ABSTRACT
BACKGROUND: EMIT-1 is a national, observational, single-arm trial designed to assess the value of the Prosigna, Prediction Analysis of Microarray using the 50 gene classifier (PAM50)/Risk of Recurrence (ROR), test as a routine diagnostic tool, examining its impact on adjuvant treatment decisions, clinical outcomes, side-effects and cost-effectiveness. Here we present the impact on treatment decisions. PATIENTS AND METHODS: Patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative pT1-pT2 lymph node-negative early breast cancer (EBC) were included. The Prosigna test and standard histopathology assessments were carried out. Clinicians' treatment decisions were recorded before (pre-Prosigna) and after (post-Prosigna) the Prosigna test results were disclosed. RESULTS: Of 2217 patients included, 2178 had conclusive Prosigna results. The pre-Prosigna treatment decisions were: no systemic treatment (NT) in 27% of patients, endocrine treatment alone (ET) in 38% and chemotherapy (CT) followed by ET (CT + ET) in 35%. Post-Prosigna treatment decisions were 25% NT, 51% ET and 24% CT + ET, respectively. Adjuvant treatment changed in 28% of patients, including 21% change in CT use. Among patients assigned to CT + ET pre-Prosigna, 45% were de-escalated to ET post-Prosigna. Of patients assigned to ET, 12% were escalated to CT + ET and 8% were de-escalated to NT; of those assigned to NT, 18% were escalated to ET/CT + ET. CT was more frequently recommended for patients aged ≤50 years. In the subgroup with pT1c-pT2 G2 and intermediate Ki67 (0.5-1.5× local laboratory median Ki67 score), the pre-Prosigna CT treatment decision varied widely across hospitals (3%-51%). Post-Prosigna, the variability of CT use was markedly reduced (8%-24%). The correlation between Ki67 and ROR score within this subgroup was poor (r = 0.25-0.39). The median ROR score increased by increasing histological grade, but the ROR score ranges were wide (for G1 0-79, G2 0-90, G3 16-94). CONCLUSION: The Prosigna test result changed adjuvant treatment decisions in all EBC clinical risk groups, markedly decreased the CT use for patients categorized as higher clinical risk pre-Prosigna and reduced treatment decision discrepancies between hospitals.
Subject(s)
Breast Neoplasms , Humans , Breast Neoplasms/pathology , Breast Neoplasms/drug therapy , Breast Neoplasms/therapy , Female , Middle Aged , Prospective Studies , Chemotherapy, Adjuvant/methods , Aged , Adult , Lymph Nodes/pathology , Aged, 80 and overABSTRACT
OBJECTIVES: In patients with epithelial ovarian cancer (EOC), the clinical efficacy of monotherapy with immune checkpoint inhibitors (ICIs) against PD-1/PD-L1 is modest. To enhance response rates to these immunotherapeutic agents and broaden the indications for their use, new approaches involving combinational therapy are needed. The immune regulator CD73 is a potential target, as it promotes tumor escape by producing immunosuppressive extracellular adenosine in the tumor microenvironment. Here, we present the results from the NSGO-OV-UMB1/ENGOT-OV-30 trial evaluating the activity of combining the anti-CD73 antibody oleclumab with the anti-PD-L1 checkpoint inhibitor durvalumab in patients with recurrent EOC. METHODS: In this phase II open-label non-randomized study, patients with CD73-positive relapsed EOC were intravenously administered oleclumab (3000 mg, Q2W) and durvalumab (1500 mg, Q4W). The primary endpoint was disease control rate (DCR) at 16 weeks. The expression of PD-L1 and CD8 was assessed by immunohistochemistry of archival tumors. RESULTS: This trial included 25 patients with a median age of 66 years (47-77 years). Twenty-two patients were evaluable for treatment activity analysis. The DCR was 27%, the median progression-free survival was 2.7 months (95% CI: 2.2-4.2) and the median overall survival was 8.4 months (95% CI: 5.0-13.4). Infiltration of CD8+ cells and PD-L1 expression on tumor cells were observed in partially overlapping sets of 74% of the tumor samples. Neither CD8- nor PD-L1-positivity were significantly associated with better DCR. CONCLUSIONS: Combined treatment with oleclumab and durvalumab was safe and demonstrated limited anti-tumor activity in patients with recurrent EOC.
