A History of Breast Imaging From a Founder
By Daniel B. Kopans, MD, FACR, FSBI
I apologize from the start. “Who cares about history? Let’s build the future!” I agree about the future, but having lived through so much of the past, I am now, more than ever, convinced if we ignore history, “we are doomed to repeat it.” We need to learn from history. This is especially true in our specialty. There has been so much misinformation that has been promulgated, even by some of our most reputable journals, that we need to constantly question and carefully read what is being promoted because misinformation keeps coming back! As Becky Zuurbier, MD, once pointed out to me, the arguments about breast cancer screening are like “WhackA-Mole.” Just as we have used science and evidence to address one issue that challenges screening, opponents of screening pop up with a new issue.1 They have even recycled old ones! This appears to be an unending effort, so my hope is that we will all learn from the past to be able to “whack” the next “mole”!
But Back to History
Back at the turn of the century (wow—I remember when that meant 1900!!), the false claims were being made that mammography was leading to “overdiagnosis.” The argument faded and then returned based on scientifically unsupportable claims in the prestigious New England Journal of Medicine (NEJM)2 that took hold despite being refuted by at least three separate reviews!3-5 The NEJM has published at least 25 papers since 1990 that draw negative conclusions about screening, particularly for women aged 40 to 49 years, while refusing to publish papers in support of screening, such as those from Dr. László Tabár’s superb Swedish Two-County Trial.
The failure of some of the medical journals is underlined by the deception at the Journal of the National Cancer Institute (JCNI) Deception? That’s a pretty strong word. I’m not sure what else you would call the fact that the JNCI has not been the National Cancer Institute’s (NCI’s) journal for over two decades! It was sold in 1998 to Oxford University Press, complete with its name.6 I am fairly certain that most, especially those in the media and the public, still think that its publications have the imprimatur of the NCI and that they have not found the small print at the bottom of a long list of “abstracting and indexing information” and “journal impact factor and ranking” where it is written, unobtrusively, “JNCI is published monthly by Oxford University Press and is not affiliated with the United States National Cancer Institute.”7
Just as has happened at the NEJM, the former editor of the JNCI (which again is not the NCI’s journal), who did not do much to alert readers to its disconnect from the NCI, refused to publish any
articles that supported breast cancer screening, particularly for women aged 40 to 49. I’ll bet many (or most?) of you didn’t know! If you don’t understand history, you can easily fall prey to misinformation and disinformation.
Most histories are written by “historians” looking back and trying to assemble what they think took place. I suspect that much that is written this way only captures revisionists’ views and not always what had actually happened. This certainly happened in a book entitled Radiology at the Massachusetts General Hospital -18962000, in which the “historian” got much of the story of the Breast Imaging Division wrong. I did not invent stereotactic-guided breast biopsy! It was invented in Sweden8 (and perhaps earlier). My understanding is that Robert Schmidt, MD, was the first to bring a prone stereotactic table here to the United States in 1986.9
The following will be my personal, mostly firsthand, and as short as I can make it to fit, understanding of what has taken place in breast imaging since the 1960s. I understand that some of our journals don’t like to cite names; however, a careful look at the past shows that individuals play a fundamental role in our national political history, and I think the same holds true in our field. There is no question that there are controversies as to who were “the first.” I apologize to anyone I have left out. Please email me at dkopans@ verizon.net. I hope to write a more complete history and am open to factual information.
Individuals Make a Difference
As My Cousin Vinny would say—the following is for the “youts” in our field. What I have learned over the decades is that individuals really matter. We have seen this in politics, and it is clear to me in our field. Myron “Mike” Moskowitz, MD, almost singlehandedly brought us through the 1970s and early 1980s by being able to go “toe-to-toe” with the epidemiologists who were trying to reduce access to and even prevent breast cancer screening. Heading one of the Breast Cancer Detection Demonstration Project (BCDDP) centers, he taught us about the potential biases in observational studies, statistical power, and how to calculate lead time, as well as the differences between “screening” and “diagnosis.” Steve Feig, MD, wrote and taught, eloquently, about the challenges of the day, from addressing the problems with thermography to radiation risk. Ed Sickles, MD, pioneered “microfocal spot magnification” and its more than 50 years of value in lesion analysis, as well as
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Daniel B. Kopans, MD, FACR, FSBI
A History of Breast Imaging From a Founder (continued from page 33)
numerous other contributions such as defining the “probably benign” category and the medical audit.10 Ed brought rigor and science to our publications, as well as leading the SBI from a group exchanging anecdotal observations to the science- and evidencebased organization that we are today. Also, kudos to Ed Hendrick, PhD, who has done so much behind the scenes, from accreditation to meta-analyses, mortality analyses, and preserving screening for women aged 40 to 49. Of course, Dr. László Tabár is off the charts. László not only proved the benefits of early detection with his landmark Two-County Trial but also taught us how to produce the highest-quality mammograms and to organize our practices with batch reading. His gargantuan efforts, including his ongoing efforts to better understand pathology by correlating imaging findings with histopathological interpretation, are unparalleled, and the world owes him a huge debt.
Someone Else Can Do the Politics
I will not spend much time on the politics within our field. I have never been asked to participate in any major way, so I do not have any firsthand knowledge. The closest I came was being a member of the Breast Cancer Task Force of the ACR in the 1980s. As the youngest member, I naively thought that ours was an important group until I found out that we were a subcommittee of the subcommittee that oversaw “buildings and grounds” at the ACR!! To paraphrase Rodney Dangerfield, “we got no respect,” but at the time, we didn’t know it! Drs. Mike Moskowitz, Ed Sickles, Steve Feig, Robert McClelland (the chair), and several others were all driven by our sense that what we were doing was very important. We developed standards, training programs, and published guidelines. It wasn’t until 2005 that the College finally realized that “Breast” was doing many of the things that none of the other commissions were doing to improve patient care, and Dr. Carol Lee was appointed the first chair of the first Breast Imaging Commission of the ACR. Among other advances we had developed the Breast Imaging Reporting and Data System (BIRADS) and the medical audit and were years ahead of others in the College in organizing and monitoring our outcomes.
Once they realized our importance, the ACR should be given great credit, along with folks like Barbara Monsees, MD, Debra Monticciolo, MD, Marie Zinninger and Pam Wilcox at the ACR, and others in the governmental relations group for starting the Mammography Accreditation Program, guiding a meaningful Mammography Quality Standards Act, supporting BI-RADS, preserving access for women aged 40 to 49 through congressional mandates, and overseeing improvements in our ability to detect and diagnose breast cancer earlier.
So much for ACR politics!
In the (Almost) Beginning
Others have written about the first use of x-ray, the first x-ray
of the breast, the earliest years, etc.11-13 I am not old enough to remember that so I will not talk about anything much before 1960. That said, it is my understanding that in the 1950s, breast cancer was believed to be systemic (metastatic) before it could be found14 and efforts were directed at developing systemic treatments.
Once Robert Egan, MD, had standardized obtaining mammograms,15 Sam Shapiro, a biostatistician, and Phillip Strax, MD, a radiologist, in the 1960s organized the first randomized controlled trial (RCT) of breast cancer screening within the Health Insurance Plan of New York (the HIP trial). In this trial 62,000 women aged 40 to 64 were randomly divided into two groups. The study group was offered mammography and clinical breast examination every year for five years. Women in the control group weren’t even told they were in a trial. This would not be considered ethical today though may actually be the ideal way to do a comparison. The HIP proved that earlier detection could, in fact, save lives. Women in the study group had a 23% reduction in deaths compared with the controls.16
The quality of mammography was poor in HIP and it appears that much of the benefit from early detection was due to the clinical examinations. As noted above, at the time, breast cancer was thought to be incurable. Women at the time of the HIP were presenting with later-stage cancers because of fear of the consequences of having breast cancer and therefore delayed seeking care. “Denial” likely deterred many women from seeking help early. Consequently, it was likely easier for any form of earlier detection to reduce deaths.
The uncertainties that were raised by HIP led to the design and execution of the Edinburgh Study in the United Kingdom, the National Breast Screening Studies (NBSS) of Canada (now called the Canadian National Breast Screening Studies [CNBSS]), and the five RCTs in Sweden, including the landmark Two-County Trial.
The BCDDP Proved That Large Numbers of Women Could Be Screened Efficiently and Effectively
You know someone is an expert when they can say the acronym BCDDP correctly and know what it stands for. It is my understanding that many agreed that the HIP had proved that early detection saves lives, but the concern was that it would not be possible to screen large numbers of women efficiently and effectively. The BCDDP was not an RCT but a true “demonstration project.”17 Between 1973 and 1980 approximately 280,000 women aged 35 to 74 were screened with two-view mammography and a clinical breast examination in 27 centers across the United States.18
In the BCDDP, the quality of mammography was markedly improved; 4275 women were diagnosed with breast cancer.19 More than a quarter were 1.0 cm or smaller. Xeroradiography was used in 22 of the centers, new screen-film mammography was used
To save lives and minimize the impact of breast cancer. .....
in four, and both were used in one. The study was under way when, in 1976, Dr. John Bailar claimed that mammography would cause more breast cancers than would be cured,20 causing the BCDDP to stop screening women younger than age 50.
