Is the biology of breast cancer changing?: An exploration of breast cancer incidence and molecular epidemiology in Scottish women

Breast cancer is the most common female cancer in Scotland, in common with many Western countries. This thesis aimed to analyse changes in the incidence and molecular epidemiology of breast cancer in Scotland. Part 1 concentrated on epidemiological research, with data derived from various agencies, and Part 2 on a laboratory project aimed at looking at changes in the molecular profile of breast cancers in two cohorts of patients in Glasgow. The period between 1987 and 1994 in which coverage of the country by the breast screening programme gradually increased was expected to raise incidence rates as seen in studies in Scandinavia and elsewhere; after 1994, incidence rates should have returned to normal in women aged 55-64, with incidence in women aged 50-54 remaining slightly above pre-existing rates. An observed/expected analysis of breast cancer incidence rates after 1994 was performed; this showed a 58% increase in rates in women aged 50-54 above that which would have been expected had the trends continued as expected in the absence of screening. In 55-59 year olds and 60-64 year olds there were 42% and 40% increases, respectively, above expected rates. Reproductive risk factors such as low parity and late age at first pregnancy are important risk factors in breast cancer. Reproductive risk factors are likely to affect the ‘birth-cohort’ incidence of breast cancer but the temporal effects of breast screening make this difficult to interpret. Breast cancer incidence in Scotland by year of birth was examined using a Lexis diagram. In women aged 50-54, 55-59 and 60-64, breast cancer incidence rates increased by birth cohort during the presence of the prevalent round of screening, a finding which is likely to have been due to detection of large numbers of asymptomatic tumours. However, in women who were offered screening after the prevalent round, incidence continued to rise with successive birth year, suggesting a contribution from risk factors. This is the first study of birth cohort incidence of breast cancer and its relation to screening (published in Breast Cancer Research and Treatment). The contribution of screening and risk factors to breast cancer incidence in Scotland was also assessed. A small rise in screening uptake between 1990 and 2001 and an increase in standardised detection ratio may indicate that screening improvements could be contributing to increasing incidence. The number of first pregnancies to women in Scotland aged 35-59 has risen from several hundred in 1976 to 2000 in 2001. A plot of completed family size in Scotland against maternal birth year shows that a steadily declining trend has been developing since the 1935 birth cohort. Based on data from the Scottish Health Surveys, the percentage of women with a BMI of over 25 has increased from 47.2% to 57.3% between 1995 and 2003. Mean BMI in women has increased from 25.7 to 26.9 over the same period. It is likely that the observed changes have contributed to changes in breast cancer incidence in Scotland. Using prescription and population data, the prevalence of HRT use in women aged 40-64 in Scotland was estimated; this estimated prevalence has increased from 13.8% in 1993 to 17% in 2001. It is difficult to know if this small increase in prevalence of HRT could have influenced breast cancer epidemiology. A study of breast cancer incidence by deprivation quintile showed that breast cancer incidence between 1991 and 2000 rose in all quintiles. Interaction analysis suggested that breast cancer incidence is rising to the same extent in deprived and affluent women. The risk factor analyses above were also applied to women of different socioeconomic standing (the results were published in Breast Cancer Research and Treatment). A laboratory project was carried out to assess whether increasing survival from breast cancer could be a result of changing molecular epidemiology. This project was an comparison of the prevalence of breast cancers which were ER, PR and Her2 positive and of different grades in two cohorts of Glasgow patients, from 1984-86 and 1996-1997. The application of current molecular techniques to stored tissue aimed to improve the quality of data compared to previous studies based on clinical databases using heterogeneous techniques. There were significant differences in grade distribution of tumours in the two cohorts (p=0.009) with fewer grade 1 and more grade 3 tumours in the second cohort. Further study showed the grade difference to be exerted by the tumours in screened women in the second cohort with there being no difference in grade between symptomatic patients in the two groups. 64.2% of the tumours in cohort 1 and 71.5% of the tumours in cohort 2 were ER positive (p=0.042); this is also likely to be a clinically significant difference. The difference between the cohorts appeared to be exerted by high percentage of screen-detected tumours in cohort 2 being ER positive; however this finding still supports a theory of changing biology. 44.9% of the tumours in cohort 1 and 49.9% of tumours in cohort 2 were PR positive (p=0.181). 21.5% of tumours in cohort 1 and 20.6% of tumours in cohort 2 were Her-2 positive; this was not a significant difference. An increase in ER positivity was seen in all age groups in the study, though multivariate analysis did suggest a contribution from a higher number of women over 60 in the more recent cohort. Kaplan-Meier analysis showed survival to be higher in the second cohort than the first. There was a significant difference in survival between ER positive and negative patients. Cox’s regression was performed; as expected this showed a multifactorial contribution to increases in survival in these cohorts rather than it being entirely due to changes in ER status. However the changes in ER status shown in a population of Glasgow patients over time may mean that the results of clinical trials carried out in many years ago need to be interpreted with caution when applying them to the women of today. The results of this project were published in the British Journal of Cancer. Overall, the epidemiological studies within this thesis shed an important new light on the factors contributing to breast cancer incidence in Scotland, with a major finding being a significant association between birth cohort and breast cancer incidence suggesting a significant impact being made by reproductive risk factors. This hypothesis is supported by the analysis of risk factor trends in Scotland undertaken within the thesis. The laboratory study has shown a significant lowering in grade and increase in ER positive status of tumours in a cohort of Glasgow women over time; while the changes are statistically explainable by known effects of a breast screening programme on tumour detection they could still represent a true change in biology. The results of all the studies contained in the thesis could have significant implications for future health service planning.