Validation of primary and outcome data quality in a Swedish population-based breast cancer quality registry.

BACKGROUND: Population-based cancer quality registries are of great importance for the improvement of cancer care. However, little is known about the quality of recurrence data in cancer quality registries. The aim of this study was to evaluate data quality in the regional Breast Cancer Quality Registry of Central Sweden, with emphasis on the validity of recorded information on recurrence. METHODS: Validation by re-abstraction was performed on a random sample of 800 women with primary invasive breast cancer stage I-III diagnosed between 1993 and 2010, of which 400 had at least one registered recurrence and 400 had no registered recurrence. Registry data were compared with data from medical records. Exact agreement, correlation and kappa values, sensitivity and specificity were calculated. RESULTS: Seven hundred forty-seven women (93%) were available for analysis. Exact agreement was high for diagnostics, tumor characteristics, surgery, and adjuvant oncological treatment (90% or more for most variables). The registry's sensitivity was low for regional recurrence (47%), but higher for local and distant recurrence (80% and 75%), whereas specificity was overall high (≥ 95%). Combining all recurrence categories irrespective of localization improved sensitivity to 90% with a specificity of 91%. In 87% of women, the date of first recurrence according to medical records fell within ± 90 days of the date recorded in the registry. CONCLUSIONS: While the quality of data in the regional Breast Cancer Quality Registry was generally high, data accuracy on recurrences was lower. The overall precision of identifying any recurrence, irrespective of localization, was high. However, the accuracy of classification of recurrences (local, regional or distant) was lower, with evidence of underreporting for each of the recurrence categories. Given the importance of recurrence-related outcomes in the assessment of quality of care, efforts should be made to improve the reporting of recurrences.

A validation of DCIS registration in a population-based breast cancer quality register and a study of treatment and prognosis for DCIS during 20 years.

AIMS: Sweden has a long history of population-based cancer registration. The aim of our study was to assess the validity of DCIS registration in a regional Breast Cancer Quality Register (BCQR) and to analyze trends in incidence, treatment and outcome of DCIS, over a 20-year period. MATERIAL AND METHODS: All patients with a diagnosis of primary DCIS reported in the BCQR of the Uppsala-Örebro healthcare region in Sweden 1992-2012 were included. Three hundred women were randomly selected and their medical records were compared to register data. The study period was divided into four time periods. RESULTS: A total of 2952 women were registered with a DCIS diagnosis. In the final validation cohort of 295 patients, 23 were found to have either recurrent DCIS or invasive breast cancer and eight had LCIS. The completeness and validity of key variables were 91-99%. Twenty of 31 local recurrences were registered (65%).The proportion of DCIS to all breast cancers was 9.5%. Tumor size increased over time. The frequency of mastectomy increased from 23.0% to 39.0%. The proportion of patients receiving radiotherapy after breast conserving surgery increased from 30.1% to 67.6%. The reported local recurrence rate was 9.7% after 10 years. Reported recurrences after BCS and mastectomy were 12.0 and 7.0%, respectively. The recurrence rate did not differ between women undergoing BCS with or without radiotherapy. CONCLUSION: Only 89.5% of reported DCIS was a primary pure DCIS. The completeness of primary treatment and tumor data was high. The proportion of reported local recurrences was disappointingly low, 65%. The proportion of DCIS was stable over time with a trend towards more intensified treatment. The reported recurrence rate was low independent of treatment and can reflect adequate patient selection, but also over treatment. Our results address the necessity to validate register data on a regular basis.

Molecular subtyping of male breast cancer using alternative definitions and its prognostic impact.

