PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (1358349)

Clipboard (0)
None

Related Articles

1.  Screening Mammography for Women Aged 40 to 49 Years at Average Risk for Breast Cancer 
Executive Summary
Objective
The aim of this review was to determine the effectiveness of screening mammography in women aged 40 to 49 years at average risk for breast cancer.
Clinical Need
The effectiveness of screening mammography in women aged over 50 years has been established, yet the issue of screening in women aged 40 to 49 years is still unsettled. The Canadian Task Force of Preventive Services, which sets guidelines for screening mammography for all provinces, supports neither the inclusion nor the exclusion of this screening procedure for 40- to 49-year-old women from the periodic health examination. In addition to this, 2 separate reviews, one conducted in Quebec in 2005 and the other in Alberta in 2000, each concluded that there is an absence of convincing evidence on the effectiveness of screening mammography for women in this age group who are at average risk for breast cancer.
In the United States, there is disagreement among organizations on whether population-based mammography should begin at the age of 40 or 50 years. The National Institutes of Health, the American Association for Cancer Research, and the American Academy of Family Physicians recommend against screening women in their 40s, whereas the United States Preventive Services Task Force, the National Cancer Institute, the American Cancer Society, the American College of Radiology, and the American College of Obstetricians and Gynecologists recommend screening mammograms for women aged 40 to 49 years. Furthermore, in comparing screening guidelines between Canada and the United States, it is also important to recognize that “standard care” within a socialized medical system such as Canada’s differs from that of the United States. The National Breast Screening Study (NBSS-1), a randomized screening trial conducted in multiple centres across Canada, has shown there is no benefit in mortality from breast cancer from annual mammograms in women randomized between the ages of 40 and 49, relative to standard care (i.e. physical exam and teaching of breast-self examination on entry to the study, with usual community care thereafter).
At present, organized screening programs in Canada systematically screen women starting at 50 years of age, although with a physician’s referral, a screening mammogram is an insured service in Ontario for women under 50 years of age.
International estimates of the epidemiology of breast cancer show that the incidence of breast cancer is increasing for all ages combined, whereas mortality is decreasing, though at a slower rate. These decreasing mortality rates may be attributed to screening and advances in breast cancer therapy over time. Decreases in mortality attributable to screening may be a result of the earlier detection and treatment of invasive cancers, in addition to the increased detection of ductal carcinoma in situ (DCIS), of which certain subpathologies are less lethal. Evidence from the SEER cancer registry in the United States indicates that the age-adjusted incidence of DCIS has increased almost 10-fold over a 20-year period (from 2.7 to 25 per 100,000).
The incidence of breast cancer is lower in women aged 40 to 49 years than in women aged 50 to 69 years (about 140 per 100,000 versus 500 per 100,000 women, respectively), as is the sensitivity (about 75% versus 85% for women aged under and over 50, respectively) and specificity of mammography (about 80% versus 90% for women aged under and over 50, respectively). The increased density of breast tissue in younger women is mainly responsible for the lower accuracy of this procedure in this age group. In addition, as the proportion of breast cancers that occur before the age of 50 are more likely to be associated with genetic predisposition as compared with those diagnosed in women after the age of 50, mammography may not be an optimal screening method for younger women.
Treatment options vary with the stage of disease (based on tumor size, involvement of surrounding tissue, and number of affected axillary lymph nodes) and its pathology, and may include a combination of surgery, chemotherapy, and/or radiotherapy.
Surgery is the first-line intervention for biopsy confirmed tumours. The subsequent use of radiation, chemotherapy, or hormonal treatments is dependent on the histopathologic characteristics of the tumor and the type of surgery. There is controversy regarding the optimal treatment of DCIS, which is noninvasive.
With such controversy as to the effectiveness of mammography and the potential risk associated with women being overtreated or actual cancers being missed, and the increased risk of breast cancer associated with exposure to annual mammograms over a 10-year period, the Ontario Health Technology Advisory Committee requested this review of screening mammography in women aged 40 to 49 years at average risk for breast cancer. This review is the first of 2 parts and concentrates on the effectiveness of screening mammography (i.e., film mammography, FM) for women at average risk aged 40 to 49 years. The second part will be an evaluation of screening by either magnetic resonance imaging or digital mammography, with the objective of determining the optimal screening modality in these younger women.
Review Strategy
The following questions were asked:
Does screening mammography for women aged 40 to 49 years who are at average risk for breast cancer reduce breast cancer mortality?
What is the sensitivity and specificity of mammography for this age group?
What are the risks associated with annual screening from ages 40 to 49?
What are the risks associated with false positive and false negative mammography results?
What are the economic considerations if evidence for effectiveness is established?
The Medical Advisory Secretariat followed its standard procedures and searched these electronic databases: Ovid MEDLINE, EMBASE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and the International Network of Agencies for Health Technology Assessment.
Keywords used in the search were breast cancer, breast neoplasms, mass screening, and mammography.
In total, the search yielded 6,359 articles specific to breast cancer screening and mammography. This did not include reports on diagnostic mammograms. The search was further restricted to English-language randomized controlled trials (RCTs), systematic reviews, and meta-analyses published between 1995 and 2005. Excluded were case reports, comments, editorials, and letters, which narrowed the results to 516 articles and previous health technology policy assessments.
These were examined against the criteria outlined below. This resulted in the inclusion of 5 health technology assessments, the Canadian Preventive Services Task Force report, the United States Preventive Services Task Force report, 1 Cochrane review, and 8 RCTs.
Inclusion Criteria
English-language articles, and English and French-language health technology policy assessments, conducted by other organizations, from 1995 to 2005
Articles specific to RCTs of screening mammography of women at average risk for breast cancer that included results for women randomized to studies between the ages of 40 and 49 years
Studies in which women were randomized to screening with or without mammography, although women may have had clinical breast examinations and/or may have been conducting breast self-examination.
UK Age Trial results published in December 2006.
Exclusion Criteria
Observational studies, including those nested within RCTs
RCTs that do not include results on women between the ages of 40 and 49 at randomization
Studies in which mammography was compared with other radiologic screening modalities, for example, digital mammography, magnetic resonance imaging or ultrasound.
Studies in which women randomized had a personal history of breast cancer.
Intervention
Film mammography
Comparators
Within RCTs, the comparison group would have been women randomized to not undergo screening mammography, although they may have had clinical breast examinations and/or have been conducting breast self-examination.
Outcomes of Interest
Breast cancer mortality
Summary of Findings
There is Level 1 Canadian evidence that screening women between the ages of 40 and 49 years who are at average risk for breast cancer is not effective, and that the absence of a benefit is sustained over a maximum follow-up period of 16 years.
All remaining studies that reported on women aged under 50 years were based on subset analyses. They provide additional evidence that, when all these RCTs are taken into account, there is no significant reduction in breast cancer mortality associated with screening mammography in women aged 40 to 49 years.
Conclusions
There is Level 1 evidence that screening mammography in women aged 40 to 49 years at average risk for breast cancer is not effective in reducing mortality.
Moreover, risks associated with exposure to mammographic radiation, the increased risk of missed cancers due to lower mammographic sensitivity, and the psychological impact of false positives, are not inconsequential.
The UK Age Trial results published in December 2006 did not change these conclusions.
PMCID: PMC3377515  PMID: 23074501
2.  Cancer Screening with Digital Mammography for Women at Average Risk for Breast Cancer, Magnetic Resonance Imaging (MRI) for Women at High Risk 
Executive Summary
Objective
The purpose of this review is to determine the effectiveness of 2 separate modalities, digital mammography (DM) and magnetic resonance imaging (MRI), relative to film mammography (FM), in the screening of women asymptomatic for breast cancer. A third analysis assesses the effectiveness and safety of the combination of MRI plus mammography (MRI plus FM) in screening of women at high risk. An economic analysis was also conducted.
Research Questions
How does the sensitivity and specificity of DM compare to FM?
How does the sensitivity and specificity of MRI compare to FM?
How do the recall rates compare among these screening modalities, and what effect might this have on radiation exposure? What are the risks associated with radiation exposure?
How does the sensitivity and specificity of the combination of MRI plus FM compare to either MRI or FM alone?
What are the economic considerations?
Clinical Need
The effectiveness of FM with respect to breast cancer mortality in the screening of asymptomatic average- risk women over the age of 50 has been established. However, based on a Medical Advisory Secretariat review completed in March 2006, screening is not recommended for women between the ages of 40 and 49 years. Guidelines published by the Canadian Task Force on Preventive Care recommend mammography screening every 1 to 2 years for women aged 50 years and over, hence, the inclusion of such women in organized breast cancer screening programs. In addition to the uncertainty of the effectiveness of mammography screening from the age of 40 years, there is concern over the risks associated with mammographic screening for the 10 years between the ages of 40 and 49 years.
The lack of effectiveness of mammography screening starting at the age of 40 years (with respect to breast cancer mortality) is based on the assumption that the ability to detect cancer decreases with increased breast tissue density. As breast density is highest in the premenopausal years (approximately 23% of postmenopausal and 53% of premenopausal women having at least 50% of the breast occupied by high density), mammography screening is not promoted in Canada nor in many other countries for women under the age of 50 at average risk for breast cancer. It is important to note, however, that screening of premenopausal women (i.e., younger than 50 years of age) at high risk for breast cancer by virtue of a family history of cancer or a known genetic predisposition (e.g., having tested positive for the breast cancer genes BRCA1 and/or BRCA2) is appropriate. Thus, this review will assess the effectiveness of breast cancer screening with modalities other than film mammography, specifically DM and MRI, for both pre/perimenopausal and postmenopausal age groups.
International estimates of the epidemiology of breast cancer show that the incidence of breast cancer is increasing for all ages combined whereas mortality is decreasing, though at a slower rate. The observed decreases in mortality rates may be attributable to screening, in addition to advances in breast cancer therapy over time. Decreases in mortality attributable to screening may be a result of the earlier detection and treatment of invasive cancers, in addition to the increased detection of ductal carcinoma in situ (DCIS), of which certain subpathologies are less lethal. Evidence from the Surveillance, Epidemiology and End Results (better known as SEER) cancer registry in the United States, indicates that the age-adjusted incidence of DCIS has increased almost 10-fold over a 20 year period, from 2.7 to 25 per 100,000.
There is a 4-fold lower incidence of breast cancer in the 40 to 49 year age group than in the 50 to 69 year age group (approximately 140 per 100,000 versus 500 per 100,000 women, respectively). The sensitivity of FM is also lower among younger women (approximately 75%) than for women aged over 50 years (approximately 85%). Specificity is approximately 80% for younger women versus 90% for women over 50 years. The increased density of breast tissue in younger women is likely responsible for the decreased accuracy of FM.
Treatment options for breast cancer vary with the stage of disease (based on tumor size, involvement of surrounding tissue, and number of affected axillary lymph nodes) and its pathology, and may include a combination of surgery, chemotherapy and/or radiotherapy. Surgery is the first-line intervention for biopsy-confirmed tumors. The subsequent use of radiation, chemotherapy or hormonal treatments is dependent on the histopathologic characteristics of the tumor and the type of surgery. There is controversy regarding the optimal treatment of DCIS, which is considered a noninvasive tumour.
