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OBJECTIVE: Although early-detected cervical cancer is associated with good survival, the prognosis for late-stage disease is poor and treatment options are sparse. Mismatch repair deficiency (MMR-D) has surfaced as a predictor of prognosis and response to immune checkpoint inhibitor(s) in several cancer types, but its value in cervical cancer remains unclear. This study aimed to define the prevalence of MMR-D in cervical cancer and assess the prognostic value of MMR protein expression. METHODS: Expression of the MMR proteins MLH-1, PMS-2, MSH-2, and MSH-6 was investigated by immunohistochemical staining in a prospectively collected cervical cancer cohort (n=508) with corresponding clinicopathological and follow-up data. Sections were scored as either loss or intact expression to define MMR-D, and by a staining index, based on staining intensity and area, evaluating the prognostic potential. RNA and whole exome sequencing data were available for 72 and 75 of the patients and were used for gene set enrichment and mutational analyses, respectively. RESULTS: Five (1%) tumors were MMR-deficient, three of which were of neuroendocrine histology. MMR status did not predict survival (HR 1.93, p=0.17). MSH-2 low (n=48) was associated with poor survival (HR 1.94, p=0.02), also when adjusting for tumor stage, tumor type, and patient age (HR 2.06, p=0.013). MSH-2 low tumors had higher tumor mutational burden (p=0.003) and higher frequency of (frameshift) mutations in the double-strand break repair gene RAD50 (p<0.01). CONCLUSION: MMR-D is rare in cervical cancer, yet low MSH-2 expression is an independent predictor of poor survival.
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Reparo de Erro de Pareamento de DNA , Proteínas de Ligação a DNA , Proteína 2 Homóloga a MutS , Neoplasias do Colo do Útero , Humanos , Feminino , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/mortalidade , Prognóstico , Pessoa de Meia-Idade , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Proteína 2 Homóloga a MutS/metabolismo , Proteína 2 Homóloga a MutS/biossíntese , Proteína 2 Homóloga a MutS/genética , Adulto , Idoso , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 1 Homóloga a MutL/metabolismo , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/biossínteseRESUMO
Cervical cancer (CC) is a major global health problem with 570,000 new cases and 266,000 deaths annually. Prognosis is poor for advanced stage disease, and few effective treatments exist. Preoperative diagnostic imaging is common in high-income countries and MRI measured tumor size routinely guides treatment allocation of cervical cancer patients. Recently, the role of MRI radiomics has been recognized. However, its potential to independently predict survival and treatment response requires further clarification. This retrospective cohort study demonstrates how non-invasive, preoperative, MRI radiomic profiling may improve prognostication and tailoring of treatments and follow-ups for cervical cancer patients. By unsupervised clustering based on 293 radiomic features from 132 patients, we identify three distinct clusters comprising patients with significantly different risk profiles, also when adjusting for FIGO stage and age. By linking their radiomic profiles to genomic alterations, we identify putative treatment targets for the different patient clusters (e.g., immunotherapy, CDK4/6 and YAP-TEAD inhibitors and p53 pathway targeting treatments).
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Imageamento por Ressonância Magnética , Neoplasias do Colo do Útero , Humanos , Feminino , Neoplasias do Colo do Útero/diagnóstico por imagem , Neoplasias do Colo do Útero/terapia , Neoplasias do Colo do Útero/patologia , Prognóstico , Pessoa de Meia-Idade , Estudos Retrospectivos , Imageamento por Ressonância Magnética/métodos , Adulto , Idoso , RadiômicaRESUMO
OBJECTIVE: Assess the added prognostic value of the updated International Federation of Gynecology and Obstetrics (FIGO) 2018 staging system, and to identify clinicopathological and radiological biomarkers for improved FIGO 2018 prognostication. METHODS: Patient data were retrieved from a prospectively collected patient cohort including all consenting patients with cervical cancer diagnosed and treated at Haukeland University Hospital during 2001-2022 (n = 948). All patients were staged according to the FIGO 2009 and FIGO 2018 guidelines based on available data for individual patients. MRI-assessed maximum tumor diameter and stromal tumor invasion, as well as histopathologically assessed lymphovascular space invasion were applied to categorize patients according to the Sedlis criteria. RESULTS: FIGO 2018 stage yielded the highest area under the receiver operating characteristic (ROC) curve (AUC) (0.86 versus 0.81 for FIGO 2009) for predicting disease-specific survival. The most common stage migration in FIGO 2018 versus FIGO 2009 was upstaging from stages IB/II to stage IIIC due to suspicious lymph nodes identified by PET/CT and/or MRI. In FIGO 2018 stage III patients, extent and size of primary tumor (p = 0.04), as well as its histological type (p = 0.003) were highly prognostic. Sedlis criteria were prognostic within FIGO 2018 IB patients (p = 0.04). CONCLUSIONS: Incorporation of cross-sectional imaging increases prognostic precision, as suggested by the FIGO 2018 guidelines. The 2018 FIGO IIIC stage could be refined by including the size and extent of primary tumor and histological type. The FIGO IB risk prediction could be improved by applying MRI-assessed tumor size and stromal invasion.
