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Review

Considerations for payers in managing hormone receptor-positive advanced breast cancer

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Pages 331-339 | Published online: 10 Jul 2014

Abstract

Breast cancer (BC) is the second most common cause of death in women. In 2010, the direct cost associated with BC care in the US was $16.5 billion, the highest among all cancers. By the year 2020, at the current rates of incidence and survival, the cost is projected to increase to approximately $20 billion. Although endocrine therapies to manage hormone receptor-positive (HR+) BC are highly effective, endocrine resistance results in disease progression. Increased understanding of endocrine resistance and the mechanisms of disease progression has led to development and subsequent approval of novel targeted treatments, resulting in the expansion of the therapeutic armamentarium to combat HR+ BC. Clear guidelines based on the safety and efficacy of treatment options exist; however, the optimal sequence of therapy is unknown, and providers, payers, and other key players in the health care system are tasked with identifying cost-effective and evidence-based treatment strategies that will improve patient outcomes and, in time, help curb the staggering increase in cost associated with BC care. Safety and efficacy are key considerations, but there is also a need to consider the impact of a given therapy on patient quality of life, treatment adherence, and productivity. To minimize cost associated with overall management, cost-effectiveness, and financial burden that the therapy can impose on patients, caregivers and managed care plans are also important considerations. To help evaluate and identify the optimal choice of therapy for patients with HR+ advanced BC, the available data on endocrine therapies and novel agents are discussed, specifically with respect to the safety, efficacy, financial impact on patients and the managed care plan, impact on quality of life and productivity of patients, and improvement in patient medication adherence.

Introduction

In 2010, the most recent year for which data are available, almost 1.6 million cases of breast cancer (BC) of all types were reported around the world.Citation1 In the United States, BC accounts for nearly one in three cancers diagnosed in women,Citation2 and more than 232,670 new BC cases are estimated to be diagnosed in the United States in 2014.Citation3 BC is the second most common cause of death because of cancer () in US women; almost 40,000 deaths from the disease are estimated in 2014.Citation3 Metastatic BC is largely incurable,Citation4 and the 5-year relative survival rate is just 23.3% compared with 98.6% for localized disease.Citation5 Women 40 years of age and older account for 95% of new BC cases in the US and for 97% of deaths.Citation2 A recent National Cancer Institute report shows that in 2010 the direct cost in the US associated with BC care was $16.5 billion (), the highest among all cancers, and with the current incidence and survival rates, the cost is projected to increase to approximately $20 billion by the year 2020.Citation6

Figure 1 Estimated cancer-related death in women.

Note: Reproduced with permission from the American Cancer Society Cancer Facts and Figures 2014. Atlanta: American Cancer Society, Inc.Citation3
Figure 1 Estimated cancer-related death in women.

Figure 2 Cost associated with breast cancer.

Note: Data from Mariotto AB, Yabroff KR, Shao Y, Feuer EJ, Brown ML. Projections of the Cost of Cancer Care in the U.S.: 2010–2020. J Natl Cancer Inst. 2011 Jan.Citation6
Figure 2 Cost associated with breast cancer.

Approximately 75% of patients diagnosed with advanced BC (ABC) have hormone receptor-positive (HR+) disease,Citation7,Citation8 which has the most favorable prognosis.Citation2,Citation9 In these patients, the NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines®) recommend the use of endocrine therapy (eg, tamoxifen or aromatase inhibitors [AIs]) with or without chemotherapy (eg, anthracyclines, taxanes, antimetabolites, or microtubule inhibitors).Citation10 A number of targeted therapies, such as bevacizumab, trastuzumab, or everolimus, may be considered in selected patients (ie, trastuzumab for patients with human epidermal growth factor receptor 2-positive disease).Citation10 Although treatment guidelines, such as those from the National Comprehensive Cancer Network® (NCCN®),Citation10 provide recommendations for treating patients with HR+ BC based on clinical trial evidence of safety and efficacy, the guidelines rarely compare different treatment options or provide guidance on how to minimize treatment cost while maximizing benefits. Additionally, guidelinesCitation10 often do not provide adequate direction regarding therapeutic options when the preferred therapeutic agent is contraindicated in a patient. Therefore, payers have an expanding and obligatory role to ensure that the plan-approved optimal endocrine therapy and subsequent treatment options provided for individual patients with HR+ ABC are evidence based.