ABSTRACT
BACKGROUND AND OBJECTIVE: Breast cancer (BC) diagnosed at ages <40 years presents with more aggressive tumour phenotypes and poorer clinical outcome compared to older BC patients. Here, we explored transcriptional BC alterations to gain a better understanding of age-related tumour biology, also subtype-stratified. METHODS: We studied publicly available global BC mRNA expression (n = 3999) and proteomics data (n = 113), exploring differentially expressed genes, enriched gene sets, and gene networks in the young compared to older patients. RESULTS: We identified transcriptional patterns reflecting increased proliferation and oncogenic signalling in BC of the young, also in subtype-stratified analyses. Six up-regulated hub genes built a novel age-related score, significantly associated with aggressive clinicopathologic features. A high 6 Gene Proliferation Score (6GPS) demonstrated independent prognostic value when adjusted for traditional clinicopathologic variables and the molecular subtypes. The 6GPS significantly associated also with disease-specific survival within the luminal, lymph node-negative and Oncotype Dx intermediate subset. CONCLUSIONS: We here demonstrate evidence of higher tumour cell proliferation in young BC patients, also when adjusting for molecular subtypes, and identified a novel age-based six-gene signature pointing to aggressive tumour features, tumour proliferation, and reduced survival-also in patient subsets with expected good prognosis.
Subject(s)
Neoplasms , Transcriptome , Humans , Prognosis , Cell Proliferation/genetics , Proteomics , Disease Progression , Biomarkers, Tumor/metabolismABSTRACT
OBJECTIVE: Correct preoperative identification of high-risk patients is important to optimise surgical treatment and improve survival. We wanted to explore if asparaginase-like protein 1 (ASRGL1) expression in curettage could predict lymph node metastases and poor outcome, potentially improving preoperative risk stratification. DESIGN: Multicentre study. SETTING: Ten hospitals in Norway, Sweden and Belgium. POPULATION: Women diagnosed with endometrial carcinoma. METHODS: ASRGL1 expression in curettage specimens from 1144 women was determined by immunohistochemistry. MAIN OUTCOME MEASURES: ASRGL1 status related to disease-specific survival, lymph node status, preoperative imaging parameters and clinicopathological data. RESULTS: ASRGL1 expression had independent prognostic value in multivariate survival analyses, both in the whole patient population (hazard ratio (HR) 1.63, 95% CI 1.11-2.37, P = 0.012) and in the low-risk curettage histology subgroup (HR 2.54, 95% CI 1.44-4.47, P = 0.001). Lymph node metastases were more frequent in women with low expression of ASRGL1 compared with women with high ASRGL1 levels (23% versus 10%, P < 0.001), and low ASRGL1 level was found to independently predict lymph node metastases (odds ratio 2.07, 95% CI 1.27-3.38, P = 0.003). CONCLUSIONS: Low expression of ASRGL1 in curettage independently predicts lymph node metastases and poor disease-specific survival. TWEETABLE ABSTRACT: Low ASRGL1 expression in curettage predicts lymph node metastasis and poor survival in endometrial carcinoma.
Subject(s)
Asparaginase/metabolism , Autoantigens/metabolism , Carcinoma/metabolism , Carcinoma/secondary , Endometrial Neoplasms/metabolism , Endometrial Neoplasms/pathology , Aged , Carcinoma/surgery , Curettage , Endometrial Neoplasms/surgery , Female , Humans , Lymphatic Metastasis , Predictive Value of Tests , Prognosis , Progression-Free Survival , Proportional Hazards Models , Risk Assessment/methods , Survival RateABSTRACT
Inflammation may initiate and promote breast cancer development, and be associated with elevated circulating levels of inflammation markers. A total of eight 130 initially healthy women, participated in the population-based Tromsø study (1994-2008). Pre-diagnostic high-sensitivity C-reactive protein (hs-CRP) was assessed. During 14.6 years of follow-up, a total of 192 women developed invasive breast cancer. These cases were followed for additional 7.2 years. Detailed medical records were obtained. We observed an overall positive dose-response relationship between pre-diagnostic hs-CRP and breast cancer risk (hazard ratio (HR) = 1.06, 95 % CI 1.01-1.11). Postmenopausal women with above median levels of hs-CRP (>1.2 mg/l) had a 1.42 (95 % CI 1.01-2.00) higher breast cancer risk compared to postmenopausal women with hs-CRP below median. Postmenopausal women, who were hormone replacement therapy non-users, and were in the middle tertile (0.8-1.9 mg/l), or highest tertile of hs-CRP (>1.9 mg/l), had a 2.31 (95 % CI 1.31-4.03) and 2.08 (95 % CI 1.16-3.76) higher breast cancer risk, respectively, compared with women in the lowest tertile. For each unit increase in pre-diagnostic hs-CRP levels (mg/l), we observed an 18 % increase in disease-free interval (95 % CI 0.70-0.97), and a 22 % reduction in overall mortality (95 % CI 0.62-0.98). Our study supports a positive association between pre-diagnostic hs-CRP and breast cancer risk. In contrast, increased pre-diagnostic hs-CRP was associated with improved overall mortality, but our findings are based on a small sample size, and should be interpreted with caution.
