Advances in Therapy

, Volume 32, Issue 3, pp 239–253 | Cite as

Cost-Effectiveness of the 21-Gene Breast Cancer Assay in Mexico

  • Juan Enrique Bargalló-Rocha
  • Fernando Lara-Medina
  • Victor Pérez-Sánchez
  • Rafael Vázquez-Romo
  • Cynthia Villarreal-Garza
  • Hector Martínez-Said
  • Robin J. Shaw-Dulin
  • Alejandro Mohar-Betancourt
  • Barnaby Hunt
  • Juliette Plun-Favreau
  • William J. Valentine
Original Research

Abstract

Introduction

The 21-gene breast cancer assay (Oncotype DX®; Genomic Health, Inc.) is a validated diagnostic test that predicts the likelihood of adjuvant chemotherapy benefit and 10-year risk of distant recurrence in patients with hormone-receptor-positive, human epidermal growth receptor 2-negative, early-stage breast cancer. The aim of this analysis was to evaluate the cost-effectiveness of using the assay to inform adjuvant chemotherapy decisions in Mexico.

Methods

A Markov model was developed to make long-term projections of distant recurrence, survival, and direct costs in scenarios using conventional diagnostic procedures or the 21-gene assay to inform adjuvant chemotherapy recommendations. Transition probabilities and risk adjustment were taken from published landmark trials. Costs [2011 Mexican Pesos (MXN)] were estimated from an Instituto Mexicano del Seguro Social perspective. Costs and clinical benefits were discounted at 5% annually.

Results

Following assay testing, approximately 66% of patients previously receiving chemotherapy were recommended to receive hormone therapy only after consideration of assay results. Furthermore, approximately 10% of those previously allocated hormone therapy alone had their recommendation changed to add chemotherapy. This optimized therapy allocation led to improved mean life expectancy by 0.068 years per patient and increased direct costs by MXN 1707 [2011 United States Dollars (USD) 129] per patient versus usual care. This is equated to an incremental cost-effectiveness ratio (ICER) of MXN 25,244 (USD 1914) per life-year gained.

Conclusion

In early-stage breast cancer patients in Mexico, guiding decision making on adjuvant therapy using the 21-gene assay was projected to improve life expectancy in comparison with the current standard of care, with an ICER of MXN 25,244 (USD 1914) per life-year gained, which is within the range generally considered cost-effective.

Keywords

Breast cancer Cost Cost-effectiveness Gene expression profiling Mexico Oncology Oncotype DX 

Introduction

Breast cancer is a major health concern worldwide, but particularly in the low- and middle-income countries, where approximately 45% of the 1 million new cases occur each year [1]. It is difficult to accurately quantify the prevalence and incidence of breast cancer in Mexico as no cancer registry exists to systematically collect data, but estimates from 2000 suggested that the burden is growing and projected approximately 16,500 new cases annually from 2020 [2]. The clinical impact of breast cancer is large, since it is the leading cause of cancer death in Mexico, and represents the second most common cause of death for women aged 30–54 years (behind diabetes mellitus) [3]. Data on the total economic burden of breast cancer in Mexico are currently lacking. However, a recent cohort study based in Mexico calculated the mean per patient annual cost of breast cancer treatment to be MXN (Mexican Pesos) 110,459 [approximately USD (United States Dollars) 8375], with costs increasing with delayed diagnosis [4].

Breast cancer is a heterogeneous disease. Patients survival and recurrence rates vary widely and are influenced by a number of factors including disease stage at diagnosis (based on tumor size, lymph node involvement and distant metastases), presence of particular molecular markers including, in particular, the estrogen and progesterone receptors (ER and PR, respectively) and the human epidermal growth factor receptor 2 (HER2). Only a small proportion of patients with early-stage ER-positive and HER2-negative invasive breast cancer derive a benefit from adjuvant chemotherapy, as shown in the NSABP B-20 trial where a 4.4% absolute benefit from addition of chemotherapy to tamoxifen at 10 years was observed across the entire population, but the 25% of patients at high risk showed a 28% absolute benefit from chemotherapy. This indicates the heterogeneity of the disease and shows that not all patients benefit equally from chemotherapy. However, a meta-analysis of adjuvant therapy recommendations recently suggested that approximately 45% of patients receive chemotherapy in usual care [5, 6, 7, 8].

The 21-gene breast cancer signature (Oncotype DX® Breast Cancer Assay, Genomic Health Inc., Redwood City, CA, USA) is a validated assay that has been shown to successfully predict the likelihood of chemotherapy benefit, as well as distant recurrence 10 years after diagnosis in patients with early-stage, node-negative and node-positive ER-positive breast cancer. The assay uses real-time reverse-transcriptase polymerase chain reaction (RT-PCR) to quantitatively examine the expression profile of 21 genes (16 cancer-related genes and 5 reference genes). The gene expression results are then combined to provide a single Recurrence Score value between 0 and 100, which corresponds to a point estimate (with 95% confidence intervals) of the 10-year risk of distant recurrence at an individual patient level [9, 10, 11, 12]. The ability to predict whether a patient is likely to benefit from chemotherapy can support physicians making individualized treatment decisions, thereby improving patient outcomes and minimizing unnecessary exposure to chemotherapy and associated adverse events in patients who are not likely to benefit from treatment. This in turn has implications in terms of reducing the economic and humanistic burden associated with breast cancer.

