PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (999956)

Clipboard (0)
None

Related Articles

1.  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
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.  The BARD1 Cys557Ser Variant and Breast Cancer Risk in Iceland 
PLoS Medicine  2006;3(7):e217.
Background
Most, if not all, of the cellular functions of the BRCA1 protein are mediated through heterodimeric complexes composed of BRCA1 and a related protein, BARD1. Some breast-cancer-associated BRCA1 missense mutations disrupt the function of the BRCA1/BARD1 complex. It is therefore pertinent to determine whether variants of BARD1 confer susceptibility to breast cancer. Recently, a missense BARD1 variant, Cys557Ser, was reported to be at increased frequencies in breast cancer families. We investigated the role of the BARD1 Cys557Ser variant in a population-based cohort of 1,090 Icelandic patients with invasive breast cancer and 703 controls. We then used a computerized genealogy of the Icelandic population to study the relationships between the Cys557Ser variant and familial clustering of breast cancer.
Methods and Findings
The Cys557Ser allele was present at a frequency of 0.028 in patients with invasive breast cancer and 0.016 in controls (odds ratio [OR] = 1.82, 95% confidence interval [CI] 1.11–3.01, p = 0.014). The alleleic frequency was 0.037 in a high-predisposition group of cases defined by having a family history of breast cancer, early onset of breast cancer, or multiple primary breast cancers (OR = 2.41, 95% CI 1.22–4.75, p = 0.015). Carriers of the common Icelandic BRCA2 999del5 mutation were found to have their risk of breast cancer further increased if they also carried the BARD1 variant: the frequency of the BARD1 variant allele was 0.047 (OR = 3.11, 95% CI 1.16–8.40, p = 0.046) in 999del5 carriers with breast cancer. This suggests that the lifetime probability of a BARD1 Cys557Ser/BRCA2 999del5 double carrier developing breast cancer could approach certainty. Cys557Ser carriers, with or without the BRCA2 mutation, had an increased risk of subsequent primary breast tumors after the first breast cancer diagnosis compared to non-carriers. Lobular and medullary breast carcinomas were overrepresented amongst Cys557Ser carriers. We found that an excess of ancestors of contemporary carriers lived in a single county in the southeast of Iceland and that all carriers shared a SNP haplotype, which is suggestive of a founder event. Cys557Ser was found on the same SNP haplotype background in the HapMap Project CEPH sample of Utah residents.
Conclusions
Our findings suggest that BARD1 Cys557Ser is an ancient variant that confers risk of single and multiple primary breast cancers, and this risk extends to carriers of the BRCA2 999del5 mutation.
Editors' Summary
Background.
About 13% of women (one in eight women) will develop breast cancer during their lifetime, but many factors affect the likelihood of any individual woman developing this disease, for example, whether she has had children and at what age, when she started and stopped her periods, and her exposure to certain chemicals or radiation. She may also have inherited a defective gene that affects her risk of developing breast cancer. Some 5%–10% of all breast cancers are familial, or inherited. In 20% of these cases, the gene that is defective is BRCA1 or BRCA2. Inheriting a defective copy of one of these genes greatly increases a woman's risk of developing breast cancer, while researchers think that the other inherited genes that predispose to breast cancer—most of which have not been identified yet—have a much weaker effect. These are described as low-penetrance genes. Inheriting one such gene only slightly increases breast cancer risk; a woman has to inherit several to increase her lifetime risk of cancer significantly.
Why Was This Study Done?
It is important to identify these additional predisposing gene variants because they might provide insights into why breast cancer develops, how to prevent it, and how to treat it. To find low-penetrance genes, researchers do case–control association studies. They find a large group of women with breast cancer (cases) and a similar group of women without cancer (controls), and examine how often a specific gene variant occurs in the two groups. If the variant is found more often in the cases than in the controls, it might be a variant that increases a woman's risk of developing breast cancer.
What Did the Researchers Do and Find?
The researchers involved in this study recruited Icelandic women who had had breast cancer and unaffected women, and looked for a specific variant—the Cys557Ser allele—of a gene called BARD1. They chose BARD1 because the protein it encodes interacts with the protein encoded by BRCA1. Because defects in BRCA1 increase the risk of breast cancer, defects in an interacting protein might have a similar effect. In addition, the Cys557Ser allele has been implicated in breast cancer in other studies. The researchers found that the Cys557Ser allele was nearly twice as common in women with breast cancer as in control women. It was also more common (but not by much) in women who had a family history of breast cancer or who had developed breast cancer more than once. And having the Cys557Ser allele seemed to increase the already high risk of breast cancer in women who had a BRCA2 variant (known as BRCA2 999del5) that accounts for 40% of inherited breast cancer risk in Iceland.
What Do These Findings Mean?
These results indicate that inheriting the BARD1 Cys557Ser allele increases a woman's breast cancer risk but that she is unlikely to have a family history of the disease. Because carrying the Cys557Ser allele only slightly increases a woman's risk of breast cancer, for most women there is no clinical reason to test for this variant. Eventually, when all the low-penetrance genes that contribute to breast cancer risk have been identified, it might be helpful to screen women for the full set to determine whether they are at high risk of developing breast cancer. This will not happen for many years, however, since there might be tens or hundreds of these genes. For women who carry BRCA2 999del5, the situation might be different. It might be worth testing these women for the BARD1 Cys557Ser allele, the researchers explain, because the lifetime probability of developing breast cancer in women carrying both variants might approach 100%. This finding has clinical implications in terms of counseling and monitoring, as does the observation that Cys557Ser carriers have an increased risk of a second, independent breast cancer compared to non-carriers. However, all these findings need to be confirmed in other groups of patients before anyone is routinely tested for the BARD1 Cys557Ser allele.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030217.
• MedlinePlus pages about breast cancer
• Information on breast cancer from the United States National Cancer Institute
• Information on inherited breast cancer from the United States National Human Genome Research Institute
• United States National Cancer Institute information on genetic testing for BRCA1 and BRCA2 variants
• GeneTests pages on the involvement of BRCA1 and BRCA2 in hereditary breast and ovarian cancer
• Cancer Research UK's page on breast cancer statistics
In a population-based cohort of 1090 Icelandic patients, a Cys557Ser missense variant of the BARD1 gene, which interacts with BRCA1, increased the risk of single and multiple primary breast cancers.
doi:10.1371/journal.pmed.0030217
PMCID: PMC1479388  PMID: 16768547
4.  Effect of a Computer-Based Decision Aid on Knowledge, Perceptions, and Intentions About Genetic Testing for Breast Cancer Susceptibility 
Context
As the availability of and demand for genetic testing for hereditary cancers increases in primary care and other clinical settings, alternative or adjunct educational methods to traditional genetic counseling will be needed.
Objective
To compare the effectiveness of a computer-based decision aid with standard genetic counseling for educating women about BRCA1 and BRCA2 genetic testing.
Design
Randomized controlled trial conducted from May 2000 to September 2002.
Setting and Participants
Outpatient clinics offering cancer genetic counseling at 6 US medical centers enrolled 211 women with personal or family histories of breast cancer.
Interventions
Standard one-on-one genetic counseling (n=105) or education by a computer program followed by genetic counseling (n=106).
Main Outcome Measures
Participants’ knowledge, risk perception, intention to undergo genetic testing, decisional conflict, satisfaction with decision, anxiety, and satisfaction with the intervention. Counselor group measures were administered at baseline and after counseling. Computer group measures were administered at baseline, after computer use, and after counseling. Testing decisions were assessed at 1 and 6 months. Outcomes were analyzed by high vs low risk of carrying a BRCA1 or BRCA2 mutation.
Results
Both groups had comparable demographics, prior computer experience, medical literacy, and baseline knowledge of breast cancer and genetic testing, and both counseling and computer use were rated highly. Knowledge scores increased in both groups (P<.001) regardless of risk status, and change in knowledge was greater in the computer group compared with the counselor group (P=.03) among women at low risk of carrying a mutation. Perception of absolute risk of breast cancer decreased significantly after either intervention among all participants. Intention to undergo testing decreased significantly after either intervention among low-risk but not high-risk women. The counselor group had lower mean scores on a decisional conflict scale (P=.04) and, in low-risk women, higher mean scores on a satisfaction-with-decision scale (P=.001). Mean state anxiety scores were reduced by counseling but were within normal ranges for both groups at baseline and after either intervention, regardless of risk status.
Conclusions
An interactive computer program was more effective than standard genetic counseling for increasing knowledge of breast cancer and genetic testing among women at low risk of carrying a BRCA1 or BRCA2 mutation. However, genetic counseling was more effective than the computer at reducing women’s anxiety and facilitating more accurate risk perceptions. These results suggest that this computer program has the potential to stand alone as an educational intervention for low-risk women but should be used as a supplement to genetic counseling for those at high risk.
doi:10.1001/jama.292.4.442
PMCID: PMC1237120  PMID: 15280342
5.  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
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.  DEAR1 Is a Dominant Regulator of Acinar Morphogenesis and an Independent Predictor of Local Recurrence-Free Survival in Early-Onset Breast Cancer 
PLoS Medicine  2009;6(5):e1000068.
Ann Killary and colleagues describe a new gene that is genetically altered in breast tumors, and that may provide a new breast cancer prognostic marker.