Subject(s)
Breast Neoplasms/mortality , Breast Neoplasms/pathology , C-Reactive Protein/metabolism , Neoplasm Recurrence, Local/pathology , Adult , Aged , Aged, 80 and over , Biomarkers/metabolism , Breast Neoplasms/metabolism , Female , Follow-Up Studies , Humans , Inflammation/metabolism , Middle Aged , Neoplasm Recurrence, Local/metabolism , Neoplasm Recurrence, Local/mortality , Postmenopause/metabolism , Risk FactorsABSTRACT
BACKGROUND: Primary breast conserving treatment (BCT) is well known to have similar long-term survival as mastectomy in breast cancer patients. However, recent studies are suggesting better survival among women treated with BCT compared with mastectomy. More knowledge is needed to understand how disease specific survival is influenced by detection mode, prognostic and predictive tumor characteristics. We aimed to investigate this issue among women targeted by the Norwegian Breast Cancer Screening Program. METHOD: Information about 9547 women aged 50-69 years diagnosed with primary invasive breast cancer without distant metastasis, who underwent either BCT or mastectomy, 2005-2011, were included in the study. Kaplan-Meier plots were used to estimate six years survival, while Cox proportional hazards models were used to estimate the hazard ratio (HR) of breast cancer death associated with surgical treatment. Information about molecular subtype, detection mode, age at diagnosis, tumor size, lymph node involvement, and histologic grade, in addition to radiation treatment, chemotherapy and endocrine therapy were included in adjusted analyses. RESULTS: BCT was performed among 61.9% of the women included in the study. Women treated with BCT had prognostic and predictive favorable tumor characteristics compared to women treated with mastectomy. Adjusted analyses revealed a 1.7 (95% CI: 1.3-2.4) higher risk of breast cancer death among women who underwent mastectomy compared with BCT. CONCLUSION: Women treated with BCT have significantly better breast cancer-specific survival and a lower risk of dying from breast cancer compared to women treated with mastectomy, independent of detection mode, prognostic and predictive tumor characteristic.
Subject(s)
Breast Neoplasms/surgery , Carcinoma, Ductal, Breast/surgery , Carcinoma, Lobular/surgery , Mastectomy, Segmental , Aged , Breast Neoplasms/diagnosis , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/diagnosis , Carcinoma, Ductal, Breast/pathology , Carcinoma, Lobular/diagnosis , Carcinoma, Lobular/pathology , Chemotherapy, Adjuvant , Cohort Studies , Early Detection of Cancer , Female , Humans , Kaplan-Meier Estimate , Mastectomy , Middle Aged , Neoplasm Grading , Neoplasm Staging , Prognosis , Proportional Hazards Models , Radiotherapy, Adjuvant , Retrospective Studies , Survival Rate , Tumor BurdenABSTRACT
PURPOSE: Our previously reported 29-gene expression signature identified an aggressive subgroup of endometrial cancer patients with PI3K activation. We here wanted to validate these findings by independent patient series. PATIENTS AND METHODS: The 29-gene expression signature was assessed in fresh frozen tumor tissue from 280 primary endometrial carcinomas (three independent cohorts), 19 metastatic lesions and in 333 primary endometrial carcinomas using TCGA data, and expression was related to clinico-pathologic features and survival. The 29-gene signature was assessed by real-time quantitative PCR, DNA oligonucleotide microarrays, or RNA sequencing. PI3K alterations were assessed by immunohistochemistry, DNA microarrays, DNA sequencing, SNP arrays or fluorescence in situ hybridization. A panel of markers of epithelial-mesenchymal transition (EMT) was also correlated to the 29-gene signature score. RESULTS: High 29-gene Endometrial Carcinoma Recurrence Score (ECARS) values consistently validated to identify patients with aggressive clinico-pathologic phenotype and reduced survival. Within the presumed favorable subgroups of low grade, endometrioid tumors confined to the uterus, high ECARS still predicted a poor prognosis. The score was higher in metastatic compared to primary lesions (P<0.001) and was significantly associated with potential measures of PI3K activation, markers of EMT and vascular invasion as an indicator of metastatic spread (all P<0.001). CONCLUSIONS: ECARS validates to identify aggressive endometrial carcinomas in multiple, independent patients cohorts. The higher signature score in metastatic compared to primary lesions, and the potential link to PI3K activation and EMT, support further studies of ECARS in relation to response to PI3K and EMT inhibitors in clinical trials of metastatic endometrial carcinoma.
Subject(s)
Endometrial Neoplasms/genetics , Endometrial Neoplasms/pathology , Epithelial-Mesenchymal Transition , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Phosphatidylinositol 3-Kinases/genetics , Biomarkers, Tumor , Endometrial Neoplasms/epidemiology , Female , HumansABSTRACT
BACKGROUND: We aimed to study the angiogenic profile based on histomorphological markers in endometrial carcinomas in relation to imaging parameters obtained from preoperative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted imaging (DWI) and to explore the potential value of these markers to identify patients with poor outcome. METHODS: In fifty-four surgically staged endometrial carcinoma patients, immunohistochemical staining with factor VIII and Ki67 allowed assessment of microvessel density (MVD) and microvascular proliferation reflecting tumour angiogenesis. In the same patients, preoperative pelvic DCE-MRI and DWI allowed the calculation of parameters describing tumour microvasculature and microstructure in vivo. RESULTS: Microvascular proliferation was negatively correlated to tumour blood flow (Fb) (r=-0.36, P=0.008), capillary permeability surface area product (PS) (r=-0.39, P=0.004) and transfer from the blood to extravascular extracellular space (EES) (Ktrans) (r=-0.40, P=0.003), and was positively correlated to tumour volume (r=0.34; P=0.004). High-tumour microvascular proliferation, low Fb and low Ktrans were all significantly associated with reduced progression/recurrence-free survival (P<0.05). CONCLUSION: Disorganised angiogenesis with coexisting microvascular proliferation and low tumour blood flow is a poor prognostic factor supporting that hypoxia is associated with progression and metastatic spread in endometrial carcinomas.
