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1.  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
2.  Poor Physical Health Predicts Time to Additional Breast Cancer Events and Mortality in Breast Cancer Survivors 
Psycho-Oncology  2011;20(3):252-259.
Background
Health-related quality of life (HRQOL) has been hypothesized to predict time to additional breast cancer events and all-cause mortality in breast cancer survivors.
Methods
Women with early stage breast cancer (n=2967) completed the SF-36 (mental and physical health-related quality of life) and standardized psychosocial questionnaires to assess social support, optimism, hostility, and depression prior to randomization into a dietary trial. Cox regression was performed to assess whether these measures of quality of life and psychosocial functioning predicted time to additional breast cancer events and all-cause mortality; hazard ratios were the measure of association.
Results
There were 492 additional breast cancer events and 301 deaths occurred over a median 7.3 years (range: 0.01–10.8 years) of follow-up. In multivariate models, poorer physical health was associated with both decreased time to additional breast cancer events and all-cause mortality (p trend=0.005 and 0.004, respectively), while greater hostility predicted additional breast cancer events only (p trend=0.03). None of the other psycho-social variables predicted either outcome. The hazard ratios comparing persons with poor (bottom two quintiles) to better (top three quintiles) physical health were 1.42 (95% CI: 1.16, 1.75) for decreased time to additional breast cancer events and 1.37 (95% CI: 1.08, 1.74) for all-cause mortality. Potentially modifiable factors associated with poor physical health included higher BMI, lower physical activity, lower alcohol consumption, and more insomnia (p<0.05 for all).
Conclusion
Interventions to improve physical health should be tested as a means to increase time to additional breast cancer events and mortality among breast cancer survivors.
doi:10.1002/pon.1742
PMCID: PMC3297415  PMID: 20878837
physical health; breast cancer; oncology; survival
3.  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
4.  Combined Impact of Health Behaviours and Mortality in Men and Women: The EPIC-Norfolk Prospective Population Study 
PLoS Medicine  2008;5(1):e12.
Background
There is overwhelming evidence that behavioural factors influence health, but their combined impact on the general population is less well documented. We aimed to quantify the potential combined impact of four health behaviours on mortality in men and women living in the general community.
Methods and Findings
We examined the prospective relationship between lifestyle and mortality in a prospective population study of 20,244 men and women aged 45–79 y with no known cardiovascular disease or cancer at baseline survey in 1993–1997, living in the general community in the United Kingdom, and followed up to 2006. Participants scored one point for each health behaviour: current non-smoking, not physically inactive, moderate alcohol intake (1–14 units a week) and plasma vitamin C >50 mmol/l indicating fruit and vegetable intake of at least five servings a day, for a total score ranging from zero to four. After an average 11 y follow-up, the age-, sex-, body mass–, and social class–adjusted relative risks (95% confidence intervals) for all-cause mortality(1,987 deaths) for men and women who had three, two, one, and zero compared to four health behaviours were respectively, 1.39 (1.21–1.60), 1.95 (1.70–-2.25), 2.52 (2.13–3.00), and 4.04 (2.95–5.54) p < 0.001 trend. The relationships were consistent in subgroups stratified by sex, age, body mass index, and social class, and after excluding deaths within 2 y. The trends were strongest for cardiovascular causes. The mortality risk for those with four compared to zero health behaviours was equivalent to being 14 y younger in chronological age.
Conclusions
Four health behaviours combined predict a 4-fold difference in total mortality in men and women, with an estimated impact equivalent to 14 y in chronological age.
From a large prospective population study, Kay-Tee Khaw and colleagues estimate the combined impact of four behaviors--not smoking, not being physically inactive, moderate alcohol intake, and at least five vegetable servings a day--amounts to 14 additional years of life.
Editors' Summary
Background.
Every day, or so it seems, new research shows that some aspect of lifestyle—physical activity, diet, alcohol consumption, and so on—affects health and longevity. For the person in the street, all this information is confusing. What is a healthy diet, for example? Although there are some common themes such as the benefit of eating plenty of fruit and vegetables, the details often differ between studies. And exactly how much physical activity is needed to improve health? Is a gentle daily walk sufficient or simply a stepping stone to doing enough exercise to make a real difference? The situation with alcohol consumption is equally confusing. Small amounts of alcohol apparently improve health but large amounts are harmful. As a result, it can be hard for public-health officials to find effective ways to encourage the behavioral changes that the scientific evidence suggests might influence the health of populations.
Why Was This Study Done?
There is another factor that is hindering official attempts to provide healthy lifestyle advice to the public. Although there is overwhelming evidence that individual behavioral factors influence health, there is very little information about their combined impact. If the combination of several small differences in lifestyle could be shown to have a marked effect on the health of populations, it might be easier to persuade people to make behavioral changes to improve their health, particularly if those changes were simple and relatively easy to achieve. In this study, which forms part of the European Prospective Investigation into Cancer and Nutrition (EPIC), the researchers have examined the relationship between lifestyle and the risk of dying using a health behavior score based on four simply defined behaviors—smoking, physical activity, alcohol drinking, and fruit and vegetable intake.
What Did the Researchers Do and Find?
Between 1993 and 1997, about 20,000 men and women aged 45–79 living in Norfolk UK, none of whom had cancer or cardiovascular disease (heart or circulation problems), completed a health and lifestyle questionnaire, had a health examination, and had their blood vitamin C level measured as part of the EPIC-Norfolk study. A health behavior score of between 0 and 4 was calculated for each participant by giving one point for each of the following healthy behaviors: current non-smoking, not physically inactive (physical inactivity was defined as having a sedentary job and doing no recreational exercise), moderate alcohol intake (1–14 units a week; a unit of alcohol is half a pint of beer, a glass of wine, or a shot of spirit), and a blood vitamin C level consistent with a fruit and vegetable intake of at least five servings a day. Deaths among the participants were then recorded until 2006. After allowing for other factors that might have affected their likelihood of dying (for example, age), people with a health behavior score of 0 were four times as likely to have died (in particular, from cardiovascular disease) than those with a score of 4. People with a score of 2 were twice as likely to have died.
What Do These Findings Mean?
These findings indicate that the combination of four simply defined health behaviors predicts a 4-fold difference in the risk of dying over an average period of 11 years for middle-aged and older people. They also show that the risk of death (particularly from cardiovascular disease) decreases as the number of positive health behaviors increase. Finally, they can be used to calculate that a person with a health score of 0 has the same risk of dying as a person with a health score of 4 who is 14 years older. These findings need to be confirmed in other populations and extended to an analysis of how these combined health behaviors affect the quality of life as well as the risk of death. Nevertheless, they strongly suggest that modest and achievable lifestyle changes could have a marked effect on the health of populations. Armed with this information, public-health officials should now be in a better position to encourage behavior changes likely to improve the health of middle-aged and older people.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050012.
The MedlinePlus encyclopedia contains a page on healthy living (in English and Spanish)
The MedlinePlus page on seniors' health contains links to many sites dealing with healthy lifestyles and longevity (in English and Spanish)
The European Prospective Investigation into Cancer and Nutrition (EPIC) study is investigating the relationship between nutrition and lifestyle and the development of cancer and other chronic diseases; information about the EPIC-Norfolk study is also available
The US Centers for Disease Control and Prevention provides information on healthy aging for older adults, including information on health-related behaviors (in English and Spanish)
The UK charity Age Concerns provides a fact sheet about staying healthy in later life
The London Health Observatory, which provides information for policy makers and practitioners about improving health and health care, has a section on how lifestyle and behavior affect health
doi:10.1371/journal.pmed.0050012
PMCID: PMC2174962  PMID: 18184033
5.  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
6.  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
7.  Gene Expression Profiling for Guiding Adjuvant Chemotherapy Decisions in Women with Early Breast Cancer 
Executive Summary
In February 2010, the Medical Advisory Secretariat (MAS) began work on evidence-based reviews of published literature surrounding three pharmacogenomic tests. This project came about when Cancer Care Ontario (CCO) asked MAS to provide evidence-based analyses on the effectiveness and cost-effectiveness of three oncology pharmacogenomic tests currently in use in Ontario.
Evidence-based analyses have been prepared for each of these technologies. These have been completed in conjunction with internal and external stakeholders, including a Provincial Expert Panel on Pharmacogenomics (PEPP). Within the PEPP, subgroup committees were developed for each disease area. For each technology, an economic analysis was also completed by the Toronto Health Economics and Technology Assessment Collaborative (THETA) and is summarized within the reports.
The following reports can be publicly accessed at the MAS website at: www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.html
Gene Expression Profiling for Guiding Adjuvant Chemotherapy Decisions in Women with Early Breast Cancer: An Evidence-Based and Economic Analysis
Epidermal Growth Factor Receptor Mutation (EGFR) Testing for Prediction of Response to EGFR-Targeting Tyrosine Kinase Inhibitor (TKI) Drugs in Patients with Advanced Non-Small-Cell Lung Cancer: An Evidence-Based and Ecopnomic Analysis
K-RAS testing in Treatment Decisions for Advanced Colorectal Cancer: an Evidence-Based and Economic Analysis
Objective
To review and synthesize the available evidence regarding the laboratory performance, prognostic value, and predictive value of Oncotype-DX for the target population.
Clinical Need: Condition and Target Population
The target population of this review is women with newly diagnosed early stage (stage I–IIIa) invasive breast cancer that is estrogen-receptor (ER) positive and/or progesterone-receptor (PR) positive. Much of this review, however, is relevant for women with early stage (I and II) invasive breast cancer that is specifically ER positive, lymph node (LN) negative and human epidermal growth factor receptor 2 (HER-2/neu) negative. This refined population represents an estimated incident population of 3,315 new breast cancers in Ontario (according to 2007 data). Currently it is estimated that only 15% of these women will develop a distant metastasis at 10 years; however, a far great proportion currently receive adjuvant chemotherapy, suggesting that more women are being treated with chemotherapy than can benefit. There is therefore a need to develop better prognostic and predictive tools to improve the selection of women that may benefit from adjuvant chemotherapy.
