Growth rate of invasive ductal carcinomas from a screened 50-74-year-old population.

Objective As breast cancer growth rate is associated with menopause, most screening programmes target mainly women aged 50-74. We studied the association between age at diagnosis and growth rate in this screening-specific age range. Methods We used data from breast cancer patients diagnosed in the screening programme in Nijmegen, the Netherlands. The data were restricted to the screening rounds when analogue mammography was used in both the screening and clinical setting. Growth rate expressed as tumour volume doubling time was based on increasing tumour size in longitudinal series of mammograms. Estimates were based on (a) tumours showing at least two measurable shadows, (b) tumours showing a shadow at detection only (left censored), and (c) tumours showing no growth (right-censored observation). All 293 tumours were consecutively diagnosed invasive ductal breast cancers in participants of the Nijmegen screening programme in the period 2000-2007. Results Depending on the assumptions made on tumour margins and mammographic density, the relation of volume doubling time with age non-significantly varies from a decrease of 3.3% to an increase of 1.4% for each year increase in age at diagnosis (all P-values ≥ 0.18). Applying left censoring on indistinct tumours, the geometric mean volume doubling time was 191 days (95% confidence interval 158-230). Conclusion We found no significant change in growth rate with age in women diagnosed with invasive ductal breast cancer in the screening age range 50-74. This outcome does not support differential screening intervals by age based solely on breast cancer growth rate for this particular group.

Automated Detection of DCIS in Whole-Slide H&E Stained Breast Histopathology Images.

This paper presents and evaluates a fully automatic method for detection of ductal carcinoma in situ (DCIS) in digitized hematoxylin and eosin (H&E) stained histopathological slides of breast tissue. The proposed method applies multi-scale superpixel classification to detect epithelial regions in whole-slide images (WSIs). Subsequently, spatial clustering is utilized to delineate regions representing meaningful structures within the tissue such as ducts and lobules. A region-based classifier employing a large set of features including statistical and structural texture features and architectural features is then trained to discriminate between DCIS and benign/normal structures. The system is evaluated on two datasets containing a total of 205 WSIs of breast tissue. Evaluation was conducted both on the slide and the lesion level using FROC analysis. The results show that to detect at least one true positive in every DCIS containing slide, the system finds 2.6 false positives per WSI. The results of the per-lesion evaluation show that it is possible to detect 80% and 83% of the DCIS lesions in an abnormal slide, at an average of 2.0 and 3.0 false positives per WSI, respectively. Collectively, the result of the experiments demonstrate the efficacy and accuracy of the proposed method as well as its potential for application in routine pathological diagnostics. To the best of our knowledge, this is the first DCIS detection algorithm working fully automatically on WSIs.

Value of audits in breast cancer screening quality assurance programmes.

OBJECTIVES: Our aim was to retrospectively evaluate the results of all audits performed in the past and to assess their value in the quality assurance of the Dutch breast cancer screening programme. METHODS: The audit team of the Dutch Reference Centre for Screening (LRCB) conducts triennial audits of all 17 reading units. During audits, screening outcomes like recall rates and detection rates are assessed and a radiological review is performed. This study investigates and compares the results of four audit series: 1996-2000, 2001-2005, 2003-2007 and 2010-2013. RESULTS: The analysis shows increased recall rates (from 0.66%, 1.07%, 1.22% to 1.58%), increased detection rates (from 3.3, 4.5, 4.8 to 5.4 per 1000) and increased sensitivity (from 64.5%, 68.7%, 70.5% to 71.6%), over the four audit series. The percentage of 'missed cancers' among interval cancers and advanced screen-detected cancers did not change (p = 0.4). CONCLUSIONS: Our audits not only provide an opportunity for assessing screening outcomes, but also provide moments of self-reflection with peers. For radiologists, an accurate understanding of their performance is essential to identify points of improvement. We therefore recommend a radiological review of screening examinations and immediate feedback as part of an audit. KEY POINTS: • Radiological review and immediate feedback are recommended as part of an audit. • For breast screening radiologists, audits provide moments of self-reflection with peers. • Radiological review of screening examinations provides insights in recall behaviour. • Accurate understanding of radiologists' performance is essential to identify points of improvement.

Breast cancer screening halves the risk of breast cancer death: a case-referent study.

Large-scale epidemiologic studies have consistently demonstrated the effectiveness of mammographic screening programs, however the benefits are still subject to debate. We estimated the effect of the Dutch screening program on breast cancer mortality. In a large multi-region case-referent study, we identified all breast cancer deaths in 2004 and 2005 in women aged 50-75 who had been invited for screening (cases). Cases were individually matched to referents from the population invited to screening. Conditional logistic regression was used to estimate the odds ratio (OR) of breast cancer death according to individual screening history. The OR was adjusted for self-selection bias using regional correction factors for the difference in baseline risk for breast cancer death between screened and unscreened women. A total of 1233 cases and 2090 referents were included in this study. We found a 58% reduction in breast cancer mortality in screened versus unscreened women (adjusted OR = 0.42, 95% CI 0.33-0.53). Screening, i.e. early detection and treatment, has resulted in a substantial reduction in breast cancer mortality, indicating that the Dutch breast cancer screening program is highly effective.