Subject(s)
Endometrial Neoplasms/blood supply , Adult , Aged , Aged, 80 and over , Disease-Free Survival , Endometrial Neoplasms/pathology , Female , Humans , Immunohistochemistry , Magnetic Resonance Imaging , Middle Aged , Neoplasm Staging , Neovascularization, Pathologic/pathology , Prospective StudiesABSTRACT
Molecular subtyping of breast cancer may provide additional prognostic information regarding patient outcome. However, its clinical significance remains to be established. In this study, the main aims were to discover whether reclassification of breast cancer into molecular subtypes provides more precise information regarding outcome compared to conventional histopathological grading and to study breast cancer-specific survival in the different molecular subtypes. Cases of breast cancer occurring in a cohort of women born between 1886 and 1928 with long-term follow-up were included in the study. Tissue microarrays were constructed from archival formalin-fixed, paraffin-embedded tissue from 909 cases. Using immunohistochemistry and in situ hybridisation as surrogates for gene expression analyses, all cases were reclassified into the following molecular subtypes: Luminal A; Luminal B (HER2-); Luminal B (HER2+); HER2 subtype; Basal phenotype; and five negative phenotype. Kaplan-Meier survival curves and Cox proportional hazards models were used in the analyses. During the first 5 years after diagnosis, there were significant differences in prognosis according to molecular subtypes with the best survival for the Luminal A subtype and the worst for HER2 and five negative phenotype. In this historic cohort of women with breast cancer, differences in breast cancer-specific survival according to subtype occur almost exclusively amongst the histopathological grade 2 tumours. From 5 years after time of diagnosis until the end of follow-up, there appears to be no difference in survival according to molecular subtype or histopathological grade.
Subject(s)
Breast Neoplasms/metabolism , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Cohort Studies , Female , Follow-Up Studies , Humans , Immunohistochemistry , In Situ Hybridization , Kaplan-Meier Estimate , Ki-67 Antigen/metabolism , Middle Aged , Norway/epidemiology , Proportional Hazards Models , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Tissue Array AnalysisABSTRACT
BACKGROUND: To quantify tumour angiogenesis, microvessel density (MVD) has been widely used. We here present a novel angiogenesis marker, microvessel proliferation (MVP), based on dual immunohistochemical staining of nestin and Ki-67. Immature endothelial cells express nestin, and when co-expressed with the proliferation marker Ki-67, the number of proliferating immature blood vessels can be measured. MATERIALS AND METHODS: Microvessel proliferation was evaluated in 178 breast cancer samples and estimated by vascular proliferation index (VPI), the ratio between the number of vessels containing proliferating endothelial cells and the total number of immature vessels. RESULTS: High VPI was strongly associated with several markers of aggressive breast cancer, such as negative oestrogen receptor (ER) status (p = 0.003), high tumour cell proliferation by Ki-67 (p = 0.004), high p53 expression (p = 0.001), and five profiles for the basal-like phenotype (odds ratios (OR); range 3.4-6.3). Also, high VPI was significantly associated with interval detected breast cancer compared with screening detected lesions (p < 0.0005), and adverse outcome in univariate and multivariate survival analysis (p = 0.034 and p = 0.022, respectively). CONCLUSION: Microvessel proliferation is a novel marker of ongoing angiogenesis and was associated with aggressive tumour features, basal-like phenotypes, interval presentation, and prognosis in this series of breast cancer.
