Mammography screening is associated with more favourable breast cancer tumour characteristics and better overall survival: case-only analysis of 3739 Asian breast cancer patients

Female breast cancer overtook lung cancer to be the most commonly diagnosed cancer type in the world in 2020, with 2.3 million cases diagnosed worldwide [1]. In the same year, 685,000 breast cancer-related deaths were recorded globally. Early detection of breast cancer when the tumour is small and manageable with less radical treatment is possible with mammography, even before symptoms appear. Mammography screening is currently the most reliable breast cancer screening tool, offering high sensitivity (77 to 95%) and specificity (94 to 97%) in detecting breast abnormalities [2]. Other forms of breast cancer screening exams include ultrasound and MRI. However, mammography is the only approach that has been proven to reduce deaths by breast cancer by early detection in the population-based screening setting [3].

The number of lives saved by mammography screening is substantial. Mammography screening programs in Europe have shown a 25–30% breast cancer mortality reduction in women between 50 and 74 years [4]. In a prospective study of 7301 patients diagnosed with invasive breast cancer by Webb et al., it was found that seven in ten deaths from breast cancer occur in women who have never gone for mammography screening prior to diagnosis (65%) or those not regularly screened according to recommended intervals (6%) [5]. In another large study by Duffy et al. comprising over half a million women residing in Sweden, mammography screening was found to reduce rates of advanced and deadly breast cancers [5]. Women who screened were found to be 41% less likely to die from breast cancer within 10 years, compared to those who did not screen. A 25% reduction in the rate of advanced breast cancers was also observed among screeners compared to non-screeners. The impact of organized mammography screening in the reduction of fatal breast cancers is independent of advances in breast cancer treatment regimens [6].

When a participation rate of 70% within the target population receives mammography, a significant reduction in breast cancer mortality at the population level can be expected after 7–10 years [7]. According to the European guidelines, 70–75% of eligible women should attend the screening. Women of non-European ancestries are known to have lower mammography screening uptake return rates compared to Caucasians [8]. Despite the presence of highly subsidized nationwide mammography screening programmes established in the early 2000s in high-income Asian countries such as Korea, Japan, Taiwan, and Singapore, uptake of screening mammography remains low. The participation rate in Korea was the highest among the three countries with organized mammography screening at 59.7% in 2015 [9]. In 2016, only 44.9% of the target women in Japan had undergone mammography screening within the past 2 years [10]. In Taiwan, the biennial participation rate was slightly below 40% in 2014 [11]. In a similar period (2015–2016), less than 40% of the target population in Singapore attended timely mammography screening according to prevailing guidelines [12]. The low screening uptake and even lower adherence to regular screening is a major public health issue in Singapore [13].

In this large case-only analysis comprising 3739 breast cancer patients in Singapore, we examined the differential effect that mammography screening has on breast cancer characteristics and overall survival, the level of awareness of women on the national screening mammography programme, and the sociodemographic determinants of mammography screening utilization.

In this large study of 3739 breast cancer patients recruited in the Singapore Breast Cancer Cohort, mammography screening attendance was associated with more favourable breast cancer tumour characteristics at diagnosis. Significantly worse overall survival was observed for both non-screeners and patients who had not heard of mammography screening before their cancer diagnosis. For the former, the associations remained significant even after adjusting for patient characteristics, but the effect sizes were attenuated and associations were no longer significant after tumour and characteristics were included in the model. Notable deterrents for attending mammography screening were identified to be lack of perceived risk and fear of side effects and cancer diagnosis. Among the motivating factors for mammography screening, four main clusters of “screening personalities” emerged: (i) those who are motivated by both extrinsic cues and innate health consciousness, (ii) those who are motivated solely by appropriate cues to action, (iii) those who are motivated by innate health consciousness, and (iv) others. When breast cancers are presented later for treatment, they are more likely to be associated with advanced stage, poor prognosis, and higher treatment cost [19, 20]. Our observation that tumours detected among recent screeners (as a proxy for screen-detected cancers) have more favourable characteristics and confer better survival than tumours detected among non-recent screeners and those unaware of screening suggests that early detection by mammography surveillance does show the benefit of picking up less advanced and less deadly cancers.

