|Home | About | Journals | Submit | Contact Us | Français|
Current clinical guidelines recommend earlier, more intensive breast cancer screening with both MRI and mammography for women with BRCA mutations. Unspecified details of screening schedules are a challenge for implementing guidelines.
A Markov Monte Carlo computer model simulated screening in asymptomatic female BRCA1 and BRCA2 mutation carriers. Three dual-modality strategies were compared with digital mammography (DM) alone: 1) DM and MRI alternating at 6-month intervals beginning at age 25 [Alt25], 2) annual MRI beginning at age 25 with alternating DM added at age 30 [MRI25/Alt30], and 3) DM and MRI alternating at 6-month intervals beginning at age 30 [Alt30]. Primary outcomes were quality-adjusted life years (QALYs), lifetime costs (in 2010 USD), and incremental cost-effectiveness ($/QALY gained). Additional outcomes included potential harms of screening, and lifetime costs stratified into component categories (screening and diagnosis, treatment, mortality, and patient time costs).
All three dual-modality screening strategies increased QALYs and costs. Alt30 screening had the lowest incremental costs per additional QALY gained: (BRCA1: $74,200/QALY; BRCA2: $215,700/QALY). False-positive test results increased substantially with dual-modality screening, occurring more frequently in BRCA2 carriers. Downstream savings in both breast cancer treatment and mortality costs were outweighed by increases in up-front screening and diagnosis costs. Results were most influenced by estimates of breast cancer risk and MRI cost.
Alternating MRI and DM screening at 6-month intervals beginning at age 30 is a clinically effective approach to applying current guidelines, and is more cost-effective in BRCA1 compared with BRCA2 gene mutation carriers.
Women with BRCA1 or BRCA2 gene mutations are at increased risk of developing breast cancer, with approximately 45–65% diagnosed with breast cancer by age 701. Multiple guidelines for this high-risk population recommend earlier breast cancer screening with both mammography and magnetic resonance imaging (MRI). However, there is variability across recommendations and in their clinical application. The National Cancer Comprehensive Network recommends screening beginning at age 252, while the American College of Radiology recommends starting at age 303. The American Cancer Society does not specify an age, recommending that “the decision regarding when to initiate screening should be based on shared decision making, taking into consideration individual circumstances and preferences”4.
Current guidelines also do not specify how to combine mammography and MRI. Published trials of MRI and mammography screening in women at increased breast cancer risk have utilized both tests within 90 days of each other and usually on the same day5. More recent studies indicate that MRI can detect cancers not identified on mammography six months earlier6, and suggest that alternating MRI and mammography every six months may provide greater life expectancy gains than contemporaneous dual-modality screening7.
Diagnostic imaging utilization, including MRI, has increased substantially over time8,9, and imaging cost increases have outpaced the rate of total cost increases in Medicare beneficiaries9. Concern over rising healthcare costs has prompted an increased focus on providing high-value, cost-conscious care10,11. This approach involves assessing both benefits and harms of diagnostic testing, to determine whether patient outcomes have been improved, and examining costs of care, including costs and savings of downstream testing, treatment, and follow-up.
We have developed a computer simulation model to project long-term health outcomes and costs of screening women with BRCA gene mutations7,12,13. Our results from a previous comparative effectiveness analysis suggest that screening with MRI and digital mammography (DM) at alternating six-month intervals provided additional survival benefit beyond contemporaneous dual-modality regimens7. Of 26 strategies evaluated, the three screening strategies with the greatest breast cancer mortality reduction were: digital mammography (DM) and MRI at alternating 6-month intervals starting at age 25, annual MRI at age 25 with alternating DM added at age 30, and alternating DM and MRI starting at age 30. In this study, we extended the model to evaluate the cost-effectiveness of these breast cancer screening strategies which alternate MRI with DM at six month intervals.
No human subject data from individual patients were used for this study; therefore, Institutional Review Board approval was not required.