BACKGROUND: Male breast cancer (MBC) is an uncommon disease and there is limited information on the prognostic impact of routinely used clinicopathological parameters. MATERIAL AND METHODS: In a retrospective setting, we reviewed 197 MBC patients with accessible paraffin-embedded tumor tissue and clinicopathological data. Immunohistochemical (IHC) stainings were performed on tissue microarrays and histological grading on conventional slides. Cox proportional regression models were applied for uni- and multivariate analyses using breast cancer death as the event. RESULTS: Estrogen receptor (ER) and progesterone receptor positivity were demonstrated in 93% and 77% of patients, respectively. Nottingham histologic grade (NHG) III was seen in 41% and HER2 positivity in 11%. Classification into molecular subtypes using IHC markers according to three alternative definitions revealed luminal A and luminal B in 81% vs. 11%; 48% vs. 44% and 41% vs. 42% of cases. Two cases of basal-like were identified, but no cases of HER2-like. Factors associated with an increased risk of breast cancer death were node positivity (HR 4.5; 95% CI 1.8-11.1), tumor size > 20 mm (HR 3.3; 95% CI 1.4-7.9) and ER negativity (HR 10.9; 95% CI 3.2-37.9). No difference in breast cancer death between the luminal subgroups was demonstrated, regardless of definition. CONCLUSION: MBC tumors were more often of high grade, whereas HER2 overexpression was as frequent as in FBC. Lymph nodes, tumor size and ER status were independent predictors of breast cancer death. The prognostic impact of molecular subtyping in MBC seems to differ from that previously established in FBC.

Adherence and discontinuation of adjuvant hormonal therapy in breast cancer patients: a population-based study.

Adherence to long-term pharmacological treatment for chronic conditions is often less than optimal. Till date, a limited number of population-based studies have assessed adherence to adjuvant hormonal therapy in breast cancer, a therapy with proven benefits in terms of reductions of recurrence and mortality. We aimed to examine rates of adherence and early discontinuation in Sweden where prescribed medications are subsidized for all residents and made available at reduced out-of-pocket costs. Individual-level data were obtained from Regional Clinical Quality Breast Cancer Registers, the Swedish Prescribed Drug Register, and several other population-based registers. Multivariate logistic regression was used to analyze factors associated with adherence to prescribed medication for a period of 3 years. Between January 1 and December 31, 2005, 1,741 patients in central Sweden were identified with estrogen receptor positive breast cancer, and at least one prescription dispensation of either tamoxifen or an aromatase inhibitor. Of these women, 1,193 (69%) were fully adherent to therapy for 3 years (medication possession ratio of 80% or higher and a maximum of 180 days between refills). During the 3-year follow-up, 215 women (12%) had prematurely discontinued therapy. Adherence was positively associated with younger age, large tumor size, being married, and being born in the Nordic countries, while no clear association was observed with education or income. During the 3 years of follow-up, 31% of women were non-adherent to therapy. Further efforts must be undertaken to promote adherence over the entire recommended treatment period.

Inflammatory cells in node-negative breast cancer.

BACKGROUND: To study the impact of inflammatory cells in a clinically well-defined cohort of women with node-negative breast cancer in a nested case-control study design. MATERIAL AND METHODS: The cohort was comprised of 190 women who died from breast cancer and 190 women still alive at the date of death for the corresponding breast cancer patients were used as controls. The inclusion criteria included; a tumour size ≤ 50 mm, no lymph node metastases and no initiation of adjuvant chemotherapy. Immunohistochemical stainings for CD3, CD4, CD8, FoxP3, CD20, tryptase and CD68 were performed on TMA blocks, evaluated and correlated to each other and to age, tumour size, histological grade, ER, PgR, Ki67 and cyclin A. RESULTS: There was no difference regarding the amount or content of inflammatory cells in the cases compared to controls. T- and B-cells were highly correlated to each other but these cell types correlated to a lesser extent to macrophages and not at all to mast cells. A weak tendency of correlations between all the subsets of inflammatory cells and histological grade, Ki67 and cyclin A was observed, although a negative correlation was seen for mast cells. CONCLUSION: The amount or content of inflammatory cells in invasive breast cancer did not appear to influence death in node-negative breast cancer.

Similarities and differences in the characteristics and primary treatment of breast cancer in men and women - a population based study (Sweden).

