How a Study Design Can Prevent Early Detection of Breast Cancer
Published research influences healthcare-as it should; given the research contains a valid design: not limited to being bias-free, and reflecting inclusive consideration of external variables potentially impacting results. Every aspect of the design should withstand challenges from critics and colleagues; from sample population selection to outcome measures. Reported results from original research are critical because they have the potential to be instrumental in the decision making process of providers and payers; these decisions invariably affect healthcare. It plays a crucial role in defining treatment options/technology, access and reimbursement which will ultimately and profoundly impact the patient.
Below is my evaluation of the study by Sprague et al: Benefits, Harms, and Cost-Effectiveness of Supplemental Ultrasonography Screening for Women With Dense Breasts which was recently published by The Annals of Internal Medicine in response to the breast density inform law adopted by 19 states in the US.
The Study
Background: Many states have laws requiring mammography facilities to tell women with dense breasts and a negative screening mammography result to discuss supplemental screening tests with their providers. The most readily available supplemental screening method is ultrasonography, but little is known about its effectiveness.
Objective: To evaluate the benefits, harms, and cost-effectiveness of supplemental ultrasonography screening for women with dense breasts.
Design: Comparative modeling with 3 validated simulation models.
Data Sources: Surveillance, Epidemiology, and End Results Program; Breast Cancer Surveillance Consortium; and medical literature.
Target Population: Contemporary cohort of women eligible for routine screening.
Time Horizon: Lifetime.
Perspective: Payer.
Intervention: Supplemental ultrasonography screening for women with dense breasts after a negative screening mammography result.
Outcome Measures: Breast cancer deaths averted, quality-adjusted life-years (QALYs) gained, biopsies recommended after a false-positive ultrasonography result, and costs.
Results of Base-Case Analysis: Supplemental ultrasonography screening after a negative mammography result for women aged 50 to 74 years with heterogeneously or extremely dense breasts averted 0.36 additional breast cancer deaths (range across models, 0.14 to 0.75 deaths), gained 1.7 QALYs (range, 0.9 to 4.7 QALYs), and resulted in 354 biopsy recommendations after a false-positive ultrasonography result (range, 345 to 421 recommendations) per 1000 women with dense breasts compared with biennial screening by mammography alone. The cost-effectiveness ratio was $325 000 per QALY gained (range, $112 000 to $766 000 per QALY gained). Supplemental ultrasonography screening for only women with extremely dense breasts cost $246 000 per QALY gained (range, $74 000 to $535 000 per QALY gained).
Results of Sensitivity Analysis: The conclusions were not sensitive to ultrasonography performance characteristics, screening frequency, or starting age.
Limitation: Provider costs for coordinating supplemental ultrasonography were not considered.
Conclusion: Supplemental ultrasonography screening for women with dense breasts would substantially increase costs while producing relatively small benefits.
Primary Funding Source: National Cancer Institute.
EVALUATION
Target Population: The study fails to include the age group (40-50 years) for whom ultrasound has been demonstrated as 13.7% more specific than mammography. [1] The study accounts for 40% of women (estimated percentage of women with dense breasts) between 50-74 years of age but does not include women aged 40-50. Since breast density decreases with age, it stands to reason that the group aged 40-50 years may have yielded an overall patient benefit more favorable to adjunct sonographic evaluation of dense breast tissue. The selected population woefully underrepresents a proportion of the population that has been shown to substantially benefit from breast sonography. Additionally, the inclusion of those aged 40-50 would have expanded the sample population by approximately 40% [2].
Methods: Evaluation of handheld sonography as an adjunct modality limits the veracity of reported results. Handheld sonography is notoriously operator-dependent; the widespread variance in technique, experience, and interpretation limits the validity of the study. Inclusion of automated breast ultrasound (ABUS), a more advanced form of breast sonography that eliminates these variables, may have returned a more promising report of patient benefit in lieu of the cost prohibitive conclusion that favors a payer’s objective.
Outcome Measures
Deaths Averted: The study fails to account for the impact of early detection/aversion of invasive diagnosis that is potentially achieved when utilizing sonography in conjunction with mammography. Approximately 78% of cancers are invasive at the time of diagnosis; invasive cancer treatment accounts for $12-16 billion dollars. The average cost per patient is 5 times greater when diagnosed at an advanced versus early/in situ stage. [3, 4] Currently deaths from breast cancer constitute approximately 10-13% of total diagnoses per year [3]. The outcome fails to assess the impact on 90% of breast cancer diagnoses. Why not measure the impact of early detection on cost, or the impact of adjunct use of breast sonography on reduction of invasive diagnoses? Either of these designs may have yielded a more impressive result than focusing primarily on death aversion.
Study Considerations: Existing factors that contribute to overall costs
Modality Accuracy: This study failed to consider current factors that contribute to the overall cost; factors that are mitigated by the addition of ultrasound as an adjunct modality to mammography in dense breast evaluation. False negative rates:mammography misses 20-28% percent of breast cancers that are present at the time of screening compared to 12.8% false negative rate of breast sonography [3]. Combined, mammography and breast sonography reduces overall multimodality screening to 4% false negative (ACRIN). False positive rate of breast sonography alone is 7.5% [5], compared to a false positive rate of 50-60% in mammography[6]
Interpretation Variance: The recommendation for breast biopsy may be exclusive of the modality in question. Instead, it may be specific to the training of the interpreting radiologist. There are standards for breast imaging interpretation outlined by the ACR (BIRAD/ACR); not all practices are accredited and/or not all radiologists follow these guidelines when interpreting breast imaging, particularly sonographic imaging. Perhaps the variance in training and interpretation of mammo/sonography is a causative factor in the number of subsequent biopsy recommendations. In addition to defensive medicine, perhaps the BIRADS guidelines should also be evaluated for classification and recommendations that may be outdated and/or contribute the the incidence of unnecessary biopsies.
Accuracy of Histology Reports. False negative rate of breast biopsies: 20-43% of biopsies are misdiagnosed during the pathological analysis of tissue specimens [7] . Training variance amongst pathologists, experience, equipment and expertise all impact the final diagnosis. This could have been explored as a potential contributor to “unnecessary biopsies” if the results were negative at the time of the study.
Summary
The accuracy of results are influenced by many factors, though expansion of the target population is warranted simply by the incidence of breast cancer in women over 40. Technologically, the incorporation of automated breast ultrasound (ABUS) as an adjunct to mammography in breast cancer detection in women with dense breasts, would likely yield greater accuracy and potentially reduce the false positives and ‘unnecessary biopsies’ attributed to handheld sonography. If the study was redesigned to include outcome measures such as detection of breast cancers earlier than they would have been diagnosed with mammography alone, the impact has the real potential to reflect a reduction in the percentage of invasive diagnoses as well as the associated cost of treatment. Another consideration is the impact that standardizing the interpretive process and tissue specimens may have on reducing costs.
When figures are reported fractionally, i.e. one third of a woman saved per thousand women–they reflect a seemingly paltry impact disproportionate to the price tag each whole woman costs (bear in mind that the study was performed from a payer’s perspective). However, when applied to the current population of females in the US, the results are a bit more human (though I can’t say the same of the payers). According to the US Census there are 76 million women in the US over age 40, 21 million are between 40-50 years, 55 million over 50. Not taking into consideration the limitations of the study and reported results, the overall impact of combining handheld ultrasound with mammography in women with dense breasts would be:
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