Risk and Mortality of Recurrent Breast Cancer in Stockholm 1985-2005

The purpose of this study was to estimate the risk and mortality of breast cancer recurrences in Swedish women, and to analyse changes over time and variations between patients in different risk groups. Such estimates are of key importance for modelling the cost-effectiveness of different strategies for adjuvant treatment of breast cancer. The study was based on all women diagnosed with breast cancer in Stockholm County between 1985 and 2005. Information about dates for locoregional recurrences, metastatic relapses, new contralateral tumours and death was collected. Cox proportional hazard and Weibull regression models were used to estimate survival functions, where year of diagnosis (dived into 5-year intervals), were included as explanatory variables in the models. The risk of recurrences has decreased during the last 20 years for all three types of recurrence; for metastatic relapse the 5-year risk was reduced from 12.9% to 6.0% from 1985-90 to 2000-2005 . Mortality has also been reduced, resulting in an increased 5-year survival from 52.6% to 64.1% after locoregional recurrence and from 10.4% to 15.5% for metastatic relapse. For contralateral tumours, with a 5-year survival rate of 74.6% in 1985-1990 and 78% 2000-2005, no significant increase was observed. Analysis of risk groups according to TNM classification showed large difference in the risk of metastatic breast cancer between the three defined groups, but small differences for the risk of locoregional recurrences and new contralateral tumours. The findings indicate that the early detection and new treatments have been successful in improving outcome for breast cancer patients and that it is important to use up-to-date information, when assessing the value of new treatment options.Breast cancer; Mortality; Survival; Recurrence; Sweden

Risk and mortality of recurrent breast cancer in Stockholm 1985 - 2005

The purpose of this study was to estimate the risk and mortality of breast cancer recurrences in Swedish women, and to analyse changes over time and variations between patients in different risk groups. Such estimates are of key importance for modelling the cost-effectiveness of different strategies for adjuvant treatment of breast cancer. The study was based on all women diagnosed with breast cancer in Stockholm County between 1985 and 2005. Information about dates for locoregional recurrences, metastatic relapses, new contralateral tumours and death was collected. Cox proportional hazard and Weibull regression models were used to estimate survival functions, where year of diagnosis (dived into 5-year intervals), were included as explanatory variables in the models. The risk of recurrences has decreased during the last 20 years for all three types of recurrence; for metastatic relapse the 5-year risk was reduced from 12.9% to 6.0% from 1985-90 to 2000-2005 . Mortality has also been reduced, resulting in an increased 5-year survival from 52.6% to 64.1% after locoregional recurrence and from 10.4% to 15.5% for metastatic relapse. For contralateral tumours, with a 5-year survival rate of 74.6% in 1985-1990 and 78% 2000-2005, no significant increase was observed. Analysis of risk groups according to TNM classification showed large difference in the risk of metastatic breast cancer between the three defined groups, but small differences for the risk of locoregional recurrences and new contralateral tumours. The findings indicate that the early detection and new treatments have been successful in improving outcome for breast cancer patients and that it is important to use up-to-date information, when assessing the value of new treatment options

Induction of p53 Expression in Skin by Radiotherapy and UV Radiation: a Randomized Study

Background: p53 protein plays an important role in the response to DNA damage, and radiotherapy can cause radiation dermatitis. p53 and p21 levels increase in vitro when DNA is damaged by UVA, UVB, or γ-radiation. To determine whether this response occurs in human skin and predicts the level of radiation dermatitis, we investigated levels of p53 and p21 in skin exposed to different types of radiation as part of a randomized study of women with breast cancer to evaluate topical steroid or emollient cream treatments for radiation dermatitis of their irradiated breast. Methods: After surgery but before receiving tangential 5-mV photo-beam radiotherapy (2 Gy and 54 Gy) to the affected breast parenchyma, multiple areas on the backs of 50 women were irradiated with UVA and other areas were irradiated with UVB. Skin biopsy samples were taken from areas of normal unirradiated skin and all irradiated areas, and p53 and p21 were detected immunohistochemically. All statistical tests are two-sided. Results: In skin irradiated with UVA or UVB, medians of 4.4% (range = 0%-40.5%) or 45.5% (range = 5.3%-74.6%) p53-positive keratinocytes, respectively, were observed. Radiotherapy produced medians of 31.0% (range = 0%-79.3%) p53-immunoreactive cells after 2 Gy of radiation and 83.2% (range = 37.6%-95.2%) after 54 Gy of radiation. Despite large interindividual differences in p53 response, comparable increases in epidermal p53 response were independent of the type of radiation. A correlation between p53 and p21 was also evident (rs = .78). In breast skin, there was no association between the p53 response and the degree of erythema (a measure of radiation dermatitis) and no statistically significant difference between treatment arms and p21/p53 responses. Conclusions: Individual responses to radiation-induced DNA damage varied widely and may be independent of the type of radiation. The epidermal p53 response does not predict the degree of radiation dermatiti

