Decline in breast cancer mortality: how much is attributable to screening?

OBJECTIVES: When estimating the decline in breast cancer mortality attributable to screening, the challenge is to provide valid comparison groups and to distinguish the screening effect from other effects. In Funen, Denmark, multidisciplinary breast cancer management teams started before screening was introduced; both activities came later in the rest of Denmark. Because Denmark had national protocols for breast cancer treatment, but hardly any opportunistic screening, Funen formed a "natural experiment", providing valid comparison groups and enabling the separation of the effect of screening from other factors. METHODS: Using Poisson regression we compared the observed breast cancer mortality rate in Funen after implementation of screening with the expected rate without screening. The latter was estimated from breast cancer mortality in the rest of Denmark controlled for historical differences between Funen/rest of Denmark. As multidisciplinary teams were introduced gradually in the rest of Denmark from 1994, the screening effect was slightly underestimated. RESULTS: Over 14 years, women targeted by screening in Funen experienced a 22% (95% confidence interval 11%-32%) reduction in breast cancer mortality associated with screening (a reduction in breast cancer mortality rate from 61 to 47 per 100,000). The estimated reduction for participants corrected for selection bias was 28% (13%-41%). Excluding deaths in breast cancer cases diagnosed after end of screening, these numbers became 26% and 31%, respectively. CONCLUSIONS: There is additional benefit in reducing breast cancer mortality from the early detection of breast cancer through mammographic screening over and above the benefits arising from improvements in treatment alone.

Overdiagnosis in screening mammography in Denmark: population based cohort study.

OBJECTIVE: To use data from two longstanding, population based screening programmes to study overdiagnosis in screening mammography. DESIGN: Population based cohort study. SETTING: Copenhagen municipality (from 1991) and Funen County (from 1993), Denmark. PARTICIPANTS: 57,763 women targeted by organised screening, aged 56-69 when the screening programmes started, and followed up to 2009. MAIN OUTCOME MEASURES: Overdiagnosis of breast cancer in women targeted by screening, assessed by relative risks compared with historical control groups from screening regions, national control groups from non-screening regions, and historical national control groups. RESULTS: In total, 3279 invasive breast carcinomas and ductal carcinomas in situ occurred. The start of screening led to prevalence peaks in breast cancer incidence: relative risk 2.06 (95% confidence interval 1.64 to 2.59) for Copenhagen and 1.84 (1.46 to 2.32) for Funen. During subsequent screening rounds, relative risks were slightly above unity: 1.04 (0.85 to 1.27) for Copenhagen and 1.14 (0.98 to 1.32) for Funen. A compensatory dip was seen after the end of invitation to screening: relative risk 0.80 (0.65 to 0.98) for Copenhagen and 0.67 (0.55 to 0.81) for Funen during the first four years. The relative risk of breast cancer accumulated over the entire follow-up period was 1.06 (0.90 to 1.25) for Copenhagen and 1.01 (0.93 to 1.10) for Funen. Relative risks for participants corrected for selection bias were estimated to be 1.08 for Copenhagen and 1.02 for Funen; for participants followed for at least eight years after the end of screening, they were 1.05 and 1.01. A pooled estimate gave 1.040 (0.99 to 1.09) for all targeted women and 1.023 (0.97 to 1.08) for targeted women followed for at least eight years after the end of screening. CONCLUSIONS: On the basis of combined data from the two screening programmes, this study indicated that overdiagnosis most likely amounted to 2.3% (95% confidence interval -3% to 8%) in targeted women. Among participants, it was most likely 1-5%. At least eight years after the end of screening were needed to compensate for the excess incidence during screening.

Danish Breast Cancer Cooperative Group--DBCG: History, organization, and status of scientific achievements at 30-year anniversary.

DBCG (Danish Breast Cancer Cooperative Group) constitutes a multidisciplinary organization established in 1975 by the Danish Surgical Society. The purpose involves first and foremost a nation-wide standardization of breast cancer treatment based on novel therapeutic principles, collaboration between experts handling diagnostic work-up, surgery, radiotherapy, medical oncology, and basic research, and, further, complete registration of relevant clinical data in a national data base attached to DBCG. Data are processed by the Secretariat personnel composed of statisticians, data managers, and data secretaries making current analyses of outcome results feasible. DBCG is run by the Executive Committee consisting of expert members appointed by their respective society. From 1978 the DBCG project gained widely accession from participating units, and since then nearly all newly diagnosed breast cancer incident cases are reported and registered in the national data base. Today, the data base includes approximately 80 000 incidents of primary breast cancer. Annually, the Secretariat receives roughly 1.5 million parameters to be entered into the data base. Over time DBCG has generated seven treatment programmes including in situ lesions and primary invasive breast cancer. Probands are subdivided into risk groups based on a given risk pattern and allocated to various treatment programmes accordingly. The scientific initiatives are conducted in the form of register- and cohort analysis or randomized trials in national or international protocolized settings. Yearly, about 4 000 new incident cases of primary invasive breast cancer and about 200 in situ lesions enter the national programmes. Further, about 600 women with hereditary disposition of breast cancer are registered and evaluated on a risk scale. The main achievements resulted in a reduction of relative risk of death amounting up to 20% and increased 5-year overall survival ascending from 60% to roughly 80%. This article is partly based on a Danish paper to be published in the Centenary Jubilee book of the Danish Surgical Society, 2008.