PURPOSE: Male breast cancer (MBC) is an uncommon disease. In the absence of randomized studies, current guidelines are mainly based on data on the management of female breast cancer (FBC). In light of concerns regarding the quality and extent of management in men, the aim of the present study was to investigate whether there are differences in tumor characteristics, treatment and outcome in male compared with FBC patients. METHODS: Cohorts of male and female breast cancer were retrospectively analyzed. All male patients diagnosed with invasive breast cancer between 1993 and 2007 were identified from the Regional Breast Cancer Register of the Uppsala-Örebro Region in Sweden. To increase the power of the study and obtain comparable cohorts we sampled four FBC patients (n = 396) for each MBC patient (n = 99) with similar age at diagnosis and time of diagnosis. RESULTS: No differences were seen in stage at diagnosis between MBC and FBC. Men underwent mastectomy more often than women (92% vs. 44%, p < 0.001). Radiotherapy was delivered less often to MBC than FBC (44% vs. 56%, p = 0.034), but radiotherapy given after mastectomy (44% vs. 39%, p = 0.47) did not differ between the groups. No differences were found regarding adjuvant chemotherapy (16% vs. 21%; p = 0.31) or adjuvant endocrine therapy (59% vs. 52%, p = 0.24). Both overall survival (41% vs. 55%, p = 0.001) and relative survival (74% vs. 88%, p = 0.015) were inferior in MBC compared to FBC. CONCLUSION: Concerns regarding less extensive treatment in MBC patients were not supported by this study. Although no differences in the stage of the disease or treatment intensity could be demonstrated, outcome was inferior in the male group.

Reductions in use of hormone replacement therapy: effects on Swedish breast cancer incidence trends only seen after several years.

Studies from Western countries have found evidence of a recent decline in breast cancer incidence rates in postmenopausal women, findings which have been hypothesized to reflect a reduced use of hormonal replacement therapy (HRT). We examined breast cancer incidence trends in Sweden between 1997 and 2007, a period characterized by a drop in the use of HRT. Incidence trends were assessed using data from three population-based Regional Clinical Registries on breast cancer covering 2/3 of the Swedish population. Information on HRT sales was obtained from national pharmacy data. The prevalence of HRT use in age group 50-59 years decreased from a peak of 36% in 1999 to 27% in 2002 and further to 9% in 2007. Incidence rates of breast cancer in women 50 years and older increased between 1997 and 2003. A significant decrease in incidence between 2003 and 2007 was confined to women 50-59 years of age, the group in which the prevalence of HRT use has been highest and the decrease in use most pronounced. As opposed to the immediate effects reported from the United States and other regions, there was a time lag between the drop in HRT use and clear reductions in breast cancer incidence. This may reflect between country differences with regard to types of HRT used, and the rate, magnitude and pattern of change in use. The present findings give further support to the notion that HRT use is a driver of breast cancer incidence trends on the population level.

Cyclin B is an immunohistochemical proliferation marker which can predict for breast cancer death in low-risk node negative breast cancer.

UNLABELLED: Patients with low-risk node negative breast cancer have an excellent prognosis with 5% breast cancer mortality at 10 years. However, prognostic factors are needed to identify poor prognostic patients who might benefit from adjuvant systemic therapy. Proliferation has been identified as the most important component of gene expression profiles. Cyclin B is a proliferative marker easily assessed by immunohistochemistry. We wanted to examine cyclin B as a prognostic factor in low-risk breast cancer patients. PATIENTS AND METHODS: Using an experimental study design, we compared women dying early from their breast cancer (n=17) with women free from relapse more than eight years after initial diagnosis (n=24). All women had stage I, node negative and hormone receptor positive disease. None had received adjuvant chemotherapy. Tumor samples were immunostained for cyclin B using commercial antibodies. RESULTS: The mean percentage of cyclin B (12%) was significantly higher (p=0.001) in women dying from their breast cancer compared with women free from relapse (5%). High cyclin B (> or =9%) identified 11/17 patients dying from breast cancer and low cyclin B identified 22/24 patients free from relapse. The sensitivity and specificity of cyclin B was 65% and 92%, respectively. DISCUSSION: We found that low-risk node negative patients with high expression of cylin B had a significantly worse outcome than patients with low expression of cyclin B. Cyclin B could separate patients with poor survival from those with good survival with 80% accuracy. We suggest that cyclin B might be a potent prognostic factor in this low-risk patient group.

