The recent report from the Canadian National Breast Screening Study (CNBSS)—published in BMJ and reviewed in this issue of The ASCO Post—concluded that annual mammography in women aged 40 to 59 does not result in a reduction in mortality from breast cancer beyond that of physical examination alone or usual care in the community. In their conclusion, the study investigators stated, “the rationale for screening by mammography should be urgently reassessed by policy makers.”1
This prompted a flurry of news reports, most notable of which was a New York Times article that described the CNBSS as “one of the largest and most meticulous studies of mammography ever done, involving 90,000 women and lasting a quarter-century.” The article noted that it “has added powerful new doubts about the value of the screening test for women of any age.”2
Flawed From the Beginning
The findings of the CNBSS are in sharp contrast to those from other mammography trials, as well as the meta-analysis conducted by the U.S. Preventive Services Task Force that reported a significant reduction in breast cancer mortality for women in this age range.3,4 While the study findings are strengthened by 25 years of outcomes in a cohort of nearly 90,000 women, many would argue with the description that the trial was “meticulously” conducted. The CNBSS has been plagued by a number of published criticisms dating back to the early 1990s.5-9 The issues identified, namely concerns regarding randomization and mammographic quality, are considered by most breast cancer experts to have rendered the CNBSS flawed from the beginning, thus eliminating any ability of the trial to accurately discern the benefits and harms of mammographic screening.
Screening is, by definition, performed in asymptomatic individuals. The diagnostic evaluation of women with palpable masses, typically with diagnostic mammography and ultrasound, falls outside the realm of breast cancer screening. However, women with palpable breast masses were allowed in the CNBSS. The fact that women with known palpable breast masses were included in the CNBSS makes the design of this screening trial questionable. This is further compounded by the timing of their allocation to the mammography or control arms of the trial.
Skewed Allocation
In order to avoid bias in the randomization process, those carrying out the allocation of participants to the study arms should not know anything about them other than the variables upon which the randomization is performed. In the CNBSS, instead of randomization being conducted at study entry, it occurred after the performance of a physical examination.1 Knowledge of the clinical breast exam findings prior to allocation to the intervention or control arms of the study creates the potential for it to influence the randomization process. Disproportionate assignment of women with a poor prognosis (ie, those with palpable masses and lymph nodes) to the intervention arm would result in more advanced breast cancers in the intervention arm.
In fact, in the CNBSS, the number of women 40 to 49 years old in the mammography arm who had breast cancers with four or more lymph node metastases exceeded that of the control group by 19:5 (380%).5 The 5-year survival for women aged 40 to 49 years who underwent mammographic screening was 75%. The women in the control arm of the CNBSS had a greater than 90% 5-year survival—even better than modern results with screening and improved therapy.7 Such a skewed allocation is unlikely to have occurred by chance and would minimize or eliminate any impact of mammographic screening on breast cancer mortality.
Although the investigators have attempted to mitigate this bias by eliminating prevalent cancers in their analysis,1 it should be understood that the CNBSS is not, by definition, a trial of screening mammography. Additionally, given that a fundamental rule of randomized controlled trials was violated, all analyses of this trial, including this analysis, are confounded by this limitation.
Imaging Quality and Interpretation
In addition to concerns regarding the randomization process in the CNBSS, concerns have been described regarding mammographic quality, acquisition of images, and image interpretation.5-7,9,10 At the start of the trial, image quality was suboptimal. Second-hand mammographic equipment was used. Images were cloudy and cancers were harder to see, as grids that reduce scatter were not utilized. The technologists were not taught proper positioning. Notably, mediolateral oblique views were not initially obtained, precluding identification of cancers in the axillary tail. The radiologists were not experienced in the interpretation of mammographic images, resulting in cancers being missed on interpretation. The reference physicist for the CNBSS stated that “...quality was far below state-of-the-art, even for that time [early 1980s]”.11
It should be noted that a retrospective review of the CNBSS mammography by three external reviewers confirmed that technical quality improved after 1984. However, this same external review showed that, for the majority of the trial (years 1–4), over half of the mammograms were judged as poor or unacceptable. It was not until the final 2 years that image quality was judged to be satisfactory in over 70% of cases.12
When mammographic technique and interpretation are unsatisfactory, the benefits of mammography cannot be assessed. This prompted one of the external reviewers to comment that “because of poor mammography, the results of this trial will always be suspect”.6 As a result of the imaging limitations, cancers were more difficult to see or were missed, resulting in cancers being diagnosed at a more advanced stage. This minimizes or eliminates the mortality reduction that might have been demonstrated by screening mammography.