This review provides an overview of some of the major payer issues that should be considered in the management of HR+ ABC. Considerations for health care stakeholders, including payers, are explored with respect to the safety and efficacy of approved therapies in patients with HR+ ABC, the cost and financial impact of the therapy on patients and the managed care plan, the impact of the therapy on quality of life (QOL) and productivity of patients, and any effect that the therapy may have on improving patient medication adherence. Relevant articles were identified by a search of the PubMed database for articles on the safety, efficacy, QOL, and cost of current treatment options in the management of HR+ ABC.

Considerations for payers

Efficacy considerations

For postmenopausal patients with HR+ ABC, there is a wealth of clinical data supporting the use of third-generation AIs (),Citation11Citation17 which are recommended as both first- and second-line treatment options.Citation4,Citation9,Citation10,Citation18,Citation19 Indeed, numerous randomized controlled trials have shown the efficacy of third-generation AIs (anastrozole, letrozole, or exemestane) with regard to response rate, disease- or recurrence-free survival, time to tumor progression, and for letrozole, overall survival;Citation11Citation13 based on the available efficacy data, the three available AIs are potentially interchangeable. Although AIs are preferred, tamoxifen, a selective estrogen receptor modulator (SERM), is an acceptable first-line therapy,Citation4,Citation10 potentially because of extensive clinical data (). In the adjuvant setting, continuation of tamoxifen for 10 years significantly lowered the risk for BC recurrence and death compared with discontinuation of treatment after 5 years.Citation20 No differences were found in terms of overall survival between tamoxifen and third-generation AIs.Citation21,Citation22 Because the available endocrine therapies are all clinically effective in treating patients with HR+ ABC, there is a clear need to carefully weigh the net clinical benefit associated with these therapies.

Table 1 Approved endocrine and targeted treatments for ABC

Endocrine resistance

Approximately 25% of patients with HR+ disease have intrinsic endocrine resistance, while responders to initial endocrine therapy will ultimately have disease progression as a result of acquired resistance.Citation23Citation25 No definitive guideline recommendation exists for the order of sequencing of endocrine treatments; however, evidence suggests that response to one endocrine therapy predicts the likelihood of a subsequent response to another endocrine agent, although duration of response is not predictable.Citation26 A clear understanding of the different mechanisms of endocrine resistance has led to the identification of a number of novel therapies that are either in clinical or early stage trials. Fulvestrant (),Citation11Citation17 a selective estrogen receptor downregulator, is an estrogen receptor antagonistCitation14,Citation27 indicated for management of HR+ ABC in postmenopausal women after unsuccessful antiestrogen therapy.Citation14,Citation28,Citation29 Based on the finding that everolimus (),Citation11Citation17 an inhibitor of the mammalian target of rapamycin (mTOR), in combination with exemestane is effective in BC patients with endocrine resistance,Citation30,Citation31 the US Food and Drug Administration recently approved this combination for treating patients with HR+ ABC refractory to prior nonsteroidal AI therapy.Citation32 In patients with endocrine-resistant metastatic BC, chemotherapy might be considered ().Citation10,Citation33 Despite numerous clinical trials, little evidence suggests significant differences in survival outcomes among chemotherapeutic agents.Citation33,Citation34