Important note: Almost 50% of the cancers in the BCDDP were detected by mammography alone. In the Canadian trials, 10 years later, the quality of mammography was so poor that only 30% were detected by mammography alone!
Radiation Risk Is Raised as a Reason to Deny Women
Access to Screening
As noted above, in 1976 Dr. Bailar raised the concern that the radiation from mammography might cause more cancers than would be cured.21 This claim led to the BCDDP terminating screening for women under the age of 50. Radiation risk has “reared its ugly head” periodically as an argument to limit access to screening, even today, but it is now clear that radiation risk is age related and it drops rapidly with increasing age. By the time a woman is age 40 there is no directly measurable risk, and even the extrapolated risk is well below even the smallest benefit.22-27
The Age of 50 Becomes a Threshold for Screening Despite This Being Scientifically Unsupportable Mammography was greatly improved by the late 1970s and RCTs in Sweden were undertaken to see if screening with mammography alone could reduce deaths, while the CNBSS (formerly called the NBSS of Canada) took the other tack to see if clinical breast examination alone was all that was needed. Unfortunately, Sam Shapiro, the biostatistician for the HIP, decided to see if menopause had any effect on his results. Having not collected data on menopause, he chose the age of 50 as a surrogate for menopause. He went on to misinterpret the HIP results, which showed an immediate benefit for women aged 50 to 64 while it was delayed for 5 to 7 years for women aged 40 to 49. In fact, based on length bias sampling (periodic screening detects moderate- and slow-growing cancers and is unlikely to show an immediate benefit), the immediate benefit for older women was almost certainly statistical fluctuation that comes with early small numbers while the delayed benefit was what actually would have been expected. Unfortunately, those who wanted to reduce access to screening jumped on the analysis and claimed that screening didn’t work until age 50. Not only was this sheer nonsense, but it was “nonscience” as well! Because analysts got stuck on the age of 50 as a threshold, years of debate have likely resulted in unnecessary deaths. Even after it was shown, conclusively, that with longer follow-up, there was statistically significant benefit for screening women aged 40 to 49 that was as strong as for older women,28 efforts have continued to try to reduce access to screening for women in their forties.
HIP had raised questions about how much mammography and clinical breast examination could reduce deaths. In particular, the trials in Sweden only employed mammography (no clinical
breast examination). The RCTs proved that early detection using mammography saves lives for women aged 40 to 74 (the ages of the women who participated in the trials).29-30
“Breast Imagining”
In 1978 I had just finished my residency at the Massachusetts General Hospital (MGH) and had secured a two-year junior staff position at the MGH to get a bit more experience before going out into private practice. The head of the xeroradiography department, where six to eight mammograms were being done each day, left for New Jersey. All the women in the department refused to read the mammograms, as did the Chest Division and the genitourinary radiologists. Efforts were under way to shine lights through the breast (called diaphanography), claiming to find cancers. To sound academic to get my junior staff position, I had told the department chair that it made more sense to try to image the breast with lasers. The chair remembered that I had said the “B” word, and he was desperate. I was his last hope and he offered to make me a division head if I would read the mammograms. As my chair, he could have told me to jump off the roof and I would have done it. I figured I could read the xeromammograms for a few years—then they would discover a cure for breast cancer—and I could do something else! That was how I became the youngest division head at MGH having had 2 weeks of xeroradiography!!
It was quite intimidating to participate in division head meetings with my “August” mentors. The use of ultrasound was exploding, along with nuclear medicine (now called the less scary molecular imaging) and the development of computed tomography (CT) and early magnetic resonance imaging (MRI). The discussion was whether we should become the Department of Imaging. The group decided to stay with the historic name—Radiology. No one cared what I did as long as the handful of xeromammograms were read each day. I was doing ultrasound, exploring transillumination, using CT, etc, so I decided that it made sense to rename my division “Breast Imaging.” My office manager was walking behind two elderly women as they passed our division on the main floor. They looked at the new sign above the door, and one turned to the other and said “Breast Imagining—I wonder what goes on in there?”
I ultimately wrote a summary of what we were doing to evaluate the breast, along with Jack Meyer, MD, and Norman Sadowsky, MD, that became the last article of mine that the NEJM would publish, which I entitled “Breast Imaging,” and our subspecialty was born. I named my talks “Breast Imaging” and ran courses using the name. Dr. Mark Homer later organized the SBI, and here we are.
Tabár: the Two-County Trial and Screening Begins in the United States
Meanwhile multiple trials under way in Sweden tested the use of mammography alone (without clinical breast examination). In 1985 Dr. Tabár, who is clearly the leader in optimizing mammography
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A History of Breast Imaging From a Founder (continued from page 35) and screening using high-quality imaging (optimized positioning and screen-film processing) published results that showed that screening with mammography alone could reduce deaths for women aged 40 to 74.31 I believe that it was the publication of Dr. Tabár’s trial that started screening in the United States on a national scale in the mid-1980s. Ultimately, their 30-year follow-up proved a mortality reduction of approximately 30%32 that continued to increase over time. Results from the other trials followed, which solidified the proof that early detection saved lives, and this could be done using mammography screening alone. The proof had been established, but impediments continued to be thrown at screening. The Stockholm trial was too small and terminated too soon. The Edinburgh trial was found to have economic differences in the demographics of the study compared to the control groups, so its results were dropped, but Malmö and Gothenburg reinforced the fact that screening and early detection saved lives.
Despite Compromised Design and Execution, the Unreliable Results of the Canadian Trials Have Been Used to Reduce Access to Screening
If I ran a trial to study a treatment for breast cancer and:
1. I used an outdated drug.
2. Before I assigned women to the treatment arm or the control arm, I examined all the women and determined who had the advanced cancers.
3. I assigned women on open lists so I could assign more women with advanced cancers to the treatment arm out of random order.
4. My data showed that I had, indeed, assigned more women with advanced cancers to the treatment arm.
5. Early in my trial there were more women who died from breast cancer in the treatment arm, and I blamed the treatment.
6. In the end there were the same number of deaths in both arms.
7. I concluded that NO DRUG could reduce deaths.
My trial would:
1. Have never passed a Research Review committee or an ethics committee.
2. If I actually performed such a trial, it would have never been accepted for publication.
If this is the correct result of such a treatment trial, why has it not been true for the CNBSS!?
In the 1980s two trials were undertaken in Canada that were known as the NBSS, later to be called the CNBSS. CNBSS1 evaluated women aged 40 to 49 and CNBSS2 looked at women aged 50 to 59. Although they had differing protocols, the two were (inappropriately) combined in the final 25-year report.33 I suspect this was done to cover the major problems with CNBSS1.34
Numerous evaluations have been written raising concerns about how these trials were designed and performed.35-49 Unlike the other trials which targeted a population, randomly divided them, and then invited the study group to participate, the CNBSS recruited volunteers. Often using outdated equipment, and with no training for the technologists and radiologists, their own study showed that the quality of the mammography was “poor to unacceptable” for much of the trials.50,51
Of even greater concern was that the data strongly suggested that there had been an allocation imbalance.52 This was possible because, in violation of the rules for RCTs, most of the women had a clinical breast examination before being assigned, and clinically evident cancers were identified prior to allocation. The coordinators who assigned the women had the results of the clinical breast examination (a second violation) and could assign women out of random order (a major violation) as the data suggested. The excess of advanced cancers in the screening arm of CNBSS1 proved to be statistically significant,53 rendering the results suspect. The trials should have been withdrawn years ago, but instead, their results, claiming no benefit from screening and despite being the outliers among the RCTs, have been used to deny women access to screening.54 In the spring of 2021, I presented a virtual talk to the Toronto Breast Imaging Society entitled “What Canadians Need to Know About the Canadian National Breast Screening Studies,”55 in which I outlined all the concerns. A technologist who was in the audience and had worked in the CNBSS contacted me and explained that the concerns about nonrandom allocation that I had outlined in my talk did happen and that she had witnessed women with clinical evidence of breast cancer assigned to the mammography arms out of random order.56 There is an ongoing effort to have the results of the trials withdrawn, but the University of Toronto has taken more than two years to review the information that has been available for decades. They appear to be trying to protect the compromised trials.
Our Clinical Colleagues Complained and BI-RADS Was Born
Ed Sickles on the West Coast and I on the East Coast had independently recognized that we needed to understand the results of what we were doing with our new screening efforts. In the late 1970s and early 1980s, we independently developed computer reporting systems (my “portable” COMPAQ computer weighed 23 lb and had a 9-inch screen!). Ed’s approach led to his formulation of all the things we needed to keep track of, which became the critical audit.57 My approach provided more refined details, and by using a computer I developed a coding system that was linked to “canned” reports so that for the same findings all my colleagues produced the same verbiage, and reports included an action determinate, or “final assessment.”
