Comprehensive Assessment of Incidence, Risk Factors, and Mechanisms of Impaired Medical and Psychosocial Health Outcomes among Adolescents and Young Adults with Cancer: Protocol of the Prospective Observational COMPRAYA Cohort Study.

Adolescent and young adult (AYA) cancer patients suffer from delay in diagnosis, and lack of centralized cancer care, age-adjusted expertise, and follow-up care. This group presents with a unique spectrum of cancers, distinct tumor biology, cancer risk factors, developmental challenges, and treatment regimens that differ from children and older adults. It is imperative for advances in the field of AYA oncology to pool data sources across institutions and create large cohorts to address the many pressing questions that remain unanswered in this vulnerable population. We will create a nationwide infrastructure (COMPRAYA) for research into the incidence, predictive/prognostic markers, and underlying mechanisms of medical and psychosocial outcomes for AYA between 18-39 years diagnosed with cancer. A prospective, observational cohort of (n = 4000), will be established. Patients will be asked to (1) complete patient-reported outcome measures; (2) donate a blood, hair, and stool samples (to obtain biochemical, hormonal, and inflammation parameters, and germline DNA); (3) give consent for use of routinely archived tumor tissue and clinical data extraction from medical records and registries; (4) have a clinic visit to assess vital parameters. Systematic and comprehensive collection of patient and tumor characteristics of AYA will support the development of evidence-based AYA care programs and guidelines.

Somatostatin receptor 2 expression in nasopharyngeal cancer is induced by Epstein Barr virus infection: impact on prognosis, imaging and therapy.

Nasopharyngeal cancer (NPC), endemic in Southeast Asia, lacks effective diagnostic and therapeutic strategies. Even in high-income countries the 5-year survival rate for stage IV NPC is less than 40%. Here we report high somatostatin receptor 2 (SSTR2) expression in multiple clinical cohorts comprising 402 primary, locally recurrent and metastatic NPCs. We show that SSTR2 expression is induced by the Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) via the NF-κB pathway. Using cell-based and preclinical rodent models, we demonstrate the therapeutic potential of SSTR2 targeting using a cytotoxic drug conjugate, PEN-221, which is found to be superior to FDA-approved SSTR2-binding cytostatic agents. Furthermore, we reveal significant correlation of SSTR expression with increased rates of survival and report in vivo uptake of the SSTR2-binding 68Ga-DOTA-peptide radioconjugate in PET-CT scanning in a clinical trial of NPC patients (NCT03670342). These findings reveal a key role in EBV-associated NPC for SSTR2 in infection, imaging, targeted therapy and survival.

Multicenter randomized crossover trial evaluating the provox luna in laryngectomized subjects.

OBJECTIVES: The aim of this study was to compare the relative compliance and the dermatological and pulmonary outcomes when the Provox Luna system (Atos Medical, Malmö, Sweden) is added during the night to the usual tracheastoma care of laryngectomized subjects. METHODS: This was a multicenter randomized crossover trial conducted in the Netherlands Cancer Institute, Erasmus Medical Center, and Maastricht University Medical Center in The Netherlands. The study included 46 laryngectomized subjects with prior heat and moisture exchanger (HME) and adhesive experience. RESULTS: A significant improvement in the number of compliant individuals was found: Luna: n = 43 of 45 (96%); usual care: n = 35 of 46 (76%), P = 0.02. The Luna period was associated with longer intervals of daily HME use (Luna 23.2 hours [range: 15.6-24.0 hours], usual care [UC]: 21.5 hours [range: 6.0-24.0 hours], P = 0.003) and an increased frequency of skin improvement overnight (Luna 3.9 days [standard deviation (SD)]: 7.0 days), Usual Care: 8.1 days ([SD: 10.8 days], P = 0.008). Fifty-six percent (n = 26) of participants wanted to continue using the Provox Luna system at the conclusion of the study. CONCLUSION: An improvement in compliance and skin recovery overnight was observed when the Provox Luna was added to the usual adhesive and HME use. Therefore, there is utility in supplementing the usual post-total laryngectomy care with the Provox Luna system at night, particularly in the setting of compliance concerns and in subjects who desire dermatological relief overnight. LEVEL OF EVIDENCE: 1b Laryngoscope, 129:2354-2360, 2019.

