Saturday, June 10, 2023
In spite of the recently published Cochrane Research meta-analysis, which examined 7 previously published studies on the value of mammographic screening, the benefit of mammography is still very much up for discussion. This last-day ASCO presentation assembled a group of 5 men (4 of them physicians, the other a statistician), 4 of whom presented extensive but conflicting interpretations of the same data sets in order to justify their opinion as to whether women should undergo routine mammography. In contrast, 5 women -- none of them physicians but all connected with national breast cancer groups, foundations, and causes -- were given a few minutes each to state their own opinions, none of which were supported by scientific data or presented in a scientific format. Why ASCO chose to stack the scientific portion of this presentation with male MDs/PhDs while the women were relegated to discuss their personal but unscientific thoughts regarding this critical issue is unclear. A far different discussion might have ensued had well-known female breast cancer physicians been invited to participate.
Donald Berry, PhD, a statistician at the M.D. Anderson Cancer Center in Houston, Texas, argued that lead time as well as length time bias have hampered the medical community's ability to objectively interpret the available data on screening mammography. The preconceived notion, not definitively proven, that early discovery of tumors usually allows for curative treatment and is always superior to later discovery, creates a lead time bias favoring early detection. Length time bias suggests that individual tumors reach the point of no return based upon distinct and separate sojourn times, and it is assumed that detecting a tumor by screening is superior to discovering a tumor by physical examination.
The Cochrane Breast Cancer Group reviewed the results of 7 randomized trials involving over half a million women, comparing mammographic screening with no mammographic screening.[1] The 2 best trials (the Malmo Mammographic Screening Program and the Canadian National Breast Screening Study), showed no survival advantage favoring either arm at 13 years. Excluding the flawed Edinburgh trial and the New York Health Insurance Plan (HIP) trial, 13-year overall mortality for all 5 remaining trials is still not significantly different between those screened and those not screened. And while the Swedish Malmo and Canadian studies fail to show a difference in breast cancer mortality at 13 years (relative risk of 0.97), all trials excluding Edinburgh and HIP show a relative risk for breast cancer mortality of 0.8 in the screened cohort.
Berry questioned whether assessing for breast cancer mortality is even appropriate, because it excludes some women who had breast cancer at time of screening or who were misclassified as having died from other causes. Other study criticisms included variable mammographic techniques between studies, lack of independent auditing in the Swedish study, unmatched numbers of patients in the HIP trial arms, and a timing mistake in the Gothenburg study that delayed mammography in the control group for 14 months, thereby adding another 14 months' lag time for the development of breast cancer in the screening population.
Subset analysis of these individual studies that identify survival benefits for arbitrarily specified periods of time (eg, years 8-11 for overall mortality) are nothing more than exercises in "cherry picking," and have no statistical validity. If such random picking and choosing is acceptable, then one might just as easily focus on a narrow reference period that demonstrates a mortality advantage in the unscreened control group.
Nystrom and colleagues[2] recently updated the Two-County and Malmo Swedish randomized, controlled trials at a median follow-up of 15.8 years. They argue that the greatest reduction in breast cancer mortality secondary to mammographic screening occurred in the 60-to 69-year-old age group (33%), whereas the reductions in younger patient sets were more modest with 3% absolute reduction in the 50-59 age group, with an overall reduction from 19% to 9% favoring the mammogram cohort. When translated into actual survival time per woman, the gains are even far more modest -- 3.2 days among women 50-59, 6.8 days among 60-69, and overall benefit of 2.7 days. Applying the same standards to the 2 Canadian Breast Cancer Screening Studies, there is a 7% mortality reduction in the 40- to 49-year-old age group, a 9% reduction in the 50-59 age group, and an overall 8% decrease in those aged 40-60. For those older than 60, the reduction in breast cancer related mortality is 24%.
It must be remembered that there are also risks to screening mammography. These include a 4% to 10% US rate of abnormal mammographic results (translating into 1-3 million annual potential abnormal readings) and all of the patient anxiety and concern that they generate, particularly since 80% to 95% of these mammograms eventually turn out to be normal. Another equally significant concern is that mammography misses between 15% and 25% of breast cancers. The overdiagnosis of ductal carcinoma in situ (DICS) also leads to unnecessary surgery, patient inconvenience, and increased amounts of pain.
In conclusion, Dr. Berry believes that the benefits of screening mammography are likely very modest in women under the age of 60. He contends that women who fall into this age category should actively participate in the decision-making process regarding their screening once they understand the risks and benefits associated with mammographic surveillance.
