Competing risks to breast cancer mortality in Catalonia

Background: Breast cancer mortality has experienced important changes over the last century. Breast cancer occurs in the presence of other competing risks which can influence breast cancer incidence and mortality trends. The aim of the present work is: 1) to assess the impact of breast cancer deaths among mortality from all causes in Catalonia (Spain), by age and birth cohort and 2) to estimate the risk of death from other causes than breast cancer, one of the inputs needed to model breast cancer mortality reduction due to screening or therapeutic interventions. Methods: The multi-decrement life table methodology was used. First, all-cause mortality probabilities were obtained by age and cohort. Then mortality probability for breast cancer was subtracted from the all-cause mortality probabilities to obtain cohort life tables for causes other than breast cancer. These life tables, on one hand, provide an estimate of the risk of dying from competing risks, and on the other hand, permit to assess the impact of breast cancer deaths on all-cause mortality using the ratio of the probability of death for causes other than breast cancer by the all-cause probability of death. Results: There was an increasing impact of breast cancer on mortality in the first part of the 20th century, with a peak for cohorts born in 1945–54 in the 40–49 age groups (for which approximately 24% of mortality was due to breast cancer). Even though for cohorts born after 1955 there was only information for women under 50, it is also important to note that the impact of breast cancer on all-cause mortality decreased for those cohorts. Conclusion: We have quantified the effect of removing breast cancer mortality in different age groups and birth cohorts. Our results are consistent with US findings. We also have obtained an estimate of the risk of dying from competing-causes mortality, which will be used in the assessment of the effect of mammography screening on breast cancer mortality in Catalonia.

Estimation of age- and stage-specific Catalan breast cancer survival functions using US and Catalan survival data

Background: During the last part of the 1990s the chance of surviving breast cancer increased. Changes in survival functions reflect a mixture of effects. Both, the introduction of adjuvant treatments and early screening with mammography played a role in the decline in mortality. Evaluating the contribution of these interventions using mathematical models requires survival functions before and after their introduction. Furthermore, required survival functions may be different by age groups and are related to disease stage at diagnosis. Sometimes detailed information is not available, as was the case for the region of Catalonia (Spain). Then one may derive the functions using information from other geographical areas. This work presents the methodology used to estimate age- and stage-specific Catalan breast cancer survival functions from scarce Catalan survival data by adapting the age- and stage-specific US functions. Methods: Cubic splines were used to smooth data and obtain continuous hazard rate functions. After, we fitted a Poisson model to derive hazard ratios. The model included time as a covariate. Then the hazard ratios were applied to US survival functions detailed by age and stage to obtain Catalan estimations. Results: We started estimating the hazard ratios for Catalonia versus the USA before and after the introduction of screening. The hazard ratios were then multiplied by the age- and stage-specific breast cancer hazard rates from the USA to obtain the Catalan hazard rates. We also compared breast cancer survival in Catalonia and the USA in two time periods, before cancer control interventions (USA 1975–79, Catalonia 1980–89) and after (USA and Catalonia 1990–2001). Survival in Catalonia in the 1980–89 period was worse than in the USA during 1975–79, but the differences disappeared in 1990–2001. Conclusion: Our results suggest that access to better treatments and quality of care contributed to large improvements in survival in Catalonia. On the other hand, we obtained detailed breast cancer survival functions that will be used for modeling the effect of screening and adjuvant treatments in Catalonia.

