US Insurance Program's Experience With a Multigene Assay for Early-Stage Breast Cancer

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The American Journal of Managed Care, May 2011, Volume 17, Issue 5

This study presents Humana's experience with a multigene breast cancer assay and provides an analysis of the clinical utility and economics of this technology.

Objective:

National guidelines recommend a 21-gene recurrence score (RS) to aid in adjuvant treatment decision in patients with estrogen receptor (ER)-positive, lymph node (LN)-negative early-stage breast cancer (ESBC). This study was performed to assess the economic implication of the assay in community practices from the perspective of a US payer.

Methods:

The study analyzed 952 women with ESBC enrolled with Humana (Louisville, KY) who were tested with the 21-gene RS between June 2006 and June 2010. The proportions of women classified by the assay according to RS risk category, use, costs of chemotherapy regimens and supportive care, and costs of adverse events were obtained from Humana. We adopted a validated Markov model to compute the cost implications of RS for a representative patient. The probability of risk of recurrence, the chemotherapy benefit, and the decision impact of RS were derived from published studies.

Results:

A total of 255 patients within the tested population received adjuvant chemotherapy. Adjuvant chemotherapy was administered to 10% of women at low risk, 36% of women at intermediate risk, and 72% of women at high risk of recurrence. On the basis of a meta-analysis in the reduction of chemotherapy after RS, the model estimated an average test saving of $1160 per patient. The immediate direct savings for chemotherapy drugs, supportive care, and management of adverse events were $1885, $2578, and $472, respectively. Prevention of recurrence through appropriate treatment of patients at high risk resulted in additional savings of $199.

Conclusion:

The adoption of the 21-gene RS led to targeted management of women with ERpositive, LN-negative ESBC and consequently directed savings to the payer.

(Am J Manag Care. 2011;17(5 Spec No.):e194-e202)

Breast cancer is a significant burden of illness in the United States, affecting 1 in 8 women. The total cost of breast cancer management is significant. Early economic analyses of novel molecular classifiers for management of early-stage breast cancer suggest that technology adoption could aid in appropriate allocation of healthcare resources.

  • This study summarizes the direct cost of care for more than 900 patients with early-stage breast cancer in a US insurance program.

  • We provide a real-life analysis of the economic impact of a multigene breast cancer assay and find it saves on costs for the health plan.

Early-stage breast cancer (ESBC) accounts for more than half of newly diagnosed cases of breast cancer per year.1,2 Surgery plus appropriate postsurgical care—such as endocrine therapy and adjuvant chemotherapy—customized to each individual’s cancer biology is now the standard of care. Prescription of endocrine treatment is largely dependent on the presence or absence of hormone receptors, which are identified via widely available laboratory tests such as immunohistochemistry staining and fluorescent in situ hybridization. Comparatively, the recommendation for adjuvant chemotherapy is less clear, as it is guided only by tumor size, grade, and the presence of unfavorable features.3

In a 2005 meta-analysis, the Early Breast Cancer Trialists Collaborative Group4 found that systematic adjuvant chemotherapy provided a 13% absolute reduction in recurrence at 15 years and a 10% absolute reduction in mortality for women younger than 50 years. For women older than 50 years, adjuvant chemotherapy provided a 5% reduction in recurrence and a 3% reduction in mortality. To contextualize the effect of adjuvant chemotherapy in this cohort, 20 women must be treated to prevent 1 recurrence, and 33 women must be treated to prevent 1 death. Molecular assays to predict risk and treatment response for ESBC have become commercially available in the past 5 years. In 2007 and 2008, the American Society of Clinical Oncology and the National Comprehensive Cancer Network (NCCN) recommended a 21-gene recurrence score (RS) as a clinically valid tool for improving individual risk assessment for systematic chemotherapy. In 2010, a meta-analysis of published decision impact studies of 21-gene RS showed that the RS reduced overall use of chemotherapy by 27%.1

Previous health economic studies of the 21-gene RS found that the test would improve women’s lives and save costs for society and payers.5,6 A limitation of these analyses, acknowledged by the investigators, was that they were based on hypothesized use of adjuvant chemotherapy according to guideline recommendations. Although such analyses are useful in the early stages of technology diffusion, policy makers are keenly interested in learning how the assay affected outcomes and costs compared with actual practice and after some period of experience with the assay. Here we incorporate the utility reported in the meta-analysis with real-world costs associated with adjuvant chemotherapy treatment as obtained from Humana (Louisville, KY) to evaluate the cost-effectiveness of the 21-gene RS.