Women at high risk for breast cancer are defined as genetic carriers of the more commonly known breast cancer genes (BRCA1, BRCA2 TP53), first degree relatives of carriers, women with varying degrees of high risk family histories, and/or women with greater than 20% lifetime risk for breast cancer based on existing risk models. Genetic carriers for this disease, primarily women with BRCA1 or BRCA2 mutations, have a lifetime probability of approximately 85% of developing breast cancer. Preventive options for these women include surgical interventions such as prophylactic mastectomy and/or oophorectomy, i.e., removal of the breasts and/or ovaries. Therefore, it is important to evaluate the benefits and risks of different screening modalities, to identify additional options for these women.
This Medical Advisory Secretariat review is the second of 2 parts on breast cancer screening, and concentrates on the evaluation of both DM and MRI relative to FM, the standard of care. Part I of this review (March 2006) addressed the effectiveness of screening mammography in 40 to 49 year old average-risk women. The overall objective of the present review is to determine the optimal screening modality based on the evidence.
Evidence Review Strategy
The Medical Advisory Secretariat followed its standard procedures and searched the following electronic databases: Ovid MEDLINE, EMBASE, Ovid MEDLINE In-Process & Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and The International Network of Agencies for Health Technology Assessment database. The subject headings and keywords searched included breast cancer, breast neoplasms, mass screening, digital mammography, magnetic resonance imaging. The detailed search strategies can be viewed in Appendix 1.
Included in this review are articles specific to screening and do not include evidence on diagnostic mammography. The search was further restricted to English-language articles published between January 1996 and April 2006. Excluded were case reports, comments, editorials, nonsystematic reviews, and letters.
Digital Mammography: In total, 224 articles specific to DM screening were identified. These were examined against the inclusion/exclusion criteria described below, resulting in the selection and review of 5 health technology assessments (HTAs) (plus 1 update) and 4 articles specific to screening with DM.
Magnetic Resonance Imaging: In total, 193 articles specific to MRI were identified. These were examined against the inclusion/exclusion criteria described below, resulting in the selection and review of 2 HTAs and 7 articles specific to screening with MRI.
The evaluation of the addition of FM to MRI in the screening of women at high risk for breast cancer was also conducted within the context of standard search procedures of the Medical Advisory Secretariat. as outlined above. The subject headings and keywords searched included the concepts of breast cancer, magnetic resonance imaging, mass screening, and high risk/predisposition to breast cancer. The search was further restricted to English-language articles published between September 2007 and January 15, 2010. Case reports, comments, editorials, nonsystematic reviews, and letters were not excluded.
MRI plus mammography: In total, 243 articles specific to MRI plus FM screening were identified. These were examined against the inclusion/exclusion criteria described below, resulting in the selection and review of 2 previous HTAs, and 1 systematic review of 11 paired design studies.
Inclusion Criteria
English-language articles, and English or French-language HTAs published from January 1996 to April 2006, inclusive.
Articles specific to screening of women with no personal history of breast cancer.
Studies in which DM or MRI were compared with FM, and where the specific outcomes of interest were reported.
Randomized controlled trials (RCTs) or paired studies only for assessment of DM.
Prospective, paired studies only for assessment of MRI.
Exclusion Criteria
Studies in which outcomes were not specific to those of interest in this report.
Studies in which women had been previously diagnosed with breast cancer.
Studies in which the intervention (DM or MRI) was not compared with FM.
Studies assessing DM with a sample size of less than 500.
Intervention
Digital mammography.
Magnetic resonance imaging.
Comparator
Screening with film mammography.
Outcomes of Interest
Breast cancer mortality (although no studies were found with such long follow-up).
Sensitivity.
Specificity.
Recall rates.
Summary of Findings
Digital Mammography
There is moderate quality evidence that DM is significantly more sensitive than FM in the screening of asymptomatic women aged less than 50 years, those who are premenopausal or perimenopausal, and those with heterogeneously or extremely dense breast tissue (regardless of age).
It is not known what effect these differences in sensitivity will have on the more important effectiveness outcome measure of breast cancer mortality, as there was no evidence of such an assessment.
Other factors have been set out to promote DM, for example, issues of recall rates and reading and examination times. Our analysis did not show that recall rates were necessarily improved in DM, though examination times were lower than for FM. Other factors including storage and retrieval of screens were not the subject of this analysis.
Magnetic Resonance Imaging
There is moderate quality evidence that the sensitivity of MRI is significantly higher than that of FM in the screening of women at high risk for breast cancer based on genetic or familial factors, regardless of age.
Radiation Risk Review
Cancer Care Ontario conducted a review of the evidence on radiation risk in screening with mammography women at high risk for breast cancer. From this review of recent literature and risk assessment that considered the potential impact of screening mammography in cohorts of women who start screening at an earlier age or who are at increased risk of developing breast cancer due to genetic susceptibility, the following conclusions can be drawn:
For women over 50 years of age, the benefits of mammography greatly outweigh the risk of radiation-induced breast cancer irrespective of the level of a woman’s inherent breast cancer risk.
Annual mammography for women aged 30 – 39 years who carry a breast cancer susceptibility gene or who have a strong family breast cancer history (defined as a first degree relative diagnosed in their thirties) has a favourable benefit:risk ratio. Mammography is estimated to detect 16 to 18 breast cancer cases for every one induced by radiation (Table 1). Initiation of screening at age 35 for this same group would increase the benefit:risk ratio to an even more favourable level of 34-50 cases detected for each one potentially induced.
Mammography for women under 30 years of age has an unfavourable benefit:risk ratio due to the challenges of detecting cancer in younger breasts, the aggressiveness of cancers at this age, the potential for radiation susceptibility at younger ages and a greater cumulative radiation exposure.
Mammography when used in combination with MRI for women who carry a strong breast cancer susceptibility (e.g., BRCA1/2 carriers), which if begun at age 35 and continued for 35 years, may confer greatly improved benefit:risk ratios which were estimated to be about 220 to one.
While there is considerable uncertainty in the risk of radiation-induced breast cancer, the risk expressed in published studies is almost certainly conservative as the radiation dose absorbed by women receiving mammography recently has been substantially reduced by newer technology.
A CCO update of the mammography radiation risk literature for 2008 and 2009 gave rise to one article by Barrington de Gonzales et al. published in 2009 (Barrington de Gonzales et al., 2009, JNCI, vol. 101: 205-209). This article focuses on estimating the risk of radiation-induced breast cancer for mammographic screening of young women at high risk for breast cancer (with BRCA gene mutations). Based on an assumption of a 15% to 25% or less reduction in mortality from mammography in these high risk women, the authors conclude that such a reduction is not substantially greater than the risk of radiation-induced breast cancer mortality when screening before the age of 34 years. That is, there would be no net benefit from annual mammographic screening of BRCA mutation carriers at ages 25-29 years; the net benefit would be zero or small if screening occurs in 30-34 year olds, and there would be some net benefit at age 35 years or older.
The Addition of Mammography to Magnetic Resonance Imaging
The effects of the addition of FM to MRI screening of high risk women was also assessed, with inclusion and exclusion criteria as follows:
Inclusion Criteria
English-language articles and English or French-language HTAs published from September 2007 to January 15, 2010.
Articles specific to screening of women at high risk for breast cancer, regardless of the definition of high risk.
Studies in which accuracy data for the combination of MRI plus FM are available to be compared to that of MRI and FM alone.
RCTs or prospective, paired studies only.
Studies in which women were previously diagnosed with breast cancer were also included.
Exclusion Criteria
Studies in which outcomes were not specific to those of interest in this report.
Studies in which there was insufficient data on the accuracy of MRI plus FM.
Intervention
Both MRI and FM.
Comparators
Screening with MRI alone and FM alone.
Outcomes of Interest
Sensitivity.
Specificity.
Summary of Findings
Magnetic Resonance Imaging Plus Mammography
Moderate GRADE Level Evidence that the sensitivity of MRI plus mammography is significantly higher than that of MRI or FM alone, although the specificity remains either unchanged or decreases in the screening of women at high risk for breast cancer based on genetic/familial factors, regardless of age.
These studies include women at high risk defined as BRCA1/2 or TP53 carriers, first degree relatives of carriers, women with varying degrees of high risk family histories, and/or >20% lifetime risk based on existing risk models. This definition of high risk accounts for approximately 2% of the female adult population in Ontario.
PMCID: PMC3377503  PMID: 23074406
3.  Immediate and delayed effects of mammographic screening on breast cancer mortality and incidence in birth cohorts 
British Journal of Cancer  2013;109(9):2467-2471.
Background:
Trend studies investigating the impact of mammographic screening usually display age-specific mortality and incidence rates over time, resulting in an underestimate of the benefit of screening, that is, mortality reduction, and an overestimate of its major harmful effect, that is, overdiagnosis. This study proposes a more appropriate way of analysing trends.
Methods:
Breast cancer mortality (1950–2009) and incidence data (1975–2009) were obtained from Statistics Netherlands, ‘Stg. Medische registratie' and the National Cancer Registry in the Netherlands for women aged 25–85 years. Data were visualised in age–birth cohort and age–period figures.
Results:
Birth cohorts invited to participate in the mammographic screening programme showed a deflection in the breast cancer mortality rates within the first 5 years after invitation. Thereafter, the mortality rate increased, although less rapidly than in uninvited birth cohorts. Furthermore, invited birth cohorts showed a sharp increase in invasive breast cancer incidence rate during the first 5 years of invitation, followed by a moderate increase during the following screening years and a decline after passing the upper age limit.
Conclusion:
When applying a trend study to estimate the impact of mammographic screening, we recommend using a birth cohort approach.
doi:10.1038/bjc.2013.627
PMCID: PMC3817344  PMID: 24113141
mammographic screening; mortality; incidence; birth cohort; The Netherlands
4.  Breast cancer screening: evidence of benefit depends on the method used 
BMC Medicine  2012;10:163.
In this article, we discuss the most common epidemiological methods used for evaluating the ability of mammography screening to decrease the risk of breast cancer death in general populations (effectiveness). Case-control studies usually find substantial effectiveness. However when breast cancer mortality decreases for reasons unrelated to screening, the case-control design may attribute to screening mortality reductions due to other causes. Studies based on incidence-based mortality have obtained contrasted results compatible with modest to considerable effectiveness, probably because of differences in study design and statistical analysis. In areas where screening has been widespread for a long time, the incidence of advanced breast cancer should be decreasing, which in turn would translate into reduced mortality. However, no or modest declines in the incidence of advanced breast cancer has been observed in these areas. Breast cancer mortality should decrease more rapidly in areas with early introduction of screening than in areas with late introduction of screening. Nonetheless, no difference in breast mortality trends has been observed between areas with early or late screening start. When effectiveness is assessed using incidence-based mortality studies, or the monitoring of advanced cancer incidence, or trends in mortality, the ecological bias is an inherent limitation that is not easy to control. Minimization of this bias requires data over long periods of time, careful selection of populations being compared and availability of data on major confounding factors. If case-control studies seem apparently more adequate for evaluating screening effectiveness, this design has its own limitations and results must be viewed with caution.
