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New Breast Cancer Mammography Controversy Over New Study Suggesting Breast Cancer Overdiagnosis
 
 
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Study Suggests Breast Cancer Overdiagnosed

As a result of mammographic screening programs, as many 1.3 million women over age 40 were overdiagnosed with breast cancer over 3 decades, researchers reported.full story

http://www.medpagetoday.com/HematologyOncology/BreastCancer/36072?utm_content=&utm_medium=email&utm_campaign=DailyHeadlines&utm_source=WC&eun=g92748d0r&userid=92748&email=julev@aol.com&mu_id=5092023

There is likely some overdiagnosis of breast cancer, argued Therese Bevers, MD, of M.D. Anderson Cancer Center in Houston, but nowhere near the 31% suggested by the authors.

Instead, she told MedPage Today, it is "much smaller, probably on the order of about 10%."

The groups argued that the assumptions in the study were wrong and that - far from there being no evidence of a screening benefit - mammograms have reduced the incidence of invasive disease


As a result of mammographic screening programs, as many 1.3 million women over age 40 were overdiagnosed with breast cancer over three decades, researchers reported.

In a study that seems certain to generate controversy -- as is apparent in MedPage Today's discussant video -- the researchers concluded that overdiagnosis is involved in up to a third of all newly discovered tumors and that screening plays only a small role in reducing breast cancer mortality.

Action Points

· This study examined trends from 1976 through 2008 in the incidence of early-stage breast cancer (ductal carcinoma in situ and localized disease) and late-stage breast cancer (regional and distant disease) among women 40 years of age or older.

· The investigators interpret the data to suggest that there is substantial overdiagnosis, accounting for nearly a third of all newly diagnosed breast cancers, and that screening is having, at best, only a small effect on the rate of death from breast cancer.

Over the past 30 years, mammogram programs have increased the detection of early-stage breast cancer, according to Archie Bleyer, MD, of Oregon Health and Science University in Portland and H. Gilbert Welch, MD, of Dartmouth University in Hanover, N.H.

But screening had little effect on the detection of late-stage disease, they reported in the Nov. 22 issue of the New England Journal of Medicine, implying that many women underwent treatment for early forms of cancer that would never have caused serious disease.

Bleyer said the finding - while suggesting that screening is largely ineffective - is actually good news, because it implies that therapy is actually more effective than had been thought.

Breast cancer mortality has been falling in the U.S., a decline usually attributed to a combination of increased screening and better treatment, Bleyer told MedPage Today. The study implies, he said, that "treatment ... is the main, if not the only, reason for the improvement" in survival.

The findings come from a retrospective analysis of annual breast cancer data from the Surveillance, Epidemiology, and End Results database, coupled with assumptions about how the incidence of the disease changed over time.

The researchers used a 3-year period near the beginning of the database - 1976 though 1978 - to develop baseline incidence estimates for breast cancer among women 40 and over.

They estimated current incidence using the 3 years from 2006 through 2008. For calculations that covered all 3 decades, they adjusted the observed incidence from 1990 through 2005 to account for increases attributed to the use of hormone replacement therapy over that period.

Finally, their main assumption about the change in background incidence over time among women over 40 was that it would parallel what was seen among younger women - an increase of 0.25% a year.

In 2006-2008, they found, the incidence of early-stage cancer was markedly higher than before screening in 1976-1978, while the incidence of late-stage disease changed minimally.

They found that, annually, there were:

· 7 cases per 100,000 women of ductal carcinoma in situ in the early period, compared with 56 per 100,000 more recently

· For localized disease, 105 per 100,000 women in 1976-1978 and 178 per 100,000 in 2006-2008

· For regional disease, 85 per 100,000 women in the earlier period and 78 per 100,000 in the later period

· 17 cases of distant disease per 100,000 women in both periods

When the figures were rounded off, Bleyer and Welch reported, there were an extra 122 early cases per 100,000 women detected in the mammogram period and a drop of eight cases of late-stage disease.

"With the assumption of a constant underlying disease burden, only 8 of the 122 additional early-stage cancers diagnosed were expected to progress to advanced disease," they argued.

In 2008, that would have amounted to overdiagnosis in 70,000 women, or about 31% of all diagnosed breast cancers, they reported.

After adjusting for the hormone-replacement era - and assuming that incidence trends in older women mirrored those in their younger counterparts -- that adds up to overdiagnosis in 1.3 million U.S. women in the past 30 years, they concluded.

The study has already generated some heated responses. Aside from the comments made by Appleton and Bevers in the accompanying video, a statement from the American College of Radiology and the Society of Breast Imaging said bluntly: "The thesis by Bleyer and Welch is simply wrong."

