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Objective: Oncotype DX, a 21-gene assay, was clinically validated as a predictor of 10-year recurrence-free survival and treatment response in patients with early-stage estrogen-receptor-positive, lymph-node negative breast cancer (ER+ LN- ESBC). This study determined “real-life” alteration in treatment decision and economic implications of Oncotype DX use in women with ER+ LN- ESBC.
Methods: Clalit Health Services (CHS, Tel Aviv, Israel), determined the proportion of women in low, intermediate and high-risk groups in the first 368 Oncotype DX assays performed, the change of adjuvant therapy recommendation following the recurrence (RS) results from Oncotype DX use, and associated chemotherapy costs. The risk of recurrence-free survival was derived from prespecified statistical protocols of NCI-sponsored trials conducted by NSABP (B-14 and B-20). Utilities were literature based. A 3% discount rate was employed.
Results: Oncotype DX altered recommendations of 40% of patients, 84% of whom were changed from hormone + chemotherapy to hormonal therapy alone. Among high-risk women, 8% switched actual treatment from hormonal therapy to hormone + chemotherapy. By reducing the chemotherapy disutility, quality-adjusted life-years (QALY) increased 0.170 years. Use of Oncotype DX costs $10,770 per QALY gained. Sensitivity analyses revealed that risk reduction in the low-risk population, the cost of adverse events, and the relative risk reduction of recurrence were the most influential variables.
Conclusion: Oncotype DX resulted in net QALY gain and increased overall costs, with an incremental cost-effectiveness ratio of $10,770. For CHS, Oncotype DX represents an effective and affordable approach to favorably affect the lives of women with ESBC.
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Approximately 90 women per 100,000 are diagnosed yearly with breast cancer in Israel . Breast cancer remains among the most common cancers in women, and the most common cause of death among women between the ages of 40 and 79 . Several large randomized clinical trials demonstrated the benefit of hormonal therapy in patients with estrogen receptor-positive (ER+) early-stage breast cancer (ESBC). An important decision for a patient with ER+, lymph node-negative (LN-) ESBC is whether to also undergo adjuvant chemotherapy after primary surgery to prevent or delay distant recurrence. Chemotherapy-related adverse events occur in almost all patients, and more than 1 in 10 women experience a serious or life-threatening event . Between 1 in 100 and 1 in 500 women die from side effects related to the administration of chemotherapy. Other adverse effects include ovarian failure, cardiotoxicity, nausea, and hair loss. Consensus guidelines recommend considering adjuvant chemotherapy if tumor size is greater than 0.6 cm . Experts do not recommend routine use of adjuvant chemotherapy for patients over 70 years old and advocate for individualized treatment with consideration of comorbid conditions .
Enhanced public health efforts to detect breast cancer, such as mammographic screening, have increased detection at earlier stages of disease . The success of these efforts has resulted in physicians and patients more regularly facing the question: Do the benefits of adjuvant chemotherapy outweigh the medical risks and known adverse effects on quality of life? The difficulty in answering this question is supported by recent evidence showing wide variation in the propensity to prescribe adjuvant chemotherapy, a variation that cannot be explained by characteristic risk factors such as age, tumor size, and histology [3,6]. Thus, an active area of oncology research is identifying additional reliable predictors of recurrence in ESBC that would assign risk more accurately and help guide the decision to prescribe adjuvant chemotherapy.
Oncotype DX (Genomic Health, Inc., Redwood City, CA, USA) is a genomic test that predicts the average rate of distant recurrence of breast cancer and response to adjuvant chemotherapy treatment. The Oncotype DX assay uses a reverse-transcriptase, polymerase chain reaction process to quantify the presence of specific mRNA for 16 cancer genes, and 5 reference genes in paraffin samples obtained from a breast cancer biopsy. The results are combined into a single score, quantified on a scale of 0 (lower risk) to 100 (higher risk). The test has the most value as a continuous variable; however, patients can be further subdivided into three risk groups: patients receiving a score of 0–17 are considered to have a low risk of recurrence, while patients with a score of 18–30 are considered to have an intermediate risk of recurrence. Patients with a score of 31 or higher are considered to have a high risk of recurrence.
Oncotype DX's clinical validity was tested in prespecified subgroup analyses of randomized clinical trials (National Surgical Adjuvant Breast and Bowel Project studies [NSABP] B-14 and B-20), and was shown to independently predict distant recurrence of breast cancer at 10 years and response to adjuvant chemotherapy using cyclophosphamide-methotrexate-5-fluorouracil regimens [7,8].
