14 Feb, 17 | by EBM
By Dr. Geoffrey Modest
This blog will bring up 2 recent studies suggesting the lack of efficacy of mammography screening coupled with significant overdiagnosis.
- An article a couple of years ago looked at screening mammography in the US, with 10 year follow-up of breast cancer incidence and mortality (see Harding C. JAMA Intern Med 2015; 175: 1483).
- This was an ecological study of 16,120,349 women 40 years of older who resided in 547 counties reporting in the Surveillance, Epidemiology, and End Results (SEER) cancer registries during the year 2000.
- 53,207 had a diagnosis of breast cancer and were followed for 10 years.
- The researchers looked at the extent of the screening in each county, and the results of both breast cancer incidence and mortality (the latter being defined as women diagnosed with breast cancer in the year 2000 who had died from the disease during the 10 year follow-up period). Overall, in the 547 counties, the overall 10-year incidence based mortality was 47.2 per 100,000 cases diagnosed in 2000.
- There was a strong positive correlation between the extent of mammography screening and the breast cancer incidence (P<0.001)
- But, there was no relationship between screening and breast cancer mortality.
- Each increase of 10 percentage points in the extent of screening was accompanied by:
- A 16% increase in breast cancer diagnoses, RR 1.16 (1.13- 1.19)
- Not even a trend to a change in breast cancer deaths, RR 1.01 (0.96-1.06)
- Analyzing by tumor size, screening led to a higher incidence of small breast cancers (<= 2 cm), but not with a decreased incidence of larger breast cancers (>2 cm )
- Each increase of 10 percentage points in screening is associated with:
- A 25% increase in the incidence of small breast cancers, RR 1.25 (1.18- 1.32)
- A 7% increase in the incidence of larger breast cancers, RR 1.07 (1.02- 1.12)
- The following figure shows that as the proportion of women had a mammogram in the past two years, the incidence of breast cancer diagnoses increased significantly yet the 10-year mortality did not budge
- So, pretty powerful large-scale epidemiologic study, finding that mammography led to a large increase in the diagnosis of small cancers, but there was no decline in the detection of larger cancers. This may be the reason why there was no significant difference in the overall death rate from breast cancer by doing mammography screening.
- What does this mean? It may mean that there are a subset of very aggressive small cancers which spread and cause clinical disease and mortality, and that screening is didn’t help for these. And that a very large number of small cancers that are picked up by mammography are in fact “overdiagnosed” (defined as: tumors that would not have become clinically evident in the remaining lifetime without screening).
- One would have expected that if screening did pick up small tumors earlier, that over time the diagnosis of larger and less treatable cancers should decrease. It is quite concerning that the number of larger breast cancers in fact continued to increase over the study. And, of course, the goal of screening is to reduce mortality, which was not found in the study. One additional finding was that increased screening would lead to more breast conserving surgical procedures; however they found no evidence of a decrease in extensive mastectomies.
- Without getting into a lot of detail, the authors present reasonable arguments that this is not just lead-time bias, or ecological bias (this latter happens when looking at group data and assuming that it applies to the individual who may or may not have had a mammogram). Also, there was no association between mortality rates even comparing those counties with much higher breast cancer incidence, reducing the potential bias of comparing counties with very different incidences of breast cancer. But, they also did not have data on women who had therapy or what the risk factors were for the women who developed breast cancer. Also, this was just a 10-year follow-up, and patients may well live more than 10 years with newer therapies, but I would have expected some evident benefit of screening by 10 years (and at least a trend to benefit…)
- There have been several important changes in technology over the past several decades, some of which may make older studies less applicable now (these older studies are the ones on which current mammogram recommendations are based). On the one hand, the sensitivity of our screening methods is greater and we are picking up much smaller tumors; and, perhaps these smaller tumors are more likely to regress than the larger ones picked up previous, leading to increased overdiagnosis. On the other hand, treatments have improved a lot, and the risk/benefit equation may have changed some. Given the potential harms of overdiagnosis (including surgery, radiotherapy, and chemotherapy), we should be looking at the new balance. In addition, there are interesting advances in genomic profiling, which are helpful in determining how aggressive a tumor is likely to be as well as how intensive therapy should be
So, a large study like this offers interesting insights, especially when looking at likely overdiagnosis (which one cannot determine in an individual patient). As with all screening tests (e.g. PSA), it would be really useful to figure out how to risk stratify patients, with more aggressive screening in those at higher risk. That is much more likely to show benefit for screening then with screening the general population.