Long-term results of breast conserving surgery vs. mastectomy for early stage invasive breast cancer: 20-year follow-up of the Danish randomized DBCG-82TM protocol.

The main objective of the present study aims at comparing the long-term efficacy of breast conserving surgery (BCS) vs. mastectomy (M) based on a randomized design. The Danish Breast Cancer Cooperative Group (DBCG) conducted the trial (DBCG-82TM) from January 1983 to March 1989 recruiting 1154 patients with invasive breast carcinoma. Follow-up time ended 1(st) May 2006 with a median follow-up time of 19.6 years (time span 17.1-23.3 years). Eligibility criteria included a one-sided, unifocal, primary operable breast carcinoma, patient age below 70 years, probability of satisfactory cosmetic outcome with BCS, and no evidence of disseminated disease. The patients accrued were grouped into three subsets: correctly randomized, suspicion of randomization error, and declining randomization. The main analyses focus on the subgroup of 793 correctly randomized patients representing 70% of the complete series. 10-year recurrence free survival (RFS) and 20-year overall survival (OS) based on intent to treat did not reveal significant differences in outcome between breast conserving surgery vs. mastectomy, p=0.95 and p=0.10, respectively. Including the complete series comprising 1133 eligible patients based on treatment in fact given similarly no significant difference between surgical options could be traced in outcome of 10-year RFS and 20-year OS, p=0.94 and p=0.24, respectively. The pattern of recurrences as a first event in breast conservation vs. mastectomy did not differ significantly irrespective of site, p=0.27. Looking into the type of local relapse, viz., new primaries vs. true recurrences, it appeared that new primaries were significantly associated to BCS, while true recurrences dominated among M treated patients (p<0.001). In conclusion, long-term data indicate that BCS in eligible patients proves as effective as mastectomy both regarding local tumour control, RFS and OS. Local failures as a first event consistent with new primaries are strongly associated with BCS, whereas true recurrence predominates after mastectomy.

Characteristics of the Danish families with multiple endocrine neoplasia type 1.

Multiple endocrine neoplasia type 1 (MEN1) is caused by autosomal dominantly inherited mutations in the MEN1 gene. Here, we report 25 MEN1 mutations - of which 12 are novel - found in 36 Danish families with MEN1 or variant MEN1 disease. Furthermore, one FIHP family was found to have an earlier reported mutation. The mutations were predominantly found in exons 9 and 10 encoding the C-terminal part of menin. Seven of the mutations were missense mutations, changing conserved residues. Furthermore screening of 93 out of 153 consecutive patients with primary hyperparathyroidism (pHPT) identified five mutation carriers. Two of these belonged to known MEN1 families, whereas the only MEN1-related disease in the other three was pHPT. Screening of 96 consecutive patients with fore-/midgut endocrine tumours revealed five mutation carries out of 28 patients with sporadic gastrinomas, whereas no mutations were found in 68 patients with other fore-/midgut endocrine tumours. Moreover, screening of 60 consecutive patients with primary prolactinoma did not identify any mutation carriers. Our data indicate that MEN1 mutation screening is efficient in patients with familial MEN1. Screening should also be offered to patients with pHPT or gastrinomas after thorough investigation into the family history. In contrast, sporadic carcinoid tumours or primary prolactinomas are rarely associated with germ-line MEN1 mutations.

A model for determining the effect of mammography service screening.

In an overview, Swedish mammography screening trials demonstrated a 29% reduction in breast cancer mortality in women aged 50-69 and no effect on total mortality. Three Danish regions introduced mammography screening in the 1990s. The authors developed a method to evaluate the effect of mammography service screening on breast cancer mortality and validated it applying it to total mortality, where no effect was expected. Study groups and historical and national control groups were analysed using Poisson regression. Total mortality in the screening regions and periods was close to that expected in the absence of screening. A small (3%) excess risk, also seen in a non-screening area, probably results from regional differences changing over time. The effect of this is inseparable from the screening effect. The design is adequate for analysing the effect of mammography service screening on breast cancer mortality.