[Effects of the population screening into breast cancer]. / Effecten van het bevolkingsonderzoek naar borstkanker.

Annually, in the Netherlands around 900,000 women between the ages of 50-75 years undergo mammography as part of a population screening into breast cancer. In this way more than 5000 cases of breast cancer are detected (0.6% of women screened); 70% of these malignancies are < stage II, which is prognostically favourable. Due to the early detection and treatment of breast cancer, the breast cancer death risk in those women who participate in the population screening is half that of women who choose not to be screened. The downside of the population screening is that participants are relatively often referred to a hospital for a diagnostic work-up (around 2%), and 70% of them are ultimately found not to have cancer. The positive predictive value of the population screening is 30%. Early discovery also leads to over-diagnosis in patients with breast cancer that without screening would never have manifested itself. Based on computer simulations it has been estimated that in the Netherlands over-diagnosis occurs in 9% of patients in whom breast cancer is detected during a population screening.

Comparison of digital screening mammography and screen-film mammography in the early detection of clinically relevant cancers: a multicenter study.

PURPOSE: To compare screen-film mammography with digital mammography in a breast cancer screening program, with a focus on the clinical relevance of detected cancers. MATERIALS AND METHODS: The study was approved by the regional medical ethics review board. Informed consent was not required. Before the nationwide transition to digital mammography in the Dutch biennial screening program, the performance of digital mammography was studied in three screening regions. For initial screening examinations, mediolateral oblique and craniocaudal views were obtained of each breast. In subsequent examinations, the mediolateral oblique view was standard. A craniocaudal view was added if indicated. Screening outcomes obtained with screen-film mammography and digital mammography, including radiologic and pathologic characteristics, were compared for initial and subsequent examinations. RESULTS: A total of 1,198,493 screening examinations were performed between 2003 and 2007. Recall was indicated in 18 896 cases (screen-film mammography: 2.6% at initial examinations, 1.3% at subsequent examinations; digital mammography: 4.4% at initial examinations, 2.1% at subsequent examinations; P < .001 for both). Breast cancer was diagnosed in 6410 women (detection rate per 1000 women with screen-film mammography: 5.6 at initial examinations, 5.2 at subsequent examinations; detection rate per 1000 women with digital mammography: 6.8 at initial examinations, 6.1 at subsequent examinations; P = .02 and P < .001, respectively). Digital mammography depicted significantly more ductal carcinoma in situ (DCIS) lesions, irrespective of screening round. Invasive carcinoma was detected significantly more often in subsequent examinations, particularly when associated with microcalcifications (P = .047). The distribution of the histopathologic differentiation grades for DCIS and invasive carcinoma were similar with both modalities. However, with digital mammography more high-grade DCIS lesions were detected at subsequent examinations (P = .013). CONCLUSION: In a population-based breast screening program, the performance of digital mammography in the detection of DCIS and invasive carcinoma was substantially better than that of screen-film mammography. There is no sign of an increase in detection of low-grade DCIS lesions-indicative of possible overdiagnosis-with digital breast cancer screening. Rather, digital mammography appears to add to the detection of high-grade DCIS.

Adjuvant therapy in stage I carcinoma of the breast: the influence of multigene analyses and molecular phenotyping.

A consensus conference was held in order to provide guidelines for the use of adjuvant therapy in patients with Stage I carcinoma of the breast, using traditional information, such as tumor size, microscopic character, Nottingham index, patient age and co-morbidities, but also incorporating steroid hormone and Her-2-neu data as well as other immunohistochemical markers. The role of the genetic analysis of breast cancer and proprietary gene prognostic signatures was discussed, along with the molecular profiling of breast cancers into several groups that may predict prognosis. These molecular data are not currently sufficiently mature to make them part of decision making algorithms of recommendations for the treatment of individual patients.

Adjuvant therapy in stage I carcinoma of the breast: the influence of multigene analyses and molecular phenotyping.