Table 2 Recommended chemotherapeutic regimens for the treatment of ABCCitation10

Safety considerations

The various BC treatments are associated with a range of adverse events (AEs). Most patients have cancer-related fatigue, which may be exacerbated by treatment.Citation35 Bone loss and arthralgia are associated with AI treatment and, depending on severity, may threaten the daily activities of patients.Citation36,Citation37 Women with a first-time diagnosis of BC had a fivefold higher risk for vertebral fracture in the subsequent 3-year period than did individuals with no BC, and the risk is more than 20-fold higher in women with recurrent BC.Citation38 Even though SERMs help preserve the bone,Citation39 they are associated with increased risk for thromboembolism, vaginal bleeding, ocular changes, and endometrial carcinoma.Citation22,Citation40 Although fulvestrant does not increase the risks commonly seen with SERMs and AIs, gastrointestinal disturbances, hot flushes/flashes, and joint disorders have been observed with this agent.Citation41 The AEs associated with everolimus include stomatitis, rash, fatigue, and digestive issues (diarrhea, decreased appetite, nausea).Citation16,Citation30 Chemotherapy can cause severe toxicity, including peripheral neuropathy,Citation35 hand-foot syndrome,Citation42 severe febrile neutropenia, cardiotoxicity,Citation43 and bone marrow suppression.

Quality-of-life considerations

Approximately 3.8 million BC survivors are estimated to be alive in 2022, largely because of significant improvements in diagnosis and treatment-related breakthroughs.Citation44 Because the survival rate of women with BC is increasing,Citation44 consideration of QOL of these patients in terms of emotional well-being, physical functioning, psychosocial well-being, socioeconomic concerns, and behavioral outcomes becomes important. Younger women with BC may have particular concerns about infertility and premature menopause, which are not an issue for postmenopausal women with BC.Citation45,Citation46 Weight gain and physical inactivity as a result of BC therapy might also be a problem resulting in negative body image, decreased libido, and comorbidity associated with obesity.Citation46 Lack of motivation, decreased productivity, and days of missed work are also factors that negatively influence the QOL of patients.Citation47 For some women with BC, dealing with adverse reaction management and potential job loss (either through inability to continue or redundancy) is a source of emotional and financial distress, whereas, for others, inability to care for children as a result of severe adverse reactions and the stress of juggling family commitments and hospital appointments might have a negative impact on QOL scores.Citation48 Caregivers of patients with BC may also develop anxiety and depression, which have been shown to have a negative impact on QOL.Citation49 Although data on the relationship between caregiver costs and decreased QOL are limited, factors such as decreased productivity, missed work days, or the cost of treating anxiety and depression in caregivers have the potential to contribute to increases in caregiver cost. The type, frequency, and severity of AEs associated with BC treatment may also significantly influence QOL.Citation50 Population-based studies show that the range of functional limitations in BC survivors is between 18% and 54%.Citation51 Even though the AE profiles of endocrine therapies vary and could affect the QOL of patients, results from large trials have not reported significant differences in QOL of patients treated with these agents.Citation52 Given that the AEs associated with everolimus are distinct from those seen with endocrine therapies, the QOL of patients may be affected by everolimus therapy. However, a recent analysis of the QOL data from the Breast Cancer Trials of Oral Everolimus-2 (BOLERO-2) suggested that everolimus plus exemestane treatment did not have a negative impact on health-related QOL, as assessed by the European Organisation for Research and Treatment of Cancer QOL core questionnaire (EORTC QLQ-C30), despite an increased incidence of major side effects, compared with exemestane alone.Citation53 Unlike the mTOR inhibitors and endocrine therapy, chemotherapy can cause severe toxicity; hence, the QOL impact profile of these agents must be carefully considered.Citation34,Citation43 To assess the QOL effect of chemotherapy treatments, the EORTC QLQ-C30 and the EORTC BC questionnaire (BR23) include questions for psychometric assessment, in addition to questions related to specific symptoms or AEs (eg, nausea, fatigue/asthenia, decreased appetite/weight, hot flashes) associated with chemotherapy treatments.Citation54,Citation55

The economic burden endured by patients during the course of therapy can affect the QOL of patients.Citation47 Economic burden in the form of changes in economic lifestyle, reduction in income, depletion of savings, declaration of bankruptcy, the need to borrow money, and sacrificing of family plans has affected the QOL of patients, even during posttreatment survivorship.Citation47