Effectiveness of early detection on breast cancer mortality reduction in Catalonia (Spain)

Background: At present, it is complicated to use screening trials to determine the optimal age intervals and periodicities of breast cancer early detection. Mathematical models are an alternative that has been widely used. The aim of this study was to estimate the effect of different breast cancer early detection strategies in Catalonia (Spain), in terms of breast cancer mortality reduction (MR) and years of life gained (YLG), using the stochastic models developed by Lee and Zelen (LZ). Methods: We used the LZ model to estimate the cumulative probability of death for a cohort exposed to different screening strategies after T years of follow-up. We also obtained the cumulative probability of death for a cohort with no screening. These probabilities were used to estimate the possible breast cancer MR and YLG by age, period and cohort of birth. The inputs of the model were: incidence of, mortality from and survival after breast cancer, mortality from other causes, distribution of breast cancer stages at diagnosis and sensitivity of mammography. The outputs were relative breast cancer MR and YLG. Results: Relative breast cancer MR varied from 20% for biennial exams in the 50 to 69 age interval to 30% for annual exams in the 40 to 74 age interval. When strategies differ in periodicity but not in the age interval of exams, biennial screening achieved almost 80% of the annual screening MR. In contrast to MR, the effect on YLG of extending screening from 69 to 74 years of age was smaller than the effect of extending the screening from 50 to 45 or 40 years. Conclusion: In this study we have obtained a measure of the effect of breast cancer screening in terms of mortality and years of life gained. The Lee and Zelen mathematical models have been very useful for assessing the impact of different modalities of early detection on MR and YLG in Catalonia (Spain).

Cost-effectiveness of early detection of breast cancer in Catalonia (Spain)

Background: Breast cancer (BC) causes more deaths than any other cancer among women in Catalonia. Early detection has contributed to the observed decline in BC mortality. However, there is debate on the optimal screening strategy. We performed an economic evaluation of 20 screening strategies taking into account the cost over time of screening and subsequent medical costs, including diagnostic confirmation, initial treatment, follow-up and advanced care. Methods: We used a probabilistic model to estimate the effect and costs over time of each scenario. The effect was measured as years of life (YL), quality-adjusted life years (QALY), and lives extended (LE). Costs of screening and treatment were obtained from the Early Detection Program and hospital databases of the IMAS-Hospital del Mar in Barcelona. The incremental cost-effectiveness ratio (ICER) was used to compare the relative costs and outcomes of different scenarios. Results: Strategies that start at ages 40 or 45 and end at 69 predominate when the effect is measured as YL or QALYs. Biennial strategies 50-69, 45-69 or annual 45-69, 40-69 and 40-74 were selected as cost-effective for both effect measures (YL or QALYs). The ICER increases considerably when moving from biennial to annual scenarios. Moving from no screening to biennial 50-69 years represented an ICER of 4,469€ per QALY. Conclusions: A reduced number of screening strategies have been selected for consideration by researchers, decision makers and policy planners. Mathematical models are useful to assess the impact and costs of BC screening in a specific geographical area.

Contribution of early detection and adjuvant treatments to breast cancer mortality reduction in Catalonia, Spain

Background: Reductions in breast cancer (BC) mortality in Western countries have been attributed to the use of screening mammography and adjuvant treatments. The goal of this work was to analyze the contributions of both interventions to the decrease in BC mortality between 1975 and 2008 in Catalonia. Methodology/Principal Findings: A stochastic model was used to quantify the contribution of each intervention. Age standardized BC mortality rates for calendar years 1975-2008 were estimated in four hypothetical scenarios: 1) Only screening, 2) Only adjuvant treatment, 3) Both interventions, and 4) No intervention. For the 30-69 age group, observed Catalan BC mortality rates per 100,000 women-year rose from 29.4 in 1975 to 38.3 in 1993, and afterwards continuously decreased to 23.2 in 2008. If neither of the two interventions had been used, in 2008 the estimated BC mortality would have been 43.5, which, compared to the observed BC mortality rate, indicates a 46.7% reduction. In 2008 the reduction attributable to screening was 20.4%, to adjuvant treatments was 15.8% and to both interventions 34.1%. Conclusions/Significance: Screening and adjuvant treatments similarly contributed to reducing BC mortality in Catalonia. Mathematical models have been useful to assess the impact of interventions addressed to reduce BC mortality that occurred over nearly the same periods.