Background
Breast cancer in young women tends to have a natural history of aggressive disease for which rates of recurrence are higher than in breast cancers detected later in life. Little is known about the genetic pathways that underlie early-onset breast cancer. Here we report the discovery of DEAR1 (ductal epithelium–associated RING Chromosome 1), a novel gene encoding a member of the TRIM (tripartite motif) subfamily of RING finger proteins, and provide evidence for its role as a dominant regulator of acinar morphogenesis in the mammary gland and as an independent predictor of local recurrence-free survival in early-onset breast cancer.
Methods and Findings
Suppression subtractive hybridization identified DEAR1 as a novel gene mapping to a region of high-frequency loss of heterozygosity (LOH) in a number of histologically diverse human cancers within Chromosome 1p35.1. In the breast epithelium, DEAR1 expression is limited to the ductal and glandular epithelium and is down-regulated in transition to ductal carcinoma in situ (DCIS), an early histologic stage in breast tumorigenesis. DEAR1 missense mutations and homozygous deletion (HD) were discovered in breast cancer cell lines and tumor samples. Introduction of the DEAR1 wild type and not the missense mutant alleles to complement a mutation in a breast cancer cell line, derived from a 36-year-old female with invasive breast cancer, initiated acinar morphogenesis in three-dimensional (3D) basement membrane culture and restored tissue architecture reminiscent of normal acinar structures in the mammary gland in vivo. Stable knockdown of DEAR1 in immortalized human mammary epithelial cells (HMECs) recapitulated the growth in 3D culture of breast cancer cell lines containing mutated DEAR1, in that shDEAR1 clones demonstrated disruption of tissue architecture, loss of apical basal polarity, diffuse apoptosis, and failure of lumen formation. Furthermore, immunohistochemical staining of a tissue microarray from a cohort of 123 young female breast cancer patients with a 20-year follow-up indicated that in early-onset breast cancer, DEAR1 expression serves as an independent predictor of local recurrence-free survival and correlates significantly with strong family history of breast cancer and the triple-negative phenotype (ER−, PR−, HER-2−) of breast cancers with poor prognosis.
Conclusions
Our data provide compelling evidence for the genetic alteration and loss of expression of DEAR1 in breast cancer, for the functional role of DEAR1 in the dominant regulation of acinar morphogenesis in 3D culture, and for the potential utility of an immunohistochemical assay for DEAR1 expression as an independent prognostic marker for stratification of early-onset disease.
Editors' Summary
Background
Each year, more than one million women discover that they have breast cancer. This type of cancer begins when cells in the breast that line the milk-producing glands or the tubes that take the milk to the nipples (glandular and ductal epithelial cells, respectively) acquire genetic changes that allow them to grow uncontrollably and to move around the body (metastasize). The uncontrolled 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 patients very ill. Generally speaking, the outlook for women with breast cancer is good. In the US, for example, nearly 90% of affected women are still alive five years after their diagnosis.
Why Was This Study Done?
Although breast cancer is usually diagnosed in women in their 50s or 60s, some women develop breast cancer much earlier. In these women, the disease is often very aggressive. Compared to older women, young women with breast cancer have a lower overall survival rate and their cancer is more likely to recur locally or to metastasize. It would be useful to be able to recognize those younger women at the greatest risk of cancer recurrence so that they could be offered intensive surveillance and adjuvant therapy; those women at a lower risk could have gentler treatments. To achieve this type of “stratification,” the genetic changes that underlie breast cancer in young women need to be identified. In this study, the researchers discover a gene that is genetically altered (by mutations or deletion) in early-onset breast cancer and then investigate whether its expression can predict outcomes in women with this disease.
What Did the Researchers Do and Find?
The researchers used “suppression subtractive hybridization” to identify a new gene in a region of human Chromosome 1 where loss of heterozygosity (LOH; a genetic alteration associated with cancer development) frequently occurs. They called the gene DEAR1 (ductal epithelium-associated RING Chromosome 1) to indicate that it is expressed in ductal and glandular epithelial cells and encodes a “RING finger” protein (specifically, a subtype called a TRIM protein; RING finger proteins such as BRCA1 and BRCA2 have been implicated in early cancer development and in a large fraction of inherited breast cancers). DEAR1 expression was reduced or lost in several ductal carcinomas in situ (a local abnormality that can develop into breast cancer) and advanced breast cancers, the researchers report. Furthermore, many breast tumors carried DEAR1 missense mutations (genetic changes that interfere with the normal function of the DEAR1 protein) or had lost both copies of DEAR1 (the human genome contains two copies of most genes). To determine the function of DEAR1, the researchers replaced a normal copy of DEAR1 into a breast cancer cell that had a mutation in DEAR1. They then examined the growth of these genetically manipulated cells in special three-dimensional cultures. The breast cancer cells without DEAR1 grew rapidly without an organized structure while the breast cancer cells containing the introduced copy of DEAR1 formed structures that resembled normal breast acini (sac-like structures that secrete milk). In normal human mammary epithelial cells, the researchers silenced DEAR1 expression and also showed that without DEAR1, the normal mammary cells lost their ability to form proper acini. Finally, the researchers report that DEAR1 expression (detected “immunohistochemically”) was frequently lost in women who had had early-onset breast cancer and that the loss of DEAR1 expression correlated with reduced local recurrence-free survival, a strong family history of breast cancer and with a breast cancer subtype that has a poor outcome.
What Do These Findings Mean?
These findings indicate that genetic alteration and loss of expression of DEAR1 are common in breast cancer. Although laboratory experiments may not necessarily reflect what happens in people, the results from the three-dimensional culture of breast epithelial cells suggest that DEAR1 may regulate the normal acinar structure of the breast. Consequently, loss of DEAR1 expression could be an early event in breast cancer development. Most importantly, the correlation between DEAR1 expression and both local recurrence in early-onset breast cancer and a breast cancer subtype with a poor outcome suggests that it might be possible to use DEAR1 expression to identify women with early-onset breast cancer who have an increased risk of local recurrence so that they get the most appropriate treatment for their cancer.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000068.
This study is further discussed in a PLoS Medicine Perspective by Senthil Muthuswamy
The US National Cancer Institute provides detailed information for patients and health professionals on all aspects of breast cancer, including information on genetic alterations in breast cancer (in English and Spanish)
The MedlinePlus Encyclopedia provides information for patients about breast cancer; MedlinePlus also provides links to many other breast cancer resources (in English and Spanish)
The UK charities Cancerbackup (now merged with MacMillan Cancer Support) and Cancer Research UK also provide detailed information about breast cancer
doi:10.1371/journal.pmed.1000068
PMCID: PMC2673042  PMID: 19536326
8.  Birth Size and Breast Cancer Risk: Re-analysis of Individual Participant Data from 32 Studies 
PLoS Medicine  2008;5(9):e193.
Background
Birth size, perhaps a proxy for prenatal environment, might be a correlate of subsequent breast cancer risk, but findings from epidemiological studies have been inconsistent. We re-analysed individual participant data from published and unpublished studies to obtain more precise estimates of the magnitude and shape of the birth size–breast cancer association.
Methods and Findings
Studies were identified through computer-assisted and manual searches, and personal communication with investigators. Individual participant data from 32 studies, comprising 22,058 breast cancer cases, were obtained. Random effect models were used, if appropriate, to combine study-specific estimates of effect. Birth weight was positively associated with breast cancer risk in studies based on birth records (pooled relative risk [RR] per one standard deviation [SD] [= 0.5 kg] increment in birth weight: 1.06; 95% confidence interval [CI] 1.02–1.09) and parental recall when the participants were children (1.02; 95% CI 0.99–1.05), but not in those based on adult self-reports, or maternal recall during the woman's adulthood (0.98; 95% CI 0.95–1.01) (p for heterogeneity between data sources = 0.003). Relative to women who weighed 3.000–3.499 kg, the risk was 0.96 (CI 0.80–1.16) in those who weighed < 2.500 kg, and 1.12 (95% CI 1.00–1.25) in those who weighed ≥ 4.000 kg (p for linear trend = 0.001) in birth record data. Birth length and head circumference from birth records were also positively associated with breast cancer risk (pooled RR per one SD increment: 1.06 [95% CI 1.03–1.10] and 1.09 [95% CI 1.03–1.15], respectively). Simultaneous adjustment for these three birth size variables showed that length was the strongest independent predictor of risk. The birth size effects did not appear to be confounded or mediated by established breast cancer risk factors and were not modified by age or menopausal status. The cumulative incidence of breast cancer per 100 women by age 80 y in the study populations was estimated to be 10.0, 10.0, 10.4, and 11.5 in those who were, respectively, in the bottom, second, third, and top fourths of the birth length distribution.
Conclusions
This pooled analysis of individual participant data is consistent with birth size, and in particular birth length, being an independent correlate of breast cancer risk in adulthood.
Editors' Summary
Background.
Last year, more than one million women discovered that they had breast cancer. In the US, nearly 200,000 women will face the same diagnosis this year and 40,000 will die because of breast cancer. Put another way, about one in eight US women will have breast cancer during her lifetime. Like all cancers, breast cancer begins when cells acquire genetic changes that allow them to divide uncontrollably and to move around the body (metastasize). This uncontrolled division leads to the formation of a lump that can be detected by mammography (a breast X-ray) or by manual examination of the breasts. 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, chemotherapy, and other treatments designed to kill any remaining cancer cells. Unlike some cancers, the outlook for women with breast cancer is good. In the US, for example, nearly 90% of affected women are still alive five years after their diagnosis.