In the 1980s it was the “Wild West” in breast imaging. The ACR tried to get ahead of a brewing controversy about the lack of
To save lives and minimize the impact of breast cancer. .....
standards and the poor quality of mammography in the United States by developing the Mammography Accreditation Program in 1986.58 Federal regulation came about because of a television report about an untrained radiologist who had no credentials and was reading poor-quality mammograms and missing cancers.59 The Mammography Quality Standards Act followed.60
Our clinical colleagues complained that mammogram reports were impossible to understand and provided little guidance.61 They were correct. Reports were dictated and transcribed separately. They were often “stream of consciousness,” giving no real guidance and multiple options—“Well, you could leave it alone or you could follow it, or you could take it out”! The ACR accepted the criticism and what would later be known as the BI-RADS Committee was born.
I was cochair of the original committee along with Carl D’Orsi, MD. Members included Ed Sickles, MD, Stephen Feig, MD, Larry Bassett, MD, Dorit Adler, MD, Jim Brenner, MD, Mike Moskowitz, MD, Michael Lopiano, MD, a pathologist (I think it was Michael Lagios, MD), and a surgeon from the American College of Surgeons, David Winship, MD. BI-RADS (I like good acronyms) was based on the computerized reporting system that I had developed at the MGH, which (in my system) had 7 final assessment categories.62 These were modified somewhat in BI-RADS. The dictionary of terms (which I suggested should be called a lexicon to sound more sophisticated!!) came from the work that Dr. Carl D’Orsi had done with Bolt Beranek and Newman,63 while Dr. Larry Bassett monitored the dictionary to be certain that the terms were appropriate. We added the medical audit that Dr. Ed Sickles had been developing. By standardizing our reports and the terminology to be used and using final assessment categories, we took the ambiguity out of breast imaging reports. Over time, most of Radiology (now Imaging) has followed our lead with various iterations of “-RADS.”
The 1993 International Workshop on Breast Cancer Screening
The NCI Uses Poor Results From the (Compromised) CNBSS and Inappropriate Unplanned Retrospective Subgroup Analysis of the Other RCTs to Drop Support for Screening Women Aged 40 to 49 There were those at the NCI who had not supported the decision by NCI’s Charles Smart, MD, to support the 1989 Consensus Guidelines that recommended screening starting at the age of 40.64 When Dr. Smart retired and this group came to power, they set out to stop screening women in their forties by using the data from CNBSS1 that were resulting in false claims that screening was leading to earlier deaths among women in their forties.65 In 1997 NCI held a loaded International Workshop on Screening for Breast Cancer, in which I was the only faculty member invited to defend screening for women aged 40 to 49!66 The chair had already written her opposition to screening women aged 40 to 49.67 None of the other RCTs were designed to look specifically
at women aged 40 to 49 as a separate subgroup, so efforts were made to combine the results. The NCI required that a “statistically significant” benefit had to be shown within five years of the start of screening. I explained that the trials individually, and even combined, lacked the statistical power to permit this “unplanned, retrospective subgroup analysis.”68 Nevertheless, the other speakers, inappropriately, used the data that were not designed to look separately at these women and claimed that, since the results for younger women were not statistically significant (ignoring the fact that it was mathematically impossible), they advised dropping support for screening women aged 40 to 49.69 Over the rest of the year, they prepared women for the change. At the end of the year, violating their own rules, the director, Samuel Broder, for the first time in NCI history, ignored the advice of the National Cancer Advisory Board (NCAB) (I and others had informed the NCAB of the NCI errors, and NCAB had counseled against changing the guidelines), dropped support for screening women aged 40 to 49 and stated that women aged 50 and over could be screened every two years.70
Efforts to Bolster the NCI Position: Grouping and Averaging Can Be Very Misleading
Despite the fact that the 1993 NCI decision to drop support for screening women aged 40 to 49 was not based on science, efforts were made to support the decision. An example is a paper by Kerlikowske et al71 that compared the cancer detection rate for women aged 30 to 49 (note no one was arguing to screen women in their 30s!) to the rate for women aged 50 to 70+ as if they were two separate and uniform groups. Including women in their 30s was likely used to pull down the lower average, which was reported as two cancers per 1000 for women aged 30 to 49 and 10 cancers per 1000 for women aged 50 on up. In fact, the data provided in the paper showed a steady increase in cancer detection with age, as would be expected, since incidence goes up steadily with increasing age, but this was not made clear in the paper. This false jump that was manufactured by grouping and averaging was nevertheless cited as a reason to delay screening until the age of 50.72 Those who continue to use the age of 50 as if it is a legitimate threshold (when it is not) have ignored data, including what we published years ago showing that age 50 is scientifically meaningless. If the cancer detection rates are evaluated by individual age and not grouped and averaged, there is a steady increase with each individual age with no sudden jump at age 50.73
The 1997 Consensus Development Conference on Breast Cancer Screening
The arguments went on over the next several years with the ACR and the American Cancer Society (ACS), led by Robert Smith, PhD, continuing to support annual screening starting at the age of 40. Dr. Broder left the NCI and was followed by Richard Klausner, MD, as director. In 1996, data from Sweden, with longer follow-up
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A History of Breast Imaging From a Founder (continued from page 37)
increasing statistical power, were showing statistically significant mortality reduction for women aged 40 to 49. In January of 1997, Dr. Klausner agreed to have the NCI guidelines reviewed by a supposedly “independent” Consensus Development Conference where experts present data to a “neutral” panel that acts as a jury. Dr. Klausner had assured me, personally, that NCI would be “hands-off.” Unfortunately, his assurances were thwarted by the fact that one of the architects of the 1993 NCI decision was chair of the organizing committee for the Consensus Development Conference and was planning another “loaded” meeting. I was able, at the last minute, to get some speakers invited to present the arguments supporting women aged 40 to 49.
Hearing the updated information at the Consensus Development Conference (I was a presenter74) we thought that the question had been answered when data from the Malmö trial,75 the Swedish trials,76 and a meta-analysis of all the trials by Ed Hendrick,77 with longer follow-up to increase the statistical power, provided statistically significant mortality reduction for women aged 40 to 49 in the trials, even when analyzed separately. To the astonishment of those of us who participated at the Consensus Development Conference, the acting chair read a summary on the last day of the day and a half of testimony that completely ignored all the new data that had been presented.78 Ignoring the fact that Jeanne Petrek, MD, a surgeon from the Memorial Sloan Kettering Cancer Center in New York, had stepped down from the panel in protest and two other panel members ultimately wrote a dissenting opinion,79 he claimed that the panel “unanimously” agreed that the data did not support screening women in their forties. Having heard the presentations, Dr. Klausner disagreed with the panel summary. He later followed the advice of the NCAB, and the NCI, once again, supported screening women aged 40 to 49. Afterward, the NCI stopped issuing guidelines!
Gøtzsche and Olsen Ignore Science and Claim No Benefit From Screening for Anyone
The next major effort to reduce access came with the publication of a paper by Gøtzsche and Olsen in the journal Lancet, with the imprimatur of the highly regarded Cochrane Collaboration. The Cochrane Collaboration had been an independent group that provided objective reviews of cancer treatment trials. This review of the RCTs of breast cancer screening by Cochrane claimed that there was no benefit from breast cancer screening for anyone.80 The two authors, ignoring scientific methods, rejected the trials that proved a benefit and dropped the results from the trials that the authors didn’t like, claiming that only the Malmö trial and the Canadian trials (!!!) had acceptable random allocation. This review was so outlandish that it was ignored by most, but criticism prompted the Lancet to allow the authors a “redo”! In 2001 they published, essentially, the same analysis despite at least three peer reviewers arguing against publication.81 This second publication
was picked up several months later by Gina Kolata at the New York Times, 82 and doubts about screening were raised once again. Numerous reviews were performed in the United States and Europe and concluded that the Cochrane authors were incorrect and that there was a benefit from mammography screening.83-91 Nevertheless, Dr. Gøtzsche continued his scientifically unsupported attacks on mammography screening.92 His efforts caused less confidence by some about breast cancer screening.
The American College of Physicians Drops Support
In 2007, claiming that the “risks” of screening outweighed the benefits, the American College of Physicians (ACP) dropped support for screening women aged 40 to 49, stating: “Potential risks of mammography include false-positive results, diagnosis and treatment for cancer that would not have become clinically evident during the patient’s lifetime, radiation exposure, false reassurance, and procedure-associated pain. False-positive mammography can lead to increased anxiety and to feelings of increased susceptibility to breast cancer, but most studies found that anxiety resolved quickly after the evaluation.” 93
The term false positive had been chosen to be pejorative. These are not women who have been falsely told that they have breast cancer. This connotes women who have been recalled from screening for a few extra pictures and/or an ultrasound. A small number of the women who are recalled will be advised to have an image-guided needle biopsy as an outpatient, and 20% to 40% of these will be found to have breast cancer (which is a higher rate than in the days when surgical biopsies were done for clinically evident lesions). None of the organizations that have argued against screening women in their forties have explained how many fewer recalls is needed to balance allowing one woman to die unnecessarily.
