Breast Cancer Diagnosis, Prognostic Factors and Treatment Considerations for The Role of
For Decision Makers in Managed Care Quarter 3 2013 Diagnosis, Prognostic Factors and Treatment Considerations for Breast Cancer The Role of Genetic Testing in Oncology New Agents Improving Outcomes for Breast Cancer Health Disparities Under the ACA: A Breast Cancer Patient Scenario PRSRT STD US Postage PAID Long Prairie MN Permit # 871 Takes Flight For more information Visit KYPROLIS.com Onyx, Onyx Pharmaceuticals, Onyx Pharmaceuticals logo, Kyprolis and Kyprolis logo are all trademarks of Onyx Pharmaceuticals, Inc. ©2013 Onyx Pharmaceuticals, Inc., South San Francisco, CA 1112-CARF-436 January 2013 mco contents features Quarter 3 | 2013 | Issue 3 10 Regulatory & Reimbursement Disparities Remaining Evident Under the Affordable Care Act departments 4 Calendar of Events Dates and locations of upcoming meetings, workshops and conferences of interest to managed care oncology professionals. 5 Correspondence by Kjel A. Johnson, Pharm.D., publisher, ManagedCare Oncology 6 Facts & Figures Data and accompanying graphics regarding breast cancer. 25 Pipeline Report New Therapies for Breast Cancer by Howard “Skip” Burris, M.D., CMO and executive director, drug development, Sarah Cannon Research Institute 31 Drug & Administration Compendia Coding, reimbursement and available therapies in breast cancer. 39 Clinical Trial Update by John W. Mucenski, B.S., Pharm.D., director of pharmacy operations, UPMC Cancer Centers A review of recent clinical trials in breast cancer, including the methods, results, conclusions and managed care implications of each trial reviewed. 46 Resources & References A comprehensive list of breast cancer sources relevant to managed care oncology professionals. by Denise K. Pierce, president, DK Pierce & Associates, Inc. While the intent of the Affordable Care Act is to broaden access to care, simply having insurance will not end health care disparities. For many low-income or underinsured women, lack of access to care is influenced by such things as their contextual understanding or health care, impact of geography and required cost share. Addressing such issues will be an ongoing challenge even after the ACA is fully implemented. 13 Drug Therapy Reviews Diagnosing, Staging and Treating Invasive Breast Cancer in the Context of Managed Care by Steven M. Sugarman, assistant chair, Department of Medicine, for Clinical Trials in the Regional Network, Memorial SloanKettering Cancer Center The therapeutic armamentarium for breast cancer has grown, resulting in more options for clinicians and improved outcomes for many patients. Meanwhile, testing for inherited susceptibility has refined the way we identify at-risk patients and bolstered our ability to provide tailored preventive interventions for breast cancer, creating an opportunity to save lives and avoid costly treatment altogether. 20 Industry Thought Leaders The Current Role and Future Potential of Genetic Testing in Oncology ManagedCare Oncology recently spoke with Nicoleta Voian, M.D., M.P.H., assistant professor of oncology and director, Clinical Genetic Service, Department of Medicine, Roswell Park Cancer Insitute, about the application of genetic testing in managed care oncology and specifically in the early detection and treatment of breast cancer. advertising index IFC..............................................................................................Onyx 28–30, IBC........................................Magellan Pharmacy Solutions BC............................................................................................Amgen managedcareoncology.com |3 For Decision Makers in Managed Care calendar of events The list of events that follows provides the dates and locations of upcoming meetings, workshops and conferences of interest to managed care oncology professionals. October 2-5 Association of Community Cancer Centers National Oncology Conference Boston, Massachusetts 13-16 American College of Clinical Pharmacy Annual Meeting Albuquerque, New Mexico 16-18 Academy