Educational level and the risk of mental disorders, substance use disorders and self-harm in different age-groups: A cohort study covering 1,6 million subjects in the Stockholm region.

OBJECTIVE: To investigate the associations between low education and risk of mental disorders, substance use disorders and self-harm in different age-groups. METHODS: All subjects in Stockholm born between 1931 and 1990 were linked to their own or their parent's highest education in 2000 and followed-up for these disorders in health care registers 2001-2016. Subjects were stratified into four age-groups: 10-18, 19-27, 28-50, and 51-70 years. Hazard Ratios with 95% Confidence Intervals (CIs) were estimated with Cox proportional hazard models. RESULTS: Low education increased the risk of substance use disorders and self-harm in all age-groups. Males aged 10-18 with low education had increased risks of ADHD and conduct disorders, and females a decreased risk of anorexia, bulimia and autism. Those aged 19-27 years had increased risks of anxiety and depression, and those aged 28-50 had increased risks of all mental disorders except anorexia and bulimia in males with Hazard Ratios ranging from 1.2 (95% CIs 1.0-1.3) for bipolar disorder to 5.4 (95% CIs 5.1-5.7) for drug use disorder. Females aged 51-70 years had increased risks of schizophrenia and autism. CONCLUSION: Low education is associated with risk of most mental disorders, substance use disorders and self-harm in all age-groups, but especially among those aged 28-50 years.

DNA methylation profiling improves routine diagnosis of paediatric central nervous system tumours: A prospective population-based study.

AIMS: Paediatric brain tumours are rare, and establishing a precise diagnosis can be challenging. Analysis of DNA methylation profiles has been shown to be a reliable method to classify central nervous system (CNS) tumours with high accuracy. We aimed to prospectively analyse CNS tumours diagnosed in Sweden, to assess the clinical impact of adding DNA methylation-based classification to standard paediatric brain tumour diagnostics in an unselected cohort. METHODS: All CNS tumours diagnosed in children (0-18 years) during 2017-2020 were eligible for inclusion provided sufficient tumour material was available. Tumours were analysed using genome-wide DNA methylation profiling and classified by the MNP brain tumour classifier. The initial histopathological diagnosis was compared with the DNA methylation-based classification. For incongruent results, a blinded re-evaluation was performed by an experienced neuropathologist. RESULTS: Two hundred forty tumours with a histopathology-based diagnosis were profiled. A high-confidence methylation score of 0.84 or more was reached in 78% of the cases. In 69%, the histopathological diagnosis was confirmed, and for some of these also refined, 6% were incongruent, and the re-evaluation favoured the methylation-based classification. In the remaining 3% of cases, the methylation class was non-contributory. The change in diagnosis would have had a direct impact on the clinical management in 5% of all patients. CONCLUSIONS: Integrating DNA methylation-based tumour classification into routine clinical analysis improves diagnostics and provides molecular information that is important for treatment decisions. The results from methylation profiling should be interpreted in the context of clinical and histopathological information.

Accumulation of DNA methylation alterations in paediatric glioma stem cells following fractionated dose irradiation.

BACKGROUND: Radiation is an important therapeutic tool. However, radiotherapy has the potential to promote co-evolution of genetic and epigenetic changes that can drive tumour heterogeneity, formation of radioresistant cells and tumour relapse. There is a clinical need for a better understanding of DNA methylation alterations that may follow radiotherapy to be able to prevent the development of radiation-resistant cells. METHODS: We examined radiation-induced changes in DNA methylation profiles of paediatric glioma stem cells (GSCs) in vitro. Five GSC cultures were irradiated in vitro with repeated doses of 2 or 4 Gy. Radiation was given in 3 or 15 fractions. DNA methylation profiling using Illumina DNA methylation arrays was performed at 14 days post-radiation. The cellular characteristics were studied in parallel. RESULTS: Few fractions of radiation did not result in significant accumulation of DNA methylation alterations. However, extended dose fractionations changed DNA methylation profiles and induced thousands of differentially methylated positions, specifically in enhancer regions, sites involved in alternative splicing and in repetitive regions. Radiation induced dose-dependent morphological and proliferative alterations of the cells as a consequence of the radiation exposure. CONCLUSIONS: DNA methylation alterations of sites with regulatory functions in proliferation and differentiation were identified, which may reflect cellular response to radiation stress through epigenetic reprogramming and differentiation cues.

