The Canadian National Breast Screening Study conducted in the 1980s and led by researchers at the University of Toronto evaluated the efficacy of breast cancer screening in reducing mortality from breast cancer. Because the research was supposedly a “gold standard” randomized controlled trial, its results, published in academic journals and reported in the media, have influenced public perceptions and informed policy on mammography screening in several countries.
However, over the past decades, flaws in this study have come to light. My colleagues and I learned of failures in randomization, and we and other researchers have found other serious problems. We think these flaws strongly suggest the publications of CNBSS results should be retracted. Despite being informed of the flaws in this study in 2021, the University of Toronto has not adequately or appropriately addressed these issues.
The CNBSS was configured as two separate randomized clinical trials, one for women in their 40s at entry and the other for women in their 50s. In CNBSS1, 50,000 women ages 40-49 were supposedly randomly assigned to the intervention arm, in which they would receive up to five annual screens with two view film mammography plus clinical breast examination by a nurse, or to the control arm, where they received a single clinical examination at entry and usual care (essentially, no screening) afterwards. In CNBSS2 for 40,000 women, the randomization was between the intervention of mammography plus a clinical breast exam versus clinical exam only.
When the results of CNBSS1 and CNBSS2 were first published in 1992, the investigators reported no difference in mortality from breast cancer between the arms in either trial. This finding contrasted with positive results in several other studies. In fact, the investigators initially, and falsely, claimed screening was leading to excess deaths from breast cancer in the younger women. That claim was eventually retracted. As well, results from CNBSS were later used by one of its principal investigators to produce unrealistically high estimates of overdiagnosis attributed to mammography screening.
I and other colleagues have criticized the CNBSS over the years for, among other serious problems, strong indications of bias in randomization. These concerns led to a forensic review in 1995 of the randomization of the trial, but, for reasons not entirely clear, the mandate of the review did not include interviewing the staff crucial to the randomization process. The review proved inconclusive and left the key question of subversion of randomization open.
In 2021, my colleagues and I became aware of eyewitness evidence staff members had steered some participants with symptoms of breast cancer into the mammography arm of the study. At all but one trial site, all women received a clinical breast examination before getting their study arm allocation. The staff registering the women into the study were aware of the exam results. Entering a woman with significant findings to the intervention arm would assure her of an immediate mammogram.
According to eyewitness testimony, well-meaning staff members could, and did, steer such individuals into the screening arm with the intention of providing a symptomatic woman with an immediate mammogram, without appreciating the consequences for randomization this entailed. As we have explained, moving even a few women from their intended random allocation in the control arm to the intervention arm after discovery of palpable abnormalities could shift the trial findings from demonstrating a mortality benefit from screening to suggesting a mortality detriment.
In light of this new evidence, later in 2021 we contacted the Canadian Cancer Society (CCS), whose subsidiary, The National Cancer Institute of Canada, had sponsored the CNBSS. The CCS then approached the University of Toronto, via the Dean of Medicine, informing them of this evidence and requesting a review. In the meantime, we published an article describing the evidence for subversion of randomization.
After several months with no response from the university, we followed with a letter to the university’s Research Ethics Board. Eventually we were informed that the matter had been referred to the Office of Research Integrity, which is the responsibility of the Vice President of Research and Innovation of the University of Toronto. Finally, in December of 2021 we were told that our concerns would be investigated and an external three-member panel would be appointed to do this. This was not consistent with the university’s established framework for investigations of research ethical issues.
After another long gap, we learned on June 14, 2022, the panel members had been selected by Lorraine Ferris, the associate vice president of research and innovation at the University of Toronto. Two of the members of this committee, Mette Kalager and Peter Jüni, had previously been on record supporting the results of the CNBSS and in one case, had co-published on issues around screening with one of the trial’s principal investigators. If CNBSS were to be invalidated, both of these individuals would have to reverse pointed statements they had made publicly. We were surprised the university would appoint either of these individuals to the committee, given their clear conflicts of interest (for the same reason, that these panel members did not immediately recuse themselves also was surprising).
We immediately raised these concerns to Prof. Ferris. In her response, she stated the investigation would go forward with this panel. She said it was challenging to find suitably qualified panel members for such a review. We explained our concerns regarding subversion of a randomized control trial do not require people with specific expertise in breast cancer screening studies to resolve them; it is largely a matter of consideration of proper conduct of any such study.
In a follow-up letter, we indicated we would continue to protest the process the university had chosen to investigate our concerns and to push for a more appropriately constituted panel. At the same time, we agreed to be interviewed by whatever review panel was appointed by the university. We did not want, by refusing to cooperate, to provide an excuse for the university to back away from its responsibility to conduct an investigation. On Aug. 2, 2022, we received a response from Prof. Ferris that she was unwilling to reconsider the composition of the panel.
The panel did interviews by Zoom in the Fall of 2022, including one with me. But the witness list was not made available to those of us who had raised the initial concerns, nor have the statements made by the various witnesses been shared.
In 2023, we were informed by Professor Ferris that she expected the review to be completed by March of 2024. However, that date passed without event. We requested a meeting with the current Provost, Trevor Young, and that was arranged for March 28 of last year. Professors Ferris and Leah Cohen, vice president of research and innovation, and strategic initiatives, were also scheduled to attend. The meeting was abruptly cancelled by the Provost on the afternoon of March 26. We have heard nothing since.
This is not the first time the University of Toronto has delayed or failed in fulfilling its responsibilities to safeguard the ethical conduct of medical research. Notably, in the late 1990s, Nancy Olivieri, a hematologist clinician researcher conducting a study with an industrial collaborator to evaluate a new drug for treating thalassemia, observed adverse effects on patients. When she attempted to discontinue the study and voice her concerns, she was faced with intense harassment by the pharmaceutical manufacturer and by some of her academic colleagues. Her request for intervention from the university –- which was in the midst of negotiating a $20 million building donation from the manufacturer — did not receive an adequate response. Ultimately the matter had to go to an external review, which vindicated her.
At this point, almost four years have elapsed since we brought our concerns to the attention of the University of Toronto and, as far as we can see, nothing has happened. Perhaps the long delay in the review suggests that, in light of overwhelming evidence, the university is no longer able to credibly support the conduct or the results of the CNBSS. Or perhaps it means that by delaying its review, the university hopes the problem will go away.
The CNBSS has influenced policy and opinions of primary healthcare providers and women, discouraged opportunities for earlier detection of cancer, and, in turn, resulted in delays in cancer detection. The publications of results from CNBSS must be retracted.
Martin J. Yaffe is a medical physicist and imaging scientist at Sunnybrook Research Institute and Professor of Medical Biophysics at The University of Toronto. His research over the past 45 years has focused on the earlier detection, diagnosis and characterization of cancer.
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