Subject(s)
Breast Neoplasms/chemistry , Carcinoma/chemistry , Endothelium/chemistry , Ki-67 Antigen/analysis , Microvessels/chemistry , Nestin/analysis , Aged , Breast Neoplasms/blood supply , Breast Neoplasms/pathology , Carcinoma/blood supply , Carcinoma/pathology , Cell Proliferation , Endothelium/physiopathology , Female , Humans , Microvessels/pathology , Microvessels/physiopathology , Middle Aged , Neoplasm Grading , Neovascularization, Pathologic/physiopathology , Prognosis , Receptors, Estrogen/analysis , Receptors, Progesterone/analysis , Tumor Suppressor Protein p53/analysisABSTRACT
BACKGROUND: Three quarter of endometrial carcinomas are treated at early stage. Still, 15 to 20% of these patients experience recurrence, with little effect from systemic therapies. Homo sapiens v-Ki-ras2 Kirsten rat sarcoma viral oncogenes homologue (KRAS) mutations have been reported to have an important role in tumorigenesis for human cancers, but there is limited knowledge regarding clinical relevance of KRAS status in endometrial carcinomas. METHODS: We have performed a comprehensive and integrated characterisation of genome-wide expression related to KRAS mutations and copy-number alterations in primary- and metastatic endometrial carcinoma lesions in relation to clinical and histopathological data. A primary investigation set and clinical validation set was applied, consisting of 414 primary tumours and 61 metastatic lesions totally. RESULTS: Amplification and gain of KRAS present in 3% of the primary lesions and 18% of metastatic lesions correlated significantly with poor outcome, high International Federation of Gynaecology and Obstetrics stage, non-endometrioid subtype, high grade, aneuploidy, receptor loss and high KRAS mRNA levels, also found to be associated with aggressive phenotype. In contrast, KRAS mutations were present in 14.7% of primary lesions with no increase in metastatic lesions, and did not influence outcome, but was significantly associated with endometrioid subtype, low grade and obesity. CONCLUSION: These results support that KRAS amplification and KRAS mRNA expression, both increasing from primary to metastatic lesions, are relevant for endometrial carcinoma disease progression.
Subject(s)
Endometrial Neoplasms/genetics , Endometrial Neoplasms/pathology , Gene Amplification , Gene Dosage , Genes, ras/genetics , Mutation , Proto-Oncogene Proteins/genetics , ras Proteins/genetics , Adult , Aged , Endometrial Neoplasms/metabolism , Endometrial Neoplasms/mortality , Female , Gene Expression Regulation, Neoplastic , Humans , Immunohistochemistry , Lymphatic Metastasis , Middle Aged , Neoplasm Grading , Oligonucleotide Array Sequence Analysis , Phenotype , Polymerase Chain Reaction , Predictive Value of Tests , Prognosis , Proto-Oncogene Proteins p21(ras) , Sequence Analysis, DNA , Tissue Array Analysis , Up-RegulationABSTRACT
BACKGROUND: Clinical and histopathological distinction between benign and malignant adrenocortical tumors can be a challenge.Report on 2 patients with cortisol producing apparently benign adrenal adenomas ≥ 5 cm in diameter with local malignant recurrence and peritoneal carcinomatosis after endoscopic surgery. RESULTS: Case 1: The 59-year-old male presented with adrenal hypercortisolism due to a 5.0 cm large adrenal tumor on the left side. A retroperitoneoscopic total adrenalectomy was performed. Histologically, a benign adrenal adenoma (Weiss score 1, Ki-67 < 2%) was found. 6 months later, the patient developed clinically and biochemically recurrent disease with recurrent tumor in the left adrenal region and peritoneal carcinomatosis. The patient died 5 months after second surgery. Case 2: The 32-year-old female was pregnant in 27th week when presenting with adrenal hypercortisolism due to a 5.5 cm large adrenal tumor on the left side. She was operated on using a laparoscopic approach and a total adrenalectomy was carried out. Histological examination revealed a benign adrenocortical adenoma (Weiss score 1, Ki-67 < 5%). 4 years later, the patient came back with clinically and biochemically recurrent disease. Imaging showed a 10 cm large tumor in the left retroperitoneum and a diffuse peritoneal carcinomatosis. The patient died 2 months after diagnosis. CONCLUSION: Cortisol producing adrenal tumors ≥ 5 cm in diameter are at risk to be misdiagnosed as apparently benign. Regular surveillance should be considered in patients presenting with large cortisol producing tumors.
