EMAS position statement: Individualized breast cancer screening versus population-based mammography screening programmes

IntroductionBreast cancer is the most prevalent cancer in women, with slightly more than ten percent developing the disease in Western countries. Mammography screening is a well established method to detect breast cancer.AimsThe aim of the position statement is to review critically the advantages and shortcomings of population based mammography screening.Materials and methodsLiterature review and consensus of expert opinion.Results and conclusionMammography screening programmes vary worldwide. Thus there are differences in the age at which screening is started and stopped and in the screening interval. Furthermore differences in screening quality (such as equipment, technique, resolution, single or double reading, recall rates) result in a sensitivity varying from 70% to 94% between studies. Reporting results of screening is subject to different types of bias such as overdiagnosis. Thus because of the limitations of population-based mammography screening programmes an algorithm for individualized screening is proposed.     

EMAS position statement: Individualized breast cancer screening versus population-based mammography screening programmes

Introduction

Breast cancer is the most prevalent cancer in women, with slightly more than ten percent developing the disease in Western countries. Mammography screening is a well established method to detect breast cancer.

Aims

The aim of the position statement is to review critically the advantages and shortcomings of population based mammography screening.

Materials and methods

Literature review and consensus of expert opinion.

Results and conclusion

Mammography screening programmes vary worldwide. Thus there are differences in the age at which screening is started and stopped and in the screening interval. Furthermore differences in screening quality (such as equipment, technique, resolution, single or double reading, recall rates) result in a sensitivity varying from 70% to 94% between studies. Reporting results of screening is subject to different types of bias such as overdiagnosis. Thus because of the limitations of population-based mammography screening programmes an algorithm for individualized screening is proposed.     

Screening the high risk patient for gynaecological cancer

It is often difficult to conclude that improvements in survival with time are due to a screening programme alone. Although a reduction in the death rate from a given cancer may reflect the benefits of early detection or improved treatment, the benefits may also result from lead time bias and over-diagnosis, the former resulting in longer survival of screen-identified cancers because the time before the cancer would have been clinically diagnosed is included in calculations. Furthermore, recent reviews on randomised clinical trials of cancer screening have provided strong evidence that misclassifications in causes of death have been a major problem, leading to an over-estimation of the effectiveness (or alternatively an under-estimation of potential harm) of screening.     

Maximising the efficiency of clinical screening programmes: balancing predictive genetic testing with a right not to know

We explored the dilemma between patients'' right not to know their genetic status and the efficient use of health-care resources in the form of clinical cancer screening programmes. Currently, in the Netherlands, 50% risk carriers of heritable cancer syndromes who choose not to know their genetic status have access to the same screening programmes as proven mutation carriers. This implies an inefficient use of health-care resources, because half of this group will not carry the familial mutation. At the moment, only a small number of patients are involved; however, the expanding possibilities for genetic risk profiling means this issue must be addressed because of potentially adverse societal and financial impact. The trade-off between patients'' right not to know their genetic status and efficient use of health-care resources was discussed in six focus groups with health-care professionals and patients from three Dutch university hospitals. Professionals prefer patients to undergo a predictive DNA test as a prerequisite for entering cancer screening programmes. Professionals prioritise treating sick patients or proven mutation carriers over screening untested individuals. Participation in cancer screening programmes without prior DNA testing is, however, supported by most professionals, as testing is usually delayed and relatively few patients are involved at present. Reducing the number of 50% risk carriers undergoing screening is expected to be achieved by: offering more psychosocial support, explaining the iatrogenic risks of cancer screening, increasing out-of-pocket costs, and offering a less stringent screening programme for 50% risk carriers.     

