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Prognostic Significance of Disseminated Tumor Cells in Bone Marrow for Endometrial Carcinoma Patients.

ABSTRACT: Background: Until now, limited clinical significance had been reported for disseminated tumor cells (DTCs) in gynecologic malignancies. DTCs were previously reported not to be associated with established risk factors, L1CAM immunoreactivity, and outcome in endometrial carcinoma (EC). This study's primary objective was to investigate potential correlations of DTCs in the bone marrow (BM) of EC patients with disease-related survival, and a secondary objective was to evaluate associations between molecular classification of EC and DTCs. Methods: Patients treated for primary EC at Tuebingen University women's hospital between 2003 and 2016 were identified. A total of 402 patients with a complete set of BM cytology, molecular, and clinical data were evaluable. Results: DTC occurrence was distributed equally among all four molecular groups (p = 0.651). DTC positivity was associated with a less favorable disease-free survival (HR: 1.86, 95% CI: 1.03-3.36, p = 0.036) and progression-free survival (HR: 1.86, 95% CI: 1.01-3.44, p = 0.045). Presence of DTCs was associated with a higher frequency of distant disease recurrence (p = 0.017). Conclusions: In line with our previous findings, tumor cell dissemination is not associated with molecular features in our large cohort of primary EC patients. Since DTCs seem to be associated with survival and location of disease recurrence, further studies are needed to decisively define their role in EC survival.

SUBMITTER: Volmer LL

PROVIDER: S-EPMC11313439 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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Prognostic Significance of Disseminated Tumor Cells in Bone Marrow for Endometrial Carcinoma Patients.

Volmer Léa Louise LL Grube Marcel M Rohner Annika A McAlpine Jessica Nell JN Talhouk Aline A Lum Amy A Matovina Sabine S Kommoss Stefan S Staebler Annette A Brucker Sara Yvonne SY Walter Christina Barbara CB

Journal of clinical medicine 20240731 15

<b>Background:</b> Until now, limited clinical significance had been reported for disseminated tumor cells (DTCs) in gynecologic malignancies. DTCs were previously reported not to be associated with established risk factors, L1CAM immunoreactivity, and outcome in endometrial carcinoma (EC). This study's primary objective was to investigate potential correlations of DTCs in the bone marrow (BM) of EC patients with disease-related survival, and a secondary objective was to evaluate associations be ...[more]

PMID: 39124757

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Project description:BackgroundCancer metastasis is the primary cause of cancer-related deaths and remains incurable. Current clinical methods for predicting metastatic recurrence are not sensitive enough to detect individual cancer cells in the body; therefore, current efforts are directed toward liquid biopsy-based assays to capture circulating and disseminated tumor cells (CTCs and DTCs) in the blood and bone marrow, respectively. The most promising strategy is fluorescence-based immunostaining using cancer cell-specific markers. However, despite recent efforts to develop robust processing and staining platforms, results from these platforms have been discordant among groups, particularly for DTC detection. While the choice of cancer cell-specific markers is a large factor in this discordance, we have found that marker-independent factors causing false signal are just as critical to consider. Bone marrow is particularly challenging to analyze by immunostaining because endogenous immune cell properties and bone marrow matrix components typically generate false staining. For immunostaining of whole tumor tissue containing ample cancer cells, this background staining can be overcome. Application of fluorescent-based staining for rare cells, however, is easily jeopardized by immune cells and autofluorescence that lead to false signal.ResultsWe have specifically found two types of background staining in bone marrow samples: autofluorescence of the tissue and non-specific binding of secondary antibodies. We systematically optimized a basic immunofluorescence protocol to eliminate this background using cancer cells spiked into human bone marrow. This enhanced the specificity of automated scanning detection software. Our optimized protocol also outperformed a commercial rare cell detection protocol in detecting candidate DTCs from metastatic patient bone marrow.ConclusionsRobust optimization to increase the signal-to-noise ratio of immunofluorescent staining of bone marrow is required in order to achieve the necessary sensitivity and specificity for rare cell detection. Background immunofluorescent staining in bone marrow causes uncertainty and inconsistency among investigators, which can be overcome by systematically addressing each contributing source. Our optimized assay eliminates sources of background signal, and is adaptable to automated staining platforms for high throughput analysis.