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Neoplasias do Colo do Útero , Feminino , Humanos , Estadiamento de Neoplasias , Neoplasias do Colo do Útero/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Prognóstico , Radiografia , Estudos RetrospectivosRESUMO
BACKGROUND: Accurate pretherapeutic prognostication is important for tailoring treatment in cervical cancer (CC). PURPOSE: To investigate whether pretreatment MRI-based radiomic signatures predict disease-specific survival (DSS) in CC. STUDY TYPE: Retrospective. POPULATION: CC patients (n = 133) allocated into training(T) (nT = 89)/validation(V) (nV = 44) cohorts. FIELD STRENGTH/SEQUENCE: T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI) at 1.5T or 3.0T. ASSESSMENT: Radiomic features from segmented tumors were extracted from T2WI and DWI (high b-value DWI and apparent diffusion coefficient (ADC) maps). STATISTICAL TESTS: Radiomic signatures for prediction of DSS from T2WI (T2rad ) and T2WI with DWI (T2 + DWIrad ) were constructed by least absolute shrinkage and selection operator (LASSO) Cox regression. Area under time-dependent receiver operating characteristics curves (AUC) were used to evaluate and compare the prognostic performance of the radiomic signatures, MRI-derived maximum tumor size ≤/> 4 cm (MAXsize ), and 2018 International Federation of Gynecology and Obstetrics (FIGO) stage (I-II/III-IV). Survival was analyzed using Cox model estimating hazard ratios (HR) and Kaplan-Meier method with log-rank tests. RESULTS: The radiomic signatures T2rad and T2 + DWIrad yielded AUCT /AUCV of 0.80/0.62 and 0.81/0.75, respectively, for predicting 5-year DSS. Both signatures yielded better or equal prognostic performance to that of MAXsize (AUCT /AUCV : 0.69/0.65) and FIGO (AUCT /AUCV : 0.77/0.64) and were significant predictors of DSS after adjusting for FIGO (HRT /HRV for T2rad : 4.0/2.5 and T2 + DWIrad : 4.8/2.1). Adding T2rad and T2 + DWIrad to FIGO significantly improved DSS prediction compared to FIGO alone in cohort(T) (AUCT 0.86 and 0.88 vs. 0.77), and FIGO with T2 + DWIrad tended to the same in cohort(V) (AUCV 0.75 vs. 0.64, p = 0.07). High radiomic score for T2 + DWIrad was significantly associated with reduced DSS in both cohorts. DATA CONCLUSION: Radiomic signatures from T2WI and T2WI with DWI may provide added value for pretreatment risk assessment and for guiding tailored treatment strategies in CC.
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Neoplasias do Colo do Útero , Feminino , Humanos , Neoplasias do Colo do Útero/diagnóstico por imagem , Neoplasias do Colo do Útero/patologia , Estudos Retrospectivos , Imageamento por Ressonância Magnética/métodos , Imagem de Difusão por Ressonância Magnética/métodos , PrognósticoRESUMO
BACKGROUND: The endometrial cancer mismatch repair (MMR) deficient subgroup is defined by loss of MSH6, MSH2, PMS2 or MLH1. We compare MMR status in paired preoperative and operative samples and investigate the prognostic impact of differential MMR protein expression levels. METHODS: Tumour lesions from 1058 endometrial cancer patients were immunohistochemically stained for MSH6, MSH2, PMS2 and MLH1. MMR protein expression was evaluated as loss or intact to determine MMR status, or by staining index to evaluate the prognostic potential of differential expression. Gene expression data from a local (n = 235) and the TCGA (n = 524) endometrial cancer cohorts was used for validation. RESULTS: We identified a substantial agreement in MMR status between paired curettage and hysterectomy samples. Individual high expression of all four MMR markers associated with non-endometrioid subtype, and high MSH6 or MSH2 strongly associated with several aggressive disease characteristics including high tumour grade and FIGO stage, and for MSH6, with lymph node metastasis. In multivariate Cox analysis, MSH6 remained an independent prognostic marker, also within the endometrioid low-grade subgroup (P < 0.001). CONCLUSION: We demonstrate that in addition to determine MMR status, MMR protein expression levels, particularly MSH6, may add prognostic information in endometrial cancer.