Relation between breast cancer mortality and screening effectiveness: systematic review of the mammography trials

The mammography screening trials have shown varying results. This could be because screening was better in some trials than in others at advancing the time of diagnosis. If so, more cancers would be identified in such trials relative to the control group, and fewer of the cancers would have reached an advanced stage. I performed a systematic review of the mammography screening trials using metaregression. Finding many cancers was not related to the size of the reduction in breast cancer mortality (p = 0.19 after seven and p = 0.73 after 13 years of follow-up). In contrast, finding few cancers in stage II and above predicted a larger reduction in breast cancer mortality (p = 0.04 and p = 0.006). This expected association was also found for node-positive cancers (p = 0.008 and p = 0.04). However, a screening effectiveness of zero (same proportion of node-positive cancers in the screened group as in the control group) predicted a significant 16% reduction in breast cancer mortality after 13 years (95% confidence interval, 9% to 23% reduction). This can only occur if there is bias. Further analyses uncovered bias in both assessment of the cause of death and of the number of cancers in advanced stages. Consequently, the differences in the reported reductions in breast cancer mortality cannot be explained by differences in screening effectiveness. Given that the size of the bias was similar to the estimated screening effect, screening appeared ineffective.     

Krebsfrüherkennung des Zervix- und des Mammakarzinoms

Screening programs for cervical cancer and breast cancer lead to a clear reduction of mortality. Starting in 2018 screening for cervical cancer will be structured as an organized program as already exists for breast cancer. In future screening for cervical cancer will be primarily performed by human papillomavirus (HPV) testing at intervals of 5 years while cytological examination (Pap smear) will also be available as an additional or alternative procedure. For breast cancer screening in Germany an annual clinical examination with palpation and mammography screening at 2?year intervals is provided for women aged between 50 and 69 years. In Germany only approximately 50?% of invited women have used the opportunity to participate in screening in recent years. Weighing the benefits against the harms of cancer screening programs is always important in the process of evaluation of different strategies.     

Measuring informed choice in population-based reproductive genetic screening: a systematic review

Genetic screening and health-care guidelines recommend that programmes should facilitate informed choice. It is therefore important that accurate measures of informed choice are available to evaluate such programmes. This review synthesises and appraises measures used to evaluate informed choice in population-based genetic screening programmes for reproductive risk. Databases were searched for studies offering genetic screening for the purpose of establishing reproductive risk to an adult population sample, in which aspects of informed choice were measured. Studies were included if, at a minimum, measures of uptake of screening and knowledge were used. Searches identified 1462 citations and 76 studies were reviewed in full text; 34 studies met the inclusion criteria. Over 20 different measures of informed choice were used. Many measures lacked adequate validity and reliability data. This systematic review will inform future evaluation of informed choice in population genetic screening programmes.     

Healthcare professionals’ behaviour regarding the implementation of shared decision-making in screening programmes: A systematic review

ObjectiveTo explore the barriers to and facilitators of healthcare professionals’ implementation of SDM regarding screening programmes.MethodA systematic review was conducted in PubMed, Cochrane Library, CINHAL, and PsyscInfo. The barriers and facilitators identified were classified into three factors based on their origin: patients, healthcare system performance, and healthcare professionals themselves.ResultsEight studies were selected: seven related to cancer screening. The most significant facilitators were literacy and interest in active participation, both of which have their origins in patients. The most significant barriers identified for the first time in a systematic review were legal conflict, lack of remuneration and lack of flexibility in clinical guidelines in screening programmes.ConclusionThe results of this study show that there are differences between barriers and facilitators for SDM when it is applied in the context of healthy people who perform preventive activities, particularly screening, in contrast to general medical consultation contexts.Practical implicationsThe authors suggest that to advance in the practice of SDM, we need to develop and disseminate training documents. Further, SDM should be incorporated into clinical guidelines. There should be more studies focusing on healthcare professionals’ behaviour within the context of the uncertainty of screening programmes.     

Model building on the basis of Dutch cervical cancer screening data

A mass screening programme for cervical cancer is in progress in three pilot regions in The Netherlands. All women living in these regions aged 35-53 are invited to undergo screening at three-year intervals. The MISCAN simulation model was developed for the analysis and optimization of screening programmes. In this paper the model-based approach to evaluation is first outlined and then illustrated by analysing data from the first two screening rounds in the pilot regions. This analysis resulted in a rather restricted range of data-compatible assumptions for the mean duration of preclinical disease (14-19 yr) and the frequency of spontaneous regression of preinvasive lesions (45-65%), as well as a rather wide sensitivity range for the Pap smear (50-90%). These preliminary findings are compared with those of a previous MISCAN analysis of cervical cancer screening in British Columbia. On the basis of an assumed 18-yr duration, 50% regression and 70% sensitivity, a number of screening policies relating to the same age ranges but with different intervals are compared. Both the analysis and the policy comparisons are preliminary, but the findings are nevertheless reasonable and consistent with those of previous studies. A more complete MISCAN-based analysis of the Dutch screening programme and subsequent optimization of screening policies will be possible when further results become available and a cost-effectiveness analysis procedure has been incorporated into the MISCAN programme.     