Project description:BackgroundSmall cell lung cancer (SCLC) is a highly aggressive disease characterized by early metastasis. Aneuploid CD31- disseminated tumor cells (DTCs) and CD31+ disseminated tumor endothelial cells (DTECs) residing in the bone marrow are generally considered as the initiators of metastatic process. However, the clinical significance of DTCs and DTECs in SCLC remains poorly understood. The aim of this study is to investigate the clinical implications of diverse subtypes of highly heterogeneous DTCs and DTECs in SCLC patients.MethodsSubtraction enrichment and immunostaining-fluorescence in situ hybridization (SE-iFISH) was applied to enrich and perform comprehensive morphologic, karyotypic, and phenotypic characterization of aneuploid DTCs and DTECs in 30 patients. Additionally, co-detection of circulating tumor cells (CTCs) and circulating tumor endothelial cells (CTECs) was conducted on 24 of the enrolled patients. Proof-of-concept of the whole exon sequencings (WES) on precisely selected different subtypes of CTCs or DTCs, longitudinally detected from a representative case with pathologically confirmed bone marrow metastasis, was validated to feasibly reveal genetic mutations in these cells.ResultsDTCs, DTECs and their subtypes were readily detectable in SCLC patients. Comparative analysis revealed that the number of DTCs and DTECs was significantly higher than that of their corresponding CTCs and CTECs (P < 0.001 for both). Positive detection of disseminated tumor microemboli (DTM) or disseminated tumor endothelial microemboli (DTEM) was associated with inferior survival outcomes (P = 0.046 and P = 0.048). Patients with EpCAM+ DTCs detectable displayed significantly lower disease control rate (DCR) (16.67% vs 73.33%, P = 0.019), reduced median progression-free survival (mPFS) and median overall survival (mOS) compared with those with EpCAM- DTCs (P = 0.028 and P = 0.002, respectively). WES analysis indicated that post-treatment DTCs isolated from bone marrow at the time of disease progression shared more homologous somatic gene mutations with pre-treatment CTCs compared with post-treatment CTCs.ConclusionsOur findings suggest that bone marrow sampling and characterization of DTC subtypes provided a valuable tool for predicting treatment response and the prognosis in SCLC. Moreover, DTCs inherit a greater amount of homologous somatic information from pre-treatment CTCs, indicating their potential role in disease progression and treatment resistance.

Project description:Background:Uterine corpus endometrial carcinoma (UCEC) is a clinically heterogeneous disease, and this heterogeneity is associated with tumor development, clinical characteristics, and prognostic outcomes. Mutant-allele tumor heterogeneity (MATH) is a novel, non-biased, quantitative measure to assess intra-tumor heterogeneity based on next-generation sequencing data. We aimed to explore the use of MATH as a measure for tumor heterogeneity and its prognostic role in UCEC patients. Methods:We calculated MATH scores from the available data of 560 UCEC patients from The Cancer Genome Atlas (TCGA) and investigated their correlations with clinical characteristics, genetic alterations, and overall survival. Predictive accuracy was quantified using the area under the receiver operating characteristic curve (AUC) and the index of concordance (C-index). Results:In total, 242 MATH scores were obtained from the UCEC cohort. MATH scores were significantly related to age, race, cancer type, clinical stage, histological grade, molecular type, targeted molecular therapy, and hormonal therapy. Furthermore, the genomic pattern on the basis of MATH scores showed that mutation rates of TP53 (tumor protein p53) and ARID1A (AT-rich interaction domain 1A) were independently associated with MATH scores. Correlation analysis revealed a significantly positive association of MATH scores with the fraction of somatic copy number alteration (SCNA). Importantly, a high MATH score was significantly associated with shorter overall survival [hazard ratio (HR), 2.342; 95% confidence interval (CI), 1.110-4.942]. Multivariate Cox regression combined with stratified analysis revealed that the MATH score is an independent prognostic factor in UCEC patients under 60 years old, and predictive quantification showed the MATH score had an AUC of 0.756 and a C-index of 0.845. Conclusions:Our results suggest that MATH, a practical and useful way to measure intra-tumor heterogeneity, may serve as a significant biomarker for the prognosis of patients with UCEC, enabling more accurate prediction of clinical outcomes.

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Prognostic Significance of Disseminated Tumor Cells in Bone Marrow for Endometrial Carcinoma Patients.

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Prognostic Significance of Disseminated Tumor Cells in Bone Marrow for Endometrial Carcinoma Patients.

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