Breast Cancer: Will Treatment Costs Outpace Effectiveness?

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Evidence-Based Oncology, December, Volume 18, Issue SP5

Breast cancer was one of the first disorders to profit from the successful application of targeted therapy, and its treatment has changed dramatically from 20 years ago. Despite these advances, breast cancer is responsible for 14% of cancer deaths among women, second only to lung cancer.1

Table 1

The death rate has decreased since 1990; however, it is projected that about 40,000 will die in 2012 due to the disease (approximately 39,500 women and 400 men),1 with the most deaths occurring among African Americans, followed by Caucasians ().2 The overall 5-year survival for 2002 to 2008 was 89%, with the longest survival rate in patients having localized disease (98%) and a much lower survival for those with metastasized disease (24%).2

An estimated 227,000 new cases will be diagnosed in 2012, and it is the most frequently diagnosed cancer in women. The incidence of breast cancer had declined by the year 2000 and has since remained stabilized.1 The highest incidence is seen in Caucasians, followed by African Americans.2 Breast cancer remains a cancer that is most often diagnosed in older women; about onefourth of the cases will be diagnosed in women between the ages of 55 and 64 years, followed closely by women between the ages of 65 and 74 years.2

Factors responsible for the reduction in deaths are reduced utilization of hormone replacement therapy for menopausal women, earlier tumor detection, and improved therapies.1

High Incidence Results in Significant Economic Burden

Direct costs in 2010 for breast cancer care were $16.5 billion, which accounted for about 13% of all direct costs attributed to cancer care in the United States.3 In a review of US cost-of-illness studies for breast cancer, the lifetime perpatient costs ranged from $20,000 to $100,000, with higher costs associated with managing patients with advanced disease.4 The Susan G. Komen Foundation estimated an average cost of $22,000 to manage the early stages of breast cancer, whereas stages 3 and 4 of the disease are associated with treatment costs in excess of $120,000.5 A Medicare analysis revealed a mean $110,000 direct lifetime cost of patients with metastatic breastcancer.6 Average direct costs of breast cancer in a managed care population were calculated to be $2896 per member per month (PMPM), with hospitalization accounting for the greatest share, followed by medications and surgical interventions.7

The indirect costs of productivity loss associated with morbidity and premature mortality are much greater: 89% of all breast cancer costs are indrect costs.8 Another study found, using 2007 data, that patients with metastatic breast cancer cost $12.2 billion, or $98,571 per patient per year (including direct medical, palliative/best supportive care, and lost productivity costs).9 Even though there are discrepancies in cost, the societal costs of breast cancer remain high, pointing to the importance of early detection and cost-effective treatment regimens with a goal of curing the disease.

Current Treatment Guided by Genetic Markers

Table 2

Breast cancers are classified according to hormone receptors and human epidermal growth factor receptor-2 (HER2) status.10 Approximately 70% of breast cancer tumors express a hormone receptor (estrogen or progesterone), and about 20% demonstrate HER2 overexpression.11,12 Recent research has found that there are 4 distinct types of breast cancer, each with its own genetic pattern (). Of special interest was that triple-negative breast cancer, also known as basal-like breast cancer, was found to have characteristics similar to ovarian cancer, thus offering new therapeutic options to be used to treat this type of cancer.13 Knowing the type of breast cancer the patient presents with guides the clinician in treating the tumor.

Treatment options include radiation, lumpectomy, mastectomy, chemotherapy, or a combination of these options.14 Chemotherapy for breast cancer includes traditional chemotherapy, hormonal therapy, and targeted therapy. Examples of chemotherapy medications are: anthracyclines (doxorubicin, epirubicin), taxanes (paclitaxel, docetaxel), anti-metabolites (capecitabine, gemcitabine), microtubules inhibitors (vinorelbine, eribulin), and others (5-fluorouracil, cyclophosphamide, mitoxantrone, cisplatin, etoposide, vinblastine, ixabepilone, and methotrexate).

Hormonal therapy includes the agents tamoxifen, toremifene, nonsteroidal aromatase inhibitors (anastrozole and letrozole), steroidal aromatase inactivator (exemestane), fulvestrant, megestrol acetate, fluoxymesterone, and ethinyl estradiol.