Why Was This Study Done?
Scientists have identified several factors that increase a woman's risk of developing breast cancer by comparing the characteristics of populations of women with and without breast cancer. Well-established risk factors include increasing age, not having children, and having a late menopause, but another potential risk factor for breast cancer is birth size. A baby's weight, length, and head circumference at birth (three related measures of birth size) depend on the levels of hormones (including estrogen, a hormone that often affects breast cancer growth) and other biological factors to which the baby is exposed during pregnancy—its prenatal environment. The idea that prenatal environment might also affect breast cancer risk in later life was first proposed in 1990, but the findings of studies that have tried to investigate this possibility have been inconsistent. Here, the researchers re-analyze individual participant data from a large number of studies into women's health conducted in Europe, Northern America, and China to get more precise information about the association between birth size and breast cancer risk.
What Did the Researchers Do and Find?
The researchers identified 32 published and unpublished studies that had collected information on birth size and on the occurrence of breast cancer. They then obtained the individual participant data from these studies, which involved more than 22,000 women who had developed breast cancer and more than 600,000 women who had not. Their analyses of these data show that birth weight was positively associated with breast cancer risk in those studies where this measurement was recorded at birth or based on parental recall during the study participant's childhood (but not in those studies in which birth weight was self-reported or maternally recalled during the participant's adulthood). For example, women with recorded birth weights of more than 4 kg or more had a 12% higher chance of developing breast cancer than women who weighed 3–3.5 kg at birth. Birth length and head circumference were also positively associated with breast cancer risk, but birth length was the strongest single predictor of risk. Finally, the amount by which birth size affected breast cancer risk was not affected by allowing for other established risk factors.
What Do These Findings Mean?
These findings provide strong evidence that birth size—in particular, birth length—is a marker of a woman's breast cancer risk in adulthood although the mechanisms underlying this association are unclear. The researchers note that the observed effect of birth size on breast cancer risk is of a similar magnitude to that of other more established risk factors and estimate that 5% of all breast cancers in developed countries could be caused by a high birth size. Because practically all the studies included in this pooled analysis were done in developed countries, these findings may not hold for developing countries. Further investigations into how the prenatal environment may affect breast cancer risk might identify new ways to prevent this increasingly common cancer.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050193.
This study is further discussed in a PLoS Medicine Perspective by Trichopoulos and Lagiou
The US National Cancer Institute provides detailed information for patients and health professionals on all aspects of breast cancer, including information on risk factors for breast cancer (in English and Spanish)
The MedlinePlus Encyclopedia provides information for patients about breast cancer; Medline Plus also provides links to many other breast cancer resources (in English and Spanish)
The UK charity Cancerbackup also provides detailed information about breast cancer
Cancer Research UK is the UK's leading charity dedicated to cancer research
doi:10.1371/journal.pmed.0050193
PMCID: PMC2553821  PMID: 18828667
9.  How should we discuss genetic testing with women newly diagnosed with breast cancer? Design and implementation of a randomized controlled trial of two models of delivering education about treatment-focused genetic testing to younger women newly diagnosed with breast cancer 
BMC Cancer  2012;12:320.
Background
Germline BRCA1 and BRCA2 mutation testing offered shortly after a breast cancer diagnosis to inform women’s treatment choices - treatment-focused genetic testing ‘TFGT’ - has entered clinical practice in specialist centers and is likely to be soon commonplace in acute breast cancer management, especially for younger women. Yet the optimal way to deliver information about TFGT to younger women newly diagnosed with breast cancer is not known, particularly for those who were not suspected of having a hereditary breast cancer syndrome prior to their cancer diagnosis. Also, little is known about the behavioral and psychosocial impact or cost effectiveness of educating patients about TFGT. This trial aims to examine the impact and efficiency of two models of educating younger women newly diagnosed with breast cancer about genetic testing in order to provide evidence for a safe and effective future clinical pathway for this service.
Design/methods
In this non-inferiority randomized controlled trial, 140 women newly diagnosed with breast cancer (aged less than 50 years) are being recruited from nine cancer centers in Australia. Eligible women with either a significant family history of breast and/or ovarian cancer or with other high risk features suggestive of a mutation detection rate of > 10% are invited by their surgeon prior to mastectomy or radiotherapy. After completing the first questionnaire, participants are randomized to receive either: (a) an educational pamphlet about genetic testing (intervention) or (b) a genetic counseling appointment at a family cancer center (standard care). Each participant is offered genetic testing for germline BRCA mutations. Decision-related and psychosocial outcomes are assessed over 12 months and include decisional conflict (primary outcome);uptake of bilateral mastectomy and/or risk-reducing salpingo-oophorectomy; cancer-specific- and general distress; family involvement in decision making; and decision regret. A process-oriented retrospective online survey will examine health professionals’ attitudes toward TFGT; a health economic analysis will determine the cost effectiveness of the intervention.
Discussion
This trial will provide crucial information about the impact, efficiency and cost effectiveness of an educational pamphlet designed to inform younger women newly diagnosed with breast cancer about genetic testing. Issues regarding implementation of the trial are discussed.
Trial registration
The study is registered with the Australian and New Zealand Clinical Trials Group (Registration no: ACTRN12610000502033)
doi:10.1186/1471-2407-12-320
PMCID: PMC3472271  PMID: 22838957
Breast cancer; Genetic testing; BRCA1; BRCA2; Treatment; Clinical practice
10.  Using a state cancer registry to recruit young breast cancer survivors and high-risk relatives: protocol of a randomized trial testing the efficacy of a targeted versus a tailored intervention to increase breast cancer screening 
BMC Cancer  2013;13:97.
Background
The Michigan Prevention Research Center, the University of Michigan Schools of Nursing, Public Health, and Medicine, and the Michigan Department of Community Health propose a multidisciplinary academic-clinical practice three-year project to increase breast cancer screening among young breast cancer survivors and their cancer-free female relatives at greatest risk for breast cancer.
Methods/design
The study has three specific aims: 1) Identify and survey 3,000 young breast cancer survivors (diagnosed at 20–45 years old) regarding their breast cancer screening utilization. 2) Identify and survey survivors’ high-risk relatives regarding their breast cancer screening utilization. 3) Test two versions (Targeted vs. Enhanced Tailored) of an intervention to increase breast cancer screening among survivors and relatives. Following approval by human subjects review boards, 3,000 young breast cancer survivors will be identified through the Michigan Cancer Registry and mailed an invitation letter and a baseline survey. The baseline survey will obtain information on the survivors’: a) current breast cancer screening status and use of genetic counseling; b) perceived barriers and facilitators to screening; c) family health history. Based on the family history information provided by survivors, we will identify up to two high-risk relatives per survivor. Young breast cancer survivors will be mailed consent forms and baseline surveys to distribute to their selected high-risk relatives. Relatives’ baseline survey will obtain information on their: a) current breast cancer screening status and use of genetic counseling; and b) perceived barriers and facilitators to screening. Young breast cancer survivors and high-risk relatives will be randomized as a family unit to receive two versions of an intervention aiming to increase breast cancer screening and use of cancer genetic services. A follow-up survey will be mailed 9 months after the intervention to survivors and high-risk relatives to evaluate the efficacy of each intervention version on: a) use of breast cancer screening and genetic counseling; b) perceived barriers and facilitators to screening; c) self-efficacy in utilizing cancer genetic and screening services; d) family support related to screening; e) knowledge of breast cancer genetics; and f) satisfaction with the intervention.
Discussion
The study will enhance efforts of the state of Michigan surrounding cancer prevention, control, and public health genomics.
Trial registration
NCT01612338
doi:10.1186/1471-2407-13-97
PMCID: PMC3599993  PMID: 23448100
Breast cancer screening; Familial breast cancer; Young breast cancer survivors; High-risk relatives; Randomized trial; Targeted and enhanced tailored intervention; Screening mammography; Genetic testing; Cancer registry; State-wide community-based sample
11.  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
12.  Family history of breast cancer: what do women understand and recall about their genetic risk? 
Journal of Medical Genetics  1998;35(9):731-738.
The current study has two aims: (1) to look at people's recall of risk information after genetic counselling and (2) to determine the impact of receiving an audiotape of the genetic consultation on level of recall, cancer related worry, and women's uptake of risk management methods. Using a prospective randomised controlled design, subjects receiving an audiotape were compared with a standard consultation group. Participants were drawn from attenders at the genetic clinics of two London hospitals and included 115 women with a family history of breast cancer. Assessment of perceived genetic risk, mental health, cancer worry, and health behaviour was made before counselling at the clinic (baseline) and by postal follow up. Usefulness of audiotapes and satisfaction with the clinical service was assessed by study specific measures. The data indicate that cancer worry is reduced by provision of an audiotape of the genetic consultation. Recall of the genetic risk figure, however, is not affected by provision of an audiotape and neither is it related to women's overall perception of being more or less at risk of breast cancer than the average woman. Forty-one percent of women accurately recalled their personal risk of breast cancer at one month follow up; however, 25% overestimated, 11% underestimated, and 23% could not remember or did not know their breast cancer risk. Recall of the risk figure is more accurate when the clinical geneticist has given this to the woman as an odds ratio rather than in other formats. Subsequent health behaviour is unaffected by whether women have an audiotape record of their genetic consultation. Results suggest that having a precise risk figure may be less important than women taking away from the consultation an impression that something can be offered to help them manage that risk. Provision of an audiotape of the consultation is of limited usefulness. The need for psychological care to be better integrated into genetic counselling at cancer family clinics was highlighted by the study. The results are discussed in terms of future service development.