Coffee polyphenols change the expression of STAT5b and ATF-2 modifying cyclin D1 levels in cancer cells

Background: Epidemiological studies suggest that coffee consumption reduces the risk of cancer, but the molecular mechanisms of its chemopreventive effects remain unknown. Objective: To identify differentially expressed genes upon incubation of HT29 colon cancer cells with instant caffeinated coffee (ICC) or caffeic acid (CA) using whole genome microarrays. Results: ICC incubation of HT29 cells caused the overexpression of 57 genes and the underexpression of 161, while CA incubation induced the overexpression of 12 genes and the underexpression of 32. Using Venn-Diagrams, we built a list of five overexpressed genes and twelve underexpressed genes in common between the two experimental conditions. This list was used to generate a biological association network in which STAT5B and ATF-2 appeared as highly interconnected nodes. STAT5B overexpression was confirmed at the mRNA and protein levels. For ATF-2, the changes in mRNA levels were confirmed for both ICC and CA, whereas the decrease in protein levels was only observed in CA-treated cells. The levels of cyclin D1, a target gene for both STAT5B and ATF-2, were dowregulated by CA in colon cancer cells and by ICC and CA in breast cancer cells. Conclusions: Coffee polyphenols are able to affect cyclin D1 expression in cancer cells through the modulation of STAT5B and ATF-2.

Interfície gràfica per a la valoració d'operadors de preprocessat d'imatge en imatges d'ultrasò

El càncer de mama és una de les causes de més mortalitat entreles dones dels països desenvolupats. És tractat d'una maneramés eficient quan es fa una detecció precoç, on les tècniques d'imatge són molt importants. Una de les tècniques d'imatge més utilitzades després dels raigs-X són els ultrasons. A l'hora de fer un processat d'imatges d'ultrasò, els experts en aquest camp es troben amb una sèrie de limitacions en el moment d'utilitzar uns filtrats per les imatges, quan es fa ús de determinades eines. Una d'aquestes limitacions consisteix en la falta d'interactivitat que aquestes ens ofereixen. Per tal de solventar aquestes limitacions, s'ha desenvolupat una eina interactiva que permet explorar el mapa de paràmetres visualitzant el resultat del filtrat en temps real, d'una manera dinàmica i intuïtiva. Aquesta eina s'ha desenvolupat dins l'entorn de visualització d'imatge mèdica MeVisLab. El MeVisLab és un entorn molt potent i modular pel desenvolupament d'algorismes de processat d'imatges, visualització i mètodes d'interacció, especialment enfocats a la imatge mèdica. A més del processament bàsic d'imatges i de mòduls de visualització, inclou algorismes avançats de segmentació, registre i moltes análisis morfològiques i funcionals de les imatges.S'ha dut a terme un experiment amb quatre experts que, utilitzantl'eina desenvolupada, han escollit els paràmetres que creien adientsper al filtrat d'una sèrie d'imatges d'ultrasò. En aquest experiments'han utilitzat uns filtres que l'entorn MeVisLab ja té implementats:el Bilateral Filter, l'Anisotropic Difusion i una combinació d'un filtrede Mediana i un de Mitjana.Amb l'experiment realitzat, s'ha fet un estudi dels paràmetres capturats i s'han proposat una sèrie d'estimadors que seran favorables en la majoria dels casos per dur a terme el preprocessat d'imatges d'ultrasò

Identification of molecular subtypes and gene expression patterns of breast cancer analysing RNA-seq data