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Reparo de Erro de Pareamento de DNA , Neoplasias do Endométrio , Feminino , Humanos , Prognóstico , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 2 Homóloga a MutS/genética , Neoplasias do Endométrio/patologia , Proteína 1 Homóloga a MutL/genéticaRESUMO
BACKGROUND: Tumor size assessment by MRI is central for staging uterine cervical cancer. However, the optimal role of MRI-derived tumor measurements for prognostication is still unclear. MATERIAL AND METHODS: This retrospective cohort study included 416 women (median age: 43 years) diagnosed with cervical cancer during 2002-2017 who underwent pretreatment pelvic MRI. The MRIs were independently read by three radiologists, measuring maximum tumor diameters in three orthogonal planes and maximum diameter irrespective of plane (MAXimaging). Inter-reader agreement for tumor size measurements was assessed by intraclass correlation coefficients (ICCs). Size was analyzed in relation to age, International Federation of Gynecology and Obstetrics (FIGO) (2018) stage, histopathological markers, and disease-specific survival using Kaplan-Meier-, Cox regression-, and time-dependent receiver operating characteristics (tdROC) analyses. RESULTS: All MRI tumor size variables (cm) yielded high areas under the tdROC curves (AUCs) for predicting survival (AUC 0.81-0.84) at 5 years after diagnosis and predicted outcome (hazard ratios [HRs] of 1.42-1.76, p < 0.001 for all). Only MAXimaging independently predicted survival (HR = 1.51, p = 0.03) in the model including all size variables. The optimal cutoff for maximum tumor diameter (≥ 4.0 cm) yielded sensitivity (specificity) of 83% (73%) for predicting disease-specific death after 5 years. Inter-reader agreement for MRI-based primary tumor size measurements was excellent, with ICCs of 0.83-0.85. CONCLUSION: Among all MRI-derived tumor size measurements, MAXimaging was the only independent predictor of survival. MAXimaging ≥ 4.0 cm represents the optimal cutoff for predicting long-term disease-specific survival in cervical cancer. Inter-reader agreement for MRI-based tumor size measurements was excellent.
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BACKGROUND: Most patients with endometrial cancer with localized disease are effectively treated and survive for a long time. The primary treatment is hysterectomy, to which surgical staging procedures may be added to assess the need for adjuvant therapy. Longitudinal data on patient-reported outcomes comparing different levels of primary treatment are lacking, especially when adjuvant radiotherapy is omitted. OBJECTIVE: We assessed the impact of lymphadenectomy and adjuvant chemotherapy on patient-reported symptoms, function, and quality of life. We hypothesized that these treatment modalities would substantially affect patient-reported outcomes at follow-up. STUDY DESIGN: We prospectively included patients with endometrial cancer enrolled in the ongoing MoMaTEC2 study (ClinicalTrials.gov Identifier: NCT02543710). Patients were asked to complete the patient-reported outcome questionnaires European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire EN24 preoperatively and at 1 and 2 years of follow-up. Functional domains and symptoms were analyzed for the whole cohort and by treatment received. To assess the effect of the individual treatment modifications, we used mixed regression models. RESULTS: Baseline data were available for 448 patients. Of these patients, 339 and 219 had reached 1-year follow-up and 2-year follow-up, respectively. Treatment included hysterectomy (plus bilateral salpingo-oophorectomy) alone (n=177), hysterectomy and lymph node staging without adjuvant therapy (n=133), or adjuvant chemotherapy irrespective of staging procedure (n=138). Overall, patients reported improved global health status and quality of life (+9 units; P<.001), increased emotional and social functioning, and increased sexual interest and activity (P<.001 for all) from baseline to year 1, and these outcomes remained stable at year 2. Means of functional scales and quality of life were similar to age- and sex-weighted reference cohorts. Mean tingling and numbness and lymphedema increased after treatment. The group who received adjuvant chemotherapy had a larger mean reduction in physical functioning (-6 vs +2; P=.002) at year 1, more neuropathy (+30 vs +5; P<.001; year 1) at years 1 and 2, and more lymphedema at year 1 (+11 vs +2; P=.007) than the group treated with hysterectomy and salpingo-oophorectomy only. In patients not receiving adjuvant chemotherapy, patient-reported outcomes were similar regardless of lymph node staging procedures. Adjuvant chemotherapy independently increased fatigue, lymphedema, and neuropathy in mixed regression models. CONCLUSION: Patients with endometrial cancer receiving adjuvant chemotherapy reported significantly reduced functioning and more symptoms up to 2 years after treatment. For patients treated by surgery alone, surgical staging did not seem to affect the quality of life or symptoms to a measurable degree at follow-up. Therefore, subjecting patients to lymph node removal to tailor adjuvant therapy seems justified from the patient's viewpoint; however, efforts should increase to find alternatives to traditional chemotherapy.
