University of Groningen Breast cancer screening in women at elevated risk Phí, Xuân Anh

University of Groningen

Breast cancer screening in women at elevated risk

Phí, Xuân Anh

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Should women with a BRCA1/2 mutation aged 60

and over be offered intensive breast

cancer screening? – A cost-effectiveness analysis

ABSTRACT

Introdu on: This study aimed to inves gate the cost-effec veness of intensified breast

cancer (BC) screening for women with a BRCA1/2 muta on aged 60-74. Simulated strategies were: (0) annual mammography as reference, (1) alterna ng annual mammography and MRI for women with dense breasts only; (2) addi on of annual MRI for women with dense breasts only; (3) addi on of annual MRI for all women.

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Methods: A validated micro-simula on model of invasive BC was updated and validated for

interval BC rates and tumor size distribu on. Incremental cost-effec veness ra os (ICER) of all three intensified strategies were compared to the next best strategy and stra fied for BRCA1 and BRCA2. Discount rates for costs and life years gained (LYG) were 1.5% and 4% for the Dutch situa on; 3% and 3% for interna onal comparison. A threshold of €20,000 per LYG was applied.

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Results: All intensified strategies showed more detected BCs and LYG, reduced BC deaths, and

increased false posi ves. The Dutch discounted ICER of intensified strategy 1 compared to annual mammography was €38,000 per LYG in women with a BRCA1 muta on and €18,000 per LYG in women with a BRCA2 muta on. Further intensified strategies showed an ICER above the threshold when compared to this strategy. With interna onal discount rate, the ICERs of all intensified strategies were above the threshold.

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Conclusion: Of the three alterna ve strategies, only alterna ng annual MRI and

mammography for women with a BRCA2 muta on and dense breasts aged 60-75 is cost-effec ve compared to annual mammography. For women with BRCA1 muta ons, none of the alterna ve strategies is cost-effec ve compared to the next best strategy.

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Key words: Breast neoplasm, screening, BRCA1, BRCA2, cost-benefit analysis

Introdu on

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Women with a BRCA1 or BRCA2 muta on are at rela vely high risk of developing breast cancer (BC) with a cumula ve risk by the age of 70 ranging from 55 to 66% for BRCA1 carriers and 55 to 64% for BRCA2 carriers (1-3). In muta on carriers, of all ages, tumors grow faster than those in women from the general popula on at the same age (4,5). These women are recommended to have an intensified screening program, usually with annual MRI and mammography, outside of the general popula on screening program. However, guidelines for screening BRCA muta on carriers with annual MRI and mammography vary between countries with respect to the age of con nued screening using both modali es. Adding MRI to mammography screening is recommended un l age 50-60 but in some se ngs the same approach is recommended for older women or without an upper age limit (6-8).

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Intensive screening with MRI in BRCA1 or a BRCA2 muta on carriers aged 60 and above is an on-going and relevant issue for several reasons. The risk of developing BCs in women with a BRCA1/2 muta on con nues to increase a er the age of 60 (1,2,9). A substan al propor on of women with a BRCA1/2 muta on remains at risk of developing BC from the age of 60 even a er risk-reducing strategies (10). Annual mammography may not be sufficiently accurate for women with a gene muta on aged 50 and older, hence MRI should be considered for screening these women (11). No guidelines for the upper age limit for screening with MRI could be iden fied in a recent meta-analysis (11). In prospec ve screening trials, BRCA muta on carriers above age 60 represented rela vely small numbers which makes it difficult to assess the effec veness of screening in this age-group (11). In the absence of data from clinical trials, a model study is an alterna ve and appropriate approach to evaluate the benefits and costs of screening this age-group in the long term and in an economic point of view.

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Using a validated breast cancer micro-simula on model, we aimed to inves gate the cost-effec veness of screening strategies that add MRI to mammography in women with a BRCA1/2 muta on aged 60-74. We es mated the addi onal benefits, harms, and costs and hence cost-effec veness of adding MRI to mammography in this older popula on of BRCA muta on carriers.

Methods

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This study is reported according to the Consolidated Health Economic Evalua on Repor ng Standards (CHEERS) checklist (12). A validated micro-simula on model (13,14) was applied to

to simulate asymptoma c women with BRCA1 or BRCA2 muta ons throughout their life-me. Intensified screening strategies adding MRI were simulated and compared to the next most effec ve strategy. Directs costs were derived from the perspec ve of the payer including costs of screening for the total simulated popula on, costs of diagnosis in case of posi ve test, and costs of treatment and hospital stay. Both Dutch and interna onal discount rates were applied. The Dutch discount rates were 1.5% and 4% for costs and LYG while the interna onal discount rates were 3% and 3% respec vely (15).