Subject(s)
Adrenocortical Adenoma/diagnosis , Cushing Syndrome/etiology , Neoplasm Recurrence, Local/surgery , Peritoneal Neoplasms/secondary , Postoperative Care , Postoperative Complications/surgery , Adrenalectomy , Adrenocortical Adenoma/pathology , Adrenocortical Adenoma/physiopathology , Adrenocortical Adenoma/surgery , Adult , Delayed Diagnosis , Diagnostic Errors , Fatal Outcome , Female , Humans , Hydrocortisone/blood , Hydrocortisone/metabolism , Male , Middle Aged , Neoplasm Recurrence, Local/diagnosis , Peritoneal Neoplasms/diagnosis , Peritoneal Neoplasms/surgery , Postoperative Complications/diagnosis , Pregnancy , Pregnancy Complications, Neoplastic/diagnosis , Pregnancy Complications, Neoplastic/pathology , Pregnancy Complications, Neoplastic/physiopathology , Pregnancy Complications, Neoplastic/surgery , Tumor BurdenABSTRACT
BACKGROUND: The G protein-coupled oestrogen receptor, GPER, has been suggested as an alternative oestrogen receptor. Our purpose was to investigate the potential of GPER as a prognostic and predictive marker in endometrial carcinoma and to search for new drug candidates to improve treatment of aggressive disease. MATERIALS AND METHOD: A total of 767 primary endometrial carcinomas derived from three patient series, including an external dataset, were studied for protein and mRNA expression levels to investigate and validate if GPER loss identifies poor prognosis and new targets for therapy in endometrial carcinoma. Gene expression levels, according to ERα/GPER status, were used to search the connectivity map database for small molecular inhibitors with potential for treatment of metastatic disease for receptor status subgroups. RESULTS: Loss of GPER protein is significantly correlated with low GPER mRNA, high FIGO stage, non-endometrioid histology, high grade, aneuploidy and ERα loss (all P-values ≤0.05). Loss of GPER among ERα-positive patients identifies a subgroup with poor prognosis that until now has been unrecognised, with reduced 5-year survival from 93% to 76% (P=0.003). Additional loss of GPER from primary to metastatic lesion counterparts further supports that loss of GPER is associated with disease progression. CONCLUSION: These results support that GPER status adds clinically relevant information to ERα status in endometrial carcinoma and suggest a potential for new inhibitors in the treatment of metastatic endometrial cancers with ERα expression and GPER loss.
Subject(s)
Endometrial Neoplasms/drug therapy , Estrogen Receptor alpha/analysis , Receptors, Estrogen/physiology , Receptors, G-Protein-Coupled/physiology , Adult , Aged , Endometrial Neoplasms/chemistry , Endometrial Neoplasms/mortality , Endometrial Neoplasms/pathology , Female , Histone Deacetylase Inhibitors/therapeutic use , Humans , Middle Aged , Receptors, Estrogen/analysis , Receptors, Estrogen/genetics , Receptors, G-Protein-Coupled/analysis , Receptors, G-Protein-Coupled/genetics , Treatment OutcomeABSTRACT
BACKGROUND: Glomeruloid microvascular proliferation (GMP), a novel histology-based angiogenesis marker, has been associated with decreased survival in several human cancers. METHODS: In this study, we evaluated the ability of GMP to predict clinical response to neoadjuvant chemotherapy in a series of locally advanced breast cancers (n=112). RESULTS: Presence of GMP (21% of the cases) was significantly associated with high-grade tumours and TP53 mutations in addition to the basal-like and HER2 subtypes of breast cancer as defined by gene expression data. GMP was correlated to a gene expression signature for tumour hypoxia response. The GMP pattern was also significantly associated with lack of treatment response and progressive disease (P=0.004). INTERPRETATION: The findings suggest that GMP might be able to predict the lack of response to neoadjuvant chemotherapy in locally advanced breast cancer. Whether GMP may be an independent predictor compared with other factors including TP53 mutation status and tumour grade needs confirmation in larger studies.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/blood supply , Breast Neoplasms/drug therapy , Carcinoma, Ductal, Breast/blood supply , Carcinoma, Ductal, Breast/drug therapy , Drug Resistance, Neoplasm , Neovascularization, Pathologic , Biomarkers, Tumor/analysis , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/pathology , Endothelium, Vascular/cytology , Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Female , Gene Expression Profiling , Humans , Middle Aged , Prospective Studies , Survival Rate , Treatment OutcomeABSTRACT
BACKGROUND: Endometrial cancer incidence is increasing in industrialised countries. High body mass index (BMI, kg m(-2)) is associated with higher risk for disease. We wanted to investigate if BMI is related to clinico-pathological characteristics, hormone receptor status in primary tumour, and disease outcome in endometrial cancer. PATIENTS AND METHODS: In total, 1129 women primarily treated for endometrial carcinoma at Haukeland University Hospital during 1981-2009 were studied. Body mass index was available for 949 patients and related to comprehensive clinical and histopathological data, hormone receptor status in tumour, treatment, and follow-up. RESULTS: High BMI was significantly associated with low International Federation of Gynaecology and Obstetrics (FIGO) stage, endometrioid histology, low/intermediate grade, and high level of progesterone receptor (PR) mRNA by qPCR (n=150; P=0.02) and protein expression by immunohistochemistry (n=433; P=0.003). In contrast, oestrogen receptor (ERα) status was not associated with BMI. Overweight/obese women had significantly better disease-specific survival (DSS) than normal/underweight women in univariate analysis (P=0.035). In multivariate analysis of DSS adjusting for age, FIGO stage, histological subtype, and grade, BMI showed no independent prognostic impact. CONCLUSION: High BMI was significantly associated with markers of non-aggressive disease and positive PR status in a large population-based study of endometrial carcinoma. Women with high BMI had significantly better prognosis in univariate analysis of DSS, an effect that disappeared in multivariate analysis adjusting for established prognostic markers. The role of PR in endometrial carcinogenesis needs to be further studied.