The Markov Monte Carlo simulation model was programmed in C++ and included breast cancer development, detection, and treatment in asymptomatic 25-year-old BRCA1/2 mutation carriers. Model input parameters were obtained through critical review of published literature and model calibration, with most parameter values reported previously7,12,13. The cumulative incidence of breast cancer to age 701 in the absence of screening was calibrated14 separately for BRCA1 and BRCA2 mutation carriers, with best fitting natural history parameters previously reported7,13. In the base case analysis, we assumed that women had not undergone prophylactic salpingo-oophorectomy, mastectomy, or chemoprevention. For each screening scenario, two million individual women were tracked until death, with their outcomes aggregated to provide cohort estimates of projected outcomes.
We examined three dual-modality screening strategies which are consistent with current guidelines2–4 (Figure 1): 1) DM and MRI alternating at six-month intervals beginning at age 25 (Alt25), 2) annual MRI at age 25 with alternating DM added at six-month intervals beginning at age 30 (MRI25/Alt30), and 3) DM and MRI alternating at six-month intervals beginning at age 30 (Alt30). Additional comparator strategies were evaluated for calculation of incremental cost-effectiveness: annual DM beginning at age 25 (DM25), annual DM beginning at age 30 (DM30), and clinical surveillance without imaging.
BRCA1 and BRCA2 cohorts were evaluated separately. Key input parameters for breast cancer detection and diagnosis are presented in Table 1. We assumed that all asymptomatic women underwent screening with perfect adherence. At screening, women received either positive or negative results based on the sensitivity and specificity of either DM7,15,16 or MRI17. Women with positive screening results underwent further diagnostic workup. Women whose diagnostic workup results were suspicious for breast cancer subsequently underwent biopsy to establish a final diagnosis of malignant or benign disease. If the biopsy results were benign, the woman was tracked as having had both a false-positive screening test and a false-positive biopsy recommendation. Women with negative screening results underwent no further intervention until the next screening event. If a cancer was missed on a screening test, cancer progression continued until the next screening event or until the cancer presented clinically as an interval cancer.
In women who were diagnosed with breast cancer, primary tumor diameter at diagnosis and method of detection determined the probability of lymph node involvement and distant metastases18. Once breast cancer was staged and treated, annual mortality from breast cancer was based on a woman’s age at diagnosis, stage of disease, and tumor estrogen-receptor status19. Competing mortality risks were obtained from United States life tables20, and adjusted to reflect the increased mortality rate from ovarian cancer in BRCA mutation carriers21.
We accounted for mammography-induced breast cancer risks using an excess relative risk model which depends on a woman’s age-at-exposure, where the risk of radiation-induced cancer is proportional to the population’s underlying breast cancer risk7,22.
Costs of screening and diagnosis were obtained from the 2010 Medicare Physician Fee Schedule23. Direct medical treatment costs and patient time costs were obtained from the published literature and adjusted to 2010 US dollars using the medical care component of the Consumer Price Index24 (Table 2).
Primary outcomes were lifetime costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ($/QALY gained). QALYs projected included 25 years of full health accrued at model entry. Both costs and QALYs were discounted at 3% annually.
Additional outcomes included total undiscounted life expectancy without quality adjustment (LE), breast cancer mortality risk reduction, and potential harms of screening (false-positive screening results, false-positive biopsies, and radiation-induced breast cancer). Component cost analysis was performed by separating lifetime costs into categories related to the direct medical costs of screening and diagnosis, patient time costs for screening and diagnosis, breast cancer treatment (including patient time costs for treatment), breast cancer mortality, and other costs (including direct medical costs unrelated to breast cancer, and non-breast cancer mortality costs).
We used standard cost-effectiveness analytic methods25. Incremental cost-effectiveness ratios (ICERs) for a strategy compared with the next most effective strategy were calculated by dividing the difference in costs by the difference in effectiveness to obtain the cost required to gain an additional QALY.
We evaluated the effect of uncertainty on model results with multiple sensitivity analyses (Tables 1 and and2).2). To characterize the random variability in individual outcomes, we analyzed the model as a Markov Monte Carlo simulation. We then performed univariate sensitivity analyses to examine the effect of additional uncertainty regarding input parameter values on model results. Two-way sensitivity analyses of diagnostic test performance were performed using additional published reports of test performance for both mammography16 and MRI26–29. Multi-parameter sensitivity analyses were performed for alternate sets of good-fitting natural history input parameters identified during model calibration14. Prophylactic oophorectomy at ages 35, 40, and 45 was also examined, with subsequent breast cancer risk reduced by half30,31. In addition, short-term quality of life decreases related to false-positive screening results were included13,32 (base case: no short-term disutilities from screening), and patient time costs were examined by varying the time lost from work between 50%–200% of base case values33,34.