Descrip on of the SIMRISC model and its components 1

Women entered the model at the age of 20 and were followed ll the end of their life. Annual screening with MRI was simulated from age 25 along with annual mammography from age 30. Women le the model when they died or developed primary BC. The model only simulated primary invasive cancer (not ductal carcinoma in situ) and did not simulate preven ve BC surgery. The women were randomly assigned a breast density with a distribu on according to age as given in table 1 (16-19) , with a decreasing breast density over life. For all women it was determined, based on incidence data, whether they would develop BC or not (1,13,20) , what the age of BC diagnosis would be, and what the age of death by all causes would be [h p://statline.cbs.nl]. Women could develop BC or die before the start of screening, or during or a er the screening period. Tumor growth was determined based on age (4,21). During screening, BCs could be screen-detected depending on the modality sensi vity (22-29) or self-detected depending on tumors size (30) . The probability of false posi ve findings was determined by the modality specificity (28,29) . The probability of BC survival was dependent on tumor size based on the work of Michaelson et al (31). More details about the model and its components are described in Supplementary material. Descrip on of the model.

Screening strategies:

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We simulated the reference strategy of annual MRI age 25-60 and subsequent annual mammography age 30-74 as the Dutch guideline (h ps://www.oncoline.nl/), and three intensified screening strategies for women with a BRCA1/2 muta on age 60 onwards (Supplementary Table 1). Strategy 1 consisted of annual mammography for women with non-dense breasts and alterna ng annual MRI and mammography for women with non-dense breasts only; strategy 2 consisted of annual mammography and annual MRI for women with dense breasts only; and strategy 3 consisted of annual mammography plus MRI for all women.

Expected benefits and harms of intensified screening

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For each BRCA status, 100,000 women were simulated 10 mes and means and standard devia on (SD) were es mated. The benefits of intensified screening with MRI were calculated as a rela ve change in comparison with the next best strategy in terms of effec veness: number of detected BCs, number of interval BCs, number of small tumors (<10mm), and number of deaths due to BCs. The harms of intensified screening were the rela ve difference with respect to the reference values in number of false-posi ve (FP) tests, and number of screens.

Cost effec veness analysis 1

Directs costs of screening, diagnosis and treatment of BCs were considered (table 1). All analyses were performed in Euro (€) at the 2017 price-level (h p://statline.cbs.nl). The discounted incremental cost-effec veness ra o (ICER) represen ng the addi onal cost for one life-year gained (LYG), was es mated as compared to the next most effec ve strategy. If the incremental cost per LYG was ≤ €20,000 the screening strategy was considered cost-effec ve [19].

External valida on of the model

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The model was previously validated for BC screening of women with a BRCA1/2 muta on and women from the general popula on (13,14). Because some of the parameters (risk of developing BC, tumor growth and sensi vity/specificity of MRI) were updated, we performed another external valida on on two independent databases regarding the number of interval cancers and the tumor size distribu on. The first database included women with a BRCA1/2 muta on that underwent biennial and annual mammography from age 60 to 81 (10) and the second database included women with a BRCA1/2 muta on that underwent annual MRI plus mammography from age 25 to 80 (11) . Only BCs in subsequent screening rounds and that were larger than 5 mm were considered.

Sensi vity analyses:

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A univariate sensi vity analysis was performed using as minimum and maximum values the lower and upper limit of the 95% confidence intervals for selected input parameters. The impact of the parameters' uncertainty on the ICERs was plo ed in Tornado graphs.

Results

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Valida on of the model

1

Considering women who underwent annual mammography plus MRI from age 60 onwards, the model showed a tumor size distribu on close to the observed data (Figure 1a). The propor on of interval cancers es mated by the model was slightly higher than that observed for women with BRCA1 muta ons and comparable for women with a BRCA2 muta on (Figure 1a). Regarding women who underwent biennial or annual mammography from age 60, the model showed a comparable propor on of interval cancers, whereas a higher propor on of small size tumors was es mated (Figure 1b, c).

Figure 1: Comparison of the propor on of interval cancers and the tumour size distribu on between the model (grey) and independent data (black) for BRCA1 (le ) and BRCA2 (right)

Benefits and harms of applying intensified strategies

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All three intensified strategies showed an increase in the number of screen-detected BCs and the number of small tumors, while the number of interval cancers and BC deaths both in BRCA1 and BRCA2 muta on carriers decreased. The changes in the number of screen-detected BCs, small tumors and BC deaths were similar for women with a BRCA1 and women with a BRCA2 muta on. For interval cancers, intensified screening in women with a BRCA2 muta on yielded a larger change compared to that in women with a BRCA1 muta on. For both women with a BRCA1 or BRCA2 muta on, intensified strategies increased the number of false-posi ves and the number of MRI screens (table 2).