See related Opinion article: http://www.biomedcentral.com/1741-7015/10/106 and Commentary http://www.biomedcentral.com/1741-7015/10/164
doi:10.1186/1741-7015-10-163
PMCID: PMC3554519  PMID: 23234249
breast cancer; case-control; effectiveness; epidemiology; incidence; mortality; screening
5.  A Simulation Model Investigating the Impact of Tumor Volume Doubling Time and Mammographic Tumor Detectability on Screening Outcomes in Women Aged 40–49 Years 
Background
Compared with women aged 50–69 years, the lower sensitivity of mammographic screening in women aged 40–49 years is largely attributed to the lower mammographic tumor detectability and faster tumor growth in the younger women.
Methods
We used a Monte Carlo simulation model of breast cancer screening by age to estimate the median tumor size detectable on a mammogram and the mean tumor volume doubling time. The estimates were calculated by calibrating the predicted breast cancer incidence rates to the actual rates from the Surveillance, Epidemiology, and End Results (SEER) database and the predicted distributions of screen-detected tumor sizes to the actual distributions obtained from the Breast Cancer Surveillance Consortium (BCSC). The calibrated parameters were used to estimate the relative impact of lower mammographic tumor detectability vs faster tumor volume doubling time on the poorer screening outcomes in younger women compared with older women. Mammography screening outcomes included sensitivity, mean tumor size at detection, lifetime gained, and breast cancer mortality. In addition, the relationship between screening sensitivity and breast cancer mortality was investigated as a function of tumor volume doubling time, mammographic tumor detectability, and screening interval.
Results
Lowered mammographic tumor detectability accounted for 79% and faster tumor volume doubling time accounted for 21% of the poorer sensitivity of mammography screening in younger women compared with older women. The relative contributions were similar when the impact of screening was evaluated in terms of mean tumor size at detection, lifetime gained, and breast cancer mortality. Screening sensitivity and breast cancer mortality reduction attributable to screening were almost linearly related when comparing annual or biennial screening with no screening. However, when comparing annual with biennial screening, the greatest reduction in breast cancer mortality attributable to screening did not correspond to the greatest gain in screening sensitivity and was more strongly affected by the mammographic tumor detectability than tumor volume doubling time.
Conclusion
The age-specific differences in mammographic tumor detection contribute more than age-specific differences in tumor growth rates to the lowered performance of mammography screening in younger women.
doi:10.1093/jnci/djq271
PMCID: PMC2923220  PMID: 20664027
6.  Association between Melanocytic Nevi and Risk of Breast Diseases: The French E3N Prospective Cohort 
PLoS Medicine  2014;11(6):e1001660.
Using data from the French E3N prospective cohort, Marina Kvaskoff and colleagues examine the association between number of cutaneous nevi and the risk for breast cancer.
Please see later in the article for the Editors' Summary
Background
While melanocytic nevi have been associated with genetic factors and childhood sun exposure, several observations also suggest a potential hormonal influence on nevi. To test the hypothesis that nevi are associated with breast tumor risk, we explored the relationships between number of nevi and benign and malignant breast disease risk.
Methods and Findings
We prospectively analyzed data from E3N, a cohort of French women aged 40–65 y at inclusion in 1990. Number of nevi was collected at inclusion. Hazard ratios (HRs) for breast cancer and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models. Associations of number of nevi with personal history of benign breast disease (BBD) and family history of breast cancer were estimated using logistic regression. Over the period 15 June 1990–15 June 2008, 5,956 incident breast cancer cases (including 5,245 invasive tumors) were ascertained among 89,902 women. In models adjusted for age, education, and known breast cancer risk factors, women with “very many” nevi had a significantly higher breast cancer risk (HR = 1.13, 95% CI = 1.01–1.27 versus “none”; ptrend = 0.04), although significance was lost after adjustment for personal history of BBD or family history of breast cancer. The 10-y absolute risk of invasive breast cancer increased from 3,749 per 100,000 women without nevi to 4,124 (95% CI = 3,674–4,649) per 100,000 women with “very many” nevi. The association was restricted to premenopausal women (HR = 1.40, ptrend = 0.01), even after full adjustment (HR = 1.34, ptrend = 0.03; phomogeneity = 0.04), but did not differ according to breast cancer type or hormone receptor status. In addition, we observed significantly positive dose–response relationships between number of nevi and history of biopsy-confirmed BBD (n = 5,169; ptrend<0.0001) and family history of breast cancer in first-degree relatives (n = 7,472; ptrend = 0.0003). The main limitations of our study include self-report of number of nevi using a qualitative scale, and self-reported history of biopsied BBD.
Conclusions
Our findings suggest associations between number of nevi and the risk of premenopausal breast cancer, BBD, and family history of breast cancer. More research is warranted to elucidate these relationships and to understand their underlying mechanisms.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In 2012, nearly 1.7 million women worldwide discovered they had breast cancer, and about half a million women died from the disease. Breast cancer begins when cells in the breast acquire genetic changes that allow them to divide uncontrollably and to move around the body (metastasize). Uncontrolled cell division leads to the formation of a lump that can be detected by mammography (a breast X-ray) or by manual breast examination. Breast cancer is treated by surgical removal of the lump, or, if the cancer has started to spread, by removal of the whole breast (mastectomy). Surgery is usually followed by radiotherapy or chemotherapy to kill any remaining cancer cells. Because the female sex hormones estrogen and progesterone stimulate the growth of some tumors, drugs that block hormone receptors are also used to treat receptor-positive breast cancer. Nowadays, the prognosis (outlook) for women with breast cancer is good, and in developed countries, nearly 90% of affected women are still alive five years after diagnosis.
Why Was This Study Done?
Several hormone-related factors affect a woman's chances of developing breast cancer. For example, women who have no children or who have them late in life have a higher breast cancer risk than women who have several children when they are young because pregnancy alters sex hormone levels. Interestingly, the development of moles (nevi)—dark skin blemishes that are risk factors for the development of melanoma, a type of skin cancer—may also be affected by estrogen and progesterone. Thus, the number of nevi might be a marker of blood hormone levels and might predict breast cancer risk. In this prospective cohort study, the researchers test this hypothesis by investigating the association between how many moles a woman has and her breast cancer risk. A prospective cohort study enrolls a group (cohort) of people, determines their baseline characteristics, and follows them over time to see which characteristics are associated with the development of specific diseases.
What Did the Researchers Do and Find?
In 1990, the E3N prospective cohort study enrolled nearly 100,000 French women (mainly school teachers) aged 40–65 years to investigate cancer risk factors. The women completed a baseline questionnaire about their lifestyle and medical history, and regular follow-up questionnaires that asked about cancer occurrence. In the initial questionnaire, the women indicated whether they had no, a few, many, or very many moles. Between 1990 and 2008, nearly 6,000 women in the cohort developed breast cancer. Using statistical methods to calculate hazard ratios (an “HR” compares how often a particular event happens in two groups with different characteristics; an HR greater than one indicates that a specific characteristic is associated with an increased risk of the event), the researchers report that women with “very many” nevi had a significantly higher breast cancer risk (a higher risk that was unlikely to have occurred by chance) than women with no nevi. Specifically, the age-adjusted HR for breast cancer among women with “very many” nevi compared to women with no nevi was 1.17. After adjustment for a personal history of benign (noncancerous) breast disease and a family history of breast cancer (two established risk factors for breast cancer), the association between nevi and breast cancer risk among the whole cohort became nonsignificant. Notably, however, the association among only premenopausal women remained significant after full adjustment (HR = 1.34), which corresponded to an increase in ten-year absolute risk of invasive breast cancer from 2,515 per 100,000 women with no nevi to 3,370 per 100,000 women with “very many” nevi.
What Do These Findings Mean?
These findings suggest that among premenopausal women there is a modest association between nevi number and breast cancer risk. This noncausal relationship may indicate that nevi and breast diseases are affected in similar ways by hormones or share common genetic factors, but the accuracy of these findings may be limited by aspects of the study design. For example, self-report of nevi numbers using a qualitative scale may have introduced some inaccuracies into the estimates of the association between nevi number and breast cancer risk. Most importantly, these findings are insufficient to support the use of nevi counts in breast cancer screening or diagnosis. Rather, together with the findings reported by Zhang et al. in an independent PLOS Medicine Research Article, they suggest that further studies into the biological mechanisms underlying the relationship between nevi and breast cancer and the association itself should be undertaken.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001660.
This study is further discussed in a PLOS Medicine Perspective by Fuhrman and Cardenas
An independent PLOS Medicine Research Article by Zhang et al. also investigates the relationship between nevi number and breast cancer risk
The US National Cancer Institute provides comprehensive information about cancer (in English and Spanish), including detailed information for patients and professionals about breast cancer; it also has a fact sheet on moles
Cancer Research UK, a not-for profit organization, provides information about cancer, including detailed information on breast cancer
The UK National Health Service Choices website has information and personal stories about breast cancer; the not-for profit organization Healthtalkonline also provides personal stories about dealing with breast cancer
More information about the E3N prospective cohort study is available; detailed information is available in French
doi:10.1371/journal.pmed.1001660
PMCID: PMC4051602  PMID: 24915306
7.  Further evidence of benefits of a (non-randomised) breast cancer screening programme: the DOM project. 
STUDY OBJECTIVE--The aim was to demonstrate the benefits of breast cancer screening on mortality. DESIGN--The study was an evaluation of a breast cancer screening programme by means of different approaches: (1) a case-control study, breast cancer deaths being the cases; (2) comparing the numbers of breast cancer deaths in screened and unscreened women; (3) comparing breast cancer mortality before and after start of the programme; (4) comparing breast cancer mortality in different large cities; (5) comparing screening activity with mortality reduction. SETTING--The setting was a breast cancer screening programme in the city of Utrecht, the DOM project, for women aged 50-64 years old at intake, birth cohort 1911-1925. The programme started in 1974, and there were five screening rounds up to 1984. Participation rate in the first round was 72% (14,697 women). MAIN RESULTS--(1) Screening was protective against dying from breast cancer, odds ratio 0.52, with a stronger effect in older women and no evidence of confounding; (2) risk ratio of dying from breast cancer for women in the response group was the same as the odds ratio, 0.52; (3) breast cancer death rate after the start of the project was nearly 20% lower than before the project started; after correcting for women who could not have benefited from screening the reduction was 33%; (4) a rise in breast cancer mortality in birth cohort 1911-1925 seen in other large cities without a screening programme due to aging of the cohort was not seen in the city of Utrecht; (5) mortality reduction followed the screening activity with a time lag of approximately 5 years. CONCLUSIONS--Early diagnosis of breast cancer by mammography reduces breast cancer mortality in women 50-64 years old at intake; different approaches to the evaluation of the project give different estimates of the screening effect, making clear that the effect depends on the intensity of the programme.
