Harms of Screening

Additional Interventions
False Sense of Security
Radiation Exposure
Anxiety
Overdiagnosis

Mammography screening may be effective in reducing breast cancer mortality in certain populations. As with any medical intervention, it has limitations, which can pose potential harm to women who participate. These limitations are best described as false-negatives (related to the sensitivity of the test), false-positives (related to the specificity), overdiagnosis (true positives that will not become clinically significant), and radiation risk.

The specificity of mammography (refer to the Mammography section of this summary for more information) affects the number of “unnecessary” interventions due to false-positive results. Even though breast cancer is the most common noncutaneous cancer in women, only a very small fraction (0.1%–0.5%, depending on age) actually have the disease when they are screened. Therefore, even though the specificity of mammography is approximately 90%, most abnormal tests are false-positives.[1] Women with abnormal screening test results have additional procedures performed to determine whether the mammographic finding is cancer. These procedures include additional mammographic imaging (e.g., magnification of the area of concern), ultrasound, and tissue sampling (by fine-needle aspiration, core biopsy, or excisional biopsy). A study of breast cancer screening in 2,400 women enrolled in a health maintenance organization found that over a 10-year period, 88 cancers were diagnosed, 58 of which were identified on mammography. During that period, one-third of the women had an abnormal mammogram result that required additional testing, including 539 additional mammograms, 186 ultrasound examinations, and 188 biopsies. The actuarial cumulative biopsy rate (the rate of true positives) due to mammographic findings was approximately 1 in 4 (23.6%). The positive predictive value (PPV) of an abnormal screening mammogram in this population was 6.3% for women aged 40 to 49 years, 6.6% for women aged 50 to 59 years, and 7.8% for women aged 60 to 69 years.[2] A subsequent analysis and modeling of data from the same cohort of women, all of whom were continuously enrolled in the Harvard Pilgrim Health Care plan from July 1983 through June 1995, estimated that the risk of having at least one false-positive mammogram was 7.4% (95% confidence interval [CI], 6.4%–8.5%) at the first mammogram, 26.0% (95% CI, 24.0%–28.2%) by the fifth mammogram, and 43.1% (95% CI, 36.6%–53.6%) by the ninth mammogram.[3] Cumulative risk of at least one false-positive by the ninth mammogram varied from 5% to 100%, depending on four patient variables and three radiologic variables. Patient variables independently associated with increased chance of a false-positive result included younger age, higher number of previous breast biopsies, family history of breast cancer, and current estrogen use. Radiologic variables included longer time between screenings, failure to compare the current and previous mammograms, and the individual radiologist’s tendency to interpret mammograms as abnormal, which ranged from 2.6% to 24.4% across 93 radiologists in the study. Overall, the largest risk factor for having a false-positive mammogram was the individual radiologist’s tendency to read mammograms as abnormal. The authors noted that CIs for estimates of false-positives beyond five mammograms were wide because of the relatively small numbers of women in the analysis with more than five mammograms.

By reviewing Medicare claims following mammographic screening in 23,172 women older than 65 years, one study [4] found that 85 per 1,000 had follow-up testing and 23 per 1,000 had biopsies. The cancer detection rate was 7 per 1,000, so the PPV for an abnormal mammogram was 8%. For women older than 70 years, the PPV was 14%. An audit of mammograms done in 1998 at a single institution revealed that 14.7% of examinations resulted in a recommendation for additional testing (Breast Imaging Reporting and Data System category 0), 1.8% resulted in a recommendation for biopsy (categories 4 and 5), and 5.7% resulted in a recommendation for short-term interval mammography (category 3). Cancer was diagnosed in 1 out of 30 of the cases referred for additional testing.[5]

The sensitivity of mammography (refer to the Mammography section of this summary for more information) ranges from 70% to 90%, depending on a woman’s age and the density of her breasts, which is affected by her genetic predisposition, hormone status, and diet. Assuming an average sensitivity of 80%, mammograms will miss approximately 20% of the breast cancers that are present at the time of screening (false-negatives). If a woman does not seek medical attention for a breast symptom or if her physician is reluctant to evaluate that symptom because she has a “normal” mammogram, she may suffer adverse consequences. Whereas the medical community has been carefully educated that a negative diagnostic mammogram should not deter work-up of a palpable lump, the medical and lay communities should be made aware that a negative screening mammogram misses one in five cancers.