Experience from several university- and community-based groups has shown that the Oncotype DX assay has influenced decisions about whether to undergo chemotherapy [9–12]. In studies conducted in the United States and Israel, 20% to 25% of women classified as low risk of distant recurrence elected to change therapy from adjuvant chemotherapy plus hormone therapy to hormone therapy only [10,13–15]. For the 25 out of 100 women predicted to have a high risk of distant recurrence, the Oncotype DX assay identified at least 1 woman per 100 who initially decided to use only hormone therapy and subsequently elected to also undergo a course of adjuvant chemotherapy based on the high Oncotype DX score .
In February 2006, Clalit Health Services (CHS), Israel's largest health-care organization with 3.6 million members, was the first public health insurer to reimburse the assay outside the United States. The coverage decision was based on the assay's clinical validation, recommendations by Israeli oncology opinion leaders, and findings of potential cost-effectiveness of the assay under a wide range of assumptions [15,16].
The primary aim of this study was to assess the validity of the cost-effectiveness of Oncotype DX compared with traditional prognostic pathways in the diagnosis and treatment of ER+, LN-, ESBC from an Israeli health-care provider perspective. A secondary aim was to assess the factors that influence the cost-effectiveness of Oncotype DX use.
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Records were assessed for the first 368 Oncotype DX assays ordered at CHS; however, the first 55 patients did not have a reported treatment recommendation prior to ordering the test. This is typical with introduction of a new technology because 1) the clinicians are learning about the technology and how to interpret the results, and 2) CHS physicians decided subsequent to first using the test to obtain prospective information about their decision-making processes. The median patient age was 57 years (range 29–81 years) (Table 2). The median tumor size was 1.5 cm (range 0.3–4.5 cm). Using criteria from the American Joint Commission on Cancer , 9% of patients had tumor grade 1, 66% had tumor grade 2, and 25% had tumor grade 3. The proportion of patients classified by the Oncotype DX assay as low-risk (score 0–17), intermediate-risk (score 18–30), and high-risk (score > 30) was 40, 45, and 16%, respectively.
Table 2. Summary of the baseline patient and tumor characteristics
| Female, %||99|
| Age, mean (range), years||57 (29–81)|
|Tumor staging|| |
| Median tumor size, cm||1.5 (0.3–4.5)|
| Tumor grade,* %|| |
|Oncotype DX risk group (score)|| |
| Low-risk ( 0–17), %||40|
| Intermediate-risk (18–30), %||45|
| High-risk (> 30), %||16|
Prior to receiving the assay results, chemotherapy was offered to 174 patients (56%) (Table 3). After receiving the assay results, 125 patients' (40%) actual treatment differed from the initial recommendation. One hundred five patients (34%) received only hormone therapy instead of the initial recommendation of adjuvant chemotherapy plus hormone therapy.
Table 3. Adjuvant chemotherapy recommended before compared with actual use after receiving information on Oncotype DX risk status
|Oncotype DX risk group||Proportion of patients by risk group||Total|
|Recommended chemotherapy prior to Oncotype DX*||Recommended chemotherapy after Oncotype DX†|
|Low risk (score 0–17)||63 (50%)||0 (0%)||127|
|Intermediate-risk (score 18–30)||72 (51%)||46 (33%)||140|
|High-risk (score > 30)||39 (85%)||43 (93%)||46|
|Total||174 (56%)||89 (28%)||313‡|
The most substantial change from the original physician recommendation occurred among patients classified as low-risk by Oncotype DX. Prior to Oncotype DX classification, 63 low-risk patients (50%) were recommended to undergo chemotherapy; none of these patients subsequently received chemotherapy (Table 3). Among patients with intermediate-risk Oncotype DX score, the proportion of patients undergoing chemotherapy declined to 33% from an initial 51% of patients recommended to receive chemotherapy. Among high-risk patients, the proportion of patients undergoing chemotherapy increased from 85% to 93% of patients recommended to undergo chemotherapy prior to receiving information on the Oncotype DX score.
Oncotype DX costs $3460 per patient (Table 4). A cost savings resulted from the reduced use of adjuvant chemotherapy. This is because a lower percentage of patients actually received adjuvant chemotherapy than were initially recommended by a physician prior to receiving information regarding their risk classification from Oncotype DX. Savings associated with chemotherapy, supportive care, and fewer adverse events were $968, $66, and $615, respectively. The proper administration of chemotherapy to high-risk patients, who switch from hormone-only treatment after Oncotype DX, resulted in $66 dollars of savings from preventing recurrence. The net average cost associated with Oncotype DX testing was $1828 per patient. For CHS, Oncotype DX increased total costs by $1,560,520 in the first year after initial diagnosis of breast cancer and genomic testing ($0.0338 per member per month). Oncotype DX was projected to cost $14,717 through risk reduction for the 8% of high-risk patients who appropriately receive adjuvant chemotherapy as a result of testing.
