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.
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.
Abstract 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.
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.
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.
We investigated relations between measured body mass index (BMI) and stature and thyroid cancer (3046 cases) in a large Norwegian cohort of more than two million individuals. The risk of thyroid ...cancer, especially of the papillary and follicular types, increased moderately with increasing BMI and height in both sexes.
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
Low ASRGL1 expression in curettage predicts lymph node metastasis and poor survival in endometrial carcinoma.
Tweetable
Low ASRGL1 expression in curettage predicts lymph node metastasis and poor survival in endometrial carcinoma.
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.
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.
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).
Strong EZH2 expression and high proliferation are associated features and both indicate improved RFS in colon cancer, but not so in rectal cancer.
Abstract 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.
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.
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.
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).
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.
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