Gene Expression Profiling Tests for Early-Stage Invasive Breast Cancer: A Health Technology Assessment.
Breast cancer is a disease in which cells in the breast grow out of control. They often form a tumour that may be seen on an x-ray or felt as a lump.Gene expression profiling (GEP) tests are intended to help predict the risk of metastasis (spread of the cancer to other parts of the body) and to identify people who will most likely benefit from chemotherapy. We conducted a health technology assessment of four GEP tests (EndoPredict, MammaPrint, Oncotype DX, and Prosigna) for people with early-stage invasive breast cancer, which included an evaluation of effectiveness, safety, cost effectiveness, the budget impact of publicly funding GEP tests, and patient preferences and values.
We performed a systematic literature search of the clinical evidence. We assessed the risk of bias of each included study using either the Cochrane Risk of Bias tool, Prediction model Risk Of Bias ASsessment Tool (PROBAST), or Risk of Bias Assessment tool for Non-randomized Studies (RoBANS), depending on the type of study and outcome of interest, and the quality of the body of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. We also performed a literature survey of the quantitative evidence of preferences and values of patients and providers for GEP tests.We performed an economic evidence review to identify published studies assessing the cost-effectiveness of each of the four GEP tests compared with usual care or with one another for people with early-stage invasive breast cancer. We adapted a decision-analytic model to compare the costs and outcomes of care that includes a GEP test with usual care without a GEP test over a lifetime horizon. We also estimated the budget impact of publicly funding GEP tests to be conducted in Ontario, compared with funding tests conducted through the out-of-country program and compared with no funding of tests in any location.To contextualize the potential value of GEP tests, we spoke with people who have been diagnosed with early-stage invasive breast cancer.
We included 68 studies in the clinical evidence review. Within the lymph-node-negative (LN-) population, GEP tests can prognosticate the risk of distant recurrence (GRADE: Moderate) and may predict chemotherapy benefit (GRADE: Low). The evidence for prognostic and predictive ability (ability to indicate the risk of an outcome and ability to predict who will benefit from chemotherapy, respectively) was lower for the lymph-node-positive (LN+) population (GRADE: Very Low to Low). GEP tests may also lead to changes in treatment (GRADE: Low) and generally may increase physician confidence in treatment recommendations (GRADE: Low).Our economic evidence review showed that GEP tests are generally cost-effective compared with usual care.Our primary economic evaluation showed that all GEP test strategies were more effective (led to more quality-adjusted life-years [QALYs]) than usual care and can be considered cost-effective below a willingness-to-pay of $20,000 per QALY gained. There was some uncertainty in our results. At a willingness-to-pay of $50,000 per QALY gained, the probability of each test being cost-effective compared to usual care was 63.0%, 89.2%, 89.2%, and 100% for EndoPredict, MammaPrint, Oncotype DX, and Prosigna, respectively.Sensitivity analyses showed our results were robust to variation in subgroups considered (i.e., LN+ and premenopausal), discount rates, age, and utilities. However, cost parameter assumptions did influence our results. Our scenario analysis comparing tests showed Oncotype DX was likely cost-effective compared with MammaPrint, and Prosigna was likely cost-effective compared with EndoPredict. When the GEP tests were compared with a clinical tool, the cost-effectiveness of the tests varied. Assuming a higher uptake of GEP tests, we estimated the budget impact to publicly fund GEP tests in Ontario would be between $1.29 million (Year 1) and $2.22 million (Year 5) compared to the current scenario of publicly funded GEP tests through the out-of-country program.Gene expression profiling tests are valued by patients and physicians for the additional information they provide for treatment decision-making. Patients are satisfied with what they learn from GEP tests and feel GEP tests can help reduce decisional uncertainty and anxiety.
Gene expression profiling tests can likely prognosticate the risk of distant recurrence and some tests may also predict chemotherapy benefit. In people with breast cancer that is ER+, LN-, and human epidermal growth factor receptor 2 (HER2)-negative, GEP tests are likely cost-effective compared with no testing. The GEP tests are also likely cost-effective in LN+ and premenopausal people. Compared with funding GEP tests through the out-of-country program, publicly funding GEP tests in Ontario would cost an additional $1 million to $2 million annually, assuming a higher uptake of tests. GEP tests are valued by both patients and physicians for chemotherapy treatment decision-making.
Ontario Health (Quality)
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Multi-gene Pharmacogenomic Testing That Includes Decision-Support Tools to Guide Medication Selection for Major Depression: A Health Technology Assessment.