Effect of tobacco control policies on the Swedish smoking quitline using intervention time-series analysis.

OBJECTIVES: To coherently examine the responsiveness of the Swedish National Tobacco Quitline (SNTQ) to different types of anti-smoking policies over an extended period of calendar time. DESIGN: Quasi-experimental design with an intervention time-series analysis based on 19 years series of data collected between January 1999 and August 2017 (224 months). Statistical inference on calling rates and rate ratios was obtained using intervention time-series models (Poisson regression and transfer functions). PARTICIPANTS: A total of 179 851 phone calls to the SNTQ. INTERVENTIONS: Recent application of the 2014/40/ European Union (EU) Tobacco Products Directive in 2016. Historical interventions such as a campaign on passive smoking in January 2001; introduction of larger text warnings on cigarette packages since September 2002; banning smoking in restaurants since June 2005; and tobacco tax increase by 10% since January 2012. OUTCOME MEASURE: Calling rates to the SNTQ expressed per 100 000 smokers. SETTING: Sweden. RESULTS: The introduction of large pictorial warnings together with text warnings on cigarette packages (May 2016) was associated with a 35% increase in SNTQ calling rate (95% CI 1.16 to 1.57). The campaign on passive smoking (Jan 2001) was associated with a 61% higher calling rate (95% CI 1.06 to 2.45). Larger text warnings on cigarette packs (Sept 2002) conferred a 28% increment in the calling rate (95% CI 1.15 to 1.42); and prohibition to smoke in restaurants (Jun 2005) was associated with a 15% increase in the calling rate (95% CI 1.01 to 1.30). The 10% tobacco tax increase (Jan 2012) was associated with a 3% higher calling rate (95% CI 0.90 to 1.19). CONCLUSIONS: Within an overall decreasing trend of daily smoking in Sweden, we found that the recent introduction of pictorial warnings together with text warnings and referral text had a discernible positive impact on the calling rates to the smoking quitline. We were also able to detect a likely impact of earlier nationwide interventions.

Screening in Primary Care for Alcohol Use Compared With Smoking, Diet, and Physical Activity: A Repeated Population Survey in Sweden.

OBJECTIVE: Screening and brief intervention in primary care for hazardous alcohol use is potentially a means to improve public health but is seldom implemented. There are few comparisons with general practitioner screening for other lifestyle habits. METHOD: Repeated cross-sectional surveys from 2004, 2008, and 2012 in Sweden were used (N = 28,935) to document general practitioner visitors' reports on being asked and advised about alcohol, tobacco, diet, and physical activity when visiting primary care. RESULTS: Screening increased for all health behaviors, with the most apparent increase found for alcohol use. CONCLUSIONS: Screening for alcohol use can efficiently be integrated into health care, along with that for other lifestyle habits.

Alcohol and type 2 diabetes: The role of socioeconomic, lifestyle and psychosocial factors.

AIMS: We investigate (a) alcohol consumption in association with type 2 diabetes, taking heavy episodic drinking (HED), socioeconomic, health and lifestyle, and psychosocial factors into account, and (b) whether a seemingly protective effect of moderate alcohol consumption on type 2 diabetes persists when stratified by occupational position. METHODS: This population-based longitudinal cohort study comprises 16,223 Swedes aged 18-84 years who answered questionnaires about lifestyle, including alcohol consumption in 2002, and who were followed-up for self-reported or register-based diabetes in 2003-2011. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated in a multivariable-adjusted logistic regression model for all participants and stratified by high and low occupational position. We adjusted for HED, socioeconomic (occupational position, cohabiting status and unemployment), health and lifestyle (body mass index (BMI), blood pressure, smoking, physical inactivity, poor general health, anxiety/depression and psychosocial (low job control and poor social support) characteristics one by one, and the sets of these factors. RESULTS: Moderate consumption was inversely associated with type 2 diabetes after controlling for health and lifestyle (OR=0.47; 95% CI: 0.29-0.79) and psychosocial factors (OR=0.40; 95% CI: 0.22-0.79) when compared to non-drinkers. When adjusting for socioeconomic factors, there was still an inverse but non-significant association (OR=0.59; 95% CI: 0.35-1.00). In those with high occupational position, there was no significant association between moderate consumption and type 2 diabetes after adjusting for socioeconomic (OR=0.67; 95% CI: 0.3-1.52), health and lifestyle (OR=0.70; 95% CI: 0.32-1.5), and psychosocial factors (OR=0.75; 95% CI: 0.23-2.46). On the contrary, in those with low occupational position, ORs decreased from 0.55 (95% CI: 0.28-1.1) to 0.35 (95% CI: 0.15-0.82) when adjusting for psychosocial factors, a decrease that was solely due to low job control. HED did not influence any of these associations. CONCLUSIONS: Moderate alcohol consumption is associated with a lower risk of type 2 diabetes, after adjusting for HED, health and lifestyle, and psychosocial characteristics. The association was inverse but non-significant after adjusting for socioeconomic factors. When stratified by occupational position, there was an inverse association only in those with low occupational position and after adjusting for low job control.