Treatment-seeking behaviour of nasopharyngeal cancer patients in Yogyakarta, Indonesia.

INTRODUCTION: Nasopharyngeal cancer ranks first among head and neck cancer. About 60-95% of nasopharyngeal cancer patients seek for treatment at advanced stage. Attitudes and behavior of cancer patients in choosing healthcare is affected by the level of socio-economic and cultural backgrounds. Surgery and treatment costs are also the reasons patients to late seek treatment. This study aims to explore what contributes the treatment seeking behavior of nasopharyngeal cancer patients. It conducted in the Yogyakarta, Indonesia. METHODS: As many as 20 patients were interviewed using questionnaire. All interviews were done using Opencode 3.6. To ensure the data validity, triangulation approach, peer debriefing and thick description were done. RESULTS: it showed that there are five factors that affect the patients in seeking treatment: disease perception, medical services perception, medical expenses, external support and assessment of treatment process. CONCLUSION: This study may help to design health education programs to raise public awareness of nasopharyngeal cancer.

Estrogen receptor α wields treatment-specific enhancers between morphologically similar endometrial tumors.

The DNA-binding sites of estrogen receptor α (ERα) show great plasticity under the control of hormones and endocrine therapy. Tamoxifen is a widely applied therapy in breast cancer that affects ERα interactions with coregulators and shifts the DNA-binding signature of ERα upon prolonged exposure in breast cancer. Although tamoxifen inhibits the progression of breast cancer, it increases the risk of endometrial cancer in postmenopausal women. We therefore asked whether the DNA-binding signature of ERα differs between endometrial tumors that arise in the presence or absence of tamoxifen, indicating divergent enhancer activity for tumors that develop in different endocrine milieus. Using ChIP sequencing (ChIP-seq), we compared the ERα profiles of 10 endometrial tumors from tamoxifen users with those of six endometrial tumors from nonusers and integrated these results with the transcriptomic data of 47 endometrial tumors from tamoxifen users and 64 endometrial tumors from nonusers. The ERα-binding sites in tamoxifen-associated endometrial tumors differed from those in the tumors from nonusers and had distinct underlying DNA sequences and divergent enhancer activity as marked by histone 3 containing the acetylated lysine 27 (H3K27ac). Because tamoxifen acts as an agonist in the postmenopausal endometrium, similar to estrogen in the breast, we compared ERα sites in tamoxifen-associated endometrial cancers with publicly available ERα ChIP-seq data in breast tumors and found a striking resemblance in the ERα patterns of the two tissue types. Our study highlights the divergence between endometrial tumors that arise in different hormonal conditions and shows that ERα enhancer use in human cancer differs in the presence of nonphysiological endocrine stimuli.

Effectiveness of a multicentre nasopharyngeal carcinoma awareness programme in Indonesia.

OBJECTIVE: To evaluate the effectiveness of a nasopharyngeal carcinoma (NPC) awareness programme on the short-term and long-term improvement of knowledge and referral of patients with NPC by primary healthcare centres (PHCCs) staff in Indonesia. DESIGN: The NPC awareness programme consisted of 12 symposia including a Train-The-Trainer component, containing lectures about early symptoms and risk factors of NPC, practical examination and the referral system for NPC suspects. Before and after training participants completed a questionnaire. The Indonesian Doctors Association accredited all activities. PARTICIPANTS: 1 representative general practitioner (GP) from each PHCC attended an NPC awareness symposium. On the basis of the Train-The-Trainer principle, GPs received training material and were obligated to train their colleagues in the PHCC. RESULTS: 703 GPs attended the symposia and trained 1349 staff members: 314 other GPs, 685 nurses and 350 midwives. After the training, respondents' average score regarding the knowledge of NPC symptoms increased from 47 points (of the 100) to 74 points (p<0.001); this increase was similar between symposium and Train-The-Trainer component (p=0.88). At 1½ years after the training, this knowledge remained significantly increased at 59 points (p<0.001). CONCLUSIONS: The initial results of this NPC awareness programme indicate that the programme effectively increases NPC knowledge in the short and long term and therefore should be continued. Effects of the improved knowledge on the stage at diagnoses of the patients with NPC will still need to be scrutinised. This awareness programme can serve as a blueprint for other cancer types in Indonesia and for other developing countries.