The use of the 21-gene assay is recommended as a decision tool to guide adjuvant chemotherapy decision making in a number of published guidelines, including the European Society for Medical Oncology (ESMO), American Society of Clinical Oncology (ASCO), and the National Comprehensive Cancer Network (NCCN) [13, 14, 15]. In addition, St. Gallen’s International Expert Consensus Panel on the primary treatment of early breast cancer in 2009 advised the use of multi-gene assays (including the 21-gene assay) if there is doubt about the indication for adjuvant chemotherapy [16]. At the St. Gallen meeting in 2011, 84% of the panel agreed that the 21-gene assay may also be used to predict chemotherapy responsiveness in an endocrine responsive cohort where uncertainty remains after consideration of other tests [17]. The IMPAKT 2012 Working Group stated that the analytical and clinical validity of the 21-gene assay had been demonstrated, but remained cautious as to the clinical utility of the test [18].

A recent systematic review of cost-effectiveness studies of multi-gene assays in breast cancer identified 18 studies evaluating the cost-effectiveness of the 21-gene assay [19]. Of these analyses, the majority were conducted in economically developed countries (five in the USA, three in Canada, two in the UK, two in Japan, two in Singapore, one in Australia, and one in Ireland) and none were conducted in Latin America. The aim of the present study was to evaluate the cost-effectiveness of using this assay in patients with early-stage breast cancer in Mexico, from the perspective of the Instituto Mexicano del Seguro Social (IMSS), the governmental organization with responsibility for funding healthcare in Mexico.

Methods

Model Overview

A Markov model was developed in Excel (Microsoft Corporation, Redmond, WA, USA), based on the model originally developed for a submission to the National Institute for Health and Clinical Excellence (NICE) and published by Holt et al. [20] in 2011. The model was designed to evaluate the long-term costs and clinical outcomes associated with introducing 21-gene assay testing to inform decisions on adjuvant chemotherapy for patient with hormone-receptor-positive, node-negative or up to 3 node-positive early-stage breast cancer in Mexico. The model made projections of life expectancy and direct costs, based on recurrence rates for low-, intermediate- and high-risk patients, as well as country-specific mortality data. A Markov model structure was chosen based on suitability for modeling recursive disease processes (e.g., annual risk of recurrence and mortality) as outlined in Fig. 1.
Fig. 1

Overview of the 21-gene assay cost-effectiveness model structure. Squares represent decision nodes, circles represent chance nodes (or Markov nodes where designated) and triangles represent transitions to health states. Health states are designated using block capitals. ESBC early-stage breast cancer, ODX Oncotype DX®, M Markov node

A time horizon of 40 years in the base case was chosen, to allow all recurrence events over patient lifetimes to be captured. Future costs and clinical benefits were discounted at 5% per annum in line with published guidance for Mexico [21]. Half-cycle correction was applied to avoid systematic over- or underestimation of survival in the model.

Patients in the model were assigned adjuvant therapy based either on the conventional approach in Mexico (usual care) or based on their Recurrence Score. There were three states in the model: recurrence-free (in which all patients start the simulation), recurrence (following a distant recurrence event after which patients were exposed to the risk of breast cancer mortality in each subsequent year of the simulation) and dead (following a mortality event). All patients started the simulation in the recurrence-free state. In each 1-year cycle of the simulation, patients were exposed to the risk of competing mortality and recurrence. Patients who had a mortality event transitioned to the dead state (absorbing state). Patients who experienced a distant recurrence event transitioned to the recurrence state, where they were exposed to the risk of breast cancer mortality in each subsequent year of the simulation.

Incremental cost-effectiveness ratios (ICERs) were calculated by dividing the difference in costs between the 21-gene assay arm and the usual care arm by the difference in life expectancy between the 21-gene assay arm and the usual care arm. Calculation of an ICER identifies whether a treatment is considered good value for money, and allows comparison across a range of therapy areas to allow healthcare payers to make informed decisions to optimize healthcare with a finite budget.

Values used to parameterize the model are outlined below, and all inputs used in the modeling analysis can be found in the online electronic supplementary material.

Clinical Parameters and Variables in the Base Case Analysis

Therapy recommendations with usual care or 21-gene assay testing were based on classification of patients at low, intermediate and high risk of distant recurrence based on a recent meta-analysis of decision impact studies of the 21-gene assay use [8]. Use of the 21-gene assay led to a change in treatment recommendation in 35% of patients (Table 1). Most commonly, this was sparing of chemotherapy. However, addition of chemotherapy to hormone therapy was also possible. This meta-analysis represents the largest available sample of the impact of incorporating the assay into routine clinical practice, comprising 1154 patients. Therefore, it comprises the most reliable data source for informing model parameters.
Table 1

Allocation of chemotherapy in early-stage breast cancer patients, with and without 21-gene assay testing

Recurrence Score group

Usual care

After 21-gene assay testing

Hormone therapy only (%)

Hormone therapy and chemotherapy (%)

