Digital Breast Tomosynthesis with Hologic 3D Mammography Selenia Dimensions System for Use in Breast Cancer Screening: A Single Technology Assessment [Internet]

Background: In Norway, breast cancer screening is offered through a publicly funded program to women in the age group 50-69 on a biennial basis. Breast cancer incidence is relatively higher among women in this age group than it is among younger women. The purpose of the screening program is to reduce breast cancer-related mortality by detecting tumors at an earlier stage. The screening technology in current use, known as digital mammography (DM), involves capturing two two-dimensional images of each breast from different angles. One of the limitations of this technology is that tumors may be “masked”, and difficult to detect, especially in dense breasts. Digital breast tomosynthesis (DBT) may, when employed in combination with DM, alleviate this problem by providing a 3D model of the breast constructed on the basis of a series of 2D images. The technology also involves an option to construct “synthetic” 2D images (S2D) similar to a standard digital mammogram. The combined systems have the potential to increase detection rates while reducing the need for patient recall to confirm or rule out the presence of a tumor. However, this means that additional tumors could be detected which do not require treatment during the patient’s lifetime, thus increasing the rate of overdiagnosis. Mammography screening involves radiation exposure, a factor which has to be taken into account when new screening technologies are evaluated.

“Bestillerforum” requested the National Institute of Public Health to perform a single technology assessment (STA) regarding “Three dimensional digital breast tomosynthesis in screening for breast cancer” (ID2015_041) on January 25, 2016. An STA focuses on a clinical effectiveness and safety assessment along with a cost-effectiveness analysis of this single-technology (device).

Objective: The objective of this single technology assessment (STA) is to assess the efficacy, safety, and cost-effectiveness of digital breast tomosynthesis in breast cancer screening in Norway.

There are several manufacturers of DBT systems, but only Hologic Inc., has to date (June 2017) submitted a documentation pack. We have performed a single technology assessment of the use of Hologic Selenia Dimensions digital mammography system for breast cancer screening, based on the submission from Hologic Inc. We do not cover the use of the system in the diagnosis of breast cancer in clinical practice by this STA.

Clinical effectiveness: The documentation submitted by the company consisted of 12 studies identified by a systematic literature search. Four publications met our inclusion criteria and are included for assessment in this STA.

We have assessed the present documentation using a pre-defined PICOS (Population, Intervention, Comparator, Outcomes and Study design), risk of bias assessment of data provided by the submission file, data extraction, and graded the certainty of the evidence for the estimates using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) assessment. We have also reviewed the cost-effectiveness analysis and budget impact analysis described in the submission.

Radiation dose and risk assessment: The submitter provided no documentation assessing the risk associated with the radiation dose with DBT. Therefore, we conducted a separate assessment of the potential risks associated with radiation exposure with DBT.

Cost-effectiveness: Hologic submitted a health economic analysis based on an American discrete event analysis model, from which they had drawn results in terms of quality-adjusted life years gained. Hologic compared the effects of DBT+DM (synthetic 2D) for a hypothetical cohort of women that was followed through 10 rounds of screening over a 20-year time horizon. The model was based on data (sensitivity and specificity) from an interim analysis of the Oslo Tomosynthesis Screening Trial. Hologic did not have access to the model, and carried out the costing calculations separately. The main cost components were screening costs and breast cancer treatment costs broken down by disease stage. Costs were applied to the model results and varied in a number of one-way sensitivity analyses.

Clinical effectiveness: Our main findings are as follows:

1. We are uncertain whether Hologic digital breast tomosynthesis in combination with digital mammography or synthesized digital mammography decreases or increases recall rates compared to digital mammography alone (very low confidence due to conflicting evidence from observational studies).

2. The intervention may increase the rate of screening-detected cancer (cancer detection rate (CDR) according to all studies (very low confidence due to sparse evidence from one observational study).

3. We are uncertain whether Hologic digital breast tomosynthesis in combination with digital mammography or synthezised digital mammography makes any difference with regard to the detection of interval cancer compared to digital mammography alone (very low confidence in the evidence due to sparse evidence from one observational study).

4. We are uncertain whether Hologic digital breast tomosynthesis in combination with digital mammography or synthezised digital mammography decreases or increases false positive rates compared to digital mammography alone (very low confidence due to conflicting evidence from observational studies).

5. The intervention may provide similar sensitivity rates, but may increase specificity rates (low confidence due to evidence from observational studies).

6. We are uncertain whether Hologic digital breast tomosynthesis in combination with digital mammography or synthesized digital mammography decreases or increases false negative rates compared to digital mammography alone (very low confidence due to sparse evidence from one observational study).