Technology of Concern
The Oncotype-DX Breast Cancer Assay (Genomic Health, Redwood City, CA) quantifies gene expression for 21 genes in breast cancer tissue by performing reverse transcription polymerase chain reaction (RT-PCR) on formalin-fixed paraffin-embedded (FFPE) tumour blocks that are obtained during initial surgery (lumpectomy, mastectomy, or core biopsy) of women with early breast cancer that is newly diagnosed. The panel of 21 genes include genes associated with tumour proliferation and invasion, as well as other genes related to HER-2/neu expression, ER expression, and progesterone receptor (PR) expression.
Research Questions
What is the laboratory performance of Oncotype-DX?
How reliable is Oncotype-DX (i.e., how repeatable and reproducible is Oncotype-DX)?
How often does Oncotype-DX fail to give a useable result?
What is the prognostic value of Oncotype-DX?*
Is Oncotype-DX recurrence score associated with the risk of distant recurrence or death due to any cause in women with early breast cancer receiving tamoxifen?
What is the predictive value of Oncotype-DX?*
Does Oncoytpe-DX recurrence score predict significant benefit in terms of improvements in 10-year distant recurrence or death due to any cause for women receiving tamoxifen plus chemotherapy in comparison to women receiving tamoxifen alone?
How does Oncotype-DX compare to other known predictors of risk such as Adjuvant! Online?
How does Oncotype-DX impact patient quality of life and clinical/patient decision-making?
Research Methods
Literature Search
Search Strategy
A literature search was performed on March 19th, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1st, 2006 to March 19th, 2010. A starting search date of January 1st, 2006 was because a comprehensive systematic review of Oncotype-DX was identified in preliminary literature searching. This systematic review, by Marchionni et al. (2008), included literature up to January 1st, 2007. All studies identified in the review by Marchionni et al. as well as those identified in updated literature searching were used to form the evidentiary base of this review. The quality of the overall body of evidence was identified as high, moderate, low or very low according to GRADE methodology.
Inclusion Criteria
Any observational trial, controlled clinical trial, randomized controlled trial (RCT), meta-analysis or systematic review that reported on the laboratory performance, prognostic value and/or predictive value of Oncotype-DX testing, or other outcome relevant to the Key Questions, specific to the target population was included.
Exclusion Criteria
Studies that did not report original data or original data analysis,
Studies published in a language other than English,
Studies reported only in abstract or as poster presentations (such publications were not sought nor included in this review since the MAS does not generally consider evidence that is not subject to peer review nor does the MAS consider evidence that lacks detailed description of methodology).
Outcomes of Interest
Outcomes of interest varied depending on the Key Question. For the Key Questions of prognostic and predictive value (Key Questions #2 and #3), the prospectively defined primary outcome was risk of 10-year distant recurrence. The prospectively defined secondary outcome was 10-year death due to any cause (i.e., overall survival). All additional outcomes such as risk of locoregional recurrence or disease-free survival (DFS) were not prospectively determined for this review but were reported as presented in included trials; these outcomes are referenced as tertiary outcomes in this review. Outcomes for other Key Questions (i.e., Key Questions #1, #4 and #5) were not prospectively defined due to the variability in endpoints relevant for these questions.
Summary of Findings
A total of 26 studies were included. Of these 26 studies, only five studies were relevant to the primary questions of this review (Key Questions #2 and #3). The following conclusions were drawn from the entire body of evidence:
There is a lack of external validation to support the reliability of Oncotype-DX; however, the current available evidence derived from internal industry validation studies suggests that Oncotype-DX is reliable (i.e., Oncotype-DX is repeatable and reproducible).
Current available evidence suggests a moderate failure rate of Oncotype-DX testing; however, the failure rate observed across clinical trials included in this review is likely inflated; the current Ontario experience suggests an acceptably lower rate of test failure.
In women with newly diagnosed early breast cancer (stage I–II) that is estrogen-receptor positive and/or progesterone-receptor positive and lymph-node negative:
There is low quality evidence that Oncotype-DX has prognostic value in women who are being treated with adjuvant tamoxifen or anastrozole (the latter for postmenopausal women only),
There is very low quality evidence that Oncotype-DX can predict which women will benefit from adjuvant CMF/MF chemotherapy in women being treated with adjuvant tamoxifen.
In postmenopausal women with newly diagnosed early breast cancer that is estrogen-receptor positive and/or progesterone-receptor positive and lymph-node positive:
There is low quality evidence that Oncotype-DX has limited prognostic value in women who are being treated with adjuvant tamoxifen or anastrozole,
There is very low quality evidence that Oncotype-DX has limited predictive value for predicting which women will benefit from adjuvant CAF chemotherapy in women who are being treated with adjuvant tamoxifen.
There are methodological and statistical limitations that affect both the generalizability of the current available evidence, as well as the magnitude and statistical strength of the observed effect sizes; in particular:
Of the major predictive trials, Oncotype-DX scores were only produced for a small subset of women (<40% of the original randomized population) potentially disabling the effects of treatment randomization and opening the possibility of selection bias;
Data is not specific to HER-2/neu-negative women;
There were limitations with multivariate statistical analyses.
Additional trials of observational design may provide further validation of the prognostic and predictive value of Oncotype-DX; however, it is unlikely that prospective or randomized data will become available in the near future due to ethical, time and resource considerations.
There is currently insufficient evidence investigating how Oncoytpe-DX compares to other known prognostic estimators of risk, such as Adjuvant! Online, and there is insufficient evidence investigating how Oncotype-DX would impact clinician/patient decision-making in a setting generalizable to Ontario.
PMCID: PMC3382301  PMID: 23074401
8.  The Alberta moving beyond breast cancer (AMBER) cohort study: a prospective study of physical activity and health-related fitness in breast cancer survivors 
BMC Cancer  2012;12:525.
Background
Limited research has examined the association between physical activity, health-related fitness, and disease outcomes in breast cancer survivors. Here, we present the rationale and design of the Alberta Moving Beyond Breast Cancer (AMBER) Study, a prospective cohort study designed specifically to examine the role of physical activity and health-related fitness in breast cancer survivorship from the time of diagnosis and for the balance of life. The AMBER Study will examine the role of physical activity and health-related fitness in facilitating treatment completion, alleviating treatment side effects, hastening recovery after treatments, improving long term quality of life, and reducing the risks of disease recurrence, other chronic diseases, and premature death.
Methods/Design
The AMBER Study will enroll 1500 newly diagnosed, incident, stage I-IIIc breast cancer survivors in Alberta, Canada over a 5 year period. Assessments will be made at baseline (within 90 days of surgery), 1 year, and 3 years consisting of objective and self-reported measurements of physical activity, health-related fitness, blood collection, lymphedema, patient-reported outcomes, and determinants of physical activity. A final assessment at 5 years will measure patient-reported data only. The cohort members will be followed for an additional 5 years for disease outcomes.
Discussion
The AMBER cohort will answer key questions related to physical activity and health-related fitness in breast cancer survivors including: (1) the independent and interactive associations of physical activity and health-related fitness with disease outcomes (e.g., recurrence, breast cancer-specific mortality, overall survival), treatment completion rates, symptoms and side effects (e.g., pain, lymphedema, fatigue, neuropathy), quality of life, and psychosocial functioning (e.g., anxiety, depression, self-esteem, happiness), (2) the determinants of physical activity and health-related fitness including demographic, medical, social cognitive, and environmental variables, (3) the mediators of any observed associations between physical activity, health-related fitness, and health outcomes including biological, functional, and psychosocial, and (4) the moderators of any observed associations including demographic, medical, and biological/disease factors. Taken together, these data will provide a comprehensive inquiry into the outcomes, determinants, mechanisms, and moderators of physical activity and health-related fitness in breast cancer survivors.
doi:10.1186/1471-2407-12-525
PMCID: PMC3534483  PMID: 23153358
Breast cancer; Exercise; Physical activity; Cardiorespiratory fitness; Muscular strength; Lymphedema; Quality of life; Exercise determinants; Recurrence; Survival
9.  Physical Activity and Survival in Postmenopausal Women with Breast Cancer: Results from the Women’s Health Initiative 
Although studies have shown that physically active breast cancer survivors have lower all-cause mortality, the association between change in physical activity from before to after diagnosis and mortality is not clear. We examined associations among pre- and postdiagnosis physical activity, change in pre- to postdiagnosis physical activity, and all-cause and breast cancer–specific mortality in post-menopausal women. A longitudinal study of 4,643 women diagnosed with invasive breast cancer after entry into the Women’s Health Initiative study of postmenopausal women. Physical activity from recreation and walking was determined at baseline (prediagnosis) and after diagnosis (assessed at the 3 or 6 years post-baseline visit). Women participating in 9 MET-h/wk or more (~3 h/wk of fast walking) of physical activity before diagnosis had a lower all-cause mortality (HR = 0.61; 95% CI, 0.44–0.87; P = 0.01) compared with inactive women in multivariable adjusted analyses. Women participating in ≥9 or more MET-h/wk of physical activity after diagnosis had lower breast cancer mortality (HR = 0.61; 95% CI, 0.35–0.99; P = 0.049) and lower all-cause mortality (HR = 0.54; 95% CI, 0.38–0.79; P < 0.01). Women who increased or maintained physical activity of 9 or more MET-h/wk after diagnosis had lower all-cause mortality (HR = 0.67; 95% CI, 0.46–0.96) even if they were inactive before diagnosis. High levels of physical activity may improve survival in postmenopausal women with breast cancer, even among those reporting low physical activity prior to diagnosis. Women diagnosed with breast cancer should be encouraged to initiate and maintain a program of physical activity.
doi:10.1158/1940-6207.CAPR-10-0295
PMCID: PMC3123895  PMID: 21464032
10.  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
11.  Combined Impact of Lifestyle-Related Factors on Total and Cause-Specific Mortality among Chinese Women: Prospective Cohort Study 
PLoS Medicine  2010;7(9):e1000339.