Hormone therapy only (%)

Hormone therapy and chemotherapy (%)

Low

30.5

23.8

52.5

1.8

Intermediate

16.2

10.5

23.7

3.0

High

8.6

10.5

3.0

16.1

Data taken from Hornberger and Chien [8]

In each cycle of the model, the risk of recurrence was evaluated for each simulated patient based on their Recurrence Score defined category of low, intermediate or high risk as reported by Paik et al. [5] for the NSABP B-20 cohort. For patients with low, intermediate and high Recurrence Scores, the 10-year risk of recurrence was 3.2%, 9.1%, and 39.5%, respectively. Risk of recurrence was adjusted based on whether patients were receiving chemotherapy as per the initial recommendations (in the standard care arm) and based on the Recurrence Score (in the 21-gene assay arm). The relative benefits of chemotherapy, in terms of distant recurrence for patients with low Recurrence Score (<18), intermediate Recurrence Score (18–30) and high Recurrence Score (≥31) results were 1.31 [95% confidence interval (CI) 0.46–3.78], 0.61 (95% CI 0.24–1.59) and 0.28 (95% CI 0.13–0.53), respectively [5]. Based on these data, the modeling analysis captured a relative risk reduction associated with chemotherapy of 74% in patients with high Recurrence Scores only (as the 95% CI of relative risk in the low and intermediate groups spanned 1).

Non-breast cancer death was captured as a competing risk in the model, based on Mexican life tables [22]. For patients experiencing distant recurrence, mean survival was 3.3 years based on a retrospective analysis of recurrence data from real-life clinical practice [23]. Baseline age was 55.5 years, based on mean age of onset of breast cancer in Mexico taken from data collected by the Instituto Nacional de Cancerología (INCan) [24].

Costs in the Base Case Analysis

Costs were accounted from an IMSS perspective, with only direct medical costs included. Costs were identified from published sources on the basis of a literature review [24, 25]. Searches of the PubMed database and gray literature based on selected key words (breast, cancer, cost and Mexico) were performed, limited to articles published in Spanish or English between 2002 and 2012. The searches produced a total of 39 hits, of which 7 articles were selected for full text review.

All costs were expressed in 2011 Mexican Pesos (MXN) and mid-point averages between fluorouracil (5FU), epirubicin and cyclophosphamide (FEC), and cyclophosphamide, methotrexate and 5FU (CMF) regimen costs were used in the analysis, resulting in an average cost of chemotherapy of MXN 154,133 (USD 11,685) in the first year, based on six cycles of chemotherapy [25, 26]. The annual costs of endocrine therapy were assumed to be MXN 5972 (USD 453) based on data from the INCan and were accrued for 8 years per patient [24]. The one-off cost of the 21-gene assay was MXN 42,871 based on the current list price (converted from USD 3250 at a rate of USD 1 = MXN 13.191), with this exchange rate used for all other currency conversions. Distant recurrence was calculated to cost MXN 404,907 (USD 30,696) per patient based on data from the INCan [24].

Sensitivity Analysis and Secondary Analysis

A series of one-way sensitivity analyses were performed to identify key drivers of model outcomes. Where possible sensitivity analyses were based on alternative data sources, but in a number of cases a lack of evidence to inform alternative values resulted in varying input values symmetrically to evaluate sensitivity (rather than uncertainty). This approach is in line with health economic guidance [27]. The cost discount rate was varied between 3% and 7%, with outcome discount rate varied between 0% and 7%, in line with pharmacoeconomic guidance for Mexico [27]. The time horizon was varied to 10, 20, and 30 years (compared to 40 years in the base case). The total cost of chemotherapy (including adverse event costs) was varied ±20%. The cohort age was varied to 45, 50 and 60 years, (55.5 years in the base case). To investigate the impact of survival following distant recurrence, post-recurrence survival was set to 1.5 years, based on data reported by Remák and Brazil [28]. To assess the importance of chemotherapy benefit, the relative risk reduction with chemotherapy in the low and intermediate Recurrence Score groups was set to 1.1% and 39%, respectively, in two sensitivity analyses, based on data reported by Paik et al. [5]. The impact of risk of distant recurrence was investigated by setting the 10-year risk of recurrence to 4.43%, 13.24%, and 27.26% in low, intermediate and high Recurrence Score groups, respectively, based on data from postmenopausal, node-negative patients in the UK (converted from annual rates) [10]. In addition to the one-way sensitivity analyses, two multi-way sensitivity analyses representing best and worst case scenarios for the 21-gene assay were performed. In the optimistic scenario, the cost of chemotherapy was increased by 20% and post-recurrence survival was set to 1.5 years. In the pessimistic scenario, the cost of chemotherapy was decreased by 20% and post-recurrence survival was set to 4.8 years.

The benefits of 21-gene assay testing may be mostly manifested in terms of reducing the level of chemotherapy over-prescribing (chemotherapy sparing). For this reason, while the primary analysis included all early-stage breast cancer patients (representing a conservative cost-effectiveness scenario), a secondary analysis was conducted focusing on the population recommended chemotherapy prior to assay testing. Data for this analysis were taken from a recent decision impact study in Mexico, as this breakdown was not available from Hornberger and Chien [8, 29]. In this population (n = 46), approximately 46% of patients had adjuvant therapy recommendations changed following assay testing. For this analysis, all other clinical and cost parameters were unchanged from the base case analysis.

