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Facts do not go away while scientists debate rival theories for explaining them.— Stephen Jay Gould, Hen’s Teeth and Horse’s Toes
The recent series of important exchanges within the long-lived mammography debate in the pages of this journal were triggered by the publication in 2014 of the 25-year follow-up of the Canadian National Breast Screening Study (cnbss) incidence and mortality data1, putting that Canadian randomized controlled trial (rct) and its authors once again at the centre of a storm of criticism and subsequent defense. The most recent stimulus for the exchanges began with Dr. Steven Narod’s detailed defense of the trial’s findings in a Countercurrents Series paper2, drawing a sustained response from Dr. Martin Yaffe and a brief rebuttal by Narod in a Point–Counterpoint exchange3,4, with some of the issues taken up independently by Dr. Dan Kopans5. Yaffe then, in his response6 to an unrelated paper7, took up one of the most contentious issues, namely, the randomization process—especially as to observed imbalances of advanced cancers and survival in the screened and control arms. Chapter Two of the debate opens in this issue with Dr. Anthony Miller’s response8 to Yaffe, and then Yaffe’s own response9 to Miller, randomization again at centre stage.
The relative merits of the reasoning in these two counter-narratives of Miller and Yaffe can be argued, but there are larger issues of interest here that put the exchange into a wider and more consequential perspective. That there is an imbalance favouring more palpable breast cancers in the mammography arm is not in dispute, and Yaffe makes a compelling case for how quite modest perturbations in the balance of advanced cancer allocation can engender consequentially large increases in the associated hazard ratios. But Miller and the Canadian trialists candidly acknowledge the imbalance, seeking to provide a corrective in the form of exclusion from consideration of prevalence-detected cancers (detected in the first screening year). The difficulties, however, could be deeper still: None of the other seven screening rcts manifested an excess of advanced cancers in the study group compared with the control group. In addition, second-year-detected cancers not previously identified by mammographic screening (possibly because of suboptimal quality of mammography in the first year) remain unadjusted, still leaving 23% more cancers identified in the mammography arm than in the control arm10, which appears beyond the reach of chance alone. The more profound scope of the problem is further suggested by the fact that even if, more aggressively, the imbalances of both the first and second years are discounted, the imbalance between the cohorts remains durable at 15% excess in the screening cohort across the remaining incidence years (years 3 through 5)10. So the excess, and the anomaly, remains.
Beyond the imbalance, however, a time-bounded limit of applicability must be recognized for all of the now decades-old screening rcts beyond just the cnbss, rendering them of limited—but not null—explanatory power and relevance projected forward into the modern epoch of mammography.
First, of the seven population-based rcts [cnbss was not a population-based trial, the participants being self-selected; it limited screening to 3–4 years after study entry (maximum 5 annual rounds) and involved participants whose ages ranged narrowly from 40 to 59 years (in whom the breast cancer incidence is typically lower)], six used only 1 mammographic view per breast instead of the current 2-view standard11, causing significant underestimation (2-view screening can dramatically increase cancer detection). Moreover, the cnbss is, definitionally, not strictly a screening trial (diagnostic assessment of palpable masses being outside the borders of breast cancer screening limited to solely asymptomatic women).
Second, of the seven population-based rcts (the exception in both cases being the hip trial12), six used supra-annual screening intervals, despite the superior benefits from annual screening. The U.S. Preventive Services Task Force guidelines13 still recommend biennial screening despite a 70% additional improvement in survival outcomes under annual screening, as found and acknowledged in their own model. The early mortality reduction from annual mammography screening in women 40–49 years of age in general, regardless of breast density, has been robustly confirmed by rct in the 17-year follow-up of the U.K. Age trial14.
Third, all the rcts used insufficient screening rounds (although the Malmö Trial15 continued screening through 10–11 years of follow-up). A significant screening-related mortality reduction emerges only once a requisite delay threshold is passed (the 6th year in the Malmö Trial), and in general, significant mortality-reduction benefits from screening emerge only after some 5–8 years after screening commencement, the study and control group mortality curves not even beginning to separate significantly before 4–5 years from screening initiation11,14.
Fourth, most trials failed to differentiate between screening invitation and screening attendance, generating a continued distortive influence from reliance on number needed to invite (which necessarily provides lower estimates of mortality benefit) rather than on the actual number needed to screen.
Finally, as previously argued7, and as the above considerations reinforce, it is imperative to move beyond the mammography debate:
Collectively, the new imaging technologies, plus advances in screening modelling, and the leveraging of insights from both in-progress clinical trials and the new radiomics, will obviate the current limitations of mammographic screening and help to obsolete many of the not-always productive controversies of the mammography debate, something that should unite screening advocates and critics alike, because we are all, independent of partisan stripe, here to enhance the breast cancer preventive and outcome-improving options and technologies available to best serve the ultimate stakeholder in the debate, screening-eligible women. Perhaps the fog is lifting.
I have read and understood Current Oncology’s policy on disclosing conflicts of interest, and I declare that I have none.