Targeted therapies for tumors that test positive for HER2 include lapatinib and trastuzumab.14 The breast cancer indication of another targeted therapy, bevacizumab, was revoked by the US Food and Drug Administration (FDA) in November 2011 owing to concerns about its effectiveness and safety.15

Everolimus, an mTOR inhibitor, was approved by the FDA in July 2012 for use in combination with exemestane to treat postmenopausal women with advanced hormone receptor—positive, HER-2 negative breast cancer after failing treatment with letrozole or anastrozole. The FDA had approved the medication for the treatment of other tumors (eg, advanced renal cell carcinoma, advanced neuroendocrine tumors ofpancreatic origin, and renal angiomyolipoma).16 Results from the phase 3 BOLERO-2 study of 724 patients comparing everolimus plus exemastane versus placebo plus exemastane indicated a plus exemastane group compared with 8 months in the combination therapy group (hazard ratio [HR], 0.45; P <.0001). The response rates were 1.7% and 12.6%, respectively. Fewer deaths were reported in the combination therapy group. However, patients older than 64 years did not experience any benefit of the combination treatment.17,18

Pertuzumab, an anti-HER2 therapy, in combination with trastuzumab and docetaxel to treat patients with HER2- positive late-stage breast cancer who have received previous anti-HER2 therapy or chemotherapy. Patients in the triple-therapy group demonstrated a median PFS of 18.5 months versus 12.4 months in the group that did not receive pertuzumab (only trastuzumabwas approved by the FDA in June 2012 and docetaxel) (HR, 0.62; P <.0002).19 Patients receiving the triple therapy had more neutropenia (199 vs 182 patients, respectively), febrile neutropenia (56 vs 30 patients), and diarrhea (32 vs 20 patients) than those receiving trastuzumab and docetaxel.20

In July 2012, GlaxoSmithKline announced that it was not pursuing FDA approval of combined use of trastuzumab and its oncology product lapatinib for women with advanced breast cancer.

Cost-effectiveness and Value Less Clear

A total of $10.2 billion was spent in 2009 on breast cancer medications.21 This is again the result of the high incidence but also the relatively high price of the treatments. Managed care plans should anticipate even higher costs with the FDA approval of everolimus and pertuzumab, as these agents will be added to existing combination drug regimens.

The monthly cost of everolimus, an oral medication, which will be administered daily, will be approximately $7500 per month.22 The clinical trials indicate that the drug will be administered for at least 4 months and potentially longer.18 This total will be added to the cost of exemastane, which has a price tag of several hundred dollars per month.23

Pertuzumab plus trastuzumab will have an even higher cost—pertuzumab will be priced at about $71,000 per year and trastuzumab presently costs $54,000 per year, totaling more than $120,000 per year.24 Both of these medications are specific for HER2-positive breast cancer. The optimal duration of therapy will be at least 6 cycles of therapy.25,26

The duration of treatment can have a major impact on the total cost of therapy. Two different trials for trastuzumab looked at different durations of therapy. The HERA trial compared 1 and 2 years of trastuzumab therapy, with the results indicating that 1 year of therapy is the standard of care.27 Similar results were found in the PHARE study that compared 6 months of trastuzumab therapy with 1 year of therapy.28 The results of these studies demonstrated that 1 year of therapy is the optimal duration of therapy for trastuzumab; however, these studies could have had the potential to either reduce the cost of therapy by 50% or increase it by 100%.

Chemotherapy has contributed to the increased life expectancy of patients with breast cancer; however, a cure remains out of reach.29 Determining the cost-effectiveness of therapies for chronic diseases remains a challenge for clinicians, patients, and society—and early-stage breast cancer is fast coming to be considered a chronic disease.

Cost-utility evaluations of trastuzumab have yielded wide-ranging results, from $29,293 to $127,149 per quality-adjusted life-year (QALY), depending on whether they were receiving monotherapy, trastuzumab plus chemotherapy, or trastuzumab plus endocrine therapy and continuing trastuzumab beyond disease progression. A cost-effectiveness analysis of lapatinib in patients with HER2-positive breast cancer who were receiving lapatinib and capecitabine compared with capecitabine monotherapy alone revealed that the combination therapy was cost-ineffective.30

Combining 2 anti-HER2 targeted agents will certainly challenge the metrics of cost-effective therapy. It will be paramount that clinical evidence be available to support such therapy.

Payer PerspectiveInterview With Patrick T. Courneya, MD

EBO: Is genomic tumor testing for breast cancer standard practice today?

Dr Courneya:

At HealthPartners we do our very best to follow the evidence. When practices, such as genomic testing, can make a significant difference in the decisionmaking process for a woman suffering breast cancer, we cover it. Rather than looking at standard of practice as the guiding principle in making these decisions, we prefer to look at standards of evidence.

Unfortunately, there are a great many examples of standard of practice racing ahead of evidence and adding no value to the patient’s care and at times even causing serious harm. The stakes become high when a company proposing a treatment measures its impact in terms of a few weeks but values its role in terms of tens or even hundreds of thousands of dollars.

EBO: Assuming that individual testing of breast neoplasms is not yet universal (and assuming it is something to be attained), what are the key challenges for making this standard practice?

