In areas included in this study, breast cancer mortality fell dramatically after 1990 with APCs ranging from −1.7% to −2.5% [1
]. Often, mortality decreases started before screening started or was offered to the majority of women. In examining trends of breast cancer by size or by stage, we expected to observe decreases in the incidence rate of advanced breast cancer. In contrast, this study found that in general, incidence rates of advanced breast cancer did not change much despite 7–15 years of good participation in mammographic screening. There were variations in some areas, with transient downward trends. These, however, were followed by increases back to pre-screening rates. For instance, in The Netherlands, trends in the falling incidence of advanced cancer for the first 7 years of screening were compatible with the results of most trials. However, incidence rates in 2003 were close to initial values in 1989 just before the launch of the national breast screening programme. Likewise, the rates of advanced breast cancer in the USA in 2000 were nearly back to levels before screening started. The fall of rates in the USA after 2001 was linked to massive drops in the use of hormone replacement treatment (HRT) after publication of the Women's Health Initiative trial, and falls of rates have affected breast cancer of all stages and of all sizes [31
]. Similar rate decreases of early and advanced breast cancer after massive cessation of HRT use by postmenopausal women have been observed in other countries [63
Comparison of breast screening activities showed that the numbers of large screen-detected cancers >20 mm were very similar in the USA and the UK in spite of considerable differences in the way screening is implemented [65
]. These elements indicate that the lower than expected decrease in advanced cancer incidence seems not attributable to age at screening, to screening frequency or to the way screening is implemented.
Randomised trials of breast cancer screening and their reviews concluded that mammographic screening of women aged 50–69 years decreases breast cancer mortality by 20% to 25% [8
]. In a previous work, we showed that in these trials, breast cancer mortality reductions were directly proportional to the fall in the incidence of advanced breast cancer [12
]. Results of this study do not concur with expectations from mammography randomised trials despite the fact that women living in areas included in this study were at least as compliant to screening and had more screening rounds than women had in the intervention groups of most randomised trials. For instance, in the Swedish Two-County trial, the cumulative incidence of advanced breast cancer steadily decreased by 4.4% per year in women allocated to mammography compared with the control group [5
]. Two to four screening rounds at 24–33 month-interval lead to a 31% reduction in advanced breast cancer incidence and 32% in breast cancer mortality [12
]. In contrast, until 2002 (when the massive discontinuation of hormone replacement treatment took place), no or only little change occurred in the incidence of advanced breast cancer in the USA, despite that over >10–15 years, most US women 40–69 years had three to five times more mammography screenings than in the Two-County Trial.
Other cancers subject to screening have shown remarkable decreases in both the incidence of advanced cancer and of mortality. For instance, in the USA, similarly to breast cancer mortality, colorectal cancer mortality has decreased by 1.8% per year from 1990 to 2006 [68
]. A substantial contribution of earlier detection to the reduction of mortality is supported by steady decreases in the incidence of regional (−2.5% per year) and of distant (−1.2% per year) colorectal cancer in the SEER data [69
]. In Iceland, age-adjusted annual mortality rate from cervical cancer decreased from 5.0 per 100 000 in 1974–78 to 2.1 in 1999–2003 [61
]. At the same time, incidence of stages II–IV cervical cancer decreased by a factor two to three, depending on age [70
What are the possible reasons for modest or no reduction in the incidence of advanced breast cancer?
First, in the absence of screening, would advanced breast cancer incidence have increased as the incidence of earlier breast cancer? This is very unlikely since generalisation of mammographic screening has been itself at the origin of sharp increases in the incidence of small breast cancers, many of which are deemed to be of low malignant potential [71
]. In The Netherlands, no increase in proportions of advanced cancers in women not attending screening was observed [53
], and there were no time changes in the incidence of advanced breast cancer in women <50 and >69 years of age in which screening is rare [8
]. In Victoria (Australia), the incidence of advanced breast cancer in non-attending women was similar to that observed among screened women [51
Second, reassurance of women with negative screening could have led to greater numbers of interval cancer >20 mm. This is unlikely to be the case. A study in The Netherlands concluded that this factor played only a minor role in breast cancer screening [72
Mammographic screening aims to detect tumours in the breast, rather than lymph node or distant metastases. Therefore, size of invasive cancer was preferred to other indicators of cancer progression. Furthermore, contrary to axillary node status, cancer size measurement has remained stable over time [12
]. In this respect, some of the fluctuations in rates of cancers classified as ‘regional or distant’ in the USA may have been due to changes over time in lymph node status assessment and improvements in the diagnosis of disseminated cancer. Changes in lymph node status assessment have also been invoked for explaining the absence of persistent downward trend of the advanced breast cancer incidence in The Netherlands [60
]. But the stable incidence in large size cancer we have observed cannot be explained by changes in lymph node status assessment.
Our study has several limitations. In Victoria, New Mexico, and Switzerland, incidence rates were reported for wider age groups than those targeted by screening. However, ~96% of breast cancers occur after age 39 [68
] and any decrease in advanced breast cancer occurrence due to screening before age 70 is expected to persist after that age. In the USA, screening after 69 years of age is common and nationwide surveys showed that in 1997–98, 57% of US women aged ≥70 received screening within 2 years [18
We did not find much published data on breast cancer incidence by cancer size or stage. This was often due to the absence of a population-based cancer registry or lack of recording of data on disease advancement by registries. Some registries reported high levels of missing stage or size data [10
]. In many countries, co-existence of centrally organised screening programmes and non-centrally organised screening activities (see additional material, available at Annals of Oncology
online) made it difficult to obtain the same quality statistics related to both types of screening.
In conclusion, there are unexpected differences between the results of randomised trials and screening with mammography as applied in general populations which require further investigation. Cancer registries should as a matter of routine collect size of breast cancers and the screening status to enable further monitoring of the impact of mammographic breast cancer screening.