Findings from the Shanghai Women's Health Study confirm those derived from other, principally Western, cohorts regarding the combined impact of lifestyle-related factors on mortality.
Background
Although cigarette smoking, excessive alcohol drinking, obesity, and several other well-studied unhealthy lifestyle-related factors each have been linked to the risk of multiple chronic diseases and premature death, little is known about the combined impact on mortality outcomes, in particular among Chinese and other non-Western populations. The objective of this study was to quantify the overall impact of lifestyle-related factors beyond that of active cigarette smoking and alcohol consumption on all-cause and cause-specific mortality in Chinese women.
Methods and Findings
We used data from the Shanghai Women's Health Study, an ongoing population-based prospective cohort study in China. Participants included 71,243 women aged 40 to 70 years enrolled during 1996–2000 who never smoked or drank alcohol regularly. A healthy lifestyle score was created on the basis of five lifestyle-related factors shown to be independently associated with mortality outcomes (normal weight, lower waist-hip ratio, daily exercise, never exposed to spouse's smoking, higher daily fruit and vegetable intake). The score ranged from zero (least healthy) to five (most healthy) points. During an average follow-up of 9 years, 2,860 deaths occurred, including 775 from cardiovascular disease (CVD) and 1,351 from cancer. Adjusted hazard ratios for mortality decreased progressively with an increasing number of healthy lifestyle factors. Compared to women with a score of zero, hazard ratios (95% confidence intervals) for women with four to five factors were 0.57 (0.44–0.74) for total mortality, 0.29 (0.16–0.54) for CVD mortality, and 0.76 (0.54–1.06) for cancer mortality. The inverse association between the healthy lifestyle score and mortality was seen consistently regardless of chronic disease status at baseline. The population attributable risks for not having 4–5 healthy lifestyle factors were 33% for total deaths, 59% for CVD deaths, and 19% for cancer deaths.
Conclusions
In this first study, to our knowledge, to quantify the combined impact of lifestyle-related factors on mortality outcomes in Chinese women, a healthier lifestyle pattern—including being of normal weight, lower central adiposity, participation in physical activity, nonexposure to spousal smoking, and higher fruit and vegetable intake—was associated with reductions in total and cause-specific mortality among lifetime nonsmoking and nondrinking women, supporting the importance of overall lifestyle modification in disease prevention.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
It is well established that lifestyle-related factors, such as limited physical activity, unhealthy diets, excessive alcohol consumption, and exposure to tobacco smoke are linked to an increased risk of many chronic diseases and premature death. However, few studies have investigated the combined impact of lifestyle-related factors and mortality outcomes, and most of such studies of combinations of established lifestyle factors and mortality have been conducted in the US and Western Europe. In addition, little is currently known about the combined impact on mortality of lifestyle factors beyond that of active smoking and alcohol consumption.
Why Was This Study Done?
Lifestyles in regions of the world can vary considerably. For example, many women in Asia do not actively smoke or regularly drink alcohol, which are important facts to note when considering practical disease prevention measures for these women. Therefore, it is important to study the combination of lifestyle factors appropriate to this population.
What Did the Researchers Do and Find?
The researchers used the Shanghai Women's Health Study, an ongoing prospective cohort study of almost 75,000 Chinese women aged 40–70 years, as the basis for their analysis. The Shanghai Women's Health Study has comprehensive baseline data on anthropometric measurements, lifestyle habits (including the responses to validated food frequency and physical activity questionnaires), medical history, occupational history, and select information from each participant's spouse, such as smoking history and alcohol consumption. This information was used by the researchers to create a healthy lifestyle score on the basis of five lifestyle-related factors shown to be independently associated with mortality outcomes in this population: normal weight, lower waist-hip ratio, daily exercise, never being exposed to spouse's smoking, and higher daily fruit and vegetable intake. The score ranged from zero (least healthy) to five (most healthy) points. The researchers found that higher healthy lifestyle scores were significantly associated with decreasing mortality and that this association persisted for all women regardless of their baseline comorbidities. So in effect, healthier lifestyle-related factors, including normal weight, lower waist-hip ratio, participation in exercise, never being exposed to spousal smoking, and higher daily fruit and vegetable intake, were significantly and independently associated with lower risk of total, and cause-specific, mortality.
What Do These Findings Mean?
This large prospective cohort study conducted among lifetime nonsmokers and nonalcohol drinkers shows that lifestyle factors, other than active smoking and alcohol consumption, have a major combined impact on total mortality on a scale comparable to the effect of smoking—the leading cause of death in most populations. However, the sample sizes for some cause-specific analyses were relatively small (despite the overall large sample size), and extended follow-up of this cohort will provide the opportunity to further evaluate the impact of these lifestyle-related factors on mortality outcomes in the future.
The findings of this study highlight the importance of overall lifestyle modification in disease prevention, especially as most of the lifestyle-related factors studied here may be improved by individual motivation to change unhealthy behaviors. Further research is needed to design appropriate interventions to increase these healthy lifestyle factors among Asian women.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000339
The Vanderbilt Epidemiology Center has more information on the Shanghai Women's Health Study
The World Health Organization provides information on health in China
The document Health policy and systems research in Chinacontains information about health policy and health systems research in China
The Chinese Ministry of Healthalso provides health information
doi:10.1371/journal.pmed.1000339
PMCID: PMC2939020  PMID: 20856900
12.  Determinants of physical activity among women treated for breast cancer in a 5-year longitudinal follow-up investigation 
Psycho-oncology  2009;18(4):377-386.
Objective
To estimate the 5-year trajectory of physical activity among women with breast cancer, and to evaluate biopsychosocial variables (health status, physical symptoms, health-related quality of life (HRQL), depressive symptoms, and social support), measured soon after breast cancer diagnosis, as predictors of the 5-year trajectory.
Methods
Women diagnosed with Stage II or III regional breast cancer (n = 227), surgically treated and awaiting the start of adjuvant therapy completed baseline assessments of medical, psychological, and behavioral functioning. Follow-up evaluations were conducted every 4 months during the first year and every 6 months during the subsequent 4 years (12 assessments total during the 5-year study). Mixed-effects modeling was utilized to estimate the baseline level of physical activity as well as rate of change over time. Measures of physical health status, HRQL, depressive symptoms, and social support were included as predictors of the physical activity trajectory.
Results
A curvilinear pattern of change in physical activity was evident over the 5-year follow-up (p = 0.002). Physical activity increased gradually during the first 18 months, then declined steadily over the subsequent 42 months. Poor physical health, depressive symptoms, and lower emotional HRQL were associated with less physical activity. Higher family support was associated with a slower decline in physical activity in the latter 42 months of the study.
Conclusions
Emotional HRQL following diagnosis with breast cancer appears to be important for sustaining physical activity in the first 1–2 years following diagnosis. Physical activity interventions among breast cancer survivors should address depressive symptoms early in the course of treatment.
doi:10.1002/pon.1519
PMCID: PMC2744438  PMID: 19241490
breast cancer; physical activity; depression; social support; quality of life; oncology
13.  Muscle-Strengthening and Conditioning Activities and Risk of Type 2 Diabetes: A Prospective Study in Two Cohorts of US Women 
PLoS Medicine  2014;11(1):e1001587.
Anders Grøntved and colleagues examined whether women who perform muscle-strengthening and conditioning activities have an associated reduced risk of type 2 diabetes mellitus.
Please see later in the article for the Editors' Summary
Background
It is well established that aerobic physical activity can lower the risk of type 2 diabetes (T2D), but whether muscle-strengthening activities are beneficial for the prevention of T2D is unclear. This study examined the association of muscle-strengthening activities with the risk of T2D in women.
Methods and Findings
We prospectively followed up 99,316 middle-aged and older women for 8 years from the Nurses' Health Study ([NHS] aged 53–81 years, 2000–2008) and Nurses' Health Study II ([NHSII] aged 36–55 years, 2001–2009), who were free of diabetes, cancer, and cardiovascular diseases at baseline. Participants reported weekly time spent on resistance exercise, lower intensity muscular conditioning exercises (yoga, stretching, toning), and aerobic moderate and vigorous physical activity (MVPA) at baseline and in 2004/2005. Cox regression with adjustment for major determinants for T2D was carried out to examine the influence of these types of activities on T2D risk. During 705,869 person years of follow-up, 3,491 incident T2D cases were documented. In multivariable adjusted models including aerobic MVPA, the pooled relative risk (RR) for T2D for women performing 1–29, 30–59, 60–150, and >150 min/week of total muscle-strengthening and conditioning activities was 0.83, 0.93, 0.75, and 0.60 compared to women reporting no muscle-strengthening and conditioning activities (p<0.001 for trend). Furthermore, resistance exercise and lower intensity muscular conditioning exercises were each independently associated with lower risk of T2D in pooled analyses. Women who engaged in at least 150 min/week of aerobic MVPA and at least 60 min/week of muscle-strengthening activities had substantial risk reduction compared with inactive women (pooled RR = 0.33 [95% CI 0.29–0.38]). Limitations to the study include that muscle-strengthening and conditioning activity and other types of physical activity were assessed by a self-administered questionnaire and that the study population consisted of registered nurses with mostly European ancestry.