Can Epstein-Barr virus DNA load in nasopharyngeal brushings or whole blood predict recurrent nasopharyngeal carcinoma in a non-endemic region? A prospective nationwide study of the Dutch Head and Neck Oncology Cooperative Group.

This study estimated the value of quantitative measurements of EBV markers in the clinical management of nasopharyngeal carcinoma in a non-endemic area. The aim was to predict prognosis and detect recurrent and residual disease. In 72 patients, EBV DNA load in blood and nasopharyngeal brushes, and IgA VCA-p18 and EBNA1 in plasma were measured at different time points. At diagnosis and post-treatment, a cut-off value was used for detecting disease [positive (PPV) and negative (NPV) predictive value]. The markers were correlated as a continuous variable with tumor stage, disease-free survival (DFS) and overall survival (OS). The Cox hazard ratio model assessed hazard ratios. At diagnosis, the markers were above the COV in 45, 92, 85 and 83 % of the patients, respectively. Post-treatment, DNA load test in blood and brush had the best discriminating power (blood DNA load test: PPV 39 % and NPV 97 %, brush for local disease: PPV 75 % and NPV 99 %). Post-treatment, DNA load in blood was the best predictor for OS and DFS [hazard ratio 3.2 (95 % CI 1.51-3.5) and 2.3 (95 % CI 1.72-5.8)]. Assessing the EBV DNA load in blood has significant prognostic value, although the clinical value is for discussion. The EBV DNA load in the brush might improve early detection of local failures post-treatment.

Current status of cancer care for young patients with nasopharyngeal carcinoma in Jakarta, Indonesia.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is endemic in Indonesia and 20% of the patients are diagnosed before the age of 31. This study evaluates presentation and treatment outcome of young patients in Jakarta, in a tertiary referral centre. METHODS: Forty-nine patients under the age of 31, diagnosed with NPC between July 2004 and January 2007, were evaluated. Baseline data included histological type, stage of disease and presenting symptoms. We intended to follow all patients after diagnosis to reveal treatment outcome and overall survival (OS). RESULTS: All but two patients had advanced stage disease (94%), 7 (14%) had distant metastasis. The median interval between start of complaints and diagnosis was 9 months. Forty-two patients were planned for curative intent treatment. Eleven patients (26%) never started treatment, 2 patients did not complete treatment and 3 patients did not return after finishing treatment. Four patients died before radiation could start. Three patients died within 4 months after treatment. Nine patients (21%) had a complete response. Due to the high number of patients who were lost to follow-up (LFU), OS was analyzed as follows: a best-case (patients censored at last contact) and a worst-case scenario (assuming that patients who did not finish treatment or had disease at last contact would have died). The 2-year OS for patients without distant metastases was 39-71%. CONCLUSION: Treatment outcome for young patients with NPC in this institute was poor. Improvement can be achieved when NPC is diagnosed at an earlier stage and when there is better treatment compliance.

A prospective study: current problems in radiotherapy for nasopharyngeal carcinoma in yogyakarta, indonesia.