PMCID: PMC1059605  PMID: 1431712
8.  Subtyping of Breast Cancer by Immunohistochemistry to Investigate a Relationship between Subtype and Short and Long Term Survival: A Collaborative Analysis of Data for 10,159 Cases from 12 Studies 
PLoS Medicine  2010;7(5):e1000279.
Paul Pharoah and colleagues evaluate the prognostic significance of immunohistochemical subtype classification in more than 10,000 breast cancer cases with early disease, and examine the influence of a patient's survival time on the prediction of future survival.
Background
Immunohistochemical markers are often used to classify breast cancer into subtypes that are biologically distinct and behave differently. The aim of this study was to estimate mortality for patients with the major subtypes of breast cancer as classified using five immunohistochemical markers, to investigate patterns of mortality over time, and to test for heterogeneity by subtype.
Methods and Findings
We pooled data from more than 10,000 cases of invasive breast cancer from 12 studies that had collected information on hormone receptor status, human epidermal growth factor receptor-2 (HER2) status, and at least one basal marker (cytokeratin [CK]5/6 or epidermal growth factor receptor [EGFR]) together with survival time data. Tumours were classified as luminal and nonluminal tumours according to hormone receptor expression. These two groups were further subdivided according to expression of HER2, and finally, the luminal and nonluminal HER2-negative tumours were categorised according to expression of basal markers. Changes in mortality rates over time differed by subtype. In women with luminal HER2-negative subtypes, mortality rates were constant over time, whereas mortality rates associated with the luminal HER2-positive and nonluminal subtypes tended to peak within 5 y of diagnosis and then decline over time. In the first 5 y after diagnosis the nonluminal tumours were associated with a poorer prognosis, but over longer follow-up times the prognosis was poorer in the luminal subtypes, with the worst prognosis at 15 y being in the luminal HER2-positive tumours. Basal marker expression distinguished the HER2-negative luminal and nonluminal tumours into different subtypes. These patterns were independent of any systemic adjuvant therapy.
Conclusions
The six subtypes of breast cancer defined by expression of five markers show distinct behaviours with important differences in short term and long term prognosis. Application of these markers in the clinical setting could have the potential to improve the targeting of adjuvant chemotherapy to those most likely to benefit. The different patterns of mortality over time also suggest important biological differences between the subtypes that may result in differences in response to specific therapies, and that stratification of breast cancers by clinically relevant subtypes in clinical trials is urgently required.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Each year, more than one million women discover they have breast cancer. Breast cancer begins when cells in the breast's milk-producing glands or in the tubes (ducts) that take milk to the nipples acquire genetic changes that allow them to divide uncontrollably and to move around the body (metastasize). The uncontrolled cell division leads to the formation of a lump that can be detected by mammography (a breast X-ray) or by manual breast examination. Breast cancer is treated by surgical removal of the lump or, if the cancer has started to spread, by removal of the whole breast (mastectomy). Surgery is usually followed by radiotherapy or chemotherapy. These “adjuvant” therapies are designed to kill any remaining cancer cells but can make women very ill. Generally speaking, the outlook (prognosis) for women with breast cancer is good. In the United States, for example, nearly 90% of affected women are still alive five years after their diagnosis.
Why Was This Study Done?
Because there are several types of cells in the milk ducts and glands, there are several subtypes of breast cancer. Luminal tumors, for example, begin in the cells that line the ducts and glands and usually grow slowly; basal-type tumors arise in deeper layers of the ducts and glands and tend to grow quickly. Clinicians need to distinguish between different breast cancer subtypes so that they can give women a realistic prognosis and can give adjuvant treatments to those women who are most likely to benefit. One way to distinguish between different subtypes is to stain breast cancer samples using antibodies (immune system proteins) that recognize particular proteins (antigens). This “immunohistochemical” approach can identify several breast cancer subtypes but its prognostic value and the best way to classify breast tumors remains unclear. In this study, the researchers investigate the survival over time of women with six major subtypes of breast cancer classified using five immunohistochemical markers: the estrogen receptor and the progesterone receptor (two hormone receptors expressed by luminal cells), the human epidermal growth factors receptor-2 (HER2, a protein marker used to select specific adjuvant therapies), and CK5/6 and EGFR (proteins expressed by basal cells).
What Did the Researchers Do and Find?
The researchers pooled data on survival time and on the expression of the five immunohistochemical markers from more than 10,000 cases of breast cancer from 12 studies. They then divided the tumors into six subtypes on the basis of their marker expression: luminal (hormone receptor-positive), HER2-positive tumors; luminal, HER2-negative, basal marker-positive tumors; luminal, HER2-negative, basal marker-negative tumors; nonluminal (hormone receptor-negative), HER2-positive tumors; nonluminal, HER2-negative, basal marker-positive tumors; and nonluminal, HER2-negative, basal marker-negative tumors. In the first five years after diagnosis, women with nonluminal tumor subtypes had the worst prognosis but at 15 years after diagnosis, women with luminal HER2-positive tumors had the worst prognosis. Furthermore, death rates (the percentage of affected women dying each year) differed by subtype over time. Thus, women with the two luminal HER2-negative subtypes were as likely to die soon after diagnosis as at later times whereas the death rates associated with nonluminal subtypes peaked within five years of diagnosis and then declined.
What Do These Findings Mean?
These and other findings indicate that the six subtypes of breast cancer defined by the expression of five immunohistochemical markers have distinct biological characteristics that are associated with important differences in short-term and long-term outcomes. Because different laboratories measured the immunohistochemical markers using different methods, it is possible that some of the tumors included in this study were misclassified. However, the finding of clear differences in the behavior of the immunochemically classified subtypes suggests that the use of the five markers for tumor classification might be robust enough for routine clinical practice. The application of these markers in the clinical setting, suggest the researchers, could improve the targeting of adjuvant therapies to those women most likely to benefit. Furthermore, note the researchers, these findings strongly suggest that subtype-specific responses should be evaluated in future clinical trials of treatments for breast cancer.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000279.
This study is further discussed in a PLoS Medicine Perspective by Stefan Ambs
The US National Cancer Institute provides detailed information for patients and health professionals on all aspects of breast cancer (in English and Spanish)
The American Cancer Society has a detailed guide to breast cancer, which includes information on the immunochemical classification of breast cancer subtypes
The UK charities MacMillan Cancer Support and Cancer Research UK also provide detailed information about breast cancer
The MedlinePlus Encyclopedia provides information for patients about breast cancer; Medline Plus provides links to many other breast cancer resources (in English and Spanish)
doi:10.1371/journal.pmed.1000279
PMCID: PMC2876119  PMID: 20520800
9.  Breast cancer incidence and mortality in Tyrol/Austria after fifteen years of opportunistic mammography screening 
BMC Public Health  2010;10:86.
Background
The aim of this study was to analyse breast cancer incidence and mortality in Tyrol from 1970 to 2006, namely after performing more than a decade of opportunistic mammography screening and just before piloting an organised screening programme. Our investigation was conducted on a population level.
Methods
To study time trends in breast cancer incidence and mortality, we applied the age-period-cohort model by Poisson regression to the official mortality data covering more than three decades from 1970 to 2006 and to the incidence data ranging from 1988 to 2006. In addition, for incidence data we analysed data on breast cancer staging and compared these with EU guidelines.
Results
For the analysis of time trend in breast cancer mortality in age groups 40-79, an age-period-cohort model fits well and shows for years 2002-2006 a statistically significant reduction of 26% (95% CI 13%-36%) in breast cancer mortality as compared to 1992-1996.
We see only slight non-significant increases in breast cancer incidence. For the past five years, incidence data show a 10% proportion of in situ cases, and of 50% for cases in stages II+.
Conclusions
The opportunistic breast cancer screening programme in Tyrol has only in part exploited the mortality reduction known for organised screening programmes. There seems to be potential for further improvement, and we recommend that an organised screening programme and a detailed screening database be introduced to collect all information needed to analyse the quality indicators suggested by the EU guidelines.
doi:10.1186/1471-2458-10-86
PMCID: PMC2843664  PMID: 20170536
10.  Breast cancer mortality in organised mammography screening in Denmark: comparative study 
Objective To determine whether the previously observed 25% reduction in breast cancer mortality in Copenhagen following the introduction of mammography screening was indeed due to screening, by using an additional screening region and five years additional follow-up.
Design We used Poisson regression analyses adjusted for changes in age distribution to compare the annual percentage change in breast cancer mortality in areas where screening was used with the change in areas where it was not used during 10 years before screening was introduced and for 10 years after screening was in practice (starting five years after introduction of screening).
Setting Copenhagen, where mammography screening started in 1991, and Funen county, where screening was introduced in 1993. The rest of Denmark (about 80% of the population) served as an unscreened control group.
Participants All Danish women recorded in the Cause of Death Register and Statistics Denmark for 1971-2006.
Main outcome measure Annual percentage change in breast cancer mortality in regions offering mammography screening and those not offering screening.
Results In women who could benefit from screening (ages 55-74 years), we found a mortality decline of 1% per year in the screening areas (relative risk (RR) 0.99, 95% confidence interval (CI) 0.96 to 1.01) during the 10 year period when screening could have had an effect (1997-2006). In women of the same age in the non-screening areas, there was a decline of 2% in mortality per year (RR 0.98, 95% CI 0.97 to 0.99) in the same 10 year period. In women who were too young to benefit from screening (ages 35-55 years), breast cancer mortality during 1997-2006 declined 5% per year (RR 0.95, CI 0.92 to 0.98) in the screened areas and 6% per year (RR 0.94, CI 0.92 to 0.95) in the non-screened areas. For the older age groups (75-84 years), there was little change in breast cancer mortality over time in both screened and non-screened areas. Trends were less clear during the 10 year period before screening was introduced, with a possible increase in mortality in women aged less than 75 years in the non-screened regions.
Conclusions We were unable to find an effect of the Danish screening programme on breast cancer mortality. The reductions in breast cancer mortality we observed in screening regions were similar or less than those in non-screened areas and in age groups too young to benefit from screening, and are more likely explained by changes in risk factors and improved treatment than by screening mammography.
doi:10.1136/bmj.c1241
PMCID: PMC2844939  PMID: 20332505
11.  Modern mammography screening and breast cancer mortality: population study 
Objective To evaluate the effectiveness of contemporary mammography screening using individual information about screening history and breast cancer mortality from public screening programmes.
Design Prospective cohort study of Norwegian women who were followed between 1986 and 2009. Within that period (1995-2005), a national mammography screening programme was gradually implemented, with biennial invitations sent to women aged 50-69 years.
Participants All Norwegian women aged 50-79 between 1986 and 2009.
Main outcome measures Multiple Poisson regression analysis was used to estimate breast cancer mortality rate ratios comparing women who were invited to screening (intention to screen) with women who were not invited, with a clear distinction between cases of breast cancer diagnosed before (without potential for screening effect) and after (with potential for screening effect) the first invitation for screening. We took competing causes of death into account by censoring women from further follow-up who died from other causes. Based on the observed mortality reduction combined with the all cause and breast cancer specific mortality in Norway in 2009, we used the CISNET (Cancer Intervention and Surveillance Modeling Network) Stanford simulation model to estimate how many women would need to be invited to biennial mammography screening in the age group 50-69 years to prevent one breast cancer death during their lifetime.