7. Information on death and quality of life was not reported.

Uncertainty regarding the effect estimates means that new research may alter the results and our conclusion.

Radiation dose and risk assessment: When compared to the current practice with DM, introducing the Hologic Selenia Dimensions DBT-system into the Norwegian Breast Cancer Screening Programme (NBCSP) will result in an increased radiation dose followed by an increased risk of radiation-induced cancer for all the evaluated interventions defined by the PICO.

Summary of findings based on doses reported in the OTST and STORM-2 trial:

1. DBT only: The dose and risk will increase by 23% to 38%, resulting in a total absorbed dose to granular tissue (AGD) of 3.7-3.9 mGy and an estimated incidence of radiation-induced breast cancer of 15 to 16 per 100,000 women and mortality of 1.2 per 100,000 women.

2. DBT + DM: The dose and risk will increase by a factor of between 2.23 and 2.37, resulting in a total AGD of 6.4-7.0 mGy and an estimated incidence of radiation-induced breast cancer of 26 to 29 per 100,000 women and mortality of 2.1 to 2.3 per 100,000 women.

3. DBT + S2D: The dose and risk will be increased by 23% to 38%, but reduced by 42% t0 45% compared to DBT + DM, resulting in the same dose and risk as DBT alone.

The estimated values for incidence of radiation-induced breast cancer and mortality must be interpreted with caution as there is a high level of uncertainty associated with them. However, the ratio between doses and risks for the different interventions provides valid input to the total risk-benefit evaluation to be done for the screening program.

Cost-effectiveness: The base case results of the submitted economic analysis of DBT+DM (S2D) vs. DM alone were 0.007 quality adjusted life years gained per woman screened. The incremental cost per QALY gained was approximately NOK 144,000. This result is estimated for a population of women with dense breasts.

Hologic based the budget impact analysis on three components: relative costs of equipment procurement, screening costs, and breast cancer treatment costs. The base case estimate was a net increase in expenditure of 77.5 million NOK in year 5 after implementation. Hologic also included sensitivity analysis in the budget impact analysis to determine the effect of varying the price, which has yet to be determined, of the DBT equipment, and to examine how changes in important assumptions would influence the results of the budget impact analysis. The net increase in expenditure reported varied significantly in the sensitivity analyses.

Clinical efficacy and safety: Compared to digital mammography alone, the use of Hologic digital breast tomosynthesis in combination with standard digital mammography or synthesized digital mammography may increase the rate of screening-detected cancer (cancer detection rate or CDR) according to all studies. The studies have provided evidence on the first screening round using DM+DBT, which could partly account for the substantial increased cancer detection rate, compared with standard screening with DM alone. Estimates of cancer detection rates for repeated DBT screening of the same populations are needed to quantify the effect of adjunct DBT on both cancer detection and false positive recalls at repeated screening rounds.

RCTs assessing the impact of adjunct DBT on interval cancer rates as a surrogate for screening benefit would provide critical evidence to underpin future population screening policy and practice. RCTs should be designed to simultaneously address additional evidence gaps such as DBT’s incremental cost-effectiveness, and detection measures at repeat screening with adjunct DBT.

Using both DBT and standard DM (dual acquisition) causes an increase in the radiation dose. DBT-systems with the possibility to generate synthetic 2D images is highly favourable compared to DBT in combination with full field digital mammography, due to its reduction in dose and associated risk. Information on radiation doses should be included in future clinical trials.

Cost-effectiveness: The results from the submitter’s health economic analysis indicated that adjunct DBT compared to current screening practice could lead to earlier detection of breast cancer and a lower recall rate, though potential cost reductions resulting from the latter are not actually modelled. The results suggest therefore that adjunct DBT could be cost-effective if adopted by the Norwegian Breast Cancer Screening Programme. However, there are a number of issues that contribute to uncertainty regarding the results. First, the uncertainty described above with regard to the clinical effectiveness, particularly with regard to sensitivity, over repeated screening visits and across different populations (e.g. with respect to breast density). Second, we do not know to what extent the potential increase in breast cancer detection may lead to increased overdiagnosis and unnecessary treatment. Third, since a coherent, adapted health economic model could not be supplied, it is difficult to ascertain the impact of various assumptions in the analysis and assess the total uncertainty regarding the health economic results.

Conclusion: There is too little evidence to conclude regarding the effects of the use of Hologic digital breast tomosynthesis in combination with digital mammography or synthesized digital mammography compared to digital mammography alone for the outcomes assessed in our report (recall rates, cancer detection rate, interval cancer rate, false positive and false negative rate, sensitivity, specificity, mortality and quality of life).

Preparation of a full health technology assessment should be considered when sufficient evidence is available.