Dr. David Atkins, Scientific Editor for the US Preventive Services Task Force, reviewed the recommendations of the 1998 Agency for Healthcare Research and Quality (AHRQ) regarding mammographic screening. He acknowledged that this agency is very conservative in its approach, but is an independent entity not beholden to the federal government or special interests. The agency was interested in determining (1) if screening decreased breast cancer mortality in women 40-74 years of age, (2) if screening decreased breast cancer mortality in the subset of women 50 years or younger, and (3) what harm screening had or could potentially cause.
The AHRQ also examined the Cochrane meta-analysis and established criteria for assessing individual trial validity, including use and maintenance of comparable treatment group arms, minimal patient loss to follow-up, reliance on measurable and rational assessment tools, the use of clear definitions to define study ends, and more. Each of the 8 studies was rated as poor, fair, or good. Four of the studies screened women with mammography alone while 4 others used mammography plus clinical breast examination (CBE). Only 1 of the 8 trials (Edinburgh) received a poor rating because of lopsided study arms as previously described and was not included in the final assessment. For the other trials, which received ratings of fair or "fair plus," there were numerous problematic flaws, among them methods of randomization, variability in reported numbers, unequal exclusion following randomization, imperfect mortality reporting criteria, as well as concerns regarding lead time and length time bias; but none of these problems was egregious enough to negate the significant mortality reductions observed within each trial.
Seven of these trials enrolled women between the ages of 40 and 49. After elimination of the Edinburgh trial, the only trial intentionally designed to include this age group demonstrated no reduction in mortality rate with annual mammography and clinical breast examination (the Canadian Study 1). Two of the 5 remaining studies (Gothenburg, Malmo) did show significant mortality reductions with screening of this population, whereas 2 others reported nonsignificant mortality reductions (HIP and the Two-County trials), and 1 (Stockholm) reported no benefit whatsoever. In general, benefit in this age group was not observed until at least 8 years after screening began, whereas in patients over age 50, this benefit appeared earlier at 3-4 years after initiation of screening. There may be some degree of overlap in which the ongoing screening, which occurred after age 50, affects the results of the screening initiated earlier when these women were still in their 40s.
In women older than 50 years of age, the consensus of these studies demonstrated a 20% relative decrease in the number of breast cancer deaths. A similar result was observed among women younger than 50. Consequently, screening mammography has been recommended every 1-2 years for women between the ages of 40 and 49, then annually in women 50 years and older, since it seems that the benefit vs harm ratio of mammography continues to rise. The age to discontinue mammographic screening has not been established, and the optimal interval for screening of all women remains uncertain.
Dr. William Wood, chief of surgery at Emory University School of Medicine in Atlanta, Georgia, commented upon the increasing number of DCIS diagnoses that have resulted from increased screening mammography. In an article published 15 years ago, a 15% incidence of DCIS was discovered among 110 consecutive autopsies in women whose ages ranged from 20 to 54.[3] Whether this translates into an increase in mortality can be examined to some degree by data published by Page at Vanderbilt, who identified 28 women with DCIS who, for some reason, were never informed of their results, and for whom long-term follow-up is available. At 10 years, 9 cases of invasive breast case had occurred with 5 breast cancer-related deaths, while at 35 years, 40% of these women had developed invasive breast cancer with no further breast cancer-related deaths. Dr. Wood makes the point that in order to assess the real impact of DCIS on breast cancer and overall mortality, such long-term follow-up will be required.
DCIS presents as a wide spectrum of disease. Some palpable tumors are of low grade without calcifications, whereas most of what is being detected on mammography represents higher-grade DCIS with microcalcifications. The only real accurate method for assessing DCIS is to examine the histology after resection. Previously, surgeons performed total mastectomies on these women, but NSABP trials, particularly NSABP 17, has forever changed this way of thinking. Currently, an ongoing Eastern Cooperative Group/Intergroup trial is re-examining NSABP 17's conclusion that radiation and tamoxifen are necessary components of therapy in all such women. Whatever the outcome, previous studies suggest that most events occur in the first 10 years following diagnosis and treatment. For small (less than 10 mm) node-negative invasive tumors completely resected with 10-mm clear margins, 10-year metastasis-free survival was 98.7% in one group of 254 women studied.[4] An identical rate of distant metastasis-free survival projected by Kaplan-Meier analysis was reported in another 282 patients with small tumors fully resected. The identification of such small tumors and their subsequent appropriate management speak loudly for early detection by screening mammography.