METHODS

Model Framework

Table 1

The model used in the study was a previously validated Markov model that simulated the distant recurrence-free survival, the overall survival, and the costs of breast cancer management with and without the use of 21-gene RS.5,6 A cycle length of 1 year until recurrence or death was used.5-7 The duration of the cycle was selected, as recommended on cost-effective guidelines,8,9 to reflect the natural history of breast cancer and the development of breast cancer—related events. This analysis was conducted from a US payer perspective. Sensitivity analyses were performed to evaluate the overall cost-effectiveness of the assay. lists the model parameters and data sources.

Test Characteristics

The 21-gene RS breast cancer assay (Oncotype DX; Genomic Health, Redwood City, CA) uses a reverse transcriptase polymerase chain reaction process to quantify the presence of specific mRNA for 16 cancer genes and 5 reference genes. The test was performed on paraffin-embedded tumor samples that were obtained from surgery. The test results were reported as a single RS quantified on a scale of 0 (lower risk) to 100 (higher risk). For example, an RS of 6 predicts a 5% (95% confidence interval [CI], 4% to 8%) 10- year risk of recurrence, whereas an RS of 30 predicts a 20% (95% CI, 15% to 25%) 10-year risk of recurrence. Women may also be classified into 3 recurrence risk groups: low risk (RS <18), intermediate risk (RS 18 to 30), and high risk (RS >30).17

The assay was validated in two prospective-retrospective clinical studies of 2 randomized clinical trials (National Surgical Adjuvant Breast and Bowel Project studies [NSABP] B-14 and B-20). These studies showed that the assay independently estimated individual patients’ risk of distant recurrence of breast cancer at 10 years and predicts the likelihood to adjuvant chemotherapy using cyclophosphamide, methotrexate, and fluorouracil regimens.10,17

The effect of adjuvant chemotherapy as a function of recurrence risk was based on analysis of the NSABP B-20 study. Women who were reported as having low recurrence risk were predicted to derive no benefit from adjuvant chemotherapy (relative risk [RR], 1.31; 95% CI, 0.46 to 3.78). Women with intermediate recurrence risk received minimal benefit from adjuvant chemotherapy (RR, 0.61; 95% CI, 0.24 to 1.59), and women with high recurrence risk benefitted significantly from adjuvant chemotherapy (RR, 0.26; 95% CI, 0.13 to 0.53).10

Decision Impact

A meta-analysis of 6 published studies on the decision impact of the 21-gene RS show that the adoption of 21-gene RS consistently reduced the use of chemotherapy.1,7,11,18-21 The weighted mean reduction in chemotherapy was approximately 27% (95% CI, 23% to 31%). Additional sensitivity analyses were performed to assess the robustness of the base case result.

Study Population

Humana affirmed payment coverage in July 2006. Its database included 925 women with LN-negative, ER-positive ESBC who did not restrict the use of their claims information and were tested with the 21-gene assay between June 2006 and June 2010.

The primary estimates obtained from the Humana database were the proportion of women predicted by the assay to have low, intermediate, and high risk of 10-year distant recurrence of breast cancer; the proportion of women receiving adjuvant chemotherapy on the basis of the assay results; the type of chemotherapy and supportive care received; the incidence of adverse events; and the costs of chemotherapy, supportive care, and adverse events.

Adjuvant chemotherapy regimens preferred by the NCCN 2009 breast cancer guidelines were identified by individual therapeutic components through Healthcare Common Procedure Coding System (J9090, J9170, J9000, J9001, J9180, J9190, J9250, J9260, and J9265). Chemotherapy-related supportive care, such as growth factors and antiemetics, were identified by codes J2505, J1440/1441, J2820, J0885, J2088, J2405, J1260, J2469, J8501, J2765, and J0780. Cost associated with adverse events cited by established adjuvant chemotherapy trials was matched between the Current Procedural Terminology (CPT- 9) and International Classification of Disease (ICD-9) diagnosis codes.12,14,22-24 All data were de-identified to protect patient’s confidentiality in accordance with the Health Insurance Portability and Accountability Act and compiled by Humana.

Quality of Life

Health utility scores were obtained from published literature and used to calculate the quality-adjusted life-year (QALY). These scores represent the quantitative value of an individual’s perspective of a specific health state; a value of 0 is equivalent to death, and a value of 1 equals perfect health. Utility scores were obtained for 3 states: breast cancer during chemotherapy, breast cancer recurrence, and second primary cancer caused by chemotherapy.13,15,25-27 Total utility scores were derived from the sum of disutility associated with chemotherapy and the disutility associated with recurrence. Analyses by Cole et al28 indicated a utility score of 0.5 to represent 6 months of chemotherapy treatment that yielded no QALY gain for patients at low risk. The utility score of 0.5 was used in the base case model to be consistent with the guideline on the use of adjuvant therapy.