Fathers' Alcohol Consumption and Long-Term Risk for Mortality in Offspring.

AIM: This study examined associations between fathers' alcohol consumption and risk for total and cause-specific mortality in offspring. SHORT SUMMARY: We examined the associations between fathers' alcohol consumption and total and cause-specific mortality in adult offspring. Fathers' alcohol consumption was associated with increased risk of alcohol-related mortality in offspring. The association appeared to be weaker for causes of death in which alcohol plays a smaller, or less direct, role. METHODS: Data on fathers' alcohol consumption, and offspring's risky use of alcohol, smoking, mental health and contact with police/childcare authorities were collected among 46,284 men (sons) aged 18-20 years, during conscription for compulsory military training in 1969/70. Data on offspring mortality were obtained from the National Cause of Death register, 1971-2008. The mortality outcomes included total mortality, alcohol-related causes of death and violent causes of death (categorized into suicides vs violent/external causes excluding suicides). RESULTS: Compared to sons whose fathers never used alcohol, the risk for total and alcohol-related mortality among sons increased with the father's consumption level. The risk of violent death was significantly elevated among sons whose fathers drank alcohol occasionally or often, but the risk of suicide increased in the highest consumption category only. After adjustment for covariates, the results remained for alcohol-related mortality whereas they were significantly attenuated, or disappeared, for total mortality, violent death and suicide. CONCLUSIONS: Fathers' alcohol consumption is associated with increased risk of alcohol-related mortality in the offspring. Alcohol use among fathers also increases the offspring's risk of later total mortality, suicide and violent death, but these associations appear to be mediated or confounded by factors related to parental drinking and/or adverse childhood psychosocial circumstances.

Clonal relatedness in tumour pairs of breast cancer patients.

BACKGROUND: Molecular classification of tumour clonality is currently not evaluated in multiple invasive breast carcinomas, despite evidence suggesting common clonal origins. There is no consensus about which type of data (e.g. copy number, mutation, histology) and especially which statistical method is most suitable to distinguish clonal recurrences from independent primary tumours. METHODS: Thirty-seven invasive breast tumour pairs were stratified according to laterality and time interval between the diagnoses of the two tumours. In a multi-omics approach, tumour clonality was analysed by integrating clinical characteristics (n = 37), DNA copy number (n = 37), DNA methylation (n = 8), gene expression microarray (n = 7), RNA sequencing (n = 3), and SNP genotyping data (n = 3). Different statistical methods, e.g. the diagnostic similarity index (SI), were used to classify the tumours as clonally related recurrences or independent primary tumours. RESULTS: The SI and hierarchical clustering showed similar tendencies and the highest concordance with the other methods. Concordant evidence for tumour clonality was found in 46% (17/37) of patients. Notably, no association was found between the current clinical guidelines and molecular tumour features. CONCLUSIONS: A more accurate classification of clonal relatedness between multiple breast tumours may help to mitigate treatment failure and relapse by integrating tumour-associated molecular features, clinical parameters, and statistical methods. Guidelines need to be defined with exact thresholds to standardise clonality testing in a routine diagnostic setting.

Hälsoutvecklingen i Stockholm bättre än i övriga landet - Jämförelse av hälsoläget utifrån globala sjukdomsbördeprojektet.