Conclusions
Our study suggests that engagement in muscle-strengthening and conditioning activities (resistance exercise, yoga, stretching, toning) is associated with a lower risk of T2D. Engagement in both aerobic MVPA and muscle-strengthening type activity is associated with a substantial reduction in the risk of T2D in middle-aged and older women.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, more than 370 million people have diabetes mellitus, a disorder characterized by poor glycemic control—dangerously high amounts of glucose (sugar) in the blood. Blood sugar levels are normally controlled by insulin, a hormone released by the pancreas. In people with type 2 diabetes (the commonest form of diabetes), blood sugar control fails because the fat and muscle cells that normally respond to insulin by removing excess sugar from the blood become less responsive to insulin. Type 2 diabetes, which was previously known as adult-onset diabetes, can often initially be controlled with diet and exercise, and with antidiabetic drugs such as metformin and sulfonylureas. However, as the disease progresses, the pancreatic beta cells, which make insulin, become impaired and patients may eventually need insulin injections. Long-term complications of diabetes, which include an increased risk of cardiovascular problems such as heart disease and stroke, reduce the life expectancy of people with diabetes by about 10 years compared to people without diabetes.
Why Was This Study Done?
Type 2 diabetes is becoming increasingly common worldwide so better preventative strategies are essential. It is well-established that regular aerobic exercise—physical activity in which the breathing and heart rate increase noticeably such as jogging, brisk walking, and swimming—lowers the risk of type 2 diabetes. The World Health Organization currently recommends that adults should do at least 150 min/week of moderate-to-vigorous aerobic physical activity to reduce the risk of diabetes and other non-communicable diseases. It also recommends that adults should undertake muscle-strengthening and conditioning activities such as weight training and yoga on two or more days a week. However, although studies have shown that muscle-strengthening activity improves glycemic control in people who already have diabetes, it is unclear whether this form of exercise prevents diabetes. In this prospective cohort study (a study in which disease development is followed up over time in a group of people whose characteristics are recorded at baseline), the researchers investigated the association of muscle-strengthening activities with the risk of type 2 diabetes in women.
What Did the Researchers Do and Find?
The researchers followed up nearly 100,000 women enrolled in the Nurses' Health Study (NHS) and the Nurses' Health Study II (NHSII), two prospective US investigations into risk factors for chronic diseases in women, for 8 years. The women provided information on weekly participation in muscle-strengthening exercise (for example, weight training), lower intensity muscle-conditioning exercises (for example, yoga and toning), and aerobic moderate and vigorous physical activity (aerobic MVPA) at baseline and 4 years later. During the study 3,491 women developed diabetes. After allowing for major risk factors for type 2 diabetes (for example, diet and a family history of diabetes) and for aerobic MVPA, compared to women who did no muscle-strengthening or conditioning exercise, the risk of developing type 2 diabetes among women declined with increasing participation in muscle-strengthening and conditioning activity. Notably, women who did more than 150 min/week of these types of exercise had 40% lower risk of developing diabetes as women who did not exercise in this way at all. Muscle-strengthening and muscle-conditioning exercise were both independently associated with reduced diabetes risk, and women who engaged in at least 150 min/week of aerobic MVPA and at least 60 min/week of muscle-strengthening exercise were a third as likely to develop diabetes as inactive women.
What Do These Findings Mean?
These findings show that, among the women enrolled in NHS and NHSII, engagement in muscle-strengthening and conditioning activities lowered the risk of type 2 diabetes independent of aerobic MVPA. That is, non-aerobic exercise provided protection against diabetes in women who did no aerobic exercise. Importantly, they also show that doing both aerobic exercise and muscle-strengthening exercise substantially reduced the risk of type 2 diabetes. Because nearly all the participants in NHS and NHSII were of European ancestry, these results may not be generalizable to women of other ethnic backgrounds. Moreover, the accuracy of these findings may be limited by the use of self-administered questionnaires to determine how much exercise the women undertook. Nevertheless, these findings support the inclusion of muscle-strengthening and conditioning exercises in strategies designed to prevent type 2 diabetes in women, a conclusion that is consistent with current guidelines for physical activity among adults.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001587.
The US National Diabetes Information Clearinghouse provides information about diabetes for patients, health-care professionals and the general public, including information on diabetes prevention (in English and Spanish)
The UK National Health Service Choices website provides information for patients and carers about type 2 diabetes and explains the benefits of regular physical activity
The World Health Organization provides information about diabetes and about physical activity and health (in several languages); its 2010 Global Recommendations on Physical Activity for Health are available in several languages
The US Centers for Disease Control and Prevention provides information on physical activity for different age groups; its Physical Activity for Everyone web pages include guidelines, instructional videos and personal success stories
More information about the Nurses Health Study and the Nurses Health Study II is available
The UK charity Healthtalkonline has interviews with people about their experiences of diabetes
MedlinePlus provides links to further resources and advice about diabetes and about physical exercise and fitness (in English and Spanish)
doi:10.1371/journal.pmed.1001587
PMCID: PMC3891575  PMID: 24453948
14.  Receptor-Defined Subtypes of Breast Cancer in Indigenous Populations in Africa: A Systematic Review and Meta-Analysis 
PLoS Medicine  2014;11(9):e1001720.
In a systematic review and meta-analysis, Isabel dos Santos Silva and colleagues estimate the prevalence of receptor-defined subtypes of breast cancer in North Africa and sub-Saharan Africa.
Please see later in the article for the Editors' Summary
Background
Breast cancer is the most common female cancer in Africa. Receptor-defined subtypes are a major determinant of treatment options and disease outcomes but there is considerable uncertainty regarding the frequency of poor prognosis estrogen receptor (ER) negative subtypes in Africa. We systematically reviewed publications reporting on the frequency of breast cancer receptor-defined subtypes in indigenous populations in Africa.
Methods and Findings
Medline, Embase, and Global Health were searched for studies published between 1st January 1980 and 15th April 2014. Reported proportions of ER positive (ER+), progesterone receptor positive (PR+), and human epidermal growth factor receptor-2 positive (HER2+) disease were extracted and 95% CI calculated. Random effects meta-analyses were used to pool estimates. Fifty-four studies from North Africa (n = 12,284 women with breast cancer) and 26 from sub-Saharan Africa (n = 4,737) were eligible. There was marked between-study heterogeneity in the ER+ estimates in both regions (I2>90%), with the majority reporting proportions between 0.40 and 0.80 in North Africa and between 0.20 and 0.70 in sub-Saharan Africa. Similarly, large between-study heterogeneity was observed for PR+ and HER2+ estimates (I2>80%, in all instances). Meta-regression analyses showed that the proportion of ER+ disease was 10% (4%–17%) lower for studies based on archived tumor blocks rather than prospectively collected specimens, and 9% (2%–17%) lower for those with ≥40% versus those with <40% grade 3 tumors. For prospectively collected samples, the pooled proportions for ER+ and triple negative tumors were 0.59 (0.56–0.62) and 0.21 (0.17–0.25), respectively, regardless of region. Limitations of the study include the lack of standardized procedures across the various studies; the low methodological quality of many studies in terms of the representativeness of their case series and the quality of the procedures for collection, fixation, and receptor testing; and the possibility that women with breast cancer may have contributed to more than one study.
Conclusions
The published data from the more appropriate prospectively measured specimens are consistent with the majority of breast cancers in Africa being ER+. As no single subtype dominates in the continent availability of receptor testing should be a priority, especially for young women with early stage disease where appropriate receptor-specific treatment modalities offer the greatest potential for reducing years of life lost.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Breast cancer is the commonest female tumor in Africa and death rates from the disease in some African countries are among the highest in the world. Breast cancer begins when cells in the breast acquire genetic changes that allow them to grow uncontrollably and to move around the body. When a breast lump is found (by mammography or manual examination), a few cells are collected from the lump (a biopsy) to look for abnormal cells and to test for the presence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) on the cells. The hormones estrogen and progesterone promote the growth of normal breast cells and of ER+ and PR+ breast cancer cells. HER2 also controls the growth of breast cells. The receptor status of breast cancer is a major determinant of treatment options and prognosis (likely outcome). ER+ tumors, for example, are more receptive to hormonal therapy and have a better prognosis than ER− tumors, whereas HER2+ tumors, which make large amounts of HER2, are more aggressive than HER2− tumors. Breast cancer is treated by surgically removing the lump or the whole breast (mastectomy) if the tumor has already spread, before killing any remaining cancer cells with chemotherapy or radiotherapy. In addition, ER+, PR+, and HER2+ tumors are treated with drugs that block these receptors (including tamoxifen and trastuzumab), thereby slowing breast cancer growth.
Why Was This Study Done?
ER+ tumors predominate in white women but the proportion of ER+ tumors among US-born black women is slightly lower. The frequency of different receptor-defined subtypes of breast cancer in indigenous populations in Africa is currently unclear but policy makers need this information to help them decide whether routine receptor status testing should be introduced across Africa. Because receptor status is a major determination of treatment options and outcomes, it would be more important to introduce receptor testing if all subtypes are present in breast cancers in indigenous African women and if no one subtype dominates than if most breast cancers in these women are ER+. In this systematic review (a study that uses pre-defined criteria to identify all the research on a given topic) and meta-analysis (a statistical approach that combines the results of several studies), the researchers examine the distribution of receptor-defined breast cancer subtypes in indigenous populations in Africa.
What Did the Researchers Do and Find?
The researchers identified 54 relevant studies from North Africa involving 12,284 women with breast cancer (mainly living in Egypt or Tunisia) and 26 studies from sub-Saharan Africa involving 4,737 women with breast cancer (mainly living in Nigeria or South Africa) and used the data from these studies to calculate the proportions of ER+, PR+, and HER2+ tumors (the number of receptor-positive tumors divided by the number of tumors with known receptor status) across Africa. The proportion of ER+ tumors varied markedly between studies, ranging between 0.40 and 0.80 in North Africa and between 0.20 and 0.70 in sub-Saharan Africa. Among prospectively collected samples (samples collected specifically for receptor-status testing; studies that determined the receptor status of breast cancers using stored samples reported a lower proportion of ER+ disease than studies that used prospectively collected samples), the overall pooled proportions of ER+ and triple negative tumors were 0.59 and 0.21, respectively.