Compliance with Ethics Guidelines

The analysis in this article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.

Results

Base Case Analysis of All Early-Stage Breast Cancer Patients

Based on the Hornberger and Chien [8] meta-analysis of decision impact studies, use of the 21-gene assay was associated with significant reduction in the number of patients receiving chemotherapy. Approximately, 66% of patients previously receiving chemotherapy were recommended to receive hormone therapy only after consideration of assay results. Furthermore, approximately 10% of those previously allocated hormone therapy alone had their recommendation changed to add chemotherapy.

Based on this optimized treatment allocation, the 21-gene assay was projected to increase mean life expectancy by 0.068 life-years per patient (Table 2). The clinical benefit was driven by the identification of patients at high risk of recurrence not receiving beneficial chemotherapy in usual care, and changing their adjuvant treatment. Mean direct costs were increased by MXN 1707 (USD 129) per patient, driven by the increased acquisition cost of the test, but this was partially offset by the reduced cost of chemotherapy and chemotherapy-related adverse events. These estimates resulted in an ICER of MXN 25,244 (USD 1914) per life-year gained.
Table 2

Summary of cost-effectiveness results for the base case analysis of all early-stage breast cancer patients

 

Usual care

21-gene assay testing

Difference

Cost (MXN)

124,999 (USD 9476)

126,706 (USD 9605)

1707 (USD 129)

Life expectancy (years)

7.976

8.043

0.068

ICER (MXN per life-year gained)

25,244 (USD 1914 per life-year gained)

ICER incremental cost-effectiveness ratio, MXN 2011 Mexican Pesos, USD 2011 United States Dollars

Sensitivity Analysis

One-way sensitivity analysis found that base case outcomes were most sensitive to changes in costs of chemotherapy and time horizon (Table 3; Fig. 2). When the cost of chemotherapy was increased by 20%, the 21-gene assay was dominant over usual care (improving clinical outcomes and reducing costs). Reducing the cost of chemotherapy by 20% resulted in an increased ICER of MXN 134,196 (USD 10,173) per life-year gained. Shortening the time horizon had a notable impact on the ICER, as might be expected with a diagnostic test that can lead to long-term benefits. At a time horizon of 10 years, the full costs of testing were accrued, but only part of the clinical benefit (resulting in an ICER of MXN 148,856 per life-year gained). At longer time horizons, as the long-term clinical benefits of using the assay were more fully captured, testing becomes increasingly cost-effective. Decreasing the age of the patient cohort to 45 years led to a fall in the ICER. This was due to reduced competing mortality, allowing patients to live for longer and accumulate the full benefit of assay testing. Increasing the cohort age to 60 years led to an unexpected decrease in the ICER. This was due to the life tables used, where the annual risk of mortality falls when patients’ age becomes above 64 years (but then increases slightly) and then falls again when patient reached 79 years. Varying discount rates for costs and benefits resulted in ICERs between MXN 7398 (USD 561) and MXN 41,739 (USD 3164) per life-year gained. Applying the alternative risk of recurrence had a notable impact on cost-effectiveness, with the ICER increasing. In the optimistic scenario, the 21-gene assay was dominant over standard care. In the pessimistic scenario, the ICER was MXN 179,238 (USD 13,588) per life-year gained.
Table 3

Summary of sensitivity analysis results for early-stage breast cancer patients in Mexico

Scenario

ICER (MXN per life-year gained) for 21-gene assay testing versus usual care

ICER (USD per life-year gained) for 21-gene assay testing versus usual care

Base case

25,244

1914

Discounting

 Costs discounted by 3% per annum, outcomes discounted by 7% per annum

33,993

2577

 Costs discounted by 7% per annum, outcomes discounted by 0% per annum

12,682

961

 Costs discounted by 3% per annum, outcomes discounted by 0% per annum

7398

561

 Costs discounted by 7% per annum, outcomes discounted by 7% per annum

41,739

3164

Time horizon

 10 years

148,856

11,285

 20 years

39,448

2991

 30 years

28,002

2123

Cohort age

 45 years

13,781

1045

 50 years

20,939

1587

 60 years

22,674

1719

Cost of chemotherapy

 Increased by 20%

Dominant

Dominant

 Decreased by 20%

134,196

10,173

 Incapacity cost not included

172,838

13,103

Clinical parameters

 Post-recurrence survival set to 1.5 years (Remák and Brazil [28])

20,550

1558

 Relative risk reduction with chemotherapy in the low Recurrence Score group set to 1.1%

25,725

1950

 Relative risk reduction with chemotherapy in the intermediate Recurrence Score group set to 39%

44,720

3390

 10-year risk of recurrence set to 4.43%, 13.24% and 27.26% in low, intermediate and high Recurrence Score groups, respectively, based on Dowsett et al. [10]

60,323

4573

Optimistic and pessimistic scenarios

 Optimistic scenario

Dominant

Dominant

 Pessimistic scenario

179,238

13,588

ICER incremental cost-effectiveness ratio, MXN 2011 Mexican Pesos, USD 2011 United States Dollars