Subject(s)
Body Mass Index , Carcinoma, Endometrioid/pathology , Endometrial Neoplasms/pathology , Receptors, Progesterone/analysis , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/analysis , Biomarkers, Tumor/metabolism , Carcinoma, Endometrioid/diagnosis , Carcinoma, Endometrioid/epidemiology , Carcinoma, Endometrioid/metabolism , Disease Progression , Endometrial Neoplasms/diagnosis , Endometrial Neoplasms/epidemiology , Endometrial Neoplasms/metabolism , Female , Follow-Up Studies , Humans , Immunohistochemistry , Middle Aged , Neoplasm Invasiveness , Neoplasm Staging , Prognosis , Receptors, Progesterone/metabolism , Retrospective StudiesABSTRACT
BACKGROUND: Putative breast cancer stem cells might express surface markers such as aldehyde dehydrogenase 1 (ALDH1) and BMI-1 proteins. The aim of this study was to explore the expression of these proteins in breast cancers from an African population and their associations with the basal-like phenotype (BLP) and other molecular characteristics. METHODS: We analysed 192 paraffin-embedded breast carcinoma samples by tissue microarrays and immunohistochemical methods. RESULTS: In total, 88 tumours (48%) expressed ALDH1, whereas 46 (25%) expressed BMI-1 protein. Expression of ALDH1 was associated with high histological grade (P<0.0005), high mitotic count (P<0.0005), high nuclear grade (P<0.0005), oestrogen receptor (ER) negativity (P<0.0005), progesterone receptor (PR) negativity (P=0.009), p53 expression (P=0.034), cytokeratin 5/6 positivity (P=0.008), epidermal growth factor receptor (EGFR) expression (P=0.015) and the BLP (P<0.0005), whereas it was inversely associated with BMI-1 staining (P=0.009). On the other hand, BMI-1 expression was associated with low histological grade (P=0.004) and ER positivity (P=0.001). CONCLUSION: There was a high prevalence of ALDH1 expression among breast carcinomas and associations with basal markers and features of aggressive tumours. Studies are required to elucidate the importance of these findings for improved understanding of breast cancer biology.
Subject(s)
Aldehyde Dehydrogenase/biosynthesis , Biomarkers, Tumor/biosynthesis , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Isoenzymes/biosynthesis , Neoplastic Stem Cells/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Aldehyde Dehydrogenase 1 Family , Black People/genetics , Breast Neoplasms/pathology , Female , Humans , Middle Aged , Nuclear Proteins/biosynthesis , Phenotype , Polycomb Repressive Complex 1 , Proto-Oncogene Proteins/biosynthesis , Repressor Proteins/biosynthesis , Retinal Dehydrogenase , Tissue Array Analysis , Uganda , Young AdultABSTRACT
BACKGROUND: Enhancer of zeste homologue 2 (EZH2) is a member of the Polycomb group of genes that is involved in epigenetic silencing and cell cycle regulation. METHODS: We studied EZH2 expression in 409 patients with colorectal cancer stages II and III. The patients were included in a randomised study, and treated with surgery alone or surgery followed by adjuvant chemotherapy. RESULTS: EZH2 expression was significantly related to increased tumour cell proliferation, as assessed by Ki-67 expression. In colon cancer, strong EZH2 expression (P=0.041) and high proliferation (>or=40%; P=0.001) were both associated with better relapse-free survival (RFS). In contrast, no such associations were found among rectal cancers. High Ki-67 staining was associated with improved RFS in colon cancer patients who received adjuvant chemotherapy (P=0.001), but not among those who were treated by surgery alone (P=0.087). In colon cancers stage III, a significant association between RFS and randomisation group was found in patients with high proliferation (P=0.046), but not in patients with low proliferation (P=0.26). Multivariate analyses of colon cancers showed that stage III (hazard ratio (HR) 4.00) and high histological grade (HR 1.80) were independent predictors of reduced RFS, whereas high proliferation indicated improved RFS (HR 0.55). CONCLUSION: Strong EZH2 expression and high proliferation are associated features and both indicate improved RFS in colon cancer, but not so in rectal cancer.
Subject(s)
Colorectal Neoplasms/pathology , DNA-Binding Proteins/analysis , Ki-67 Antigen/analysis , Transcription Factors/analysis , Adult , Aged , Colorectal Neoplasms/chemistry , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/mortality , Enhancer of Zeste Homolog 2 Protein , Female , Humans , Immunohistochemistry , Male , Middle Aged , Neoplasm Staging , Polycomb Repressive Complex 2 , PrognosisABSTRACT
Although 75% of endometrial cancers are treated at an early stage, 15% to 20% of these recur. We performed an integrated analysis of genome-wide expression and copy-number data for primary endometrial carcinomas with extensive clinical and histopathological data to detect features predictive of recurrent disease. Unsupervised analysis of the expression data distinguished 2 major clusters with strikingly different phenotypes, including significant differences in disease-free survival. To identify possible mechanisms for these differences, we performed a global genomic survey of amplifications, deletions, and loss of heterozygosity, which identified 11 significantly amplified and 13 significantly deleted regions. Amplifications of 3q26.32 harboring the oncogene PIK3CA were associated with poor prognosis and segregated with the aggressive transcriptional cluster. Moreover, samples with PIK3CA amplification carried signatures associated with in vitro activation of PI3 kinase (PI3K), a signature that was shared by aggressive tumors without PIK3CA amplification. Tumors with loss of PTEN expression or PIK3CA overexpression that did not have PIK3CA amplification also shared the PI3K activation signature, high protein expression of the PI3K pathway member STMN1, and an aggressive phenotype in test and validation datasets. However, mutations of PTEN or PIK3CA were not associated with the same expression profile or aggressive phenotype. STMN1 expression had independent prognostic value. The results affirm the utility of systematic characterization of the cancer genome in clinically annotated specimens and suggest the particular importance of the PI3K pathway in patients who have aggressive endometrial cancer.