The USPSTF Drops Support
In 2002 the US Preventive (not “Preventative”!) Services Task Force (USPSTF) had supported screening women in their forties, stating: “The USPSTF recommends screening mammography, with or without clinical breast examination, every one to two years for women aged 40 and older (B recommendation).” 94
In 2009 the USPSTF, following their close allies at the ACP and ignoring science,95 dropped support for screening women in their forties.96 Rather incredibly, both the ACP and the USPSTF, nevertheless, agreed that screening saves lives for these women.
The USPSTF stated: “The USPSTF found adequate evidence that mammography screening reduces breast cancer mortality in women aged 40 to 74 years.”97 The ACP stated: “Screening mammography has been shown to decrease the number of deaths from breast cancer in women ages 40 to 74.”98
Yet they both advised waiting until the age of 50 and screening every two years. The outrage was that these organizations
intentionally excluded anyone with expertise in breast cancer screening from their panels. In fact, none of the panels opposing screening included anyone who provided breast cancer care.
The American Cancer Society Compromises
For over 30 years, the ACS had been the champion of screening for breast cancer that included women aged 40 to 49. After the turn of the century, I suspect that there was a major change in leadership at the ACS and that politics reversed their direction. Assembling another panel that contained only one individual who had any expertise in breast cancer screening, the ACS came up with a hybrid set of recommendations. Although they stated that: “women should have the opportunity to begin annual screening between the ages of 40 and 44 years (qualified recommendation),” their 2015 guidelines, nevertheless, have been interpreted as advising that women wait until the age of 45 to start annual screening and to switch to biennial screening at age 55.99 Given their “neither here nor there” position, the ACS has lost some credibility with regard to breast cancer screening.
The ACR and SBI Support Science
Throughout all these controversial decisions that replaced science with the personal concerns of the inexpert panel members, the ACR and the SBI, the experts in screening, have stood fast and based their guidelines on science, which had proved that screening and early detection saves lives for women aged 40 to 74 (and probably older).
USPSTF Returns (Almost) to Science
In 2023, after years of effort, we finally convinced the USPSTF to advise women to begin screening starting at the age of 40. The data have always supported this, and they finally agreed, claiming that they changed their guidelines due to the increasing rate of breast cancer in younger women. We are still hoping that they will advise annual screening, but for now they suggest biennial. The ACP and ACS have not yet returned to science.
The CISNET Models: Screening Thresholds and Screening Interval
Since 2000, the NCI has supported six (there had been seven) centers that have developed independent computer models for various cancers, including breast cancer, that have been used to predict various approaches to screening. These are known as the Cancer Intervention and Surveillance Modeling Network (CISNET).100 Since there will not likely be any new RCTs to test the fundamentals of screening, the various advisory groups have used the CISNET models to test differing approaches. For example, there has never been an RCT to test annual screening versus other intervals. However, the CISNET models have always shown that annual screening starting at the age of 40 saves the most lives.101 Arleo et al have shown the differences between the various differing recommendations.102 Annual screening starting at the age of 40 reduces deaths by 39.6% (29,369 lives). The hybrid ACS would reduce deaths by 30.8% (22,829 lives), while the old USPSTF guidelines, still supported by the ACP, only reduce deaths by 23.2%
(15,999 lives). More recently, Monticciolo et al used the CISNET models to show that screening annually from age 40 to 79 (note it is now age 79) was superior to all other approaches.103 Annual screening from age 40 to 79 reduced mortality by 41.7%, while the new USPSTF guideline of biennial screening ages 40 to 74 reduced deaths by 30%. Biennial screening among women aged 50 to 74 (ACP recommendation) reduced mortality by 25.4%. Annual screening for women aged 40 to 79 saved the most lives (11.5 lives/1000) and resulted in the most life-years gained. Recalls from screening were estimated to be lowest among women aged 40 to 79 screened annually at 6.5% and had the lowest number of benign biopsies at 0.88%.103 The CISNET models continue to clearly show that annual screening for women aged 40 to 79 saves the most lives.
“Overdiagnosis” Is “Overexaggerated”
The concern that there are breast cancers that would never become clinically relevant goes back decades.104 There have been periodic reports of clinically evident breast cancers that disappeared without therapy.105 Opponents of screening ignored the fact that these were all clinically evident cancers and that the phenomenon was so rare that they could be classified as true miracles. Despite the fact that none of these were found by screening, it has been falsely claimed that mammography screening finds invasive cancers (there are legitimate questions about ductal carcinoma in situ [DCIS]) that would never become clinically evident and would disappear if left undetected.106 Allowing women to die unnecessarily by stopping screening is like removing the engines from our cars to prevent accidents.
Claims
of Massive Overdiagnosis Are Based on Ignoring the Fact That the Incidence of Breast Cancer Has Been Increasing Steadily Since 1940
All the other false claims about screening that have been raised over the years have been refuted. “Overdiagnosis” has now become the leading argument against early detection. The argument is that “overdiagnosis” leads to “overtreatment,” which is the unnecessary treatment of “things” that look like cancer to a pathologist but, apparently, aren’t!? There is certainly legitimate debate about the treatment of lesions categorized as DCIS, but opponents of screening have claimed that large numbers of invasive cancers, found by mammography, would never be clinically important. Of course, the “diagnosis” is made by pathologists, and oncologists decide on treatment. Those promoting this false claim argue that if these “fake” (my term) cancers are left alone they would regress and disappear.107,108 In fact, the unspoken foundation for delaying screening until the age of 50 is that if we don’t screen women in their 40s their “fake” cancers will disappear by age 50, and they will not be overdiagnosed and overtreated.
One of the more recent arguments that falsely claimed massive overdiagnosis was based on ignoring the facts. The authors argued that, based on the Surveillance, Epidemiology, and End Results
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A History of Breast Imaging From a Founder (continued from page 39) (SEER) program that started in 1974, the incidence of breast cancer, prior to the start of screening in the mid-1980s, had been increasing with an annual percentage change (APC) of 0.25% per year.109 They used this APC to extrapolate what they “guessed” the incidence of breast cancer would have been in 2008. The actual incidence of breast cancer in 2008 was much higher than their estimate and they claimed that the difference was due to excess “fake” (my term again) cancers detected by mammography screening. It is stunning that this paper passed peer review when the authors faulted mammography screening, based on the SEER database, given that SEER has never tracked how cancers are detected in the United States. In fact, we are trying, 50 years after the start of SEER, to get them to finally include method of detection, which should have been done decades ago and will help to answer many questions. Ignoring the fact that the authors had no idea which cancers were detected by screening mammography, they were allowed to blame screening for what they claimed was massive overdiagnosis! Incredibly, 4 years later, one of the authors, Dr. Gilbert Welch, published an additional analysis that used the same SEER data but this time claimed the incidence of breast cancer would have been flat with an APC of 0.0%!110 Same data, same journal, major altered claim! Nice peer review and editorial oversight!!
In fact, both were incorrect. The Connecticut Tumor Registry (CTR) is one of the oldest continuously operating registries in the country, with data going back more than 80 years. It has been part of SEER since the beginning. Most investigations that I can find that have evaluated the incidence of breast cancer in the United States prior to SEER have relied on the CTR data.111-115 The CTR data show that the incidence of breast cancer has been increasing steadily since 1940 by 1% to 2% each year.116 In order to suit their claims, Welch and colleagues have repeatedly ignored the CTR data and used the SEER data, which do not provide a reliable baseline. SEER only began collecting data in 1974. In that year the wives of the president and vice-president of the United States were diagnosed with breast cancer, and there was a brief flurry of ad hoc screening, which caused an opening blip in SEER incidence data. Almost certainly there was a postscreening drop below the expected incidence (since some future cancers had been removed by screening), and then in the mid1980s, widespread screening began with a long prevalence peak117 as more and more women participated and had their first mammogram. All this made the early years of SEER unreliable for establishing a prescreening baseline. In fact, following the prolonged prevalence peak that ended in 1990 with a drop in incidence, the incidence of breast cancer has resumed its prescreening annual increase.118 Had the opponents of screening used the correct baseline (an APC that was increasing at 1%-2% per year), they would have found no overdiagnosis. In fact, the incidence of invasive cancer is actually lower than expected. There is no way to prove this, but I suspect it is likely due to the removal of DCIS lesions over the years leading to fewer subsequent invasive cancers.
save lives and minimize the impact of breast cancer.
Delaying Screening Will Have No Effect on Overdiagnosis
No one has ever seen a mammographically detected breast cancer disappear or even regress without treatment.119 If there are overdiagnosed cancers among women in their 40s, they will still be there at the age of 50 and with 2 years between screens, yet Hendrick et al estimate that almost 100,000 lives will be unnecessarily lost by delaying screening!120 The only “harms” of screening (opponents like pejorative terms) that delaying it until age 50 and screening every two years will reduce are the recalls (pejoratively called false positives) for a few extra pictures or an ultrasound! What they have never explained is how many fewer recalls is needed to balance allowing one woman to die unnecessarily.
“All-Cause Mortality”!!!! Are You Kidding Me??!!