Fig. 2

Tornado diagram of sensitivity analysis results. Note that the optimistic scenario and the scenario with chemotherapy costs increased by 20% are not included in the figure as the 21-gene assay was found to be dominant in these analyses and no calculation of an ICER is possible. ICER incremental cost-effectiveness ratio, MXN 2011 Mexican Pesos, RRR relative risk reduction with chemotherapy

Secondary Analysis of Patients Previously Allocated Chemotherapy in Standard Care

In the population originally recommended chemotherapy prior to assay testing, use of the assay was associated with significant reduction in the number of patients receiving chemotherapy, based on the Mexican decision impact study [30]. Approximately, 46% of patients previously receiving chemotherapy were recommended to receive hormone therapy only after use of the assay. Based on these changes, the assay was projected to save MXN 27,414 (USD 2078) per patient compared with current clinical practice over a 40-year time horizon (Table 4). Clinical outcomes, in terms of mean life expectancy, remained unchanged with and without use of the assay.
Table 4

Summary of cost-effectiveness results for the secondary analysis of patients allocated chemotherapy in usual care

 

Usual care

21-gene assay testing

Difference

Cost (MXN)

207,063 (USD 13,588)

179,649 (USD 15,697)

−27,414 (−USD 2078)

Life expectancy (years)

8.015

8.015

0

ICER (MXN per life-year gained)

Cost saving

ICER incremental cost-effectiveness ratio, MXN 2011 Mexican Pesos, USD 2011 United States Dollars

Discussion

The present long-term modeling study, which represents the first cost-effectiveness evaluation of a molecular diagnostic assay in breast cancer in Latin America, found that use of the 21-gene assay was associated with an ICER of MXN 25,244 (USD 1914) per life-year gained in patients with early-stage breast cancer in Mexico. Decision making around whether a new healthcare intervention is cost-effectives is subjective, depending on the willingness-to-pay for improvements in healthcare, which may be affected by a wide variety of factors. To date, no willingness-to-pay threshold is evident for the Mexican setting. The World Health Organization recommends the use of a willingness-to-pay threshold of three times the gross domestic product per capita per quality-adjusted life-year gained. In the Mexican setting, this would equate to a threshold of MXN 432,000 (USD 32,750) per quality-adjusted life-year gained. However, the present analysis captured only life expectancy, and not quality of life. A conservative approach is to assume that the willingness-to-pay threshold for a life-year is the same as for a quality-adjusted life-year. Based on this approach, while fully acknowledging its assumptions and weaknesses, use of the 21-gene assay is likely to be cost-effective in Mexico for patients with hormone-receptor-positive, HER2-negative, node-negative or up to 3 node-positive early-stage breast cancer.

A limitation of the present analysis is that quality of life is not captured in the results. Therefore, only life expectancy gains associated with identifying patients at high risk of distant recurrence not receiving beneficial chemotherapy in usual care are captured. While undertreatment is a key issue, as it denies patients treatment that would substantially reduce the high risk of distant recurrence, overtreatment is more prevalent in adjuvant breast cancer care, as shown by the meta-analysis by Hornberger and Chien [8], where 66% of patients originally recommended chemotherapy (29.5% of the total population) received endocrine therapy only following 21-gene assay testing. The impact of chemotherapy on health-related quality of life is substantial, with both short- and long-term adverse events playing a significant role [30, 31, 32]. This detrimental effect in patients who will not experience any benefit from chemotherapy can be avoided when the assay is used to guide adjuvant decision making. This is of particular note in patients who are allocated chemotherapy in usual care, as in the secondary analysis, where 46% of the total population had chemotherapy removed from their treatment regimen. While life expectancy was not found to increase in the analysis of patients previously allocated chemotherapy, inclusion of utilities to capture quality of life changes associated with chemotherapy treatment and its adverse event profile is highly likely to be associated with an improvement in quality-adjusted life expectancy. ICERs calculated based on quality-adjusted life expectancy are likely to be lower than those calculated on life expectancy.

A further potential limitation of the analysis is the reliance on clinical data collected from outside Mexico. The risk of recurrence data and relative risk reduction with chemotherapy were taken from a USA-based study, while survival post-recurrence was estimated from a UK-based study [5, 23]. This data represents the best available evidence to parameterize the model, as clinical data specific to the Mexican setting is not currently available. However, it may not be generalizable to current care in Mexico. In high-income countries such, as the USA and the UK, the majority of breast cancer cases are identified in the early stages, but in Mexico only 10% of breast cancer cases are identified at the lymph node-negative or one lymph node-positive stage of progression [33]. Improved patient outcomes are associated with early detection, and the 21-gene assay is validated in early-stage breast cancer patients. However, detection is likely to become earlier in Mexico in the future, with evidence showing that the proportion of women screened for breast cancer is increasing, with the most substantial increase in the population aged over 45 years [3]. As detection of breast cancer occurs earlier in Mexico, the full utility of the 21-gene assay may be realized.