Incremental cost effec veness ra o

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For women with a BRCA1 muta on, the more intensive the screening, the higher the ICER: all ICERs were above the threshold of €20,000 per LYG whether applying Dutch or interna onal discount rates (table 2).

For women with a BRCA2 muta on intensified strategy 1 had an ICER of €18,500 per LYG when Dutch discoun ng was applied. All other intensified strategies had ICERs above the threshold of €20,000 per LYG compared to the next most effec ve strategy. When applying interna onal discount rates, the ICER of all intensified strategies remained above €20,000 per LYG (table 2). Sensi vity analysis

1

The ICERs of all intensified strategies were most sensi ve to the uncertainty in self-detec on size, tumor doubling me age >50 and cumula ve life- me risk (Supplementary Figure 1, Supplementary Figure 2). The uncertainty in sensi vity/specificity of MRI, specificity of mammography, and sensi vity of mammography in BI-RADS1, 2 and 4 only had a minor impact on ICERs.

Discussion

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We report the results of a cost-effec veness study comparing intensive screening strategies screening in older BRCA1/2 muta on carriers. Using a micro-simula on model, validated in terms of interval cancers and tumor size distribu on in this work, we es mated that intensified breast cancer screening a er age 60 in women with BRCA1/2 muta ons increased the number of screen-detected BCs, the number of small tumors, and the number of

life-Table 2. Eff ecv eness and cos t-e ff ecv eness of in tensified str at egies as compar ed to the ne xt bes t s tr at egy per 100,000 w omen

NA: not applicable; In brackets: absolute dif

ference

the number of screen-detected BCs, the number of small tumors, and the number of life-years gained, and decreased the number of BC deaths. However, these gains were at a trade-off of increased financial costs and substan ally more false-posi ves and MRI screens. Compared to screening women with a BRCA1 muta on, intensified screening in BRCA2 muta on carriers over age 60 yielded more LYG and had less costs. Compared to annual mammography, using a threshold of €20,000 per LYG and Dutch discount rates, intensified strategy 1 was cost effec ve in BRCA2 women but not in BRCA1 women. Intensified strategy 2 and 3 were not cost-effec ve for either group of BRCA1/2 women.

Breast cancer screening in women with a BRCA1/2 muta on has been implemented in several countries. The age at which MRI screening is recommended to end differs across guidelines, usually within the age range of 50-60 (6-8) with the argument that mammography sensi vity improves with age and MRI is rela vely more expensive. In contrast, prospec ve studies inves ga ng the effec veness of screening with annual MRI as an adjunct to mammography support screening with annual MRI both in women younger and older than 50, from the perspec ve of enhanced cancer detec on (11). In general, screening women with a BRCA1/2 muta on with annual MRI plus mammography compared to annual mammography alone is considered to be cost-effec veness (32-34). However, studies have focused on screening of women below the age of 60 or throughout the whole screening period, and there is no compara ve data for women older than 60 (32-34). Our study addresses this evidence gap by specifically comparing different screening strategies in women with a BRCA1/2 muta on aged 60-74 year in the Dutch context and considered breast density as a determinant for different screening modali es.

The results of our simula on showed that screening women with a BRCA2 muta on age 60-74 was more beneficial and less costly than screening the same-age women with a BRCA1 muta on. This can be explained by the input parameters including rela vely higher cumula ve life- me risk and slower tumor growth rate in BRCA2 women. Due to the slower growth rate, BRCA2-associated BCs are more likely to be detected by screening and there were fewer interval cancers. This emphasizes the need for different screening strategies based on BRCA muta on type.

Although the SIMRISC model has been applied in previous works and is well validated (13,14), updated values for some of the input parameter (life- me risk, tumor doubling me and accuracy of MRI) were applied. Firstly, the life- me risk to develop BCs in women with a BRCA1/2 muta on was updated (1). The life- me risk we applied is lower than es mates

from a recent prospec ve cohort (3). The main explana on for this higher es mate is the case selec on in the prospec ve study, as in this study only incidence cases were included (3). As these proven carriers are usually from a family with higher risk and have more follow-up than unaffected rela ves, which is probably associated with higher risk es mates, we s ck to es mates based on a Kaplan Meier method including index cases and propor on of untested first degree rela ves which was shown to be the most consistent method for carriers counselled in the clinic (1). In addi on, sensi vity analysis showed that the uncertainty in

life-me risk did not have a large impact on ICERs. Secondly, the tumor doubling life-me used in our model was based on a rela vely small number of tumors in mostly BRCA1 carriers together with results from a simula on study (4,21). There is li le data on the tumor doubling me of BRCA1/2 associated BCs. Although sensi vity analysis showed that the model is sensi ve to the uncertainty in the tumor doubling me, all ICERs remained not cost-effec ve and well above the threshold of €20,000. Further, the accuracy data of MRI was obtained from literature which may underes mate the accuracy of MRI in current prac ce. However, the uncertainty in MRI sensi vity or specificity did not significantly alter es mated ICERs (Supplementary Figure 1 and Supplementary Figure 2).

