Health Economic Analysis of Breast Cancer Index in Patients With ER+, LN- Breast Cancer

September 10, 2014
Gary Gustavsen, MS
Gary Gustavsen, MS

,
Brock Schroeder, PhD
Brock Schroeder, PhD

,
Patrick Kennedy, BE
Patrick Kennedy, BE

,
Kristin Ciriello Pothier, MS
Kristin Ciriello Pothier, MS

,
Mark G. Erlander, PhD
Mark G. Erlander, PhD

,
Catherine A. Schnabel, PhD
Catherine A. Schnabel, PhD

,
Haythem Ali, MD
Haythem Ali, MD

Volume 20, Issue 8

This study projected that the breast cancer index assay is cost saving when used either at diagnosis or at 5 years post diagnosis.

Objectives

Breast Cancer Index (BCI) is a novel gene expression-based test

for patients with estrogen receptor positive (ER+), lymph node

negative (LN—) breast cancer that predicts risk of recurrence over

10 years, and also specifically predicts risk of late (≥5 y) recurrences

and likelihood of benefit from extended (≥5 y) endocrine

therapy. The objective of this study was to evaluate cost utility of

BCI from a US third-party payer perspective.

Study Design

Two fact-based economic models were developed to project

the cost and effectiveness of BCI in a hypothetical population of

patients with ER+, LN— breast cancer compared with standard

clinicopathologic diagnostic modalities.

Methods

Costs associated with adjuvant chemotherapy, toxicity, followup,

endocrine therapy, and recurrence were modeled over 10

years. The models examined cost utility compared with standard

practice when used at diagnosis and in patients disease-free at 5

years post diagnosis.

Results

Use of BCI was projected to be cost saving in both models. In the

newly diagnosed population, net cost savings were $3803 per

patient tested. In the 5 years post diagnosis population, BCI was

projected to yield a net cost savings of $1803 per patient tested.

Sensitivity analyses demonstrated that BCI was cost saving

across a wide range of clinically relevant input assumptions.

Conclusions

BCI was projected to be cost saving when used either at diagnosis

or at 5 years post diagnosis. Cost savings are achieved through

projected impact on adjuvant chemotherapy use, extended

endocrine therapy use, and endocrine therapy compliance. These

findings require validation in additional cohorts, including studies

of real-world clinical practice.

Am J Manag Care. 2014;20(8):e302-e310

This health economic analysis demonstrated that use of Breast Cancer Index in patients

with estrogen receptor positive, lymph node negative early breast cancer is cost saving

compared with standard management.

  • From a third-party payer perspective, use of this test may result in substantially lower overall medical costs.
  • The test resulted in cost savings when used either at diagnosis or at 5 years post diagnosis.
  • Cost savings were driven by a reduction in adjuvant chemotherapy in patients unlikely to derive benefit (when used at diagnosis), and optimization of extended endocrine therapy utilization in patients likely to receive substantial benefit (when used at either time point).

Each year more than 230,000 women are diagnosed

with breast cancer in the United States.1 The clinical

subset of patients with estrogen receptor positive

(ER+), lymph node negative (LN—) breast cancer has

a better overall prognosis than patients in other clinical

subsets (eg, triple negative breast cancer, human epidermal

growth factor receptor 2—positive [HER2+] breast cancer).

However, one of the hallmarks of ER+ breast cancer is the

persistent risk of recurrence that extends greater than 15

years after initial diagnosis and treatment.2 In addition to

surgical intervention and 5 years of endocrine-based therapy,

patients and physicians have 2 important therapeutic

considerations: first, whether or not to receive adjuvant

chemotherapy; and second, whether to extend endocrinebased

therapy beyond 5 years. These difficult clinical decisions,

which are multifactorial and must balance the

potential risks and benefits of therapy, have led to the development

of multiple prognostic and predictive tools to

assist with clinical decision making.