It's "back to school" for genetic screening

Implementation of population genetic screening programmes requires consideration of strategies for reaching the greatest proportion of the target population in order to achieve maximum awareness. This article reviews the current strategy of school-based population genetic screening programmes. The school environment is an ideal setting for offering relevant genetic screening programmes as it provides an opportunity to engage people at a time when they are exposed to a range of educational experiences and are sufficiently mature to be involved in decision-making processes. Such programmes allow all students, not only those studying biology, an opportunity to be educated and experience genetic screening in a supportive environment, ultimately increasing understanding and empowering students. While the major form of genetic screening in schools has been for reproductive health information (eg carrier screening for TaySachs disease and cystic fibrosis), genetic screening in schools for other conditions may be a timely proposition.     

Detection, management, and follow-up of pre-malignant cervical lesions and the role for human papillomavirus

Cervical cytological pathology is common. Prevention of cervical cancer by detecting the disease process at an early and pre-malignant stage is practised globally either through population-based screening programmes (PSP) or through non-organised ones. High-grade cervical intraepithelial neoplasia (CIN) detected by cervical cytological screening is extensively visualised by colposcopy and successively treated by, for instance, large loop electro-surgical excision of the transformation zone. Persistent infections with certain high-risk human papillomavirus (hr-HPV) genotypes play an essential role in cervical cancer carcinogenesis by mechanisms discussed in this review. HPV assessment, either DNA detection or HPV genotyping, could enhance the current cervical cancer screening programmes. Furthermore, primary prevention of cervical cancer through the introduction of HPV vaccines looks promising although the current vaccines merely protect against two hr-HPV genotypes, leaving a niche for at least 11 other hr-HPV's. Cervical screening in the post-vaccination era cannot be abolished but could be altered, as discussed in this review. Algorithms with the primary objective of hr-HPV testing followed by subjective cytology assessment in HPV-positive women could be a solution for both pre- and post-vaccination screening.     

Neoplasms of the central nervous system in Norway. V. Meningioma and cancer of other sites. An analysis of the occurrence of multiple primary neoplasms in meningioma patients in Norway from 1955 through 1986

The association between meningioma and a primary malignant neoplasm at another site was studied. The data from the population-based Norwegian Cancer Registry were analysed according to whether the meningioma occurred before or after the malignant neoplasm. Male patients with meningioma showed a raised risk for developing a subsequent renal cancer. A significant association was found between meningioma and subsequent breast cancer in females 50-64 years old at time of meningioma diagnosis and between breast cancer and subsequent occurrence of meningioma. Breast cancer patients with symptoms of an intracranial neoplasm may therefore have a potentially curable meningioma and female meningioma patients over 50 years should be considered for breast cancer screening programmes.     

Colorectal cancer in HNPCC: cumulative lifetime incidence, survival and tumour distribution. A report of 121 families with proven mutations

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant condition caused by inactivating mutations of DNA mismatch repair (MMR) genes. An accurate estimation of colorectal cancer risk for mutation carriers is essential for counselling and rationalizing screening programmes. Families were referred on the basis of clinical criteria. Tumour immunohistochemistry and microsatellite testing were performed. Appropriate patients underwent sequencing of all relevant exons of the MMR genes. Proven and obligate mutation carriers and first-degree relatives (FDRs) with an HNPCC spectrum cancer were considered mutation carriers, as were a proportion of untested, unaffected FDRs based on the proportion of unaffected relatives testing positive in each age group. The cumulative lifetime risk was calculated by Kaplan–Meier analysis. Three hundred and forty-one colorectal cancers in 839 proven, obligate, or assumed mutation carriers were analysed. The cumulative risk to age 70 years for all mutation carriers combined was 50.4% (95% CI 47.8–52.9). The cumulative risk in males was 54.3% (95% CI 50.7–57.8), which was significantly higher than in females (log rank p = 0.02) who had a risk of 46.3% (95% CI 42.8–49.9). These penetrance estimates from HNPCC families attending high-risk clinics have been corrected for ascertainment bias and are appropriate risks for those referred to a high-risk clinic. Current colonoscopic screening guidelines are appropriate.     