Previous studies in Sweden have focused on a number of indicators to assess and compare health conditions at regional levels over time. In this study we aimed to give a more complete picture of the health situation in Stockholm County compared to the rest of Sweden, by using the DALY measure (disability-adjusted life years). DALY combines life lost to premature death (YLL) and years lived with disability (YLD) in one measure, and also allow comparisons of fatal and non-fatal conditions. This approach reveals that low back and neck pain and ischemic heart disease dominated the disease burden in 2015. Moreover, the health progress in Stockholm County has been better than the rest of Sweden since 1990, and the main reason is the decrease in premature death (YLL). This can partly be explained by a decrease in risk factors such as unhealthy diets, high blood pressure, tobacco smoking, high BMI and physical inactivity. The development of YLD has been relatively constant since 1990 in both Stockholm County and the rest of Sweden, implying that Sweden has been more successful in preventing death than reducing disability.

Pediatric brain tumor cells release exosomes with a miRNA repertoire that differs from exosomes secreted by normal cells.

High-grade gliomas (HGGs) are very aggressive brain tumors with a cancer stem cell component. Cells, including cancer stem cells, release vesicles called exosomes which contain small non-coding RNAs such as microRNAs (miRNAs). These are thought to play an important role in cell-cell communication. However, we have limited knowledge of the types of exosomal miRNAs released by pediatric HGG stem cells; a prerequisite for exploring their potential roles in HGG biology. Here we isolated exosomes released by pediatric glioma stem cells (GSCs) and compared their repertoire of miRNAs to genetically normal neural stem cells (NSCs) exosomes, as well as their respective cellular miRNA content. Whereas cellular miRNAs are similar, we find that the exosomal miRNA profiles differ between normal and tumor cells, and identify several differentially expressed miRNAs. Of particular interest is miR-1290 and miR-1246, which have previously been linked to 'stemness' and invasion in other cancers. We demonstrate that GSC-secreted exosomes influence the gene expression of receiving NSCs, particularly targeting genes with a role in cell fate and tumorigenesis. Thus, our study shows that GSCs and NSCs have similar cellular miRNA profiles, yet differ significantly in the repertoire of exosomal miRNAs and these could influence malignant features of HGG.

Stem cell cultures derived from pediatric brain tumors accurately model the originating tumors.

Brain tumors are the leading cause of cancer-related death in children but high-grade gliomas in children and adolescents have remained a relatively under-investigated disease despite this. A better understanding of the cellular and molecular pathogenesis of the diseases is required in order to improve the outcome for these children. In vitro-cultured primary tumor cells from patients are indispensable tools for this purpose by enabling functional analyses and development of new therapies. However, relevant well-characterized in vitro cultures from pediatric gliomas cultured under serum-free conditions have been lacking. We have therefore established patient-derived in vitro cultures and performed thorough characterization of the cells using large-scale analyses of DNA methylation, copy-number alterations and investigated their stability during prolonged time in culture. We show that the cells were stable during prolonged culture in serum-free stem cell media without apparent alterations in morphology or growth rate. The cells were proliferative, positive for stem cell markers, able to respond to differentiation cues and initiated tumors in zebrafish and mice suggesting that the cells are cancer stem cells or progenitor cells. The cells accurately mirrored the tumor they were derived from in terms of methylation pattern, copy number alterations and DNA mutations. These unique primary in vitro cultures can thus be used as a relevant and robust model system for functional studies on pediatric brain tumors.

Asymmetric cationic liposomes designed for heat-activated association with cells.

Improved anticancer drugs and drug carriers are needed in combination therapies, such as hyperthermia-assisted chemotherapy. Liposomal drug carriers with advanced functions are attractive candidates for targeted accumulation and drug release in response to heat stimulus. We report on the design of liposomes with a heat-activated surface function. Our design is based on asymmetric lipid membranes with a defined gel to liquid-crystalline phase-transition temperature around 41°C. Asymmetry between the inner and the outer membrane leaflets was generated through selective PEGylation of cationic lipids in the outer membrane leaflet. In a physiological buffer, the PEGylated asymmetric liposomes had a neutral zeta potential and did not bind to planar anionic model membranes. In contrast, following upon heat-activation, binding of liposomes to the model membranes occurred. Release of a hydrophilic dye encapsulated in the asymmetric liposomes occurred at 40°C. Enhanced uptake of the asymmetric liposomes by hypopharyngeal carcinoma cells (FaDu cells) was observed when hyperthermia was applied compared to experiments performed at 37°C. These results show the potential of asymmetric liposomes for localized delivery of drugs into cells in response to (external) temperature stimulus.

Cannabis, Tobacco, Alcohol Use, and the Risk of Early Stroke: A Population-Based Cohort Study of 45 000 Swedish Men.