Dr Courneya:

Again, evidence that will carry the day. The other real hurdle is to create a reliable approach to consistent application of evidence-based use of these new technologies. There is wide variation in the practice of medicine that has no explanation. This leads to patient harm and failure to realize the full potential of care innovations.

EBO: According to the Centers for Disease Control and Prevention, breast screening rates have actually fallen among Caucasians in the last decade (tobelow 70%), remained stable among African Americans (68%), and actually increased significantly among Asians (to 66%). Is it realistic to expect to attain greater percentages? What type of focused interventions may help?

Dr Courneya:

We can expect higher rates of screening. Part of what we need to do is harmonize the recommendations for screening. The conflicting recommendations coming out over the last several years have created confusion. This confusion can discredit the concept of screening, because it leaves patients with the impression that even the experts can’t reconcile the balance of risks and benefits in a way that is reasonable, simple, and consistent. That does not mean that recommendations should be frozen, but I think the recommendations would gain much greater traction if they were consistent, based on a clear-eyed and consistent review of the evidence, and then implemented in a reliable way.

As for focused interventions, we have had success closing disparities in screening rates by doing whatever we can to eliminate barriers to screening. One effective example is same-day screening for women who come to our clinics (HealthPartners is an integrated care delivery and finance organization). This has led to a significant decrease in the difference in screening rates among the different populations we serve, with the greatest benefit evident in our African American patients.

EBO: Do you believe that HER2 targeted agents may be used in combination in the future? If so, do you think combinations of specialty biologics will be the wave of the future in breast cancer therapy?

Dr Courneya:

I may sound redundant, but it is the evidence that will drive this, as well. The industry has 2 real big problems to solve. First, the treatment and testing changes need to reflect real innovation that has a more significant impact on outcomes than yet seen. Second, the struggle our society faces with the cost of health and

healthcare needs to be added to the equation. A new development is not an innovation unless it can show its superiority to current treatments and can deliver higher performance, better outcomes at a better cost. We simply can’t ignore that anymore.

EBO: How does HealthPartners gauge value of therapy in breast cancer? Do you think that managed care in general will more actively manage the category as the cost of treatments rises?

Dr Courneya:

As we move forward, the stakes continue to rise. Our mission is to bring the benefit of innovation to our members, where the evidence shows it can make a meaningful difference. Assuring that new treatments are not used indiscriminately is also important. We will use the evidence supplied by investigators and the advice of experts in the field to help us make those decisions. The objective is to assure that what is new is truly innovative, that we are thoughtfully directing the innovations to those who can benefit, and to work to be sure the costs of the treatments reflect the degree of added benefit they bring to current approaches to care.

EBO: In what ways might care in an accountable care organization (ACO) setting improve the patient experience (for those patients with oncologic disorders) compared with relatively integrated organizations such as HealthPartners?

Dr Courneya:

We believe the objective of the ACO concept is to deliver care in a way that combines the objectives of truly improving the health of the communities served, to make the experience of care exceptional, and to make it affordable for our society. As an organization, we have been working in that direction for many years, and so we believe we have a head start on this objective. In that spirit, we don’t believe we can wait for others to continue along that path.

If an ACO sets itself up to deliver this kind of Triple Aim Performance, we think they can close the gap with us quickly and that will be good for our community and for the country as a whole. To the degree that an ACO focuses on only one or two of these aims, the experience of patients will suffer, the value of the resources we use in healthcare will be diminished, and the day when we get reliable high-quality care will be further away. Where regional markets compete based on the triple aim, the people in those communities will be healthier and the economies will be more stable and more vital.

Dr Courneya is chief medical officer at HealthPartners in Minneapolis, MN.Funding Source: None.

Author Disclosures: Mr Mehr reports receiving payment for involvement in the preparation of this article. Ms Zimmerman reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept and design (SRM); acquisition of data (MPZ, SRM); analysis and interpretation of data (MPZ, SRM); drafting of the manuscript (MPZ, SRM); critical revision of the manuscript for important intellectual content (MPZ, SRM); and supervision (SRM).1. Cancer Facts & Figures 2012. Atlanta: American Cancer Society 2012. www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-031941.pdf. Accessed September 11, 2012.

2. Surveillance, Epidemiology, and End Results (SEER) Program. SEER Stat Fact Sheets: Breast. National Cancer Institute 2012. www.seer.cancer.gov/statfacts/html/breast.html. Accessed September 11, 2012.

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4. Campbell JD, Ramsey SD. The costs of treating breast cancer in the US: a synthesis of published evidence. Pharmacoeconomics. 2009;27(3):199-209.