In breast cancer treatment trials, it is important to look at deaths from causes other than breast cancer to be certain that the treatment is not having unintended consequences. For example, by looking at “all-cause” mortality, it was found that radiation therapy for breast cancer could lead to deaths from coronary artery damage. However, in treatment trials where everyone has the cancer, the vast majority of deaths will be due to that cancer, so reducing deaths from the cancer should also reduce all-cause mortality. It is astonishing (I’m being polite) that “analysts” have challenged the benefit of early detection and the decline in breast cancer deaths because there was not a significant concurrent decline in deaths from all causes in the screening trials!121 In screening trials of women from the general population, the vast majority of deaths will be from causes other than breast cancer. In the United States approximately 3% of all deaths (“all cause”) each year are due to breast cancer. If screening reduces breast cancer deaths by 30% this means that in the general population (as in a screening trial), it would be expected to reduce deaths from all causes by 1%. Tabár et al have estimated that it would take a screening trial of more than 2.5 million women to prove that saving women from dying from breast cancer will significantly reduce all-cause mortality!122 If you are interested in all-cause mortality it makes more sense to look at women who are diagnosed with breast cancer in the trials (comparable to a treatment trial) and Tabár et al have shown that, indeed, among these women, the reduction in breast cancer deaths did, in fact, reduce their all-cause mortality.
Bottom Line in the “Debate”
With the USPSTF finally once again supporting screening starting at the age of 40, we are still waiting for the ACP to follow suit. The remaining debate will be annual versus biennial screening. Hopefully, reason and the CISNET results will prevail, and everyone will support annual screening starting at the age of 40— but I have been fooled before!
While All These Contrived Concerns About Screening Were Being Raised and Refuted, There Have Been Numerous Technological Advances in Breast Evaluation Since Film Mammography
Industrial Film
First there was film! These were sheets of material coated with light-sensitive silver halide crystals that when hit by x-rays caused the silver to turn black. Things that blocked x-rays prevented this from happening. The film was developed in processors full of chemicals in dark rooms where you could only turn on a red light to avoid exposing the film. The processing took several minutes to wash away the silver (from the clear base) that had not been converted to black (or shades of gray) by the x-rays (or light from “screens”) so that areas that were radiolucent and let a lot of x-ray through were black, and those that were radiopaque were clear and let the light of a lightbox on which the images were viewed (hence view box) pass through, making them look white (hence today’s convention of black to white).
Robert L. Egan, MD, was the first to standardize positioning and the mammography device.123 His approach was used in the HIP. Mammography first used “industrial” x-ray film (surprise—used in industrial processes). A sheet of film was put into a lightproof envelope and placed under the breast. This permitted high resolution, but the film was insensitive and needed to be “hit over the head” with lots of radiation to produce an image. The amounts of radiation were high enough that Dr. Bailar warned in the 1970s, “I regretfully conclude that there seems to be a possibility that the routine use of mammography in screening asymptomatic women may eventually take almost as many lives as it saves. would cause more cancers from the radiation than would be cured.”124
This caused the BCDDP to stop screening women in their 40s and fed the false claim that the age of 50 was a legitimate threshold for screening (it is not). Of course, the good news is that more data and better analyses showed that radiation risk to the breast was age related and fell off rapidly so that by the age of 40 there was no measurable risk and even the extrapolated risk was well below even the smallest benefit.125 The early studies did not use any breast compression, and the film that was used had a narrow exposure latitude, which meant that the thin front of the breast was often overexposed and thicker back of the breast was underpenetrated. Without grids, scatter radiation could hide cancers.
Xeroradiography
Because of radiation concerns, efforts were made to lower the dose and improve the imaging. It turned out that the Xerox technique (yup—the one for making copies), which uses an aluminum plate coated with selenium forming a semiconductor, could be used to image the breast. In an insulated “conditioner,” the surface of the plate was charged to 2000 V and the plate was inserted into an insulated “cassette.” The cassette was placed under the breast.
X-rays passed through the breast and hit the plate, which caused a variable discharge over the surface of the plate that was in proportion to the amount of radiation that reached it. The cassette was then placed in a processor where the plate was removed, and toner (again yup—the same—except it was blue!) was blown over the plate and electrostatic forces collected the toner in areas where little discharge had occurred, while in more radiolucent areas (greater discharge), less toner accumulated. Fibroglandular tissues and cancers were dark blue and radiolucent tissues lighter, tending toward almost white (air). The advantage of xeroradiography was that it had a wide exposure latitude, so cancers were well seen in all areas of the breast, and edge enhancement (the piling up of toner at edges like iron filings near a magnet) made cancers and calcifications stand out and we thought that compression was not needed! Xerograms were read in room light with reflected light just like a picture on the wall! View boxes were not used. I know—much more relaxing!
John Wolfe was the pioneer in the use of xeroradiography and was the first to link tissue patterns (parenchymal patterns) to the risk of breast cancer. His original claim was that the densest pattern (which he called DY for dysplastic) was the highest risk, at 40 times the risk of the all-fat pattern, which he called N1, with P1 for some “ducts” and P2 for “prominent ductal pattern” in between. And the doses needed for xerography were lower than for plain film! Most of the BCDDP centers in the 1970s used xerograms.
This all sounds so old-fashioned, but except for GE, most of the modern digital mammography system detectors use the same semiconductor plate, but instead of toner, the residual charge is read electronically, directly from the exposed plate. History repeats!!
And Then There Were Screens!
Over the same period of time, the film companies were busy. Fluorescent screens were developed that, when hit by x-rays, converted the x-rays into visible light, which was much more efficient in exposing film. They still had narrow exposure latitudes so that dedicated mammography machines were developed. Companies began to develop new focal spot materials, especially molybdenum, which had a low energy spectrum that improved the contrast between soft tissues. Breast compression systems were developed to hold the breast steady, pull it away from the chest wall to permit maximum tissue interrogation, even out the thickness because screen-film combinations still had narrow exposure latitudes, reduce motion, reduce scatter, push the tissue closer to the detector to reduce geometric unsharpness, and reduce the doses needed for appropriate exposure. By the way, for the women who have complained “I’d like to get your you-know-whats” in the machines, Wende Logan, MD, was one of the early promoters of breast compression,126 and our “you-know-whats” are comparable to ovaries and not breasts!
László Tabár had honed mammographic positioning and processing
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A History of Breast Imaging From a Founder (continued from page 41)
the film and image quality to its pinnacle. It was going to be a contest between Xerox and screen-film. When Xerox capitulated and withdrew their systems, screen-film mammography took over.
Magnification Mammography
In the 1970s Ed Sickles worked with Radiological Sciences Inc and an Israeli company called Elscint and obtained one of the first mammography systems with a very small 0.1-mm (“microfocus”) focal spot that allowed for magnification mammography and improved evaluation of the margins of masses and morphology of calcifications that became part of standard diagnostic evaluation127 as is still used today.
Dedicated Mammography Systems
Mammography systems progressed from film and standard x-ray tubes to xeroradiography, which was performed with standard overhead x-ray tubes and literally a balloon on the end of a coneshaped collimator to hold the breast in position. The patient was lying on her side for lateral mammograms. For craniocaudal views the cassette was on a patient table and the patient sat with her breast on the cassette.
With the development of screen-film systems and their narrow exposure latitude, machines were developed with improved x-ray tubes, ultimately with molybdenum targets to produce the low energy spectrum needed to provide contrast for breast imaging. Because they had a narrow exposure latitude and for the reasons enumerated earlier, rigid compression was developed along with automatic exposure controls and phototiming that took the guesswork out of imaging.
Grids were developed to reduce scatter on mammograms. Rhodium focal spots were used to raise the energy spectrum for larger breasts and different filters were developed to improve mammograms.
Thermography
Numerous methods have been attempted in an effort to detect breast cancers earlier. In the 1970s, in response to the radiation scare, it was claimed that thermographic analysis to image the infrared radiation from the breast could detect early cancers and avoid the need for mammograms. Thermography obtained US Food and Drug Administration (FDA) approval at a time when only safety and not efficacy was required, and it is still “grandparented in” although the FDA warns against its use in place of mammography.128 Unfortunately, thermography can only measure the skin temperature and not much deeper. The breast is a good insulator, and the vascular system takes away heat that might be generated by a cancer. You can see this when thermographic systems are used to measure the energy efficiency of a house by imaging heat leaks. If the house is well insulated you can have a fire in the fireplace but it will be undetectable by a thermogram from the outside. Dr. Steve Feig looked into thermography years ago
and found it had no role in breast cancer detection.129
Technologists Lead the Way
As the technical components improved, Dr. Tabár also taught us that positioning was critical to image as much of the breast as possible, and we realized the critical importance of the x-ray technologists. My office manager, Dorothy “Dottie” McGrath, recognized the fundamental importance of those who obtained the mammograms, and at her urging, we organized training programs that integrated the education of radiologists interpreting the images with technologists who obtained the images, and the “team approach” was started. This was supported by the incredible dedication and pioneering efforts of Rita Heinlein, RT(R)(M), Debra Diebel, RT(R)(M), and Louise Miller, RT(R)(M) (all honorary SBI fellows), who worked literally day and night to improve the quality of mammograms by teaching and training technologists and radiologists in the United States and around the world about the importance of positioning, compression, exposure, and supportive interaction with the patient.
