBM Corp., Armonk, NY, USA) was used for receiver operating characteristic (ROC) curve analysis.ResultsThe molecular typing ratio of the 86 cases of endometrial carcinoma was calculated to be 16.28% for POLE type, 17.44% for MSI-H type, 47.67% for CN-L type, 12.79% for CN-H type, 5.81% for unclassified case. A comparison between IHC ProMisE-based subtyping and NGS-based subtyping of the 45 cases revealed that 3 cases were classified as MSI-H by IHC but as MSS by NGS. Among these cases, 1 case was deficient in MLH1 expression and PMS2 protein expression but had wild-type P53 protein, and the P53 sequencing data of this sample showed a missense mutation. Good overall consistency between the 2 determination methods was shown. Receiver operating characteristic (ROC) analysis showed that NGS had particularly high specificity and sensitivity for detecting the MSI and CN subtypes [area under the curve (AUC) =0.893>0.5, P=0.000029<0.01].ConclusionsThe present study suggested that NGS-based subtyping could serve as an effective approach for the molecular typing of EC. Both NGS and IHC bear their own unique advantages and challenges in clinical practice.
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