BACKGROUND: Breast Health International and the Kimmel Cancer Center of Thomas Jefferson University cosponsored a consensus conference that included an international group of experts. METHODS: Since the adoption of adjuvant chemotherapy for stage I, lymph node-negative breast cancers in 1988, investigators have tried to "fine-tune" the treatment criteria. At this consensus conference, the group debated recommendations for adjuvant hormone and cytotoxic chemotherapy in stage I breast cancers. RESULTS: Discussions during the conference addressed issues of adjuvant therapy for stage I breast cancer and the influence of multigene analyses and molecular phenotyping. The panelists discussed various demographic, morphologic, biologic, and genetic factors expressed by individual tumors and their influence on treatment decisions. CONCLUSIONS: The panel tried to create guidelines for the consideration of adjuvant treatment of these patients, including both hormone and cytotoxic regimens. They also encouraged further research into the molecular analysis of breast cancers and the introduction of clinical trials based on current data, although they concluded that it is too early to add any of those analyses into the decision-making algorithms of recommendations for the treatment of stage I breast cancer.

Breast cancer among women over 75 years: an important public health problem?

Women aged >75 years are not invited for mammographic screening; if diagnosed with breast cancer, due to their anticipated short-life expectancy, they are expected to die of other causes. To describe the breast cancer health problem in women aged >75 years, we estimated breast cancer incidence in this age group and the risk of breast cancer death in patients diagnosed after 75 years of age in Nijmegen, the Netherlands. Our findings demonstrate that in this age group, 3.3% of the women will be diagnosed with breast cancer, and that one in three of these incident cases die of this disease. These patients could have benefited from continued screening.

Effective biennial mammographic screening in women aged 40-49.

BACKGROUND: The United Kingdom is currently moving the age limit for invitation in its national breast screening programme downwards from 50 to 47. In contrast, the US Preventive Services Task Force concluded that, because of borderline statistical significance on effectiveness of mammographic screening, the current evidence is insufficient to advise screening in women aged 40-49. MATERIAL AND METHODS: We designed a case-referent study to investigate the effect of biennial mammographic screening on breast cancer mortality for women in their forties. In Nijmegen, the Netherlands, screening started in 1975. A total of 272 breast cancer deaths were identified, and 1360 referents aged 40-69 were sampled from the population invited for screening. Effectiveness was estimated by calculating the odds ratio (OR) indicating the breast cancer death rate in screened versus unscreened women. RESULTS: In women aged 40-49, the effect of screening was OR = 0.50 (95% confidence interval (CI) = 0.30-0.82). This result is similar to those aged 50-59 (OR = 0.54; 95% CI = 0.35-0.85) and 60-69 (OR = 0.65; 95% CI = 0.38-1.13). CONCLUSION: Our results add convincing evidence about the effectiveness of biennial mammographic screening in women aged 40-49.

Precise correlation between MRI and histopathology - exploring treatment margins for MRI-guided localized breast cancer therapy.

BACKGROUND: Magnetic resonance imaging (MRI) is more often considered to guide, evaluate or select patients for partial breast irradiation (PBI) or minimally invasive therapy. Safe treatment margins around the MRI-visible lesion (MRI-GTV) are needed to account for surrounding subclinical occult disease. PURPOSE: To precisely compare MRI findings with histopathology, and to obtain detailed knowledge about type, rate, quantity and distance of occult disease around the MRI-GTV. METHODS AND MATERIALS: Patients undergoing MRI and breast-conserving therapy were prospectively included. The wide local excision specimens were subjected to detailed microscopic examination. The size of the invasive (index) tumor was compared with the MRI-GTV. The gross tumor volume (GTV) was defined as the pre-treatment visible lesion. Subclinical tumor foci were reconstructed at various distances to the MRI-GTV. RESULTS: Sixty-two patients (64 breasts) were included. The mean size difference between MRI-GTV and the index tumor was 1.3mm. Subclinical disease occurred in 52% and 25% of the specimens at distances ≥10mm and ≥20mm, respectively, from the MRI-GTV. CONCLUSIONS: For MRI-guided minimally invasive therapy, typical treatment margins of 10mm around the MRI-GTV may include occult disease in 52% of patients. When surgery achieves a 10mm tumor-free margin around the MRI-GTV, radiotherapy to the tumor bed may require clinical target volume margins >10mm in up to one-fourth of the patients.

A remarkable reduction of breast cancer deaths in screened versus unscreened women: a case-referent study.

OBJECTIVE: We designed a case-referent study to investigate the effect of mammographic screening at the individual level, looking at the association of breast cancer death with screening history. METHODS: The study population included all women aged 50-75 in the province of Limburg, the Netherlands who had been invited to the screening program from 1989 to 2006. From this population, 118 cases originated who died of breast cancer in 2004 or 2005. The screening history of these cases was collected and compared with a sample of the invited population. The breast cancer death rate in the screened relative to the unscreened women was estimated as the odds ratio (OR). This OR was adjusted for self-selection bias, the difference in baseline risk for breast cancer death between screened and unscreened women. RESULTS: Analysis of the data showed a breast cancer mortality reduction of 70% in the screened versus the unscreened women (OR = 0.30, 95% CI 0.14-0.63). The magnitude of self-selection was estimated specifically for Limburg. After correction for self-selection bias, the effect of screening increased to 76% (OR = 0.24, 95% CI 0.10-0.58). CONCLUSION: Screening resulted in a remarkable reduction in breast cancer mortality. Contrary to findings in other countries, adjustment for self-selection in Limburg had no influence on the impact of screening. Thanks to a well-organized centralized screening program, similar results are expected in other regions of the Netherlands.