PMCID: PMC1051425  PMID: 9733031
13.  Randomized Trial of a Decision Aid for BRCA1/BRCA2 Mutation Carriers: Impact on Measures of Decision Making and Satisfaction 
Objective
Genetic testing is increasingly part of routine clinical care for women with a family history of breast cancer. Given their substantially elevated risk for breast cancer, BRCA1/BRCA2 mutation carriers must make the difficult decision whether or not to opt for risk reducing mastectomy. To help BRCA1/2 carriers make this decision, we developed a computer-based interactive decision aid which we tested against usual care in a randomized controlled trial.
Design
Following the completion of genetic counseling, 214 female (aged 21–75) BRCA1/BRCA2 mutation carriers were randomized to Usual Care (UC; N=114) or Usual Care plus Decision Aid (DA; N=100) arms. UC participants received no additional intervention. DA participants were sent the CD-ROM decision aid to view at home.
Main Outcome Measures
We measured final management decision, decisional conflict, decisional satisfaction and receipt of risk reducing mastectomy at 1-, 6-, and 12-months post-randomization.
Results
Longitudinal analyses revealed that the DA was effective among carriers who were initially undecided about how to manage their breast cancer risk. Within this group, the DA led to an increased likelihood of reaching a management decision (OR=3.09, 95% CI=1.62, 5.90; p<.001), decreased decisional conflict (B=−.46, z=−3.1, p<.002), and increased satisfaction (B=.27, z=3.1, p=0.002) compared to UC. Among carriers who had already made a management decision by the time of randomization, the DA had no benefit relative to UC.
Conclusion
These results demonstrate that BRCA1/BRCA2 mutation carriers who are having difficulty making a breast cancer risk management decision can benefit from adjunct decision support.
doi:10.1037/a0013147
PMCID: PMC3580845  PMID: 19210013
BRCA1; BRCA2; decision aid; risk reducing mastectomy
14.  Injectable and Oral Contraceptive Use and Cancers of the Breast, Cervix, Ovary, and Endometrium in Black South African Women: Case–Control Study 
PLoS Medicine  2012;9(3):e1001182.
A case-control study conducted in South Africa provides new estimates of the risk of specific cancers of the female reproductive system associated with use of injectable and oral contraceptives.
Background
Oral contraceptives are known to influence the risk of cancers of the female reproductive system. Evidence regarding the relationship between injectable contraceptives and these cancers is limited, especially in black South Africans, among whom injectable contraceptives are used more commonly than oral contraceptives.
Methods and Findings
We analysed data from a South African hospital-based case–control study of black females aged 18–79 y, comparing self-reported contraceptive use in patients with breast (n = 1,664), cervical (n = 2,182), ovarian (n = 182), and endometrial (n = 182) cancer, with self-reported contraceptive use in 1,492 control patients diagnosed with cancers with no known relationship to hormonal contraceptive use. We adjusted for potential confounding factors, including age, calendar year of diagnosis, education, smoking, alcohol, parity/age at first birth, and number of sexual partners. Among controls, 26% had used injectable and 20% had used oral contraceptives. For current and more recent users versus never users of oral or injectable contraceptives, the odds ratios (ORs) for breast cancer were significantly increased in users of oral and/or injectable contraceptives (OR 1.66, 95% CI 1.28–2.16, p<0.001) and separately among those exclusively using oral (1.57, 1.03–2.40, p = 0.04) and exclusively using injectable (OR 1.83, 1.31–2.55, p<0.001) contraceptives; corresponding ORs for cervical cancer were 1.38 (1.08–1.77, p = 0.01), 1.01 (0.66–1.56, p = 0.96), and 1.58 (1.16–2.15, p = 0.004). There was no significant increase in breast or cervical cancer risk among women ceasing hormonal contraceptive use ≥10 y previously (p = 0.3 and p = 0.9, respectively). For durations of use ≥5 y versus never use, the ORs of ovarian cancer were 0.60 (0.36–0.99, p = 0.04) for oral and/or injectable contraceptive use and 0.07 (0.01–0.49, p = 0.008) for injectable use exclusively; corresponding ORs for endometrial cancer were 0.44 (0.22–0.86, p = 0.02) and 0.36 (0.11–1.26, p = 0.1).
Conclusions
In this study, use of oral and of injectable hormonal contraceptives was associated with a transiently increased risk of breast and cervical cancer and, for long durations of use, with a reduced risk of ovarian and endometrial cancer. The observed effects of injectable and of oral contraceptives on cancer risk in this study did not appear to differ substantially.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Hormonal contraceptives are among the most commonly used medications. Globally, more than 210 million women currently use either hormonal contraceptive pills or injectable contraceptives. Contraceptive pills usually contain manmade versions of the female sex hormones estrogen and progesterone (the combined oral contraceptive, or “pill”); most injectable hormonal contraceptives contain only manmade progesterone preparations. Hormonal contraceptives, which prevent pregnancy by disrupting the cyclical changes in estrogen and progesterone levels that prepare the body for pregnancy, have revolutionized birth control since they first became available in the early 1960s. However, it is now known that taking the pill also influences women's risk of developing cancers of the female reproductive system. Current and recent users have an increased risk of developing breast and cervical cancer (the cervix is the structure that connects the womb to the vagina) compared to never users, although this increased risk quickly disappears when women stop taking the pill. By contrast, women who have used the pill have a reduced risk of developing ovarian cancer and cancer of the womb (endometrial cancer) compared to never users that increases with the duration of pill use and persists for many years after use ceases. These effects on reproductive system cancers are thought to occur because these cancers depend on naturally occurring sex hormones for their development and growth.
Why Was This Study Done?
Although the evidence that the pill influences the risk of developing cancers of the female reproductive system is extensive, much less is known about how injectable hormonal contraceptives affect cancer risk. In this hospital-based case–control study (a study that compares the characteristics of people with and without a specific condition), the researchers investigate the relationship between the use of oral and injectable hormonal contraceptives and cancers of the breast, cervix, ovary, and endometrium among black South African women. Injectable contraceptives have been used for longer in South Africa than elsewhere and are used more commonly than oral contraceptives among black South African women.
What Did the Researchers Do and Find?
As part of the Johannesburg Cancer Case Control Study, which recruits black patients attending Johannesburg public referral hospitals for cancer treatment, the researchers compared hormonal contraceptive use in women with breast, cervical, ovarian, or endometrial cancer with contraceptive use in women diagnosed with other cancers such as lung, colon, and rectal cancers, which are not known to be influenced by hormonal contraceptives. Among the controls, a quarter had used injectable contraceptives and a fifth had used oral contraceptives. After adjusting for other factors that might influence cancer risk such as age, smoking, and number of sexual partners, the odds ratio (OR) of breast cancer among current and recent users of oral and/or injectable contraceptives compared to never users was 1.66. That is, the risk of developing breast cancer among current and recent users of hormonal contraceptives was 1.66 times that among never users. For women using oral contraceptives exclusively or injectable contraceptives exclusively, the ORs of breast cancer were 1.57 and 1.83, respectively. There were also increases in cervical cancer risk among current and recent users of hormonal contraceptives compared to never users, but no significant increase in breast or cervical cancer risk among women who had ceased hormonal contraceptive use more than ten years previously. Finally, the use of hormonal contraceptives for more than five years reduced the risk of both ovarian and endometrial cancer.
What Do These Findings Mean?
These findings indicate that, among black women in South Africa, the use of oral or injectable hormonal contraceptives is associated with a transiently increased risk of breast and cervical cancer, and that extended use of these contraceptives is associated with a reduced risk of ovarian and endometrial cancer. Moreover, they suggest that the effects of oral versus injectable contraceptives on cancer risk do not differ substantially, although for endometrial and ovarian cancer the small number of cases exposed to injectable contraceptives limits the accuracy of the risk estimates. Other limitations of this study include the possibility that the findings may be affected by uncontrolled confounding. That is, women who used hormonal contraceptives may have shared other unidentified characteristics that affected their cancer risk. Nevertheless, these findings provide new information about the effects of oral and injectable hormonal contraceptives on cancer risk that should help women make informed decisions about their choice of contraceptive method.
Additional Information
Please access these web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001182.
The US National Cancer Institute provides information on breast cancer (including personal stories from breast cancer survivors), cervical cancer, ovarian cancer, and endometrial cancer for patients and health professionals, and a fact sheet on oral contraceptives and cancer risk (in English and Spanish)
Cancer Research UK also provides information on breast cancer, cervical cancer, ovarian cancer, and endometrial cancer and information about the birth control pill and cancer risk
Eyes on the Prize, an online support group for women who have had cancers of the female reproductive system, has personal stories; further personal stories about breast, cervical, and ovarian cancer are provided by the charity Healthtalkonline
doi:10.1371/journal.pmed.1001182
PMCID: PMC3295825  PMID: 22412354
15.  Polymorphic repeat in AIB1 does not alter breast cancer risk 
Breast Cancer Research : BCR  2000;2(5):378-385.