Sensitivity Analysis

Appendix A1

We conducted one-way sensitivity analysis and probabilistic sensitivity analysis (PSA). In the one-way sensitivity analysis, we varied the model driver individually and noted the impact of each parameter on key model outputs such as incremental cost, incremental QALY, and cost per QALY gained. The range of the one-way sensitivity analysis represents the 95% probable values computed through 1000 model simulations (). These drivers were ordered according to decreasing level of importance and plotted in a tornado diagram with the order of importance on the vertical axis and the total cost to the plan on the horizontal axis.

Appendix A2

PSA used a Monte Carlo simulation to evaluate the effect of uncertainty on key parameters of the total cost to the plan. These model drivers varied independently according to predetermined probability distributions, which were developed to capture the likely range for each parameter. In the PSA, each driver is modeled according to the distribution standard recommended for a specific type of parameter ().29

RESULTS

Mean age of the study population was 59 years. A total of 502 patients (53%) were classified by the assay as being at low risk, 329 patients (35%) were classified as being at intermediate risk, and 121 patients (13%) were classified as being at high risk. Out of 255 women (27%) who received adjuvant chemotherapy, 50 (10%) of the women were classified as being at low risk by the assay received adjuvant chemotherapy compared with 118 (36%) of the women at intermediate risk and 87 (72%) of the women at high risk.

Among the 255 women who received adjuvant chemotherapy, 105 (41%) were selected for docetaxel-based regimens, and 46 (18%) were treated with docetaxel and cyclophosphamide. Other adjuvant chemotherapy regimens identified were docetaxel and doxorubicin plus cyclophosphamide (4%); doxorubicin and cyclophosphamide plus paclitaxel (2%); cyclophosphamide, methotrexate, and fluorouracil (2%); fluorouracil, doxorubicin, and cyclophosphamide (1%); and fluorouracil, epirubicin, and cyclophosphamide (4%). Twenty-eight percent of the treated population received other chemotherapy regimens that did not match the NCCN recommendations.

Table 2

At baseline, we projected that the 21-gene RS provided the women at low risk with an average of 0.134 QALYs gained from avoiding chemotherapy-related complications. For the women who were reclassified as being at high risk by the 21- gene assay, the adoption of 21-gene RS provided 0.027 QALYs gained in preventing distant recurrence. Humana spent $3,784,200 for 952 assays. The model projects that Humana had a net savings of $1,104,320 or an average of $1160 per test. The immediate savings associated with reduction in chemotherapy costs, supportive care costs, and management of adverse events per woman tested was $1885, $2578, and $472, respectively. The model estimates an average of $199 saved per woman tested in the prevention of distant recurrence ().

In a separate analysis, we accounted for chemotherapyinduced second primary cancer, a distant long-term adverse event not captured in the immediate adverse event costs. We applied the incidence rate of second primary cancer as reported by Schaapveld et al30 and adjusted it for the average of treated patients. We estimated that approximately 3.1% of the treated women might be at risk of a second primary cancer induced by chemotherapy. Including this potential long-term adverse effect, the model projected $1,503,423 in net savings. Savings from prevention of this rare but serious adverse event increased to $897 per woman. Women who were spared adjuvant chemotherapy and risk of developing a chemotherapy-induced second primary cancer gained 0.076 QALYs.

Figure A

The one-way sensitivity analysis showed that the topmost influential cost driver is the RR of recurrence with chemotherapy for patients with RS low risk. Other highly influential parameters in ranked order are cost of supportive care and percent of patients with RS low risk who are recommended to chemotherapy before RS testing (Appendix A2). illustrates the impact of each parameter on the total cost to the health plan. In early 2010, Lo et al1 reported a prospective study on the decision impact of the 21-gene RS on adjuvant treatment. Applying the chemotherapy distribution reported by Lo et al to the Humana cohort, the model showed that the assay led to a modest net total saving of $23,932 to $337,883 for the plan.

Figure B

We ran 1000 probabilistic scenarios to predict the cost per QALY gained under a variety of conditions. presents the cost-effectiveness acceptability curve from the PSA. The curve shows an 81% probability that the 21-gene RS would be cost saving to a health plan.