Breast cancer mortality in Copenhagen after introduction of mammography screening: cohort study.

OBJECTIVES: To evaluate the effect on breast cancer mortality during the first 10 years of the mammography service screening programme that was introduced in Copenhagen in 1991. DESIGN: Cohort study. SETTING: The mammography service screening programme in Copenhagen, Denmark. PARTICIPANTS: All women ever invited to mammography screening in the first 10 years of the programme. Historical, national, and historical national control groups were used. MAIN OUTCOME MEASURES: The main outcome measure was breast cancer mortality. We compared breast cancer mortality in the study group with rates in the control groups, adjusting for age, time period, and region. RESULTS: Breast cancer mortality in the screening period was reduced by 25% (relative risk 0.75, 95% confidence interval 0.63 to 0.89) compared with what we would expect in the absence of screening. For women actually participating in screening, breast cancer mortality was reduced by 37%. CONCLUSIONS: In the Copenhagen programme, breast cancer mortality was reduced without severe negative side effects for the participants.

Unsuccessful radioiodine treatment of a non-toxic goiter: a case report.

A middle-aged woman with a large right-sided, non-toxic goiter with low iodine uptake was admitted to the Department of Endocrinology with the purpose of volume reduction of the goiter. Thyroid pertechnetate scintigraphy showed homogenous and diffuse uptake in both lobes. Initially thyroxine treatment was given without volume-reducing effect. Radioiodine was administered twice to deliver a total radiation dose of 70 mCi iodine (I)-131. Subsequent pertechnetate scintigraphy showed that the normal-sized, normally functioning left lobe had disappeared after radioiodine, whereas the enlarged right lobe appeared unchanged. During the following years the size of the right lobe increased, and compression symptoms developed. The thyroid gland finally had to be removed by surgery. A large solitary thyroid nodule was removed, but no left lobe was identified. After surgery the patient had no thyroid tissue and had to be substituted by thyroid hormones. Despite good results of iodine treatment of non-toxic goiters, this case describes an unintended outcome leaving a patient without thyroid tissue, and a protracted course could have been avoided if the patient had undergone surgery earlier. However, this reported case should not discredit the use of radioiodine treatment of non-toxic goiters, but focus on patients with a single large solitary adenoma in whom this treatment may be inappropriate.

Effect of breast-conserving therapy versus radical mastectomy on prognosis for young women with breast carcinoma.

BACKGROUND: Among middle-aged and older women with early breast carcinoma, breast-conserving therapy (BCT) has been shown to have an effect on survival that is similar to that of modified radical mastectomy (RM). Nonetheless, it remains to be established whether BCT also is the optimal treatment option for early breast carcinoma in young women, because these women generally have more aggressive disease and a higher frequency of local recurrence compared with older women. METHODS: We investigated a cohort of 9285 premenopausal women with primary breast carcinoma who were age < 50 years at diagnosis. These women were identified from a population-based Danish breast carcinoma database containing detailed information on patient and tumor characteristics, predetermined treatment regimens, and survival. RESULTS: In total, 7165 patients (77.2%) were treated with RM, and 2120 patients (22.8%) were treated with BCT. We calculated the relative risk of death within the first 10 years after diagnosis according to surgical treatment and age, both before and after adjustment for known prognostic factors. No increased risk of death was observed among women who received BCT compared with women who underwent RM, regardless of age at diagnosis (< 35 years, 35-39 years, 40-44 years, or 45-49 years), despite the increased risk of local recurrence among young women. Restricting the analysis to women with small tumors (size < 2 cm) yielded similar results. CONCLUSIONS: Despite having a higher rate of local recurrence, young women with breast carcinoma who receive BCT are similar to young women treated with RM in terms of survival.

[Regional function in thyroid surgery. Assessment of the specialty function and surgical risk factors]. / Landsdelsfunktion i thyroideakirurgi. Evaluering af specialefunktionen og kirurgiske risikofaktorer.