Results During 15 193 034 person years of observation (1986-2009), deaths from breast cancer occurred in 1175 women with a diagnosis after being invited to screening and 8996 women who had not been invited before diagnosis. After adjustment for age, birth cohort, county of residence, and national trends in deaths from breast cancer, the mortality rate ratio associated with being invited to mammography screening was 0.72 (95% confidence interval 0.64 to 0.79). To prevent one death from breast cancer, 368 (95% confidence interval 266 to 508) women would need to be invited to screening.
Conclusion Invitation to modern mammography screening may reduce deaths from breast cancer by about 28%.
doi:10.1136/bmj.g3701
PMCID: PMC4061379  PMID: 24951459
12.  History of medical screening: from concepts to action 
Postgraduate Medical Journal  2004;80(946):463-469.
The objective of medical screening is to identify disease in its preclinical, and therefore hopefully still curable, phase. This may have been an old quest in medicine but it became historically possible when at least four conditions were met: the availability of simple, valid and acceptable forms of tests, the discovery of effective treatments, the establishment of a theory of screening, and the wide access to health care. Five selected examples that illustrate the history of medical screening are reviewed: screening for psychiatric disorders in the United States army as it is one of the oldest screening programmes; screening for syphilis as it used one of the earliest screening tests; screening for diabetes as one of the first modern forms of mass screening; screening for cervical cancer using the Pap test as one of the greatest successes of screening; and screening for breast cancer by mammography as this offers a good opportunity to discuss the development of modern evaluation of screening programmes. The evaluation of the impact of screening on human health slowly progressed, from obvious changes in the vital statistics such as the decline in incidence of syphilis, to less obvious changes such as the decline in mortality of cancer of the uterus, to finally more subtle changes, such as the impact of mammographic screening on breast cancer mortality. Methods of evaluation had therefore to adapt, evolving from simple surveys to case-control studies and randomised trials. The history of screening is short, but very rich and mostly still to be written.
doi:10.1136/pgmj.2003.018226
PMCID: PMC1743082  PMID: 15299156
13.  A case–control study of the impact of the East Anglian breast screening programme on breast cancer mortality 
British Journal of Cancer  2007;98(1):206-209.
Although breast cancer screening has been shown to work in randomised trials, there is a need to evaluate service screening programmes to ensure that they are delivering the benefit indicated by the trials. We carried out a case–control study to investigate the effect of mammography service screening, in the NHS breast screening programme, on breast cancer mortality in the East Anglian region of the UK. Cases were deaths from breast cancer in women diagnosed between the ages of 50 and 70 years, following the instigation of the East Anglia Breast Screening Programme in 1989. The controls were women (two per case) who had not died of breast cancer, from the same area, matched by date of birth to the cases. Each control was known to be alive at the time of death of her matched case. All women were known to the breast screening programme and were invited, at least once, to be screened. There were 284 cases and 568 controls. The odds ratio (OR) for risk of death from breast cancer in women who attended at least one routine screen compared to those who did not attend was 0.35 (CI: 0.24, 0.50). Adjusting for self-selection bias gave an estimate of the breast cancer mortality reduction associated with invitation to screening of 35% (OR=0.65, 95% CI: 0.48, 0.88). The effect of actually being screened was a 48% breast cancer mortality reduction (OR=0.52, 95% CI: 0.32, 0.84). The results suggest that the National Breast Screening Programme in East Anglia is achieving a reduction in breast cancer deaths, which is at least consistent with the results from the randomised controlled trials of mammographic screening.
doi:10.1038/sj.bjc.6604123
PMCID: PMC2359716  PMID: 18059396
breast cancer mortality; screening; case–control
14.  Effect of Flexible Sigmoidoscopy-Based Screening on Incidence and Mortality of Colorectal Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials 
PLoS Medicine  2012;9(12):e1001352.
A systematic review and meta-analysis of randomized trials conducted by B. Joseph Elmunzer and colleagues reports that that flexible sigmoidoscopy-based screening reduces the incidence of colorectal cancer in average-risk patients, as compared to usual care or no screening.
Background
Randomized controlled trials (RCTs) have yielded varying estimates of the benefit of flexible sigmoidoscopy (FS) screening for colorectal cancer (CRC). Our objective was to more precisely estimate the effect of FS-based screening on the incidence and mortality of CRC by performing a meta-analysis of published RCTs.
Methods and Findings
Medline and Embase databases were searched for eligible articles published between 1966 and 28 May 2012. After screening 3,319 citations and 29 potentially relevant articles, two reviewers identified five RCTs evaluating the effect of FS screening on the incidence and mortality of CRC. The reviewers independently extracted relevant data; discrepancies were resolved by consensus. The quality of included studies was assessed using criteria set out by the Evidence-Based Gastroenterology Steering Group. Random effects meta-analysis was performed.
The five RCTs meeting eligibility criteria were determined to be of high methodologic quality and enrolled 416,159 total subjects. Four European studies compared FS to no screening and one study from the United States compared FS to usual care. By intention to treat analysis, FS-based screening was associated with an 18% relative risk reduction in the incidence of CRC (0.82, 95% CI 0.73–0.91, p<0.001, number needed to screen [NNS] to prevent one case of CRC = 361), a 33% reduction in the incidence of left-sided CRC (RR 0.67, 95% CI 0.59–0.76, p<0.001, NNS = 332), and a 28% reduction in the mortality of CRC (relative risk [RR] 0.72, 95% CI 0.65–0.80, p<0.001, NNS = 850). The efficacy estimate, the amount of benefit for those who actually adhered to the recommended treatment, suggested that FS screening reduced CRC incidence by 32% (p<0.001), and CRC-related mortality by 50% (p<0.001).
Limitations of this meta-analysis include heterogeneity in the design of the included trials, absence of studies from Africa, Asia, or South America, and lack of studies comparing FS with colonoscopy or stool-based testing.
Conclusions
This meta-analysis of randomized controlled trials demonstrates that FS-based screening significantly reduces the incidence and mortality of colorectal cancer in average-risk patients.
Please see later in the article for the Editors' Summary
Editor's Summary
Background
Colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States. Regular CRC screening has been shown to reduce the risk of dying from CRC by 16%, and CRC screening can identify early stage cancers in otherwise healthy people, which allows for early treatment and management of the disease. Screening for colorectal cancer is frequently performed using a flexible sigmoidoscopy (FS), which is a thin, flexible tube with a tiny camera and light on the end, allowing a doctor to look at the inside wall of the bowel and remove any small growths or polyps. Although screening may detect early cancers, the life-saving and health benefits of screening are uncertain because the polyp may not necessarily progress. This could lead to anxiety and unnecessary interventions and treatments amongst those screened. Randomized controlled trials (RCTs) are needed to determine all of the risks involved in cancer screenings, however the guidelines that recommend FS-based screening do not rely upon RCT data. Recently, the results of four large-scale RCTs evaluating FS screening for CRC have been published. The conflicting results with respect to the incidence and mortality of CRC in these studies have called into question the effectiveness of endoscopic screening.
Why Was This Study Done?
The results of RCTs measuring the risks and outcomes of CRC screening have shown varying estimates of the benefits of using FS screening. If better estimates of the risks and benefits of FS screening are developed, then the current CRC screening guidelines may be updated to reflect this new information. In this study, the authors show the results of a meta-analysis of published RCTs, which more precisely estimates the effects of FS-based screening on the incidence and mortality of colorectal cancer.
What Did the Researchers Do and Find?
The researchers used the Medline and Embase databases to find relevant studies from 1966 to May 28, 2012. After screening 3,319 citations and 29 potentially relevant articles, five RCTs of high methodologic quality and 416,159 total subjects evaluating the effect of FS screening on the incidence and mortality of CRC were identified. The data were extracted and random effects meta-analysis was performed. The meta-analysis revealed that FS-based screening was associated with an 18% relative risk reduction in the incidence of CRC (0.82, 95% CI 0.73–0.91, p<0.001, number needed to screen (NNS) to prevent one case of CRC = 361), a 33% reduction in the incidence of left-sided CRC (RR 0.67, 95% CI 0.59–0.76, p<0.001, NNS = 332), and a 28% reduction in the mortality of CRC (RR 0.72, 95% CI 0.65–0.80, p<0.001, NNS = 850). The amount of benefit for those who adhered to the recommended treatment suggested that FS screening reduced CRC incidence by 32% (p<0.001), and CRC-related mortality by 50% (p<0.001).
What Do These Findings Mean?
This meta-analysis of RCTs evaluating the effect of FS on CRC incidence and mortality demonstrates that a FS-based strategy for screening is very effective in reducing the incidence and mortality of CRC in patients. The current recommendations for endoscopic screening are based on observational studies, which may not accurately reflect the effect of FS-based screening on the incidence and mortality of CRC. Here, the authors performed a systematic review and meta-analysis of five recent RCTs to better estimate the true effect of FS-based screening on the incidence and mortality of CRC. Thus, the results of this meta-analysis may affect health policy, and directly impact patients and clinicians.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001352.
Cancer research UK provides comprehensive information about screening for colorectal cancers as does the UK National Screening Committee
PubMed Health has general information about colon cancer
The National Cancer Institute also has comprehensive resources on colorectal cancer and treatment
The Mayo Clinic provides an overview of all aspects of colon cancer
doi:10.1371/journal.pmed.1001352
PMCID: PMC3514315  PMID: 23226108
15.  Understanding recent trends in incidence of invasive breast cancer in Norway: age-period-cohort analysis based on registry data on mammography screening and hormone treatment use 
Objective To quantify the separate contributions of menopausal hormone treatment and mammography screening activities on trends in incidence of invasive breast cancer between 1987 and 2008.
Design Population study using aggregated data analysed by an extended age-period-cohort model.
Setting Norway.
Population Norwegian women aged 30-90 between 1987 and 2008, including 50 102 newly diagnosed cases of invasive breast cancer.
Main outcomes measures Attributable proportions of mammography screening and hormone treatment to recent incidence of invasive breast cancer, and the remaining variation in incidence after adjustment for mammography screening and hormone treatment.
Results The incidence of invasive breast cancer in Norway increased steadily until 2002, levelled off, and then declined from 2006. All non-linear changes in incidence were explained by use of hormone treatment and mammography screening activities, with about similar contributions of each factor. In 2002, when the incidence among women aged 50-69 was highest, an estimated 23% of the cases in that age group could be attributed to mammography screening and 27% to use of hormone treatment.
Conclusions Changes in incidence trends of invasive breast cancer since the early 1990s may be fully attributed to mammography screening and hormone treatment, with about similar contributions of each factor.
doi:10.1136/bmj.e299
PMCID: PMC3268754  PMID: 22290099
16.  Receptor-Defined Subtypes of Breast Cancer in Indigenous Populations in Africa: A Systematic Review and Meta-Analysis 
PLoS Medicine  2014;11(9):e1001720.