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Neoplasias do Endométrio/tratamento farmacológico , Idoso , Quimioterapia Adjuvante , Estudos de Coortes , Intervalo Livre de Doença , Neoplasias do Endométrio/mortalidade , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/cirurgia , Feminino , Humanos , Histerectomia , Estudos Longitudinais , Excisão de Linfonodo , Metástase Linfática , Estadiamento de Neoplasias , Noruega , Medidas de Resultados Relatados pelo Paciente , Estudos Prospectivos , Inquéritos e Questionários , SobreviventesRESUMO
The purpose of this study was to establish a gene signature that may predict CIN3 regression and that may aid in selecting patients who may safely refrain from conization. Oncomine mRNA data including 398 immune-related genes from 21 lesions with confirmed regression and 28 with persistent CIN3 were compared. L1000 mRNA data from a cervical cancer cohort was available for validation (n = 239). Transcriptomic analyses identified TDO2 (p = 0.004), CCL5 (p < 0.001), CCL3 (p = 0.04), CD38 (p = 0.02), and PRF1 (p = 0.005) as upregulated, and LCK downregulated (p = 0.01) in CIN3 regression as compared to persistent CIN3 lesions. From these, a gene signature predicting CIN3 regression with a sensitivity of 91% (AUC = 0.85) was established. Transcriptomic analyses revealed proliferation as significantly linked to persistent CIN3. Within the cancer cohort, high regression signature score associated with immune activation by Gene Set enrichment Analyses (GSEA) and immune cell infiltration by histopathological evaluation (p < 0.001). Low signature score was associated with poor survival (p = 0.007) and large tumors (p = 0.01). In conclusion, the proposed six-gene signature predicts CIN regression and favorable cervical cancer prognosis and points to common drivers in precursors and cervical cancer lesions.
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Despite recent advances in the prevention of cervical cancer, the disease remains a leading cause of cancer-related deaths in women worldwide. By applying the GISTIC2.0 and/or the MutSig2CV algorithms on 430 whole-exome-sequenced cervical carcinomas, we identified previously unreported significantly mutated genes (SMGs) (including MSN, GPX1, SPRED3, FAS, and KRT8), amplifications (including NFIA, GNL1, TGIF1, and WDR87) and deletions (including MIR562, PVRL1, and NTM). Subset analyses of 327 squamous cell carcinomas and 86 non-squamous cell carcinomas revealed previously unreported SMGs in BAP1 and IL28A, respectively. Distinctive copy number alterations related to tumors predominantly enriched for *CpG- and Tp*C mutations were observed. CD274, GRB2, KRAS, and EGFR were uniquely significantly amplified within the Tp*C-enriched tumors. A high frequency of aberrations within DNA damage repair and chromatin remodeling genes were detected. Facilitated by the large sample size derived from combining multiple datasets, this study reveals potential targets and prognostic markers for cervical cancer.
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BACKGROUND: Advanced cervical cancer carries a particularly poor prognosis, and few treatment options exist. Identification of effective molecular markers is vital to improve the individualisation of treatment. We investigated transcriptional data from cervical carcinomas related to patient survival and recurrence to identify potential molecular drivers for aggressive disease. METHODS: Primary tumour RNA-sequencing profiles from 20 patients with recurrence and 53 patients with cured disease were compared. Protein levels and prognostic impact for selected markers were identified by immunohistochemistry in a population-based patient cohort. RESULTS: Comparison of tumours relative to recurrence status revealed 121 differentially expressed genes. From this gene set, a 10-gene signature with high prognostic significance (p = 0.001) was identified and validated in an independent patient cohort (p = 0.004). Protein levels of two signature genes, HLA-DQB1 (n = 389) and LIMCH1 (LIM and calponin homology domain 1) (n = 410), were independent predictors of survival (hazard ratio 2.50, p = 0.007 for HLA-DQB1 and 3.19, p = 0.007 for LIMCH1) when adjusting for established prognostic markers. HLA-DQB1 protein expression associated with programmed death ligand 1 positivity (p < 0.001). In gene set enrichment analyses, HLA-DQB1high tumours associated with immune activation and response to interferon-γ (IFN-γ). CONCLUSIONS: This study revealed a 10-gene signature with high prognostic power in cervical cancer. HLA-DQB1 and LIMCH1 are potential biomarkers guiding cervical cancer treatment.