Because radiation exposure is a known risk factor for the development of breast cancer, it is ironic that ionizing radiation is our best screening tool. The major predictors of risk are young age at the time of radiation exposure and the radiation dose. For women older than 40 years, the benefits of annual mammograms may outweigh any potential risk of radiation exposure due to mammography.[6] It is speculated that certain subpopulations of women may have an inherited susceptibility to ionizing radiation damage,[7,8] but mammography has never been shown to be harmful in these, or any, subgroups. In the United States, the mean glandular dose for screening mammography is 1 mGy to 2 mGy (100–200 mrad) per view or 2 mGy to 4 mGy (200–400 mrad) per standard two-view exam.[9,10]

Because large numbers of women have false-positive tests, the issue of psychological distress—which may be provoked by the additional testing—has been studied. A telephone survey of 308 women performed 3 months after screening mammography revealed that about one-fourth of the 68 women with a “suspicious” result were still experiencing worry that affected their mood or functioning, even though subsequent testing had ruled out a cancer diagnosis.[11] Several studies,[12-14] however, show that the anxiety following evaluation of a false-positive test leads to increased participation in future screening examinations.[15]

Overdiagnosed disease is a neoplasm that would never become clinically apparent prior to a patient’s death without screening. An example is a tumor that is found by mammographic screening that would never be evident otherwise.

Autopsy studies have found tumors in people who died of causes unrelated to the tumors. The studies indicate that lesions exist that fulfill the histologic criteria of cancer but that were not clinically apparent in the woman's lifetime. An overview of seven autopsy studies documents a median prevalence of 1.3% for undiagnosed invasive breast cancer (range, 0%–1.8%) and 8.9% for undiagnosed ductal carcinoma in situ (range, 0%–14.7%).[16,17] Finding such cancers by mammography would be overdiagnosis. Because cancers that will progress cannot be distinguished with certainty from those that will not, these tumors are often treated (with surgery and possibly with radiation, chemotherapy, and hormonal therapy). This treatment would constitute overtreatment because it would not confer a benefit to the woman.

It is difficult to determine the proportion of screen-detected cancers that are overdiagnosed. A widely accepted estimation method is to compare breast cancer incidence over time in a screened population with that of an unscreened population. Randomized screening trials are the most credible, but the period of screening versus control is limited in all the trials. If a woman complies with not being screened during the study period but gets screened afterwards, then a breast cancer that would have been found had the woman been assigned to screening would likely be found shortly thereafter. (Most of the women in the control group in the Swedish trials were assigned to receive a control mammogram at the end of the study period.) Such delayed screening will also find overdiagnosed cancers; the cumulative incidence of cancers will be similar in the two groups, irrespective of the magnitude of overdiagnosis.

Population-based studies suffer from the same problem as randomized trials, although to a lesser extent. However, the population-based studies have their own problems. Unbiased estimates would only be possible if the screened and nonscreened populations were the same except for screening, but the populations may differ in time, in geography, in culture, and by the use of postmenopausal hormone therapy. In addition, investigators differ in their assessments of overdiagnosis regarding how and whether to adjust for characteristics such as lead-time bias.[18,19] As a consequence, the magnitude of overdiagnosis due to mammographic screening is controversial, with estimates ranging from 7% to 50%.[18-21]

Several observational population-based comparisons consider breast cancer incidence before and after adoption of screening.[22-26] If there were no overdiagnosis—and other aspects of screening were unchanged—there would be a rise in incidence followed by a decrease to below the prescreening level, and the cumulative incidence would be similar. Such results have not been observed. Breast cancer incidence rates increase at the initiation of screening without a compensatory drop in later years. For example, in Sweden, the age-specific incidence rates doubled between 1986 and 2002 for all age groups participating in screening.[22] Another study in 11 rural Swedish counties showed a persistent increase in breast cancer incidence following the advent of screening.[23] A population-based study from Norway and Sweden showed increases in invasive breast cancer incidence of 54% in Norway and 45% in Sweden in women aged 50 to 69 years, following the introduction of nationwide screening programs. No corresponding decline in incidence in women older than age 69 years was ever seen.[27] Similar findings suggestive of overdiagnosis have been reported from the United Kingdom [24] and the United States.[25,26]

References

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2. Elmore JG, Barton MB, Moceri VM, et al.: Ten-year risk of false positive screening mammograms and clinical breast examinations. N Engl J Med 338 (16): 1089-96, 1998.  [PUBMED Abstract]
   
   
3. Christiansen CL, Wang F, Barton MB, et al.: Predicting the cumulative risk of false-positive mammograms. J Natl Cancer Inst 92 (20): 1657-66, 2000.  [PUBMED Abstract]
   
   
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7. Helzlsouer KJ, Harris EL, Parshad R, et al.: Familial clustering of breast cancer: possible interaction between DNA repair proficiency and radiation exposure in the development of breast cancer. Int J Cancer 64 (1): 14-7, 1995.  [PUBMED Abstract]
   
   
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10. Suleiman OH, Spelic DC, McCrohan JL, et al.: Mammography in the 1990s: the United States and Canada. Radiology 210 (2): 345-51, 1999.  [PUBMED Abstract]
    
    
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