By Jeffrey T. Jensen, MD, MPH
Leon Speroff Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland
Dr. Jensen reports he is a consultant for Teva Pharmaceuticals and MicroChips; and is a consultant for and receives grant research support from HRA Pharma, Bayer Healthcare, Merck, Agile Pharm, Population Council, AbbVie, Evofem, and ContraMed.
SYNOPSIS: The decision to undergo screening mammography requires a consideration of benefits and harms. Harms include false-positive exams leading to unnecessary interventions, and true-positive exams that lead to overdiagnosis.
SOURCES: Nelson HD, et al. Harms of breast cancer screening: Systematic review to update the 2009 U.S. Preventive Services Task Force Recommendation. Ann Intern Med 2016;164:256-267.
Melnikow J, et al. Supplemental screening for breast cancer in women with dense breasts: A systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2016;164:205-214.
Last month, we reviewed the new breast cancer screening guidelines from the U.S. Preventive Services Task Force (USPSTF). The USPSTF recommends biennial screening mammography for all women aged 50 to 74 years. For women younger than 50 years of age, the recommendation for screening mammography received a “C” grade (moderate certainty that the net benefit of screening, while positive, is small). As we discussed, the decision to undergo screening more frequently than every other year or before age 50 requires an evaluation of potential benefits and harms. This article will focus on the potential harms of mammogram screening and the role of supplemental screening tests, particularly in women with dense breasts.
Nelson et al reviewed the available English literature to evaluate the potential harms of routine breast cancer screening, and how they differ by age, risk factor, screening interval, and screening modality. The authors considered potential harms to include both false-positive and false-negative mammography results, overdiagnosis, anxiety and other psychological responses, pain during procedures, and radiation exposure.
Overdiagnosis was defined as a diagnosis of ductal carcinoma in situ (DCIS) or invasive breast cancer considered unlikely to become clinically important in the woman during her lifetime in the absence of screening. Harms associated with an overdiagnosis of breast cancer include unnecessary surgical procedures and medical treatments as well as the emotional burden of receiving a cancer diagnosis. Unfortunately, there is no consensus definition of overdiagnosis, so studies evaluating this harm are highly heterogeneous. It is also important to keep in mind that it is difficult to determine the significance of a breast cancer diagnosis to an individual woman. In other words, overdiagnosis remains a population medicine construct that offers little guidance to individual women and their doctors. The analysis of the Nelson et al paper can be summarized follows.
FALSE-POSITIVE AND FALSE-NEGATIVE RESULTS
Nelson et al reviewed data from the Breast Cancer Surveillance Consortium database to evaluate rates of false-positive results in 405,191 women aged 40-89 years who had routine screening with digital mammography between 2003 and 2011. They found rates of false-positive results and recommendations for additional imaging were highest among women aged 40-49 years and decreased with increasing age. Annual screening is associated with a greater risk of false-positive mammogram results and unnecessary biopsies. For example, the cumulative probability of receiving at least one false-positive mammography result after 10 years for a woman who begins screening at age 40 is 61% with annual screening and 42% with biennial screening; 7% will receive a biopsy with annual screening compared to 5% screened every 2 years. For women ages 50-59 years, the probability of unnecessary biopsy is reduced by one-third (from 9% to 6%) when screening is moved from annually to every 2 years. Women with extremely dense breasts who undergo annual mammography, and are either aged 40-49 years or using combined hormonal therapy, have the highest rates of false-positive mammograms and unnecessary biopsy. The lowest rates of false-positive results were seen in women aged 50-74 years without dense breasts screened every 2 or 3 years. In contrast, false-negative results and recommendations for biopsy did not differ greatly by age. False-positive rates were higher for women with risk factors, particularly family history of breast cancer; previous benign breast biopsy result; high breast density; and, for younger women, low body mass index.