The groups argued that the assumptions in the study were wrong and that - far from there being no evidence of a screening benefit - mammograms have reduced the incidence of invasive disease.

In particular, they argued, the assumption that the change in incidence is just 0.25% a year - or even 0.5% a year, in what Bleyer and Welch called an "extreme" scenario - is not backed up by the facts.

"The incidence of invasive breast cancer has actually increased by 1% per year for decades," the groups said in the statement. "If such misinformation is used to determine screening guidelines and recommendations, the cost may be lost lives," the statement concluded.

There is likely some overdiagnosis of breast cancer, argued Therese Bevers, MD, of M.D. Anderson Cancer Center in Houston, but nowhere near the 31% suggested by the authors.

Instead, she told MedPage Today, it is "much smaller, probably on the order of about 10%."

"It is my feeling, based on data from randomized trials and not retrospective data such as these, that the benefits (of screening) outweigh the harms," Bevers said.

Even if there's a risk of overtreatment, she said, "we really don't understand which cancers we really don't need to be treating" and both patients and their doctors feel more comfortable with therapy rather than watchful waiting.

Catherine M. Appleton, MD, of Washington University St. Louis Medical Center, joined Bevers in expressing concerns about the study, as seen in the discussant video accompanying this article.

For his part, Bleyer said he's convinced that the assumptions in the study are conservative and that doctors and patients need to be aware of the harm associated with overdiagnosis as well as any potential benefit from early diagnosis.

The remedy, Bleyer told MedPage Today, would be to reduce the scope of mammographic screening in line with the 2009 recommendations of the U.S. Preventive Services Task Force.

The panel recommended against routine screening mammography for women younger than 50 and said the recommended screening interval for women 50 and older should be every 2 years instead of annually.

"There's no question about continuing mammography," Bleyer said, but widespread adoption of those recommendations would go far to reducing overdiagnosis and overtreatment of early-stage breast cancer.

----------------------------

Clinical Decisions

Mammography Screening for Breast Cancer

N Engl J Med 2012

Case Vignette

A 40-year-old woman presents to her primary care physician for a routine health maintenance examination. Overall, she has been feeling well. She takes no medications. She lives with her husband and their two children, who are 7 and 11 years of age. She underwent menarche at the age of 12. Before the birth of her first child, she took combined oral contraceptives for 6 years. She breast-fed each of her children for approximately 1 year. For the past 4 years, she has used a levonorgestrel intrauterine device for contraception. She works as an accountant and exercises on the weekends. Her diet includes regular consumption of fish, chicken, and vegetables, and she eats red meat once a week. She does not smoke, and she consumes an average of four glasses of wine each week. Her family history is notable for prostate cancer in her father that was diagnosed when he was 75 years of age and hypertension in her mother that was diagnosed when she was 60 years of age. There is no history of colon cancer, lung cancer, or breast cancer among her parents or grandparents. She undergoes a complete physical examination, including a clinical breast examination. All findings are normal. She has never undergone mammography, and she asks her primary care physician about recommendations regarding mammography screening.

Treatment Options

Which one of the following approaches do you find appropriate for women who, like the woman in the vignette, are at average risk? Base your choice on the published literature, your own experience, recent guidelines, and other sources of information, as appropriate.

· Option 1: Recommend Screening Mammography Starting at the Age of 40

· Option 2: Recommend Screening Mammography Starting at the Age of 50

· Option 3: Do Not Recommend Screening Mammography

Option 1

Recommend Screening Mammography Starting at the Age of 40

Robert A. Smith, Ph.D.

From the Cancer Control Science Department, American Cancer Society, Atlanta.

At what age should women begin breast-cancer screening, and what information can women and their clinicians use to help inform this decision? One school of thought asserts that progress in therapy has eclipsed the benefit of early detection and that harms associated with screening are excessive and outweigh the benefits.1,2 There is substantial evidence to the contrary,3 however, and the methodologic flaws that lead to these claims have been clearly identified.4,5

Another school of thought discourages initiation of screening until the age of 50, emphasizing that the 10-year risk of breast cancer is lower when a woman is in her 40s than when she is in her 50s (1 case among 69 women vs. 1 among 42), that mammography reduces the risk of death from breast cancer by only 15%, that 1904 women 40 to 49 years of age need to be invited to be screened over a period of 11 to 20 years to save one life, and that the harms, principally false positive findings, are considerable.6

A third school of thought - one that supports screening starting at the age of 40 - is more compelling. Our ability to predict population risk is reasonably accurate, yet we are not able to tell a woman with confidence that it is safe to postpone - not probably safe to postpone - beginning screening until the age of 50. Furthermore, 73.6% of non-Hispanic white women in their 40s have an absolute risk of breast cancer that is greater than that of a 50-year-old woman without risk factors.7 In addition, one in six breast-cancer deaths is attributable to a diagnosis that was made when the woman was in her 40s, and breast cancer is a leading cause of premature death among women; one third of all the years of life lost as a result of breast cancer are due to diagnoses that were made when the women were in their 40s.8 Breast cancer among women in their 40s is a considerable, not small, fraction of the overall burden of this disease.