INTRODUCTION: It is recommended that a subset of benign thyroid operations, defined by The Danish National Board as potentially complicated thyroid surgery, is referred to surgical units specialised in thyroid surgery. The aim of the present study was to compare indications for operation and operative complications in patients referred as high risk operations with patients referred from the primary catchment area to a surgical unit specialising in thyroid surgery. MATERIAL AND METHODS: The study includes 570 consecutive operations performed between January 1st 1994 and December 31st 1998. RESULTS: Out of 570 operations, 239 were referred as high risk operations. Complications were significantly more frequent after high risk operations. Delayed wound bleeding requiring reoperation occurred in 3.3 per cent vs. 0.3 per cent of cases (p = 0.01), whereas the risk of unilateral recurrent nerve palsy (1 per cent vs 0.5 per cent, p = 0.3) and permanent hypocalcemia in 1.7 per cent vs. 0 per cent (p = 0.06) was statistically insignificant between the two risk groups. DISCUSSION: The study confirms an elevated risk of complications in the defined high risk group and demonstrates that the referring hospitals comply with the recommendations laid down by the National Board of Health.

Integrating proteomic and functional genomic technologies in discovery-driven translational breast cancer research.

The application of state-of-the-art proteomics and functional genomics technologies to the study of cancer is rapidly shifting toward the analysis of clinically relevant samples derived from patients, as the ultimate aim of translational research is to bring basic discoveries closer to the bedside. Here we describe the essence of a long-term initiative undertaken by The Danish Centre for Translational Breast Cancer Research and currently underway for cancer biomarker discovery using fresh tissue biopsies and bio-fluids. The Centre is a virtual hub that brings together scientists working in various areas of basic cancer research such as cell cycle control, invasion and micro-environmental alterations, apoptosis, cell signaling, and immunology, with clinicians (oncologists, surgeons), pathologists, and epidemiologists, with the aim of understanding the molecular mechanisms underlying breast cancer progression and ultimately of improving patient survival and quality of life. The unifying concept behind our approach is the use of various experimental paradigms for the prospective analysis of clinically relevant samples obtained from the same patient, along with the systematic integration of the biological and clinical data.

Cardiovascular events before and after surgery for primary hyperparathyroidism.

Cardiovascular disease [atherosclerosis and subsequent myocardial infarction (MI)] has been associated with primary hyperparathyroidism. We aimed at studying cardiovascular events before and after surgery and mortality after surgery for primary hyperparathyroidism using a historical follow-up design. A total of 674 patients who underwent surgery at three Danish centers between January 1, 1979 and December 31, 1997 were compared with 2021 age- and gender-matched controls. There was an increased incidence of acute MI up to 10 years prior to surgery [relative risk (RR) 2.5, 95% confidence interval (95% CI) 1.5-4.2] and within the first year following surgery (RR 3.6, 95% CI 1.7-7.6). The risk of MI subsequently declined to a normal level more than 1 year after surgery. Patients with MI prior to diagnosis also had a higher postoperative risk of new infarction than did patients without [odds ratio (OR) 6.0, 95% CI 1.2-30.0]. The risk of hypertension, stroke, congestive heart failure, and diabetes was increased before surgery. More than 1 year after surgery only hypertension and congestive heart failure were more frequent in patients than controls. Preoperative cardiovascular disease was associated with an increased risk of death (RR 1.8, 95% CI 1.1-2.8). Mortality following surgery was higher than in the general population between 1979 and 1990 but not between 1991 and 1997. We concluded that there was an increase in acute MI up to 10 years prior to surgery. The risk of MI decreased to a normal level after surgery, which may be important for preventing cardiovascular disease in patients with primary hyperparathyroidism.

Risk of renal stone events in primary hyperparathyroidism before and after parathyroid surgery: controlled retrospective follow up study.

AIM: To study the risk of renal stone episodes and risk factors for renal stones in primary hyperparathyroidism before and after surgery. DESIGN: Register based, controlled retrospective follow up study. SETTING: Tertiary hospitals in Denmark. PARTICIPANTS: 674 consecutive patients with surgically verified primary hyperparathyroidism. Each patient was compared with three age- and sex-matched controls randomly drawn from the background population. Hospital admissions for renal stone disease were compared between patients and controls. Risk factors for renal stones among patients were assessed. MAIN OUTCOME MEASURES: Number of renal stone episodes; comparison of hospital admissions for renal stones in patients and controls; assessment of risk factors for renal stones. RESULTS: Relative risk of a stone episode was 40 (95% confidence interval 31 to 53) before surgery and 16 (12 to 23) after surgery. Risk was increased 10 years before surgery, and became normal more than 10 years after surgery. Stone-free survival 20 years after surgery was 90.4% in patients and 98.7% in controls (risk difference 8.3%, 4.8% to 11.7%). Patients with preoperative stones had 27 times the risk of postoperative stone incidents than controls. Before surgery, males had more stone episodes than females and younger patients had more stone episodes than older patients. Neither parathyroid pathology, weight of removed tissue, plasma calcium levels, nor skeletal pathology (fractures) influenced the risk of renal stones. After surgery, younger age, preoperative stones and ureteral strictures were significant risk factors for stones. CONCLUSIONS: The risk of renal stones is increased in primary hyperparathyroidism and decreases after surgery. The risk profile is normal 10 years after surgery. Preoperative stone events increase the risk of postoperative stones. Stone formers and non-stone formers had the same risk of skeletal complications.