Lifetime costs, QALYs, and ICERs are shown in Table 3. For women with BRCA1 mutations, adding alternating MRI to annual DM beginning at age 30 (Alt30) increased QALYs and costs, with an ICER of $74,200/QALY gained. The MRI25/Alt30 and Alt25 strategies had minimal additional QALY gains and increased lifetime costs, with substantially higher ICERs.
For women with BRCA2 mutations, Alt30 screening had a considerably higher ICER compared with DM30 ($215,700/QALY gained), and was also the least costly dual-modality screening strategy evaluated. MRI25/Alt30 screening provided minimal additional QALYs and increased lifetime costs. Alt25 was eliminated as a screening strategy because it provided no additional QALYs and increased lifetime costs, relative to MRI25/DM30.
Because Alt30 screening was the least costly approach for implementing dual-modality screening guidelines in both BRCA1 and BRCA2 mutation carriers, we focused on this strategy for subsequent analyses on additional outcomes, component costs, and sensitivity analysis.
Alt30 screening reduced breast cancer mortality compared with DM alone (Table 4). False-positive screening results and false-positive biopsies increased substantially with Alt30 screening compared to DM30 alone, and occurred more frequently in BRCA2 carriers. Radiation-induced breast cancers represented <2% of all diagnosed breast cancers and remained stable when MRI screening was added, since MRI does not use ionizing radiation.
Lifetime and component costs increased with dual-modality breast cancer screening (Table 5). The increase in total lifetime costs associated with Alt30 screening was driven primarily by increased screening and diagnosis costs. While breast cancer treatment and mortality costs decreased in the setting of dual-modality screening, these downstream cost savings only partially offset the increased costs of earlier and more intensive screening. Patient time costs for screening and diagnosis more than doubled when alternating MRI was added to DM30 screening.
Univariate and multi-parameter sensitivity analyses indicated that in BRCA1 mutation carriers (Figure 2A), the most influential parameters for the ICER of Alt30 screening compared with DM30 screening were related to breast cancer risk and MRI cost. As breast cancer risk decreased, either from decreased cumulative probability of breast cancer or from prophylactic oophorectomy, dual-modality screening became less cost-effective(increasing ICER). Varying MRI cost from 50–200% of the base case value of $619 caused the ICER to range from approximately $44,000–$134,000/QALY gained. When examining additional reports of MRI test performance, dual-modality screening became more cost-effective if MRI performance at the highest published values27–29 could be achieved, with ICERs <$50,000/QALY gained.
For BRCA2 mutation carriers (Figure 2B), the ICER for Alt30 screening compared with DM30 screening was similarly influenced by breast cancer risk and MRI cost, with the ICER increasing substantially with decreasing breast cancer risk. Including short-term quality of life decreases related to false-positive screening results further decreased the cost-effectiveness of Alt30 screening, likely related to the substantially higher frequency of false-positive results in these women.
This analysis evaluated the health outcomes and associated costs of three dual-modality screening strategies in women with BRCA gene mutations. Because a prior comparative effectiveness study7 indicated that dual-modality screening at alternating six-month intervals would be more effective than combined screening on the same day, this analysis focused on the cost-effectiveness of alternating strategies only. Our results indicate that alternating DM and MRI screening starting at age 30 is clinically effective, providing life expectancy gains and breast cancer mortality reduction, and is also the least costly approach for implementing current screening guidelines.