Correlation test to assess low-level processing of high-density oligonucleotide microarray data

BACKGROUND: There are currently a number of competing techniques for low-level processing of oligonucleotide array data. The choice of technique has a profound effect on subsequent statistical analyses, but there is no method to assess whether a particular technique is appropriate for a specific data set, without reference to external data. RESULTS: We analyzed coregulation between genes in order to detect insufficient normalization between arrays, where coregulation is measured in terms of statistical correlation. In a large collection of genes, a random pair of genes should have on average zero correlation, hence allowing a correlation test. For all data sets that we evaluated, and the three most commonly used low-level processing procedures including MAS5, RMA and MBEI, the housekeeping-gene normalization failed the test. For a real clinical data set, RMA and MBEI showed significant correlation for absent genes. We also found that a second round of normalization on the probe set level improved normalization significantly throughout. CONCLUSION: Previous evaluation of low-level processing in the literature has been limited to artificial spike-in and mixture data sets. In the absence of a known gold-standard, the correlation criterion allows us to assess the appropriateness of low-level processing of a specific data set and the success of normalization for subsets of genes

Time from breast cancer diagnosis to therapeutic surgery and breast cancer prognosis : a population-based cohort study

Theoretically, time from breast cancer diagnosis to therapeutic surgery should affect survival. However, it is unclear whether this holds true in a modern healthcare setting in which breast cancer surgery is carried out within weeks to months of diagnosis. This is a population- and register-based study of all women diagnosed with invasive breast cancer in the Stockholm-Gotland healthcare region in Sweden, 2001 - 2008, and who were initially operated. Follow-up of vital status ended 2014. 7017 women were included in analysis. Our main outcome was overall survival. Main analyses were carried out using Cox proportional hazards models. We adjusted for likely confounders and stratified on mode of detection, tumor size and lymph node metastasis. We found that a longer interval between date of morphological diagnosis and therapeutic surgery was associated with a poorer prognosis. Assuming a linear association, the hazard rate of death from all causes increased by 1.011 (95% CI 1.006 to 1.017) per day. Comparing, e.g., surgery 6 weeks after diagnosis to surgery 3 weeks after diagnosis, thereby confers a 1.26-fold increased hazard rate. The increase in hazard rate associated with surgical delay was strongest in women with largest tumors. Whilst there was a clear association between delays and survival in women without lymph node metastasis, the association may be attenuated in subgroups with increasing number of lymph node metastases. We found no evidence of an interaction between time to surgery and mode of detection. In conclusion, unwarranted delays to primary treatment of breast cancer should be avoided.Swedish Research CouncilSwedish Cancer SocietyStockholm County CouncilFORTEAccepte

Farlig avfall fra husholdningen: Hvordan ulike innsamlingsløsninger påvirker innsamlingsgrad og klima