What Do These Findings Mean?
Although these findings highlight the scarcity of data on hormone receptor and HER2 status in breast cancers in indigenous African populations, they provide new information about the distribution of breast cancer subtypes in Africa. Specifically, these findings suggest that although slightly more than half of breast cancers in Africa are ER+, no single subtype dominates. They also suggest that the distribution of receptor-defined breast cancer subtypes in Africa is similar to that found in Western populations. The accuracy of these findings is likely to be affected by the low methodological quality of many of the studies and the lack of standardized procedures. Thus, large well-designed studies are still needed to accurately quantify the distribution of various breast cancer subtypes across Africa. In the meantime, the current findings support the introduction of routine receptor testing across Africa, especially for young women with early stage breast cancer in whom the potential to improve survival and reduce the years of life lost by knowing the receptor status of an individual's tumor is greatest.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001720.
This study is further discussed in a PLOS Medicine Perspective by Sulma i Mohammed
The US National Cancer Institute (NCI) provides comprehensive information about cancer (in English and Spanish), including detailed information for patients and professionals about breast cancer including an online booklet for patients
Cancer Research UK, a not-for profit organization, provides information about cancer; its detailed information about breast cancer includes sections on tests for hormone receptors and HER2 and on treatments that target hormone receptors and treatments that target HER2
Breastcancer.org is a not-for-profit organization that provides up-to-date information about breast cancer (in English and Spanish), including information on hormone receptor status and HER2 status
The UK National Health Service Choices website has information and personal stories about breast cancer; the not-for profit organization Healthtalkonline also provides personal stories about dealing with breast cancer
doi:10.1371/journal.pmed.1001720
PMCID: PMC4159229  PMID: 25202974
15.  The roles of herbal remedies in survival and quality of life among long-term breast cancer survivors - results of a prospective study 
BMC Cancer  2011;11:222.
Background
Few data exist on survival or health-related quality of life (QOL) related to herbal remedy use among long-term breast cancer survivors. The objective of this report is to examine whether herbal remedy use is associated with survival or the health-related QOL of these long-term breast cancer survivors.
Methods
In 1999-2000, we collected the information of herbal remedy use and QOL during a telephone interview with 371 Los Angeles Non-Hispanic/Hispanic white women who had survived more than 10 years after breast cancer diagnosis. QOL was measured using the Medical Outcomes Study Short Form-36 (SF-36) questionnaire. Patients were followed for mortality from the baseline interview through 2007. 299 surviving patients completed a second telephone interview on QOL in 2002-2004. We used multivariable Cox proportional hazards methods to estimate relative risks (RR) and 95% confidence intervals (CI) for mortality and applied multivariable linear regression models to compare average SF-36 change scores (follow-up - baseline) between herbal remedy users and non-users.
Results
Fifty-nine percent of participants were herbal remedy users at baseline. The most commonly used herbal remedies were echinacea, herbal teas, and ginko biloba. Herbal remedy use was associated with non-statistically significant increases in the risks for all-cause (44 deaths, RR = 1.28, 95% CI = 0.62-2.64) and breast cancer (33 deaths, RR = 1.78, 95% CI = 0.72-4.40) mortality. Both herbal remedy users' and non-users' mental component summary scores on the SF-36 increased similarly from the first survey to the second survey (P = 0.16), but herbal remedy users' physical component summary scores decreased more than those of non-users (-5.7 vs. -3.2, P = 0.02).
Conclusions
Our data provide some evidence that herbal remedy use is associated with poorer survival and a poorer physical component score for health-related QOL among women who have survived breast cancer for at least 10 years. These conclusions are based on exploratory analyses of data from a prospective study using two-sided statistical tests with no correction for multiple testing and are limited by few deaths for mortality analysis and lack of information on when herbal remedy use was initiated or duration of or reasons for use.
doi:10.1186/1471-2407-11-222
PMCID: PMC3126792  PMID: 21645383
herb; breast cancer; survival; mortality; QOL
16.  Cancer-Specific Concerns and Physical Activity Among Recently Diagnosed Breast and Prostate Cancer Survivors 
Integrative cancer therapies  2012;12(3):206-212.
Background
Cancer treatment-related side effects may have a negative impact on quality of life among cancer survivors, and may limit participation in physical activity.
Hypothesis
Cancer-specific concerns will be reduced throughout a 10-month diet and exercise intervention among recently-diagnosed cancer survivors. Additionally, participants reporting greater levels of physical activity will also report fewer cancer-specific concerns.
Study Design
This study is an exploratory analysis of 452 recently diagnosed, early stage breast and prostate cancer survivors who participated in the FRESH START diet and exercise trial. Data were collected at baseline and 1-year follow-up via telephone administration of the Functional Assessment of Cancer Therapy (FACT) instrument and the 7-Day Physical Activity Recall.
Results
At baseline, chief concerns among prostate cancer survivors included ability to have an erection (mean score [SD]: 1.0 [1.3]) and urinary frequency (2.5 [1.4]), whereas among breast cancer survivors eminent concerns were not feeling sexually attractive (2.0 [1.3]) and worry about cancer in other members of their family (2.1 [1.3]). At 1 year, there was a significant improvement in cancer-specific concerns on breast cancer specific-concerns (p<0.01), but not on prostate cancer-specific concerns. Physical activity (PA) was generally not related to cancer-specific concerns, though at baseline women who were self-conscious about their dress had higher levels of PA, whereas men reporting issues with incontinence reported lesser increases in PA in response to the intervention.
Conclusion
While cancer survivors have several cancer-specific concerns, these concerns diminish over time, especially among breast cancer survivors. Furthermore, this reduction appears independent of changes in physical activity. Among prostate cancer survivors, incontinence is a significant barrier that hinders benefit from PA interventions. Thus, there is a need either for medical interventions to ameliorate incontinence or for behavioral interventions to address this issue among survivors, especially given the importance of PA for overall health.
doi:10.1177/1534735412449734
PMCID: PMC3764991  PMID: 22879576
breast neoplasms; prostatic neoplasms; physical activity; quality of life
17.  Birth Outcome in Women with Previously Treated Breast Cancer—A Population-Based Cohort Study from Sweden 
PLoS Medicine  2006;3(9):e336.
Background
Data on birth outcome and offspring health after the appearance of breast cancer are limited. The aim of this study was to assess the risk of adverse birth outcomes in women previously treated for invasive breast cancer compared with the general population of mothers.
Methods and Findings
Of all 2,870,932 singleton births registered in the Swedish Medical Birth Registry during 1973–2002, 331 first births following breast cancer surgery—with a mean time to pregnancy of 37 mo (range 7–163)—were identified using linkage with the Swedish Cancer Registry.
Logistic regression analysis was used. The estimates were adjusted for maternal age, parity, and year of delivery. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate infant health and mortality, delivery complications, the risk of preterm birth, and the rates of instrumental delivery and cesarean section.
The large majority of births from women previously treated for breast cancer had no adverse events. However, births by women exposed to breast cancer were associated with an increased risk of delivery complications (OR 1.5, 95% CI 1.2–1.9), cesarean section (OR 1.3, 95% CI 1.0–1.7), very preterm birth (<32 wk) (OR 3.2, 95% CI 1.7–6.0), and low birth weight (<1500 g) (OR 2.9, 95% CI 1.4–5.8). A tendency towards an increased risk of malformations among the infants was seen especially in the later time period (1988–2002) (OR 2.1, 95% CI 1.2–3.7).
Conclusions
It is reassuring that births overall were without adverse events, but our findings indicate that pregnancies in previously treated breast cancer patients should possibly be regarded as higher risk pregnancies, with consequences for their surveillance and management.
The large majority of births from women previously treated for breast cancer had no adverse events, but such pregnancies might benefit from increased surveillance and management.
Editors' Summary
Background.
More women of all ages are developing breast cancer than ever before. In the US, one woman in eight will now develop this disease during her lifetime. For most of these women, their breast cancer diagnosis will come late in life, but a fifth of breast cancers are diagnosed before the age of 50. These days, the long-term outlook for women with breast cancer is quite good; 80% of women who receive a diagnosis of breast cancer survive more than five years. These figures, together with a trend towards starting families later in life—since the late 1970s birth rates for women in their late 30s and 40s have more than doubled in the US, and in Sweden the average age for having a first baby is now 29 years—mean that many women who have had breast cancer want to have children. One estimate is that up to 7% of women who are fertile after treatment for breast cancer will later have children.
Why Was This Study Done?
Pregnancy seems to have no adverse affects on women who have had breast cancer—there is no evidence that pregnancy can trigger a relapse. However, little is known about whether the chemotherapy and radiotherapy used to treat breast cancer have any long-lasting effects that might result in a poor birth outcome such as stillbirth, low birth weight, premature delivery, or abnormalities in the baby (congenital abnormalities). In this study, the researchers assessed the risk of adverse birth outcomes in women previously treated for breast cancer in Sweden.
What Did the Researchers Do and Find?
Nearly three million singleton births that occurred between 1973 and 2002 are recorded in the Swedish Medical Birth Registry. The researchers linked this information with that in the Swedish Cancer Registry to identify 331 first births after treatment for invasive breast cancer (cancer that has spread from where it started to grow in the breast). The birth registry includes details on maternal age and health, child's birth weight, whether the delivery was preterm, and whether the child had any congenital abnormalities, so the researchers were able to compare birth outcomes in these 331 births with those in the general population. They discovered that most births after breast cancer treatment went smoothly. There was no increase in stillbirths, but there were slightly more delivery complications in the women who had had breast cancer than in the general population, and a slight increase in babies born prematurely or with low birth weight. Finally, a few more babies with congenital abnormalities were born to women after breast cancer treatment than to women in the general population.