Although a meta-analysis of randomized, controlled trials showed a 15% reduction in mortality among women randomly assigned to be invited to undergo screening mammography in their 40s,6 individual randomized, controlled trials and recent evaluations of modern mammography screening have shown substantially greater reductions in mortality. Consider the recent Swedish study showing that among women who underwent screening, there were 29% fewer deaths from breast cancer after 16 years in counties that offered mammography than in those that did not.3 The estimate that 1904 women 39 to 49 years of age need to be invited to be screened to save one life is an imprecise and nebulous surrogate for the number needed to screen because it is influenced by deaths among women in the invited group who did not undergo screening and by variable follow-up periods (ranging from 11 to 20 years) in the individual studies. In contrast, on the basis of direct observation of women 39 to 49 years of age who actually underwent screening mammography over a 7-year period and were followed for 20 years, the number needed to screen was 7269 - a number that is less even than the estimated number needed to invite (1339) for women in their 50s.6

What about harms? The risk of a false positive finding is greater than 50% during a decade of regular screening,10 and false positives are associated with temporary anxiety.6 Nevertheless, women have reported that they accept the trade-off of false positives in favor of finding breast cancer early.11 Estimates of overdiagnosis have ranged from 0 to more than 50%, but the rates are small (<10%) in studies that properly adjust for lead time and trends in incidence.12 We should also consider the harms associated with electing not to be screened before the age of 50. A recent case series showed that women whose breast cancer was not diagnosed by mammography were more likely to be diagnosed with a stage II or higher tumor than were women in whom breast cancer was diagnosed by mammography (66% vs. 27%) and were more likely to have a mastectomy (47% vs. 25%); undergo surgery, radiation therapy, and chemotherapy (59% vs. 31%); and have poorer 5-year survival rates.13

Screening can be thought of as a kind of insurance. As with all insurance, there are costs for protection against adverse events that have a low probability of occurrence but could be catastrophic if they occurred without the insurance.14 In that context, given the evidence, there are good reasons to begin screening at the age of 40.

Option 2

Recommend Screening Mammography Starting at the Age of 50


Karla Kerlikowske, M.D., Diana L. Miglioretti, Ph.D.

When evidence-based guidelines for breast-cancer screening are developed, the primary consideration is whether the benefits outweigh the harms. The benefits of screening mammography include breast-cancer deaths averted and life-years gained by the detection of biologically significant cancers before they become apparent clinically. The harms of screening healthy women include false positive tests, radiation exposure from screening and follow-up imaging, invasive follow-up procedures, and overdiagnosis. The balance of benefits and harms is tipped to favor more benefit than harm if screening mammography is routinely offered to average-risk women starting at 50 years of age.

High-quality evidence is available from randomized, controlled trials and from U.S. population-based simulation models, and the two sources show similar findings regarding screening mammography.15,16 Among women 50 to 74 years of age screened every 2 years, 12 rounds of screening 1000 women result in 7.5 breast-cancer deaths averted, 121 life-years gained, and 940 false positive mammography results requiring diagnostic imaging leading to 66 false positive biopsy results. By comparison, if 1000 women start screening at 40 years of age and are screened every 2 years, 5 more screening rounds would result in an additional 0.7 breast-cancer deaths averted, 21 life-years gained, 4921 mammograms performed, and 470 false positive mammography results requiring diagnostic imaging leading to 33 false positive biopsy results. The ratio of benefit to harm with screening mammography is more favorable among women 50 to 74 years of age than among younger women because mammography is less accurate in younger women, and the low incidence of disease results in a higher rate of false positive results and a lower rate of breast-cancer deaths averted. Furthermore, increasing the frequency of screening from every 2 years to every year almost doubles the harms,10 without increasing the benefit.