Farlig avfall utgjør en stor miljø, - og helseutfordring, og håndteringen av avfallsfraksjonen krever spesifikke strategier for å redusere risikoen for mennesker, dyr og miljø. I denne oppgaven er det gjennomført mengdeanalyser og livsløpsvurderinger for å identifisere effektiviteten og miljøpåvirkningen ved tre ulike innsamlingsløsninger for farlig avfall fra husholdningen. Det er også sett nærmere på innsamlingen og behandlingen av de farlige avfallsfraksjonene: Maling og Alkaliske batterier. Remiks drifter innsamlingsløsningen som samlet inn mest farlig avfall per innbygger med 11,5 kg, via en hybridløsning med gjenvinningsstasjon, returpunkter og en mobil innsamlingsløsning. Vesar har innsamlingsløsningen som samler inn størst mengde farlig avfall fra husholdningene, og har stasjonære miljøstasjoner rundt om i Vestfold. Stavanger kommune har en rød-boks løsning, hvor det farlige avfallet hentes hos privatpersonene. Det er denne løsningen som får tilsynelatende dårligst resultater fra mengdeanalysene. Plukk-analysene for hver innsamlingsløsning viser derimot at det er mindre variasjon i mengden farlig avfall i restavfallet til hver avfallsinnsamler. Remiks og Stavanger kommune hadde 1,4% farlig avfall i restavfallet sitt, mens Vesar hadde 1,3%. Dette indikerer at effektiviteten til hver innsamlingsløsning er tilnærmet lik, til tross for variasjonene i innsamlede mengder. Innsamlingsløsningen basert på henteordning har betraktelig lavere klimapåvirkning enn innsamlingsløsningene basert på en bringeordning. Dette skyldes i all hovedsak at bringeordningene krever at privatpersonene kjører avfallet til innsamlingspunkter, da dette utgjør majoriteten av utslippene. Stavanger kommune har lavest miljøpåvirkning, med 0,63 kg CO2-ekvivalenter. Remiks og Vesar sine innsamlingsløsninger har en miljøpåvirkning på henholdsvis 1,47 og 2,52 kg CO2-ekvivalenter. Det ble gjennomført to ulike livsløpsvurderinger for innsamling og behandling av maling, og alkaliske batterier. Et felles funn for begge analysene er en generell mangel på studier og dokumentasjon for sorterings, - og behandlingsprosesser for disse avfallsfraksjonene. Dette funnet preger analysene, da det ikke var mulig å inkludere alle tiltenkte prosesser på grunn av mangel på informasjon. Denne oppgaven kan være nyttig for både offentlige og private aktører i avfallsbransjen, som håndterer farlig avfall. Oppgaven kan også være relevant for å skape bedre beslutningsgrunnlag for fremtidig utforming av innsamlingsløsninger for farlig avfall fra husholdninger.Hazardous waste poses significant environmental and health challenges, and managing this waste fraction requires specific strategies to reduce the risks it poses to humans, animals, and the environment. In this thesis, quantity analyses and life cycle assessments have been conducted to identify the efficiency and environmental impact of three different collection solutions for hazardous household waste. The collection and treatment of hazardous waste fractions, such as Paint and Alkaline batteries, have also been examined in detail. Remiks operates the collection solution that gathers the most hazardous waste per capita, with 11.5 kg, through a hybrid solution of a recycling station, return points, and a mobile collection solution. Vesar has a collection solution that gathers the largest amount of hazardous waste from households and has stationary environmental stations throughout Vestfold. Stavanger municipality has a red-box solution, where hazardous waste is collected from private individuals. This solution appears to yield the poorest results from the quantity analyses. However, “pick analyses” for each collection solution show that there is less variation in the amount of hazardous waste in the residual waste of each waste collector. Remiks and Stavanger municipality had 1.4% hazardous waste in their residual waste, while Vesar had 1.3%. This indicates that the efficiency of each collection solution is approximately the same, despite variations in collected amounts. The collection solution based on a pickup system has considerably lower climate impact than the collection solutions based on a bring-in system. This is primarily because the bring-in systems require private individuals to drive the waste to collection points, as this constitutes the majority of the emissions. Stavanger municipality has the lowest environmental impact, with 0.63 kg CO2 equivalents. Remiks and Vesar's collection solutions had environmental impacts of 1.47 and 2.52 kg CO2 equivalents, respectively. Two different life cycle assessments were conducted for the collection and treatment of paint and alkaline batteries. A common finding for both analyses is a general lack of studies and documentation for the sorting and treatment processes for these waste fractions. This finding affects the analyses, as it was not possible to include all intended processes due to lack of information. This thesis can be useful for both public and private actors in the waste management industry who handle hazardous waste. The thesis may also be relevant for creating a better decision-making basis for the future design of collection solutions for hazardous waste from households

Long-term and real-life incidence of cancer therapy-related cardiovascular toxicity in patients with breast cancer: a Swedish cohort study