While the cost-effectiveness of screening BRCA mutation carriers with annual combined film mammography and MRI has previously been studied13,35–37, this analysis included the evaluation of digital mammography, as well as the assessment of alternating dual-modality regimens, which reflect more contemporary clinical practice6. Our model estimated the frequency of radiation-induced breast cancers and false-positive test results in addition to projecting long-term health benefits, to more fully determine the consequences of more intensive screening. Our results estimate that radiation exposure accounts for a very small proportion of detected breast cancers, suggesting that the benefits of screening outweigh the concern over this issue in this patient population. Additionally, a recent study of 1993 women with BRCA mutations demonstrated that exposure to diagnostic radiation before age 30 was associated with increased risk of breast cancer (hazard ratio 1.90, 95% CI, 1.20–3.00)38, supporting our findings that there is limited benefit from mammographic screening before age 30.
To date, no randomized controlled trials focused on the long-term outcomes of dual-modality screening in high risk women have been conducted, making it difficult to validate our results with published studies. A recent study of 594 BRCA mutation carriers found that contemporaneous annual screening with mammography and MRI resulted in overall survival at six years of 92.7% (95% CI, 79.0–97.6)39. When this strategy was simulated by our model in a cohort of the same mean age, overall survival at six years was 95.1%.
Dual-modality screening is more cost-effective in BRCA1 carriers than in BRCA2 carriers, primarily due to higher breast cancer incidence in BRCA1 carriers. Sensitivity analyses indicated that as breast cancer risk increased, dual-modality screening became more cost-effective. Decreasing MRI costs also improved the cost-effectiveness of screening. Short-term quality of life decreases from false-positive testing decreased cost-effectiveness in BRCA2 carriers but had little effect on the cost-effectiveness of screening BRCA1 carriers. This can be attributed to BRCA2 carriers having lower breast cancer risk than BRCA1 carriers and thus a greater number of false-positive examinations over a lifetime horizon. While this current analysis indicates that alternating dual-modality screening beginning at age 30 is the most cost-effective approach to implementing current guidelines for women with either BRCA1 or BRCA2 mutations, our results also suggest that alternative screening strategies not considered in this analysis may be more cost-effective for BRCA2 carriers, and is an important area for further study. It is also important to note that if MRI test performance as high as the most optimistic reports in the literature can be achieved, MRI screening would be more cost-effective than projected in our base case analysis.
Understanding the impact of screening on component cost categories is critical as we increasingly focus on providing high-value, cost-conscious health care10,11,40. Our evaluation of lifetime and component costs related to dual-modality screening revealed that the increased costs of additional MRI screening exceeded the downstream reduction in breast cancer treatment and mortality costs. This is due in part to screening costs applying to all women and accruing in the nearer future while breast cancer treatment and mortality costs occur in fewer women and occur many years later. Patient time costs for screening and diagnosis more than doubled when MRI screening was added.
Simplifying assumptions of this model included the use of some parameter values from studies of breast cancer in the general population18,19,21. While we would have preferred to use BRCA carrier-specific parameters throughout the model, use of general population input values occurred only when BRCA-specific data were sparse or unavailable. Because the magnitude of any differences, if present, is not known, it is difficult to anticipate their effects on the model, and we recognize that model results may change if additional information becomes available. We focused on detecting the first primary breast cancer, and assumed perfect adherence to screening and treatment protocols. Medicare reimbursement was used to determine costs of screening and diagnosis, even though most of the simulated screening events occurred in women younger than 65 years of age, because Medicare reimbursement is a generalizable and transparent proxy for United States healthcare costs. Finally, while Alt30 screening appears to be a cost-effective dual-modality screening approach for BRCA mutation carriers, women in families where breast cancer has been diagnosed before age 35 may benefit from starting screening before age 30.
In conclusion, this analysis suggests that screening with MRI and digital mammography at alternating 6-month intervals beginning at age 30 is a clinically effective approach to applying current clinical guidelines, and is considerably more cost-effective in BRCA1 compared with BRCA2 gene mutation carriers.
Provision of selected model input parameter values by the Breast Cancer Surveillance Consortium (BCSC) was supported by the National Cancer Institute (U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, U01CA70040, HHSN261201100031C).
Funding: NIH K07-CA128816 (JML), NIH K25-CA133141 (CYK), NIH R00-CA126147 (PMM), Harvard Medical School Office for Enrichment Programming (KPL)
Financial Disclosures: Dr. Gazelle has served as a consultant for GE Healthcare. There is no direct conflict with the content of this article.