Significant focus has been placed on supporting the adjuvant

chemotherapy decision. Over the past decade, a number

of molecular assays designed to predict risk of recurrence

and chemotherapy benefit for ER+ patients have become

commercially available. These molecular assays have been

incorporated into clinical practice, have been shown to impact

clinical decision making regarding the use of adjuvant

chemotherapy,3-5 and have been incorporated into clinical

guidelines.6,7 Finally, gene expression—based assays have

been shown to be cost saving, through more appropriate patient

stratification and utilization of adjuvant chemotherapy.

While significant progress has been made in the area of adjuvant

chemotherapy guidance, little progress had been made,

until recently, in assessing risk of late (post 5-year) recurrence

and in determining the duration of endocrine therapy patients

would receive. Focus on this area has grown, given the results

of several randomized, prospective clinical trials (eg, MA.17,

ATLAS, aTTom) demonstrating clinical benefit of extend

ing endocrine-based therapy beyond 5

years.8-11 While statistically significant

clinical benefit was observed in all 3 trials,

the absolute benefits were relatively

small (approximately 3%-6%); this suggests

the need, so far unaddressed, to

stratify patients based on risk of late recurrence

and likelihood of benefit from

extended endocrine therapy.

Breast Cancer Index (BCI; bioTheranostics,

San Diego, California) is a

gene expression-based biomarker with a novel mechanism

of action. BCI was developed through the algorithmic combination

of 2 complementary biomarkers: molecular grade

index (MGI), which recapitulates tumor grade/proliferation

status; and HOXB13:IL17BR ratio [BCI (H/I)], which

interrogates estrogen-signaling pathways. In clinical validation

studies, BCI has been demonstrated to significantly predict

overall (10-year) risk of recurrence, and also specifically

predict risk of early (0- to 5-year) and late (≥5-year) recurrence

in ER+, LN— breast cancer patients.12,13 In addition,

in a prospective-retrospective analysis of the randomized

MA.17 trial, BCI (H/I) was shown to be predictive of extended

endocrine therapy benefit. Letrozole treatment led

to a reduction in the absolute risk of recurrence at 5 years of

16.5% in patients with high BCI (H/I) (

P

= .007) while there

was no statistically significant benefit (

P

= .35) in patients

with a low BCI (H/I) gene expression ratio.14

Although BCI has been clinically validated in prospective

clinical trial cohorts, the health economic impact of

BCI has not been investigated, particularly with respect to

the novel functionality in predicting extended endocrine

therapy benefit. BCI can be ordered at initial diagnosis to

assess risk of overall, early, and late recurrence, and the

likelihood of extended endocrine therapy benefit. In addition,

BCI can be used in the prevalent population—those

patients who are recurrence-free after approximately 5 years

of endocrine-based therapy—to assess risk of late recurrence

and likelihood of benefit from continued endocrine

therapy. Therefore, the purpose of this study was to assess

the health economic impact associated with implementing

BCI at diagnosis or with utilizing BCI in patients who are

recurrence-free 5 years after diagnosis and who are considering

extended endocrine therapy.

METHODS

Models

A deterministic, decision-analytic model was developed

from the payer perspective to project cost and clinical outcomes

of using BCI compared with standard clinicopathologic

evaluation to guide ER+, LN— breast cancer patient

management for decisions of adjuvant chemotherapy and

duration of endocrine-based therapy. Treatment of a hypothetical

cohort of ER+, LN— breast cancer patients was

simulated with patient flow models, the structures of which

were developed according to the 2012 National Comprehensive

Cancer Network guidelines for management of

such patients.7 Branches represented patient management

under 2 scenarios: using standard clinicopathologic diagnostic

modalities alone versus incorporating BCI. The hypothetical

patient cohort was followed through the models

that tracked costs across a variety of possible health states

including adjuvant chemotherapy, complications, endocrine

therapy, observation, recurrence, and death over a

10-year follow-up. Two separate models were developed:

the first evaluated BCI ordered at diagnosis and included

impact on adjuvant chemotherapy decision making and

decision making regarding extended endocrine therapy;

the second evaluated BCI when ordered at 5 years post

diagnosis for the hypothetical population of patients who

were recurrence-free at 5 years post diagnosis, and included

impact on decision making for duration of endocrinebased

therapy.