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Cadeias beta de HLA-DQ/genética , Proteínas com Domínio LIM/genética , Transcriptoma , Neoplasias do Colo do Útero/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Cadeias beta de HLA-DQ/fisiologia , Humanos , Proteínas com Domínio LIM/fisiologia , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Análise de Sobrevida , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/patologiaRESUMO
PURPOSE: This study estimated time without symptoms or toxicity (TWiST) with niraparib compared with routine surveillance (RS) in the maintenance treatment of patients with recurrent ovarian cancer. PATIENTS AND METHODS: Mean progression-free survival (PFS) was estimated for niraparib and RS by fitting parametric survival distributions to Kaplan-Meier data for 553 patients with recurrent ovarian cancer who were enrolled in the phase III ENGOT-OV16/NOVA trial. Patients were categorized according to the presence or absence of a germline BRCA mutation-gBRCAmut and non-gBRCAmut cohorts. Mean time with toxicity was estimated based on the area under the Kaplan-Meier curve for symptomatic grade 2 or greater fatigue, nausea, and vomiting adverse events (AEs). Time with toxicity was the number of days a patient experienced an AE post-random assignment and before disease progression. TWiST was estimated as the difference between mean PFS and time with toxicity. Uncertainty was explored using alternative PFS estimates and considering all symptomatic grade 2 or greater AEs. RESULTS: In the gBRCAmut and non-gBRCAmut cohorts, niraparib treatment resulted in a mean PFS benefit of 3.23 years and 1.44 years, respectively, and a mean time with toxicity of 0.28 years and 0.10 years, respectively, compared with RS. Hence, niraparib treatment resulted in a mean TWiST benefit of 2.95 years and 1.34 years, respectively, compared with RS, which is equivalent to more than four-fold and two-fold increases in mean TWiST between niraparib and RS in the gBRCAmut and non-gBRCAmut cohorts, respectively. This TWiST benefit was consistent across all sensitivity analyses, including modeling PFS over 5-, 10-, and 15-year time horizons. CONCLUSION: Patients who were treated with niraparib compared with RS experienced increased mean TWiST. Thus, patients who were treated with niraparib in the ENGOT-OV16/NOVA trial experienced more time without symptoms or symptomatic toxicities compared with control.
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Indazóis/administração & dosagem , Recidiva Local de Neoplasia , Neoplasias Ovarianas/tratamento farmacológico , Piperidinas/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Proteína BRCA1/genética , Proteína BRCA2/genética , Progressão da Doença , Esquema de Medicação , Feminino , Mutação em Linhagem Germinativa , Humanos , Indazóis/efeitos adversos , Quimioterapia de Manutenção , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Piperidinas/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Fatores de TempoRESUMO
PURPOSE: In the ENGOT-OV16/NOVA trial (ClinicalTrials.gov identifier: NCT01847274), maintenance therapy with niraparib, a poly(ADP-ribose) polymerase inhibitor, prolonged progression-free survival in patients with platinum-sensitive, recurrent ovarian cancer who had a response to their last platinum-based chemotherapy. The objective of the study was to assess the clinical benefit and patient-reported outcomes in patients who had a partial response (PR) and complete response (CR) to their last platinum-based therapy. PATIENTS AND METHODS: A total of 553 patients were enrolled in the trial. Of 203 patients with a germline BRCA mutation (gBRCAmut), 99 had a PR and 104 had a CR to their last platinum-based therapy; of 350 patients without a confirmed gBRCAmut (non-gBRCAmut), 173 had a PR and 177 had a CR. Post hoc analyses were carried out to evaluate safety and the risk of progression in these patients according to gBRCAmut status and response to their last platinum-based therapy. Ovarian cancer-specific symptoms and quality of life were assessed using the Functional Assessment of Cancer Therapy-Ovarian Symptom Index. RESULTS: Progression-free survival was improved in patients treated with niraparib compared with placebo in both the gBRCAmut cohort (PR: hazard ratio [HR], 0.24; 95% CI, 0.131 to 0.441; P < .0001; CR: HR, 0.30; 95% CI, 0.160 to 0.546; P < .0001) and the non-gBRCAmut cohort (PR: HR, 0.35; 95% CI, 0.230 to 0.532; P < .0001; CR: HR, 0.58; 95% CI, 0.383 to 0.868; P = .0082). The incidence of any-grade and grade 3 or greater adverse events was manageable. No meaningful differences were observed between niraparib and placebo in PR and CR subgroups with respect to patient-reported outcomes. CONCLUSION: Patients achieved clinical benefit from maintenance treatment with niraparib regardless of response to the last platinum-based therapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Indazóis/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Piperidinas/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Feminino , Humanos , Quimioterapia de Manutenção , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Intervalo Livre de ProgressãoRESUMO
High-grade serous ovarian carcinoma (HGSOC) is characterised by alterations in the p53 pathway. The expression levels of p53 isoforms have been shown to be associated with patient survival in several cancers. This study examined the predictive and prognostic effects of the expression levels of TP53 pre-mRNA splicing isoforms and TP53 mutations in tumour tissues in 40 chemotherapy responders and 29 non-responders with HGSOC. The mRNA expression levels from total p53, and total Δ133p53, p53ß, p53γ isoforms were determined by RT-qPCR, and TP53 mutation status by targeted massive parallel sequencing. The results from these analyses were correlated with the clinical outcome parameters. No differential expression of p53 isoforms could be detected between the chemosensitive and chemoresistant subgroups. In a multivariate Cox regression model, high levels of total Δ133p53 were found to be an independent prognosticator for improved overall survival (HR = 0.422, p = 0.018, 95% CI: 0.207-0.861) and reached borderline significance for progression-free survival (HR = 0.569, p = 0.061, 95% CI: 0.315-1.027). TP53 mutations resulting in loss of function or located at known hotspots were predictive of tumour characteristics and disease progression. These findings suggest that total Δ133p53 mRNA can be a biomarker for survival in HGSOC.