This study has some limita ons. Firstly, we modelled invasive BCs and not ductal carcinoma in-situ (DCIS), which may have underes mated the benefits of screening. DCIS accounts for about 20% of the BCs diagnosed in BRCA1/2 carriers [35]. However, because knowledge about the progression of DCIS to invasive is not conclusive, we only modelled growth of invasive cancers. Secondly, the sensi vity of mammography was determined by the woman's breast density, and not as a func on of tumor size. Thus, the chance of detec ng a small or large size tumor was equal given a certain breast density, which might possibly overes mate the benefits of screening, although valida on of the model was reasonably good. Thirdly, although we incorporated radia on induc on risk in the model, the lag- me ( me interval between exposure and the development of BC) was not specifically modelled. When applying lag- me, induced tumors will develop at older age (15-20 years a er exposure), which will increase the ICER. This effect will be small and does not change the outcomes of our study since the impact of tumor induc on on the ICER was only minor according to the sensi vity analysis. Finally, we evaluated intensified screening in women age 60-74 but modelled the same screening program during age 25-60 years for both BRCA1 and BRCA2 muta on carriers. If different screening strategies were applied by BRCA status during age 25-60, the popula on entering screening a er age 60 will be different for each BRCA status. However for each BRCA status, the popula on entering intensified screening will be the same for all the

intensified strategies. The model results are not expected to be altered since we only consider differences from age 60 onwards.

Using this validated model, alterna ng MRI and mammography annually for women with a BRCA2 muta on and dense breasts age 60-75 was cost-effec ve compared to annual mammography but it was not cost-effec ve for women with a BRCA1 muta on. Adding MRI to annual mammography in women with BRCA1/2 muta ons, whether restricted to women with dense breasts or for all women, was not cost-effec ve. Screening guidelines should consider different recommenda ons for older women with BRCA1 and BRCA2 muta ons. Our study indicates that women with a BRCA2 muta on age 60-74 should be offered annual mammography if they have non-dense breasts, and alterna ng MRI and mammography annually if they have dense breasts. Women with a BRCA1 muta on aged 60-74 should con nue to be screened with annual mammography.

Funding: This work did not receive any external funding. N. Houssami receives research support

through a Na onal Breast Cancer Founda on (NBCF, Australia) Breast Cancer Research Leadership Fellowship.

Supplementary materials Descrip on of the model

The tumor doubling me and tumor size at self-detec on was assigned randomly from a log-normal distribu on with a mean and standard devia on as shown in the table 1 in the main text. In this way the age of onset of the tumor was assigned for every woman who would develop BC.

Between the age of onset of the tumor and age at self-detec on of the tumor, the BC could be screen-detected by mammography or MRI based on the sensi vity of these modali es which were derived from a systema c literature search (22-29). A systema c error of 10% was used for mammography (14), which accounted for 10% of the tumors which could not be detected by mammography due to their characteris cs (lobular carcinomas, and loca on near thorax wall). The model simulated mammography screening first and only when the is no BC detected, MRI was performed. When there was posi ve test (both true posi ve and false posi ve), diagnos c test (biopsy under ultrasound guidance) was performed.

If a developing BC was not screen-detected, it could become clinically manifest between two screening years, and was considered an interval cancer. Based on the length of the preclinical phase, the tumor doubling me and me of detec on or clinical manifesta on, the tumor size at diagnosis was calculated.

The probability of BC survival was dependent on tumor size based on the work of Michaelson et al (31) . In the SIMRISC model, the BC survival rate func on was a func on of tumor size and the number of years a er diagnosis. The probability of breast cancer survival F(D,T) was dependent on tumor size D and me a er diagnosis T

The constants a to d were es mated by fi ng the equa ons to the observed data (20). The values of the constants (the uncertain es) are:

Supplementary Figure 1. Univariate sensi vity analyses in women with a BRCA1 muta on

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Digital Breast Tomosynthesis -

a potential modality for

breast cancer screening