of Managed Care Pharmacy 2013 Educational Conference San Antonio, Texas 21-22 American Society of Health-System Pharmacists 18th Annual Conference for Leaders in Health-System Pharmacy Chicago, Illinois 21-23 Self-Insurance Institute of America, Inc. 33rd Annual National Educational Conference and Expo Chicago, Illinois 27-30 American Society for Healthcare Risk Management 2013 Annual Conference and Exhibition Austin, Texas 28-29 Pharmaceutical Care Management Association Annual Meeting Rancho Palos Verdes, California Published by: Magellan Pharmacy Solutions 6870 Shadowridge Dr., Suite 111 Orlando, FL 32812 Tel: 866-66i-core Fax: 866-99i-core [email protected] www.icorehealthcare.com Publishing Staff Media Managers Erika Ruiz-Colon Kayla Killian Advertising and Sales For information on advertising in ManagedCare Oncology, contact: Dean Mather M.J. Mrvica Associates, Inc. 856-768-9360 [email protected] © 2013 Magellan Pharmacy Solutions, a Magellan Health Company. ManagedCare Oncology is published in conjunction with Krames StayWell. All rights reserved. All trademarks are the property of their respective owners. Printed in the U.S.A. The content of ManagedCare Oncology — including text, graphics, images and information obtained from third parties, licensors and other material (“Content”) — is for informational purposes only. The Content is not intended to be a substitute for professional medical advice, diagnosis or treatment. ManagedCare Oncology does not verify any claims or other information appearing in any of the advertisements contained in the publication and cannot take responsibility for any losses or other damages incurred by readers in reliance on such content. ManagedCare Oncology Editorial Advisory Board Chandra P. Belani, M.D. Miriam Beckner Professor of Medicine, Penn State College of Medicine; Deputy Director, Penn State Cancer Institute at Penn State Milton S. Hershey Medical Center Howard A. “Skip” Burris III, M.D. Director of Drug Development, Sarah Cannon Research Institute Richard Cook, Pharm.D. Pharmacy Manager, Clinical and Quality Programs, Blue Care Network of Michigan Jeffrey Crawford, M.D. Chief of Medical Oncology, Duke University Medical Center William J. Gradishar, M.D. Professor of Medicine, Director of Breast Medical Oncology, Northwestern University, Feinberg School of Medicine Cliff Hudis, M.D. Chief, Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center Deborah Partsch, Pharm.D. Director, Pharmacy Operations, Highmark Blue Cross Blue Shield Dan Petrylak, M.D. Associate Professor of Medicine, Columbia University Medical Center November 3-6 Employer Healthcare and Benefits Congress Las Vegas, Nevada December 7-10 American Society of Hematology Annual Meeting and Exposition New Orleans, Louisiana Don’t Miss an Issue! Online link makes it easy to manage your subscription. If you would like to subscribe to ManagedCare Oncology, please use the link below. If you already receive this magazine regularly, we’d like you to confirm your subscription information so you don’t miss an issue. Visit www.managedcareoncology.com/subscribe-.aspx and complete the brief form. Then, if anything changes, it will be easy to update your information. Thanks, and we hope you find the magazine useful. | 4 managedcareoncology Quarter 3 2013 correspondence Chemotherapy Is Going Global and So Am I … Goodbye, Readership If you develop cancer, thank your lucky stars that you are in this country. Today, the U.S. has about 316 million people, while the world has about 7.1 billion,1 so we are 4 percent of the world’s population. However, the U.S. is responsible for 39 percent of the global chemotherapy spend. Interestingly, the portion of U.S. chemotherapy spend is decreasing over time (as shown in Figure 1) ... but why? The emerging markets, such as Russia, China and others are now getting access to these life-saving medications — but not how you think. We have discussed the United Kingdom’s National Institute for Health and Care Excellence (NICE)2 in the past, but to summarize, it has an annual budget (yes, a budget!) for