Breast cancer is the most common diagnosed cancer and the leading cause of cancer death among females worldwide. It is considered a highly heterogeneous disease and it must be classified into more homogeneous groups. Hence, the purpose of this study was to classify breast tumors based on variations in gene expression patterns derived from RNA sequencing by using different class discovery methods. 42 breast tumors paired-samples were sequenced by Illumine Genome Analyzer and the data was analyzed and prepared by TopHat2 and htseq-count. As reported previously, breast cancer could be grouped into five main groups known as basal epithelial-like group, HER2 group, normal breast-like group and two Luminal groups with a distinctive expression profile. Classifying breast tumor samples by using PAM50 method, the most common subtype was Luminal B and was significantly associated with ESR1 and ERBB2 high expression. Luminal A subtype had ESR1 and SLC39A6 significant high expression, whereas HER2 subtype had a high expression of ERBB2 and CNNE1 genes and low luminal epithelial gene expression. Basal-like and normal-like subtypes were associated with low expression of ESR1, PgR and HER2, and had significant high expression of cytokeratins 5 and 17. Our results were similar compared with TGCA breast cancer data results and with known studies related with breast cancer classification. Classifying breast tumors could add significant prognostic and predictive information to standard parameters, and moreover, identify marker genes for each subtype to find a better therapy for patients with breast cancer.

Estimation of age- and stage-specific Catalan breast cancer survival functions using US and Catalan survival data

During the last part of the 1990s the chance of surviving breast cancer increased. Changes in survival functions reflect a mixture of effects. Both, the introduction of adjuvant treatments and early screening with mammography played a role in the decline in mortality. Evaluating the contribution of these interventions using mathematical models requires survival functions before and after their introduction. Furthermore, required survival functions may be different by age groups and are related to disease stage at diagnosis. Sometimes detailed information is not available, as was the case for the region of Catalonia (Spain). Then one may derive the functions using information from other geographical areas. This work presents the methodology used to estimate age- and stage-specific Catalan breast cancer survival functions from scarce Catalan survival data by adapting the age- and stage-specific US functions. Methods: Cubic splines were used to smooth data and obtain continuous hazard rate functions. After, we fitted a Poisson model to derive hazard ratios. The model included time as a covariate. Then the hazard ratios were applied to US survival functions detailed by age and stage to obtain Catalan estimations. Results: We started estimating the hazard ratios for Catalonia versus the USA before and after the introduction of screening. The hazard ratios were then multiplied by the age- and stage-specific breast cancer hazard rates from the USA to obtain the Catalan hazard rates. We also compared breast cancer survival in Catalonia and the USA in two time periods, before cancer control interventions (USA 1975–79, Catalonia 1980–89) and after (USA and Catalonia 1990–2001). Survival in Catalonia in the 1980–89 period was worse than in the USA during 1975–79, but the differences disappeared in 1990–2001. Conclusion: Our results suggest that access to better treatments and quality of care contributed to large improvements in survival in Catalonia. On the other hand, we obtained detailed breast cancer survival functions that will be used for modeling the effect of screening and adjuvant treatments in Catalonia

Rapid increase in incidence of breast ductal cancer in situ in Girona, Spain 1983-2007

Introduction: The aim of this study was to describe breast ductal cancer in situ (DCIS) incidence trends in women in the Girona province during a period of 25 years. The influence of age, use of mammography and implementation of the breast cancer screening programs was explored. Incidence of subsequent invasive breast cancers (IBC) and DCIS treatment was also considered. Materials and Methods: Cases diagnosed with primary pure DCIS (n=416) during 1983-2007 were extracted from the population-based Girona Cancer Registry. The estimated annual percent change was estimated using joinpoint analysis. Results: DCIS incidence showed a sharp rise until 1998, followed by a less marked upward trend. Among women aged 50-69 the increase was particularly important between 1992 and in 1996, reflecting the spread in mammography use. Conclusion: The upward trend of DCIS was mainly related to an increase in mammography use either opportunistic or as a result of screening implementation

Reliability of intraoperative ultrasound in margin status assessment in women undergoing breast conserving surgery

