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Two risk factors may be most relevant in determining when to start regular breast cancer screening

A family history of breast cancer and dense breast tissue each indicate a twofold increase in breast cancer risk for women in their 40s, according to a study led by an Oregon Health & Science University investigator

A family history of breast cancer and dense breast tissue each increase the risk of breast cancer by at least twofold for women in their 40s, according to a study led by an Oregon Health & Science University (OHSU) researcher. The importance of these two risk factors could help determine when women should start having regular screening mammograms.

The study's analysis of cancer risk for women in their 40s is at the heart of two articles in the May 1 edition of Annals of Internal Medicine. One article presents the evaluation of risk factors that are most relevant for women between the ages of 40 and 50 who would be considering routine screening under current guidelines. The second article reports how population models were used to weigh the benefits of screening with potential downsides, such as false-positive test readings that lead to unnecessary medical procedures. The study found that women in their 40s, who have at least double the risk for breast cancer compared with average-risk women, share the same level of benefit, weighed against the potential downsides, from biennial screening as women who are 50 to 74 years old.

"This study focuses on risk data specific to women in their 40s," said Heidi D. Nelson, M.D., M.P.H., who is a research professor of medical informatics and clinical epidemiology and medicine and an investigator with the Oregon Evidence-based Practice Center at OHSU and medical director of cancer prevention and screening for the Providence Cancer Center in Portland. Nelson, who is first author on "Risk Factors for Breast Cancer for Women Aged 40 to 49 Years" and who co-authored the second paper, added that it was surprising to see that many potential risk factors weren't statistically relevant to this age group.

"Our results indicate that we can focus on just a few significant risk factors to simplify approaches to risk-based screening for women in their 40s," Nelson said.

These studies address questions raised in 2009 when updated breast cancer screening guidelines were released by the U.S. Preventive Services Task Force. Those guidelines call for screening mammography every two years for women who are 50 to 74 years old. The guidelines recommend that women in their 40s consider their personal values regarding the benefits and potential negative outcomes of a false-positive reading. However, there was a lack of research available to assess the risks and benefits for this particular age group, which had previously been advised to receive regular mammograms.

"Mainly, we wanted to find out the tipping point: what level of increased risk women in their 40s needed to have to reach the same benefit-to-harm ratio for screening mammography as women aged 50 to 74," said Diana Miglioretti, Ph.D., a Group Health Research Institute senior investigator who contributed to both articles, the second of which is titled, "Tipping the Balance of Benefits and Harms to Favor Screening Mammography Starting at Age 40 Years."

The international research team used data from the Breast Cancer Surveillance Consortium (BCSC), a U.S. research network of mammography registries. The BCSC is the nation's largest longitudinal collection of breast imaging data, covering 9.5 million mammograms, 2.3 million women, and 114,000 breast cancer cases so far. By continuously collecting information on breast cancer screening, risk factors, and cancer outcomes, the BCSC provides long-term data on screening as it occurs in everyday clinical practice to help answer preventive health care questions.

In one of the articles, Nicolien van Ravesteyn, M.Sc., Jeanne Mandelblatt, M.D., M.P.H., and colleagues, including Miglioretti and Diana Buist, used four independent well-established simulation models that are part of the National Cancer Institute's Cancer Intervention and Surveillance Modeling Network (CISNET) collaborative to identify the threshold of risk needed for women aged 40 to 49 to have comparable benefits and harms as seen when average-risk women aged 50 to 74 are screened every other year using mammography. Van Ravesteyn is a researcher at Erasmus Medical Center in Rotterdam, The Netherlands; and Mandelblatt is the associate director for population sciences at Georgetown University Medical Center's Lombardi Comprehensive Cancer Center in Washington, DC.

"Our population models show what can be expected across populations with different risk levels," Mandelblatt said. "The models cannot determine outcomes for individual women. Policymakers can use them to inform guidelines for populations."

Nelson, who is also a member of the OHSU Knight Cancer Institute, conducted a rigorous review of previous studies from 66 publications selected for their relevance and quality along with Buist and Miglioretti and colleagues, including Group Health Research Institute Research Associate Ellen O'Meara, Ph.D. They also conducted new analyses using BCSC data on more than 380,000 women who were 40 to 49 when they had a screening mammogram from 1994 to 2010, to see how family history and other risk factors affected breast cancer risk for women in their 40s.

Results indicated that:

  • Having a first-degree relative with breast cancer, especially one younger than 50, increased a woman's cancer risk by more than twofold.
  • Women with extremely dense breasts on a mammogram increased risk by more than twofold.
  • A previous benign breast biopsy, a second-degree relative with breast cancer, or breast tissue that was heterogeneously dense on a mammogram increased risk between 1.5-fold and twofold.

Other potential risk factors that they evaluated — such as race/ethnicity, body mass index, physical activity, and using alcohol, tobacco, or hormone therapy — had effects that were either small, undetectable or equivocal.

The research in the two articles was possible because three national research groups — BCSC, CISNET, and the Evidence-based Practice Center — joined forces. Each contributed unique strengths: extensive data, comprehensive breast cancer models and data interpretation. The U.S. Preventive Services Task Force previously used information from the three groups to develop its current breast cancer screening recommendations.

The authors called for additional research based on the findings, to see how well these risk estimates, which are based on large numbers of women, predict risks for individual women.

Funding for the research was provided by the National Cancer Institute. The collaboration between BCSC, CISNET and the Evidence-based Practice Center was supported in part by the 2009 American Recovery and Reinvestment Act (ARRA) and by the National Cancer Institute, which recently awarded a $20 million National Cancer Institute Program Project grant, co-led by Miglioretti, to the BCSC.

Nelson, van Ravesteyn, Mandelblatt, Buist, Miglioretti and O'Meara's collaborators were Bernadette Zakher, M.B.B.S., Amy Cantor, M.D., M.P.H., Rongwei Fu, Ph.D., and Jessica Griffin, M.S., of the Oregon Evidence-based Practice Center at OHSU; Eveline A.M. Heijnsdijk, Ph.D., and Harry J. de Koning, M.D., Ph.D., of Erasmus MC, in Rotterdam, The Netherlands; Karla Kerlikowske, M.D., M.S., of the University of California San Francisco; Amy Trentham-Dietz, Ph.D., and Oguzhan Alagoz, Ph.D., of the University of Wisconsin, Madison; Natasha K. Stout, Ph.D., of Harvard Medical School in Boston; Sandra J. Lee, DSc, and Hui Huang, M.S., of Dana-Farber Cancer Institute in Boston; Clyde B. Schechter, M.D., M.A., of Albert Einstein College of Medicine in New York; and Aimee M. Near, M.P.H., of Georgetown University Medical Center and Lombardi Comprehensive Cancer Center in Washington, DC.

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