What Do These Findings Mean?
Overall, these results should reassure women who are thinking about having children after breast cancer about the health of their future offspring. However, they do suggest that these women may need careful monitoring during late pregnancy and delivery. This result was not predicted by the researchers who performed the study. Before starting the study, they thought that there would be no difference in birth outcomes between patients previously treated for breast cancer and the general population. Furthermore, a recently published similar study in Denmark found no increased risk of preterm birth, low birth weight, or congenital abnormalities after breast cancer. Differences between the two countries in the accuracy of their registries or in the use of chemotherapy and radiotherapy treatments may account for this difference in results. Additional studies are now needed in other populations to resolve this discrepancy and to provide more information about how breast cancer treatment might affect birth outcomes. For example, the current study did not provide any information about whether specific chemotherapy regimens or different types of breast cancer might put women at a higher risk of adverse birth outcomes, or whether the time between the cancer diagnosis and treatment and the pregnancy made a difference.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030336.
MedlinePlus encyclopedia entry on breast cancer
National Cancer Institute information for patients and physicians on breast cancer, including links to pages on breast cancer and pregnancy
Cancer Research UK's information on breast cancer for patients, and statistics on breast cancer in the UK
• Wikipedia page on breast cancer (note: Wikipedia is a free online encyclopedia that anyone can edit)
Royal College of Obstetricians and Gynaecologists guidelines for physicians on pregnancy and breast cancer
doi:10.1371/journal.pmed.0030336
PMCID: PMC1564170  PMID: 16968117
18.  Move more for life: the protocol for a randomised efficacy trial of a tailored-print physical activity intervention for post-treatment breast cancer survivors 
BMC Cancer  2012;12:172.
Background
Due to early detection and advances in treatment, the number of women surviving breast cancer is increasing. Whilst there are many positive aspects of improved survival, breast cancer survival is associated with many long-term health and psychosocial sequelae. Engaging in regular physical activity post-diagnosis can reduce this burden. Despite this evidence, the majority of breast cancer survivors do not engage in regular physical activity. The challenge is to provide breast cancer survivors with appealing and effective physical activity support in a sustainable and cost-effective way. This article describes the protocol for the Move More for Life Study, which aims to assess the relative efficacy of two promising theory-based, print interventions designed to promote regular physical activity amongst breast cancer survivors.
Method and design
Breast cancer survivors were recruited from across Australia. Participants will be randomised into one of three groups: (1) A tailored-print intervention group, (2) a targeted-print intervention group, or (3) a standard recommendation control group. Participants in the tailored-print intervention group will receive 3 tailored newsletters in the mail over a three month period. Participants in the targeted-print group will receive a previously developed physical activity guidebook designed specifically for breast cancer survivors immediately after baseline. Participants in the standard recommendation control will receive a brochure detailing the physical activity guidelines for Australian adults. All participants will be assessed at baseline, and at 4 and 10 months post-baseline. Intervention efficacy for changing the primary outcomes (mins/wk aerobic physical activity; sessions/exercises per week resistance physical activity) and secondary outcomes (steps per day, health-related quality life, compliance with physical activity guidelines, fatigue) will be assessed. Mediation and moderation analyses will also be conducted.
Discussion
Given the growing number of cancer survivors, distance-based behaviour change programs addressing physical activity have the potential to make a significant public health impact.
Trial registration
Australian New Zealand Clinical Trials Registry (ANZCTR) identifier: ACTRN12611001061921
doi:10.1186/1471-2407-12-172
PMCID: PMC3518246  PMID: 22569139
19.  Weight, inflammation, cancer-related symptoms and health-related quality of life among breast cancer survivors 
Maintaining weight is important for better prognosis of breast cancer survivors. The associations between weight and cancer-related symptoms are not known. We examined associations among weight, weight change, inflammation, cancer-related symptoms, and health-related quality of life (HRQOL) in a cohort of stage 0-IIIA breast cancer survivors. Participants were recruited on average 6 months (2–12 months) after diagnosis. Height, weight, and c-reactive protein (CRP) were assessed at approximately 30 months post-diagnosis; cancer-related symptoms (chest wall and arm symptoms, vasomotor symptoms, urinary incontinence, vaginal symptoms, cognition/mood problems, sleep, sexual interest/function), and HRQOL (SF-36) were assessed at approximately 40 months post-diagnosis. Weight was measured at baseline in a subset. Data on 661 participants were evaluable for body mass index (BMI); 483 were evaluable for weight change. We assessed associations between BMI (<25.0, 25.0–29.9, ≥30.0 kg/m2), post-diagnosis weight change (lost ≥5%, weight change <5%, gained ≥5%), and CRP (tertile) with cancer-related symptoms and HRQOL using analysis of covariance (ANCOVA). Higher symptoms scores indicate more frequent or severe symptoms. Higher HRQOL scores indicate better HRQOL. Compared with those with BMI<25kg/m2, women with BMI ≥30 kg/m2 had scores that were: increased for arm symptoms (+25.0%), urinary incontinence (+40.0%), tendency to nap (+18.9%) and poorer physical functioning (−15.6%, all p<0.05). Obese women had lower scores in trouble falling asleep (−9.9%; p<0.05). Compared with weight change <5%, participants with ≥5% weight gain had lower scores in physical functioning (−7.2%), role-physical (−15.5%) and vitality (−11.2%), and those with weight loss ≥5% had lower chest wall (−33.0%) and arm symptom scores (−35.5%, all p<0.05). Increasing CRP tertile was associated with worse scores for chest wall symptoms, urinary incontinence, physical functioning, role-physical, vitality and physical component summary scores (all Ptrend<0.05). Future studies should examine whether interventions to maintain a healthy weight and reduce inflammation could alleviate cancer-related symptoms and improve HRQOL.
doi:10.1007/s10549-013-2594-y
PMCID: PMC3772666  PMID: 23797178
Breast cancer survivors; body weight; inflammation; cancer-related symptoms; quality of life
20.  Cost-Effectiveness of Interventions to Promote Physical Activity: A Modelling Study 
PLoS Medicine  2009;6(7):e1000110.
Linda Cobiac and colleagues model the costs and health outcomes associated with interventions to improve physical activity in the population, and identify specific interventions that are likely to be cost-saving.
Background
Physical inactivity is a key risk factor for chronic disease, but a growing number of people are not achieving the recommended levels of physical activity necessary for good health. Australians are no exception; despite Australia's image as a sporting nation, with success at the elite level, the majority of Australians do not get enough physical activity. There are many options for intervention, from individually tailored advice, such as counselling from a general practitioner, to population-wide approaches, such as mass media campaigns, but the most cost-effective mix of interventions is unknown. In this study we evaluate the cost-effectiveness of interventions to promote physical activity.
Methods and Findings
From evidence of intervention efficacy in the physical activity literature and evaluation of the health sector costs of intervention and disease treatment, we model the cost impacts and health outcomes of six physical activity interventions, over the lifetime of the Australian population. We then determine cost-effectiveness of each intervention against current practice for physical activity intervention in Australia and derive the optimal pathway for implementation. Based on current evidence of intervention effectiveness, the intervention programs that encourage use of pedometers (Dominant) and mass media-based community campaigns (Dominant) are the most cost-effective strategies to implement and are very likely to be cost-saving. The internet-based intervention program (AUS$3,000/DALY), the GP physical activity prescription program (AUS$12,000/DALY), and the program to encourage more active transport (AUS$20,000/DALY), although less likely to be cost-saving, have a high probability of being under a AUS$50,000 per DALY threshold. GP referral to an exercise physiologist (AUS$79,000/DALY) is the least cost-effective option if high time and travel costs for patients in screening and consulting an exercise physiologist are considered.
Conclusions
Intervention to promote physical activity is recommended as a public health measure. Despite substantial variability in the quantity and quality of evidence on intervention effectiveness, and uncertainty about the long-term sustainability of behavioural changes, it is highly likely that as a package, all six interventions could lead to substantial improvement in population health at a cost saving to the health sector.
Please see later in the article for Editors' Summary
Editors' Summary
Background
The human body needs regular physical activity throughout life to stay healthy. Physical activity—any bodily movement produced by skeletal muscles that uses energy—helps to maintain a healthy body weight and to prevent or delay heart disease, stroke, type 2 diabetes, colon cancer, and breast cancer. In addition, physically active people feel better and live longer than physically inactive people. For an adult, 30 minutes of moderate physical activity—walking briskly, gardening, swimming, or cycling—at least five times a week is sufficient to promote and maintain health. But at least 60% of the world's population does not do even this modest amount of physical activity. The daily lives of people in both developed and developing countries are becoming increasingly sedentary. People are sitting at desks all day instead of doing manual labor; they are driving to work in cars instead of walking or cycling; and they are participating less in physical activities during their leisure time.
Why Was This Study Done?
In many countries, the chronic diseases that are associated with physical inactivity are now a major public-health problem; globally, physical inactivity causes 1.9 million deaths per year. Clearly, something has to be done about this situation. Luckily, there is no shortage of interventions designed to promote physical activity, ranging from individual counseling from general practitioners to mass-media campaigns. But which intervention or package of interventions will produce the optimal population health benefits relative to cost? Although some studies have examined the cost-effectiveness of individual interventions, different settings for analysis and use of different methods and assumptions make it difficult to compare results and identify which intervention approaches should be give priority by policy makers. Furthermore, little is known about the cost-effectiveness of packages of interventions. In this study, the researchers investigate the cost-effectiveness in Australia (where physical inactivity contributes to 10% of deaths) of a package of interventions designed to promote physical activity in adults using a standardized approach (ACE-Prevention) to the assessment of the cost-effectiveness of health-care interventions.