Cost considerations

A study published in 2008, based on claims data collected in 2004, estimated that annual health care cost is significantly higher (≥$12,828 per annum in 2004 dollars, equivalent to ~$15,600 in 2012 dollars) for a BC patient than that for a woman without BC.Citation56 A more recent report published in 2012, using claims data from 2003–2008, shows that the total health care cost per patient within the first year of BC treatment was $42,401 (equivalent to ~$48,300 in 2012 dollars).Citation57 The high cost of BC management is due to a number of factors.Citation58 Hospitalizations incurred the highest rate of expense, with costs for women with BC 7.4-fold higher than for those without BC; laboratory testing and diagnostics for BC also incurred substantial monthly costs.Citation56 Few research results have been published on the indirect cost of ABC, including loss of income due to absenteeism or early retirement and caregiver burden, although these would be expected to be significant and may help to differentiate among cancer management interventions. A recent report estimated that loss of productivity accounted for 21% of ABC expenditure, totaling $2.6 billion in 5 years.Citation58 Treatment-related costs have accounted for 44% of the ABC management expenditure.Citation58 The average wholesale prices of endocrine therapies and mTOR inhibitors currently approved to treat patients with HR+ ABC varies, with tamoxifen being the least costly ().Citation11Citation17 Cost and copays associated with therapies are increasingly a cause for concern for patients and their families, and one in ten patients taking oral anticancer medications discontinued therapy because of high cost, whereas one in four patients with a cost sharing >$500 abandoned the oral oncolytic prescription.Citation59 To minimize the financial burden on patients and to help improve adherence to therapy, understanding whether additional cost is likely because of AEs specific to one drug class or agent rather than another (eg, a requirement for additional cardiac or bone density monitoring, antihypertensive drugs, statins, or anticoagulants) is important. Evidence shows that treatment with bisphosphonates effectively counteracts bone loss induced by AIs;Citation37 nevertheless, in patients treated with AIs, cost associated with addition of bisphosphonates and management of bone-related issues must be considered. Cost associated with additional interventions that might be necessary to manage thromboembolism or endometrial cancer, among others, must be considered if SERMs are the endocrine therapy chosen. Similarly, cost associated with management of severe gastrointestinal disturbances and other AEs associated with fulvestrant or cost associated with interventions for managing stomatitis or rash, among others, related to everolimus use must be considered by providers, patients, payers, and all other stakeholders of the health care system. The current review focuses on the management of BC from a US perspective. In a recent guidance publication by the National Institute for Health and Care Excellence, the appraisal committee indicated that everolimus was not considered a cost-effective treatment option for the National Health Service in the UK.Citation60 This highlights the challenges that non-US countries may face in the management of BC, which may arise because of variations in a number of factors, including treatment practices, cost structures, and payer health care systems.

Considerations of cost associated with treatment adherence

To optimally manage BC and to achieve treatment goals, adherence to therapy is critical in improving long-term clinical outcomes, including disease recurrence and survival.Citation61,Citation62 Furthermore, poor medication adherence negatively affects patients and increases the number of subsequent hospitalizations,Citation62 thereby increasing the cost associated with treatment of these patients. In a recent retrospective, longitudinal study evaluating adherence to hormone therapy with tamoxifen or AIs by Medicaid beneficiaries with BC, suboptimal adherence was associated with higher medical costs over the 4-year study period.Citation63 Use of AIs, although more expensive than tamoxifen (),Citation11Citation17 have reduced health care resources, including the number of hospitalizations and outpatient visits and the use of chemotherapy.Citation64 Cost savings per patient before and after disease progression were significant for anastrozole over tamoxifen (P<0.01), an important consideration when choosing ABC treatment.Citation64 Letrozole was also a cost-effective alternative to tamoxifen in treating patients with ABC.Citation65 Fulvestrant has been a cost-effective treatment option when added as a second- or third-line hormonal therapy for ABC.Citation66 Fulvestrant as a second-line hormone therapy provided an additional 56 life-years and 41 quality-adjusted life-years (QALYs) per 1000 women, at an additional cost of ~$10,400 (converted from British pounds) per life-year gained and ~$12,000 per QALY. As a third-line option, fulvestrant provided an increase in health benefit of 27 QALYs for the whole cohort, at a mean overall cost reduction of ~$689 per patient.Citation66 The economic viability of newer agents such as everolimus for the management of BC remains to be established, although a recent cost-effectiveness analysis of the BOLERO-2 trial indicated that everolimus plus exemestane seemed to be cost-effective in the treatment of metastatic BC.Citation67 A recent analysis showed that total budget impact of adding everolimus as first treatment after unsuccessful nonsteroidal AI therapy in HR+ human epidermal growth-factor receptor 2-negative ABC patients in a hypothetical managed care organization with 1 million members would be $0.014 per member per month, whereas it would be $0.030 per member per month if added as a second treatment.Citation68 Therefore, as multiple treatment options become available for treating patients with ABC, there is a clear need to look for therapies that provide the most value, thereby helping to minimize the financial impact on patients and on managed care plans.

