Because the majority of the world’s trials screened women aged 40 to 49 at randomization at an interval of 24 months, faster tumor progression in women in this age group meant that they were less likely to benefit from mammography than would women aged 50 and older. The consequence of screening all women at the same 24-month interval becomes further evident when cumulative mortality trends are examined by age and tumor histology. When cumulative mortality trends are compared for ductal grade 3 tumors, a benefit begins to appear after 5 years among women aged 50 to 74 but is not evident in the follow-up period among women aged 40 to 49. These higher malignancy grade tumors are more aggressive, have a worse prognosis, and, compared with ductal grade 2, medullary, and invasive lobular cancers, account for a higher proportion of breast cancer deaths that occur sooner after diagnosis. When comparing trends in the invited versus control group in the trial for ductal, grade 2, lobular, and medullary carcinoma, women aged 40 to 49 and 50 to 74 showed similar trends in cumulative mortality.
Furthermore, for both women younger and older than age 50 who were diagnosed with these less aggressive cancers, the mortality benefit does not appear until after 7 to 8 years of follow-up, consistent with the observation that survival is better for these tumor types and that associated mortality occurs later. When examining the overall trend in cumulative mortality by age, these same trends are evident; in other words, for the groups invited to screening, a mortality benefit begins to emerge after approximately 5 years for women aged 50 to 74 and after 8 years for women aged 40 to 49.
The organizers of the Falun meeting concluded that the screening interval of 24 or more months was differentially effective in reducing mortality among women aged 40 to 49 versus women aged 50 and older. Whereas this interval was equally effective in both age groups for grade 2, medullary, and invasive lobular tumors, and effective in reducing deaths among grade 3 tumors diagnosed in women aged 50 and older, it was entirely ineffective for grade 3 tumors diagnosed in women aged 40 to 49. New results from Gothenburg, which screened women aged 39 to 49 at 18-month intervals, show that the timing of the benefit, which appears at 6 to 8 years, is similar to that observed for women aged 50 and older.
Additional insights into these observations come from earlier analysis of Swedish Two-County data comparing long-term survival by tumor size, extent of disease, and histologic grade. When tumors are grouped by size, grade, and nodal involvement, there is little difference in observed survival by age. However, Tabar and colleagues have also observed that the likelihood that a tumor will have progressed to grade 3 at the time of diagnosis is higher in women younger than age 50 than in women aged 50 and older, indicating that one important difference between breast cancer in premenopausal women compared with postmenopausal women is the greater likelihood of tumor dedifferentiation to less favorable histology.
As shown in earlier work, the influence of tumor grade on survival becomes increasingly pronounced once tumors are greater than 10 mm in size. As a general rule, it is important to diagnose tumors at the earliest opportunity, but these data suggest that this goal is especially important in premenopausal women.
The fundamental conclusion that can be drawn from these data is that the common screening interval of 2 or more years in the trials contributed to sufficiently favorable lead times for most tumor types in women aged 50 and older and failed to provide that same benefit to the more aggressive tumors in women younger than age 50.
More than any other explanation, a mismatch between the estimated mean sojourn time and the screening interval contributed to poorer performance in the trials among women aged 40 to 49 and also to the longer period of observation required to see a benefit. The observation that some eventual benefit accrued to women aged 40 to 49 who were invited to the screening is a function of the heterogeneity of breast cancer. Although the wide screening interval provided little benefit to women in their 40s in whom aggressive tumors developed, the detection of less aggressive tumors was still beneficial and appeared later in the follow-up period.
If the screening interval is greater than the mean sojourn time, the potential for the program to reduce the rate of advanced disease is compromised, because a higher proportion of cancers will progress undetected to the point at which they become clinically evident and appear as interval cancers. In Gothenburg, which screened women aged 40 to 49 every 18 months and showed a 44% reduction in breast cancer mortality, the proportional interval cancer incidence was only 18% in the first 12 months after a negative screen but increased to more than 50% in the period from 12 to 18 months.
In the University of California at San Francisco screening program, sensitivity declined at twice the rate in the interval between 1 and 2 years for women in their 40s compared with women aged 50 and older, reflecting faster growth rates for women in their 40s. According to Sickles, interval cancer rates for women aged 40 to 49 with annual screening are approximately equivalent to interval cancer rates in women aged 50 years and older who are screened every 2 years.
Robert A. Smith and Carl J. D’Orsi
R. A. Smith: Cancer Screening, Department of Cancer Control, American Cancer Society, Atlanta, Georgia
C. J. D’Orsi: Diagnostic Radiology, University of Massachusetts Memorial Medical Center, Worchester, Massachusetts