Educational level, management and outcomes in small-cell lung cancer (SCLC): A population-based cohort study.

OBJECTIVES: To examine if educational status is associated with outcome in patients with Small Cell Lung Cancer (SCLC). The study also investigated differences in patterns of management (lead times and treatment intensity) between educational levels. MATERIAL AND METHODS: This nationwide cohort study was based on data from Lung Cancer Data Base Sweden (LCBaSe) generated by record linkages between the Swedish National Lung Cancer Register and several other population-based registers. Educational level was categorized by number of years of schooling: low (≤ 9 years), medium (10-12 years) and high (≥ 13 years). Risk of death expressed as hazard ratios (HR) with 95 % confidence interval (CI) were estimated in multi-variable analyses adjusted for age, sex, disease stage at diagnosis, household size and performance status (PS). Analyses stratified by sex and stage were also performed. RESULTS AND CONCLUSIONS: The study population encompassed 4256 patients with an SCLC diagnosis between 2002 and 2011. Higher education was associated with a significantly lower risk of death in univariable and multivariable models. The univariable HR comparing high to low level of education was 0.84 (95 % CI: 0.75-0.93), an estimate that was attenuated following adjustments (HR 0.88; 95 % CI: 0.80-0.98). Compared to men with a low level of education, the risk of death was significantly lower in men with a high education; HR 0.84 (95 % CI: 0.73-0.98). In Limited Disease (LD), the prognosis was significantly better in both men and women with high compared low education (HR 0.76; 95 % CI: 0.58-0.98). In Swedish men with SCLC, and among patients with LD-SCLC, a low level of education was associated with a poorer prognosis compared to patients with high education.

Aberrant expression of cyclin E in low-risk node negative breast cancer.

BACKGROUND: Cyclin E is a cell cycle regulatory protein which occurs in G1, peaks in late G1 and is degraded in early S-phase. Cyclin E overexpression appears to be an independent prognostic factor for overall survival in breast cancer. Nuclear cyclin A is a reliable marker for S-and G2-phases. Consequently, aberrant expression of cyclin E can be detected by simultaneous immunostainings for cyclin A and cyclin E. Studies have shown that aberrant cyclin E might provide additional prognostic information compared to that of cyclin E alone. This study aimed to investigate cyclin E and aberrant cyclin E expression in low-risk node negative breast cancer. MATERIAL AND METHODS: We compared women that died from their breast cancer (n=17) with women free from relapse > 8 years after initial diagnosis (n=24). All women had stage I, low risk breast cancer. The groups were matched regarding tumour size, receptor status, adjuvant chemotherapy and tumour differentiation. Tumour samples were analysed regarding expression of cyclin A, cyclin E and double-stained tumour cells using immunoflourescence staining and digital microscopy. RESULTS: No differences were seen regarding expression of cyclin E or aberrant cyclin E in cases compared to controls. DISCUSSION: We conclude that neither cyclin E nor aberrant cyclin E is a prognostic factor in low-risk node negative breast cancer patients.

Time trends in T3 to T4 laryngeal cancer: a population-based long-term analysis.

BACKGROUND: A decline in laryngectomies and survival in laryngeal cancer has been reported, especially among patients with advanced tumors. METHODS: Of 1058 patients with laryngeal cancer diagnosed from 1978 to 2007 in the Uppsala-Örebro region in Sweden, 263 T3 to T4 tumors treated with curative intent were studied retrospectively. Two time periods were defined, 1978 to 1992 and 1993 to 2007. RESULTS: Glottic tumors decreased constituting 68.6% of cases in 1978 to 1992 and 47.9% in 1993 to 2007. Laryngectomies were performed in 38.8% and 34.5% in the corresponding time periods. The use of laryngectomy was not strongly prognostic. A decline in overall survival (OS) over time could only be identified for the first year of follow-up. Chemotherapy was only used in a minority of cases. CONCLUSION: The marked decrease of glottic site may mark a shift in etiology. Laryngectomy was not strongly associated with improved survival. The absence of improved survival calls for intensified research.