BackgroundThe administration of anticancer drugs in females with comorbidity increases the risk for cancer therapy-related cardiovascular toxicity (CTR-CVT), which in turn contributes to cardiovascular disease (CVD). Furthermore, a pathophysiological connection between cancer and cardiovascular disease may exist.ObjectiveTo assess the long-term risks and predictors of CTR-CVT, including clinical hypertension (HT), coronary artery disease (CAD), heart failure (HF), atrial fibrillation (AF), as well as all-cause mortality in women diagnosed with early breast cancer (BC) and eligible for adjuvant chemotherapy in Sweden.MethodsData were extracted from Swedish registers and medical records on 433 women, 18-60 years of age, diagnosed 1998-2002 with lymph node-positive BC, and considered for adjuvant chemotherapy. CTR-CVT was defined as HT, CAD, HF, or AF after the diagnosis of BC. Follow-up was from the date of BC diagnosis until November 30, 2021, or death. Prevalence of CTR-CVT and all-cause mortality were calculated. Hazard ratios (HR) were determined for factors associated with CTR-CVT.ResultsThe median age was 50 (interquartile range (IQR) 32) years. 910 CTR-CVT events were diagnosed in 311 women with a median of 19.3 (IQR 15,3) years follow-up. The proportions of CTR-CVT events were: HT 281 (64%); CAD 198 (46%); HF 206 (47%); and AF 225 (51%). The cumulative incidence of CTR-CVT was 71.8%, and 50% of all 433 patients developed CTR-CVT within 11.7 years of BC diagnosis (standard deviation (SD) 0.57, 95% confidence interval (CI) 10.6-12.9). Age was a risk factor for CTR-CVT. Anthracycline increased the risk for HF (p=0,001; HR 2,0; 95%CI 1,4-2,8), CAD (p= 0,002; HR 1,7; 95% CI 1,2-2,4), and AF (p=0,013; HR 1,5; 95% CI 1,0-2,0). At the end of the 24-year study period, 227 of the 433 women were alive, and the total cumulative mortality was 47,6%.ConclusionThe prevalence of CTR-CVT and all-cause mortality is high after BC diagnosis and treatment, particularly in older patients and those receiving anthracyclines. These findings and the onset of CTR-CVT support cardio-oncology guidelines recommending initial risk stratification and cardiovascular monitoring during treatment, followed by long-term annual screening for cardiovascular risk factors and CTR-CVT among BC survivors

Sequencing of breast cancer stem cell populations indicates a dynamic conversion between differentiation states in vivo

Peer reviewe

Exome sequencing of primary breast cancers with paired metastatic lesions reveals metastasis-enriched mutations in the A-kinase anchoring protein family (AKAPs)

Background: Tumor heterogeneity in breast cancer tumors is today widely recognized. Most of the available knowledge in genetic variation however, relates to the primary tumor while metastatic lesions are much less studied. Many studies have revealed marked alterations of standard prognostic and predictive factors during tumor progression. Characterization of paired primary- and metastatic tissues should therefore be fundamental in order to understand mechanisms of tumor progression, clonal relationship to tumor evolution as well as the therapeutic aspects of systemic disease. Methods: We performed full exome sequencing of primary breast cancers and their metastases in a cohort of ten patients and further confirmed our findings in an additional cohort of 20 patients with paired primary and metastatic tumors. Furthermore, we used gene expression from the metastatic lesions and a primary breast cancer data set to study the gene expression of the AKAP gene family. Results: We report that somatic mutations in A-kinase anchoring proteins are enriched in metastatic lesions. The frequency of mutation in the AKAP gene family was 10% in the primary tumors and 40% in metastatic lesions. Several copy number variations, including deletions in regions containing AKAP genes were detected and showed consistent patterns in both investigated cohorts. In a second cohort containing 20 patients with paired primary and metastatic lesions, AKAP mutations showed an increasing variant allele frequency after multiple relapses. Furthermore, gene expression profiles from the metastatic lesions (n = 120) revealed differential expression patterns of AKAPs relative to the tumor PAM50 intrinsic subtype, which were most apparent in the basal-like subtype. This pattern was confirmed in primary tumors from TCGA (n = 522) and in a third independent cohort (n = 182). Conclusion: Several studies from primary cancers have reported individual AKAP genes to be associated with cancer risk and metastatic relapses as well as direct involvement in cellular invasion and migration processes. Our findings reveal an enrichment of mutations in AKAP genes in metastatic breast cancers and suggest the involvement of AKAPs in the metastatic process. In addition, we report an AKAP gene expression pattern that consistently follows the tumor intrinsic subtype, further suggesting AKAP family members as relevant players in breast cancer biology.Peer reviewe