health care. If a therapy has a cost per quality-adjusted life year (QALY) saved of less than £20,000 (that’s about US$35,000), it is deemed covered. If greater than £30,000, it is deemed not covered. When I asked an English oncologist what they did with Provenge, he asked, “What drug?” He hadn’t even heard of it, since it was never even submitted for coverage review. Similarly, in 2004 Germany started the Institute for Quality and Economic Efficiency in Health Care (Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen [IQWiG]),3 sometimes referred to as Figure 1. U.S. Dominates Global Chemotherapy Sales, but Emerging Markets Are Getting Traction 2002 Onco Sales Split: 2012 Onco Sales Split: 15% 14% 3% 51% 10% 14% 21% Japan 10% 39% Pharmerging 24% ROW EU5 USA ROW = rest of world Source: IMS Health, MIDAS, Dec 2012 the “German NICE.” In this system, assessments of therapies are conducted by the “Joint Federal Committee” of physicians and health insurance funds (Gemeinsamer Bundesausschuss [G-BA]). Australia, in keeping with such a review process, has the Australian Pharmaceutical Benefits Advisory Committee. I think these systems are pretty reasonable, actually. However, things are vastly different in other geographies. For example, in Russia, China and developing countries, only generics are covered. Interestingly, the middle class is burgeoning in such emerging markets, and thus the middle class for the first time can have access to branded chemotherapies — by paying for them in cash. There are no subsidies whatsoever. You can see by these examples that the extent of provision of chemotherapies varies wildly from country to country, but one way or another, coverage is improving. It is pretty interesting stuff, really. We founded ManagedCare Oncology five years ago with the intent of providing timely therapeutic, cost and management information regarding cancer care to our readership, which has grown to nearly 20,000 subscribers today. As of today, I turn the publishing of this fine journal to the ready and able hands of my colleagues at ICORE/Magellan Health. I am off to see how this global cancer care business really works, and hopefully give insights and tools to those who need to understand the value of chemotherapy and caring for their countries’ citizens. It has been a fun ride … see you down the road. Kjel A. Johnson, Pharm.D. Publisher ManagedCare Oncology References 1. U.S. and World Population Clock. United States Census Bureau website. http://www.census.gov/popclock. Accessed July 23, 2013. 2. National Institute for Health and Care Excellence website. http://www.nice.org.uk. Accessed July 23, 2013. 3. Conrad C. The German IQWiG — It’s Not NICE Benefit Assessment in Germany — New Sense or Nuisance? ISPOR Connections. 2006;12(5). http://www.ispor.org/news/articles/oct06/german_policy.asp. Accessed July 23, 2013. managedcareoncology.com |5 facts & figures In every issue, Facts & Figures provides snapshots of information key to managed care oncology professionals. This installment features data regarding breast cancer. We hope you find these facts and figures of value as you review your own health plan data. Magellan Pharmacy Solutions analyzed paid medical claims for health plan members from October 2011 through September 2012 with a breast cancer diagnosis (primary ICD-9-CM diagnosis codes 174 through 175). The following table illustrates these claims across Medicare and commercial lines of business (LOBs), with an average of approximately $24.3 million in allowed drug claims per 1 million member lives for those with a breast cancer diagnosis code. Although claims for many other solid cancers tend to be more heavily weighted toward the Medicare LOB — consistent with an advanced average age at the time of diagnosis — allowed dollars for breast cancer reflect an incidence of disease that is more evenly distributed across younger and older demographics. Medical Claims for Diagnosis Codes 174 through 175 per 1M Lives — Line of Business (LOB)* LOB Description Average Allowed per 1M Average Units per 1M Average Claims