Heidi D. Nelson, MD, MPH; Bernadette Zakher, MBBS; Amy Cantor, MD, MPH; Rongwei Fu, PhD; Jessica Griffin, MS; Ellen S. O'Meara, PhD; Diana S.M. Buist, PhD, MPH; Karla Kerlikowske, MD, MS; Nicolien T. van Ravesteyn, MSc; Amy Trentham-Dietz, PhD; Jeanne S. Mandelblatt, MD, MPH; Diana L. Miglioretti, PhD
Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.
Note: Each cancer registry and the Statistical Coordinating Center have received institutional review board approval for either active or passive consenting processes or a waiver of consent to enroll participants, link data, and perform analytic studies. All procedures are compliant with the Health Insurance Portability and Accountability Act, and all registries and the Statistical Coordinating Center have received a federal Certificate of Confidentiality and other protection for the identities of women, physicians, and facilities participating in this research. A list of the BCSC investigators and procedures for requesting BCSC data for research purposes is provided at http://breastscreening.cancer.gov/.
Acknowledgment: The authors thank the participating women, mammography facilities, and radiologists for the data they have provided for this study. Rose Relevo, MLIS, MS, and Robin Paynter, MA-LIS, conducted literature searches, and Katie Reitel, BA, provided assistance; all are affiliated with Oregon Health & Science University.
Grant Support: By a National Cancer Institute Activities to Promote Research Collaboration supplement (U01CA086076-10S1). Data collection was supported by the National Cancer Institute–funded BCSC cooperative agreements (U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, and U01CA70040). Providence Health & Services provided additional support for Dr. Nelson, and the Veterans Affairs Fellowship in Health Issues of Women Veterans provided support for Dr. Cantor. The collection of BCSC cancer data used in this study was supported in part by several state public health departments and cancer registries throughout the United States. For a full description of these sources, please see www.breastscreening.cancer.gov/work/acknowledgement.html.
Potential Conflicts of Interest: Dr. Nelson: Grant (money to institution): NCI; Support for travel to meetings for the study or other purposes (money to institution): NCI. Dr Fu: Grant (money to institution): AHRQ. Ms. Griffin: Grant (money to institution): NCI. Dr. O'Meara: Grant (money to institution): NCI; Employment: Group Health Research Institute. Dr. Buist: Grant (money to institution): NCI. Ms. van Ravesteyn: Grant (money to institution): NCI. Dr. Trentham-Dietz: Grant (money to institution): NCI; Support for travel to meetings for the study or other purposes: NCI. Dr. Mandelblatt: Grant (money to institution): NCI; Support for travel to meetings for the study or other purposes (money to institution): NCI. Dr. Miglioretti: Grant (money to institution): NIH. Disclosures can be also viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-2350.
Requests for Single Reprints: Heidi D. Nelson, MD, MPH, Oregon Evidence-based Practice Center, Oregon Health & Science University, Mail Code BICC, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098; e-mail, mailto:firstname.lastname@example.org.
Current Author Addresses: Drs. Nelson, Zakher, Cantor, and Fu and Ms. Griffin: 3181 SW Sam Jackson Park Road, Mail Code BICC, Portland, OR 97239.
Drs. O'Meara, Buist, and Miglioretti: 1730 Minor Avenue, Suite 1600, Seattle, WA 98101.
Dr. Kerlikowske: 4150 Clement Street, San Francisco, CA 94121.
Ms. van Ravesteyn: PO Box 2040, Rotterdam 3000, the Netherlands.
Dr. Trentham-Dietz: 307 WARF Building, 610 Walnut Street, Madison, WI 53726.
Dr. Mandelblatt: Suite 4100, 3300 Whitehaven Street NW, Washington, DC 20007.
Author Contributions: Conception and design: H.D. Nelson, D.S.M. Buist, K. Kerlikowske, N. van Ravesteyn, A. Trentham-Dietz, J. Mandelblatt, D. Miglioretti.
Analysis and interpretation of the data: H.D. Nelson, B. Zakher, A. Cantor, R. Fu, J. Griffin, E.S. O'Meara, D.S.M. Buist, K. Kerlikowske, A. Trentham-Dietz, J. Mandelblatt.
Drafting of the article: H.D. Nelson, B. Zakher, A. Cantor, R. Fu, J. Griffin, E.S. O'Meara, K. Kerlikowske, J. Mandelblatt.
Critical revision of the article for important intellectual content: H.D. Nelson, B. Zakher, A. Cantor, R. Fu, D.S.M. Buist, K. Kerlikowske, N. van Ravesteyn, A. Trentham-Dietz, J. Mandelblatt, D. Miglioretti.
Final approval of the article: H.D. Nelson, B. Zakher, R. Fu, J. Griffin, E.S. O'Meara, D.S.M. Buist, K. Kerlikowske, N. van Ravesteyn, J. Mandelblatt, D. Miglioretti.
Provision of study materials or patients: H.D. Nelson, D.S.M. Buist, K. Kerlikowske.