Ultrasound
The story of ultrasound for breast evaluation has been long and progressive. Peter Dempsey, MD, has written a comprehensive history.130 In the 1960s, Jack Jellins, PhD, and George Kossoff were early pioneers of modern breast ultrasound. There has been a steady improvement in ultrasound evaluation of the breast from cyst/solid differentiation to improvements in evaluating masses and evaluating axillary lymph nodes and, perhaps most importantly, image-guided needle biopsy. My first exposure was in the 1970s during my residency. The earliest writing that I had read was by Toshiji Kobayashi, MD,131 who described the fundamental findings and differences between benign and malignant structures. The progression from barely interpretable images to those of today is even greater than the improvements in mammographic imaging.
The radiation scare of the mid-1970s led to false claims, with no scientific support, that automated whole-breast ultrasound could replace mammography. I remember seeing Life Instruments on a morning news program demonstrating a whole-breast water bath system, with the patient lying prone with her breast in an opening in the tabletop and a shadowing structure on the monitor showing a huge breast cancer, with the claim that it could replace mammography! Somewhat later the owner visited me, and I asked him how he could make such a claim and he stated, “That is what it was built for. If it can’t do that then it has no reason to exist!” (science in the 1970s!). Of course, the scientific evidence showed that, at the time, this was a false claim.132
For years ultrasound was, primarily, for cyst/solid differentiation. Ultrasound originated from a transducer that was attached to an articulated arm that allowed the technologist to move the transducer over the breast and was able to “paint” a plane through
it. Black and white images gave way to grayscale, and as technology improved, “real-time” scanning became possible with spatial resolution improving steadily.
Investigators found that lesions could be characterized in more detail than with older systems.133 Thomas Kolb, MD, found that improvements in ultrasound permitted the detection of cancers that were not evident on mammograms.134 Wendie Berg, MD, proved this in the ACRIN 6666 trial.135 The RCTs of mammography screening have proved that early detection saves lives. We could argue that the RCTs proved that any method that detects breast cancers earlier will save lives. Unfortunately, the “powers that be” require specific RCTs to prove efficacy, and there has never been an RCT of ultrasound screening with mortality as the end point. Once a technology is available, like digital breast tomosynthesis (DBT) (see below), and being used in most of the community, it is difficult to drop it, so unless the technology is without any value, doing RCTs after a technology has gained acceptance will likely have no value,136 or even worse, if not properly designed and executed, may be used to deny women access to screening.137 An RCT of ultrasound screening with mortality as the end point is long overdue. It is argued that these take too long. Had ACRIN 6666 been such a trial, we would (likely) have the proof today that ultrasound screening can save additional lives.
Whole-breast ultrasound systems, which were not capable of screening back in the 1980s,138 have been improved. They are still not ideal. Correlating what is seen on ultrasound, with the patient supine, with full-field digital mammography (FFDM, increasingly DBT), with the patient upright and the breast compressed, is still problematic. I have tried for decades to get the manufacturers to put ultrasound in mammography systems (and now in DBT systems) to provide simultaneously coregistered images that would greatly facilitate the use of both for screening. GE and Siemens built prototypes and then dropped the development for unexplained reasons. Given that ultrasound clearly detects cancers that are missed by mammography, even DBT, simultaneously gathered images could have a major impact and further drive down deaths.
Accurate Needle Localization Allowed for Aggressive Diagnosis and Removal of Early Small Cancers
Note: I receive royalties for the Izi Inc spring-hook wire localization system.
Screening began in the United States on a national level in the mid-1980s, but some of us were seeing more and more asymptomatic women for screening in the 1970s. We were finding very early cancers, but concerns were raised, and efforts made to curtail screening because we were sending surgeons after small, indeterminate lesions, most of which (70%-80%) were proving to be benign.139 In the 1970s and early 1980s the only way to determine if a lesion detected in the breast was malignant was surgical excision performed in the operating rooms under general anesthesia. At the MGH we had surgeons who were taking out
quadrants of the breast for what proved to be benign lesions.
Gerald Dodd, MD, was, apparently, the first to put needles in the breast, based on the mammogram, to guide surgeons to nonpalpable lesions seen on mammography.140 This method allowed a surgeon to have a better idea of the location of the lesion, but the needles often fell out and did not provide a three-dimensional guide. In 1976 Howard Frank, MD, and Ferris Hall, MD, described bending the end of a wire into a short hook and putting the long end into the tip of a needle with the hook outside the needle tip. Through a scalpel-made incision, the needle with the wire hook protruding was pushed into the breast in the direction of a lesion. The needle was removed, leaving a wire that was fairly stable in its relationship to the lesion.141 The two main problems were the need for an incision and the fact that it was very difficult to accurately position the needle (and hence the wire) since you got only one chance and couldn’t reposition the needle/wire.
Being asked to use these wires by one of our surgeons, but wanting to be able to very accurately position the wire, I set out to improve on the approach. I wanted to be able to position and to reposition a needle before putting in a wire guide, but if I tried to pass a wire that had been bent back in a hook through the accurately positioned needle, the wire stayed bent and would not reform in the breast. I finally found that with the correct malleability and tensile strength of the wire, I could overbend the hook to form a spring142 that allowed me to pass the guide completely through the needle. In this way I could very accurately position (and reposition if necessary) the needle and then pass the “spring-hook” wire through the needle from its hub, with a hook that would reform in the breast when the needle was pulled out, anchoring the guide.143 I developed methods to accurately position wires based on the goal of safe and accurate removal of small lesions.144,145 I added a thick segment just proximal to the hook to further assist in accurate surgical guidance. The guide could routinely be placed through or alongside a lesion, facilitating the surgery and the accurate removal of the lesion with minimal trauma or cosmetic damage.146 This also made it possible for excisional biopsies to be performed safely in outpatient settings using local anesthesia.
Other methods were developed, such as the Homer wire, which was a curved hook that could be retracted into the needle147 but, consequently, had less holding power, and the Hawkins system, in which the wire came out a hole in the side of the needle to hold the needle in place. The Hawkins had 1.4 times the holding power of the Kopans wire and 7 times that of the Homer system148 but required protection for the needle/wire that protruded outside the breast.
Accurate needle localization to guide surgeons to suspicious lesions permitted the safe and aggressive detection and removal of early breast cancers and the major decline that we have seen in breast cancer mortality.
Continued on page
A History of Breast Imaging From a Founder
(continued from page 43)
More recently a number of wireless markers have been promoted to guide surgeons. These include radioactive seeds, magnetic seeds, and radiofrequency transmitters. The advantage of these is that they can be placed days prior to surgery for the convenience of the patients and surgeons and so the operating room is not delayed waiting for other guides to be placed on the day of surgery; however, the cost of these “guides” is at least 10 times that of simple hook wires. It has been falsely claimed that the newer systems permit more complete excision of lesions, but this is completely untrue. No guide can determine the exact extent of a cancer; therefore, no guide, placed in or alongside a lesion, has any advantage in excisions to clear margins.
Image-Guided Needle Biopsy
A major advance in the care of women with breast lesions came with the ability to accurately position a needle to first cytologically analyze lesions and then, ultimately, histopathologically sample breast lesions. Paula Gordon, MD, in the early 1980s, was among the first doing fine-needle aspiration (FNA).149 In 1989 I provided an overview of what was needed before FNA could be substituted for surgical biopsy.150 Not only was the skill of the operator critical for obtaining adequate and accurate samples but a skilled cytopathologist was also critical for accurate interpretation. In the early years of needle biopsy, ultrasound was employed to target a lesion. Stereotacticguided biopsies were developed in Sweden.151 I believe the first stereotactic biopsy system was brought to the United States by Bob Schmidt, MD, and his group. They performed the first stereotacticguided needle biopsies in the United States.152
The major advance that allowed for ubiquitous adoption of needle biopsies came with the development of large-gauge needles that permitted “core” samples of tissue to be removed percutaneously, which were histological samples and could be interpreted by any breast pathologist. Steve Parker, MD, was one of the early promoters of the technology.153
In the early years of ultrasound, the technology did not have the capability of imaging a biopsy needle in the breast. As technology improved, the needle could be imaged to facilitate accurate coreneedle biopsies. The approach spread and has only gotten better with time.
Image-guided needle biopsies for diagnosis in outpatient settings have replaced open surgical biopsies for most breast lesions, greatly reducing the trauma and cost of diagnosing screen-detected (and even clinically detected) lesions.