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Regulação Neoplásica da Expressão Gênica , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/tratamento farmacológico , Prognóstico , Isoformas de Proteínas/genética , RNA Mensageiro/genética , Análise de SobrevidaRESUMO
BACKGROUND: Uterine serous carcinoma (USC) is a rare but aggressive subtype of endometrial carcinoma. Large-scale comprehensive efforts have resulted in an improved molecular understanding of its pathogenesis, and the p53 pathway has been proposed as a key player and is potentially targetable. Here we attempt to further portray the p53 pathway in USC by assessing p53 isoform expression. METHODS: We applied quantitative Real-Time PCRs (RT-qPCR) for expression analyses of total p53 mRNA as well as quantitative distinction of p53ß, p53γ, and the total mRNA of amino-terminal truncated Δ40p53 and Δ133p53 in a retrospective cohort of 37 patients with USC. TP53 mutation status was assessed by targeted massive parallel sequencing. Findings were correlated with clinical data. RESULTS: The p53 isoform expression landscape in USCs was heterogeneous and dominated by total Δ133p53, while the distinct p53ß and p53γ variants were found at much lower levels. The isoform expression profiles varied between samples, while their expression was independent of TP53 mutation status. We found high relative p53γ expression to be associated with reduced progression-free survival (PFS). CONCLUSIONS: This is the first indication that elevated p53γ expression is associated with reduced PFS in USC. This single-center study may offer some insight in the landscape of p53 isoform expression in USC, but further validation studies are crucial to understand the context-dependent and tissue-specific role of the p53 isoform network in gynecological cancer.
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Cistadenocarcinoma Seroso/genética , Proteína Supressora de Tumor p53/genética , Neoplasias Uterinas/genética , Idoso , Idoso de 80 Anos ou mais , Cistadenocarcinoma Seroso/mortalidade , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Intervalo Livre de Progressão , Isoformas de Proteínas/genética , RNA Mensageiro/análise , Estudos Retrospectivos , Proteína Supressora de Tumor p53/fisiologia , Neoplasias Uterinas/mortalidadeRESUMO
INTRODUCTION: Women with cervical cancer in the Nordic countries are increasingly undergoing pretreatment imaging by ultrasound, magnetic resonance imaging (MRI), positron emission tomography-computed tomography (PET-CT) or computed tomography, or sentinel lymph node procedure. The present survey reports the influence of pretreatment imaging findings on the recorded clinical International Federation of Gynecology and Obstetrics (FIGO) stage in Nordic countries and its impact on treatment planning and preferred surgical approach in cervical cancer. MATERIAL AND METHODS: The Nordic Society of Gynecological Oncology Surgical Subcommittee developed a questionnaire-based survey that was conducted from 1 January to 31 March 2017. All the 22 Nordic Gynecological Oncology Centers (Denmark 5, Finland 5, Iceland 1, Norway 4, and Sweden 7) were invited to participate. RESULTS: The questionnaires were returned by 19 of 22 (86.3%) centers. The median number (range) of women with cervical cancer treated at each center annually was 32 (15-120). In 58% (11/19) of the centers, imaging findings were reported to influence the clinical staging. MRI in combination with PET-CT was the preferred imaging method and the results influenced treatment planning. Robotic-assisted radical hysterectomy was the preferred surgical method in 72% (13/18) of the centers. Sentinel lymph node procedure was not routinely implemented in the majority of the Nordic centers. CONCLUSION: More than half of the Nordic Gynecological Oncology Centers already report a clinical FIGO stage influenced by pretreatment imaging findings. The trend in preferred treatment is robotic-assisted radical hysterectomy and the sentinel lymph node procedure is gradually being introduced.