The Paik et al. [5] study assessed the 10-year risk of recurrence in patients receiving tamoxifen monotherapy as hormone therapy, while more modern regimens rely on an aromatase inhibitor. However, data from the transATAC study have demonstrated that Recurrence Score results are validated in patients treated with either tamoxifen or an aromatase inhibitor [10]. Moreover, patients in the Paik et al. [5] study received CMF or MF (methotrexate and 5-FU), rather than CMF or FEC as assumed in our analysis. It is not clear how variation in chemotherapy regimens is likely to impact on the risk of distant recurrence and therefore cost-effectiveness of the 21-gene assay.

The data to inform standard care without the 21-gene assay and the decision impact of the use of the test were taken from a meta-analysis of decision impact studies [8]. This took data from a number of settings worldwide and represents the most comprehensive assessment of the effect of use of the 21-gene assay on clinical practice (the total number of included patients was 1154). Therefore, this was considered the most appropriate data source to inform the base case analysis. A potential weakness of the present base case analysis is that this data is not specific to the Mexican setting. More recently, a decision impact study has been conducted in the Mexican setting and this study has been used in a secondary analysis [30]. A key aspect to be considered is how the impact of 21-gene assay may vary in Mexico compared to other settings. The proportion of patients identified at low, intermediate and high Recurrence Scores was similar in the Mexican setting and in the meta-analysis. Chemotherapy allocation at baseline was also similar, but a greater proportion of the high Recurrence Score patients received chemotherapy in standard care in Mexico. Since a greater proportion of patients with high Recurrence Scores were already receiving chemotherapy in the Mexican study, fewer patients were switched to receive chemotherapy. Furthermore, fewer patients with low or intermediate Recurrence Scores were switched from chemotherapy plus hormone therapy to hormone therapy only in the Mexican decision impact study compared to the meta-analysis, despite similar treatment allocation without use of the test. It is likely that as use of the 21-gene assay becomes more prevalent and accepted in the Mexican setting that patients with low or intermediate Recurrence Scores will be switched to receive hormone therapy only. Therefore, the results of the meta-analysis used to inform the base case analysis will become more applicable to the Mexican setting as use of the 21-gene assay increases.

The results of the present analysis concur with previous cost-effectiveness evaluations of the 21-gene assay, conducted in a variety of countries, including the UK (using the model adapted for this study), Australia, USA, Hungary, Israel, Japan and Singapore [20, 34, 35, 36, 37, 38]. In all of these studies, the assay has been projected to improve clinical outcomes, in terms of life expectancy and quality-adjusted life expectancy, versus conventional care. In countries where chemotherapy use is very high in standard care, such as USA, use of the assay was associated with reductions in direct costs, as the savings due to chemotherapy sparing offset the cost of the test. In countries where chemotherapy use is less prevalent in standard care, the assay was associated with increased direct costs, but was still considered cost-effective in all settings.

A key aspect of the present study is the transferability to other low-income countries. In countries with a low income, resources available for healthcare expenditure are generally very restricted. Therefore, the cost savings as a result of avoided chemotherapy following 21-gene assay testing can be very significant, as it allows resources to be spent on other areas of healthcare which would otherwise not have received funding. Use of the 21-gene assay can also lead to substantial improvements in clinical outcomes. This may be particularly important for healthcare systems aiming to maximize health outcomes with a low budget. In countries where undertreatment of patients at high risk of recurrence is prevalent, the 21-gene assay can be used to target chemotherapy to those who are likely to experience a life expectancy benefit. Furthermore, chemotherapy sparing for patients who will not experience a benefit will lead to an increase in quality of life (although duration will not be affected).

Conclusion

The use of the 21-gene assay has a considerable influence on chemotherapy treatment recommendations in patients with hormone-receptor-positive, HER2-negative, node-negative or up to 3 node-positive early-stage breast cancer [8]. It is associated with substantial chemotherapy sparing in patients likely to derive little or no benefit from treatment and assists in the identification of patients currently considered at low risk who will in fact benefit from chemotherapy. Based on this modeling study, guiding decision making on adjuvant therapy using the 21-gene assay was projected to improve life expectancy in comparison with the current standard of care in Mexico, with an ICER of MXN 25,244 (USD 1914) per life-year gained, which is within the range generally considered cost-effective.

Notes

Acknowledgments

Sponsorship and article processing charges for this study were funded by Genomic Health, Inc. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.

Conflict of interest

Juliette Plun-Favreau is an employee of Genomic Health International. William Valentine is an employee of Ossian Health Economics and Communications. Barnaby Hunt is an employee of Ossian Health Economics and Communications. Ossian received funding from Genomic Health International to support the present study. Juan Enrique Bargalló-Rocha, Fernando Lara-Medina, Victor Pérez-Sánchez, Rafael Vázquez-Romo, Cynthia Villarreal-Garza, Hector Martínez-Said, Robin J Shaw-Dulin, and Alejandro Mohar-Betancourt have no conflicts of interest to declare.

Compliance with ethics guidelines

The analysis in this article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.