We assessed the association between a glutamine repeat polymorphism in AIB1 and breast cancer risk in a case-control study (464 cases, 624 controls) nested within the Nurses' Health Study cohort. We observed no association between AIB1 genotype and breast cancer incidence, or specific tumor characteristics. These findings suggest that AIB1 repeat genotype does not influence postmenopausal breast cancer risk among Caucasian women in the general population.
Introduction:
A causal association between endogenous and exogenous estrogens and breast cancer has been established. Steroid hormones regulate the expression of proteins that are involved in breast cell proliferation and development after binding to their respective steroid hormone receptors. Coactivator and corepressor proteins have recently been identified that interact with steroid hormone receptors and modulate transcriptional activation [1]. AIB1 (amplified in breast 1) is a member of the steroid receptor coactivator (SRC) family that interacts with estrogen receptor (ER)α in a ligand-dependent manner, and increases estrogen-dependent transcription [2]. Amplification and overexpression of AIB1 has been observed in breast and ovarian cancer cell lines and in breast tumors [2,3]. A polymorphic stretch of glutamine amino acids, with unknown biologic function, has recently been described in the carboxyl-terminal region of AIB1 [4]. Among women with germline BRCA1 mutations, significant positive associations were observed between AIB1 alleles with 26 or fewer glutamine repeats and breast cancer risk [5]
Aim:
To establish whether AIB1 repeat alleles are associated with breast cancer risk and specific tumor characteristics among Caucasian women.
Patients and methods:
We evaluated associations prospectively between AIB1 alleles and breast cancer risk in the Nurses' Health Study using a nested case-control design. The Nurses' Health Study was initiated in 1976, when 121 700 US-registered nurses between the ages of 30 and 55 years returned an initial questionnaire reporting medical histories and baseline health-related exposures. Between 1989 and 1990 blood samples were collected from 32 826 women. Eligible cases in this study consisted of women with pathologically confirmed incident breast cancer from the subcohort who gave a blood specimen. Cases with a diagnosis anytime after blood collection up to June 1, 1994, with no previously diagnosed cancer except for nonmelanoma skin cancer were included. Controls were randomly selected participants who gave a blood sample and were free of diagnosed cancer (except nonmelanoma skin cancer) up to and including the interval in which the cases were diagnosed, and were matched to cases on year of birth, menopausal status, postmenopausal hormone use, and time of day, month and fasting status at blood sampling. The nested case-control study consisted of 464 incident breast cancer cases and 624 matched controls. The protocol was approved by the Committee on Human Subjects, Brigham and Womens' Hospital, Boston, Massachusetts USA. Information regarding breast cancer risk factors was obtained from the 1976 baseline questionnaire, subsequent biennial questionnaires, and a questionnaire that was completed at the time of blood sampling. Histopathologic characteristics, such as stage, tumor size and ER and progesterone receptor (PR) status, were ascertained from medical records when available and used in case subgroup analyses.
AIB1 repeat alleles were determined by automated fluorescence-based fragment detection from polymerase chain reaction (PCR)-amplified DNA extracted from peripheral blood lymphocytes. Fluorescent 5' -labeled primers were utilized for PCR amplification, and glutamine repeat number discrimination was performed using the ABI Prism 377 DNA Sequencer (Perkin-Elmer, Foster City, CA, USA). Genotyping was performed by laboratory personnel who were blinded to case-control status, and blinded quality control samples were inserted to validate genotyping identification procedures (n = 110); concordance for the blinded samples was 100%. Methods regarding plasma hormone assays have previously been reported [6]. Conditional and unconditional logistic regression models, including terms for the matching variables and other potential confounders, were used to assess the association of AIB1 alleles and breast cancer characterized by histologic subtype, stage of disease, and ER and PR status. We also evaluated whether breast cancer risk associated with AIB1 genotype differed within strata of established breast cancer risk factors, and whether repeat length in AIB1 indirectly influenced plasma hormone levels.
Results:
The case-control comparisons of established breast cancer risk factors among these women have previously been reported [7], and are generally consistent with expectation. The mean age of the women was 58.3 (standard deviation [SD] 7.1) years, ranging from 43 to 69 years at blood sampling. There were 188 premenopausal and 810 postmenopausal women, with mean ages of 48.1 (SD 2.8) years and 61.4 (SD 5.0) years, respectively, at blood sampling. Women in this study were primarily white; Asians, African-Americans and Hispanics comprised less than 1% of cases or controls.
The distribution of AIB1 glutamine repeat alleles and AIB1 genotypes for cases and controls are presented in Table 1. Women with AIB1 alleles of 26 glutamine repeats or fewer were not at increased risk for breast cancer (odds ratio [OR] 1.01, 95% confidence interval [CI] 0.75-1.36; Table 2). Results were also similar by menopausal status and in analyses additionally adjusting for established breast cancer risk factors. Among premenopausal women, the OR for women with at least one allele with 26 glutamine repeats or fewer was 0.82 (95% Cl 0.37-1.81), and among postmenopausal women the OR was 1.09 (95% Cl 0.78-1.52; Table 2). We did not observe evidence of a positive association between shorter repeat length and advanced breast cancer, defined as women with breast cancer having one or more involved nodes (OR 1.07, 95% Cl 0.64-1.78), or with cancers with a hormone-dependent phenotype (ER-positive: OR 1.16, 95% Cl 0.81-1.65; Table 3). No associations were observed among women who had one or more alleles with 26 glutamine repeats or fewer, with or without a family history of breast cancer (family history: OR 1.09; 95% Cl 0.46-2.58; no family history: OR 0.94; 95% Cl 0.68-1.31; test for interaction P = 0.65). We also did not observe associations with breast cancer risk to be modified by other established breast cancer risk factors. Among postmenopausal controls not using postmenopausal hormones, geometric least-squared mean plasma levels of estrone sulfate and estrone were similar among carriers and noncarriers of AIB1 alleles with 26 glutamine repeats or fewer (both differences: ≤ +3.5%; P >0.50). Mean levels of estradiol were slightly, but nonsignificantly elevated among carriers of alleles with 26 glutamine repeats or fewer (+11.6%; P = 0.08).
Discussion:
In this population-based nested case-control study, women with at most 26 repeating glutamine codons (CAG/CAA) within the carboxyl terminus of AIB1 were not at increased risk for breast cancer. We did not observe shorter repeat alleles to be positively associated with breast cancer grouped by histologic subtype, stage of disease, or by ER and PR status. These data suggest that AIB1 repeat length is not a strong independent risk factor for postmenopausal breast cancer, and does not modify the clinical presentation of the tumor among Caucasian women in the general population.
PMCID: PMC13920  PMID: 11056690
AIB1 polymorphism; breast cancer; genetic susceptibility; molecular epidemiology
16.  Smoking and high-risk mammographic parenchymal patterns: a case-control study 
Breast Cancer Research  1999;2(1):59-63.
Current smoking was strongly and inversely associated with high-risk patterns, after adjustment for concomitant risk factors. Relative to never smokers, current smokers were significantly less likely to have a high-risk pattern. Similar results were obtained when the analysis was confined to postmenopausal women. Past smoking was not related to the mammographic parenchymal patterns. The overall effect in postmenopausal women lost its significance when adjusted for other risk factors for P2/DY patterns that were found to be significant in the present study, although the results are still strongly suggestive. The present data indicate that adjustment for current smoking status is important when evaluating the relationship between mammographic parenchymal pattern and breast cancer risk. They also indicate that smoking is a prominent potential confounder when analyzing effects of other risk factors such as obesity-related variables. It appears that parenchymal patterns may act as an informative biomarker of the effect of cigarette smoking on breast cancer risk.
Introduction:
Overall, epidemiological studies [1,2,3,4] have reported no substantial association between cigarette smoking and the risk of breast cancer. Some studies [5,6,7] reported a significant increase of breast cancer risk among smokers. In recent studies that addressed the association between breast cancer and cigarette smoking, however, there was some suggestion of a decreased risk [8,9,10], especially among current smokers, ranging from approximately 10 to 30% [9,10]. Brunet et al [11] reported that smoking might reduce the risk of breast cancer by 44% in carriers of BRCA1 or BRCA2 gene mutations. Wolfe [12] described four different mammographic patterns created by variations in the relative amounts of fat, epithelial and connective tissue in the breast, designated N1, P1, P2 and DY. Women with either P2 or DY pattern are considered at greater risk for breast cancer than those with N1 or P1 pattern [12,13,14,15]. There are no published studies that assessed the relationship between smoking and mammographic parenchymal patterns.
Aims:
To evaluate whether mammographic parenchymal patterns as classified by Wolfe, which have been positively associated with breast cancer risk, are affected by smoking. In this case-control study, nested within the European Prospective Investigation on Cancer in Norfolk (EPIC-Norfolk) cohort [16], the association between smoking habits and mammographic parenchymal patterns are examined. The full results will be published elsewhere.