In our study, we observed that compared to screeners, non-screeners and those unaware were significantly less likely to develop HER2-negative cancers and were significantly more likely to develop HER2-overexpressed breast cancers. No significant association was found between mammography behaviour and oestrogen or progesterone receptor status. Our finding that non-screeners are more likely to be HER2-overexpressed is consistent with existing literature. An Irish population-based study (n = 7161) found that compared to women with screen-detected cancer, non-participants of screening programme were more likely to develop HER2-overexpressing or triple-negative subtype, accompanied with poorer prognosis [21]. In our population, non-screeners and those unaware have significantly higher parity and were more likely to have a history of benign lump compared to screeners, both of which are factors linked to an increased risk of HER2-overexpressed subtype [22, 23].

Our study did not find a significant association between ER status and screening behaviour. In contrast, Niraula et al. studied 1687 breast cancer diagnoses in 69,025 women and found that breast cancers that were not screen-detected (interval breast cancers, non-programme-detected cancers, and noncompliant cancers) were significantly more likely to be ER-negative [24]. The discrepancy in our findings and what is reported in the literature may be due to other considerations, factors such as mammographic density and body mass index. These factors play important roles in determining the molecular subtypes and hormone receptor statuses of breast cancer [22]. However, we were unable to properly account for the effects of these factors due to the lack of information. Additionally, our definitions of subgroups are different from those in the various studies mentioned, which can contribute to the differences in results. Importantly, we did not have information as to whether or not the screeners had screen-detected cancer or diagnostic-detected cancer, which is one of the main criteria in differentiating the subgroups [24].

Screeners have been consistently shown to be associated with a survival benefit [5, 6]. In agreement, screeners in our study exhibited improved overall survival compared to their counterparts. It should be noted that the better overall survival experienced by screeners could be attributed to a number of reasons, such as better prognosis, sociodemographic and lifestyle factors, and treatment adherence. A study done by He et al. showed that non-participants of mammography were more likely to discontinue adjuvant hormone therapy and subsequently experience worse prognosis compared to screening participants [25]. In our study, we observed that even after adjusting for disease and treatment characteristics, screeners continued to show better overall survival, although the association was no longer significant. This implies that mammography behaviour as well as sociodemographic factors may play a bigger role in determining survival compared to disease and treatment characteristics in our study population. Due to the type of treatment information collected, we were unable to explore the relationship between mammography behaviour and treatment adherence in a more in-depth manner.

Despite widespread knowledge about mammography (94.4%), the proportion of women of the appropriate age group (50 to 69 years old) who get screened for breast cancer (38.7%) remains below the ideal participation rate to see a significant reduction in breast cancer mortality at the population level [7, 26]. Several studies have examined the reasons that contribute to the low response to mammography screening in Singapore using qualitative and quantitative approaches. Data from a prospective survey by Straughan and Seow highlighted fatalistic attitudes, perceived barriers, and perceived efficacy of early detection as significant predictors of free mammography screening uptake in the National Breast Screening Project [27]. The authors also noted the importance of social support from the family helped to improve screening behaviour. In a separate study by Straughan and Seow using a focus group approach to uncover barriers and motivators of mammography screening among Chinese women in Singapore, similar conclusions were drawn. Fatalistic attitudes, misinformation regarding the screening modality, and perceived costs (not limited to financial considerations, including burdens of time, effort, and psychological stress) were found to impede screening behaviour [28]. In contrast, confidence in medicine and the influence of informal social support networks to view mammography screening positively facilitated screening behaviour [28].

In addition, Straughan et al. conducted a survey-based study which was administered in-person to 300 attenders and 260 non-attenders to reveal factors contributing to the acceptance of mammographic screening among women in Singapore [29]. It was observed that being Chinese, employment outside the home, history of attending a screening for other conditions, perceived risk of developing cancer, and encouragement from family members are predictors of mammography screening attendance [29]. In yet another study using questionnaire data administered to 208 cancer-free Asian women in Singapore, Teo et al. reported lack of time and cost to be the leading deterrents for attending mammography screening [30]. The authors observed that “being Chinese, having higher education, mammography knowledge, positive motivator scores, and receiving reminders were predictors to regular mammography” [30]. Seetoh et al. reiterated the same factors (i.e. cost of screening, ethnicity, prior screening history, and attitudes towards mammography screening) to be predictors of mammography screening attendance in the results of a quasi-randomized pragmatic trial [31]. In other studies, misconceptions related to screening (pain and discomfort), cost, efficacy, and fatalistic beliefs were found to be recurring themes [32, 33]. The overlapping themes and predictors identified by the various studies and our results suggest that barriers to mammography screening have remained similar and have persisted over the years despite targeted efforts.