Clinical Inputs

Clinical Decision Making. Key assumptions driving

adjuvant chemotherapy decision making are highlighted

in

Table 1

. BCI risk categorization was derived from a

real-world clinical validation cohort in the indicated

patient population.11 Clinical decision making based

on risk categorization and estimates of disease-free survival

were estimated based on published studies evaluating

impact of Recurrence Score (21-gene assay).3,15 Key

assumptions driving use of extended endocrine-based

therapy are also highlighted in Table 1. In the scenario

without BCI, inputs were estimated based on interviews

with disease-state experts. In the scenario with BCI, the

model assumes that patients with high BCI (H/I) would

receive extended endocrine therapy, and patients with

low BCI (H/I) would stop endocrine therapy after 5

years based on the published outcomes from the MA.17

study.13 Disease-free survival in years 5 to 10 was modeled

based on BCI risk categorization status and utiliza

tion of extended endo crine therapy as reported in the

MA.17 cohort.13

Compliance

. To account for the potential effect of patient

compliance with endocrine therapy on the effect of

therapy and the likelihood of recurrence, compliance to

endocrine therapy and the associated impact on disease

recurrence was modeled according to previously observed

rates.16,17 The model also incorporated impact of a high

BCI (H/I) on patient compliance, based on a published

meta-analysis evaluating improvement in adherence following

information interventions.18,19 Compliance assumptions

are highlighted in Table 1.

Costs.

A variety of sources were used to build cost assumptions

applied to patients as they moved through

health states within the models (

Table 2

). Adjuvant chemotherapy

costs were derived from an observational study in

a Humana breast cancer population.3 Follow-up and recurrence

costs were based on breast cancer system economic

studies and considered total cost to the payer including

office visits, tumor-marker and imaging studies, systemic

treatments, complication management, and end-of-life

care.3,20 Adjuvant endocrine drug costs were based on a

RED BOOK analysis of average sale prices across various

manufacturers, factoring in generic drug pricing for both

tamoxifen and aromatase inhibitors.21 Alongside endocrine

therapy, additional costs associated with supportive

care (ie, bisphosphonate therapy) and complications (ie,

fractures) were included as well. Finally, the cost of the assay

was based on the manufacturer’s suggested retail pricing.

Analysis

For each model, impact on total cost was evaluated

based on effect from adjuvant chemotherapy decision

making, extended endocrine-based therapy decision making,

and impact on compliance

Figure 1

. One-way sensitivity

analyses were conducted to evaluate the impact of

parameter input uncertainty on model outcomes. Probabilities

and cost parameters were varied over a range of

clinically relevant conservative and aggressive estimates.

()

RESULTS

Model: BCI at Diagnosis

The base case model representing treatments based

on standard clinicopathologic variables and 10 years of

follow-up resulted in mean costs of $45,437 per patient.

Use of BCI at diagnosis resulted in mean costs of $41,634,

resulting in an average savings of $3803 per patient tested

after accounting for the cost of the test. These savings

can be traced to individual contributing cost drivers including

targeted use of adjuvant chemotherapy, targeted

use of extended endocrine therapy, and increased patient

compliance (

Figure 2A

).

Key outputs of the sensitivity analysis are illustrated

in

Figure 3A

. The model was most sensitive to the percentage

of patients classified as BCI (H/I) high, to BCI

test cost, and to the percentage of BCI (H/I) high patients

receiving extended endocrine therapy. None of the sensitivity

analyses resulted in cost savings of less than $2800

per patient tested, while more aggressive scenarios (eg,

percentage of patients classified as BCI (H/I) high, and

cost of recurrence) predicted cost savings of over $4000

per patient tested.