Methods:
Study subjects were members of the EPIC cohort in Norwich who also attended the prevalence screening round at the Norwich Breast Screening Centre between November 1989 and December 1997, and were free of breast cancer at that screening. Cases were defined as women with a P2/DY Wolfe's mammographic parenchymal pattern on the prevalence screen mammograms. A total of 203 women with P2/DY patterns were identified as cases and were individually matched by date of birth (within 1 year) and date of prevalence screening (within 3 months) with 203 women with N1/P1 patterns who served as control individuals.
Two views, the mediolateral and craniocaudal mammograms, of both breasts were independently reviewed by two of the authors (ES and RW) to determine the Wolfe mammographic parenchymal pattern.
Considerable information on health and lifestyle factors was available from the EPIC Health and Lifestyle Questionnaire [16]. In the present study we examined the subjects' personal history of benign breast diseases, menstrual and reproductive factors, oral contraception and hormone replacement therapy, smoking, and anthropometric information such as body mass index and waist:hip ratio.
Odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated by conditional logistic regression [17], and were adjusted for possible confounding factors.
Results:
The characteristics of the cases and controls are presented in Table 1. Cases were leaner than controls. A larger percentage of cases were nulliparous, premenopausal, current hormone replacement therapy users, had a personal history of benign breast diseases, and had had a hysterectomy. A larger proportion of controls had more than three births and were current smokers.
Table 2 shows the unadjusted and adjusted OR estimates for Wolfe's high-risk mammographic parenchymal patterns and smoking in the total study population and in postmenopausal women separately. Current smoking was strongly and inversely associated with high-risk patterns, after adjustment for concomitant risk factors. Relative to never smokers, current smokers were significantly less likely to have a high-risk pattern (OR 0.37, 95% CI 0.14-0.94). Similar results were obtained when the analysis was confined to postmenopausal women. Past smoking was not related to mammographic parenchymal patterns. The overall effect in postmenopausal women lost its significance when adjusted for other risk factors for P2/DY patterns that were found to be significant in the present study, although the results were still strongly suggestive. There was no interaction between cigarette smoking and body mass index.
Discussion:
In the present study we found a strong inverse relationship between current smoking and high-risk mammographic parenchymal patterns of breast tissue as classified by Wolfe [12]. These findings are not completely unprecedented; Greendale et al [18] found a reduced risk of breast density in association with smoking, although the magnitude of the reduction was unclear. The present findings suggest that this reduction is large.
Recent studies [9,10] have suggested that breast cancer risk may be reduced among current smokers. In a multicentre Italian case-control study, Braga et al [10] found that, relative to nonsmokers, current smokers had a reduced risk of breast cancer (OR 0.84, 95% CI 0.7-1.0). These findings were recently supported by Gammon et al [9], who reported that breast cancer risk in younger women (younger than 45 years) may be reduced among current smokers who began smoking at an early age (OR 0.59, 95% CI 0.41-0.85 for age 15 years or younger) and among long-term smokers (OR 0.70, 95% CI 0.52-0.94 for those who had smoked for 21 years or more).
The possible protective effect of smoking might be due to its anti-oestrogenic effect [1,2,19]. Recently there has been renewed interest in the potential effect of smoking on breast cancer risk, and whether individuals may respond differently on the basis of differences in metabolism of bioproducts of smoking [20,21]. Different relationships between smoking and breast cancer risk have been suggested that are dependent on the rapid or slow status of acetylators of aromatic amines [20,21]. More recent studies [22,23], however, do not support these findings.
The present study design minimized the opportunity for bias to influence the findings. Because subjects were unaware of their own case-control status, the possibility of recall bias in reporting smoking status was minimized. Systematic error in the assessment of mammograms was avoided because reading was done without knowledge of the risk factor data. Furthermore, the associations observed are unlikely to be explained by the confounding effect of other known breast cancer risk factors, because we adjusted for these in the analysis. We did not have information on passive smoking status, however, which has recently been reported to be a possible confounder [5,6,21,24].
The present data indicate that adjustment for current smoking status is important when evaluating the relationship between mammographic parenchymal pattern and breast cancer risk. They also indicate smoking as a prominent potential confounder when analyzing effects of other risk factors such as obesity-related variables. It seems that parenchymal patterns may act as an informative biomarker of the effect of cigarette smoking on breast cancer risk.
PMCID: PMC13911  PMID: 11056684
mammography; screening; smoking; Wolfe's parenchymal patterns
17.  Familial breast cancer: a controlled study of risk perception, psychological morbidity and health beliefs in women attending for genetic counselling. 
British Journal of Cancer  1996;74(3):482-487.
The present study set out to evaluate perceptions of risk, psychological morbidity and health behaviours in women with a family history of breast cancer who have attended genetic counselling and determine how these differ from general population risk women. Data were collected from 62 genetic counselees (cases) attending the Royal Marsden and Mayday University Hospital genetic counselling services and 62 matched GP attenders (controls). Levels of general psychological morbidity were found to be similar between cases and controls; however, cases reported significantly higher breast cancer-specific distress despite clinic attendance [mean (s.d.) total Impact of Event Scale score, 14.1 (14.3) cases; 2.4 (6.7) controls, P < 0.001]. Although cases perceived themselves to be more susceptible to breast cancer, many women failed correctly to recall risk figures provided by the clinic; 66% could not accurately recall their own lifetime chance. Clinics appeared to have a positive impact on preventive behaviours and cases tended to engage more regularly in breast self-examination (monthly, 66% of cases vs 47% of controls), although few differences were found between groups in terms of health beliefs. We conclude that counselees and GP controls showed considerable similarities on many of the outcome measures, and risk of breast cancer was not predictive of greater psychological morbidity; although cases were more vulnerable to cancer-specific distress. Despite genetic counselling, many cases continued to perceive their risk of breast cancer inaccurately.
PMCID: PMC2074635  PMID: 8695370
18.  Behavioral and psychosocial effects of rapid genetic counseling and testing in newly diagnosed breast cancer patients: Design of a multicenter randomized clinical trial 
BMC Cancer  2011;11:6.
Background
It has been estimated that between 5% and 10% of women diagnosed with breast cancer have a hereditary form of the disease, primarily caused by a BRCA1 or BRCA2 gene mutation. Such women have an increased risk of developing a new primary breast and/or ovarian tumor, and may therefore opt for preventive surgery (e.g., bilateral mastectomy, oophorectomy). It is common practice to offer high-risk patients genetic counseling and DNA testing after their primary treatment, with genetic test results being available within 4-6 months. However, some non-commercial laboratories can currently generate test results within 3 to 6 weeks, and thus make it possible to provide rapid genetic counseling and testing (RGCT) prior to primary treatment. The aim of this study is to determine the effect of RGCT on treatment decisions and on psychosocial health.
Methods/Design
In this randomized controlled trial, 255 newly diagnosed breast cancer patients with at least a 10% risk of carrying a BRCA gene mutation are being recruited from 12 hospitals in the Netherlands. Participants are randomized in a 2:1 ratio to either a RGCT intervention group (the offer of RGCT directly following diagnosis with tests results available before surgical treatment) or to a usual care control group. The primary behavioral outcome is the uptake of direct bilateral mastectomy or delayed prophylactic contralateral mastectomy. Psychosocial outcomes include cancer risk perception, cancer-related worry and distress, health-related quality of life, decisional satisfaction and the perceived need for and use of additional decisional counseling and psychosocial support. Data are collected via medical chart audits and self-report questionnaires administered prior to randomization, and at 6 month and at 12 month follow-up.
Discussion
This trial will provide essential information on the impact of RGCT on the choice of primary surgical treatment among women with breast cancer with an increased risk of hereditary cancer. This study will also provide data on the psychosocial consequences of RGCT and of risk-reducing behavior.
Trial registration
The study is registered at the Netherlands Trial Register (NTR1493) and ClinicalTrials.gov (NCT00783822).
doi:10.1186/1471-2407-11-6
PMCID: PMC3022885  PMID: 21219598
19.  The Effectiveness of Community Action in Reducing Risky Alcohol Consumption and Harm: A Cluster Randomised Controlled Trial 
PLoS Medicine  2014;11(3):e1001617.
In a cluster randomized controlled trial, Anthony Shakeshaft and colleagues measure the effectiveness of a multi-component community-based intervention for reducing alcohol-related harm.
Background
The World Health Organization, governments, and communities agree that community action is likely to reduce risky alcohol consumption and harm. Despite this agreement, there is little rigorous evidence that community action is effective: of the six randomised trials of community action published to date, all were US-based and focused on young people (rather than the whole community), and their outcomes were limited to self-report or alcohol purchase attempts. The objective of this study was to conduct the first non-US randomised controlled trial (RCT) of community action to quantify the effectiveness of this approach in reducing risky alcohol consumption and harms measured using both self-report and routinely collected data.