Major depression is a substantial public health concern that can affect personal relationships, reduce people's ability to go to school or work, and lead to social isolation. Multi-gene pharmacogenomic testing that includes decision-support tools can help predict which depression medications and dosages are most likely to result in a strong response to treatment or to have the lowest risk of adverse events on the basis of people's genes.We conducted a health technology assessment of multi-gene pharmacogenomic testing that includes decision-support tools for people with major depression. Our assessment evaluated effectiveness, safety, cost-effectiveness, the budget impact of publicly funding multi-gene pharmacogenomic testing, and patient preferences and values.
We performed a systematic literature search of the clinical evidence. We assessed the risk of bias of each included study using the Cochrane Risk of Bias Tool and the Risk of Bias Assessment Tool for Nonrandomized studies (RoBANS) and the quality of the body of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria.We performed a systematic literature search of the economic evidence to review published cost-effectiveness studies on multi-gene pharmacogenomic testing that includes a decision-support tool in people with major depression. We developed a state-transition model and conducted a probabilistic analysis to determine the incremental cost of multi-gene pharmacogenomic testing versus treatment as usual per quality-adjusted life-year (QALY) gained for people with major depression who had inadequate response to one or more antidepressant medications. In the reference case (with GeneSight-guided care), we considered a 1-year time horizon with an Ontario Ministry of Health perspective. We also estimated the 5-year budget impact of publicly funding multi-gene pharmacogenomic testing for people with major depression in Ontario.To contextualize the potential value of multi-gene pharmacogenomic testing that includes decision-support tools, we spoke with people who have major depression and their families.
We included 14 studies in the clinical evidence review that evaluated six multi-gene pharmacogenomic tests. Although all tests included decision-support tools, they otherwise differed greatly, as did study design, populations included in studies, and outcomes reported. Little or no improvement was observed on change in HAM-D17 depression score compared with treatment as usual for any test evaluated (GRADE: Low-Very Low). GeneSight- and NeuroIDgenetix-guided medication selection led to statistically significant improvements in response (GRADE: Low-Very Low) and remission (GRADE: Low-Very Low), while treatment guided by CNSdose led to significant improvement in remission rates (GRADE: Low), but the study did not report on response. Results were inconsistent and uncertain for the impact of Neuropharmagen, and no significant improvement was observed for Genecept or another unspecified test for either response or remission (GRADE: Low-Very Low). Neuropharmagen may reduce adverse events and CNSDose may reduce intolerability to medication, while no difference was observed in adverse events with GeneSight, Genecept, or another unspecified test (GRADE: Moderate-Very Low). No studies reported data on suicide, treatment adherence, relapse, recovery, or recurrence of depression symptoms.Our review included four model-based economic studies and found that multi-gene pharmacogenomic testing was associated with greater effectiveness and cost savings than treatment as usual, over long-term (i.e., 3-,5-year and lifetime) time horizons. Since none of the included studies was fully applicable to the Ontario health care system, we conducted a primary economic evaluation.Our reference case analysis over the 1-year time horizon found that multi-gene pharmacogenomic testing (with GeneSight) was associated with additional QALYs (0.03, 95% credible interval [CrI]: 0.005; 0.072) and additional costs ($1,906, 95% Crl: $688; $3,360). An incremental cost-effectiveness ratio was $60,564 per QALY gained. The probability of the intervention being cost-effective (vs. treatment as usual) was 36.8% at a willingness-to-pay amount of $50,000 per QALY (i.e., moderately likely not to be cost-effective), rising to 70.7% at a willingness-to-pay amount of $100,000 per QALY (i.e., moderately likely to be cost-effective). Evidence informing economic modeling of the reference case with GeneSight and other multi-gene pharmacogenomic tests was of low to very low quality, implying considerable uncertainty or low confidence in the effectiveness estimates. The price of the test, efficacy of the intervention on remission, time horizon, and analytic perspective were major determinants of the cost-effectiveness results. If the test price were assumed to be $2,162 (compared with $2,500 in the reference case), the intervention would be cost-effective at a willingness-to-pay amount of $50,000 per QALY; moreover, if the price decreased to $595, the intervention would be cost saving (or dominant) compared with treatment as usual.At an increasing uptake of 1% per year and a test price of $2,500, the annual budget impact of publicly funding multi-gene pharmacogenomic testing in Ontario over the next 5 years ranged from an additional $3.5 million in year 1 (at uptake of 1%) to $16.8 million in year 5. The 5-year budget impact was estimated at about $52 million.People with major depression and caregivers generally supported multi-gene pharmacogenomic testing because they believed it could provide guidance that fit their values. They hoped such guidance would speed symptom relief, would reduce side effects and help inform their medication choices. Some patients expressed concerns over maintaining confidentiality of test results and the possibility that physicians would sacrifice patient-centred care to follow pharmacogenomic guidance.