Double Reading
It had long been known that experienced radiologists could overlook important findings on chest radiographs.154 The Swedish, British, and other national screening programs recognized the fact that all of us can look at something and not see it. How often do
save lives and minimize the impact of breast cancer.
we look for our keys in the morning and cannot find them until someone points to them in plain view! We even have a saying: “They’re right in front of your nose!” It is disappointing that looking for a cancer is no more a guarantee that an observer will see it than looking for our keys, but the fact is that our psychovisual system is far from perfect. Numerous studies found that having a second reader review screening mammograms increased the cancer detection rate by as much as 15%155,156 and could simultaneously reduce the recall rates. Richard E. Bird, MD, in the United States found that double reading increased cancer detection by 5%.157 We had a similar increase in cancer detection (5%-7%),158 but since insurance never paid for double reading, our program was halted when computer-aided detection (CAD) was introduced (see below), which was ultimately reimbursed even though its value has never been clearly proven.
Computed Tomography of the Breast
In the 1970s, CT was developed for body imaging and was rapidly becoming the major imaging study that it is today. GE developed a dedicated CT scanner for breast evaluation and sited two units. One was placed at the Mayo Clinic, but they could not find any value for breast evaluation. Joseph Chang, MD, in Kansas, recognized the potential for CT.159 When GE withdrew their prototype dedicated breast CT systems, Dr. Chang and his group continued using wholebody systems and, I believe, were the first to show that cancers enhanced with iodinated contrast material.160 Based on his work, we used CT to evaluate and localize lesions close to the chest wall that were not amenable to standard needle localization,161,162 but the fact that standard CT systems required irradiation of much of the chest and could not achieve the resolution needed, along with the steady improvement in ultrasound, prevented their widespread use.
Efforts have been made by a group led by Ruola Ning, PhD,163 and another by John Boone, PhD,164 to develop dedicated CT systems for breast evaluation with the patient lying prone and the scanner circling the breast, which is pendent through a hole in the table. The main problem for CT in this configuration is the fact that the deep (close to the chest wall) tissues of the breast, and especially the upper outer quadrant and axillary tail, where many cancers develop, are not easily imaged.
Full-Field Digital Mammography
Before there was direct digital mammography, screen-film images were “digitized” so that they could be computerized. This permitted the sharing of images and even the long-distance transmission of images by satellite and back with no loss of data, which Richard Moore proved years ago at the MGH.
Once x-ray images were available for computers, the effort to acquire images directly using electronics and computers began in earnest in all branches of radiology. There were scattered efforts to obtain digital mammograms as far back as the early 1980s.165
Jorge Oestmann led our effort to develop “stimulable phosphors” for mammography,166 but these did not have sufficient resolution.
Martin Annis, PhD, and Paul Bjorkholm, PhD, at American Science and Engineering produced a highly advanced line scanning system that we tried to develop at the MGH in the mid-1980s.167 It virtually eliminated scatter radiation and had higher resolution than any system in use today, but it was too advanced for the time (the RAM to hold one image was a cube 3 feet on a side!) and could not be commercialized. Marttin Yaffe, PhD, developed a modification that became the basis for a device built by Morgan Nields at Fischer Imaging. Charge-coupled devices (CCDs) were developed, but they had too small a field of view. Hologic combined 12 CCD cameras in a large array but ultimately switched to a selenium detector similar to the xeroradiographic plate, but with the charge read directly from the plate. This is the same basic approach used today by Hologic and the other FFDM manufacturers, such as Siemens. The exception is GE, which developed its own proprietary system in which cesium iodide crystals are grown in columns “epitaxially” over the electronics. X-rays are converted to light by the crystals which are then converted to electronic signals.
In 1992 Etta Pisano, MD, with Martin Yaffe, PhD, and Donald Plewes, PhD, from Sunnybrook in Canada, organized the Digital Mammography Development Group, which became the National Digital Mammography Group and later the International Digital Mammography Development Group, to try to organize and steer (not surprisingly!) the development of digital mammography. I was very interested in developing tomosynthesis so my group, with Richard Moore as head of breast imaging research and Loren Niklason, PhD, our department physicist at the MGH, partnered with GE, whose detector at the time could read out fast enough for what we wanted to do. Steve Feig, MD, partnered with Fischer Imaging, which was developing a scanning system. My group was quickly impressed with the GE detector, and we did studies that showed that their images were equal to standard screen-film images.
Most digital x-ray imaging that was being developed for other organ systems was approved by the FDA using the 510(k) process. Essentially you take an image with your new device and compare it to an image with a previously approved (“predicate”) device (eg, screen-film). If the images are comparable to the predicate device, then the FDA will approve it. Digital chest, digital bone, digital abdomen, etc, were all approved with the simpler and much less expensive 510(k) process.
The FDA has always been sensitive about issues surrounding breast cancer screening. An individual who had been at the NCI and involved in the effort to reduce access to screening in the early 1990s moved over to the FDA. He was not a radiologist, but it is my understanding that he convinced the FDA that digital mammography was so new that radiologists would not know what we were looking
at and this would result in many more recalls from screening. The government hates recalls! Consequently, and unfortunately, the FDA required companies developing FFDM to go through the premarket approval (PMA) process as if it was a new device with no predicate. The PMA is a much more complicated, time-consuming, and expensive process. The PMA would require large reader studies using receiver operating characteristic analysis to compare FFDM to screen-film mammography. In addition, as they do with some drug approvals, they were going to require large postapproval screening trials to validate the systems. Morgan Nields, the head of his small company, Fischer Imaging, went to Congress concerned that his company could not afford a postapproval screening trial. Congress earmarked $25 million to support such trials.
GE was the first company to go to the FDA for approval. The FDA brought together a committee to review their application and I went down to Bethesda on my own to testify. I explained that FFDM was as good as screen-film mammography. It shouldn’t have been a PMA (but it was too late to change that!), but it certainly didn’t need a postapproval trial.168 I showed them a screen-film mammogram of a patient with breast cancer and the FFDM image of the same patient. I told them I couldn’t tell the difference and they couldn’t tell the difference. They were completely comparable. I told them that we understood the physics, and that GE’s FFDM should be approved, and I added that a postapproval screening trial was not needed. The committee agreed with me, and GE’s PMA was approved. They also advised the FDA that the postapproval trial was not needed. FDA agreed. GE’s FFDM was approved, and the postapproval requirement was dropped.
DMIST Wastes Money
I will not go into the details, but in 2000 we were informed that some money had become available for breast imaging research. In the late 1990s my colleague Priscilla Slanetz, MD, had found that MRI could detect breast cancers that were not evident on mammography.169 I urged that the money be used for an RCT of MRI screening. Instead, the money ($25 million) was used to pay for the Digital Mammographic Imaging Screening Trial (DMIST).170 This was unfortunate.171 The FDA had dropped the requirement for a postapproval RCT of FFDM, but I suspect the money used for DMIST was the money that Congress had earmarked and so it could have only been spent on a study of FFDM. Had an RCT of MRI screening been done at the time, we would know by now that MRI was probably the best way to detect early cancer! Lewin et al did a large comparison of FFDM to screen-film mammography and found comparable cancer detection rates and somewhat lower recall rates for FFDM.172 Their study was a model for studying new technology, given that both modalities were used on the same patients at the same time. This is the ideal way to compare new technologies. FFDM was no better than screenfilm mammography (DMIST made it appear better, but this was
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statistical “sleight-of-hand”), but we all know the many advantages of having digital images. Screen-film mammography was slowly replaced by FFDM over many years.
Computer-Aided Detection
Digitization resulted in the first efforts to have computers analyze mammograms, and CAD was born. CAD showed great initial promise, with computers identifying cancers on mammograms a year or more prior to their being detected by a human review.173 For the development of CAD, radiologists provided the criteria that computer experts programmed into the computer to “look” for the things that we look for to identify cancers.174 Given that computers “never forget a case,” are never distracted, and don’t get fatigued, it is unclear why this was never superior to having a human searching for cancer, but CAD was never able to come close to replacing humans. Now that computers are teaching themselves what to look for (artificial intelligence [AI]), it is unclear why they are not far superior to humans in detecting cancers (see below).
Magnetic
Resonance Imaging
We first began to see MRI of the breast in the early 1980s.175,176 Initially it was thought that MRI could be done without any contrast material, but those who tried were soon disappointed (except for implant evaluation). Intravenous contrast material began to be used177,178 and the importance of MRI has increased dramatically since then. Unfortunately, although it is clear that MRI detects many more cancers than FFDM, ultrasound, and DBT, it has never been tested in an RCT with mortality as the end point. I had recommended this in 2000, but DMIST was undertaken instead. Since MRI is only being used for high-risk women, there is still the opportunity to test it for early detection in the general population. I suspect that this has not been supported because the “powers that be” do not want to have to deal with the fact that access is very limited and it would be very expensive for use in the general population. MRI detects many more cancers than we would have initially predicted. However, our analysis suggests that to maintain the detection of one to six cancers per 1000 women each year, there is a much larger pool of women in the population who have breast cancers that are currently below the level of detection growing slowly over many years179 but that will ultimately become detectable, with lethal potential anywhere along the way. There is no doubt in my mind that if used for screening, MRI would further decrease deaths from breast cancer, but it is unlikely this will ever be shown and applied unless the technology becomes less expensive and more available. There was an effort years ago to market a dedicated MRI device for breast cancer screening,180 but, for various reasons, it appears to have ultimately failed in the marketplace.