Model: BCI at 5 Years Post Diagnosis

In the second model, evaluating use of BCI in patients

who were recurrence-free at 5 years post diagnosis and

initial therapy, the base case resulted in mean costs of

$22,708 per patient without the use of BCI. Use of BCI at

this time point resulted in mean costs of $20,904, resulting

in a savings of $1803 per patient after accounting for

the cost of the test (

Figure 2B

). The cost benefit was predominantly

driven by targeted use of extended endocrine

therapy ($5194 savings per patient).

Key outputs of the sensitivity analysis for this model

are illustrated in

Figure 3B

. The model was most sensitive

to the percentage of patients classified as BCI (H/I)

high, to the percentage of BCI (H/I) high patients receiving

extended endocrine therapy, and to the total cost of

a recurrence. None of the sensitivity analyses resulted in

a cost savings under $300 per patient tested, while more

aggressive scenarios (eg, percentage of patients classified

as BCI (H/I) high, and cost of recurrence) predicted cost

savings of over $2300 per patient tested.

DISCUSSION

This health economic model projects the impact on

patient management and healthcare cost of a secondgeneration

molecular test for breast cancer recurrence

risk in patients with ER+, LN— breast cancer. The study

has 2 primary findings. First, the ability of BCI to predict

likelihood of benefit from extended endocrine therapy

adds additional cost savings on top of those cost savings

previously described for first-generation assays evaluating

the impact on adjuvant chemotherapy decision making

alone.3,19 BCI is projected to save an additional $2644 per

patient above the cost savings associated with optimizing

adjuvant chemotherapy alone. Second, the study demonstrated

that use of BCI in patients who are recurrence-free

after 5 years is cost saving as well. Optimizing the use of

extended endocrine therapy in these patients is projected

to save $1803 per patient tested after accounting for the

test cost in this setting.

As discussed, BCI has been estimated to save additional

costs beyond optimization of adjuvant chemotherapy,

the majority of which is driven by optimization of

extended endocrine therapy. Several large, randomized,

prospective clinical trials (eg, MA.17, ATLAS, aTTom)

have recently brought significant attention to the decision

of whether to extend endocrine therapy. While these trials

demonstrated treatment benefit, they showed only a

small absolute benefit in recurrence rates with extended

endocrine therapy in the unselected population.8-10 Given

the significant toxicities and side effects associated with

endocrine therapy, there exists an unmet need to identify

which patients should receive extended endocrine

therapy based on a higher risk of recurrence and likelihood

of benefit.22,23 BCI may be a tool to help address this

unmet need by stratifying patients based on their risk of

recurrence and likelihood of benefit, thereby increasing

extended endocrine therapy use in patients expected to

derive the most benefit while avoiding further treatment

and minimizing drug-related side effects in patients who

are unlikely to receive benefit. The results of this study

indicate that this additional clinical value proposition

translates into further system economic benefit for this

assay. With generic aromatase inhibitors now available,

extended endocrine therapy is highly cost effective and

substantially reduces recurrences in patients with high

BCI (H/I).

The magnitude of the cost savings generated by optimization

of extended endocrine therapy depends on

when the assay is used over the course of diagnosis and

follow-up. When used at initial diagnosis, this clinical

value proposition adds an additional $2165 to the per patient

tested cost savings. When used for recurrence-free

patients at 5 years post diagnosis (the decision point for

extending endocrine therapy), this clinical value proposition

adds $5194 to the per patient cost savings. The per

patient tested cost benefit is greater when the test is used

at 5 years post diagnosis because it is only used in the

subset of women who are eligible for extended endocrine

therapy (ie, not including women who have a recurrence

or discontinuation within the first 5 years), and therefore

do not realize the additional savings due to this component

of the test.

in

This study has a number of limitations. First, as an

silico

modeling study, many assumptions were based on

published clinical literature and expert interviews rather

than prospective real-world data of test economic impact.