Supplementary material

12325_2015_190_MOESM1_ESM.pdf (239 kb)
Supplementary material 1 (PDF 238 kb)
12325_2015_190_MOESM2_ESM.pdf (269 kb)
Supplementary material 2 (PDF 268 kb)

References

  1. 1.
    Porter P. “Westernizing” women’s risks? Breast cancer in lower-income countries. N Engl J Med. 2008;358(3):213–6.CrossRefPubMedGoogle Scholar
  2. 2.
    Rodríguez-Cuevas S, Macías C, Labastida S. Cáncer de mama en México: ¿enfermedad de mujeres jóvenes? Ginecol Obstet Mex. 2000;68(5):185–90.PubMedGoogle Scholar
  3. 3.
    Knaul FM, Nigenda G, Lozano R, Arreola-Ornelas H, Langer A, Frenk J. Breast cancer in Mexico: a pressing priority. Reprod Health Matters. 2008;16(32):113–23.CrossRefPubMedGoogle Scholar
  4. 4.
    Knaul FM, Arreola-Ornelas H, Velázquez E, Dorantes J, Méndez O, Avila-Burgos L. The health care costs of breast cancer: the case of the Mexican Social Security Institute. Salud Publica Mex. 2009;51(Suppl 2):s286–95.CrossRefPubMedGoogle Scholar
  5. 5.
    Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006;24(23):3726–34.CrossRefPubMedGoogle Scholar
  6. 6.
    Early Breast Cancer Trialists’ Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365:1687–717.CrossRefGoogle Scholar
  7. 7.
    Hassett MJ, Hughes ME, Niland JC, et al. Chemotherapy use for hormone receptor–positive, lymph node–negative breast cancer. J Clin Oncol. 2008;26(34):5553–60.CrossRefPubMedCentralPubMedGoogle Scholar
  8. 8.
    Hornberger J, Chien R. Meta-analysis of the decision impact of the 21-gene breast cancer recurrence score in clinical practice. In: San Antonio Breast Cancer Symposium 2010. Poster Presentation #P3-09-06.Google Scholar
  9. 9.
    Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351(27):2817–26.CrossRefPubMedGoogle Scholar
  10. 10.
    Dowsett M, Cuzick J, Wale C, et al. Prediction of risk of distant recurrence using the 21-gene recurrence score in node-negative and node-positive postmenopausal patients with breast cancer treated with anastrozole or tamoxifen: a TransATAC study. J Clin Oncol. 2010;28:1829–34.CrossRefPubMedGoogle Scholar
  11. 11.
    Habel LA, Shak S, Jacobs MK, et al. A population-based study of tumor gene expression and risk of breast cancer death among lymph node-negative patients. Breast Cancer Res. 2006;8(3):R25.CrossRefPubMedCentralPubMedGoogle Scholar
  12. 12.
    Albain KS, Barlow WE, Shak S, et al. Prognostic and predictive value of the 21-gene recurrence score assay in a randomized trial of chemotherapy for postmenopausal, node-positive, estrogen receptor-positive breast cancer. Lancet Oncol. 2010;11(1):55–65.CrossRefPubMedCentralPubMedGoogle Scholar
  13. 13.
    Aebi S, Davidson T, Gruber G, Castiglione M, ESMO Guidelines Working Group. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21(Suppl 5):v9–14.CrossRefPubMedGoogle Scholar
  14. 14.
    Harris L, Fritsche H, Mennel R, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol. 2007;25(33):5287–312.CrossRefPubMedGoogle Scholar
  15. 15.
    NCCN Clinical Practice Guidelines in Oncology™ Breast Cancer, (Version 1.2011). Available at: http://www.nccn.org. Accessed Mar 4, 2013.
  16. 16.
    Goldhirsch A, Ingle JN, Gelber RD, et al. Thresholds for therapies: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2009. Ann Oncol. 2009;20(8):1319–29.CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Goldhirsch A, Wood WC, Coates AS, et al. Strategies for subtypes–dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol. 2011;22(8):1736–47.CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    Azim HA Jr, Michiels S, Zagouri F, et al. Utility of prognostic genomic tests in breast cancer practice: the IMPAKT 2012 Working Group Consensus Statement. Ann Oncol. 2013;24(3):647–54.CrossRefPubMedGoogle Scholar
  19. 19.
    Rouzier R, Pronzato P, Chéreau E, Carlson J, Hunt B, Valentine WJ. Multigene assays and molecular markers in breast cancer: systematic review of health economic analyses. Breast Cancer Res Treat. 2013;139(3):621–37.CrossRefPubMedCentralPubMedGoogle Scholar
  20. 20.
    Holt SDH, Bennett H, Bertelli G, Valentine WJ, Phillips CJ. Cost-effectiveness of the Oncotype DX® breast cancer assay in clinical practice in the UK. In: Poster presented at the 34th Annual San Antonio Breast Cancer Symposium, 2011.Google Scholar
  21. 21.
    International Society for Health Economics and Outcomes Research. Pharmacoeconomic guidelines around the world. Available at http://www.ispor.org/PEguidelines/countrydet.asp?c=37&t=1. Accessed Mar 12, 2013.