INTRODUCTION: Nasopharyngeal carcinoma (NPC) has a high incidence in Indonesia. Previous study in Yogyakarta revealed a complete response of 29% and a median overall survival of less than 2 years. These poor treatment outcome are influenced by the long diagnose-to-treatment interval to radiotherapy (DTI) and the extended overall treatment time of radiotherapy (OTT). This study reveals insight why the OTT and DTI are prolonged. METHOD: All patients treated with curative intent radiotherapy for NPC between July 2011 until October 2012 were included. During radiotherapy a daily diary was kept, containing information on DTI, missed radiotherapy days, the reason for missing and length of OTT. RESULTS: Sixty-eight patients were included. The median DTI was 106 days (95% CI: 98-170). Fifty-nine patients (87%) finished the treatment. The median OTT for radiotherapy was 57 days (95% CI: 57-65). The main reason for missing days was an inoperative radiotherapy machine (36%). Other reasons were patient's poor condition (21%), public holidays (14%), adjustment of the radiation field (7%), power blackout (3%), inoperative treatment planning system (2%) and patient related reasons (9%). Patient's insurance type was correlated to DTI in disadvantage for poor people. CONCLUSION: Yogyakarta has a lack of sufficient radiotherapy units which causes a delay of 3-4 months, besides the OTT is extended by 10-12 days. This influences treatment outcome to a great extend. The best solution would be creating sufficient radiotherapy units and better management in health care for poor patients. The growing economy in Indonesia will expectantly in time enable these solutions, but in the meantime solutions are needed. Solutions can consist of radiation outside office hours, better maintenance of the facilities and more effort from patient, doctor and nurse to finish treatment in time. These results are valuable when improving cancer care in low and middle income countries.

Primary treatment results of Nasopharyngeal Carcinoma (NPC) in Yogyakarta, Indonesia.

INTRODUCTION: Nasopharyngeal Carcinoma (NPC) is a major health problem in southern and eastern Asia. In Indonesia NPC is the most frequent cancer in the head and neck area. NPC is very sensitive to radiotherapy resulting in 3-year disease-free and overall survival of approximately 70% and 80%, respectively. Here we present routine treatment results in a prospective study on NPC in a top referral; university hospital in Indonesia. METHODS: All NPC patients presenting from September 2008 till January 2011 at the ear, nose and throat (ENT) department of the Dr. Sardjito General Hospital, Universitas Gadjah Mada, Yogyakarta, Indonesia, were possible candidates. Patients were included if the biopsy was a histological proven NPC without distant metastasis and were assessed during counselling sessions prior to treatment, as being able to complete the entire treatment. RESULTS: In total 78 patients were included for treatment analysis. The median time between diagnosis and start of radiotherapy is 120 days. Forty-eight (62%) patients eventually finished all fractions of radiotherapy. The median duration of the radiotherapy is 62 days for 66 Gy. Median overall survival is 21 months (95% CI 18-35) from day of diagnosis. CONCLUSION: The results presented here reveal that currently the treatment of NPC at an Indonesian hospital is not sufficient and cannot be compared to the treatment results in literature. Main reasons for these poor treatment results are (1) a long waiting time prior to the start of radiotherapy, (2) the extended overall duration of radiotherapy and (3) the advanced stage of disease at presentation.

Lower mortality from nasopharyngeal cancer in The Netherlands since 1970 with differential incidence trends in histopathology.

OBJECTIVE: Nasopharyngeal carcinoma (NPC) is rare in western countries albeit affected by common and unrelated phenomena: smoking less in men, more in women and immigration from China and North Africa. We studied trends in NPC incidence, tumour morphology, survival and mortality in order to assess progress against this cancer. MATERIALS AND METHODS: A trend analysis was performed with nationwide incidence and survival data (from The Netherlands Cancer registry in 1989-2009), followed by analysis of mortality (data from Statistics Netherlands) covering the period 1970-2009, and calculating estimated percentages of change (EAPC) in both. According to the WHO classification we distinguished keratinizing SCC (WHO-I), differentiated (WHO-IIA) and undifferentiated (WHO-IIB) non-keratinizing carcinoma. RESULTS: NPC incidence significantly decreased since 1989, especially in males (EAPC 1989-2009: -1.3; 95% CI: -2.5, -0.2) and in patients with keratinizing SCC (WHO-I) (EAPC: -3.6; 95% CI: -5.3, -1.8). By contrast, the incidence of differentiated non-keratinizing tumours (WHO-IIA) significantly increased in the same period (EAPC: 9.6; 95% CI: 5.6, 13.5). One- and three-year relative survival, as an indicator of disease-specific survival increased slightly from 79% to 81% and from 57% to 65% since 1989. NPC mortality significantly decreased since 1970 (EAPC: -1.2; 95% CI: -1.8, -0.5) and more pronounced since 1989 (EAPC: -3.0; 95% CI: -4.3, -1.6). CONCLUSION: During the past two decades, the incidence of NPC in The Netherlands decreased mainly by less keratinizing, supposedly smoking-related NPC (WHO-I). However, the incidence of non-keratinizing NPC (WHO-IIA, B) increased, most likely due to EBV infection and thus related to higher immigration levels of people from high-incidence areas.