Statistical expertise: H.D. Nelson, R. Fu, K. Kerlikowske, D. Miglioretti.
Obtaining of funding: H.D. Nelson, D.S.M. Buist, K. Kerlikowske, J. Mandelblatt, D. Miglioretti.
Administrative, technical, or logistic support: H.D. Nelson, J. Griffin, D.S.M. Buist.
Collection and assembly of data: H.D. Nelson, B. Zakher, A. Cantor, R. Fu, J. Griffin, D.S.M. Buist, K. Kerlikowske, D. Miglioretti.
Nelson HD, Zakher B, Cantor A, Fu R, Griffin J, O'Meara ES, et al. Risk Factors for Breast Cancer for Women Aged 40 to 49 Years: A Systematic Review and Meta-analysis. Ann Intern Med. 2012;156:635-648. doi: 10.7326/0003-4819-156-9-201205010-00006
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Published: Ann Intern Med. 2012;156(9):635-648.
Identifying risk factors for breast cancer specific to women in their 40s could inform screening decisions.
To determine what factors increase risk for breast cancer in women aged 40 to 49 years and the magnitude of risk for each factor.
MEDLINE (January 1996 to the second week of November 2011), Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (fourth quarter of 2011), Scopus, reference lists of published studies, and the Breast Cancer Surveillance Consortium.
English-language studies and systematic reviews of risk factors for breast cancer in women aged 40 to 49 years. Additional inclusion criteria were applied for each risk factor.
Data on participants, study design, analysis, follow-up, and outcomes were abstracted. Study quality was rated by using established criteria, and only studies rated as good or fair were included. Results were summarized by using meta-analysis when sufficient studies were available or from the best evidence based on study quality, size, and applicability when meta-analysis was not possible. Data from the Breast Cancer Surveillance Consortium were analyzed with proportional hazards models by using partly conditional Cox regression. Reference groups for comparisons were set at U.S. population means.
Sixty-six studies provided data for estimates. Extremely dense breasts on mammography or first-degree relatives with breast cancer were associated with at least a 2-fold increase in risk for breast cancer. Prior breast biopsy, second-degree relatives with breast cancer, or heterogeneously dense breasts were associated with a 1.5- to 2.0-fold increased risk; current use of oral contraceptives, nulliparity, and age 30 years or older at first birth were associated with a 1.0- to 1.5-fold increased risk.
Studies varied by measures, reference groups, and adjustment for confounders, which could bias combined estimates. Effects of multiple risk factors were not considered.
Extremely dense breasts and first-degree relatives with breast cancer were each associated with at least a 2-fold increase in risk for breast cancer in women aged 40 to 49 years. Identification of these risk factors may be useful for personalized mammography screening.
National Cancer Institute.
Knowing which factors influence breast cancer risk for women younger than 50 years might help target screening efforts.
This review found that the following factors increased risk for breast cancer in women aged 40 to 49 years: extremely dense breasts or first-degree relatives with breast cancer (≥2-fold increase); prior breast biopsy, second-degree relatives with cancer, or heterogeneously dense breasts (1.5- to 2.0-fold increase); current oral contraceptive use, nulliparity, and age 30 years or older at first birth (1.0- to 1.5-fold increase).
Confounding may have affected some risk estimates.
Risk factor information could help personalize decisions about breast cancer screening in women aged 40 to 49 years.
Population Distribution of Risk Factors for Women Aged 40 to 49 Years
Summary of evidence search and selection.
BMI = body mass index; OC = oral contraceptive.
* Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews.
† Reference lists, Scopus, and studies suggested by experts.
‡ Some articles are included for more than 1 risk factor.
§ Published meta-analyses.
∥ No articles met inclusion criteria for race and ethnicity, menopausal stage and type (surgical or nonsurgical), age at menopause, and menopausal hormone use.
¶ Although some studies met inclusion criteria for the systematic review, they did not provide data for the meta-analysis because they used dissimilar categories or different measures from the other included studies.