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8. Broekx S, Den Hond E, Rorfs R, et al. The costs of breast cancer prior to and following diagnosis. Eur J Health Econ. 2011;12(4):311-317.

9. Sorensen SV, Goh JW, Chen C, et al. Incidence-based cost-of-illness model for metastatic breast cancer in the United States. Int J Technol Assess Health Care. 2012;28(1):12-21.

10. Creighton CJ. The molecular profile of luminal B breast cancer. Biologics. 2012;6:289-297.

11. Lim E, Metzger-Fiho O, Winer EP. The natural history of hormone receptor-positive breast cancer. Oncology (Williston Park). 2012;26(8):688- 694, 696.

12. Jeyakumar A, Younis T. Trastuzumab for HER-2 positive metastatic breast cancer; clinical and economic considerations. Clin Med Insights Oncol. 2012;6:179-187.

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15. FDA Commissioner announces Avastin decision: drug not shown to be safe and effective in breast cancer patients (press release). US Food and Drug Administration; November 18, 2011. www.fda.gov/NewsEvents/Newsroom/Press Announcements/ucm280536.htm. Accessed September 11, 2012.

16. FDA approves Afinitor for advanced breast cancer (press release). US Food and Drug Administration; July 20, 2012. www.fda.gov/newsevents/newsroom/pressannouncements/ucs312965.htm. Accessed September 11, 2012.

17. Drugs: everolimus. US Food and Drug Administration. July 23, 2012. www.fda.gov/drugs/informationondrugs/approveddrugs/ucm313008.htm. Accessed September 12, 2012.

18. Piccart-Gebhart MJ, Noguchi S, Pritchard KI, et al. Everolimus for postmenopausal women with advanced breast cancer: updated results of the BOLERO-2 phase III trial. J Clin Oncol. 2012;30:abstract 559.

19. Miles, D, Swain SM, Im YH, et al. Concordance between independently and investigatorassessed progression-free survival in CLEOPATRA. J Clin Oncol. 2012;30:abstract e11055.

20. Baselga J, Cortes J, Im SA, et al. Adverse events with pertuzumab and trastuzumab; evolution during treatment with and without docetaxel in CLEOPATRA. J Clin Oncol. 2012;30: abstract 597

21. Taylor L. Breast cancer drug market “set to be static” to 2019. PharmaTimes Online. www.pharmatime.com/article/11-04-14/Breast_cancer_drug_market_set_to_be_static_to_2019.aspx. Published April 14, 2011. AccessedSeptember 12, 2012.

22. Pollack A. FDA approves drugs for cancer and myeloma. New York Times; July 20, 2012.www.nytimes.com/2012/07/21/health/research/fda-approves-afinitor-and-kyprolisfor-breast-cancer-and-myeloma.html. Accessed September 12, 2012.

23. Aromasin. Breast cancer.org. www.breastcancer.org/treatment/hormonal/aromatase_inhibitors/aromasin.jsp. Published June 5, 2012. Accessed September 12, 2012.

24. Staton T. FDA approves Roche’s pricey new Herceptin partner, Perjeta. Fiercepharma; June 11, 2012. www.fiercepharma.com/story/fda-approves-roches-pricey-new-herceptinopartner-perject/2012-06-11. Accessed September 12, 2012.

25. Miles, D, Swain SM, Im YH, et al. Concordance between independently and investigatorassessed progression-free survival in CLEOPATRA. J Clin Oncol. 2012;30:abstract e11055.

26. Baselga J, Cortes J, Im SA, et al. Adverse events with pertuzumab and trastuzumab: evolution during treatment with and without docetaxel in CLEOPATRA. J Clin Oncol. 2012;30: abstract 597.

27. Gelber RD, Goldhirsch A, Piccart M, et al. HERA trial: 2 years versus 1 year of trastuzumab after adjuvant chemotherapy in women with HER2-positive early breast cancer at 8 years of median follow up. Presented at the 2012 Congress of the European Society for Medical Oncology, Vienna, October 1, 2012. http://abstracts.webges.com/myitinerary/title.html. Accessed October 8, 2012.

28. Pivot X, Romieu G, Bonnefoi H, et al. PHARE trial results comparing 6 to 12 months of trastuzumab in adjuvant early breast cancer. Presented at the 2012 Congress of the European Society for Medical Oncology, Vienna, October 1, 2012. http://abstracts.webges.com/myitinerary/ title.html. Accessed October 10, 2012.

29. O’Shaughnessy J. Extending survival with chemotherapy in metastatic breast cancer. Oncologist. 2005;10(suppl 3):20-29.

30. Le QA, Hay JW. Cost-effectiveness analysis of lapatinib in HER-2 positive advanced breast cancer. Cancer. 2009;115(3):489-498.