Dr. Robert Smith, head of cancer prevention for the American Cancer Society, admitted that perceptions regarding breast cancer screening have changed over the past year following publication of the Cochrane report, even though many major medical societies, including the American Medical Association and the American Cancer Society, have announced that this report is terribly flawed. Moreover, current breast cancer statistics from the United States, the United Kingdom, Sweden, The Netherlands, and Denmark, refute the Cochrane report conclusions by demonstrating an approximately 35% decrease in breast cancer mortality among women over 50 who undergo screening mammography.
No other rational explanation has been offered to account for these trends, but if these population trends are incorrect, then the benefits observed must be secondary to a combination of confounding factors, including lead time bias, length bias, and selection bias. One would then expect the results to be far more inconsistent than they are. Dr. Smith argues that the evidence from most screening trials is both solid and compelling, and that early detection of small lesions before lymph node metastasis is clearly affected by annual mammography. The real challenge for today is to address the incidence of breast cancer in women between the ages of 30 and 49, who account for 40% of all breast cancer mortality. If this means that increased biopsies should be performed in younger women who tend to have much denser breasts, there is public support for this approach. Women would rather have more false-positive biopsies than positive ones. The increased incidence of DCIS detection over the last several years means that fewer invasive cancers are being detected because of early intervention, and these efforts should be supported.
Zora Brown, president of the Breast Cancer Resource Committee spoke in support of current screening standards, but encouraged the panel to bring more underserved women into the fold, since the incidence of advanced breast cancers remain highest in minority, low income, and non-English-speaking communities. Judy Perotti of the Y-ME National Breast Cancer Organization, also supported screening mammography for women beginning at age 40. She emphasized that women do need to take a more active role in coordination with their doctors regarding individual screening preferences, but she fully supported annual mammograms after the age of 50. Women also need to be reminded that mammograms are not 100% effective, thus increasing the need for clinical breast examination and self-screening. Finally, she disagreed with the term "unnecessary" biopsies, arguing that a negative biopsy results does not imply that the biopsy was inappropriately recommended. Negative biopsies are, in large, "good things!"
Jan Platner, from the National Breast Cancer Coalition, asserted that the United States measure quality of breast cancer care not by the number of women diagnosed with breast cancer and saved from their breast cancers, but by the numbers of women who are screened annually. She stated that screening is only half the battle, and that many women do not receive the care that they need once a problem has been identified. If the money devoted to screening were diverted to providing all women with basic healthcare, the number of lives saved would far exceed the benefits provided by current breast cancer screening recommendations. Finally, Ms. Platner pleaded that the benefits of screening should not be exaggerated, nor the risks associated with current screening practices minimized.
Amy Langer from the National Alliance of Breast Cancer Organizations stated that she advocates initiation of mammography at the age of 40 with annual clinical breast examination and monthly self-examination. These efforts are supported by dramatic shifts in recent SEER data, showing a decline in breast cancer mortality and a dramatic increase in early-stage tumors. She is concerned that the media have created a much greater controversy over screening data that is warranted, and worries that the information being disseminated is no longer clear or balanced. While advocating that women become involved in screening decisions, Ms. Langer admits that many women will have real trouble sorting through all of the divergent opinions in order to fashion a standard of care that is acceptable to them.
She dismisses those who would argue against routine screening, stating that much of the data supporting their opinions made use of older mammographic technology and mammogram technicians. Her greatest fear is that all of the current controversy, including the trend to litigation, will drive away good physicians and others interested in becoming more involved with women's health management. Finally, she agreed with Ms. Brown that we must do more to bring disenfranchised women into the screening fold.
Susan Braun, chief executive officer for the Susan G. Komen Breast Cancer Foundation, conceded that mammography, while not perfect, is the best that we have for now, and should be used to its fullest extent while research dollars attempt to find and exploit even better technologies. She and her organization consider breast cancer screening to be a public health issue, and worry about who will pay for mammography for the many who are either not covered by insurance or cannot afford it. The current debate over breast cancer screening has politicized the entire issue so that it is no longer just a health or an economic concern. She believes that most analyses support the use of mammography in screening, and also support screening in younger women aged 40-49. Finally, she points out that the more mammograms a woman has over her lifetime, the less likely she is to have false-positive readings, thereby reducing the need for unnecessary biopsies and other forms of intervention.
And so the debate continues....the naysayers conceding little, and the screening advocates both concerned about promoting women's health, but with different perspectives on how to accomplish this goal.