OVERDIAGNOSIS
The authors analyzed 18 new studies, including three randomized, controlled trials to evaluate the potential harm of overdiagnosis. The randomized studies offer the best estimates, as they provide a direct comparison of breast cancer diagnosis (both invasive cancer and DCIS) and mortality in the presence and absence of screening. Since the 2009 USPSTF publication, extended 25-year follow-up from the Canadian National Breast Screening Study was published.1 The conclusion of the Canadian study was that 22% of screen-detected invasive breast cancers were overdiagnosed. In absolute numbers, this represented one over-diagnosed breast cancer for every 424 women who received mammography screening in the trial. The risk of overdiagnosis appears higher for women aged 40-49 years than for older women.
ANXIETY, DISTRESS, AND OTHER PSYCHOLOGICAL RESPONSES
No randomized studies have evaluated the psychological effects of breast cancer screening, and most of the observational studies have a variety of methodologic limitations (small enrollment, narrowly selected subjects, or other methodologic flaws). Given these limitations, the conclusion that women who are recalled for additional testing after screening mammography suffer from more anxiety, breast cancer-specific worry, and distress than women with negative screening should be viewed with caution. Of particular concern, however, were studies which suggest that women with false-positive results were less likely to return for their next screening.
PAIN ASSOCIATED WITH SCREENING
Pain related to screening could influence whether a woman presents for future screening. A number of individual studies and systematic reviews were evaluated to address this question. Most studies did not support that pain associated with screening has a major impact on the decision to represent for a future mammogram.
RADIATION EXPOSURE
Although radiation exposure from standard two-view digital mammography is considered low-dose, repeated studies theoretically could result in harmful effects. No studies have directly measured the association between radiation exposure from mammography screening and the incidence of breast cancer and death. Nelson et al evaluated two modeling studies which estimated that the number of deaths due to radiation-induced breast cancer ranged from 2/100,000 in women aged 50-59 years screened biennially to 11/100,000 in women aged 40-59 years screened annually.2 However, this potential risk should be interpreted with great caution due to the assumptions based in the model, and the absolute risk of death is tiny and is dwarfed by the net benefit of screening (80 deaths averted among 100,000 women aged 50-59 years who were screened).
DIFFERENCES BETWEEN SCREENING MODALITIES AND USE OF SUPPLEMENTAL SCREENING
The task force concluded that the evidence for benefits and harms of digital breast tomosynthesis (DBT) as a primary screening method for breast cancer was insufficient (I statement). The task force also found the current evidence insufficient to assess the benefits and harms of adjunctive screening modalities (breast ultrasonography, magnetic resonance imaging, DBT, or other methods) in women identified to have dense breasts on an otherwise negative screening mammogram (I statement). In a separate paper, Melnikow et al found that in good-quality studies with U.S. radiologists, a sizable number of women (13-19%) were reclassified from “nondense” to “dense” or vice versa with sequential screening examinations. This may result in differences in mandated communications in states with breast density notification laws and introduce confusion. Although limited evidence suggests that supplemental ultrasound and MRI screening of women with dense breasts will lead to the detection of more invasive breast cancer cases, no studies have shown that supplemental screening leads to improved clinical outcomes or reduces overdiagnosis. Supplemental screening of women with dense breasts with ultrasound or MRI is also associated with increased recall rates for diagnostic investigation among women without breast cancer.
SUMMARY
Overall, mammography screening results in early diagnosis of breast cancer and saves lives. Unfortunately, screening also leads to potential harms from both false-positive and true-positive screens. Clinicians should discuss these potential harms along with benefits in a balanced fashion. Supplemental imaging modalities may improve screening results, but the evidence is currently insufficient to determine whether this results in the diagnosis of more serious breast cancers or simply an increase in overdiagnosis. In keeping with the USPSTF, I recommend screening every 2 years beginning at age 50 and ending at age 74 as an evidence-based conservative approach.
REFERENCES
- Miller AB, et al. Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: Randomised screening trial. BMJ 2014;348:g366.
- Yaffe MJ, Mainprize JG. Risk of radiation-induced breast cancer from mammographic screening. Radiology 2011;258:98-105.
The decision to undergo screening mammography requires a consideration of benefits and harms. Harms include false-positive exams leading to unnecessary interventions, and true-positive exams that lead to overdiagnosis.
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