As was the case with first-generation breast cancer

risk recurrence assays, future studies must assess the impact

of the assay in collaboration with third-party payers

to illustrate cost savings in a real-world setting. Second,

sensitivity analyses highlighted that cost savings were

most sensitive to the cost of the assay, to the proportion

of patients classified as high BCI (H/I), and to the percentage

of those patients following the recommendation

to receive extended endocrine therapy. The base scenario

of the model assumes optimal alignment between

test recommendation and physician/patient decision

on extended endocrine therapy. As has been observed

in real-world studies of first-generation assays, test recommendations

are incorporated with other clinical and

patient-specific factors, and thus are not followed in all

cases. Furthermore, it is important to note that the model

assumed that physicians may treat post menopausal patients

with extended aromatase inhibitor therapy following

an initial 5 years of aromatase inhibitor therapy. This

assumption was directly informed by interviews with disease-

state experts, per the study methodology. While definitive

data on the effectiveness of 10 years of aromatase

inhibitor treatment versus 5 years is not yet available,

the assumption is based on the effectiveness of extended

endocrine therapy demonstrated in 4 different randomized,

clinical trials.8-11 These assumptions and limitations

should be a focus for ongoing real-world studies. However,

it is important to note that the sensitivity analysis

reveals that even with a 20% discrepancy between test

recommendation and patient management, the test remains

highly cost-effective. Third, in a rapidly evolving

therapeutic landscape such as that of breast cancer treatment,

it is difficult to fully characterize the downstream

costs of recurrent cancer, as the treatment landscape

will likely involve new therapies by the time this patient

cohort experiences recurrences. With the emergence of

new higher-priced targeted therapy for metastatic disease,

costs for patients with recurrent breast cancer are

likely to rise.24,25 To examine this limitation, sensitivity

analyses revealed that as the cost of breast cancer recurrence

increases, BCI cost-effectiveness increases. Given

these trends, the base case assumes a relatively conservative

value for recurrence costs based on recent data,

leaving room for potential upside as treatment costs rise.

Finally, clinical data evaluating the benefit of adjuvant

chemotherapy based on BCI risk stratification are not

available, thus assumptions related to chemotherapy

utilization and patient outcomes are modeled based on

published RS studies. Notably, BCI has been investigated

in a neoadjuvant chemotherapy study, and demonstrated

ability to predict response to chemotherapy (as

assessed by pathologic complete response).26 In addition,

the sensitivity analyses demonstrate that a reduction in

chemotherapy benefit predictability of 25% results in

only a minor decrease in cost savings. Thus, while this

is an important limitation of the study, it is unlikely to

significantly alter the study’s conclusions.

In conclusion, this health economic analysis demonstrates

that use of BCI in patients with ER+, LN— early

breast cancer is cost saving compared with management

without the use of a molecular assay. From a third-party

payer perspective, use of this test may result in substantially

lower overall medical costs. These cost savings are

primarily driven by a reduction in adjuvant chemotherapy

in patients unlikely to derive benefit and an increase

in extended endocrine therapy utilization in patients

likely to receive substantial benefit. Additional studies on

clinical practice in real-world populations are needed to

validate these results.

Author Affiliations: Health Advances, LLC, Weston, MA (GG, PK,

KCP); bioTheranostics, Inc, San Diego, CA (BS, MGE, CAS); and Henry

Ford Health System, Detroit, MI (HA).

Funding Source: This study was funded by bioTheranostics, Inc.

Author Disclosures: bioTheranostics, Inc, markets the test described

in this manuscript.

Authorship Information: Concept and design (MGE, GG, PK, KCP,

BS, CAS); acquisition of data (PK, BS, CAS); analysis and interpretation

of data (HA, MGE, GG, PK, BS, CAS); drafting of the manuscript (GG,

BS, CAS); critical revision of the manuscript for important intellectual

content (HA, KCP, BS, CAS); administrative, technical, or logistic support

(MGE, BS, CAS); and supervision (HA, KCP).

Address correspondence to: Gary Gustavsen, MS, Health Advances,

LLC, 9 Riverside Rd, Weston, MA 02493. E-mail: ggustavsen@healthadvances.

com.

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