Tumor stage affects risk and prognosis of contralateral breast cancer: results from a large Swedish-population-based study.

PURPOSE: The number of breast cancer survivors at risk of developing contralateral breast cancer (CBC) is increasing. However, ambiguity remains regarding risk factors and prognosis for women with CBC. PATIENTS AND METHODS: In a cohort of 42,670 women with breast cancer in the Uppsala/Örebro and Stockholm regions in Sweden in 1992 to 2008, we assessed risk factors for and prognosis of metachronous CBC by using survival analysis. Breast cancer-specific survival for women with CBC was evaluated and compared with results for women with unilateral breast cancer (UBC) by using time-dependent Cox-regression modeling. RESULTS: An increased risk for CBC was observed among women who had primary breast cancer with ≥ 10 involved lymph nodes compared with node-negative women (adjusted hazard ratio [HR], 1.8; 95% CI, 1.2 to 2.7). The prognosis was poorer in women with CBC than with UBC. The hazard of dying from breast cancer was especially high for women with a short interval time to CBC (adjusted HR, 2.3; 95% CI, 1.8 to 2.8 for CBC diagnosed ≤ 5 years v UBC) and gradually decreased with longer follow-up time but remained higher than the hazard originating from the primary tumor for ≥ 10 years. CONCLUSION: Women with advanced-stage primary breast cancer had an increased risk of developing CBC. CBC is associated with an increased risk of dying from breast cancer throughout a long period of follow-up after the primary tumor. Our findings suggest that the event of CBC marks a new clinical situation in terms of investigations for metastases, treatment considerations, and follow-up strategy.

Impact of age at diagnosis on prognosis and treatment in laryngeal cancer.

BACKGROUND: The aims of this study were to analyze how age affects treatment and treatment outcome, and to determine whether tumor characteristics differ between different age groups with laryngeal cancer. METHODS: Patients with laryngeal cancer during 1978-2004 in the Uppsala-Orebro region in Sweden were retrospectively studied. RESULTS: There were no significant differences in the 945 cases between age groups concerning major patient and tumor characteristics, such as male/female ratio, distribution of glottic/supraglottic tumors, stage, or site of recurrence. Overall survival (OS) and disease-specific survival (DSS) were worse among the oldest, although a significant proportion was cured. Relapse risk was lower among the oldest (12%) compared with the youngest (23%). The risk of never becoming tumor-free was 25% among the oldest and 7% in the youngest. Among the most elderly, only 1 late recurrence occurred. CONCLUSION: Elderly patients with laryngeal carcinoma cope well with treatment. Undertreatment may determine outcome more than age. The oldest group should be followed for a minimum of 2 years.

Cyclin A is a proliferative marker with good prognostic value in node-negative breast cancer.

BACKGROUND: Proliferative markers are not recommended as prognostic factors for clinical use in breast cancer due to lack of standardization in methodology. However, proliferation is driving several gene expression signatures emphasizing the need for a reliable proliferative marker for clinical use. Studies suggest that cyclin A is a prognostic marker with satisfying reproducibility. We investigated cyclin A as a prognostic marker in node-negative breast cancer using previously defined cutoff values. PATIENTS AND METHODS: In a case-control study, we defined 190 women who died from breast cancer as cases and 190 women alive at the time for the corresponding case's death as controls. Inclusion criteria were tumor size

Increased risk of recurrence after hormone replacement therapy in breast cancer survivors.