Table 4. Results
|End point||Mean value|
|Costs, per patient tested|| |
| Oncotype DX||$3460|
| Reduced use of adjuvant chemotherapy (actual*)|| |
| Chemotherapy drugs||($968)|
| Supportive care||($66)|
| Adverse events||($615)|
| Recurrence costs (projected)||$17|
|Total costs per plan*|| |
| First year after diagnosis and testing||$1,560,520|
| After first year from reduced recurrence risk||($52,422)|
|QALYs gained|| |
| Chemotherapy related||0.136|
|Cost per QALY gained||$10,770|
The average QALY gained per patient associated with reduced use of adjuvant chemotherapy was 0.136 years (Table 4). For the 8% of high-risk patients who initially were recommended hormone therapy only and then switched to also receive adjuvant chemotherapy, the average QALY associated with reduction in recurrence was 0.034 years. The net QALY gained was 0.170 years per patient. The resulting cost per QALY gained was $10,770.
Figure 2 shows the results of the one-way sensitivity analyses. The cost per QALY gained was less than $20,000 for all variables. The three most influential variables influencing the cost-effectiveness of Oncotype DX were relative risk reduction in the low risk population, the cost of adverse events, and the relative risk reduction of recurrence in the intermediate risk population. There is a 5% probability that the cost per QALY gained exceeds $35,000 (Fig. 3).
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Adjuvant chemotherapy is a widely prescribed treatment in ER+, LN- ESBC. Because the likelihood of distant recurrence within 10 years among all tamoxifen-treated patients is less than 20%, professional commentators have claimed that at least 80% of patients would be overtreated with adjuvant chemotherapy if it were offered to everyone . Prior to testing with Oncotype DX, more than 50% of patients at CHS were recommended to undergo adjuvant chemotherapy.
Oncotype DX was developed, in part, to more reliably predict who would benefit from adjuvant chemotherapy, which then should reduce the unnecessary use of adjuvant chemotherapy among low-risk patients and increase the use of adjuvant chemotherapy among high-risk patients. Oncotype DX has undergone rigorous clinical validation using prespecified statistical protocols applied to randomized controlled trials [7,8], and has been endorsed by guidelines of the American Society of Clinical Oncology and the National Comprehensive Cancer Network as a means to reduce risk and costs for cancer patients [4,27].
We project that patients' lives will be extended and improved by the avoidance of adjuvant chemotherapy among low-risk patients and the use of adjuvant chemotherapy among high-risk patients. With the CHS, use of Oncotype DX increases overall costs by approximately $1828 per patient tested. Nevertheless, as a consequence of improved quality-adjusted survival, the assay costs no more on average than $11,000 per QALY gained. Extensive sensitivity analyses showed that incremental cost-effectiveness is likely to remain less than $12,000 under the most reasonable assumptions, a value that is substantially below thresholds of acceptable cost-effectiveness among countries in the Organisation for Economic Co-operation and Development, such as Israel .
This study has several limitations. First, the clinical data on which the analyses were based came from a nonrandomly selected sample of patients at CHS. It is possible that these patients could potentially yield a higher proportion of patients' decisions altered by Oncotype DX than the population at large. For example, physicians may have selected patients in whom the physician has substantial uncertainty about the optimal treatment recommendation. Second, the utilities applied in the model were derived from the English-speaking literature and may not fully characterize the preferences of patients in Israel. Third, the validation of the assay was based on clinical trials conducted in the United States [7,8]. Studies are underway in other countries, such as Japan, to assess whether the findings of the pivotal trials are maintained in other settings . Fourth, we omitted some potential long-term implications of breast cancer and its treatments, such as the risk of local recurrence and risk of second primary tumors associated with chemotherapy, as a result of limited data [15,16,30]. Fifth, we examined the effect of the test from the payer's perspective. As such, we have not included savings associated with lower indirect costs accruing to patients, such as reduced work absenteeism associated with the chemotherapy regimen and management of its adverse events.
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The CHS found that testing 368 patients with ER+, LN-, ESBC with Oncotype DX increased their health-care costs by $1,500,000. These higher overall costs associated with testing in Israel, relative to cost-savings that have been estimated for the United States, is likely consequence of the higher expenditures per patient in the Israel for adjuvant chemotherapy and its administration. The benefits realized by patients were associated with the avoidance of a loss in quality of life related to the lower incidence of early adverse events (e.g., nausea/vomiting, hair loss, and infections) from the reduced use of adjuvant chemotherapy. Patients at low risk of recurrence who decided to forego adjuvant chemotherapy can be reasonably expected to worry less about the risk of late adverse events, such as cognitive dysfunction, infertility, and second primary tumors. Among patients at high risk of recurrence who switched to receiving adjuvant chemotherapy, they were projected to benefit from a 25% to 30% lower risk of recurrence and associated mortality from breast cancer. Overall, Oncotype DX was projected to cost on average no more than $11,000 per QALY gained, a value that is less than one-half of generally accepted cost-effectiveness thresholds in developed countries such as Israel .