Subject(s)
Endometrial Neoplasms/enzymology , Endometrial Neoplasms/genetics , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Genome, Human/genetics , Phosphatidylinositol 3-Kinases/metabolism , Biomarkers, Tumor/metabolism , Class I Phosphatidylinositol 3-Kinases , Cluster Analysis , Endometrial Neoplasms/diagnosis , Endometrial Neoplasms/pathology , Enzyme Activation , Female , Gene Dosage , Humans , Loss of Heterozygosity/genetics , Prognosis , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins p21(ras) , Stathmin/metabolism , Survival Analysis , ras Proteins/metabolismABSTRACT
AIMS: BRCA1-related breast cancer is associated with a basal-like phenotype, and is frequently oestrogen receptor (ER) and HER2 negative. The expression of epidermal growth factor receptor (EGFR) has been considered to be one component of the basal-like phenotype, but no standard criteria exist. This study investigates the relationship between EGFR expression, BRCA1 status and basal markers with respect to clinicopathological associations and prognosis, in addition to evaluating different criteria for EGFR assessment by immunohistochemistry. METHODS: A tissue microarray comprising 230 available cases, from a series of primary invasive breast cancer diagnosed in Ashkenazi Jewish women during 1980-1995, was stained for EGFR using the Dako PharmDX kit, and evaluated by Webslide virtual microscopy. RESULTS: EGFR was positive in 9-19% according to different criteria. Expression was associated with BRCA1 carrier status and basal-like markers as negative ER, positive cytokeratin 5/6 and positive P-cadherin staining. EGFR was prognostically significant by univariate and multivariate analysis within the group carrying germ-line BRCA1 mutations. Histological grade, axillary lymph node status and P-cadherin status had significant independent value in the final multivariate model including all cases, whereas EGFR was not significant in this model. All five scoring systems gave comparable results concerning clinicopathological associations and patient outcome, although the most restrictive criteria (EGFR-HI) tended to be most sensitive in predicting BRCA1 status, a basal phenotype, and patient prognosis. CONCLUSIONS: EGFR expression, being present in 9-19% of the cases, was prognostically significant among BRCA1 mutated cases only. In multivariate survival analysis of all cases, no independent effect was seen. However, EGFR immunostaining might be relevant to predict the response to targeted therapy, and this should be studied further.
Subject(s)
Biomarkers, Tumor/metabolism , Breast Neoplasms/metabolism , ErbB Receptors/metabolism , Genes, BRCA1 , Adult , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Female , Genetic Predisposition to Disease , Humans , Immunoenzyme Techniques , Middle Aged , Neoplasm Proteins/metabolism , Prognosis , Retrospective Studies , Survival Analysis , Tissue Array Analysis/methodsABSTRACT
We studied the expression of polycomb group (PcG) protein BMI-1 in a large population-based patient series of endometrial carcinomas in relation to clinical and molecular phenotype. Also, 57 fresh frozen endometrial carcinomas were studied for the relationship between BMI-1 protein expression, BMI-1 mRNA level, and activation of an 11-gene signature reported to represent a BMI-1-driven pathway. BMI-1 protein expression was significantly weaker in tumours with vascular invasion (P<0.0001), deep myometrial infiltration (P=0.004), and loss of oestrogen receptor (ER) (P<0.0001) and progesterone receptors (PR) (P=0.03). Low BMI-1 protein expression was highly associated with low BMI-1 mRNA expression (P=0.002), and similarly low BMI-1 mRNA expression correlated significantly with vascular invasion, ER and PR loss, and histologic grade 3. In contrast, activation of the reported 11-gene signature, supposed to represent a BMI-1-driven pathway, correlated with low mRNA expression of BMI-1 (P<0.001), hormone receptor loss, presence of vascular invasion, and poor prognosis. We conclude that BMI-1 protein and mRNA expression are significantly correlated and that BMI-1 expression is inversely associated with activation of the 11-gene signature. Loss of BMI-1 seems to be associated with an aggressive phenotype in endometrial carcinomas.