Multi-gene pharmacogenomic testing that includes decision-support tools to guide medication selection for depression varies widely. Differences between individual tests must be considered, as clinical utility observed with one test might not apply to other tests. Overall, effectiveness was inconsistent among the six multi-gene pharmacogenomic tests we identified. Multi-gene pharmacogenomic tests may result in little or no difference in improvement in depression scores compared with treatment as usual, but some tests may improve response to treatment or remission from depression. The impact on adverse events is uncertain. The evidence, however, is uncertain, and therefore our confidence that these observed effects reflect the true effects is low to very low.For the management of major depression in people who had inadequate response to at least one medication, some multi-gene pharmacogenomic tests that include decision support tools are associated with additional costs and QALYs over the 1-year time horizon, and maybe be cost-effective at the willingness-to-pay amount of $100,000 per QALY. Publicly funding multi-gene pharmacogenomic testing in Ontario would result in additional annual costs of between $3.5 million and $16.8 million, with a total budget impact of about $52 million over the next 5 years.People with major depression and caregivers generally supported multi-gene pharmacogenomic testing because they believed it could provide guidance that fit their values. They hoped such guidance would speed symptom relief, would reduce side and help inform their medication choices. Some patients expressed concerns over maintaining confidentiality of test results and the possibility that physicians would sacrifice patient-centred care to follow pharmacogenomic guidance.
Ontario Health (Quality)
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Supplemental Screening as an Adjunct to Mammography for Breast Cancer Screening in People With Dense Breasts: A Health Technology Assessment.
Screening with mammography aims to detect breast cancer before clinical symptoms appear. Among people with dense breasts, some cancers may be missed using mammography alone. The addition of supplemental imaging as an adjunct to screening mammography has been suggested to detect breast cancers missed on mammography, potentially reducing the number of deaths associated with the disease. We conducted a health technology assessment of supplemental screening with contrast-enhanced mammography, ultrasound, digital breast tomosynthesis (DBT), or magnetic resonance imaging (MRI) as an adjunct to mammography for people with dense breasts, which included an evaluation of effectiveness, harms, cost-effectiveness, the budget impact of publicly funding supplemental screening, the preferences and values of patients and health care providers, and ethical issues.
We performed a systematic literature search of the clinical evidence published from January 2015 to October 2021. We assessed the risk of bias of each included study using the Cochrane Risk of Bias or RoBANS tools, and the quality of the body of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. We performed a systematic economic literature review and conducted cost-effectiveness analyses with a lifetime horizon from a public payer perspective. We also analyzed the budget impact of publicly funding supplemental screening as an adjunct to mammography for people with dense breasts in Ontario. To contextualize the potential value of supplemental screening for dense breasts, we spoke with people with dense breasts who had undergone supplemental screening; performed a rapid review of the qualitative literature; and conducted an ethical analysis of supplemental screening as an adjunct to mammography.
We included eight primary studies in the clinical evidence review. No studies evaluated contrast-enhanced mammography. Nonrandomized and randomized evidence (GRADE: Very low to Moderate) suggests that mammography plus ultrasound was more sensitive and less specific, and detected more cancers compared to mammography alone. Fewer interval cancers occurred after mammography plus ultrasound (GRADE: Very low to Low), but recall rates were nearly double that of mammography alone (GRADE: Very low to Moderate). Evidence of Low to Very low quality suggested that compared with supplemental DBT, supplemental ultrasound was more sensitive, detected more cancers, and led to more recalls. Among people with extremely dense breasts, fewer interval cancers occurred after mammography plus supplemental MRI compared to mammography alone (GRADE: High). Supplemental MRI after negative mammography was highly accurate in people with extremely dense breasts and heterogeneously dense breasts in nonrandomized and randomized studies (GRADE: Very Low and Moderate). In people with extremely dense breasts, MRI after negative mammography detected 16.5 cancers per 1,000 screens (GRADE: Moderate), and up to 9.5% of all people screened were recalled (GRADE: Moderate). Contrast-related adverse events were infrequent (GRADE: Moderate). No study reported psychological impacts, breast cancer-specific mortality, or overall mortality.We included nine studies in the economic evidence, but none of the study findings was directly applicable to the Ontario context. Our lifetime cost-effectiveness analyses showed that supplemental screening with ultrasound, MRI, or DBT found more screen-detected cancers, decreased the number of interval cancers, had small gains in life-years or quality-adjusted life-years (QALYs), and was associated with savings in cancer management costs. However, supplemental screening also increased imaging costs and the number of false-positive cases. Compared to mammography alone, the incremental cost-effectiveness ratios (ICERs) for supplemental