Providers take into account many factors of patient treatment to minimize drug discontinuation, to ensure adherence, and to prevent or delay relapse or disease progression. Patient preference for oral or injectable agents is also considered.Citation4 Many of the available endocrine therapies and the newer novel targeted therapies are orally administered ().Citation11Citation17 Complicated daily dosing schedules or cognitive issues may cause patients to overdose or miss doses.Citation61 Conversely, patients who are afraid of needles could have reduced QOL if required to have weekly or monthly injections. In addition, physician visits and follow-up appointments must be convenient for patients to reduce potential treatment gaps.Citation61 Patients who do not understand the rationale behind their therapy or who do not believe that a particular agent will benefit them are more likely to discontinue treatment.Citation61,Citation62 The lengthy duration of treatment associated with ABC may also increase nonadherence in patients as they experience side effects or as additional comorbidity develops.Citation61,Citation62,Citation69 Clearly, education regarding AEs that might occur and prompt amelioration of symptomsCitation4 are critical to ensure that patients adhere to therapies that provide clinical benefit. Therefore, from the perspective of the providers, payers, and other stakeholders in the health care system, ensuring that patients adhere to cancer therapies and other interventions to manage any AE will help improve the overall outcome for the patient and help control the cost associated with cancer management.

Conclusion

Despite many advances in screening and treatment, BC is one of the most common causes of cancer-related death, and advanced disease has a particularly poor prognosis. The direct cost of $16.5 billion associated with BC care in 2010 was the highest among all cancers, and this is projected to increase every year. With recent approval of new treatments and combinations to overcome endocrine resistance, the therapeutic tools available to combat HR+ ABC in patients are expanding. Although guideline recommendations regarding endocrine and novel therapies exist, the optimal treatment sequence is unknown. Hence, it is critical that the providers, payers, and other stakeholders in the health care system have a clear understanding of the differences among therapeutic agents in terms of safety, efficacy, potential impact on QOL of patients, and more importantly, cost associated with therapy and with overall management. In addition to the pharmacotherapy-related factors described herein, patient medical history, overall treatment goals (improve survival, stabilize disease, reduce metastases), and patient personal preference (ability to continue to be productive, minimize financial burden, minimize disability caused by AEs, retain health for a family holiday, survive for a birthday or other special event, or reduce pain or other specific symptom) are all important patient-specific factors for all stakeholders in the health care system to consider when assessing optimal treatment strategies. Treatment selection based on the patient and therapy-related factors will help to slow the staggering cost associated with cancer management, while providing patients with quality care of ABC and cost-effective, evidence-based treatment options.

Acknowledgments

The authors thank Sally Mitchel, PhD, Matthew Grzywacz, PhD, and ApotheCom (Yardley, PA, USA) for editorial and technical assistance in the development of this manuscript. Novartis Pharmaceuticals, Inc., provided funding for editorial and technical assistance with the development of this manuscript.

Disclosure

The authors report no conflicts of interest in this work.

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