BACKGROUND: Hormone replacement therapy (HT) is known to increase the risk of breast cancer in healthy women, but its effect on breast cancer risk in breast cancer survivors is less clear. The randomized HABITS study, which compared HT for menopausal symptoms with best management without hormones among women with previously treated breast cancer, was stopped early due to suspicions of an increased risk of new breast cancer events following HT. We present results after extended follow-up. METHODS: HABITS was a randomized, non-placebo-controlled noninferiority trial that aimed to be at a power of 80% to detect a 36% increase in the hazard ratio (HR) for a new breast cancer event following HT. Cox models were used to estimate relative risks of a breast cancer event, the maximum likelihood method was used to calculate 95% confidence intervals (CIs), and chi(2) tests were used to assess statistical significance, with all P values based on two-sided tests. The absolute risk of a new breast cancer event was estimated with the cumulative incidence function. Most patients who received HT were prescribed continuous combined or sequential estradiol hemihydrate and norethisterone. RESULTS: Of the 447 women randomly assigned, 442 could be followed for a median of 4 years. Thirty-nine of the 221 women in the HT arm and 17 of the 221 women in the control arm experienced a new breast cancer event (HR = 2.4, 95% CI = 1.3 to 4.2). Cumulative incidences at 5 years were 22.2% in the HT arm and 8.0% in the control arm. By the end of follow-up, six women in the HT arm had died of breast cancer and six were alive with distant metastases. In the control arm, five women had died of breast cancer and four had metastatic breast cancer (P = .51, log-rank test). CONCLUSION: After extended follow-up, there was a clinically and statistically significant increased risk of a new breast cancer event in survivors who took HT.

The impact of organized mammography service screening on breast carcinoma mortality in seven Swedish counties.

BACKGROUND: The evaluation of organized mammographic service screening programs is a major challenge in public health. In particular, there is a need to evaluate the effect of the screening program on the mortality of breast carcinoma, uncontaminated in the screening epoch by mortality from 1) cases diagnosed in the prescreening period and 2) cases diagnosed among unscreened women (i.e., nonattenders) after the initiation of organized screening. METHODS: In the current study, the authors ascertained breast carcinoma deaths in the prescreening and screening epochs in 7 Swedish counties from tumors diagnosed in these epochs and in the age group 40-69 years in 6 counties and 50-69 years in 1 county. Data regarding deaths were obtained from the Uppsala Regional Oncologic Center in conjunction with the National Cause of Death Register. The total number of women in the eligible age range living in each county was obtained from the annual population data of Statistics Sweden. Detailed screening data were provided by the screening centers in the seven counties, including the number of invited, the number attended, and whether each individual breast carcinoma case was exposed (screen-detected and interval cases combined) or unexposed (not-invited or nonattenders) to mammographic screening. There were 2044 breast carcinoma deaths from 14,092 incident tumors diagnosed in the prescreening and screening epochs, and the total number of person-years was 7.5 million. Data were analyzed using Poisson regression with corrections for self-selection bias and lead-time bias when appropriate. RESULTS: The mortality reduction for breast carcinoma in all 7 counties combined for women actually exposed to screening compared with the prescreening period was 44% (relative risk [RR] = 0.56; 95% confidence interval [95% CI], 0.50-0.62). When all incident tumors were considered, both those exposed and those unexposed to screening combined, counties with > 10 years of screening were found to demonstrate a significant 32% mortality reduction (RR = 0.68; 95% CI, 0.60-0.77) and counties with < or = 10 years of screening showed a significant 18% reduction in breast carcinoma mortality (RR = 0.82; 95% CI, 0.72-0.94) for the screening epoch compared with the prescreening epoch. Within the screening epoch, after adjustment for self-selection bias, a 39% mortality reduction (RR = 0.61; 95%CI, 0.55-0.68) was observed in association with invitation to screening. CONCLUSIONS: Organized service screening in 7 Swedish counties, covering approximately 33% of the population of Sweden, resulted in a 40-45% reduction in breast carcinoma mortality among women actually screened. The policy of offering screening is associated with a mortality reduction in breast carcinoma of 30% in the invited population, exposed and unexposed combined. The results of the current study indicate that the majority of the breast carcinoma mortality reduction is indeed due to the screening.