As now reported in the Journal, Bleyer and Welch1 suggest that the benefits of screening mammography are modest and raise the question of whether the effectiveness can be improved. One approach is to target women who are at an increased risk for breast cancer and advanced-stage disease, because their tumors are more likely to become metastatic and fatal, and thus are more likely to benefit from earlier diagnosis. Factors that increase the risk of breast cancer and advanced stage at diagnosis include high breast density, use of postmenopausal estrogen plus progestin for 5 or more years, and postmenopausal obesity.17,18 Risk-based screening could also decrease the potential harms by identifying women at low risk for breast cancer who could begin screening at a later age and be screened less often, such as women with fatty breast density.19

Given this evidence, we agree with the U.S. Preventive Services Task Force and with most countries with breast-cancer screening programs, which recommend that women undergo screening mammography every 2 years beginning at the age of 50. Average-risk women 40 to 49 years of age, for whom the benefits of screening are small and the potential for harms great, should be given the opportunity to make an informed decision about screening by being made aware of the potential benefits of mammography (1 death from breast cancer averted for every 1430 to 1900 women invited to be screened for 10 years),15,16 their chances of having a false positive mammography result and of having a false positive breast biopsy result (42% and 5%, respectively, after 5 biennial screening rounds and 61% and 7%, respectively, after 10 annual screening rounds),10 and their chances of overdiagnosis and overtreatment. Targeting screening to women 40 to 49 years of age with combinations of risk factors that increase the risk of breast cancer by a factor of 2 to 4, such as high breast density, a family history of breast cancer, or a history of breast biopsy, would maximize the benefit and limit the harms of screening in this group.19,20 Women at the highest risk for breast cancer, such as those who carry the BRCA1 or BRCA2 mutation, should undergo breast magnetic resonance imaging and mammography before the age of 40.

Source Information

From the Department of Epidemiology and Biostatistics and the General Internal Medicine Section, Department of Veterans Affairs, University of California, San Francisco, San Francisco (K.K.); and the Group Health Research Institute, Group Health Cooperative, and the Department of Biostatistics, University of Washington - both in Seattle (D.L.M.).

Option 3

Do Not Recommend Screening Mammography

Mette Kalager, M.D., Ph.D.

The small absolute benefit of screening for 40-year-old women has been known for years. Of greater concern is that the harms are greater than previously anticipated and may outweigh the benefits. The most harmful side effect of screening is overdiagnosis, which results in unnecessary treatment, including surgery, radiation, hormonal treatment, and chemotherapy. As Bleyer and Welch now convincingly show in the Journal, as many as 31% of all breast cancers in the United States are overdiagnosed.1 The 10-year risk of breast cancer (including overdiagnosis) for a 40-year-old woman is 1.90%.21 The corresponding risk without screening would be 1.46%. Thus, 0.44% of 40-year-old U.S. women are harmed by screening mammography - 10 to 20 times as many as those who benefit from screening mammography as a result of reduced mortality. Furthermore, the balance of benefits and harms for 50-year-old women is similar to that for 40-year-old women (Figure 1). On the basis of the small absolute benefit and the substantial harms, I do not currently recommend screening mammography for average-risk women of any age.

More than 600,000 women were enrolled in several randomized trials of mammography screening more than 30 years ago. The trials showed a reduction in breast-cancer mortality but no effect on all-cause mortality. In recent decades, breast-cancer treatment has improved greatly, resulting in reduced mortality even among women with advanced disease. Thus, the reduction in mortality from mammography screening may be significantly smaller today than when the trials were performed.

What is the absolute benefit of breast-cancer screening for a 40-year-old woman? First of all, the 10-year risk of dying from breast cancer for a 40-year-old woman is low (0.17%).21 There is heated debate on whether screening reduces breast-cancer death by 25% (as observed in the early randomized trials) or 10% (as observed in more recent studies2,24,25); however, the difference is not clinically meaningful. A 25% relative reduction results in an absolute benefit of 0.04 percentage points, and a 10% reduction would result in an absolute benefit of 0.02 percentage points.

The benefits of mammography screening are smaller than those of other interventions, such as the use of aspirin to reduce cancer mortality (Figure 1). The use of aspirin for 5 years, as compared with no use of aspirin, reduced the 10-year risk of death from cancer by 1.3 percentage points but increased the risk of major bleeding by 0.4 percentage points.22,23 Clearly, the benefits are much smaller and the harms much greater with mammography screening. Would we discuss aspirin as a preventive measure against cancer death if the effects were smaller than the harms? Probably not.

The decision regarding screening mammography depends on the balance of benefits and harms and the way in which a woman and her physician weigh these competing factors. In my view, the benefits do not exceed the harms. Thus, given the data currently available, I do not recommend mammography screening for average-risk women of any age. I would ask the woman in the vignette to come back when she is 50 years of age. In 10 years, we might have more data to provide a different recommendation for her.

Source Information

From the Department of Health Management and Health Economics, University of Oslo, and Telemark Hospital - both in Oslo; and the Department of Epidemiology, Harvard School of Public Health, Boston.

---------------------------------

Effect of Three Decades of Screening Mammography on Breast-Cancer Incidence

Archie Bleyer, M.D., and H. Gilbert Welch, M.D., M.P.H.