Methods and Findings
We conducted a cluster RCT comprising 20 communities in Australia that had populations of 5,000–20,000, were at least 100 km from an urban centre (population ≥ 100,000), and were not involved in another community alcohol project. Communities were pair-matched, and one member of each pair was randomly allocated to the experimental group. Thirteen interventions were implemented in the experimental communities from 2005 to 2009: community engagement; general practitioner training in alcohol screening and brief intervention (SBI); feedback to key stakeholders; media campaign; workplace policies/practices training; school-based intervention; general practitioner feedback on their prescribing of alcohol medications; community pharmacy-based SBI; web-based SBI; Aboriginal Community Controlled Health Services support for SBI; Good Sports program for sports clubs; identifying and targeting high-risk weekends; and hospital emergency department–based SBI. Primary outcomes based on routinely collected data were alcohol-related crime, traffic crashes, and hospital inpatient admissions. Routinely collected data for the entire study period (2001–2009) were obtained in 2010. Secondary outcomes based on pre- and post-intervention surveys (n = 2,977 and 2,255, respectively) were the following: long-term risky drinking, short-term high-risk drinking, short-term risky drinking, weekly consumption, hazardous/harmful alcohol use, and experience of alcohol harm. At the 5% level of statistical significance, there was insufficient evidence to conclude that the interventions were effective in the experimental, relative to control, communities for alcohol-related crime, traffic crashes, and hospital inpatient admissions, and for rates of risky alcohol consumption and hazardous/harmful alcohol use. Although respondents in the experimental communities reported statistically significantly lower average weekly consumption (1.90 fewer standard drinks per week, 95% CI = −3.37 to −0.43, p = 0.01) and less alcohol-related verbal abuse (odds ratio = 0.58, 95% CI = 0.35 to 0.96, p = 0.04) post-intervention, the low survey response rates (40% and 24% for the pre- and post-intervention surveys, respectively) require conservative interpretation. The main limitations of this study are as follows: (1) that the study may have been under-powered to detect differences in routinely collected data outcomes as statistically significant, and (2) the low survey response rates.
Conclusions
This RCT provides little evidence that community action significantly reduces risky alcohol consumption and alcohol-related harms, other than potential reductions in self-reported average weekly consumption and experience of alcohol-related verbal abuse. Complementary legislative action may be required to more effectively reduce alcohol harms.
Trial registration
Australian New Zealand Clinical Trials Registry ACTRN12607000123448
Please see later in the article for the Editors' Summary
Editors' Summary
Background
People have consumed alcoholic beverages throughout history, but alcohol use is now an increasing global public health problem. According to the World Health Organization's 2010 Global Burden of Disease Study, alcohol use is the fifth leading risk factor (after high blood pressure and smoking) for disease and is responsible for 3.9% of the global disease burden. Alcohol use contributes to heart disease, liver disease, depression, some cancers, and many other health conditions. Alcohol also affects the well-being and health of people around those who drink, through alcohol-related crimes and road traffic crashes. The impact of alcohol use on disease and injury depends on the amount of alcohol consumed and the pattern of drinking. Most guidelines define long-term risky drinking as more than four drinks per day on average for men or more than two drinks per day for women (a “drink” is, roughly speaking, a can of beer or a small glass of wine), and short-term risky drinking (also called binge drinking) as seven or more drinks on a single occasion for men or five or more drinks on a single occasion for women. However, recent changes to the Australian guidelines acknowledge that a lower level of alcohol consumption is considered risky (with lifetime risky drinking defined as more than two drinks a day and binge drinking defined as more than four drinks on one occasion).
Why Was This Study Done?
In 2010, the World Health Assembly endorsed a global strategy to reduce the harmful use of alcohol. This strategy emphasizes the importance of community action–a process in which a community defines its own needs and determines the actions that are required to meet these needs. Although community action is highly acceptable to community members, few studies have looked at the effectiveness of community action in reducing risky alcohol consumption and alcohol-related harm. Here, the researchers undertake a cluster randomized controlled trial (the Alcohol Action in Rural Communities [AARC] project) to quantify the effectiveness of community action in reducing risky alcohol consumption and harms in rural communities in Australia. A cluster randomized trial compares outcomes in clusters of people (here, communities) who receive alternative interventions assigned through the play of chance.
What Did the Researchers Do and Find?
The researchers pair-matched 20 rural Australian communities according to the proportion of their population that was Aboriginal (rates of alcohol-related harm are disproportionately higher among Aboriginal individuals than among non-Aboriginal individuals in Australia; they are also higher among young people and males, but the proportions of these two groups across communities was comparable). They randomly assigned one member of each pair to the experimental group and implemented 13 interventions in these communities by negotiating with key individuals in each community to define and implement each intervention. Examples of interventions included general practitioner training in screening for alcohol use disorders and in implementing a brief intervention, and a school-based interactive session designed to reduce alcohol harm among young people. The researchers quantified the effectiveness of the interventions using routinely collected data on alcohol-related crime and road traffic crashes, and on hospital inpatient admissions for alcohol dependence or abuse (which were expected to increase in the experimental group if the intervention was effective because of more people seeking or being referred for treatment). They also examined drinking habits and experiences of alcohol-related harm, such as verbal abuse, among community members using pre- and post-intervention surveys. After implementation of the interventions, the rates of alcohol-related crime, road traffic crashes, and hospital admissions, and of risky and hazardous/harmful alcohol consumption (measured using a validated tool called the Alcohol Use Disorders Identification Test) were not statistically significantly different in the experimental and control communities (a difference in outcomes that is not statistically significantly different can occur by chance). However, the reported average weekly consumption of alcohol was 20% lower in the experimental communities after the intervention than in the control communities (equivalent to 1.9 fewer standard drinks per week per respondent) and there was less alcohol-related verbal abuse post-intervention in the experimental communities than in the control communities.
What Do These Findings Mean?
These findings provide little evidence that community action reduced risky alcohol consumption and alcohol-related harms in rural Australian communities. Although there was some evidence of significant reductions in self-reported weekly alcohol consumption and in experiences of alcohol-related verbal abuse, these findings must be interpreted cautiously because they are based on surveys with very low response rates. A larger or differently designed study might provide statistically significant evidence for the effectiveness of community action in reducing risky alcohol consumption. However, given their findings, the researchers suggest that legislative approaches that are beyond the control of individual communities, such as alcohol taxation and restrictions on alcohol availability, may be required to effectively reduce alcohol harms. In other words, community action alone may not be the most effective way to reduce alcohol-related harm.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001617.
The World Health Organization provides detailed information about alcohol; its fact sheet on alcohol includes information about the global strategy to reduce the harmful use of alcohol; the Global Information System on Alcohol and Health provides further information about alcohol, including information on control policies around the world
The US National Institute on Alcohol Abuse and Alcoholism has information about alcohol and its effects on health
The US Centers for Disease Control and Prevention has a website on alcohol and public health that includes information on the health risks of excessive drinking
The UK National Health Service Choices website provides detailed information about drinking and alcohol, including information on the risks of drinking too much, tools for calculating alcohol consumption, and personal stories about alcohol use problems
MedlinePlus provides links to many other resources on alcohol
More information about the Alcohol Action in Rural Communities project is available
doi:10.1371/journal.pmed.1001617
PMCID: PMC3949675  PMID: 24618831
20.  Longitudinal Changes in Patient Distress following Interactive Decision Aid Use among BRCA1/2 Carriers: A Randomized Trial 
Background
Increasingly, women with a strong family history of breast cancer are seeking genetic testing as a starting point to making significant decisions regarding management of their cancer risks. Individuals who are found to be carriers of a BRCA1 or BRCA2 mutation have a substantially elevated risk for breast cancer and are frequently faced with the decision of whether or not to undergo risk reducing mastectomy.
Objective
In order to provide BRCA1/2 carriers with ongoing decision support for breast cancer risk management, a computer-based interactive decision aid was developed and tested against usual care in a randomized controlled trial.
Design
Following genetic counseling, 214 female (aged 21-75) BRCA1/2 mutation carriers were randomized to Usual Care (UC; N=114) or Usual Care plus Decision Aid (DA; N=100) arms. UC participants received no further intervention; DA participants were sent the CD-ROM based decision aid to view at home.
Main Outcome Measures
The authors measured general distress, cancer specific distress and genetic testing specific distress at 1-, 6- and 12-month follow up time points, post-randomization.
Results
Longitudinal analyses revealed a significant longitudinal impact of the DA on cancer specific distress (B= 5.67, z = 2.81, p = 0.005) which varied over time (DA group by time; B = -2.19, z = -2.47, p = 0.01) and on genetic testing specific distress (B = 5.55, z = 2.46, p = 0.01) which also varied over time (DA group by time; B= -2.46, z = -2.51, p = 0.01). Individuals randomized to UC reported significantly decreased distress in the month following randomization, whereas individuals randomized to the DA maintained their post-disclosure distress over the short-term. By 12-months, the overall decrease in distress between the two groups was similar.
Conclusion
This report provides new insight into the long-term longitudinal effects of DAs.
doi:10.1177/0272989X10381283
PMCID: PMC3935602  PMID: 20876346
21.  Breast Cancer in Canadian Women 
BMC Women's Health  2004;4(Suppl 1):S12.
Health issue
Although lung cancer is the leading cause of cancer deaths for Canadian women, breast cancer is the most frequently diagnosed. About 5400 women are expected to die from this disease in 2003. In 1998, a woman's lifetime risk of breast cancer was about one in nine.
