Background:
Breast cancer (BC) is the most common cancer among women and leading contributor
to cancer mortality, hence constitutes a major public health issue worldwide. In
Scotland, over 4,000 women are diagnosed with BC every year and around a 1,000 die
from this disease. Monitoring incidence, mortality and survival trends is key for
surveillance of disease progression. BC is heterogeneous, with multiple subtypes
defined by molecular markers, such as the oestrogen receptor (ER), that have different
aetiology, targeted treatments and prognosis, yet standard reporting of incidence and
mortality rates is not usually done using tumour marker data. The Scottish Cancer
Registry was the first registry in the UK to collect molecular marker data and therefore,
constitutes an excellent opportunity to explore incidence and survival trends over time
by molecular subtypes. This PhD aims to describe temporal trends in BC incidence
and survival by molecular subtypes in Scotland to inform public health prevention
programmes, diagnostic and therapeutic services.
Methods:
A systematic review was conducted to determine the extent of available data on BC
incidence trends by ER in population-based studies of women of European ancestry.
In addition, the Scottish Cancer registry data on over 72,000 women diagnosed with
incident primary BC from 1997 to 2016 (the focus of most analyses for this
dissertation) was used to describe trends in incidence and survival in Scotland. Age-standardised incidence rates (ASiR) and age-specific incidence were estimated by BC
subtype after imputation of molecular marker data. Joinpoint regression and age-period-cohort (APC) models were used to assess whether significant differences were
observed in incidence trends by ER, the human epidermal growth factor receptor 2
(HER2) and the immunohistochemistry (IHC) defined molecular subtypes. Kaplan-Meier (KM) estimates and traditional and extended Cox proportional hazards models
were computed to assess breast cancer specific survival (BCSS) by BC subtypes.
Sensitivity analysis was carried out to compare results for the Cox models from
complete case analysis (CCA) and multiple imputation analysis (MIA). The effect of
individual, tumour characteristics and treatments on BCSS for each subtype was also
investigated. Trends in 5-year survival by age, grade and stage characteristics for the
different subtypes (ER+ and ER-) were investigated to identify the characteristics of
women showing greatest and lowest improvements over time. Other causes of death
were also explored and cumulative incidence functions (CIF) were investigated.
Results:
The systematic review showed that ER+ BC incidence increased and ER- BC
incidence decreased in the last four decades (EAPCs ranging from 0.8% to 3% for ER+
tumours and -2.1% to -3.4% for ER- tumours) and that the rise in overall incidence
trends is mainly driven by increases of ER+ tumours in women of screening age. In
Scotland, BC incidence rates showed the same divergent pattern between ER+ and
ER- tumours observed in other countries. ER+ tumour incidence increased by 0.4%
per year from 1997 to 2011 and increases were mainly among routinely screened
women aged 50 to 69 years. In contrast, ER- tumour incidence decreased among all
ages by -2.5% per year over the study period. Apart from the period effects observed,
APC models showed that older cohorts of women born in 1912-1940 had lower
incidence rate ratios (IRR) for ER+ tumours, and younger cohort of women born in
1960-1986 had lower IRR for ER- tumours, compared to women from the 1941-1959
birth cohorts. Results for the IHC defined subtypes showed that luminal A tumours,
that account for more than half of all tumours, had similar patterns to those observed
for ER+ tumours, with increases until 2011. In contrast, luminal B tumours declined
over time, particularly in women over 50 years of age. There was no clear trend for
HER2-enriched or triple negative breast cancers (TNBC) overall but TNBC tumours
seemed to increase in younger women aged 20 to 49 years.
BCSS also differed between subtypes with ER+ tumours having better survival than
ER- tumours, luminal A tumours having the best survival of all IHC defined subtypes
and TNBC having the worst survival. Age, grade, stage, screening and surgery were
the most important prognostic factors irrespective of tumour subtype, with women who
had older age, higher grade, stages III-IV, tumours not screen detected and who did
not have surgery having worse survival. Deprivation was also associated with lower
BCSS, with women living in the most deprived areas of Scotland having increased
BC-specific mortality when compared to women in the least deprived areas and this
relationship was observed for all subtypes with slightly higher HR for HER2-enriched
subtypes (but wider CI). Five-year BCSS trends showed improvements in the last two
decades, especially for women aged 50 to 69 years. The greatest gains in survival were
seeing in women with advanced tumours (high grade or stage III-IV tumours) and ER-tumours seemed to have greatest improvements than ER+ tumours, although their
survival remained lower than for ER+ tumours. The improvements observed for
women with high grade and stage III-IV tumours were observed in both screen and not
screen detected tumours but the rise was sharper amongst women with screen detected
tumours. Women younger than 50 years showed similar improvements than those
observed in women aged 50 to 69 years. Older women aged 70 years or more showed
no consistent survival improvements over time and over 50% of women in that age
had a primary cause of death other than BC with cardiovascular diseases (CVD) being
a major contributor (22% of all deaths).
Conclusions:
This project is the first in the UK to describe incidence and survival trends by
molecular subtypes of BC using population-based data. Divergent incidence trends
found in Scotland are similar to those observed in other countries and confirm different
aetiology of BC molecular subtypes. Increases in the incidence of hormone sensitive
tumours are likely to be driven by the implementation of mammographic screening
programmes, population aging and changes in risk factors (RFs) that have differential
effects on the subtypes, such as, reproductive factors and obesity. Survival
improvements in Scotland are likely due to multiple contributors with two major
factors such as screening and the improvement and development of new treatments
likely playing a role. This PhD has allowed us to further understand disease
progression of the different subtypes in Scotland and has identified groups of women
(those with advanced tumour characteristics, living in the most deprived regions of
Scotland or women aged 70 years or older) with lower survival and/or lower
improvements in survival trends that could benefit from further prevention and
treatment programmes. This PhD also highlights the importance of monitoring future
incidence and survival by molecular subtypes to inform clinical planning and cancer
control programmes