Pre-school development screening in a health centre — the problem of non-attendance

Poor attendance at a health centre pre-school child screening clinic (total default rate 41·2 per cent) raises the question of whether selective screening would be a more realistic alternative to comprehensive screening. Furthermore, an analysis of the outcome of screening over one year has shown a low prevalence of abnormalities and underlines the need to justify such programmes as worthwhile screening tests.

The most efficient method of detecting child-hood abnormalities at an early a stage as possible remains an open question, but with present financial restrictions and staff shortages, whatever programmes are used, rigorous continuing evaluation is essential.

     

Multiplex Polymerase Chain Reaction for the Detection of High-risk-Human Papillomavirus Types in Formalin-fixed Paraffin-embedded Cervical Tissues

Detecting high-risk-human papillomavirus (HPV) types has become an integral part of the cervical cancer screening programmes. This study aimed to develop a multiplex polymerase chain reaction (PCR) for identification of HPV types 16 and 18 along with the beta globin gene in formalin-fixed and paraffin-embedded cervical biopsy specimens. A total of 59 samples from patients with cervical abnormalities were tested. HPV 16 positivity was 50% in cervical cancers and 52.9% in cervical intraepithelial neoplasia. Our multiplex PCR protocol can be used as a simple and cost-effective tool for high-risk-HPV detection in cervical cancer screening programmes.     

Population genetic screening programmes: principles, techniques, practices, and policies

This paper examines the professional and scientific views on the principles, techniques, practices, and policies that impact on the population genetic screening programmes in Europe. This paper focuses on the issues surrounding potential screening programmes, which require further discussion before their introduction. It aims to increase, among the health-care professions and health policy-makers, awareness of the potential screening programmes as an issue of increasing concern to public health. The methods comprised primarily the review of the existing professional guidelines, regulatory frameworks and other documents related to population genetic screening programmes in Europe. Then, the questions that need debate, in regard to different types of genetic screening before and after birth, were examined. Screening for conditions such as cystic fibrosis, Duchenne muscular dystrophy, familial hypercholesterolemia, fragile X syndrome, hemochromatosis, and cancer susceptibility was discussed. Special issues related to genetic screening were also examined, such as informed consent, family aspects, commercialization, the players on the scene and monitoring genetic screening programmes. Afterwards, these questions were debated by 51 experts from 15 European countries during an international workshop organized by the European Society of Human Genetics Public and Professional Policy Committee in Amsterdam, The Netherlands, 19-20, November, 1999. Arguments for and against starting screening programmes have been put forward. It has been questioned whether genetic screening differs from other types of screening and testing in terms of ethical issues. The general impression on the future of genetic screening is that one wants to 'proceed with caution', with more active impetus from the side of patients' organizations and more reluctance from the policy-makers. The latter try to obviate the potential problems about the abortion and eugenics issues that might be perceived as a greater problem than it is in reality. However, it seems important to maintain a balance between a 'professional duty of care' and 'personal autonomy'.     

Sequence interruptions confer differential stability at microsatellite alleles in mismatch repair-deficient cells