Digital Breast Tomosynthesis and TMIST
I remember in 1978 recognizing how clear an excised lesion was
on specimen radiography when it had been so difficult to see when it was in the breast. Tomosynthesis181 provided the opportunity to remove the “structure noise” of the breast,182 but I had to wait for digital detectors in the 1990s to show how much better the planar information was than two-dimensional (2D) images alone. Loren Niklason, PhD, our physicist at the MGH; his wife, Laura Niklason, MD, PhD; and their friend Bradley Christian, PhD, worked out the physics and we were issued a patent in 1999.183 GE licensed our patent with the promise that they would have a system for women by 2005, but then they sat on the technology until 2013. Trying to foster competition to keep technology moving forward, we convinced and helped Hologic and Siemens to develop their systems. Although GE had a three-year head start, Hologic was the first to obtain FDA approval in 2011. They named their system “3D Mammography” to avoid our patent.
Anyone who uses DBT for screening knows that there are cancers that are only evident on the DBT planes, and since DBT should also include 2D mediolateral oblique and craniocaudal images, there is no debate—DBT is, absolutely, superior to 2D alone.
Funding for the development of improved breast cancer detection is very difficult to obtain. The Tomosynthesis Mammographic Imaging Screening Trial (TMIST), which is claiming to compare FFDM and DBT,184 is wasting $100 million. I have published a detailed explanation of the problems.185 TMIST is using surrogate end points, which are known to underestimate benefit.186 Since the trial will not include anyone under the age of 45 its results will be used to exclude anyone aged 40 to 44 from DBT screening. It is screening older women every two years, so it will be used to deny women annual screening. By the time the results are known, DBT will be the standard of care and the results will have little positive effect.
As we were developing DBT, it became apparent that 2D images were needed to facilitate comparison with prior studies. Although DBT is superior to 2D FFDM for evaluating calcifications,187 they can be overlooked when “paging through” the planes. This is less likely on 2D images. 2D images are also important for efficient comparison with prior studies. Consequently, every DBT screening study should also include FFDM 2D craniocaudal and mediolateral oblique images.
In 2000, Richard Moore was the first to put the planes back together to create synthetic images. The various manufacturers have now developed their own synthetic mammography (SM) using the data from the multiple projections. The problem is that all the studies I have seen comparing FFDM and SM have been historical between different populations. With a modification such as this and the high stakes involved (we don’t want to miss cancers with one approach that would have been found with the other), before SM is fully adopted to replace FFDM as part of a DBT examination, blinded comparisons need to be done on the same patient. Standard FFDM
images should be obtained and compared to the SM images created at the same time. This could be done at the time of the interpretation by randomly presenting the FFDM images first and SM second, alternating with presenting SM first and FFDM second. This is the only way to know if SM can replace FFDM as part of the DBT study. We also need to be cautious. If there are differences between two approaches, it is not sufficient that the difference is not statistically significant. Either they must be exactly the same or one is better than the other and therefore should be used. Finding cancers using 2D FFDM with DBT is the best we can do. I would not adopt SM if it is “almost as good” when there is no good scientific reason to switch.
Contrast-Enhanced Mammography
Breast CT proved that breast cancers enhance following the intravenous infusion of iodinated contrast material. With the development of digital mammography, this could be applied to breast cancer detection. Following dual-energy mammograms that we obtained of a tumor in an animal model that showed poorly formed, leaky tumor vessels, we injected iodinated contrast material in a volunteer while her breast was compressed and made the “brilliant” discovery that breast compression prevented intravenous contrast material from entering the compressed breast! The group in Toronto did the same but did not compress the breast and showed the vascular blush of breast cancers,188 but motion was a problem between the precontrast and postcontrast studies. John Lewin, MD, PhD, was the first to infuse iodinated contrast material intravenously, wait for several minutes before compressing the breast, and then use dual-energy subtraction mammography to enhance the visualization of the contrast material.189 Vascular blushes due to irregular tumor neovascularity and leakage from tumor vessels can be identified using this method.
As has been noted, several studies have been and are being conducted unnecessarily, “after the horse is out of the barn.” The DMIST was an example, as is the TMIST. Contrast-enhanced mammography (CEM) has been around for many years but has not yet caught on. There is still time to do a trial to really define its capabilities and see if adoption is warranted. Most studies have been reader studies comparing detection rates, etc, using P values. This can make approaches seem comparable, but if we are interested in detecting cancers and each case is critical, absolute detection comparisons are needed with direct comparisons in the same patients. It is of some concern that, in a study by Lawson et al, CEM had a lower cancer detection rate than MRI (full or abbreviated) where patients had CEM, abbreviated MRI, and full-protocol MRI.190 CEM was inferior to both. I would think that MRI has the absolute advantage since it images the entire breast and axilla. CEM (like DBT) is only as complete as the ability to position the entire breast in the field of view (unlikely for either modality). If we are going to inject an intravenous contrast agent, I would urge that the best system with the highest cancer detection rate be used. This may
not be a problem if CEM is able to detect more cancers than DBT (which includes FFDM) at a time when cure is possible, if there is no access for women to MRI screening (which should still have an RCT with mortality as the end point).
From what I can tell, the Contrast-Enhanced Mammography
Imaging Screening Trial (CMIST) is reasonable191 by performing both studies on the same women. “The CMIST study seeks to determine if contrast-enhanced mammography (CEM) provides more accurate cancer detection compared to digital breast tomosynthesis (DBT) in women with dense breasts.”192
Large trials of new technologies should be undertaken when they show significant promise and before they come into general use, to determine if general use is warranted. Now is the time for a CMIST trial, although it is almost certain that CEM will be better at detecting breast cancers than DBT in women with dense breasts. However, if we are going to be injecting women with contrast material, I would think that, given the results from Lawson, it would be best to screen, if possible, using MRI because of its higher sensitivity.
Magnification of the First Pass of Contrast Material Through a Lesion Should Be the Goal
Both MRI and CEM are actually limited. A physicist once told me that the first pass of contrast material through a lesion provides the most information. Not only would this provide the best dynamic information (wash in/wash out) but it would also allow us to image the microvasculature of a lesion, which may well allow us to differentiate benign from malignant lesions. CEM now evaluates lesions after many passes of the contrast material so that the vessels are lost in the diffusion and leakage of contrast material. I don’t think that MRI can do this at high enough spatial resolution. Magnification breast CT offers the opportunity, for the first time, to analyze the microvasculature by imaging during the first pass of contrast material at high spatial resolution. I don’t think there is, currently, any other way to do this.
Artificial Intelligence
The initial excitement about CAD proved to be, ultimately, unfulfilled. Computers have become more powerful, and with AI, instead of radiologists training the computer what to look for, “neural networks” emulating the human brain are being shown thousands of cases, from normal to those with cancer, and the computers are teaching themselves “what to look for.” I put this in quotes since the neural network is a “black box.” At this time, the computer cannot provide us with its reasoning. We are unable to know why it is concerned about an area on the mammogram. I have to admit that I am somewhat surprised that AI is not yet routinely superior to humans. Unlike humans the computer never forgets a case. It is not distracted and does not tire! I am certain it will get there, but it is the inability to explain why it makes the decisions that it makes that is problematic. How can we be sure that AI is
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actually an advantage? In a study a few years ago, AI was given the wording of pathology reports as well as the images and it did a fairly good job of determining which core-needle biopsy cases that showed atypia were likely to be upgraded with surgical excision.193 However, it was impossible to tell whether the computer based its decision on the imaging or the words in the report! And who will be responsible for decisions made by AI?
Given the stress and concentration that is needed to interpret screening studies, I think that radiologists will benefit greatly if computers can be relied upon to interpret screening examinations. There is plenty of diagnostic work for us to do! I have no doubt that computers will get there, but there are major issues that need to be resolved before AI can replace humans.
The
Future
Unfortunately, because of their costs, RCTs with mortality as the end point are not being supported for testing new approaches to early detection. This is paradoxical because, thus far, “the powers that be” will only accept RCTs with decreased mortality as the only proof of benefit from screening tests. The argument has been made that RCTs take too long and the technology moves faster. I would point out that for breast imaging, the technology has steadily improved, but it has taken years for advances to be adopted. Had we done an MRI screening trial in 2000 instead of DMIST, we would know today that MRI is the best way to detect breast cancers early.
RCTs should be performed before tests have become routinely accepted for clinical care. For example, DBT has almost completely replaced FFDM such that the results from TMIST, even if it had been planned properly, will be too late to have any major influence. Now is a good time to study CEM since it is not yet in widespread use.
Ultrasound screening may add significantly to decreasing the death rate from breast cancer. An RCT using ultrasound screening is years (decades) overdue.
MRI screening is probably the best way to find early breast cancers. It has the advantage, unlike DBT and CEM, that it covers the entire breast and axilla. An RCT of MRI with mortality as the end point should be undertaken as soon as possible. It may well be that, if our ability to detect early cancer is more effective, we might be able to extend the time between screens, but this too remains to be proved.
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