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Ginecologia/normas , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/cirurgia , Adulto , Feminino , Diretrizes para o Planejamento em Saúde , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias/métodos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Padrões de Prática Médica/normas , Países Escandinavos e Nórdicos , Tomografia Computadorizada por Raios X , Neoplasias do Colo do Útero/patologiaRESUMO
Background In vivo magnetic resonance spectroscopy (MRS) enables non-invasive measurements of tumor metabolites. Choline-containing metabolites play a key role in tumor metabolism. Purpose To explore whether preoperative MRS-derived tumor choline levels are associated with clinical and histological features in endometrial carcinomas. Material and Methods Preoperative pelvic magnetic resonance imaging (MRI) (1.5T), including structural and diffusion-weighted imaging and localized multivoxel proton MR (1H-MR) spectroscopy, was performed in 77 prospectively included patients with histologically confirmed endometrial carcinomas. Relative levels of total choline-containing metabolites (tCho) in tumor and myometrium were measured using the ratios: tCho/Creatine; tCho/Water; and tCho/Noise. MRS parameters were analyzed in relation to histological subtype and grade, surgicopathological staging parameters, MRI-measured tumor volume, and tumor apparent diffusion coefficient (ADC) value and clinical outcome. Results Tumor tissue had significantly higher ratios for tCho/Creatine, tCho/Water, and tCho/Noise than normal myometrial tissue ( P < 0.001 for all). High tumor tCho/Water ratio was significantly associated with high tumor grade in endometrioid tumors ( P = 0.02). Tumor tCho/Creatine ratio was positively correlated to MRI-measured tumor volume (rs = 0.25; P = 0.03). Conclusion High choline levels in tumor are associated with high-risk features. In vivo MRS may potentially aid in the preoperative risk stratification in endometrial cancer.
Assuntos
Neoplasias do Endométrio/diagnóstico por imagem , Neoplasias do Endométrio/patologia , Espectroscopia de Ressonância Magnética/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Endométrio/diagnóstico por imagem , Endométrio/patologia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Valor Preditivo dos Testes , Estudos Prospectivos , Curva ROC , Reprodutibilidade dos TestesRESUMO
PURPOSE: Distinguishing complex atypical hyperplasia (CAH) from grade 1 endometrioid endometrial cancer (EECG1) preoperatively may be valuable in order to prevent surgical overtreatment, particularly in patients wishing preserved fertility or in patients carrying increased risk of perioperative complications. MATERIAL AND METHODS: Preoperative histological diagnosis and radiological findings were compared to final histological diagnosis in patients diagnosed with CAH and EECG1. Imaging characteristics at preoperative magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography/computer tomography (FDG-PET/CT) were compared with tumor DNA oligonucleotide microarray data, immunohistochemistry findings and clinicopathological annotations. RESULTS: MRI assessed tumor volume was higher in EECG1 than in CAH (p=0.004) whereas tumor apparent diffusion coefficient value was lower in EECG1 (p=0.005). EECG1 exhibited increased metabolism with higher maximum and mean standard uptake values (SUV) than CAH (p≤0.002). Unsupervised clustering of EECG1 and CAH revealed differentially expressed genes within the clusters, and identified PDZ-binding kinase (PBK) as a potential marker for selecting endometrial lesions with less aggressive biological behavior. CONCLUSION: Both PBK expression and preoperative imaging yield promising biomarkers that may aid in the differentiation between EECG1 and CAH preoperatively, and these markers should be further explored in larger patient series.
RESUMO
Surgery is the cornerstone in primary endometrial cancer treatment, and with curative intent it constitutes total hysterectomy and bilateral salpingo-oopherectomy. In addition, lymphadenectomy is performed in selected patients dependent on a preoperative risk assessment. Recent reports from the surgical approach to esophageal cancer reveal worse outcome when esophagectomy is performed later in the week. On this basis, we set out to explore weekday of surgery in relation to long-term outcome in 1302 endometrial cancer patients prospectively included in the MoMaTEC multicenter study. Day of surgery was dichotomized as early-week (Monday-Tuesday) or late-week (Wednesday-Friday), and evaluated as a discrete variable. Adjusted for patient age, Body Mass Index (BMI), FIGO stage, and histology, surgery performed later in the week was associated with 50.9% increased risk of all-cause death (p = 0.029). Among high-stage patients (FIGO stage III and IV), 5-year disease-specific survival proportions were 53.0% for early-week operated vs. 40.2% for late-week operated (p = 0.005 for difference). In multivariate survival analysis of high-stage patients, late-week surgery correlated with an increased risk of disease-specific death by 88.7% and all-cause death by 76.4% (p<0.017). Evaluating only patients who underwent lymphadenectomy, the adverse prognostic effect of being operated late-week remained for both disease-specific and all-cause death (HR 2.151 and HR 1.912, p = 0.004). Whether surgery was performed early- or late-week was not influenced by patient age, BMI, preoperative histology risk classification, FIGO stage or postoperative histology (all p>0.05). In conclusion, endometrial cancer surgery conducted late-week is associated with worse long-term outcome. Our findings are most evident among patients with higher FIGO stages, and patients who underwent more extensive surgical procedure (lymphadenectomy). With support from other studies, our results suggest that high-risk patients may benefit from surgery earlier in the week.
