Overdiagnosis in mammography screening for breast cancer in Sweden and Norway

1. Overdiagnosis in mammography screening for breast cancer in Sweden and Norway Senior Statistician Per-Henrik Zahl, MA MD PhD Norwegian Institute of Public Health Professor Jan Mæhlen, MD PhD Department of Pathology, Ullevål University Hospital July 29th, 2004

2. The aim of mammography screening is to diagnose the tumour when it is small and before tumour spread occurs since such small stage I tumours have favourable prognosis.

3. Many small tumours (stage I) are detected at the mammography screening Mammogramme with small breast cancer (T) Macroscopic picture of excised tumor (T) T T

4. Background • Prior to the introduction of mammography screening in Sweden and Norway the breast cancer incidence increased less than 1% annually (Rostgaard et al, Stat Med 2001) • Coinciding with the introduction of mammography screening the incidence of breast cancer in the invited age group 50-69 years increased about 50% (Zahl, Strand, Mæhlen BMJ 2004)

5. Ductal breast carcinomaLobular breast carcinoma

6. Definition: Overdiagnosis is the diagnosis of disease that (without screening) would not have given symptoms during the lifetime of the patient

7. May these three factors explain the incidence increase? • There was an underlying increase in breast cancer incidence rates in the periods before the screening programmes started. • In the first screening round a large number of slow-growing tumours that would have occurred in the future are diagnosed earlier. • In the following screening rounds some excess of breast cancer will persist due to a combined effect of lead-time and incidence increase with age.

8. While the Swedish mammography screening programme started in 1986, the Norwegian programme started in 1996.

9. Estimation of the level of overdiagnosis • Overdiagnosis is calculated as the incidence increase in the screened age group minus the subsequent incidence decline that occurs when these women reach the age when they are no longer invited to screening. If no overdiagnosis occurs, this difference should be zero. • The level of overdiagnosis can also be estimated as the proportion of the total cancer cases that would not have been diagnosed in the absence of screening.

10. During the introduction of mammography screening in Sweden the breast cancer incidence increased by nearly 50% in the screened age group. No similar fall in breast cancer incidence in women above age 70 years has emerged.

11. Overdiagnosis in the Swedish screening programme • The incidence increase is 50% in the age group 50-69 years. • The incidence decline is 0% in the age group 70-74 years and 12% in the age group 75-79 years. This decrease compensates less than 3% of the incidence increase in the screened age group. No incidence decline is expected among women above age 79 years. • We conclude that nearly all of the incidence increase in Sweden are caused by cancers that would not have been diagnosed in the absence of screening.

12. During the introduction of mammography screening in Norway the breast cancer incidence increased >50% in the screened age groups. Only an 11 % reduction in breast cancer incidence occurred in previously screened women aged 70-74 yrs in 2000-1.

13. Table 1

14. Overdiagnosis in the Norwegian screening programme (AORH-counties) • The incidence increase is 52-54% in the age group 50-69 years. • The incidence decline is 13% in the age group 70-74 years. This decline compensates only 3% of the increase in the screened age group. No incidence decline is expected in women above age 74 years. • We conclude that nearly all of the incidence increase in Norway are caused by cancers that would not have been diagnosed in the absence of screening.

15. Incidence rates among those attending and those not attending screening in the age group 50-69 years in four Norwegian counties

16. Definition of interval cancer • Interval cancer is breast cancer detected clinically in the time interval between two mammography screenings. • The incidence rate of interval cancer in the Norwegian screening programme has been 190 cases per 100 000 per 2 year (i.e. close to 50% of the predicted rate in the absence of screening). • Compared to the incidence rate of cancer in the absence of screening, the rate of interval cancer is 30% in the first year and 70% in the second year after screening.

17. Cancer incidence in those leaving the screening program at age 69 years reflects the interval cancer incidence If the incidence reduction is 70% in the first year, 30% in the second year, 15 % in the third year, 5% in the fourth year and return to the background in the fifth year, the overall reduction in age group 70-74 year is 13% (assuming 75% attendance rate at the last screening at age 68-69 years).

18. Lead-time • Lead-time is defined as the time the diagnosis is brought forward by the screening. • The average lead-time in the randomized trials has been estimated to about 4 years. • When we adjust for overdiagnosis in the Norwegian programme, we estimated lead-time to be 1.2 years. • The high rate of interval cancer at the end of a screening interval support the idea that the lead-time is short.

19. Is it sensible to expect a mortality reduction when • The average lead time in the Norwegian screening programme after adjusting for overdiagnosis is much smaller than in the screening trials; 1.2 years vs. 4 years. • The rate of interval cancer in the Norwegian screening programme is much higher than in the screening trials (the rate in the Norwegian programme is twice the rate in the Swedish WE-study).

20. In the randomized screening trials the mortality decline was observed after four years. Since Sweden started mammography screening more than ten years before Norway one would expect: • In the 1990s the decline in the Swedish breast cancer mortality rates should be substantially larger than the decline in the Norwegian rates. • In Sweden the breast cancer mortality rates should decline substantially more in the age group 55-74 years than in the other age groups. As shown in the next slide none of these phenomena have been observed.

21. Age-adjusted breast cancer mortality rates in Norway and Sweden in 1978-2001 for the age groups 45-54, 55-74 and 75-84 years

22. What is known about overdiagnosed cancers in other locations? • Screening for prostate cancer leads to 30% overdiagnosis (Etzioni et al, JNCI 2002). In this organ sub-clinical cancer is very frequent at autopsy (prevalence 50% after age 80 years, Liavag I, Harbitz TB, Haugen OA. Latent carcinoma of the prostate. Recent Results Cancer Res. 1972;39:131-7). • Screening of children for neuroblastoma leads to substantial overdiagnosis. For such tumours spontaneous regression without treatment is the most likely outcome, therefore these patients do not benefit from earlier diagnosis (Schilling et al, N Eng J Med 2002).

23. After three biennial screenings in Norway the accumulated breast cancer incidence was substantially higher than the accumulated breast cancer incidence after prevalence screening of previously un-screened women. • This observation suggests that in the absence of screening many small and localized invasive breast cancers undergo spontaneous regression.

24. Summary • Overdiagnosis of breast cancer in national mammography screening programmes is substantial. • In Sweden the decline in breast cancer mortality rates after 10-15 years of screening is much smaller than expected from the randomized trials. In fact, a very similar small decline in breast cancer mortality has also occurred in Norway before the screening started. • Our results show that many small tumours detected by mammography behave as benign lesions although they fulfill the histological criteria for invasive cancers. We propose that such lesions normally undergo spontaneous regression.