In a systematic review and meta-analysis, Isabel dos Santos Silva and colleagues estimate the prevalence of receptor-defined subtypes of breast cancer in North Africa and sub-Saharan Africa.
Please see later in the article for the Editors' Summary
Background
Breast cancer is the most common female cancer in Africa. Receptor-defined subtypes are a major determinant of treatment options and disease outcomes but there is considerable uncertainty regarding the frequency of poor prognosis estrogen receptor (ER) negative subtypes in Africa. We systematically reviewed publications reporting on the frequency of breast cancer receptor-defined subtypes in indigenous populations in Africa.
Methods and Findings
Medline, Embase, and Global Health were searched for studies published between 1st January 1980 and 15th April 2014. Reported proportions of ER positive (ER+), progesterone receptor positive (PR+), and human epidermal growth factor receptor-2 positive (HER2+) disease were extracted and 95% CI calculated. Random effects meta-analyses were used to pool estimates. Fifty-four studies from North Africa (n = 12,284 women with breast cancer) and 26 from sub-Saharan Africa (n = 4,737) were eligible. There was marked between-study heterogeneity in the ER+ estimates in both regions (I2>90%), with the majority reporting proportions between 0.40 and 0.80 in North Africa and between 0.20 and 0.70 in sub-Saharan Africa. Similarly, large between-study heterogeneity was observed for PR+ and HER2+ estimates (I2>80%, in all instances). Meta-regression analyses showed that the proportion of ER+ disease was 10% (4%–17%) lower for studies based on archived tumor blocks rather than prospectively collected specimens, and 9% (2%–17%) lower for those with ≥40% versus those with <40% grade 3 tumors. For prospectively collected samples, the pooled proportions for ER+ and triple negative tumors were 0.59 (0.56–0.62) and 0.21 (0.17–0.25), respectively, regardless of region. Limitations of the study include the lack of standardized procedures across the various studies; the low methodological quality of many studies in terms of the representativeness of their case series and the quality of the procedures for collection, fixation, and receptor testing; and the possibility that women with breast cancer may have contributed to more than one study.
Conclusions
The published data from the more appropriate prospectively measured specimens are consistent with the majority of breast cancers in Africa being ER+. As no single subtype dominates in the continent availability of receptor testing should be a priority, especially for young women with early stage disease where appropriate receptor-specific treatment modalities offer the greatest potential for reducing years of life lost.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Breast cancer is the commonest female tumor in Africa and death rates from the disease in some African countries are among the highest in the world. Breast cancer begins when cells in the breast acquire genetic changes that allow them to grow uncontrollably and to move around the body. When a breast lump is found (by mammography or manual examination), a few cells are collected from the lump (a biopsy) to look for abnormal cells and to test for the presence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) on the cells. The hormones estrogen and progesterone promote the growth of normal breast cells and of ER+ and PR+ breast cancer cells. HER2 also controls the growth of breast cells. The receptor status of breast cancer is a major determinant of treatment options and prognosis (likely outcome). ER+ tumors, for example, are more receptive to hormonal therapy and have a better prognosis than ER− tumors, whereas HER2+ tumors, which make large amounts of HER2, are more aggressive than HER2− tumors. Breast cancer is treated by surgically removing the lump or the whole breast (mastectomy) if the tumor has already spread, before killing any remaining cancer cells with chemotherapy or radiotherapy. In addition, ER+, PR+, and HER2+ tumors are treated with drugs that block these receptors (including tamoxifen and trastuzumab), thereby slowing breast cancer growth.
Why Was This Study Done?
ER+ tumors predominate in white women but the proportion of ER+ tumors among US-born black women is slightly lower. The frequency of different receptor-defined subtypes of breast cancer in indigenous populations in Africa is currently unclear but policy makers need this information to help them decide whether routine receptor status testing should be introduced across Africa. Because receptor status is a major determination of treatment options and outcomes, it would be more important to introduce receptor testing if all subtypes are present in breast cancers in indigenous African women and if no one subtype dominates than if most breast cancers in these women are ER+. In this systematic review (a study that uses pre-defined criteria to identify all the research on a given topic) and meta-analysis (a statistical approach that combines the results of several studies), the researchers examine the distribution of receptor-defined breast cancer subtypes in indigenous populations in Africa.
What Did the Researchers Do and Find?
The researchers identified 54 relevant studies from North Africa involving 12,284 women with breast cancer (mainly living in Egypt or Tunisia) and 26 studies from sub-Saharan Africa involving 4,737 women with breast cancer (mainly living in Nigeria or South Africa) and used the data from these studies to calculate the proportions of ER+, PR+, and HER2+ tumors (the number of receptor-positive tumors divided by the number of tumors with known receptor status) across Africa. The proportion of ER+ tumors varied markedly between studies, ranging between 0.40 and 0.80 in North Africa and between 0.20 and 0.70 in sub-Saharan Africa. Among prospectively collected samples (samples collected specifically for receptor-status testing; studies that determined the receptor status of breast cancers using stored samples reported a lower proportion of ER+ disease than studies that used prospectively collected samples), the overall pooled proportions of ER+ and triple negative tumors were 0.59 and 0.21, respectively.
What Do These Findings Mean?
Although these findings highlight the scarcity of data on hormone receptor and HER2 status in breast cancers in indigenous African populations, they provide new information about the distribution of breast cancer subtypes in Africa. Specifically, these findings suggest that although slightly more than half of breast cancers in Africa are ER+, no single subtype dominates. They also suggest that the distribution of receptor-defined breast cancer subtypes in Africa is similar to that found in Western populations. The accuracy of these findings is likely to be affected by the low methodological quality of many of the studies and the lack of standardized procedures. Thus, large well-designed studies are still needed to accurately quantify the distribution of various breast cancer subtypes across Africa. In the meantime, the current findings support the introduction of routine receptor testing across Africa, especially for young women with early stage breast cancer in whom the potential to improve survival and reduce the years of life lost by knowing the receptor status of an individual's tumor is greatest.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001720.
This study is further discussed in a PLOS Medicine Perspective by Sulma i Mohammed
The US National Cancer Institute (NCI) provides comprehensive information about cancer (in English and Spanish), including detailed information for patients and professionals about breast cancer including an online booklet for patients
Cancer Research UK, a not-for profit organization, provides information about cancer; its detailed information about breast cancer includes sections on tests for hormone receptors and HER2 and on treatments that target hormone receptors and treatments that target HER2
Breastcancer.org is a not-for-profit organization that provides up-to-date information about breast cancer (in English and Spanish), including information on hormone receptor status and HER2 status
The UK National Health Service Choices website has information and personal stories about breast cancer; the not-for profit organization Healthtalkonline also provides personal stories about dealing with breast cancer
doi:10.1371/journal.pmed.1001720
PMCID: PMC4159229  PMID: 25202974
17.  A case-control evaluation of the effect of breast cancer screening in the United Kingdom trial of early detection of breast cancer. 
OBJECTIVE--The aim was to assess the extent to which selection bias affects a case-control study of breast cancer screening in which attenders and non-attenders for screening are compared. DESIGN--There were two retrospective case-control studies, one estimating the risk of death from breast cancer in women in the screening district relative to those in the comparison district (study A), the second estimating the relative risk for women who had ever been screened compared with women who had never been screened in the screening district alone (study B). For cases and controls in study B, the women's screening history was summarised for the time period from date of entry to diagnosis of the case, or the equivalent time from date of entry for the matched controls. For cases detected by screening, the screen at which cancer was detected was included in the screening history. SUBJECTS--Cases were deaths from breast cancer in women with disease diagnosed after entry to the trial, up to 31 December 1986 or a maximum of seven years from date of entry, in one of the screening districts (Guildford) and one of the comparison districts (Stoke) participating in the UK Trial of Early Detection of Breast Cancer: study A: 198 deaths in Guildford and Stoke; study B: 51 deaths in Guildford only. There were five age matched controls for each case, with length of follow up at least as great as the time from entry to death of the case. MAIN RESULTS--The estimate of the risk of death from breast cancer in the screening district relative to the comparison district from study A was 0.76, thus implying a reduction of 24% in the screening district, similar to that obtained from a cohort analysis of data from the two districts. In contrast, the relative risk in study B for ever v never screened women was 0.51, which, taking the 72% compliance into account, would result in a relative risk of 0.65 for the screening district if there were no selection bias. The risk of breast cancer mortality in the never screened relative to the comparison district was 1.13, despite the fact that incidence rates in the two populations were similar. This suggested that cancers in the never screened group had a particularly poor prognosis, contributing to selection bias. CONCLUSIONS--The possible existence of selection bias should lead to caution in interpretation of the results of case-control studies of the effect of breast cancer screening on mortality.
PMCID: PMC1059600  PMID: 1431707
18.  Risk Prediction for Breast, Endometrial, and Ovarian Cancer in White Women Aged 50 y or Older: Derivation and Validation from Population-Based Cohort Studies 
PLoS Medicine  2013;10(7):e1001492.
Ruth Pfeiffer and colleagues describe models to calculate absolute risks for breast, endometrial, and ovarian cancers for white, non-Hispanic women over 50 years old using easily obtainable risk factors.
Please see later in the article for the Editors' Summary
Background
Breast, endometrial, and ovarian cancers share some hormonal and epidemiologic risk factors. While several models predict absolute risk of breast cancer, there are few models for ovarian cancer in the general population, and none for endometrial cancer.
Methods and Findings
Using data on white, non-Hispanic women aged 50+ y from two large population-based cohorts (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial [PLCO] and the National Institutes of Health–AARP Diet and Health Study [NIH-AARP]), we estimated relative and attributable risks and combined them with age-specific US-population incidence and competing mortality rates. All models included parity. The breast cancer model additionally included estrogen and progestin menopausal hormone therapy (MHT) use, other MHT use, age at first live birth, menopausal status, age at menopause, family history of breast or ovarian cancer, benign breast disease/biopsies, alcohol consumption, and body mass index (BMI); the endometrial model included menopausal status, age at menopause, BMI, smoking, oral contraceptive use, MHT use, and an interaction term between BMI and MHT use; the ovarian model included oral contraceptive use, MHT use, and family history or breast or ovarian cancer. In independent validation data (Nurses' Health Study cohort) the breast and ovarian cancer models were well calibrated; expected to observed cancer ratios were 1.00 (95% confidence interval [CI]: 0.96–1.04) for breast cancer and 1.08 (95% CI: 0.97–1.19) for ovarian cancer. The number of endometrial cancers was significantly overestimated, expected/observed = 1.20 (95% CI: 1.11–1.29). The areas under the receiver operating characteristic curves (AUCs; discriminatory power) were 0.58 (95% CI: 0.57–0.59), 0.59 (95% CI: 0.56–0.63), and 0.68 (95% CI: 0.66–0.70) for the breast, ovarian, and endometrial models, respectively.