Breast Cancer Risk Associated With Personal Factors for Women Aged 40 to 49 Years
Breast Cancer Risk Associated With Family History, Breast Density, and Breast Procedures for Women Aged 40 to 49 Years
Breast Cancer Risk Associated With Reproductive Factors for Women Aged 40 to 49 Years
Summary of Evidence for Studies Providing Data for Risk Estimates
Factors Significantly Associated With Increased Breast Cancer Risk for Women Aged 40 to 49 Years
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PhilippeAutier, Research Director
International Prevention research Institute
May 28, 2012
Personalized screening counseling of women 40-49 years of age should be based on risk factors for breast cancer death
Screening is more effective when the incidence of the target disease is high, that is, more deaths will be prevented while a lower proportion of positive screening tests will be false positives. The idea of optimizing screening effectiveness in women 40 to 49 years of age by targeting women with greater risk to develop a breast cancer is appealing. The review of breast risk factors among by Nelson and Colleagues (1) may provide guidance on how to provide personalized counseling to pre- menopausal women about the likely benefits and side-effects of mammography screening. The review found that breast radiological density, family history, reproductive history, use of oral contraceptives and prior benign breast biopsy were factors associated with higher breast cancer incidence in women aged 40-49 years. However, since the primary goal of breast screening being to decrease the risk to die from breast cancer, screening would be more effective for women at higher risk to die from this cancer, and not just a higher risk to be diagnosed with that cancer. The caveat that risk factors for breast cancer occurrence would have a similar influence on the risk of breast cancer death is not correct. Few studies have been done on risk factors associated with breast cancer death, but they show that reproductive factors have little influence on the risk to die from breast cancer (2). High breast density is associated with more aggressive cancer and this factor is thus relevant to both incidence and mortality (3). Adiposity is associated with reduced breast cancer risk in pre-menopausal women, and therefore, this factor was not selected by the review. However, the risk of breast cancer death in pre-menopausal women increases with adiposity (4) and obese women would probably benefit more from screening than lean women. Women giving birth in their forties become increasingly common, and breast cancers occurring in the two years following childbirth are known to be more lethal (5). So, these women should probably be offered screening shortly after discontinuation of breast feeding. The risk of breast cancer death associated with use of oral contraceptives and prior benign breast biopsy are not known. In conclusion, compared to risk factors for breast cancer occurrence, personalized screening counseling based on risk factors for breast cancer mortality may be more effective and identify different women likely to benefit from screening.
1. Nelson HD, Zakher B, Cantor A, Fu R, Griffin J, OMeara ES, et al. Risk factors for breast cancer for women aged 40 to 49 years. Ann Int Med. 2012; 156: 635-48.
2. Barnett GC, Shah M, Redman K, Easton DF, Ponder BAJ, Pharoah PDP Risk factors for the incidence of breast cancer: Do they affect survival from the disease? J Clin Oncol. 2008; 26:3310-6.
3. Chiu SY, Duffy S, Yen AF, Tab?r L, Smith RA, Chen H. Effect of baseline breast density on breast cancer incidence, stage, mortality, and screening parameters: 25-year follow-up of a swedish mammographic screening. Cancer Epidemiol Biomarkers Prev. 2010; 19; 1219-28.
4. Loi S, Milne RL, Friedlander ML, McCredie MRE, Giles GG, Hopper JL, Phillips K. Obesity and outcomes in premenopausal and postmenopausal breast cancer. Cancer Epidemiol Biomarkers Prev. 2005; 14:1686-91.
5. Daling JR, Malone KE, Doody DR, Anderson BO, Porter PL. The relation of reproductive factors to mortality from breast cancer. Cancer Epidemiol Biomarkers Prev. 2002;11: 235-41.
Heidi D. Nelson, MD, MPH, Bernadette Zakher, MBBS, Amy Cantor, MD, MPH
Oregon Health & Science University, Portland, OR
June 19, 2012
Authors’ Response to Letters
We agree with comments from Dr. Autier that identifying factors associated with increased risk of breast cancer mortality, not just breast cancer incidence, to guide breast cancer screening for women in their forties would be useful. However, it is also correct that few studies have reported these associations.
Our systematic review focused on the many published studies of risk factors for breast cancer incidence specifically for women in their forties who would be candidates for mammography screening under current U.S. guidelines (1). Our results indicated that extremely dense breasts on mammography and first-degree relatives with breast cancer were each associated with at least a 2-fold increase in risk; prior benign breast biopsy, second-degree relatives with breast cancer, and heterogeneously dense breasts with 1.5 to 2.0 fold increase; and current oral contraceptive use, nulliparity, and age at first birth 30 years and older with 1.0 to 1.5 increase. Several other risk factors were not statistically significantly associated with breast cancer incidence. Increased BMI was associated with reduced breast cancer risk, an inverse relationship that reverses for women above age 50. We did not emphasize risk factors related to reduced risk because this project was intended to identify risks above general population levels in collaboration with the development of population screening models that did not consider reduced-risk scenarios (2).
Although our risk estimates may help inform clinical decision making about screening, they were derived from epidemiologic data and their application in predicting risks for individual women has not been evaluated. Next steps in this work would be to improve risk models and demonstrate their effectiveness in clinical applications. Mortality estimates would also contribute to this effort.
Heidi D. Nelson, MD, MPH
Bernadette Zakher, MBBS
Amy Cantor, MD, MPH
Oregon Health & Science UniversityPortland, Oregon 97239
1. Nelson HD, Zakher B, Cantor A, Fu R, Griffin J, O'Meara ES, et al. Risk factors for breast cancer for women aged 40 to 49 years. Ann Intern Med. 2012; 156: 635-48.
2. van Ravesteyn NT, Miglioretti DL, Stout NK, Lee SJ, Schechter CB, Buist DSM, et al. What level of risk tips the balance of benefits and harms to favor screening mammography starting at age 40 years? Ann Intern Med. 2012;156:609-617.
Breast Cancer, Cancer Screening/Prevention, Hematology/Oncology, Prevention/Screening.
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