Short-term effect of different teaching methods on nasopharyngeal carcinoma for general practitioners in Jakarta, Indonesia.

UNLABELLED: In Indonesia, Nasopharyngeal Carcinoma (NPC) is the most frequent cancer of the head and neck region. At first presentation in the hospital most patients already have advanced NPC. Our previous study showed that general practitioners (GPs) working in Yogyakarta, Indonesia lack the knowledge necessary for early detection of NPC. By providing training on early symptoms of NPC we hope that the diagnosis and referral will occur at an earlier stage. Here we assess the current NPC knowledge levels of GPs in Jakarta, evaluate improvement after training, compare the effectiveness of two training formats, and estimate the loss of recall over a two week period. METHODS: Two Indonesian GPs visited 31 Primary Health Care Centres (PHCCs) and provided a lecture on NPC. The alternative format consisted of a symposium at the Universitas Indonesia, Jakarta, presented by local head and neck surgeons, with all GPs in the region being invited. To evaluate the effect of both formats a questionnaire was conducted before and after. RESULTS: The lecture in the PHCCs was attended by 130 GPs. Sixty-six GPs attended the training in the university hospital and 40 GPs attended both. Pre training the NPC knowledge level was poor with an average of 1.6 symptoms being correctly identified out of a potential maximum of 12, this was increased to 4.9 post training (p<0.0001). GPs attending the PHCC course recorded a greater increase in correct symptoms than those attending the symposium (3.8 vs. 2.8; p = 0.01). After a two week period the knowledge levels had declined slightly from 5.5 correctly identified symptoms to 4.2 (p = 0.25). CONCLUSION: These results confirm our findings regarding GPs insufficient knowledge of NPC. Lectures in the PHCC and a symposium have both been proven to be effective training tools in the education of GPs.

Can an online clinical data management service help in improving data collection and data quality in a developing country setting?

BACKGROUND: Data collection by electronic medical record (EMR) systems have been proven to be helpful in data collection for scientific research and in improving healthcare. For a multi-centre trial in Indonesia and the Netherlands a web based system was selected to enable all participating centres to easily access data. This study assesses whether the introduction of a clinical trial data management service (CTDMS) composed of electronic case report forms (eCRF) can result in effective data collection and treatment monitoring. METHODS: Data items entered were checked for inconsistencies automatically when submitted online. The data were divided into primary and secondary data items. We analysed both the total number of errors and the change in error rate, for both primary and secondary items, over the first five month of the trial. RESULTS: In the first five months 51 patients were entered. The primary data error rate was 1.6%, whilst that for secondary data was 2.7% against acceptable error rates for analysis of 1% and 2.5% respectively. CONCLUSION: The presented analysis shows that after five months since the introduction of the CTDMS the primary and secondary data error rates reflect acceptable levels of data quality. Furthermore, these error rates were decreasing over time. The digital nature of the CTDMS, as well as the online availability of that data, gives fast and easy insight in adherence to treatment protocols. As such, the CTDMS can serve as a tool to train and educate medical doctors and can improve treatment protocols.

PKA-induced phosphorylation of ERα at serine 305 and high PAK1 levels is associated with sensitivity to tamoxifen in ER-positive breast cancer.