Cosmetic outcome and breast morbidity in breast-conserving treatment--results from the Danish DBCG-82TM national randomized trial in breast cancer.

A total of 266 recurrence-free breast cancer patients from the randomized DBCG-82TM breast conservation trial were called in for a follow-up investigation to study the impact of surgical and radiation treatment factors on the cosmetic and functional outcome after breast conservation. The patients were interviewed and examined after a median follow-up time of 6.6 years, and 194 of them (73%) regarded the cosmetic result as excellent or good. Morbidity assessments showed that breast fibrosis, skin telangiectasia, and breast retraction were significantly associated with a less satisfactory cosmetic result. On univariate analysis, it was found that treatment with a direct anterior electron field produced more morbidity and inferior cosmetic outcomes compared with tangential photon treatment, while increasing breast size was associated with increased breast retraction and breast fibrosis. Treatment characteristics that emerged as independent prognostic factors of a poor cosmetic outcome on multivariate analysis were the use of a direct anterior electron field (OR = 2.15, CI 1.25-3.70) and adjuvant systemic therapy (OR = 2.13, 1.22-3.71). A significant but relatively low level of concordance was found between the patients' and the clinician's evaluations of cosmetic results but self-assessments of breast morbidity and psychological distress were significantly related to the observed treatment-induced side effects after breast-conserving treatment, indicating that subjective perceptions and observations as reported by the patients are relevant for the identification of treatment factors that impact on normal tissue reactions.

[Mammographic screening in the county of Copenhagen. Clinical consequences of the first three screening rounds]. / Mammografiscreening i Københavns Kommune. Kliniske konsekvenser efter de første tre screeningsrunder.

INTRODUCTION: Service mammography has been offered biennially to women aged 50-69 years in the municipality of Copenhagen since 1991. The results were compared to breast cancer cases before initiation of screening. The comparison concerns prognostic factors and the treatment-related consequences. MATERIAL AND METHODS: Data from the Copenhagen service mammography screening were linked to data from the DBCG database. RESULTS: Before screening, 16% of breast cancer cases had a tumour size of 10 mm or less, this percentage increased to 41 in the screen-detected cases. Sixty per cent of breast cancer cases showed no evidence of metastatic spread to axillary lymph nodes before screening; this percentage increased to 78 per cent in the screen-detected cases. Forty per cent of ductal carcinomas showed a malignancy grade I before screening, compared to 53% in the screen-detected cases. Thirteen per cent were treated with breast conserving therapy before screening, as opposed to 48% in the screen-detected cases. Forty-one per cent needed postoperative adjuvant treatment before screening, compared with 21% in the screen-detected cases. DISCUSSION: A marked improvement was seen in the prognostic and treatment-related characteristics of the screen-detected breast cancer cases, as compared to breast cancer cases from the same area before screening was initiated.

[Mammography screening in the county of Copenhagen. Results of the first three screening rounds]. / Mammografiscreening i Københavns Kommune. Populationsresultater fra de første tre screeningsrunder.

INTRODUCTION: Biennial service mammography screening for breast cancer has been offered to women aged 50-69 years in the municipality of Copenhagen since 1991. We report the results of the first three invitation rounds. MATERIAL AND METHODS: Data were collected from the Copenhagen service mammography screening database and other Danish registers. RESULTS: The average participation rate during the first three invitation rounds was 66%. The breast cancer detection rate was 10/1,000 screened in the first invitation round and 5/1,000 in the consecutive rounds. The probability of a false positive mammography was 6% at the prevalent screen, and this was reduced to 3% at incidence screens. Fifty-two cases of interval cancer were seen after the first invitation round. The expected number was 152, which gives a proportional interval cancer rate of 0.34. The sensitivity was 86% and the specificity 94% after the first round. DISCUSSION: The detection rate of breast cancer was high, especially in the prevalence round. The trend in the incidence of breast cancer at the subsequent rounds was similar to that before screening, which indicates that mammography screening does not lead to any greater over-diagnosis. The rate of false positive mammography was high at the initial screening round, but was acceptable at subsequent rounds, and a false positive mammography does not seem to have affected participation in subsequent rounds. The Copenhagen screening programme conforms to international quality assurance guidelines for process evaluation.