BACKGROUND AND PURPOSE: Current knowledge on cannabis use in relation to stroke is based almost exclusively on clinical reports. By using a population-based cohort, we aimed to find out whether there was an association between cannabis use and early-onset stroke, when accounting for the use of tobacco and alcohol. METHODS: The cohort comprises 49 321 Swedish men, born between 1949 and 1951, who were conscripted into compulsory military service between the ages of 18 and 20. All men answered 2 detailed questionnaires at conscription and were subject to examinations of physical aptitude, psychological functioning, and medical status. Information on stroke events up to ≈60 years of age was obtained from national databases; this includes strokes experienced before 45 years of age. RESULTS: No associations between cannabis use in young adulthood and strokes experienced ≤45 years of age or beyond were found in multivariable models: cannabis use >50 times, hazard ratios=0.93 (95% confidence interval [CI], 0.34-2.57) and 0.95 (95% CI, 0.59-1.53). Although an almost doubled risk of ischemic stroke was observed in those with cannabis use >50 times, this risk was attenuated when adjusted for tobacco usage: hazards ratio=1.47 (95% CI, 0.83-2.56). Smoking ≥20 cigarettes per day was clearly associated both with strokes before 45 years of age, hazards ratio=5.04 (95% CI, 2.80-9.06), and with strokes throughout the follow-up, hazards ratio=2.15 (95% CI, 1.61-2.88). CONCLUSIONS: We found no evident association between cannabis use in young adulthood and stroke, including strokes before 45 years of age. Tobacco smoking, however, showed a clear, dose-response shaped association with stroke.

MethPed: an R package for the identification of pediatric brain tumor subtypes.

BACKGROUND: DNA methylation profiling of pediatric brain tumors offers a new way of diagnosing and subgrouping these tumors which improves current clinical diagnostics based on histopathology. We have therefore developed the MethPed classifier, which is a multiclass random forest algorithm, based on DNA methylation profiles from many subgroups of pediatric brain tumors. RESULTS: We developed an R package that implements the MethPed classifier, making it easily available and accessible. The package can be used for estimating the probability that an unknown sample belongs to each of nine pediatric brain tumor diagnoses/subgroups. CONCLUSIONS: The MethPed R package efficiently classifies pediatric brain tumors using the developed MethPed classifier. MethPed is available via Bioconductor: http://bioconductor.org/packages/MethPed/.

Cannabis use and psychological distress: An 8-year prospective population-based study among Swedish men and women.

BACKGROUND: Previous studies have reported positive associations between cannabis use and mental health problems. However, it has not been possible to draw a definitive conclusion regarding the causal direction between cannabis use and impaired mental health. This study aimed at examining possible associations between cannabis use and psychological distress (as measured by the General Health Questionnaire, GHQ-12) in men and women respectively, using both measures as both exposure and outcome. METHODS: Data were obtained from a cohort study (the Stockholm Public Health Cohort) with an 8-year follow-up in the general population in Stockholm County, Sweden. The study sample comprised 19,327 men and women, aged 18-84years, who answered surveys in 2002 and 2010. RESULTS: Cannabis use was associated with increased odds ratios (OR) for psychological distress in women at 8-year follow-up, with OR=1.37 [1.1-1.7, 95% CI], but not in men; OR=1.14 [0.9-1.5, 95% CI]. In women, this association remained when adjusted for potential confounders (tobacco smoking, alcohol consumption, socioeconomic position (SEP) and unemployment); OR=1.27 [1.0-1.6, 95% CI]. Moreover, women reporting psychological distress at baseline had an increased risk of cannabis use at follow-up; OR=1.40 [1.1-1.8 95% CI]. However, this association was no longer statistically significant when adjustments were made for baseline cannabis use, OR=1.10 [0.8-1.5, 95% CI]. CONCLUSIONS: This study revealed that, in women, cannabis use was associated with an increased risk of psychological distress eight years later. Optimal interventions to identify these women seem warranted.

Cannabis use, depression and anxiety: A 3-year prospective population-based study.

