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Clinicopathological features and prognostic significance of CTNNB1 mutation in low-grade, early-stage endometrial endometrioid carcinoma.

ABSTRACT: Low-grade and early-stage endometrioid endometrial carcinomas (EECs) have an overall good prognosis but biomarkers identifying patients at risk of relapse are still lacking. Recently, CTNNB1 exon 3 mutation has been identified as a potential risk factor of recurrence in these patients. We evaluate the prognostic value of CTNNB1 mutation in a single-centre cohort of 218 low-grade, early-stage EECs, and the correlation with beta-catenin and LEF1 immunohistochemistry as candidate surrogate markers. CTNNB1 exon 3 hotspot mutations were evaluated by Sanger sequencing. Immunohistochemical staining of mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6), p53, beta-catenin, and LEF1 was performed in representative tissue microarrays. Tumours were also reviewed for mucinous and squamous differentiation, and MELF pattern. Nineteen (8.7%) tumours harboured a mutation in CTNNB1 exon 3. Nuclear beta-catenin and LEF1 were significantly associated with CTNNB1 mutation, showing nuclear beta-catenin a better specificity and positive predictive value for CTNNB1 mutation. Tumours with CTNNB1 exon 3 mutation were associated with reduced disease-free survival (p = 0.010), but no impact on overall survival was found (p = 0.807). The risk of relapse in tumours with CTNNB1 exon 3 mutation was independent of FIGO stage, tumour grade, mismatch repair protein expression, or the presence of lymphovascular space invasion. CTNNB1 exon 3 mutation has a negative impact on disease-free survival in low-grade, early-stage EECs. Nuclear beta-catenin shows a higher positive predictive value than LEF1 for CTNNB1 exon 3 mutation in these tumours.

SUBMITTER: Ruz-Caracuel I

PROVIDER: S-EPMC8724178 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Our aim was to investigate whether molecular classification can be used to refine prognosis in grade 3 endometrial endometrioid carcinomas (EECs). Grade 3 EECs were classified into 4 subgroups: p53 abnormal, based on mutant-like immunostaining (p53abn); MMR deficient, based on loss of mismatch repair protein expression (MMRd); presence of POLE exonuclease domain hotspot mutation (POLE); no specific molecular profile (NSMP), in which none of these aberrations were present. Overall survival (OS) and recurrence-free survival (RFS) rates were compared using the Kaplan-Meier method (Log-rank test) and univariable and multivariable Cox proportional hazard models. In total, 381 patients were included. The median age was 66 years (range, 33 to 96?y). Federation Internationale de Gynecologie et d'Obstetrique stages (2009) were as follows: IA, 171 (44.9%); IB, 120 (31.5%); II, 24 (6.3%); III, 50 (13.1%); IV, 11 (2.9%). There were 49 (12.9%) POLE, 79 (20.7%) p53abn, 115 (30.2%) NSMP, and 138 (36.2%) MMRd tumors. Median follow-up of patients was 6.1 years (range, 0.2 to 17.0?y). Compared to patients with NSMP, patients with POLE mutant grade 3 EEC (OS: hazard ratio [HR], 0.36 [95% confidence interval, 0.18-0.70]; P=0.003; RFS: HR, 0.17 [0.05-0.54]; P=0.003) had a significantly better prognosis; patients with p53abn tumors had a significantly worse RFS (HR, 1.73 [1.09-2.74]; P=0.021); patients with MMRd tumors showed a trend toward better RFS. Estimated 5-year OS rates were as follows: POLE 89%, MMRd 75%, NSMP 69%, p53abn 55% (Log rank P=0.001). Five-year RFS rates were as follows: POLE 96%, MMRd 77%, NSMP 64%, p53abn 47% (P=0.000001), respectively. In a multivariable Cox model that included age and Federation Internationale de Gynecologie et d'Obstetrique stage, POLE and MMRd status remained independent prognostic factors for better RFS; p53 status was an independent prognostic factor for worse RFS. Molecular classification of grade 3 EECs reveals that these tumors are a mixture of molecular subtypes of endometrial carcinoma, rather than a homogeneous group. The addition of molecular markers identifies prognostic subgroups, with potential therapeutic implications.

Project description:Study designRetrospective cohort study.IntroductionDebates remain regarding the role of lymphadenectomy in patients with apparent stage IA endometrial cancer, especially subtypes with a favorable prognosis. This study aimed to explore the prognostic value of staging surgeries in apparent stage IA endometrial endometrioid cancer patients in a retrospective cohort study.MethodsCases from June 1, 2010 to June 1, 2017 were reviewed in patients with pathologically confirmed endometrial endometrioid carcinoma limited to <1/2 of the myometrium, without extrauterine metastasis on preoperative evaluation and during surgical inspection. Survival outcomes were compared between patients with and without lymphadenectomy and between patients with and without metastasis to lymph nodes.ResultsIn total, 1,312 eligible patients were included, among which 836 underwent staging surgeries and 476 underwent simple hysterectomy. Twenty-eight patients were found with metastasis to retroperitoneal lymph nodes. After a median follow-up of 57.4 months, lost to follow-up, recurrence, death, and cancer-specific death occurred in 28, 39, 24, and 16 patients, respectively. In a univariate analysis, lymphadenectomy of the pelvis with or without para-aortic lymph nodes had no significant impact on disease-free survival, overall survival or cancer-specific overall survival (p values >0.05). However, after adjusting for important baseline risk factors [menopausal status, tumor differentiation, maximum diameter and location, lymph-vascular space invasion (LVSI) status, and postoperative adjuvant therapy), lymphadenectomy resulted in significantly improved survival outcomes (p values <0.05). Menopause (odds ratio [OR] 4.7, 95% confidence interval [CI] 1.3-16.4, p=0.015), tumor diameter larger than 2 cm (OR 4.6, 95% CI 1.3-16.0, p=0.016), grade 3 tumors (OR 3.0, 95% CI 1.0-8.5, p=0.042), positive LVSI (OR 8.7, 95% CI 3.7-20.4, p<0.001) and lower uterine segment involvement (OR 3.1, 95% CI 1.4-7.2, p=0.007) had more extrauterine metastases.ConclusionIn cases of apparent stage IA endometrioid endometrial carcinoma, staging surgeries should be considered in patients with larger, higher grade tumors, positive LVSI, or lower uterine segment involvement.

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Clinicopathological features and prognostic significance of CTNNB1 mutation in low-grade, early-stage endometrial endometrioid carcinoma.

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