DISCUSSION

Breast cancer is a significant burden of illness in the United States; it ranks as the second most common cancer in the nation. Although the exact economic cost of breast cancer management is unknown, a Medicare- Surveillance, Epidemiology, and End Results claims study by Warren et al31 shows an increasing trend in the costs of breast cancer care from 1991 to 2002. This study also reported a significant increase in the use of chemotherapy and an increase in the mean Medicare payment per therapy. Given the growing cost of the healthcare system, the economic implications of new health technologies should be carefully evaluated and validated.

The economics of 21-gene RS was first published in 20056 and then in 2007,5 in the context of the present standard of care, under the best-practice scenario. In this study, we present a real practice economic validation of 21-gene RS in the US setting. In the base case, we estimated that the use of 21- gene RS led to more than one million dollars in net savings to the Humana plan during the study period. The model also projected approximately 2 to 3 months of QALY gained for the tested patients. For the patients at low risk, 21-gene RS adoption represented improved quality of life through avoidance of chemotherapy-related complications and potential chemotherapy-induced secondary cancers; for the patients at high risk, 21-gene RS demonstrates appropriate and justified used of adjuvant chemotherapy.

The Humana study shows the community distribution of RS risk groups and supports the validation trial by Paik et al that approximately 50% of the tested population could be classified as being at low risk.17 Moreover, this study presents the actual post—RS-directed treatment patterns in the community setting. We noted a variation in RS risk distribution and the subsequent treatment plan between the Humana cohort and the patient population (n = 89) from the study by Lo et al.1 This suggests that there is considerable heterogeneity in breast cancer practice.

The result of our analysis is sensitive to the current chemotherapy prescribing patterns and those of breast cancer management. Twenty-one-gene RS saves the most cost in a healthcare setting with significant use of chemotherapy. Without an extensive chart review on the treatment process for all 925 patients in the Humana cohort, we set our baseline decision impact of the assay on meta-analysis of the published studies and performed detailed sensitivity analyses on the basis of this parameter.

There are a number of potential limitations to this study. First, the cost-effectiveness of the 21-gene RS is highly influenced by the cost of adjuvant chemotherapy and supportive care. In our analysis, these costs were representative of the Humana network. As such, we recognize that the economic impact of 21-gene RS will vary according to healthcare systems. Second, the analysis is conducted from Humana’s perspective and did not account for the patients’ out-of-pocket costs or patients’ indirect costs. In addition, the costs of monthly laboratory workups and outpatient office visits related to treatment were not included in this study—as such, the total societal saving of the 21-gene RS may have been underestimated in this study.

Within the base case parameters, analysis of Humana’s claims data shows that the 21-gene RS testing of 925 women with LN-negative ESBC decreased their total plan cost by close to one million dollars. For patients at low risk of recurrence who decided against adjuvant chemotherapy, the benefit of 21-gene RS was realized in the avoidance of chemotherapy— related complications and long-term adjuvant chemotherapy-related adverse events, such as infertility and second primary tumors.

Patients at high risk of recurrence who elected adjuvant treatment on the basis of the 21-gene RS results were estimated to receive a 20% to 30% reduction in the risk of breast cancer recurrence and associated mortality. This study demonstrates the cost saving potential of the 21-gene RS and projects it as a cost-effective treatment decision tool with a 95% probability of cost-effectiveness ratio that exceeded $16,500 per QALY gained—a value much less than the acceptability threshold value of $50,000 per QALY.

Acknowledgment

We thank Julie Doberne, BA, for her contributions to the early stages of this article.

Authors’ Disclosures of Potential Conflicts of Interest. Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: Katie Krebs, Humana (C); Louis Hochheiser, Humana (C). Consultant or Advisory Role: None. Stock Ownership: None. Honoraria: None. Research Funding: John Hornberger, Genomic Health; Rebecca Chien, Genomic Health. Expert Testimony: None. Other Remuneration: None.

Author Contributions

Conception and design: John Hornberger, Rebecca Chien, Louis Hochheiser. Financial support: John Hornberger. Administrative support: John Hornberger, Rebecca Chien, Katie Krebs. Provision of study material or patients: Katie Krebs, Louis Hochheiser. Collection and assembly of data: John Hornberger, Rebecca Chien, Katie Krebs. Data analysis and interpretation: John Hornberger, Rebecca Chien, Katie Krebs, Louis Hochheiser. Manuscript writing: John Hornberger, Rebecca Chien, Louis Hochheiser. Final approval of manuscript: John Hornberger, Rebecca Chien, Katie Krebs, Louis Hochheiser.

Address Correspondence to: John Hornberger, MD, MS, 3715 Haven Ave, Ste 100, Menlo Park, CA 94025; e-mail: jhornberger@cedarecon.com.

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