What Did the Researchers Do and Find?
The researchers selected six interventions for their study: general practitioner “prescription” of physical activity; general practitioner referral to an exercise physiologist; a mass-media campaign to promote physical activity; the TravelSmart car use reduction program; a campaign to encourage the use of pedometers to increase physical activity; and an internet-based program. Using published data on the effects of physical activity on the amount of illness and death caused by breast and colon cancer, heart disease, stroke, and type 2 diabetes and on the effectiveness of each intervention, the researchers calculated the health outcomes of each intervention in disability-adjusted life years (DALY; a year of healthy life lost because of premature death or disability) averted over the lifetime of the Australian population. They also calculated the costs associated with each intervention offset by the costs associated with the five conditions listed above. These analyses showed that the pedometer program and the mass-media campaign were likely to be the most cost-effective interventions. These interventions were also most likely to be cost-saving. Referral to an exercise physiologist was the least cost-effective intervention. The other three interventions, though unlikely to be cost-saving, were likely to be cost-effective. Finally, a package of all six interventions would be cost-effective and would avert 61,000 DALYs, a third of what could be achieved if every Australian did 30 minutes of physical activity five times a week.
What Do These Findings Mean?
As in all modeling studies, these findings depend on the quality of the data and on the assumptions included by the researchers in their calculations. Unfortunately, there was substantial variability in the quantity and quality of evidence on the effectiveness of each intervention and uncertainty about the long-term effects of each intervention. Nevertheless, the findings presented in this study suggest that the assessment of the cost-effectiveness of a combination of interventions designed to promote physical activity might provide policy makers with some guidance about the best way to reduce the burden of disease caused by physical inactivity. More specifically, for Australia, these findings suggest that the package of the six interventions considered here is likely to provide a cost-effective way to substantially improve the health of the nation.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000110.
The World Health Organization provides information about physical activity and health (in several languages); it also provides an explanation of DALYs
The US Centers for Disease Control and Prevention provides information on physical activity for different age groups and for health professionals
The UK National Health Service information source Choices also explains the benefits of regular physical activity
MedlinePlus has links to other resources about exercise and physical fitness (in English and Spanish)
The University of Queensland Web site has more information on ACE-Prevention (Assessing Cost-Effectiveness Prevention)
doi:10.1371/journal.pmed.1000110
PMCID: PMC2700960  PMID: 19597537
21.  A randomized trial of exercise on well-being and function following breast cancer surgery: the RESTORE trial 
Objectives
This study aimed to determine the effect of a moderate, tailored exercise program on health-related quality of life, physical function, and arm volume in women receiving treatment for nonmetastatic breast cancer.
Methods
Women who were within 4–12 weeks of surgery for stage I–III breast cancer were randomized to center-based exercise and lymphedema education intervention or patient education. Functional Assessment of Cancer Therapy–Breast Cancer (FACT-B), 6-min walk, and arm volume were performed at 3-month intervals through 18 months. Repeated measures analysis of covariance was used to model the total meters walked over time, FACT-B scores, and arm volume. Models were adjusted for baseline measurement, baseline affected arm volume, number of nodes removed, age, self-reported symptoms, baseline SF-12 mental and physical component scores, visit, and treatment group.
Results
Of the recruited 104 women, 82 completed all 18 months. Mean age (range) was 53.6 (32–82) years; 88% were Caucasian; 45% were employed full time; 44% were overweight; and 28% obese. Approximately, 46% had breast-conserving surgery; 79% had axillary node dissection; 59% received chemotherapy; and 64% received radiation. The intervention resulted in an average increase of 34.3 ml (SD=12.8) versus patient education (p=0.01). Changes in FACT-B scores and arm volumes were not significantly different.
Conclusions
With this early exercise intervention after breast cancer diagnosis, a significant improvement was achieved in physical function, with no decline in health-related quality of life or detrimental effect on arm volume.
Implications for cancer survivors
Starting a supervised exercise regimen that is tailored to an individual’s strength and stamina within 3 months following breast cancer surgery appears safe and may hasten improvements in physical functioning.
doi:10.1007/s11764-011-0208-4
PMCID: PMC3900279  PMID: 22160629
Breast cancer; Survivorship; Exercise; Physical activity
22.  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
23.  Leisure Time Physical Activity of Moderate to Vigorous Intensity and Mortality: A Large Pooled Cohort Analysis 
PLoS Medicine  2012;9(11):e1001335.
Analyzing data from over 650,000 individuals, Dr. Steven Moore and colleagues report that greater amounts of leisure-time physical activity were associated with higher life expectancy across a wide range of activity levels and body mass index groups.
Background
Leisure time physical activity reduces the risk of premature mortality, but the years of life expectancy gained at different levels remains unclear. Our objective was to determine the years of life gained after age 40 associated with various levels of physical activity, both overall and according to body mass index (BMI) groups, in a large pooled analysis.
Methods and Findings
We examined the association of leisure time physical activity with mortality during follow-up in pooled data from six prospective cohort studies in the National Cancer Institute Cohort Consortium, comprising 654,827 individuals, 21–90 y of age. Physical activity was categorized by metabolic equivalent hours per week (MET-h/wk). Life expectancies and years of life gained/lost were calculated using direct adjusted survival curves (for participants 40+ years of age), with 95% confidence intervals (CIs) derived by bootstrap. The study includes a median 10 y of follow-up and 82,465 deaths. A physical activity level of 0.1–3.74 MET-h/wk, equivalent to brisk walking for up to 75 min/wk, was associated with a gain of 1.8 (95% CI: 1.6–2.0) y in life expectancy relative to no leisure time activity (0 MET-h/wk). Higher levels of physical activity were associated with greater gains in life expectancy, with a gain of 4.5 (95% CI: 4.3–4.7) y at the highest level (22.5+ MET-h/wk, equivalent to brisk walking for 450+ min/wk). Substantial gains were also observed in each BMI group. In joint analyses, being active (7.5+ MET-h/wk) and normal weight (BMI 18.5–24.9) was associated with a gain of 7.2 (95% CI: 6.5–7.9) y of life compared to being inactive (0 MET-h/wk) and obese (BMI 35.0+). A limitation was that physical activity and BMI were ascertained by self report.
Conclusions
More leisure time physical activity was associated with longer life expectancy across a range of activity levels and BMI groups.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Regular physical activity is essential for human health. It helps to maintain a healthy body weight and prevents or delays heart disease, type 2 diabetes, and some cancers. It also makes people feel better and increases life expectancy. The World Health Organization (WHO) currently recommends that adults do at least 150 minutes of moderate- to vigorous-intensity physical activity every week. Moderate-intensity physical activities (for example, brisk walking and gardening) require a moderate amount of effort and noticeably increase the heart rate; vigorous-intensity physical activities (for example, running or fast swimming) require a large amount of effort and cause rapid breathing and a substantial heart rate increase. Worryingly, people in both developed and developing countries are becoming increasingly physically inactive. People are sitting at desks all day instead of doing manual labor; they are driving to work in cars instead of walking or cycling; and they are participating in fewer leisure time physical activities.
Why Was This Study Done?
Although various studies suggest that physical activity increases life expectancy, few have quantified the years of life gained at distinct levels of physical activity. Moreover, the difference in life expectancy between active, overweight individuals and inactive, normal weight individuals has not been quantified. Thus, it is hard to develop a simple public health message to maximize the population benefits of physical activity. In this pooled prospective cohort analysis, the researchers determine the association between levels of leisure time physical activities, such as recreational walking, and years of life gained after age 40, both overall and within body mass index (BMI) groups. A pooled prospective cohort analysis analyzes the combined data from multiple studies that have followed groups of people to investigate associations between baseline characteristics and outcomes such as death. BMI is a ratio of weight to height, calculated by dividing a person's weight by their height squared; normal weight is defined as a BMI of 18.5–24.9 kg/m2, obesity (excessive body fat) is defined as a BMI of more than 30 kg/m2.
What Did the Researchers Do and Find?
The researchers pooled self-reported data on leisure time physical activities and BMIs from nearly 650,000 individuals over the age of 40 years enrolled in one Swedish and five US prospective cohort studies, most of which were investigating associations between lifestyle factors and disease risk. They used these and other data to calculate the gain in life expectancy associated with specific levels of physical activity. A physical activity level equivalent to brisk walking for up to 75 minutes per week was associated with a gain of 1.8 years in life expectancy relative to no leisure time activity. Being active—having a physical activity level at or above the WHO-recommended minimum of 150 minutes of brisk walking per week—was associated with an overall gain of life expectancy of 3.4–4.5 years. Gains in life expectancy were seen also for black individuals and former smokers, groups for whom relatively few data had been previously available. The physical activity and life expectancy association was also evident at all BMI levels. Being active and normal weight was associated with a gain of 7.2 years of life compared to being inactive and class II+ obese (having a BMI of more than 35.0 kg/m2). However, being inactive but normal weight was associated with 3.1 fewer years of life compared to being active but class I obese (having a BMI of 30–34.9 kg/m2).
What Do These Findings Mean?
These findings suggest that participation in leisure time physical activity, even below the recommended level, is associated with a reduced risk of mortality compared to participation in no leisure time physical activity. This result may help convince currently inactive people that a modest physical activity program may have health benefits, even if it does not result in weight loss. The findings also suggest that physical activity at recommended levels or higher may increase longevity further, and that a lack of leisure time physical activity may markedly reduce life expectancy when combined with obesity. Although the accuracy and generalizability of these findings may be limited by certain aspects of the study's design (for example, some study participants may have overestimated their leisure time physical activity), these findings reinforce the public health message that both a physically active lifestyle and a normal body weight are important for increasing longevity.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001335.
