A breast cancer screening programme incorporating polygenic risk scores could be implemented in Singapore to improve the current age-based mammogram screening programme. The cost effectiveness of genetic risk tailored screening policies have been studied in the United Kingdom [17], Canada [34], and the United States [35]. However, little is known of the cost effectiveness of such policies in Asia. Hence, we developed a cost effectiveness model to examine the feasibility of a genetic risk, tailored screening approach in Singapore, where individuals are advised on a screening strategy based on their predicted risk.
The cost effectiveness model estimated approximately 25.5 cases of breast cancer per 1,000 women, over the 35–74 years old time horizon in the tailored screening arm. In the mammogram only screening arm, the model estimated 31.2 cases per 1,000 women. Based on 2018 statistics from Globocan, women in Singapore have a cumulative risk of 6.39% of developing breast cancer, which equates to 60.9 cases per 1,000 women. While this shows that the model may underestimate the number of breast cancer cases, it has to be noted that the model considers women aged 35–74, a subset of all women in Singapore.
Results from the cost effectiveness analysis suggest that a polygenic risk-based tailored screening approach may offer improvements in detecting breast cancer cases promptly over the current age-based mammogram only screening programme in Singapore. An ICER of − 3,713.80 SGD/QALY not only makes polygenic risk-based tailored screening more cost effective than the current mammogram screening programme, but the incremental cost of -SGD3,709 shows that tailored screening may be cheaper. This is supported by a number of Western studies that indicate that a polygenic risk-stratification component may improve cost effectiveness of a breast cancer screening programme [17, 34, 35]. In terms of ending age, we opted for the age of 74 based on American recommendations, over mirroring the current strategy’s ending age of 69, which in comparison would give an ICER of -3,717.72 SGD/QALY.
The observed small difference in QALYs of 0.9853 suggests that tailored screening does not differ considerably from mammogram only screening in terms of QALYs gained, with almost one QALY gained per individual. This implies that tailored screening does not result in a significant stage shift in terms of stage distribution of breast cancer cases. We believe that this is a positive finding, as it ensures that there will be no harm inflicted onto individuals in transitioning from mammogram only screening to polygenic risk tailored screening. These findings indicate that there is no significant difference in cancer survival, as quality of life is tied to cancer staging and survival time. It was also observed that the probability of death over lifetime per individual also does not differ significantly between the two arms, 13.0% in the tailored screening arm and 13.4% in the mammogram screening arm. This further demonstrates that there are no adverse outcomes to the patient when switching to the tailored screening programme.
We compared outcomes using different percentile cutoffs for the low, intermediate, and high risk groups to examine their influence on model outcomes. We examined cutoffs that range from 5th to 10th percentile for the high risk group, and 40th to 60th percentile for the low risk group, assigning any remainder into the intermediate risk group. Among the three additional scenarios (60L-30I-10H, 40L-55I-5H, 40L-50I-10H, with base case 60L-35I-5H), all had an ICER value in the south east quadrant of the cost effectiveness plane, indicating lower costs and higher QALYs. Notably, the 40L-55I-10H scenario has an ICER of -74.00 SGD/QALY. Results from PSA on this scenario indicate approximately 57% probability that tailored screening dominates mammogram only screening when WTP is 1 SGD/QALY. This is due to a shift in screening frequencies, with more screening done in the high risk groups due to the higher proportions, resulting in higher costs, which drives the ICER up. Nonetheless, at the approximate maximum WTP of 1,820 SGD/QALY, tailored screening is 100% cost effective.
Both one-way and probabilistic sensitivity analysis were carried out to assess parameter uncertainty. The results of the one-way sensitivity analysis indicate that risk multipliers for low and high risk groups, breast cancer stage II costs and mammography sensitivity had substantially higher impact on the ICER compared to the other parameters. These findings for the risk multipliers are to be expected, as they are the main drivers for influencing proportions of cases in each risk group. Mammography sensitivity was a limitation on this study, as scarcity and age of the data may impact the final results. The Singapore MOH Clinical Practice Guidelines 2010 estimated the sensitivity of mammography to range from “68% to over 90%” [31]. As such, we set our mammography sensitivity parameter to a base case value of 80%, while studying the possible effects of mammogram sensitivity in which we varied from 64–96% in the one-way sensitivity analysis. The effects of breast cancer stage II costs may be due to the breast cancer stage specific proportions of 43% in a screened group and 57% in an unscreened group. This means that in our model, an individual is most likely to be diagnosed with stage II breast cancer compared to other stages. Hence, stage II cancer cost featured more prominently.
This study used model-based estimates based on assumptions. The model assumes 100% attendance and compliance to breast cancer screening and follow ups. This would not be representative of real-world situations. A 2010 national health survey showed that only 39.6% of women aged 50–69 years old have attended screening in the previous two years [38]. In comparison, screening attendance according to national guidelines was 61.1% in South Korea in 2010 [39]. In the United Kingdom, 73.4% of women aged 45 to 74 years old have attended a mammogram screen from 2010–2011 [40]. At lower attendance rates, there is expected to be higher rates of clinically detected breast cancer cases compared screen detected cases. Consequently, there will be a stage shift to later, symptomatic breast cancer stages, resulting in lower quality of life and higher mortality. To improve screening attendance, the Singapore Government extended the use of the national health savings scheme, Medisave, as well as subsidies to pay for screening procedures since July 2011. A 2017 focus group study examining Singaporean women’s views towards breast cancer screening concluded that there were numerous barriers to consistent mammogram attendance, such as laziness and pain [30, 31]. Interestingly, Singaporean women were found to be generally receptive to SNP testing, citing only a need for additional information, such as test accuracy and cost, before getting tested, which may indicate the public’s favour for a screening programme incorporating genetic testing. Further studies and pilot testing will be carried out to validate the findings from the study.
Another limitation of this cost effectiveness study is that the natural history of breast cancer is not fully modeled. Progression between stages of breast cancer is not modeled due to the lack of local data on transition probabilities between stages, alongside ethical issues in collecting such data. While this may be problematic, it is consistent between both arms and any significant effect may be minimized. Treatment, remission and follow ups after diagnosis are also not modeled. This means that individuals diagnosed with breast cancer simply remain in the diseased state until the age of 75 or eventually progress to the death state. Due to a lack of Singaporean data on ductal carcinoma in situ (DCIS), a non-invasive form of breast cancer, DCIS was not also modeled. Nonetheless, for a cost effectiveness study examining the incorporation of genetic testing and risk stratification to an age-based mammography screening programme, these limitations may not have too adverse an impact on the final model outcomes.