Determinants of instability at a given microsatellite repeat merits investigation in view of relevance to understanding evolution of mutations at such sequences in human populations. The microsatellite D2S123 was studied as a paradigm CA repeat marker. Furthermore, this marker is one of a recommended panel used in molecular screening for hereditary non-polyposis colorectal cancer (HNPCC). In this investigation we show that the mutation rate at the D2S123 locus is markedly influenced by intra-allelic sequence variation within the repetitive tract itself. We employed a novel approach to characterize the nature of instability at D2S123, by utilizing cells derived from a non-tumour lineage, which harbour a dominant negative mismatch repair (MMR) mutation and a mutator phenotype. Individual alleles were typed using a semi-quantitative small pool PCR technique and this demonstrated substantial allele-these specific bias in susceptibility to mutation at the D2S123 locus. In support of these in vitro data, bias in allele mutation rate was also observed in tumours from 41 HNPCC patients, which was dependent on constitutional genotype. Sequencing of cell line and patient DNAs revealed that short alleles are significantly more susceptible to mutation due to the presence of uninterrupted CA repeats. Long D2S123 alleles are intrinsically more stable because of a TA interspersion within the repetitive tract. In addition to extending understanding of mutation at CA repeat dinucleotide tracts, these findings have considerable relevance both to screening programmes and to correlation of microsatellite instability (MSI) with colon cancer survival. The manifestation of tumour MSI may be substantially influenced by constitutional genotype.     

Carrier screening for Beta-thalassaemia: a review of international practice

β-thalassaemia is one of the most common single-gene inherited conditions in the world, and thalassaemia carrier screening is the most widely performed genetic screening test, occurring in many different countries. β-thalassaemia carrier screening programmes provide a unique opportunity to compare the delivery of carrier screening programmes carried out in different cultural, religious and social contexts. This review compares the key characteristics of β-thalassaemia carrier screening programmes implemented in countries across the world so that the differences and similarities between the programmes can be assessed. The manner in which thalassaemia carrier screening programmes are structured among different populations varies greatly in several aspects, including whether the programmes are mandatory or voluntary, the education and counselling provided and whether screening is offered pre-pregnancy or antenatally. National and international guidelines make recommendations on the most appropriate ways in which genetic carrier screening programmes should be conducted; however, these recommendations are not followed in many programmes. We discuss the implications for the ethical and acceptable implementation of population carrier screening and identify a paucity of research into the outcomes of thalassaemia screening programmes, despite the fact that thalassaemia screening is so commonly conducted.     

Quality assurance in screening strategies

The pre-requisites for successful screening programmes include understanding and acceptance of the necessity for tests with achieved high coverage of those at risk for the disease, provision of screening tests, provision of facilities for treatment of abnormalities, and acceptance by women of the necessity for further investigation of abnormalities, all requiring attention to quality assurance. Screening programmes for cancer of the cervix have been very effective in many developed countries but in very few developing countries. In general, the failures in developing countries can be directly related to failure to achieve adequate quality in one or other component of a programme. Some of these failures occur at the level of the laboratory, but in several Latin American countries, there are superb laboratories, but overall the programme has failed to achieve the expected impact. In some countries this has led to alternatives to the cytology smear being evaluated, without recognition that it is not the test that has failed, but another essential component of an effective programme. The solution is attention to management and organisation at all levels, with quality assurance at each. This is required at the level of: definition of the target population, identification of the individual women in the target population, recruitment of the at risk woman to screening, administration of the screening test, laboratory examination of the test, communication of results from the laboratory to the woman and her physician, ensuring the woman attends for investigation and management of abnormal screening tests, ensuring adequate therapy of lesions identified by the diagnostic process, ensuring adequate follow-up of treated women, ensuring women with negative screening tests return for re-screening at the appropriate intervals, and monitoring and evaluation of the programme.     

A cross-border comparison of breast and cervical cancer screening uptake

This study investigated differences in uptake of breast and cervical cancer screening relating to socio-economic characteristics in the Republic and Northern Ireland. Multivariate analyses were performed using data from population-based surveys that detail breast and cervical cancer screening participation in the preceding 12 months in the two jurisdictions. Cervical screening rates were significantly higher in Northern Ireland where 536/1764 (30%) eligible women attended screening in comparison to the Republic where only 780/4472 (17%) eligible women attended screening. Differences in participation related to socio-economic group and education were also observed in screening programmes for cervical cancer (Wald: p = 0.000; p = 0.010) and related to education for breast cancer (Wald: p = 0.008) in the Republic of Ireland. Differences in participation across socio-economic groups in respect of breast and cervical cancer screening were not replicated in Northern Ireland. These differences may contribute to inequalities in treatment and outcomes across socio-economic groups in the Republic of Ireland.