Background: Effective treatment for breast cancer requires accurate preoperative planning, developing and implementing a consistent definition of margin clearance, and using tools that provide detailed real-time intraoperative information on margin status. Intraoperative ultrasound (IOUS) may fulfil these requirements and may offer few advantages that other preoperative localization and intraoperative margin assessment techniques may notPurpose: The goal of the present work is to determine how accurate the intraoperative ultrasound should be to acquire complete surgical excision with negative histological margins in patients undergoing Breast Conservative SurgeryDesign: A diagnostic test study with a cross-sectional design carried out in a tertiary referral hospital in Girona within a Breast Pathology UnitParticipants: Women diagnosed with breast cancer undergoing a Breast Conservative Surgery in the Breast Pathology Unit at Hospital Universitari de Girona Dr. Josep Trueta

Implementing a Cancer Fast-track programme between primary and specialised care in Catalonia(Spain): amixed methods study

BACKGROUND: The Cancer Fast-track Programme's aim was to reduce the time that elapsed between well-founded suspicion of breast, colorectal and lung cancer and the start of initial treatment in Catalonia (Spain). We sought to analyse its implementation and overall effectiveness. METHODS: A quantitative analysis of the programme was performed using data generated by the hospitals on the basis of seven fast-track monitoring indicators for the period 2006-2009. In addition, we conducted a qualitative study, based on 83 semistructured interviews with primary and specialised health professionals and health administrators, to obtain their perception of the programme's implementation. RESULTS: About half of all new patients with breast, lung or colorectal cancer were diagnosed via the fast track, though the cancer detection rate declined across the period. Mean time from detection of suspected cancer in primary care to start of initial treatment was 32 days for breast, 30 for colorectal and 37 for lung cancer (2009). Professionals associated with the implementation of the programme showed that general practitioners faced with suspicion of cancer had changed their conduct with the aim of preventing lags. Furthermore, hospitals were found to have pursued three specific implementation strategies (top-down, consensus-based and participatory), which made for the cohesion and sustainability of the circuits. CONCLUSION: The programme has contributed to speeding up diagnostic assessment and treatment of patients with suspicion of cancer, and to clarifying the patient pathway between primary and specialised care.

Freqüência de realização e acurácia do auto-exame das mamas na detecção de nódulos em mulheres submetidas à mamografia

Realizamos um estudo transversal prospectivo cujo objetivo foi avaliar a acurácia do auto-exame de mamas (AEM) na detecção de nódulos mamários palpáveis e a relação com sua freqüência. Foram entrevistadas 2672 mulheres que realizaram mamografia na Região do Vale dos Sinos/RS no período de janeiro de 94 a julho de 97, questionando-se quanto à freqüência da realização de AEM. As mulheres foram divididas em dois grupos: grupo I (mensalmente), grupo II (quase nunca). As mulheres que relataram realizar o AEM ocasionalmente foram excluídas da análise principal. Foi perguntado à paciente se ela ou seu médico haviam palpado alguma lesão mamária. Comparou-se os achados de palpação da paciente com os do médico (relatados pela paciente). A sensibilidade do AEM foi maior no grupo I comparado ao II (57,4% versus 33,3%; P <0,05). Concluímos que existe uma associação entre a realização mensal de AEM e uma maior sensibilidade na detecção de nódulos mamários palpáveis.