Conclusions
These models predict absolute risks for breast, endometrial, and ovarian cancers from easily obtainable risk factors and may assist in clinical decision-making. Limitations are the modest discriminatory ability of the breast and ovarian models and that these models may not generalize to women of other races.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In 2008, just three types of cancer accounted for 10% of global cancer-related deaths. That year, about 460,000 women died from breast cancer (the most frequently diagnosed cancer among women and the fifth most common cause of cancer-related death). Another 140,000 women died from ovarian cancer, and 74,000 died from endometrial (womb) cancer (the 14th and 20th most common causes of cancer-related death, respectively). Although these three cancers originate in different tissues, they nevertheless share many risk factors. For example, current age, age at menarche (first period), and parity (the number of children a woman has had) are all strongly associated with breast, ovarian, and endometrial cancer risk. Because these cancers share many hormonal and epidemiological risk factors, a woman with a high breast cancer risk is also likely to have an above-average risk of developing ovarian or endometrial cancer.
Why Was This Study Done?
Several statistical models (for example, the Breast Cancer Risk Assessment Tool) have been developed that estimate a woman's absolute risk (probability) of developing breast cancer over the next few years or over her lifetime. Absolute risk prediction models are useful in the design of cancer prevention trials and can also help women make informed decisions about cancer prevention and treatment options. For example, a woman at high risk of breast cancer might decide to take tamoxifen for breast cancer prevention, but ideally she needs to know her absolute endometrial cancer risk before doing so because tamoxifen increases the risk of this cancer. Similarly, knowledge of her ovarian cancer risk might influence a woman's decision regarding prophylactic removal of her ovaries to reduce her breast cancer risk. There are few absolute risk prediction models for ovarian cancer, and none for endometrial cancer, so here the researchers develop models to predict the risk of these cancers and of breast cancer.
What Did the Researchers Do and Find?
Absolute risk prediction models are constructed by combining estimates for risk factors from cohorts with population-based incidence rates from cancer registries. Models are validated in an independent cohort by testing their ability to identify people with the disease in an independent cohort and their ability to predict the observed numbers of incident cases. The researchers used data on white, non-Hispanic women aged 50 years or older that were collected during two large prospective US cohort studies of cancer screening and of diet and health, and US cancer incidence and mortality rates provided by the Surveillance, Epidemiology, and End Results Program to build their models. The models all included parity as a risk factor, as well as other factors. The model for endometrial cancer, for example, also included menopausal status, age at menopause, body mass index (an indicator of the amount of body fat), oral contraceptive use, menopausal hormone therapy use, and an interaction term between menopausal hormone therapy use and body mass index. Individual women's risk for endometrial cancer calculated using this model ranged from 1.22% to 17.8% over the next 20 years depending on their exposure to various risk factors. Validation of the models using data from the US Nurses' Health Study indicated that the endometrial cancer model overestimated the risk of endometrial cancer but that the breast and ovarian cancer models were well calibrated—the predicted and observed risks for these cancers in the validation cohort agreed closely. Finally, the discriminatory power of the models (a measure of how well a model separates people who have a disease from people who do not have the disease) was modest for the breast and ovarian cancer models but somewhat better for the endometrial cancer model.
What Do These Findings Mean?
These findings show that breast, ovarian, and endometrial cancer can all be predicted using information on known risk factors for these cancers that is easily obtainable. Because these models were constructed and validated using data from white, non-Hispanic women aged 50 years or older, they may not accurately predict absolute risk for these cancers for women of other races or ethnicities. Moreover, the modest discriminatory power of the breast and ovarian cancer models means they cannot be used to decide which women should be routinely screened for these cancers. Importantly, however, these well-calibrated models should provide realistic information about an individual's risk of developing breast, ovarian, or endometrial cancer that can be used in clinical decision-making and that may assist in the identification of potential participants for research studies.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001492.
This study is further discussed in a PLOS Medicine Perspective by Lars Holmberg and Andrew Vickers
The US National Cancer Institute provides comprehensive information about cancer (in English and Spanish), including detailed information about breast cancer, ovarian cancer, and endometrial cancer;
Information on the Breast Cancer Risk Assessment Tool, the Surveillance, Epidemiology, and End Results Program, and on the prospective cohort study of screening and the diet and health study that provided the data used to build the models is also available on the NCI site
Cancer Research UK, a not-for-profit organization, provides information about cancer, including detailed information on breast cancer, ovarian cancer, and endometrial cancer
The UK National Health Service Choices website has information and personal stories about breast cancer, ovarian cancer, and endometrial cancer; the not-for-profit organization Healthtalkonline also provides personal stories about dealing with breast cancer and ovarian cancer
doi:10.1371/journal.pmed.1001492
PMCID: PMC3728034  PMID: 23935463
19.  Breast cancer mortality trends in England and the assessment of the effectiveness of mammography screening: population-based study 
Objective
To investigate whether mortality statistics show an effect of mammographic screening on population-based breast cancer mortality in England.
Design
Joinpoint regression analyses, and other analyses, of population-based mortality data.
Setting
Analysis of mortality rates in the Oxford region, UK (1979–2009) because, unlike the rest of England, all causes of death mentioned on each death certificate for its residents (not just the underlying cause) are available prior to commencement of the English National Breast Screening Programme (NHSBSP). In addition, analysis of English national breast cancer mortality rates (1971–2009).
Participants
Women who died from breast cancer in the Oxford region (1979--2009) and England (1971--2009)
Main outcome measures
Age-specific mortality rates, and age-standardized mortality rates. Joinpoint regression analysis was used to estimate years (‘joinpoints’) in which trends changed, and annual percentage change between joinpoints, with confidence intervals.
Results
In the Oxford region, trends for breast cancer mortality based on underlying cause and on mentions were very similar. For all ages combined, mortality rates peaked for both underlying cause and mentions in 1985 and then started to decline, prior to the introduction of the NHSBSP in 1988. Between 1979 and 2009, for mortality measured as underlying cause, rates declined by −2.1% (95% CI −2.7 to −1.4) per year for women aged 40–49 years (unscreened), and by the same percentage per year (−2.1% [−2.4 to −1.7]) for women aged 50–64 years (screened). In England, the first estimated changes in trend occurred prior to the introduction of screening, or before screening was likely to have had an effect (between 1982 and 1989). Thereafter, the downward trend was greatest in women aged under 40 years: −2.0% per year (−2.8 to −1.2) in 1988–2001 and −5.0% per year (−6.7 to −3.3) in 2001–2009. There was no evidence that declines in mortality rates were consistently greater in women in age groups and cohorts that had been screened at all, or screened several times, than in other (unscreened) women, in the same time periods.
Conclusions
Mortality statistics do not show an effect of mammographic screening on population-based breast cancer mortality in England.
doi:10.1177/0141076813486779
PMCID: PMC3705415  PMID: 23761583
20.  Efficacy of Early Diagnosis and Treatment in Women with a Family History of Breast Cancer 
Disease Markers  2002;15(1-3):179-186.
BACKGROUND: Surveillance programmes for women at increased genetic risk of breast cancer are being established worldwide but little is known of their efficacy in early detection of cancers and hence reduction in mortality.
METHODS: Data were contributed from seven centres participating in the EU Demonstration Programme on Clinical Services for Familial Breast Cancer. All breast tumours (n = 161) detected prospectively, from the time of enrolment of women in a screening programme, were recorded. Analysis took account of age at diagnosis, whether tumours were screen-detected or not, their pathological stage and outcome by Kaplan—Meier survival plots.
RESULTS: Mean age at diagnosis was 48.6 years. Overall, 75% of tumours were detected in the course of planned examinations. For women under age 50 at diagnosis, this figure was 68%. Eighteen percent were mammographically negative, (23% in patients under age 50). At first (“prevalence”) round and at follow-up screening, 16% and 22% of tumours respectively were carcinoma in situ (CIS) while 27% and 22% respectively had evidence of nodal or distant spread (CaN+). Comparison of screen-detected and other tumours showed that the latter were more frequently mammogram-negative and CaN+. Overall five-year survival was 89% and five-year event-free survival 86%. Five-year event-free survival was 100% for CIS, 88% for invasive cancer without nodal or distant spread and 67% for CaN+.
CONCLUSIONS: The majority of cancers arising in women at increased genetic risk of breast cancer can be detected by planned screening, even in those under age 50. Surveillance should include regular expert clinical examination and teaching of “breast awareness” as well as mammography. Attention to the logistics of screening programmes may improve still further the proportion of tumours that are screen-detected. The trend towards earlier pathological stage in tumours detected during follow-up rounds and the preliminary findings on survival analysis suggest that this approach will prove to be of long-term benefit for breast cancer families.
doi:10.1155/1999/805420
PMCID: PMC3851417  PMID: 10595275
inherited; familial; breast cancer; prognosis; stage; diagnosis; survival; screening; mammography
21.  Impact of screening mammography on mortality from breast cancer before age 60 in women 40 to 49 years of age 
Current Oncology  2014;21(5):217-221.
Background
Whether screening mammography programs should include women in their 40s is controversial. In Canada, screening of women aged 40–49 years has not been shown to reduce mortality from breast cancer. Given that screening mammography reduces mean tumour size and that tumour size is inversely associated with survival, the lack of benefit seen with screening is puzzling and suggests a possible adverse effect on mortality of mammography or subsequent treatment (or both) that counterbalances the expected benefit derived from downstaging.
Methods
We followed 50,436 women 40–49 years of age until age 60 for mortality from breast cancer. Of those women, one half had been randomly assigned to annual mammography and one half to no mammography. The impact of mammography on breast cancer mortality was estimated using a left-censored Cox proportional hazards model.
Results
Of 256 deaths from breast cancer recorded in the study cohort, 134 occurred in women allocated to mammography, and 122 occurred in those receiving usual care and not allocated to mammography. The cumulative risk of death from breast cancer to age 60 was 0.53% for women assigned to mammography and 0.48% for women not so assigned. The hazard ratio for breast cancer–specific death associated with 1 or more screening mammograms before age 50 was 1.10 (95% confidence interval: 0.86 to 1.40).
Conclusions
Mammography in women 40–49 years of age is associated with a small but nonsignificant increase in the risk of dying of breast cancer before age 60. Caution should be exercised when recommending mammographic screening to women before age 50.
doi:10.3747/co.21.2067
PMCID: PMC4189562  PMID: 25302030
Breast cancer; screening; mammography; mortality
22.  Advanced breast cancer incidence following population-based mammographic screening 
Annals of Oncology  2011;22(8):1726-1735.
Background: Breast cancer mortality is declining in many Western countries. If mammography screening contributed to decreases in mortality, then decreases in advanced breast cancer incidence should also be noticeable.
Patients and methods: We assessed incidence trends of advanced breast cancer in areas where mammography screening is practiced for at least 7 years with 60% minimum participation and where population-based registration of advanced breast cancer existed. Through a systematic Medline search, we identified relevant published data for Australia, Italy, Norway, Switzerland, The Netherlands, UK and the USA. Data from cancer registries in Northern Ireland, Scotland, the USA (Surveillance, Epidemiology and End Results (SEER), and Connecticut), and Tasmania (Australia) were available for the study. Criterion for advanced cancer was the tumour size, and if not available, spread to regional/distant sites.