BACKGROUND: Whether or not cannabis use may increase the risk for depression and/or anxiety is not clear. For one thing, it has not been possible to draw a definitive conclusion regarding the direction of causality, i.e. whether cannabis use increases the risk for depression/anxiety or vice versa. This study aimed at examining possible associations between cannabis use, depression and anxiety, using all three measures as both exposure and outcome. METHODS: Data were obtained from a longitudinal cohort study comprising 8598 Swedish men and women, aged 20-64, with a three-year-follow-up. RESULTS: Adjusted for sex and age, cannabis use at baseline was associated with an increased relative risk (RR) for depression and anxiety at follow-up, with RR=1.22 [1.06-1.42 Cl 95%] for depression and RR=1.38 [1.26-1.50 Cl 95%] for anxiety. Adjusted for all confounders (alcohol and illicit drug use, education, family tension, place of upbringing), the associations were no longer statistically significant; RR=0.99 [0.82-1.17 Cl 95%] for depression and RR=1.09 [0.98-1.20 Cl 95%] for anxiety. Age-adjusted, reporting depression or anxiety at baseline increased the risk of cannabis onset at follow-up three years later; RR=1.62 [1.28-2.03 CI 95%] and RR=1.63 [1.28-2.08 CI 95%] respectively. However, adjusted for other illicit drug use the associations were no longer statistically significant. LIMITATIONS: Lack of information on frequency of cannabis use and of age of initiation of use. CONCLUSIONS: We found no longitudinal associations between cannabis use and incidence of depression/anxiety, or between depression/anxiety and later cannabis use onset.

Transcriptional Profiling of Breast Cancer Metastases Identifies Liver Metastasis-Selective Genes Associated with Adverse Outcome in Luminal A Primary Breast Cancer.

PURPOSE: The complete molecular basis of the organ-specificity of metastasis is elusive. This study aimed to provide an independent characterization of the transcriptional landscape of breast cancer metastases with the specific objective to identify liver metastasis-selective genes of prognostic importance following primary tumor diagnosis. EXPERIMENTAL DESIGN: A cohort of 304 women with advanced breast cancer was studied. Associations between the site of recurrence and clinicopathologic features were investigated. Fine-needle aspirates of metastases (n = 91) were subjected to whole-genome transcriptional profiling. Liver metastasis-selective genes were identified by significance analysis of microarray (SAM) analyses and independently validated in external datasets. Finally, the prognostic relevance of the liver metastasis-selective genes in primary breast cancer was tested. RESULTS: Liver relapse was associated with estrogen receptor (ER) expression (P = 0.002), luminal B subtype (P = 0.01), and was prognostic for an inferior postrelapse survival (P = 0.01). The major variation in the transcriptional landscape of metastases was also associated with ER expression and molecular subtype. However, liver metastases displayed unique transcriptional fingerprints, characterized by downregulation of extracellular matrix (i.e., stromal) genes. Importantly, we identified a 17-gene liver metastasis-selective signature, which was significantly and independently prognostic for shorter relapse-free (P < 0.001) and overall (P = 0.001) survival in ER-positive tumors. Remarkably, this signature remained independently prognostic for shorter relapse-free survival (P = 0.001) among luminal A tumors. CONCLUSIONS: Extracellular matrix (stromal) genes can be used to partition breast cancer by site of relapse and may be used to further refine prognostication in ER positive primary breast cancer.

Contrasting breast cancer molecular subtypes across serial tumor progression stages: biological and prognostic implications.

The relevance of the intrinsic subtypes for clinical management of metastatic breast cancer is not comprehensively established. We aimed to evaluate the prevalence and prognostic significance of drifts in tumor molecular subtypes during breast cancer progression. A well-annotated cohort of 304 women with advanced breast cancer was studied. Tissue microarrays of primary tumors and synchronous lymph node metastases were constructed. Conventional biomarkers were centrally assessed and molecular subtypes were assigned following the 2013 St Gallen guidelines. Fine-needle aspirates of asynchronous metastases were transcriptionally profiled and subtyped using PAM50. Discordant expression of individual biomarkers and molecular subtypes was observed during tumor progression. Primary luminal-like tumors were relatively unstable, frequently adopting a more aggressive subtype in the metastases. Notably, loss of ER expression and a luminal to non-luminal subtype conversion was associated with an inferior post-recurrence survival. In addition, ER and molecular subtype assessed at all tumor progression stages were independent prognostic factors for post-recurrence breast cancer mortality in multivariable analyses. Our results demonstrate that drifts in tumor molecular subtypes may occur during tumor progression, conferring adverse consequences on outcome following breast cancer relapse.