  22. 22.
    Secretaría de Salud. http://sinais.salud.gob.mx. Accessed Nov 13, 2012.
  23. 23.
    Thomas RJ, Williams M, Marshall C, Glen J, Callam M. The total hospital and community UK costs of managing patients with relapsed breast cancer. Br J Cancer. 2009;100(4):598–600.CrossRefPubMedCentralPubMedGoogle Scholar
  24. 24.
    Instituto Nacional de Cancerología. http://incan-mexico.org/. Accessed Nov 13, 2012.
  25. 25.
    Gómez-Rico JA, Altagracia-Martínez M, Kravzov-Jinich J, Cárdenas-Elizalde R, Rubio-Poo C. The costs of breast cancer in a Mexican public health institution. Risk Manag Healthcare Pol. 2008;1:15–21.Google Scholar
  26. 26.
    Partridge AH, Burstein HJ, Winer EP. Side effects of chemotherapy and combined chemohormonal therapy in women with early-stage breast cancer. J Natl Cancer Inst Monogr. 2001;30:135–42.CrossRefPubMedGoogle Scholar
  27. 27.
    Briggs AH, Weinstein MC, Fenwick EA, et al. Model parameter estimation and uncertainty: a report of the ISPOR-SMDM Modeling Good Research Practices Task Force–6. Value Health. 2012;15(6):835–42.CrossRefPubMedGoogle Scholar
  28. 28.
    Remák E, Brazil L. Cost of managing women presenting with stage IV breast cancer in the United Kingdom. Br J Cancer. 2004;91(1):77–83.CrossRefPubMedCentralPubMedGoogle Scholar
  29. 29.
    Bargallo JER, Lara F, Shaw Dulin RJ, et al. A study of the impact of the 21-gene breast cancer assay on the use of adjuvant chemotherapy in women with breast cancer in a Mexican public hospital. In: Poster presented at European Society for Medical Oncology Congress, 2012.Google Scholar
  30. 30.
    Conner-Spady BL, Cumming C, Nabholtz JM, Jacobs P, Stewart D. A longitudinal prospective study of health-related quality of life in breast cancer patients following high-dose chemotherapy with autologous blood stem cell transplantation. Bone Marrow Transplant. 2005;36(3):251–9.CrossRefPubMedGoogle Scholar
  31. 31.
    Canadian Breast Cancer Network. Breast Cancer: Economic Impact and Labour Force Re-Entry. 2010. Available at: http://www.cbcn.ca/index.php?pageaction=content.page&id=2912&lang=en. Accessed Nov 17, 2011.
  32. 32.
    Peugniez C, Fantoni S, Leroyer A, Skrzypczak J, Duprey M, Bonneterre J. Return to work after treatment for breast cancer: single center experience in a cohort of 273 patients. Bull Cancer. 2011;98(7):E69–79.PubMedGoogle Scholar
  33. 33.
    López-Carrillo L, Torres-Sánchez L, López-Cervantes M, et al. Identificación de lesions mamarias en México. Salud Pública de México. 2001;43(3):199–202.CrossRefPubMedGoogle Scholar
  34. 34.
    O’Leary B, Yoshizawa C, Foteff C, Chao C. Cost-effectiveness of the Oncotype DX assay in Australia: an exploratory analysis. In: Presented at ISPOR 4th Asia-Pacific Conference, Phuket. 2010.Google Scholar
  35. 35.
    Hornberger J, Cosler LE, Lyman GH. Economic analysis of targeting chemotherapy using a 21-gene RT-PCR assay in lymph-node-negative, estrogen-receptor-positive, early-stage breast cancer. Am J Manag Care. 2005;11(5):313–24.PubMedGoogle Scholar
  36. 36.
    Madaras B, Rózsa P, Gerencsér Z, et al. The Impact of chemotherapeutic regimens on the cost-utility analysis of Oncotype DX assay. In: Presented at EBCC 8, Vienna. 2012.Google Scholar
  37. 37.
    Klang SH, Hammerman A, Liebermann N, Efrat N, Doberne J, Hornberger J. Economic implications of 21-gene breast cancer risk assay from the perspective of an Israeli-managed health-care organization. Value Health. 2010;13(4):381–7.CrossRefPubMedGoogle Scholar
  38. 38.
    de Lima Lopes G, Chien R, Hornberger JC. Cost-benefit analysis of a 21-gene recurrence score for early-stage breast cancer in Singapore. In: Presented at 12th St. Gallen International Breast Cancer Conference, St Gallen. 2011.Google Scholar

Copyright information

© Springer Healthcare 2015

Authors and Affiliations

  • Juan Enrique Bargalló-Rocha
    • 1
  • Fernando Lara-Medina
    • 1
  • Victor Pérez-Sánchez
    • 1
  • Rafael Vázquez-Romo
    • 1
  • Cynthia Villarreal-Garza
    • 1
  • Hector Martínez-Said
    • 1
  • Robin J. Shaw-Dulin
    • 1
  • Alejandro Mohar-Betancourt
    • 1
  • Barnaby Hunt
    • 2
  • Juliette Plun-Favreau
    • 3
  • William J. Valentine
    • 2
  1. 1.Instituto Nacional de CancerologiaMexico CityMexico
  2. 2.Ossian Health Economics and CommunicationsBaselSwitzerland
  3. 3.Genomic Health InternationalGenevaSwitzerland

Personalised recommendations