MAMMOGRAPHY BENEFITS SOME WOMEN 40-49 YEAR OLDS

May 1, 2012 — Mammography benefits may outweigh harm among women in their forties at increased risk for breast cancer, according to 2 related studies published online April 30 in Annals of Internal Medicine.

The first study, a meta-analysis of data obtained from published studies and the Breast Cancer Surveillance Consortium (BCSC), revealed that the presence of extremely dense breast tissue or a having a first-degree relative with breast cancer more than doubled the risk for disease relative to the general population. The risk was further increased in women who had more than 1 stricken first-degree relative, or if the relative was diagnosed before age 50.

Factors that increased breast cancer risk by a factor of 1.5 to 2 included prior breast biopsy, heterogeneously dense breasts, and having second-degree relatives with breast cancer.

Current use of oral contraceptives, nulliparity, and being primipara after age 30 increased a woman's breast cancer risk by 1.0- to 1.5-fold.

These findings were supported by data from the second study, in which investigators used 4 independent mathematical models to investigate the tipping points in the risk-benefit analysis. The models suggested that women in their forties at 1.6- to 2-fold increased risk for breast cancer had a harm-benefit ratio for mammography similar to that of average-risk women age 50-74 years.

"It is widely accepted that screening women aged 40 to 49 years can reduce mortality, but some concern exists about the high ratio of harm to benefit in this age group," writes Otis W. Brawley, MD, in an accompanying editorial. Harmful events include false-positive results, false-positive biopsy results, radiation exposure, procedural pain, and overdiagnosis.

"By identifying those aged 40 to 49 years at higher risk, one may be able to maximize the benefits and minimize the harms," Dr. Brawley added, noting that such "personalized medicine" would be a more effective use of resources and has the potential to save more lives than the current practice of routine screening.

Dr. Brawley is chief medical and scientific officer and executive vice president of the American Cancer Society.

Pooled Data From 66 Published Studies

To determine risk factors for breast cancer in women aged 40 to 49 years, researchers led by Heidi D. Nelson, MD, MPH, from the Oregon Health & Science University in Portland evaluated data derived from 66 published articles and the BCSC.

A meta-analysis revealed that those having first-degree relatives with breast cancer were more than twice as likely to develop cancer (relative risk [RR], 2.14; confidence interval [CI], 1.92 - 2.38), a factor that increased among those with 2 relatives (RR, 3.84; 95% CI , 2.37 - 6.22) and 3 or more afflicted first-degree relatives (RR, 12.05; 95% CI, 1.70 - 55.16). BCSC data confirmed the increased risk among women having any vs no first-degree relatives with breast cancer (RR, 1.86; 95% CI, 1.69 - 2.06).

Women with 1 or more second-degree relatives were also found to be at increased risk (RR, 1.7; 95% CI: , 1.4 - 2.0).

Both sets of data suggested increased risk for women whose first-degree relatives were diagnosed before age 50 (age < 40: RR, 3.0 [95% CI, 1.8 - 4.9]; age 40 - 49: RR, 2.0 [95% CI, 1.5 - 2.8]; none vs age < 50: RR, 2.17 [95% CI, 1.86 - 2.53]). Risk was decreased when breast cancer was diagnosed in the relatives at age 60 years or older (RR, 1.7; 95% CI, 1.3 - 2.1).

Breast density also proved to be a relevant factor: A published BCSC study showed an increased risk among women with extremely or heterogeneously dense tissue compared with those who had scattered fibroglandular densities (RR, 2.04 [95% CI, 1.84 - 2.26] and RR, 1.62 [95% CI, 1.51 - 1.75], respectively).

Study data also revealed that women who had never had a child were at greater risk than parous women (RR, 1.16; 95% CI, 1.04 - 1.26), as were those who had their first child after age 30 rather than in their middle to late twenties (RR, 1.20; 95% CI, 1.02 - 1.42). BCSC results did not confirm these findings but indicated a decreased risk among women having their first child at age 20 or younger.

Current use of oral contraceptives was also linked to an increased for breast cancer compared with former users or never-users (RR, 1.30; 95% CI, 1.13 - 1.49), as was a history of breast biopsy or fine-needle aspiration (RR, 1.51; 95% CI, 1.36 - 1.67).

"Although the results of this review are consistent with previous research, our estimates of risk are unique and relevant to current clinical dilemmas about mammography screening for women in their 40s...Focusing on high breast density and first-degree family history of breast cancer may be a more clinically feasible approach to personalized screening," the authors write.

Modeling Hazard-Benefit Ratios

To determine what level of risk tips the risk-benefit ratio in favor of screening mammography, researchers led by Nicolien T. van Ravesteyn, MSc, from the Erasmus Department of Public Health in the Netherlands used 4 independent models developed as part of the US Cancer Intervention and Surveillance Modeling Network.

The models compared mammography screening starting at age 40 vs age 50 using digital or film mammography, and sought to determine whether annual or biannual screening yielded the most benefit (deaths avoided and life-years gained) and the least harm (false-positive results).

Results showed that the harm-benefit ratio for digital mammography in women aged 40 to 49 years at 2-fold increased risk for cancer was similar to that of average-risk women aged 50 to 74 years (median threshold RR, 1.9; range across models, 1.5 - 4.4).

For screening with film mammography, the threshold RRs were somewhat lower (median, 1.6; range, 1.5 - 3.7) because of its high specificity for women in their forties.

All models showed small benefit for adding annual screening.

"The evidence suggests that for women at twice the average risk for breast cancer, biennial screening beginning at age 40 has more benefits than harms," said Ms. van Ravesteyn in a news release. "These results provide important information toward developing more individualized, risk-based screening guidelines."

Individualized Screening Recommendations Needed

Current recommendations from the US Preventive Services Task Force recommend routine mammographic screening for women aged 50 to 74 years, but there is substantial disagreement about whether screening should occur annually or biannually, and whether women in their forties should be included.

Thus far, the Task Force has left the decision to undergo screening before age 40 to the individual, based on patient values regarding specific benefits and harms.

"I worry that the public perceives mammography as a better technology than it actually is," writes Dr. Brawley, noting that screening accounts for only 15% to 40% of the 32.3% decrease in breast cancer mortality from 1990 to 2008.

"By all estimates, the positive effects of nonmammographic early detection through breast awareness and improvements in treatment are substantial; indeed, they account for at least half of the decrease in mortality if not most," Dr. Brawley notes.

Moreover, routine screening is associated with more harm than good in women in their forties. About 50% of women getting an annual mammogram for 10 years starting at age 40 will have at least 1 false-positive result requiring additional tests and more than 5% will undergo biopsy.

In the future, more emphasis will be placed on individualized risk-based screening guidelines, such as a baseline mammogram at age 40 to identify risk factors (eg, breast density). There may also be recommendations for annual testing in high-risk women, biennial testing in those at intermediate risk, and a later start date for those at average risk for breast cancer, Dr. Brawley suggests.

"This will be challenging because many health care providers and members of the lay community do not understand screening and the concept of risk. Specific tools designed to educate them need to be developed and rigorously assessed," Dr. Brawley concludes.

The studies were funded by the National Cancer Institute. The authors and editorialist have disclosed no relevant financial relationships.

Ann Intern Med. 2012;156:609-617, 635-648, 662-663. van Ravesteyn abstract   Nelson abstract   Editorial extract