Key findings
A number of risk factors for breast cancer have been identified. These include advancing age, hormonal factors (eg. early menarche, late menopause and late age at first full-term pregnancy), familial risk, BRCA-1 and BRCA-2 gene mutations, diet and postmenopausal obesity.
Several interventions have been introduced to assist women at high risk for breast cancer, including genetic counseling and testing for women who have strong family histories of breast cancer; selective estrogen receptor modifiers, such as tamoxifen, that has been shown to reduce breast cancer rates; prophylactic mastectomy and screening.
Data gaps and recommendations
Guidelines are unclear in several areas, particularly in screening. Where clinical guidelines are available, health services research or ongoing monitoring (by provincial/territorial cancer agencies) is needed to assess compliance with the guidelines and to ensure equity of access within the provinces/territories.
Key components of organized screening programs need to be established, in part to ensure that screening is carried out in high-quality, co-ordinated programs. There is also a need to develop ways to involve women fully in informed decision-making and to address several policy issues to prevent disparities in access to high-quality services. Patenting issues associated with genetic tests also need to be clarified.
doi:10.1186/1472-6874-4-S1-S12
PMCID: PMC2096672  PMID: 15345075
22.  To know or not to know? Not the only question in familial breast cancer risk communication 
ecancermedicalscience  2011;5:239.
Background
Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in females, 5–10% of these breast cancers occur in women because of an inherited mutation. The term ‘risk’ in relation to familial cancer can have multiple meanings for both clinicians and patients. Failing to identify and address this may impair effective communication and informed decision making and adversely affect the quality of patient care.
The aim of this research for the Eurocancercoms project was to explore patients' experience of risk communication in breast cancer and to investigate a mechanism for sharing these experiences using a filmed round-table discussion (RTD).
Methods
A filmed RTD with six women who had experience of, or some connection with familial breast cancer was conducted. Criteria for inclusion included a willingness and ability to participate in the discussion in English and to be prepared for the discussion to be hosted online with opportunities for others to view and comment.
Results
The main findings are presented as key themes and issues arising from the RTD. There was consistency in the group on the need for improvements to the risk communication process as a whole and in particular around onward diffusion of information i.e. ‘Telling the family’. There were differences regarding ‘wanting to know’ their genetic status.
Conclusions
The perception of cancer risk in the narratives stems not only from the way risks are stated, but from family history, personal experiences, cultural norms and beliefs and therefore a multifaceted approach to risk communication addressing these issues is necessary to ensure the patient fully understands the potential risks. There is a balance when attending to patient's information needs, as to what level and amount of information is required by the individual at a particular time and communicators need to be able to tailor information accordingly.
doi:10.3332/ecancer.2011.239
PMCID: PMC3251510  PMID: 22276070
23.  Chemoprevention of breast cancer: A joint guideline from the Canadian Task Force on Preventive Health Care and the Canadian Breast Cancer Initiative's Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer 
Objective
To assist women and their physicians in making decisions regarding the prevention of breast cancer with tamoxifen and raloxifene.
Evidence
Systematic review of English-language literature published from 1966 to August 2000 retrieved from MEDLINE, HealthSTAR, Current Contents and Cochrane Library.
Values
The strength of evidence was evaluated using the methods of the Canadian Task Force on Preventive Health Care and the Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer.
Recommendations
· Women at low or normal risk of breast cancer (Gail risk assessment index < 1.66% at 5 years): There is fair evidence to recommend against the use of tamoxifen to reduce the risk of breast cancer in women at low or normal risk of the disease (grade D recommendation). · Women at higher risk of breast cancer (Gail index ≥ 1.66% at 5 years): Evidence supports counselling women at high risk on the potential benefits and harms of breast cancer prevention with tamoxifen (grade B recommendation). The cutoff for defining high risk is arbitrary, but the National Surgical Adjuvant Breast and Bowel Project P-1 Study included women with a 5-year projected risk of at least 1.66% according to the Gail index, and the average risk of patients entered in the trial was 3.2%. Examples of high-risk clinical situations are 2 first-degree relatives with breast cancer, a history of lobular carcinoma in situ or a history of atypical hyperplasia. As the risk of breast cancer increases above 5% and the benefits outweigh the harms, a woman may choose to take tamoxifen. The duration of tamoxifen use in such situations is 5 years based on the results from trials of tamoxifen involving women with early breast cancer. If a woman raises concerns or has already been evaluated and is calculated to be at high risk, then individuals experienced and skilled in counselling may discuss the potential benefits and harms of tamoxifen use.
Important additional issues
· Prevention of breast cancer with raloxifene: Current evidence does not support recommending chemoprevention of breast cancer with raloxifene outside of a clinical trial setting. · Screening using the Gail risk assessment index: This index was the main eligibility criterion for enrolling women in the one study that showed potential benefit from chemoprevention. However, it has not been evaluated for use as a routine screening or case-finding instrument; validation of the index is required. Overall, current evidence does not support a shift to its routine use in physicians' offices for screening or case finding. However, when a woman or her physician is concerned about the woman's increased risk of breast cancer, the index can be a useful tool in deciding whether to pursue an in-depth discussion of the potential benefits and harms of chemoprevention. Hence, the approach to identifying women at higher risk who warrant counselling and shared decision-making will vary across practices. (The risk assessment index is available online at http://bcra.nci.nih.gov/brc/). [A patient version of these guidelines appears in Appendix 2.]
Validation
The authors' original text was revised by both the Canadian Task Force on Preventive Health Care and the Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer. The final document reflects a consensus of these contributors.
Sponsor
Health Canada.
Completion date
February 2001.
PMCID: PMC81154  PMID: 11450210
24.  Communicating Side Effect Risks in a Tamoxifen Prophylaxis Decision Aid: The Debiasing Influence of Pictographs 
Patient education and counseling  2008;73(2):209-214.
Objective:
To experimentally test whether using pictographs (image matrices), incremental risk formats, and varied risk denominators would influence perceptions and comprehension of side effect risks in an online decision aid about prophylactic use of tamoxifen to prevent primary breast cancers.
Methods:
We recruited 631 women with elevated breast cancer risk from two healthcare organizations. Participants saw tailored estimates of the risks of 5 side effects: endometrial cancer, blood clotting, cataracts, hormonal symptoms, and sexual problems. Presentation format was randomly varied in a three factor design: (A) Risk information was displayed either in pictographs or numeric text; (B) presentations either reported total risks with and without tamoxifen or highlighted the incremental risk most relevant for decision making; and (C) risk estimates used 100 or 1000 person denominators. Primary outcome measures included risk perceptions and gist knowledge.
Results:
Incremental risk formats consistently lowered perceived risk of side effects but resulted in low knowledge when displayed by numeric text only. Adding pictographs, however, produced significantly higher comprehension levels.
Conclusions:
Pictographs make risk statistics easier to interpret, reducing biases associated with incremental risk presentations.
Practice Implications:
Including graphs in risk communications is essential to supporting an informed treatment decision making process.
doi:10.1016/j.pec.2008.05.010
PMCID: PMC2649664  PMID: 18602242
risk communication; decision aids; cognitive biases; patient education
25.  Breast density as indicator for the use of mammography or MRI to screen women with familial risk for breast cancer (FaMRIsc): a multicentre randomized controlled trial 
BMC Cancer  2012;12:440.
Background
To reduce mortality, women with a family history of breast cancer often start mammography screening at a younger age than the general population. Breast density is high in over 50% of women younger than 50 years. With high breast density, breast cancer incidence increases, but sensitivity of mammography decreases. Therefore, mammography might not be the optimal method for breast cancer screening in young women. Adding MRI increases sensitivity, but also the risk of false-positive results. The limitation of all previous MRI screening studies is that they do not contain a comparison group; all participants received both MRI and mammography. Therefore, we cannot empirically assess in which stage tumours would have been detected by either test.
The aim of the Familial MRI Screening Study (FaMRIsc) is to compare the efficacy of MRI screening to mammography for women with a familial risk. Furthermore, we will assess the influence of breast density.
Methods/Design
This Dutch multicentre, randomized controlled trial, with balanced randomisation (1:1) has a parallel grouped design. Women with a cumulative lifetime risk for breast cancer due to their family history of ≥20%, aged 30–55 years are eligible. Identified BRCA1/2 mutation carriers or women with 50% risk of carrying a mutation are excluded. Group 1 receives yearly mammography and clinical breast examination (n = 1000), and group 2 yearly MRI and clinical breast examination, and mammography biennially (n = 1000).
Primary endpoints are the number and stage of the detected breast cancers in each arm. Secondary endpoints are the number of false-positive results in both screening arms. Furthermore, sensitivity and positive predictive value of both screening strategies will be assessed. Cost-effectiveness of both strategies will be assessed. Analyses will also be performed with mammographic density as stratification factor.
Discussion
Personalized breast cancer screening might optimize mortality reduction with less over diagnosis. Breast density may be a key discriminator for selecting the optimal screening strategy for women < 55 years with familial breast cancer risk; mammography or MRI. These issues are addressed in the FaMRIsc study including high risk women due to a familial predisposition.
Trial registration
Netherland Trial Register NTR2789
doi:10.1186/1471-2407-12-440
PMCID: PMC3488502  PMID: 23031619
Breast cancer; Familial risk; Screening; MRI; Breast density; Cost-effectiveness

Results 1-25 (999956)