Assuntos
Neoplasias do Endométrio/cirurgia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Neoplasias do Endométrio/mortalidade , Neoplasias do Endométrio/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Excisão de Linfonodo/mortalidade , Metástase Linfática , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Período Pós-Operatório , Prognóstico , Estudos Prospectivos , Risco , Fatores de TempoRESUMO
BACKGROUND: Cervical cancer is a major health problem worldwide. Identification of effective clinicopathologic and molecular markers is vital to improve treatment stratification. OBJECTIVES: The purpose of this study was to validate a set of well-defined clinicopathologic features in a large population-based, prospectively collected cervical cancer cohort to support their use in the clinic. Further, we explored p53 and human epidermal growth factor receptor 2 as potential prognostic markers in cervical cancer. STUDY DESIGN: Tissue was collected from 401 patients with cervical cancer. Clinical data that included follow-up evaluations were collected from patient journals. Histopathologic data were evaluated and revised by an expert pathologist. The prognostic impact of selected clinicopathologic variables was analyzed in the whole cohort. Tissue microarrays were prepared from 292 carcinomas, and p53 and human epidermal growth factor receptor 2 protein levels were evaluated by immunohistochemistry. Fresh frozen samples from overlapping cervical carcinomas previously were subjected to human papilloma virus typing (n=94), whole exome (n=100) and RNA (n=79) sequencing; the results were available for our analyses. RESULTS: Among the clinicopathologic variables, vascular space invasion, histologic type, and tumor size were verified as strong independent prognostic markers. High p53 protein levels were associated significantly with markers for aggressive phenotype and survival, also in multivariate survival analysis, but did not reflect TP53 mutational status. High human epidermal growth factor receptor 2 protein levels were identified in 21% of all tumors. ERBB2 amplification was associated with poor outcome (P=.003); human epidermal growth factor receptor 2 protein level was not. CONCLUSIONS: Our findings support that the Féderation Internationale de Gynécologie et d'Obstétrique s guidelines should include vascular space invasion and tumor size 2-4 cm and that careful selection of histologic type is essential for stratification of patient risk groups. High p53 levels independently predict poor survival yet do not reflect mutational status in cervical cancer. Amplified ERBB2 significantly links to poor survival, while HercepTest does not. With optimal stratification, human epidermal growth factor receptor 2-based therapy may improve cervical cancer treatment.
Assuntos
Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismo , Adulto , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/mortalidade , Carcinoma/patologia , Estudos de Coortes , Feminino , Deleção de Genes , Genes erbB-2 , Genes p53 , Papillomavirus Humano 16/isolamento & purificação , Papillomavirus Humano 18/isolamento & purificação , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Mutação , Invasividade Neoplásica , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/patologia , Prognóstico , Receptor ErbB-2/metabolismo , Análise de Sequência , Análise Serial de Tecidos , Proteína Supressora de Tumor p53/metabolismo , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/patologiaRESUMO
BACKGROUND: Chemotherapy in platinum-resistant ovarian cancer (PROC) aims for palliation and prolonging of progression-free survival (PFS). This study compares Health-related Quality of Life (HRQoL) and efficacy between single-agent chemotherapy and tamoxifen in PROC. METHODS: Patients with PROC were randomised (2 : 1) to chemotherapy (weekly paclitaxel 80 mg m-2 or four weekly pegylated liposomal doxorubicin 40 mg m-2) or tamoxifen 40 mg daily. The primary end point was HRQoL. Secondary end points were PFS by RECIST and overall survival (OS). RESULTS: Between March 2002 and December 2007, 156 and 82 patients were randomised to chemotherapy and tamoxifen, respectively. In the chemotherapy arm, a significantly larger proportion of patients experienced a worsening in their social functioning. There was no difference in the proportion of patients experiencing improvement of gastrointestinal symptoms. Median PFS on tamoxifen was 8.3 weeks (95% CI, 8.0-10.4) compared with 12.7 weeks (95% CI, 9.0-16.3) on chemotherapy (HR, 1.54; 95% CI, 1.16-2.05; log-rank P=0.003). There was no difference in OS between the treatment arms. CONCLUSIONS: Patients on chemotherapy had longer PFS but experienced more toxicity and poorer HRQoL compared with tamoxifen. Control over gastrointestinal symptoms was not better on chemotherapy. These data are important for patient counselling and highlight the need to incorporate HRQoL end points in studies of PROC.