N Engl J Med Nov 22 2012; 367:1998-2005

Background

To reduce mortality, screening must detect life-threatening disease at an earlier, more curable stage. Effective cancer-screening programs therefore both increase the incidence of cancer detected at an early stage and decrease the incidence of cancer presenting at a late stage.

Methods

We used Surveillance, Epidemiology, and End Results data to examine trends from 1976 through 2008 in the incidence of early-stage breast cancer (ductal carcinoma in situ and localized disease) and late-stage breast cancer (regional and distant disease) among women 40 years of age or older.

Results

The introduction of screening mammography in the United States has been associated with a doubling in the number of cases of early-stage breast cancer that are detected each year, from 112 to 234 cases per 100,000 women - an absolute increase of 122 cases per 100,000 women. Concomitantly, the rate at which women present with late-stage cancer has decreased by 8%, from 102 to 94 cases per 100,000 women - an absolute decrease of 8 cases per 100,000 women. With the assumption of a constant underlying disease burden, only 8 of the 122 additional early-stage cancers diagnosed were expected to progress to advanced disease. After excluding the transient excess incidence associated with hormone-replacement therapy and adjusting for trends in the incidence of breast cancer among women younger than 40 years of age, we estimated that breast cancer was overdiagnosed (i.e., tumors were detected on screening that would never have led to clinical symptoms) in 1.3 million U.S. women in the past 30 years. We estimated that in 2008, breast cancer was overdiagnosed in more than 70,000 women; this accounted for 31% of all breast cancers diagnosed.

Conclusions

Despite substantial increases in the number of cases of early-stage breast cancer detected, screening mammography has only marginally reduced the rate at which women present with advanced cancer. Although it is not certain which women have been affected, the imbalance suggests that there is substantial overdiagnosis, accounting for nearly a third of all newly diagnosed breast cancers, and that screening is having, at best, only a small effect on the rate of death from breast cancer.

There are two prerequisites for screening to reduce the rate of death from cancer.1,2 First, screening must advance the time of diagnosis of cancers that are destined to cause death. Second, early treatment of these cancers must confer some advantage over treatment at clinical presentation. Screening programs that meet the first prerequisite will have a predictable effect on the stage-specific incidence of cancer. As the time of diagnosis is advanced, more cancers will be detected at an early stage and the incidence of early-stage cancer will increase. If the time of diagnosis of cancers that will progress to a late stage is advanced, then fewer cancers will be present at a late stage and the incidence of late-stage cancer will decrease.3

In the United States, clinicians now have more than three decades of experience with the widespread use of screening mammography in women who are 40 years of age or older. We examined the temporal effects of mammography on the stage-specific incidence of breast cancer. Specifically, we quantified the expected increase in the incidence of early-stage cancer and determined the extent to which this has led to a corresponding decrease in the incidence of late-stage cancer.

Methods

Overview


We obtained trend data on the use of screening mammography and the stage-specific incidence of breast cancer among women 40 years of age or older. To calculate the number of additional women with a diagnosis of early-stage cancer (as well as the reduction in the number of women with a diagnosis of late-stage cancer), we determined a baseline incidence before screening, calculated the surplus (or deficit) incidence relative to the baseline in each subsequent calendar year, and transformed data on the change in incidence to data on nationwide counts.

We used the direct method to adjust the incidence rates according to age in the U.S. standard population in the year 2000. All analyses were performed with the use of either (SEER*Stat or Microsoft Excel software. In an effort to make our method transparent, the data on Surveillance, Epidemiology, and End Results (SEER) stage-specific incidence and all calculations are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org. Both authors vouch for the completeness and accuracy of the reported data and analysis and the fidelity of the study to the protocol.

Data Sources

We obtained trend data from the National Health Interview Survey on the proportion of women 40 years of age or older who underwent screening mammography.4,5 Trend data on incidence and survival rates were obtained from the nine long-standing SEER areas6; these data accounted for approximately 10% of the U.S. population.7 Annual estimates of the population of women 40 years of age or older were obtained from the U.S. Census.8

Stage at Diagnosis

We used SEER historic stage A as the foundation for our categorization of early- and late-stage cancer. The four stages in this system are the following: in situ disease; localized disease, defined as invasive cancer that is confined to the organ of disease origin; regional disease, defined as disease that extends outside of and adjacent to or contiguous with the organ of disease origin (in breast cancer, most regional disease indicates nodal involvement, not direct extension9); and distant disease, defined as metastasis to organs that are not adjacent to the organ of disease origin. We restricted in situ cancers to ductal carcinoma in situ (DCIS), specifically excluding lobular carcinoma in situ, as done in other studies.10 We defined early-stage cancer as DCIS or localized disease, and late-stage cancer as regional or distant disease.