screening with handheld ultrasound, MRI, or DBT for people with dense breasts were $119,943, $314,170, and $212,707 per QALY gained, respectively. The ICERs for people with extremely dense breasts were $83,529, $101,813, and $142,730 per QALY gained, respectively. In sensitivity analyses, the diagnostic test sensitivity of mammography alone and of mammography plus supplemental screening had the greatest effect on ICER estimates. The total budget impact of publicly funding supplemental screening with handheld ultrasound, MRI, or DBT for people with dense breasts over the next 5 years is estimated at $15 million, $41 million, or $33 million, respectively. The corresponding total budget impact for people with extremely dense breasts is $4 million, $10 million, or $9 million.We engaged directly with 70 people via interviews and an online survey. The participants provided diverse perspectives on broad access to supplemental screening for people with dense breasts in Ontario. Themes discussed in the interviews included self-advocacy, patient-doctor partnership, preventive care, and a shared preference for broad access to screening modalities that are clinically effective in detecting breast cancer in people with dense breasts.We included 10 studies in the qualitative evidence rapid review. Thematic synthesis of these reports yielded three analytical themes: coming to know and understand breast density, which included introductions to and making sense of breast density; experiences of vulnerability, which influenced or were influenced by understandings and misunderstandings of breast density and responses to breast density; and choosing supplemental screening, which was influenced by knowledge and perception of the risks and benefits of supplemental screening, and the availability of resources.The ethics review determined that the main harms of supplemental screening for people with dense breasts are false-positives and overdiagnosis, both of which lead to unnecessary and burdensome health care treatments. Screening programs raise inherent tensions between individual- and population-level interests; they may yield population-level benefit, but are statistically of very little benefit to individuals. Entrenched cultural beliefs about the value of breast cancer screening, combined with uncertainty about the effects of supplemental screening on some outcomes and the discomfort of many health care providers in discussing screening options for people with dense breasts suggest that it may be difficult to ensure that patients can provide informed consent to engage in supplemental screening. Funding supplemental screening for people with dense breasts may lead to improved equity in the effectiveness of identifying cancers in people with dense breasts (compared to mammography alone), but it is not clear whether it would lead to equity in terms of improved survival and decreased morbidity.
Supplemental screening with ultrasound, DBT, or MRI as an adjunct to mammography detected more cancers and increased the number of recalls and biopsies, including false-positive results. Fewer interval cancers tended to occur after supplemental screening compared to mammography alone. It is unclear whether supplemental screening as an adjunct to mammography would reduce breast cancer-related or overall mortality among people with dense breasts.Supplemental screening with ultrasound, DBT, or MRI as an adjunct to mammography in people aged 50 to 74 years improved cancer detection but increased costs. Depending on the type of imaging modality, publicly funding supplemental screening in Ontario over the next 5 years would require additional total costs between $15 million and $41 million for people with dense breasts, and between $4 million and $10 million for people with extremely dense breasts.The people we engaged with directly valued the potential clinical benefits of supplemental screening and emphasized that patient education and equitable access should be a requirement for implementation in Ontario. Our review of the qualitative literature found that the concept of breast density is poorly understood, both by people with dense breasts and by some general practitioners. People with dense breasts who receive routine mammography (especially those who receive health care in their nonpreferred language or are perceived to have lower economic status or health literacy) and their general practitioners may not have the awareness or knowledge to make informed decisions about supplemental screening. Some people with dense breasts experienced emotional distress from barriers to accessing supplemental screening, and many wanted to engage in supplemental screening, even when educated about its potential harms, including false-positives and overdiagnosis.Given an overall lack of robust evidence about morbidity and mortality associated with supplemental screening for people with dense breasts, it is not possible to determine whether funding supplemental screening for dense breasts delivers on the ethical duties to maximize benefits and minimize harms for populations and individuals. It is likely that existing inequities in access to breast screening and cancer treatment will persist, even if supplemental screening for dense breasts is funded. Continued efforts to address these inequities by removing barriers to screening might mitigate this concern. It will be important to identify and minimize sources of uncertainty related to benefits and risks of supplemental screening for dense breasts to optimize the capacity for everyone involved to live up to their ethical obligations. Some of these may be resolved with further evidence related to the outcomes of supplemental screening for dense breasts.
Ontario Health (Quality)
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