Although we rely on evidence from trials of screening mammography dating back to the 1960s, it is important to realize that the technology of today’s mammograms is vastly superior. It is analogous to comparing a 1960s television to the high-definition viewing that is enjoyed today. We are finding cancers on today’s screening mammograms at a significantly smaller size than seen on early mammograms, certainly much smaller than the average size of 1.9 cm in the mammography arm in the CNBSS.1
Conclusions
The strengths of the CNBSS are contrasted by a vast collection of flaws that render any findings, past or present, meaningless. As a result, the study does not provide any data in regard to the benefits of mammography that would influence breast cancer screening recommendations. It is well recognized that, even in the era of adjuvant therapy, women with early-stage breast cancer have a better survival than those who present with late-stage disease. At this time, our greatest tool for the early detection of breast cancer remains screening mammography. ■
Disclosure: Dr. Bevers reported no potential conflicts of interest.
References
1. Miller AB, Wall C, Baines CJ, et al: Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: A randomised screening trial. BMJ 348:g366, 2014.
2. Kolata G: Vast study casts doubts on value of mammograms. New York Times Feb 11, 2014.
3. Tabar L, Vitak B, Chen TH, et al: Swedish two-county trial: Impact of mammographic screening on breast cancer mortality during 3 decades. Radiology 260:658-663, 2011.
4. Nelson HD, Tyne K, Naik A, et al: Screening for breast cancer: An update for the U.S. Preventive Services Task Force. Ann Intern Med 151:727-737, 2009.
5. Warren Burhenne LJ, Burhenne HJ: The Canadian National Breast Screening Study: A Canadian critique. AJR Am J Roentgenol 161:761-763, 1993.
6. Kopans DB: The Canadian Screening Program: A different perspective. AJR Am J Roentgenol 155:748-749, 1990.
7. Kopans DB, Feig SA: The Canadian National Breast Screening Study: A critical review. AJR Am J Roentgenol 161:755-760, 1993.
8. Kopans DB: Canadian National Breast Screening Study. Lancet 350:810,1997.
9. Tarone RE: The excess of patients with advanced breast cancers in young women screened with mammography in the Canadian National Breast Screening Study. Cancer 75:997-1003, 1995.
10. American College of Radiology and Society of Breast Imaging: BMJ article on breast cancer screening effectiveness: Incredibly flawed and misleading. Posted February 11, 2014. Available at www.acr.org/News-Publications/News/News-Articles/2014/ACR/BMJ-Article-on-Breast-Cancer-Screening-Effectiveness-Incredibly-Flawed-and-Misleading. Accessed February 16, 2014.
11. Yaffe MJ: Correction: Canada Study. Letter to the editor. J Natl Cancer Inst 155:748-749, 1993.
12. Baines CJ, Miller AB, Kopans DB, et al: Canadian National Breast Screening Study: assessment of technical quality by external review. AJR Am J Roentgenol 155:743-747, 1990.
Dr. Bevers is Professor in the Department of Clinical Cancer Prevention at The University of Texas MD Anderson Cancer Center, Houston. She chairs the National Comprehensive Cancer Network’s guideline panels on Breast Cancer Screening and Diagnosis and Breast Cancer Risk Reduction.
The Opinions expressed are her own and are not meant to represent the consensus of the NCCN panel.