The World Health Organization provides information about physical activity and health (in several languages); its 2010 Global Recommendations on Physical Activity for Health is available in several languages
The US Centers for Disease Control and Prevention provides information on physical activity for different age groups; its Physical Activity for Everyone webpages include guidelines, instructional videos, and personal success stories
The UK National Health Service information source NHS Choices also explains the benefits of regular physical activity and includes physical activity guidelines, tips for exercising, and some personal stories
MedlinePlus has links to other resources about exercise and physical fitness (in English and Spanish)
doi:10.1371/journal.pmed.1001335
PMCID: PMC3491006  PMID: 23139642
24.  The Fall and Rise of US Inequities in Premature Mortality: 1960–2002 
PLoS Medicine  2008;5(2):e46.
Background
Debates exist as to whether, as overall population health improves, the absolute and relative magnitude of income- and race/ethnicity-related health disparities necessarily increase—or derease. We accordingly decided to test the hypothesis that health inequities widen—or shrink—in a context of declining mortality rates, by examining annual US mortality data over a 42 year period.
Methods and Findings
Using US county mortality data from 1960–2002 and county median family income data from the 1960–2000 decennial censuses, we analyzed the rates of premature mortality (deaths among persons under age 65) and infant death (deaths among persons under age 1) by quintiles of county median family income weighted by county population size. Between 1960 and 2002, as US premature mortality and infant death rates declined in all county income quintiles, socioeconomic and racial/ethnic inequities in premature mortality and infant death (both relative and absolute) shrank between 1966 and 1980, especially for US populations of color; thereafter, the relative health inequities widened and the absolute differences barely changed in magnitude. Had all persons experienced the same yearly age-specific premature mortality rates as the white population living in the highest income quintile, between 1960 and 2002, 14% of the white premature deaths and 30% of the premature deaths among populations of color would not have occurred.
Conclusions
The observed trends refute arguments that health inequities inevitably widen—or shrink—as population health improves. Instead, the magnitude of health inequalities can fall or rise; it is our job to understand why.
Nancy Krieger and colleagues found evidence of decreasing, and then increasing or stagnating, socioeconomic and racial inequities in US premature mortality and infant death from 1960 to 2002.
Editors' Summary
Background
One of the biggest aims of public health advocates and governments is to improve the health of the population. Improving health increases people's quality of life and helps the population be more economically productive. But within populations are often persistent differences (usually called “disparities” or “inequities”) in the health of different subgroups—between women and men, different income groups, and people of different races/ethnicities, for example. Researchers study these differences so that policy makers and the broader public can be informed about what to do to intervene. For example, if we know that the health of certain subgroups of the population—such as the poor—is staying the same or even worsening as the overall health of the population is improving, policy makers could design programs and devote resources to specifically target the poor.
To study health disparities, researchers use both relative and absolute measures. Relative inequities refer to ratios, while absolute inequities refer to differences. For example, if one group's average income level increases from $1,000 to $10,000 and another group's from $2,000 to $20,000, the relative inequality between the groups stays the same (i.e., the ratio of incomes between the two groups is still 2) but the absolute difference between the two groups has increased from $1,000 to $10,000.
Examining the US population, Nancy Krieger and colleagues looked at trends over time in both relative and absolute differences in mortality between people in different income groups and between whites and people of color.
Why Was This Study Done?
There has been a lot of debate about whether disparities have been widening or narrowing as overall population health improves. Some research has found that both total health and health disparities are getting better with time. Other research has shown that overall health gains mask worsening disparities—such that the rich get healthier while the poor get sicker.
Having access to more data over a longer time frame meant that Krieger and colleagues could provide a more complete picture of this sometimes contradictory story. It also meant they could test their hypothesis about whether, as population health improves, health inequities necessarily widen or shrink within the time period between the 1960s through the 1990s during which certain events and policies likely would have had an impact on the mortality trends in that country.
What Did the Researchers Do and Find?
In order to investigate health inequities, the authors chose to look at two common measures of population health: rates of premature mortality (dying before the age of 65 years) and rates of infant mortality (death before the age of 1).
To determine mortality rates, the authors used death statistics data from different counties, which are routinely collected by state and national governments. To be able to rank mortality rates for different income groups, they used data on the median family incomes of people living within those counties (meaning half the families had income above, and half had incomes below, the median value). They calculated mortality rates for the total population and for whites versus people of color. They used data from 1960 through 2002. They compared rates for 1966–1980 with two other time periods: 1960–1965 and 1981–2002. They also examined trends in the annual mortality rates and in the annual relative and absolute disparites in these rates by county income level.
Over the whole period 1960–2002, the authors found that premature mortality (death before the age of 65) and infant mortality (death before the age of 1) decreased for all income groups. But they also found that disparities between income groups and between whites and people of color were not the same over this time period. In fact, the economic disparities narrowed then widened. First, they shrank between 1966 and 1980, especially for Americans of color. After 1980, however, the relative health inequities widened and the absolute differences did not change. The authors conclude that if all people in the US population experienced the same health gains as the most advantaged did during these 42 years (i.e., as the whites in the highest income groups), 14% of the premature deaths among whites and 30% of the premature deaths among people of color would have been prevented.
What Do These Findings Mean?
The findings provide an overview of the trends in inequities in premature and infant mortality over a long period of time. Different explanations for these trends can now be tested. The authors discuss several potential reasons for these trends, including generally rising incomes across America and changes related to specific diseases, such as the advent of HIV/AIDS, changes in smoking habits, and better management of cancer and cardiovascular disease. But they find that these do not explain the fall then rise of inequities. Instead, the authors suggest that explanations lie in the social programs of the 1960s and the subsequent roll-back of some of these programmes in the 1980s. The US “War on Poverty,” civil rights legislation, and the establishment of Medicare occurred in the mid 1960s, which were intended to reduce socioeconomic and racial/ethnic inequalities and improve access to health care. In the 1980s there was a general cutting back of welfare state provisions in America, which included cuts to public health and antipoverty programs, tax relief for the wealthy, and worsening inequity in the access to and quality of health care. Together, these wider events could explain the fall then rise trends in mortality disparities.
The authors say their findings are important to inform and help monitor the progress of various policies and programmes, including those such as the Healthy People 2010 initiative in America, which aims to increase the quality and years of healthy life and decrease health disparities by the end of this decade.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed. 0050046.
Healthy People 2010 was created by the US Department of Health and Human Services along with scientists inside and outside of government and includes a comprehensive set of disease prevention and health promotion objectives for the US to achieve by 2010, with two overarching goals: to increase quality and years of healthy life and to eliminate health disparities
Johan Mackenbach and colleagues provide an overview of mortality inequalities in six Western European countries—Finland, Sweden, Norway, Denmark, England/Wales, and Italy—and conclude that eliminating mortality inequalities requires that more cardiovascular deaths among lower socioeconomic groups be prevented, as well as more attention be paid to rising death rates of lung cancer, breast cancer, respiratory disease, gastrointestinal disease, and injuries among women and men in the lower income groups.
The WHO Health for All program promotes health equity
A primer on absolute versus relative differences is provided by the American College of Physicians
doi:10.1371/journal.pmed.0050046
PMCID: PMC2253609  PMID: 18303941
25.  Effects of Home-Based Diet and Exercise on Functional Outcomes Among Older, Overweight Long-Term Cancer Survivors: The RENEW: Randomized Clinical Trial 
Context
Five-year survival rates for early-stage colorectal, breast and prostate cancer currently exceed 90% and are increasing. Cancer survivors are at greater risk for second malignancies, other co-morbidities, and accelerated functional decline. Lifestyle interventions may provide benefit, but it is unknown whether long-term cancer survivors can modify their lifestyle behaviors sufficiently to improve functional status.
Objective
To determine whether a telephone counseling and mailed material-based diet-exercise intervention is effective in reorienting functional decline in older, overweight cancer survivors.
Design
Randomized controlled trial in which survivors were randomly assigned to intervention (Intervention, n=319) or delayed-intervention control arms (Control, n=322).
Setting
Home-based from Canada, United Kingdom and 21 United States
Participants
641 overweight (body mass index [BMI] ≥ 25), long-term (≥ 5 years) survivors (ages 65–91) of colorectal, breast and prostate cancer recruited July 2005-May 2007.
Intervention
12-month home-based tailored program of telephone counseling and mailed materials promoting exercise, improved diet quality, and modest weight loss. Control group wait-listed for 12 months.
Main Outcome Measures
Change in self-reported physical function (SF-36 physical function subscale: 0–100, high score indicates better function) from baseline to 12 months was the primary endpoint. Secondary outcomes included changes in basic and advanced lower extremity function (0–100), physical activity, BMI, and overall health quality-of-life.
Results
From an average baseline score of 75.7 to 12-month follow-up, SF-36 function scores declined less rapidly in Intervention [−2.15(95% CI-0.36,−3.93)] versus Control [−4.84(−3.04,−6.63)] arms (p=0.03). Likewise, changes in basic lower extremity function were +0.34(−0.84,1.52) versus −1.89(−0.70,−3.09) from an average baseline score of 78.2, p=0.005. Physical activity, dietary behaviors and overall quality of life increased significantly in Intervention versus Control arms, and weight loss also was greater, −2.06(−1.69, −2.43) versus −0.92 (−0.51,−1.33) kg, respectively (p<0.0001).
Conclusion
Among older long-term colorectal, breast, and prostate cancer survivors, a diet and exercise intervention reduced the rate of self-reported functional decline compared to no intervention.
doi:10.1001/jama.2009.643
PMCID: PMC2752421  PMID: 19436015

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