Biópsia Percutânea Estereotáxica no Diagnóstico das Lesões Mamárias Subclínicas

Objetivo: avaliar a eficácia da biópsia percutânea estereotáxica (BPE) no diagnóstico das lesões mamárias subclínicas, comparando seus resultados com a biópsia cirúrgica precedida de localização estereotáxica com fio guia. Métodos: no período de janeiro de 1995 a fevereiro de 1997, realizamos um estudo transversal com 41 casos de lesões não-palpáveis em pacientes com idade superior a 35 anos, no Instituto de Ginecologia da Universidade Federal do Rio de Janeiro. Os casos foram classificados radiologicamente como benignos, provavelmente benignos, suspeitos e malignos. Para fins de análise estatística, as lesões benignas e provavelmente benignas foram estudadas em conjunto. O laudo histopatológico da BPE foi classificado em: inadequado para diagnóstico, ausência de malignidade, suspeito e maligno. O laudo histopatológico da biópsia cirúrgica foi classificado em: ausência de malignidade, pré-maligno e maligno. Calculamos a sensibilidade, a especificidade e os valores preditivos da BPE, assim como as razões de verossimilhança da mamografia e da BPE com a finalidade de predizer a probabilidade de câncer de mama. Resultados: a BPE coincidiu com a biópsia cirúrgica em 86,2% dos 29 casos de ausência de malignidade. Todos os casos suspeitos à BPE foram malignos à biópsia cirúrgica. Todos os casos de malignidade à BPE estiveram acordes com a biópsia cirúrgica. A sensibilidade e a especificidade da BPE foram 36,4% e 100%, respectivamente. O valor preditivo positivo do método foi 100% e o negativo 78,1%. No grupo classificado como maligno à mamografia, a razão de verossimilhança foi 9,7, sendo 1,3 para os casos suspeitos e 0,1 para o laudo provavelmente benigno. A razão de verossimilhança da BPE foi infinita (¥) para as lesões suspeitas e malignas, 0,4 para os casos classificados como ausência de malignidade e 1,4 para os casos inadequados para diagnóstico. Conclusões: após análise dos resultados, por meio da razão de verossimilhança, concluímos que o laudo de ausência de malignidade pela BPE não nos permitiu afastar o diagnóstico de patologia maligna. Nestes casos, se não houver concordância entre o laudo histopatológico e o laudo mamográfico, deve-se prossseguir na investigação. Quando o laudo era suspeito à BPE, a probabilidade da lesão corresponder a carcinoma de mama foi muito alta. Deve-se proceder à biópsia cirúrgica para diagnóstico de certeza, pois o carcinoma infiltrante possui terapêutica diversa do carcinoma in situ e da hiperplasia atípica. Quando o laudo histopatológico era de malignidade, foi elevada a probabilidade da lesão corresponder a câncer e não observamos falso-positivos. Nestes casos, a BPE permite diagnóstico mais rápido, sem necessidade de biópsia cirúrgica.

Auto-exame das mamas entre estudantes de medicina

Objetivo: avaliar o nível de conhecimento e prática do auto-exame da mama entre os estudantes do curso médico e determinar possíveis fatores associados a esta prática. Métodos: foi utilizado um questionário que continha informações sobre os alunos e o seu conhecimento a respeito do auto-exame, permitindo ainda, verificar entre as alunas a prática do mesmo. Utilizaram-se os testes do qui quadrado e "t" de Student, quando aplicáveis, para verificar a associação de alguns fatores com o auto-exame. Resultados: dos 348 questionários respondidos, 55 (16%) pertenciam aos alunos do 5º ano (estudantes que haviam cursado a Disciplina de Ginecologia da Universidade Federal de Goiás), 43% eram mulheres, 62% tinham familiares médicos e 17% apresentavam história familiar de câncer de mama. Em relação ao conhecimento do auto-exame, 95% conheciam o método. Das 149 estudantes, apenas 64% o praticavam. Os motivos para não fazê-lo eram: por ser muito jovem (24%), por não acreditar que pudesse acontecer com ela (4%), por medo (9%) e por preguiça (19%), sendo que 44% das alunas não souberam explicar o motivo. Tanto o conhecimento quanto a prática do auto-exame não estiveram associados ao ano do curso médico, história familiar de câncer de mama ou à presença de familiar médico. Conclusão: o auto-exame é conhecido por praticamente todos os estudantes de medicina mesmo assim, um terço das estudantes não o praticam. Com isso ressalta-se a importância do auto-exame no curso médico, a fim de que os alunos possam levar mais informações à população, não limitando esta tarefa aos meios de comunicação.