- A more recent article look specifically at breast cancer overdiagnosis by mammography screening in Denmark (see doi:10.7326/M16-0270)). The study looked at women aged 35 to 84, from 1980 to 2010.
- Denmark had a perhaps unique opportunity to look at the results of mammography screening both because it has rigorous databases (the Danish Breast Cancer Group, DBCG, and the Danish Cancer Registry, DCR) as well as a 17-year screening program which involved 20% of the population aged 50 to 69. This differential access to mammography screening allowed for real-world comparisons to a large, essentially randomized non-screening populations. Clinical breast exams were not included.
- The DBCG database included 90,665 women aged 35 to 94 who were diagnosed with invasive breast cancer, and 4267 diagnosed with DCIS
- For the mammography group in DBCG, they divided tumors into two groups: large (>20 mm) and small (<20 mm), considering the large tumors as “advanced” because they are equivalent to T2 or greater in the TNM classification system
- The screening routine, somewhat different from what we do in the US, was biennial screening with a 2-view mammography on the first round, with 1-view mammography at subsequent screens except for women with dense breasts who always received a 2-view mammogram.
- The DCR provided individual data on tumor size in women with invasive breast cancer.
- For women aged 35 to 69: in non-screening areas the incidence of advanced cancer increased throughout the observation period.
- For women 70 to 84: in the non-screening areas the incidence of advanced cancer also increased throughout the observation period, and was most pronounced in the later years.
- The incidence of non-advanced tumors increased in the screening versus prescreening periods, incidence ratio 1.49 (1.43- 1.54), i.e. a 49% increase
- Looking just at nonadvanced tumors, there were 711 invasive tumors and 180 cases of DCIS that were overdiagnosed in 2010 (overdiagnosis rate of 48.3% including DCIS and 38.6% excluding DCIS
- There was no reduction in the incidence of advanced cancers through mammography screening.
- Their conclusion: “it is likely that one in every three invasive tumors in cases of DCIS diagnosed and women offered screening represents overdiagnosis (incidence increase of 48.3%)”
- This study is quite remarkable since it is reasonably close to a really large-scale randomized controlled trial, in which for 17 years 20% of women got mammograms and the rest didn’t. And there was no difference in advanced breast cancers through consistent mammography screening
- See below for other blogs on the poor utility of mammography screening, also showing almost no decrease in breast cancer mortality but large numbers of overdiagnosed mammogram-detected cancer.
- A lot of the “overdiagnosis” is from DCIS (about 25% of all new breast cancer diagnoses), which the National Cancer Institute now classifies as a “noninvasive condition” (an observational study of 108,196 women with DCIS in the SEER registries found an overall breast cancer death rate of 3.3% over 20 years, similar to the general population: see Narod SA. JAMA Oncol 2015; 1(7):888
- All of this reinforces the fact that early detection of breast cancer is fraught. For breast cancer, there are 230,815 diagnoses/year in women, 2109 in men; and 40,860 breast cancers deaths/year in women and 464 in men, and affects 1 in 8 women!!!; yet mammography screening has perhaps minimal benefit. Which really brings up the issue of prevention (which, it turns out, does not get much funding). As noted in prior blogs, one big unknown is the prevalence of industrial toxins (many of which are estrogenic, including pesticides, BPA, others used in plastics, etc etc) which are in our environment and may well be carcinogenic. Large numbers of new chemicals are being used and thousands of new ones are introduced each year with minimal attempts to look at potential toxicity. In addition, it is reasonably clear from the studies that healthy diet, weight control, and exercise are helpful. It seems to me that it would likely be much more useful to devote our national resources into preventing breast cancer by regulating environmental toxins and promoting healthy lifestyles than attempting early detection.
See http://blogs.bmj.com/ebm/2016/10/13/primary-care-corner-with-geoffrey-modest-md-radiologist-variability-in-mammography-readings/ which documents the quite remarkable discordance in radiologists’ reading of breast densities
See http://blogs.bmj.com/ebm/2014/02/13/primary-care-corner-with-geoffrey-modest-md-mammography-another-hit/ for the 25-year results from the Canadian National Breast Screening Study finding NO benefit from mammography screening but that 22% of mammography-detected breast cancers were overdiagnosed.
See http://blogs.bmj.com/ebm/2014/04/22/primary-care-corner-with-geoffrey-modest-md-mammograms-again/ for a 2014 meta-analysis, finding that mammography yielded very small changes in breast cancer mortality (e.g. screening women in their 50s would lead to 3-32/10,000 decrease in breast cancer mortality, but have 6130 false positive and 30-137 overdiagnoses). As mentioned above, these studies were older ones.