Baseline Incidence

The incidence data from the first year in which breast-cancer incidence was recorded (1973) were almost certainly spuriously low (which would bias our estimates of excess detection upward). The data from the subsequent 2 years (1974 and 1975) were above average for the decade, reflecting the sharp uptick in early detection after First Lady Betty Ford's breast-cancer diagnosis.11 Consequently, we chose the 3-year period 1976 through 1978 to obtain our estimate of the baseline incidence of breast cancer that was detected without mammography. During this period, the incidence of breast cancer was stable and few cases of DCIS were detected; these findings are compatible with the very limited use of screening mammography.

Current Incidence and Removal of the Effect of Hormone-Replacement Therapy

We based our estimate of the current incidence of breast cancer on the 3-year period from 2006 through 2008. To eliminate the effect of hormone-replacement therapy, we truncated the observed incidence each year from 1990 through 2005 if it was higher than the estimate of the current incidence (Table S2 and Fig. S1 in the Supplementary Appendix). In other words, we did not allow the annual incidence of DCIS to exceed 56.5 cases, localized disease to exceed 177.5 cases, regional disease to exceed 77.6 cases, and distant disease to exceed 16.6 cases (all expressed per 100,000 women) during the period from 1990 through 2005. Other researchers have dated the end of the effect of hormone-replacement therapy at 2006.12 Thus, our approach was simply to remove all excess incidence in previous years.

Estimates of the Number of Women Affected

Base-Case Estimate


For each year after 1978, we calculated the absolute change in the incidence of early- and late-stage cancer relative to the 1976-1978 baseline incidence (after removing the transient increase in incidence associated with hormone-replacement therapy during the period from 1990 through 2005, as described above). To calculate the excess in the number of women with a diagnosis of early-stage cancer detected on screening mammography, we multiplied the absolute increase in incidence observed in a given year by the number of women in the population who were 40 years of age or older in the same year. We used a similar approach to calculate the reduction in the number of women with a diagnosis of late-stage cancer. Finally, we summed the data across the three decades.

Subsequent Estimates

The base-case estimate implicitly assumes that, with the exception of the effect of hormone-replacement therapy, the underlying incidence of breast cancer is constant. To make an inference about any other changes in the underlying incidence, we examined incidence trends in the portion of the population that generally did not have exposure to screening: women younger than 40 years of age. In this age group, the SEER calculation for the annual percent change from 1979 through 2008 was 0.25% per year (95% confidence interval [CI], 0.04 to 0.47). To account for this growth, we repeated our analysis, allowing our baseline incidence among women 40 years of age or older to increase by 0.25% per year (applied to both early- and late-stage disease). We called this estimate the "best guess."

Finally, we wanted to provide estimates that were clearly biased in favor of screening mammography - ones that would minimize the surplus diagnoses of early-stage cancer and maximize the deficit of diagnoses of late-stage cancer. First, we assumed that the underlying incidence was increasing at a rate of 0.5% per year - twice as high as that observed among the population of women who were younger than 40 years of age. We called this estimate the "extreme" assumption. Second, in addition to the increase of 0.5% per year, we revised the baseline incidence of late-stage breast cancer by using the highest incidence observed in the data (113 cases per 100,000 women in 1985) - thereby maximizing the deficit of diagnoses of late-stage cancer. We called this estimate the "very extreme assumption."

Results

Changes in Incidence Associated with Implementation of Screening


Figure 1A shows the substantial increase in the use of screening mammography during the 1980s and early 1990s among women 40 years of age or older in the United States. Figure 1A also shows that there was a substantial concomitant increase in the incidence of early-stage breast cancer among these women. In addition, a small decrease is evident in the incidence of late-stage breast cancer. As shown in Figure 1B, there was little change in breast-cancer incidence among women who generally did not have exposure to screening mammography - women younger than 40 years of age.

Table 1 shows the changes in the stage-specific annual incidence of breast cancer over the past three decades among women 40 years of age or older. The large increase in cases of early-stage cancer (from 112 to 234 cancers per 100,000 women - an absolute increase of 122 cancers per 100,000) reflects both detection of more cases of localized disease and the advent of the detection of DCIS (which was virtually not detected before mammography was available). The smaller decrease in cases of late-stage cancer (from 102 to 94 cases per 100,000 women - an absolute decrease of 8 cases per 100,000 women) largely reflects detection of fewer cases of regional disease. If a constant underlying disease burden is assumed, only 8 of the 122 additional early diagnoses were destined to progress to advanced disease, implying a detection of 114 excess cases per 100,000 women. Table 1 also shows the estimated number of women affected by these changes (after removal of the transient excess cases associated with hormone-replacement therapy). These estimates are shown in terms of both the surplus in diagnoses of early-stage breast cancers and the reduction in diagnoses of late-stage breast cancers - again, under the assumption of a constant underlying disease burden.