Phosphorylation of estrogen receptor α at serine 305 (ERαS305-P) by protein kinase A (PKA) or p21-activated kinase 1 (PAK1) has experimentally been associated with tamoxifen sensitivity. Here, we investigated the clinical application of this knowledge to predict tamoxifen resistance in ER-positive breast cancer patients. Using immunohistochemistry, a score including PAK1 and co-expression of PKA and ERαS305-P (PKA/ERαS305-P) was developed on a training set consisting of 103 patients treated with tamoxifen for metastatic disease, and validated on 231 patients randomized between adjuvant tamoxifen or no treatment. In the training set, PAK1 levels were associated with tumor progression after tamoxifen (HR 1.57, 95% CI 0.99-2.48), as was co-expression of PKA and ERαS305-P (HR 2.00, 95% CI 1.14-3.52). In the validation set, a significant tamoxifen benefit was found among the 73% patients negative for PAK1 and PKA/ERαS305-P (HR 0.54, 95% CI 0.34-0.87), while others (27%) were likely to have no benefit from tamoxifen (HR 0.88, 95% 0.42-1.82). The test for interaction showed a significant difference in recurrence-free survival between groups defined by PAK1 and PKA/ERαS305-P (P = 0.037). Elevated PAK1 and PKA/ERαS305-P appeared to influence tamoxifen sensitivity. Both PAK1 and PKA/ERαS305-P levels were associated with sensitivity to tamoxifen in breast tumors and the combination of these variables should be considered in predicting tamoxifen benefit.

Knowledge of general practitioners about nasopharyngeal cancer at the Puskesmas in Yogyakarta, Indonesia.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is one of the leading causes of cancer death in Indonesia. At initial diagnosis, 80% of the patients present with advanced stage disease. In Indonesia, primary medical care is generally provided by the health care centres; named Puskesmas. The lack of knowledge of various aspects of NPC of the General practitioners (GPs) working in these centers might contribute to the diagnostic delay. The aim of this study was to assess the knowledge of these GPs on different aspects of NPC including symptoms, risk factors and incidence. METHODS: One hundred six GPs in the Puskesmas in the Yogyakarta province were subjected to a questionnaire on different aspects of NPC based on literature and interviews with Head and Neck Surgeons. RESULTS: All GPs approached participated and in total 106 questionnaires were filled in. All participants were aware of NPC as a disease and 89% confirmed that it is a serious problem in Indonesia. However, 50% of the participants believed NPC has a low incidence in their region. The question on early symptoms gave a mean 4.2 answers of which 50% were incorrect.The GPs provided a total of 318 answers when asked for the risk factors of NPC, 75% of which were incorrect. Fifty seven GPs (54%) stated that they did not receive sufficient education on NPC at the university and insufficient knowledge was gained during daily practice. Ninety-two percent of the GPs were interested in additional education, preferably in form of lectures, meetings or folders. CONCLUSION: This study revealed that GPs in the Puskesmas in Yogyakarta lack knowledge on all aspects of NPC. This is an important finding as NPC is endemic in Indonesia and the Puskesmas are the institutions which provide primary medical health care in the country. Further education of the GPs in these endemic areas could be a first step to increase the rate of early detection. Therefore, we suggest 1) to conduct a medical awareness campaign for GPs on the most important subjects concerning NPC, and 2) as soon as NPC awareness among GPs has risen, provide further education on the risk factors, the early symptoms and the incidence, education to the community. We propose to extend this study to other areas in Indonesia (i.e. Jakarta, Surabaya, Central Java), using models that have been developed in Yogyakarta.

Genomic profile of endometrial tumors depends on morphological subtype, not on tamoxifen exposure.