Life expectancy of screen-detected invasive breast cancer patients compared with women invited to the Nijmegen screening program.

BACKGROUND: Screening can lead to earlier detection of breast cancer and thus to an improvement in survival. The authors studied the life expectancy of women with screen-detected invasive breast cancer (patients) compared with women invited to the breast cancer screening program in Nijmegen, the Netherlands (comparison group). METHODS: Each patient diagnosed between 1975 and 2006 was randomly age-matched with a woman invited in the same calendar year and free from breast cancer at the time of diagnosis of the patient. Survival analyses were performed to study differences in life expectancy. RESULTS: The life expectancy for 858 patients was 6 years shorter than for the comparison group. However, for 360 patients with small (<15 mm) invasive breast cancer, life expectancy was similar to that of the comparison group. In contrast, for patients detected with larger tumors (> or = 15 mm) the life expectancy was 6 to 12 years shorter, depending on tumor size. Furthermore, life expectancy was modified by screening history. For patients who had a negative screening examination 2 years before the detection of their breast cancer, the difference in life expectancy from the comparison group became smaller for the larger tumor sizes (> or = 15 mm). CONCLUSIONS: In conclusion, about 40% (360 of 858) of all women with invasive screen-detected breast cancer have the same life expectancy as women from the comparison group (reflecting the general population). For women diagnosed with larger tumors at diagnosis, life expectancy diminishes with increasing tumor size and is modified by screening history.

League tables of breast cancer screening units: worst-case and best-case scenario ratings helped in exposing real differences between performance ratings.

OBJECTIVES: Data on the performance of health boards, hospitals and medical specialists, etc., are being collected at various levels in the health-care system and are often presented as league tables. These tables ignore natural variation and/or confounders, and this introduces uncertainty about their interpretation. The purpose of this study was to devise and illustrate a method to expose the real difference between the ratings in league tables. METHODS: Two values per rating were added to the league tables: the best-case scenario and the worst-case scenario. True performance will lie somewhere between these two values. The method is illustrated using data from the Dutch breast cancer screening programme. RESULTS: By focusing on one performance indicator and one confounder, it was possible to show shifts in the rating order of breast cancer screening units and thus expose the uncertainty about the true performance of each screening unit. CONCLUSIONS: The worst-case and best-case scenario ratings demonstrated the uncertainty within the ratings of a league table. League tables should therefore only be used with great caution and after providing the public with sufficient information.

Proceedings of the international consensus conference on breast cancer risk, genetics, & risk management, April, 2007.

A consensus conference including thirty experts was held in April, 2007, to discuss risk factors for breast cancer and their management. Four categories of risk were outlined, from breast cancer "average" through "very high" risk, the latter including individuals with high penetrance BRCA1/2 gene mutations. Guidelines for management of patients in each of these categories were discussed, with the major portion of the conference being devoted to individuals with BRCA1/2 mutations. Prevalence of these mutations in the general populations was estimated to be 1 in 250-500 individuals, with an increased prevalence in Ashkenazic Jews and other founder groups. Risk reduction strategies for these individuals include surveillance, with or without chemoprevention drugs, or surgical procedures to remove the organs at risk, i.e., bilateral mastectomy and/or bilateral salpingo-oophorectomy. These risk reduction strategies were evaluated fully, and recommendations were made for the care of patients in each of the risk categories. These guidelines for patient care were approved by the entire group of experts.

Proceedings of the international consensus conference on breast cancer risk, genetics, & risk management, April, 2007.

A consensus conference including 30 experts was held in April, 2007, to discuss risk factors for breast cancer and their management. Four categories of risk were outlined, from "average" through "very high" risk, the latter including individuals with high penetrance BRCA1/2 gene mutations. Guidelines for management of patients in each of these categories were discussed, with the major portion of the conference devoted to individuals with BRCA1/2 mutations. Prevalence of these mutations in the general population was estimated to be 1 in 250-500 individuals, with an increased prevalence in Ashkenazi Jews and other founder groups. Risk-reduction strategies for these individuals included surveillance, with or without chemoprevention drugs, or surgical procedures to remove the organs at risk, ie, bilateral mastectomy and/or bilateral salpingo-oophorectomy. These risk reduction strategies were evaluated fully, and recommendations were made for the care of patients in each risk category. These guidelines for patient care were approved by the entire group of experts.