In a meta-analysis by Yabroff et al. which included 63 interventions in 43 studies based in the USA, it was reported that behavioural strategies (i.e. strategies that alter cues or stimuli associated with screening behaviour, such as reminders to screen via telephone or mail by healthcare professionals) increased screening by 13.2% compared with non-intervention [34]. In addition, the authors examined cognitive interventions (i.e. provide new information and education, increase existing knowledge, and clarify misperceptions) and sociological interventions (i.e. social norms or peers). The results showed that cognitive interventions using generic education strategies had little impact on screening, but those that used theory-based education (e.g. health belief model), especially when delivered interactively, increased rates by 23.6% when compared to the no intervention group. Sociological interventions were also found to increase screening rates by ~12.6%. Improvements in mammography utilization using these interventions will largely depend on the subgroups in different study populations. The distinct behavioural patterns (22.9% motivated by both innate health consciousness and extrinsic cues, 27.1% motivated solely by innate health consciousness, 24.3% motivated solely by extrinsic cues, and 25.6% motivated by a combination of other factors) among screeners who have had recent mammography support the use of a mixture of different approaches to improve rates of ongoing screening. Nonetheless, the success of targeted interventions among those who are either non-regular screeners or those who are unaware of mammography screening remains to be seen.

The main merit of this study is the large study cohort from multiple hospital sites in Singapore that see a majority of the breast cancer patients in the country. The availability of detailed sociodemographic, screening behaviour, clinical and survival data for the same study population is an added advantage that helps in giving a comprehensive overview of mammography screening behaviour and the associations with disease characteristics and survival. The organized population-based mammography screening programme in Singapore, which is heavily subsidized, reduces the likelihood of selection bias resulting from the accessibility and cost of screening. Additionally, the clinical data of breast cancer characteristics and outcomes were well kept and retrieved from well-maintained electronic databases, accounting for little missing data. Loss to follow-up due to emigration is expected to be minimal for the duration of the study.

Although the group of breast cancer patients classified as screeners had their most recent mammogram in the past 2 years, information was unavailable as to whether it was the first screen, and whether or not the tumour was screen-detected. While mammography screening behaviour can be correlated to tumour characteristics and survival by sampling breast cancer patients, self-selection bias may occur. Women who are at higher risk of developing breast cancer, such as those with a family history of the disease (breast cancer patients have a higher load of this familial risk), may actively choose to attend mammography screening [35]. However, we did not observe an excess of recent screeners in our study population compared to the national average. Additionally, sociodemographic information collected through the questionnaire was not optimized for this study. As a result, there might be over- or under-estimations of the role of various factors (education, income, and social support) on mammography behaviour. To establish a more direct relationship between these factors and mammography or health-seeking behaviour, a validated questionnaire should be used instead. Due to the nature of data collected, we did not have information on breast cancer-specific mortality and could only rely on data on all-cause mortality. However, in Singapore, around 76% of breast cancer patients die of breast cancer, making breast cancer the most common cause of death amongst breast cancer patients [36]. Hence, all-cause mortality remains as a good estimation for this study population. Moreover, there could be residual confounding and effect modification that could have been missed with our study design. As with all the other epidemiological studies, a causal relationship cannot be conclusively drawn because of various potential confounders. For example, the possibility that the lower cancer stage associated with better mammography behaviour (i.e. screeners) may be attributed to other factors, such as their lifestyle (diet, physical activity levels), cannot be excluded. To establish a causal effect of mammography behaviour on breast cancer, large randomized trials should be planned.

Furthermore, being a case-only retrospective study, recall bias and selection bias cannot be eliminated. We were also unable to fully evaluate the effectiveness of attending mammography screening. However, we were able to derive other plausible benefits of screening, such as that of being diagnosed at earlier stages of disease. As this study involves the evaluation of screening effectiveness, common screening programme-related biases such as lead-time, length-time, and immortal time bias must be considered when interpreting the results [37]. To address these biases, several analytical approaches were taken. Firstly, we explored the association between mammography behaviour and survival amongst incident cases only. The slight differences in the results observed from the different subsets suggest that survivor bias cannot be eliminated, and should be considered during the interpretation of the results. Secondly, disease characteristics, such as stage at diagnosis, were adjusted for in the survival analyses. However, the results from these additional analyses were not appreciably different.

In summary, our results show that mammography screening is associated with both better breast cancer tumour features and survival and that the survival benefit is largely a result of the better tumour characteristics. However, the nationwide screening mammography service is currently underutilized and various studies, including ours, looking into mammography screening behaviour have highlighted largely similar concerns and barriers to entry. A shift in focus to how to tailor interventions to meet individual healthcare needs is needed to increase the number of breast cancers detected early and achieve positive health outcomes.