Overdiagnosed Cancer and Effect of Screening on Regional and Distant Disease

Table 2 shows the effects of relaxing the assumption of a constant underlying disease burden on the estimate of the number of women with cancer that was overdiagnosed. The base-case estimate incorporates the data in Table 1. In the best-guess estimate, it was assumed that the trend in the underlying incidence was best approximated by the incidence observed among women younger than 40 years of age (Figure 1B). This approach suggests that the excess detection attributable to mammography in the United States involved more than 1.3 million women in the past 30 years. In the extreme and very extreme estimates, it was assumed that the underlying incidence was increasing at double the rate observed among women younger than 40 years of age. Finally, in the very extreme estimate, it was assumed that the incidence of late-stage cancer was the highest incidence ever observed (thereby maximizing the deficit of diagnoses of late-stage cancer).

Regardless of the approach used, our estimate of overdiagnosed cancers attributable to mammography over the past 30 years involved more than 1 million women. In 2008, the number of women 40 years of age or older with overdiagnosed cancers was more than 70,000 per year according to the best-guess estimate, more than 60,000 per year according to the extreme estimate, and more than 50,000 per year according to the very extreme estimate. The corresponding estimates of the proportions of cancers that were overdiagnosed are 31%, 26%, and 22%.

Figure 2 shows the trends in regional and distant late-stage breast cancer. The variable pattern in late-stage cancer (which includes the excess diagnoses associated with hormone-replacement therapy in the late 1990s and early 2000s) was virtually entirely attributable to changes in the incidence of regional (largely node-positive) disease. The incidence of distant (metastatic) disease, however, has remained unchanged (95% CI for the annual percent change, -0.19 to 0.14)

Discussion

Screening can result in both the benefit of a reduction in mortality and the harm of overdiagnosis. Our analysis suggests that whatever the mortality benefit, breast-cancer screening involved a substantial harm of excess detection of additional early-stage cancers that was not matched by a reduction in late-stage cancers. This imbalance indicates a considerable amount of overdiagnosis involving more than 1 million women in the past three decades - and, according to our best-guess estimate, more than 70,000 women in 2008 (accounting for 31% of all breast cancers diagnosed in women 40 years of age or older).

Over the same period, the rate of death from breast cancer decreased considerably. Among women 40 years of age or older, deaths from breast cancer decreased from 71 to 51 deaths per 100,000 women - a 28% decrease.6 This reduction in mortality is probably due to some combination of the effects of screening mammography and better treatment. Seven separate modeling exercises by the Cancer Intervention and Surveillance Modeling Network investigators provided a wide range of estimates for the relative contribution of each effect: screening mammography might be responsible for as little as 28% or as much as 65% of the observed reduction in mortality (the remainder being the effect of better treatment).13

Our data show that the true contribution of mammography to decreasing mortality must be at the low end of this range. They suggest that mammography has largely not met the first prerequisite for screening to reduce cancer-specific mortality - a reduction in the number of women who present with late-stage cancer. Because the absolute reduction in deaths (20 deaths per 100,000 women) is larger than the absolute reduction in the number of cases of late-stage cancer (8 cases per 100,000 women), the contribution of early detection to decreasing numbers of deaths must be small. Furthermore, as noted by others,14 the small reduction in cases of late-stage cancer that has occurred has been confined to regional (largely node-positive) disease - a stage that can now often be treated successfully, with an expected 5-year survival rate of 85% among women 40 years of age or older.15,16 Unfortunately, however, the number of women in the United States who present with distant disease, only 25% of whom survive for 5 years,15 appears not to have been affected by screening.

Whereas the decrease in the rate of death from breast cancer was 28% among women 40 years of age or older, the concurrent rate decrease was 42% among women younger than 40 years of age.6 In other words, there was a larger relative reduction in mortality among women who were not exposed to screening mammography than among those who were exposed. We are left to conclude, as others have,17,18 that the good news in breast cancer - decreasing mortality - must largely be the result of improved treatment, not screening. Ironically, improvements in treatment tend to deteriorate the benefit of screening. As treatment of clinically detected disease (detected by means other than screening) improves, the benefit of screening diminishes. For example, since pneumonia can be treated successfully, no one would suggest that we screen for pneumonia.

Our finding of substantial overdiagnosis of breast cancer with the use of screening mammography in the United States replicates the findings of investigators in other countries (Table S5 in the Supplementary Appendix). Nevertheless, our analysis has several limitations. Overdiagnosis can never be directly observed and thus can only be inferred from that which is observed - reported incidence. Figure 1 and Figure 2 are based on unaltered, long-standing, carefully collected federal data that are generally considered to be incontrovertible. Table 1 and Table 2, however, are based on assumptions that warrant a more critical evaluation.