Tamoxifen has been a very effective treatment for breast cancer for several decades, however, at the same time increases the risk of endometrial cancer, especially after prolonged exposure. In addition, tamoxifen has been associated with a higher proportion of unfavorable uterine tumor subtypes (carcinosarcomas and serous adenocarcinomas) with worse survival. We investigated whether endometrial tumors, which developed after prolonged tamoxifen treatment for breast cancer, are genetically different from endometrial tumors without preceding tamoxifen exposure. Array CGH was used on archival formalin-fixed paraffin embedded endometrial tumors to determine genomic aberrations. We compared the genomic profiles of 52 endometrial tumors from breast cancer patients after long-term (>or=2 years) tamoxifen use (endometrioid adenocarcinomas, n = 26; carcinosarcomas, n = 14; and serous adenocarcinomas, n = 12) with endometrial tumors from unexposed breast cancer patients (n = 45). Genomic profiles were correlated with tamoxifen exposure, tumor subtypes, and histopathological characteristics of the endometrial tumors. The common uterine corpus cancers of the endometrioid subtype show few genomic aberrations. Tumors with many genomic aberrations were in general ER-negative. In contrast, carcinosarcomas and serous adenocarcinomas showed many aberrations; however, they were indistinguishable from each other. Tumors that developed after prolonged tamoxifen use did not show more or different aberrations than unexposed tumors. This was true for all tumor subtypes. Thus, endometrial carcinomas that develop after prolonged tamoxifen use cannot be distinguished from nonusers on basis of their tumor genomic profile.

Mammosphere-derived gene set predicts outcome in patients with ER-positive breast cancer.

Tumourigenic subpopulations with stem cell-like features have been identified in breast tumours and breast cancer cell lines. The hormone receptor status, molecular characteristics and clinical significance of these cells are still matters of debate. Enrichment for tumourigenic cells without the requirement of surface markers can be achieved by the in vitro mammosphere culture assay. Here we compared the hormone receptor status and genome-wide gene expression profiles of mammospheres derived from four oestrogen-receptor (ER) positive breast cancer cell lines with those of the respective parental cells. Immunohistochemistry and gene expression profiling revealed a significant reduction in the expression of progesterone receptor, proliferation and cell cycle regulated genes in mammospheres when compared to parental cell lines. The 200 most differentially expressed genes between mammospheres and parental cell lines were used to generate a 'mammosphere-derived' gene set. Hierarchical clustering of gene expression profiles of two independent cohorts of primary ER-positive cancers based on the 'mammosphere-derived' gene set revealed that the subgroup of breast cancers with profiles similar to those of mammospheres has a significantly longer overall survival. In conclusion, tumour-initiating breast cancer cells grown in mammospheres seem to reside in a quiescent state. ER-positive breast cancers with expression profiles similar to those of mammospheres have a better outcome, providing evidence in support of the concept that outcome of patients with ER-positive disease is for a large part determined by cell cycle and proliferation activity.

Prognosis of uterine corpus cancer after tamoxifen treatment for breast cancer.

Tamoxifen increases the risk of uterine corpus cancer. Since only few, mostly small, studies have examined prognosis of uterine corpus cancer following tamoxifen, we conducted a large retrospective cohort study to further investigate this. We examined histopathologic and immunohistochemical characteristics of 332 patients with uterine corpus cancer following breast cancer, according to tamoxifen use. Survival was examined in the same patients combined with 309 patients from a previous study with updated follow-up. Histological review of all cancers was performed. Long-term tamoxifen users showed a higher proportion of non-endometrioid tumors than non-users (32.7% vs. 17.4%, P=0.004), especially serous adenocarcinomas and carcinosarcomas. An increased proportion of FIGO stage III and IV tumors was also observed (20.0% vs. 11.3%, P=0.049). Within FIGO stage I, both short-term and long-term tamoxifen users showed a higher proportion of tumors limited to the endometrium than non-users (35.7% vs. 22.9%, P=0.049 and 0.004 respectively). Uterine corpus cancers in long-term tamoxifen users were more often steroid receptor-negative (ERalpha, PRA and PRB, P<0.05) and P53-positive (P=0.015). Three-year uterine corpus cancer-specific survival was worse for long-term tamoxifen users than for non-users (82% vs. 93% P=0.0001). The survival difference remained after adjustment for histopathologic and immunohistochemical characteristics (hazard ratio (HR) for >or=2 years tamoxifen=2.4; 95% CI=1.2-4.6). In conclusion, this large study clearly shows that tamoxifen-associated tumors have less favorable histological features and a worse survival. Our results can be applied when weighing risks and benefits of tamoxifen versus other hormonal agents used in the prevention and treatment of breast cancer.