Results: Age-adjusted annual percent changes (APCs) were stable or increasing in ten areas (APCs of −0.5% to 1.7%). In four areas (Firenze, the Netherlands, SEER and Connecticut) there were transient downward trends followed by increases back to pre-screening rates.
Conclusions: In areas with widespread sustained mammographic screening, trends in advanced breast cancer incidence do not support a substantial role for screening in the decrease in mortality.
doi:10.1093/annonc/mdq633
PMCID: PMC3144633  PMID: 21252058
breast cancer; cancer registry; incidence; screening; stage
23.  An ongoing case-control study to evaluate the NHS breast screening programme 
BMC Cancer  2013;13:596.
Background
In England, a national breast screening programme (NHSBSP) has been in place since 1988, and assessment of its impact on breast cancer incidence and mortality is essential to ensure that the programme is indeed doing more good than harm. This article describes large observation studies designed to estimate the effects of the current programme in terms of the benefits on breast cancer incidence and mortality and detrimental effect in terms of overdiagnosis. The case-control design of the cervical screening programme evaluation was highly effective in informing policy on screening intervals and age ranges. We propose innovative selection of cases and controls and gathering of additional variables to address new outcomes of interest and develop new methodologies to control for potential sources of bias.
Methods/Design
Traditional case-control evaluation of breast screening uses women who have died from breast cancer as cases, and women known to be alive at the time of case death as controls. Breast screening histories prior to the cases’ date of first diagnosis are compared. If breast screening is preventing mortality from breast cancer, cases will be characterised by a lesser screening history than controls. All deaths and incident cases of primary breast cancer in England within each 2-year study period will be included in this ongoing evaluation. Cases will be age- and area-matched to controls and variables related to cancer treatment and breast tumour pathology will be obtained to investigate the interplay between screening and treatment, and the effect of screening on incidence of advanced stage disease. Screening attendance at other national screening programmes will also be collected to derive superior adjustment for self-selection bias.
The study is registered and has received full ethics approval.
doi:10.1186/1471-2407-13-596
PMCID: PMC3866937  PMID: 24330588
Breast cancer; Case–control; Incidence; Mortality; Overdiagnosis; Advanced stage; Bias
24.  Association between Cutaneous Nevi and Breast Cancer in the Nurses' Health Study: A Prospective Cohort Study 
PLoS Medicine  2014;11(6):e1001659.
Using data from the Nurses' Health Study, Jiali Han and colleagues examine the association between number of cutaneous nevi and the risk for breast cancer.
Please see later in the article for the Editors' Summary
Background
Cutaneous nevi are suggested to be hormone-related. We hypothesized that the number of cutaneous nevi might be a phenotypic marker of plasma hormone levels and predict subsequent breast cancer risk.
Methods and Findings
We followed 74,523 female nurses for 24 y (1986–2010) in the Nurses' Health Study and estimate the relative risk of breast cancer according to the number of cutaneous nevi. We adjusted for the known breast cancer risk factors in the models. During follow-up, a total of 5,483 invasive breast cancer cases were diagnosed. Compared to women with no nevi, women with more cutaneous nevi had higher risks of breast cancer (multivariable-adjusted hazard ratio, 1.04, 95% confidence interval [CI], 0.98–1.10 for 1–5 nevi; 1.15, 95% CI, 1.00–1.31 for 6–14 nevi, and 1.35, 95% CI, 1.04–1.74 for 15 or more nevi; p for continuous trend = 0.003). Over 24 y of follow-up, the absolute risk of developing breast cancer increased from 8.48% for women without cutaneous nevi to 8.82% (95% CI, 8.31%–9.33%) for women with 1–5 nevi, 9.75% (95% CI, 8.48%–11.11%) for women with 6–14 nevi, and 11.4% (95% CI, 8.82%–14.76%) for women with 15 or more nevi. The number of cutaneous nevi was associated with increased risk of breast cancer only among estrogen receptor (ER)–positive tumors (multivariable-adjusted hazard ratio per five nevi, 1.09, 95% CI, 1.02–1.16 for ER+/progesterone receptor [PR]–positive tumors; 1.08, 95% CI, 0.94–1.24 for ER+/PR− tumors; and 0.99, 95% CI, 0.86–1.15 for ER−/PR− tumors). Additionally, we tested plasma hormone levels according to the number of cutaneous nevi among a subgroup of postmenopausal women without postmenopausal hormone use (n = 611). Postmenopausal women with six or more nevi had a 45.5% higher level of free estradiol and a 47.4% higher level of free testosterone compared to those with no nevi (p for trend = 0.001 for both). Among a subgroup of 362 breast cancer cases and 611 matched controls with plasma hormone measurements, the multivariable-adjusted odds ratio for every five nevi attenuated from 1.25 (95% CI, 0.89–1.74) to 1.16 (95% CI, 0.83–1.64) after adjusting for plasma hormone levels. Key limitations in this study are that cutaneous nevi were self-counted in our cohort and that the study was conducted in white individuals, and thus the findings do not necessarily apply to other populations.
Conclusions
Our results suggest that the number of cutaneous nevi may reflect plasma hormone levels and predict breast cancer risk independently of previously known factors.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
One woman in eight will develop breast cancer during her lifetime. Breast cancer begins when cells in the breast acquire genetic changes that allow them to divide uncontrollably (which leads to the formation of a lump in the breast) and to move around the body (metastasize). The treatment of breast cancer, which is diagnosed using mammography (a breast X-ray) or manual breast examination and biopsy, usually involves surgery to remove the lump, or the whole breast (mastectomy) if the cancer has started to metastasize. After surgery, women often receive chemotherapy or radiotherapy to kill any remaining cancer cells and may also be given drugs that block the action of estrogen and progesterone, female sex hormones that stimulate the growth of some breast cancer cells. Globally, half a million women die from breast cancer each year. However, in developed countries, nearly 90% of women affected by breast cancer are still alive five years after diagnosis.
Why Was This Study Done?
Several sex hormone–related factors affect breast cancer risk, including at what age a woman has her first child (pregnancy alters sex hormone levels) and her age at menopause, when estrogen levels normally drop. Moreover, postmenopausal women with high circulating levels of estrogen and testosterone (a male sex hormone) have an increased breast cancer risk. Interestingly, moles (nevi)—dark skin blemishes that are a risk factor for the development of melanoma, a type of skin cancer—often darken or enlarge during pregnancy. Might the number of nevi be a marker of hormone levels, and could nevi counts therefore be used to predict an individual's risk of breast cancer? In this prospective cohort study, the researchers look for an association between number of nevi and breast cancer risk among participants in the US Nurses' Health Study (NHS). A prospective cohort study enrolls a group of people, determines their baseline characteristics, and follows them over time to see which characteristics are associated with the development of certain diseases. The NHS, which enrolled 121,700 female nurses aged 30–55 years in 1976, is studying risk factors for cancer and other chronic diseases in women.
What Did the Researchers Do and Find?
In 1986, nearly 75,000 NHS participants (all of whom were white) reported how many nevi they had on their left arm. Over the next 24 years, 5,483 invasive breast cancers were diagnosed in these women. Compared to women with no nevi, women with increasing numbers of nevi had a higher risk of breast cancer after adjustment for known breast cancer risk factors. Specifically, among women with 1–5 nevi, the hazard ratio (HR) for breast cancer was 1.04, whereas among women with 15 or more nevi the HR was 1.35. An HR compares how often a particular event occurs in two groups with different characteristics; an HR greater than one indicates that a specific characteristic is associated with an increased risk of the event. Over 24 years of follow-up, the absolute risk of developing breast cancer was 8.48% in women with no nevi but 11.4% for women with 15 or more nevi. Notably, postmenopausal women with six or more nevi had higher blood levels of estrogen and testosterone than women with no nevi. Finally, in a subgroup analysis, the association between number of nevi and breast cancer risk disappeared after adjustment for hormone levels.
What Do These Findings Mean?
These findings support the hypothesis that the number of nevi reflects sex hormone levels in women and may predict breast cancer risk. Notably, they show that the association between breast cancer risk and nevus number was independent of known risk factors for breast cancer, and that the risk of breast cancer increased with the number of nevi in a dose-dependent manner. These findings also suggest that a hormonal mechanism underlies the association between nevus number and breast cancer risk. Because this study involved only white participants, these findings may not apply to non-white women. Moreover, the use of self-reported data on nevus numbers may affect the accuracy of these findings. Finally, because this study is observational, these findings are insufficient to support any changes in clinical recommendations for breast cancer screening or diagnosis. Nevertheless, these data and those in an independent PLOS Medicine Research Article by Kvaskoff et al. support the need for further investigation of the association between nevi and breast cancer risk and of the mechanisms underlying this relationship.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001659.
An independent PLOS Medicine Research Article by Kvaskoff et al. also investigates the relationship between nevi and breast cancer risk
The US National Cancer Institute provides comprehensive information about cancer (in English and Spanish), including detailed information for patients and professionals about breast cancer; it also has a fact sheet on moles
Cancer Research UK, a not-for profit organization, provides information about cancer, including detailed information on breast cancer
The UK National Health Service Choices website has information and personal stories about breast cancer; the not-for profit organization Healthtalkonline also provides personal stories about dealing with breast cancer
More information about the Nurses' Health Study is available
doi:10.1371/journal.pmed.1001659
PMCID: PMC4051600  PMID: 24915186
25.  Competing risks to breast cancer mortality in Catalonia 
BMC Cancer  2008;8:331.
Background
Breast cancer mortality has experienced important changes over the last century. Breast cancer occurs in the presence of other competing risks which can influence breast cancer incidence and mortality trends. The aim of the present work is: 1) to assess the impact of breast cancer deaths among mortality from all causes in Catalonia (Spain), by age and birth cohort and 2) to estimate the risk of death from other causes than breast cancer, one of the inputs needed to model breast cancer mortality reduction due to screening or therapeutic interventions.
Methods
The multi-decrement life table methodology was used. First, all-cause mortality probabilities were obtained by age and cohort. Then mortality probability for breast cancer was subtracted from the all-cause mortality probabilities to obtain cohort life tables for causes other than breast cancer. These life tables, on one hand, provide an estimate of the risk of dying from competing risks, and on the other hand, permit to assess the impact of breast cancer deaths on all-cause mortality using the ratio of the probability of death for causes other than breast cancer by the all-cause probability of death.
Results
There was an increasing impact of breast cancer on mortality in the first part of the 20th century, with a peak for cohorts born in 1945–54 in the 40–49 age groups (for which approximately 24% of mortality was due to breast cancer). Even though for cohorts born after 1955 there was only information for women under 50, it is also important to note that the impact of breast cancer on all-cause mortality decreased for those cohorts.
Conclusion
We have quantified the effect of removing breast cancer mortality in different age groups and birth cohorts. Our results are consistent with US findings. We also have obtained an estimate of the risk of dying from competing-causes mortality, which will be used in the assessment of the effect of mammography screening on breast cancer mortality in Catalonia.
doi:10.1186/1471-2407-8-331
PMCID: PMC2636833  PMID: 19014473

Results 1-25 (1358349)