First, our results might be sensitive to the period (1976 through 1978) that we chose to obtain data for the baseline incidence of breast cancer (before mammography). If the period were expanded to begin with the first years of SEER data (i.e., 1973 through 1978), the baseline incidence of early-stage cancer would be slightly lower (0.9%) and the incidence of late-stage cancer would be slightly higher (1.4%). These changes offset each other and have a negligible effect on our estimates.

Second, our ability to remove the effect of hormone-replacement therapy (Fig. S1 in the Supplementary Appendix) is admittedly imprecise. Although there is general agreement that this effect had largely ceased by 2006, its onset is not as discrete. We chose to cap the incidence of each disease stage as far back as 1990. However, the pattern of regional disease (Figure 2) suggests that the bulk of the effect of hormone-replacement therapy probably began later, in the mid-1990s, such that our assumption probably overcorrects for the effect of hormone-replacement therapy.

Third, we were forced to make some assumptions about the pattern of the underlying incidence - the incidence that would have been observed in the absence of screening. The simplest approach was to assume that the underlying incidence was constant (the base case). In our best-guess estimate, however, we posited that the underlying incidence was that observed in the population of women without exposure to mammography; this underlying incidence was increasing at a rate of 0.25% per year. Our assumption of an increase of 0.5% per year (in the extreme and very extreme estimates) was admittedly arbitrary. It was twice the rate of increase observed among women younger than 40 years of age and was outside the 95% confidence interval. Perspective on the uncertainty about the underlying incidence, however, is provided in Figure 2. The finding of a stable rate of distant disease argues against dramatic changes in the underlying incidence of breast cancer.

Fourth, our best-guess estimate of the frequency of overdiagnosis - 31% of all breast cancers - did not distinguish between DCIS and invasive breast cancer. Our method did not allow us to disentangle the two. We did, however, estimate the frequency of overdiagnosis of invasive breast cancer under the assumption that all cases of DCIS were overdiagnosed. This analysis suggested that invasive disease accounted for about half the overdiagnoses shown in Table 2 and that about 20% of all invasive breast cancers were overdiagnosed; these findings replicate those of other studies.19

Finally, some investigators might point out that our best-guess estimate of the frequency of overdiagnosis - 31% - was based on the wrong denominator. Our denominator was the number of all diagnosed breast cancers. Many investigators would argue that because overdiagnosis is the result of screening, the correct denominator is screening-detected breast cancers. Unfortunately, because the SEER program does not collect data on the method of detection, we were unable to distinguish screening-detected from clinically detected cancers. Self-reported data from the National Health Interview Survey, however, suggest that approximately 60% of all breast cancers were detected by means of screening in the period from 2001 through 2003.20

Breast-cancer overdiagnosis is a complex and sometimes contentious issue. Ideally, reliable estimates about the magnitude of overdiagnosis would come from long-term follow-up after a randomized trial.21 Among the nine randomized trials of mammography, the lone example of this is the 15-year follow-up after the end of the Malmš Trial,22 which showed that about a quarter of mammographically detected cancers were overdiagnosed.23 Unfortunately, trials also provide a relatively narrow view involving one subgroup of patients, one research protocol, and one point in time. We are concerned that the trials - now generally three decades old - no longer provide relevant data on either the benefit with respect to reduced mortality (because treatment has improved) or the harm of overdiagnosis (because of enhancements in mammographic imaging and lower radiologic and pathological diagnostic thresholds).

Our investigation takes a different view, which might be considered the view from space. It does not involve a selected group of patients, a specific protocol, or a single point in time. Instead, it considers national data over a period of three decades and details what has actually happened since the introduction of screening mammography. There has been plenty of time for the surplus of diagnoses of early-stage cancer to translate into a reduction in diagnoses of late-stage cancer - thus eliminating concern about lead time.24 This broad view is the major strength of our study.

Our study raises serious questions about the value of screening mammography. It clarifies that the benefit of mortality reduction is probably smaller, and the harm of overdiagnosis probably larger, than has been previously recognized. And although no one can say with certainty which women have cancers that are overdiagnosed, there is certainty about what happens to them: they undergo surgery, radiation therapy, hormonal therapy for 5 years or more, chemotherapy, or (usually) a combination of these treatments for abnormalities that otherwise would not have caused illness. Proponents of screening should provide women with data from a randomized screening trial that reflects improvements in current therapy and includes strategies to mitigate overdiagnosis in the intervention group. Women should recognize that our study does not answer the question "Should I be screened for breast cancer?" However, they can rest assured that the question has more than one right answer.

 
 
 
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