per 1M Average Members per 1M $20,745,589.10 657,917 48,342 12,628 Medicare $27,859,660.63 1,076,225 75,533 18,649 Grand total $48,605,249.72 1,734,142 123,875 31,277 Commercial Using the same data, Magellan Pharmacy Solutions analyzed these claims by site of service (SOS), revealing that the vast majority of breast cancer drug administration services — in terms of average units, claims and members per 1 million — were received in the physician’s office. This follows the fact that the physician’s office tends to be the most economical site of care for all stakeholders. The SOS view by request confirms this assertion, with the hospital inpatient/specialty pharmacy and hospital outpatient settings carrying significantly higher average costs per claim than the physician’s office. Medical Claims for Diagnosis Codes 174 through 175 per 1M Lives — Site of Service (SOS)* SOS Average Members per 1M HI/SPP 63 Hospital OP 5,248 Average Allowed per 1M $154,080.76 $9,873,494.20 $139,875.03 Average Units per 1M Average Claims per 1M 6,298 219 N/A 14,860 Other 423 5,698 652 Physician 7,296 $11,051,651.36 461,895 34,408 Grand total 13,029 $21,219,101.35 473,891 50,139 SOS* SOS Average Units per Claim HI/SPP 29 $702.14 Hospital OP N/A $664.44 Other 9 $214.69 Physician 13 $321.19 Grand total 51 $1,902.47 N/A — data integrity issues for units on hospital claims | Average $ per Claim 6 managedcareoncology Quarter 3 2013 Among the leading drugs on these breast cancer claims, the humanized monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2; trastuzumab) featured the highest average allowed claims per 1 million lives. Another biologic in the top 10 drugs for breast cancer, bevacizumab, previously had a breast cancer indication that has since been revoked by FDA. Several supportive care agents appear among the leading drugs on these breast cancer claims, including two agents for bone-related complications (the monoclonal antibody denosumab and zoledronic acid), a colony-stimulating factor (CSF; pegfilgrastim) and an antiemetic (palonosetron). A number of traditional chemotherapeutics account for the remaining agents in the top 10 for breast cancer claims — docetaxel, paclitaxel and protein-bound paclitaxel — in addition to ixabepilone (for disease resistant to paclitaxel) and fulvestrant (for estrogen receptor-positive disease). Breast Cancer Drug Spend — Average Allowed Claims per 1M Lives for Diagnosis Codes 174 through 175* Drug Average Allowed per 1M Average Units per 1M Average Claims per 1M Average Members per 1M Injection, trastuzumab, 10 mg $5,979,314.57 69,117 1,987 228 Injection, pegfilgrastim, 6 mg $2,799,419.22 736 759 258 Injection, docetaxel, 1 mg $1,942,627.83 107,548 901 243 Chemotherapy administration, intravenous infusion technique; up to 1 hour, single or initial substance/drug $1,281,045.52 4,814 4,887 733 Injection, fulvestrant, 25 mg $1,008,582.35 10,637 597 109 Injection, paclitaxel protein-bound particles, 1 mg $1,000,696.34 88,057 437 54 Injection, bevacizumab, 10 mg $847,302.06 9,974 119 20 Injection, zoledronic acid (Zometa), 1 mg $624,012.06 2,297 602 196 Injection, denosumab, 1 mg (For billing prior to 1/1/12 use J3590 or C9272) $616,945.12 37,353 333 113 Injection, palonosetron hydrochloride, 25 mcg $428,990.25 17,420 1,790 344 Injection, ixabepilone, 1 mg $299,024.88 3,748 91 18 Injection, paclitaxel, 30 mg $287,202.37 5,262 862 174 Injection, eribulin mesylate, 0.1 mg (For billing prior to 1/1/12 use J9999 or C9280) $245,012.32 2,434 118 22 Therapeutic, prophylactic or diagnostic injection (specify substance or drug); each additional sequential intravenous push of a new substance/drug (List separately in addition to code for primary procedure) (Use 96375 in conjunction with 96365, 96374, 96409, 96413) $242,049.09 4,482 2,885 536 Chemotherapy administration, intravenous infusion technique; each additional sequential infusion (different substance/drug), up to 1 hour (List separately in addition to code for primary procedure) (Use 96417 in conjunction with 96413) $230,891.96 1,372 1,228 322 Injection, fosaprepitant, 1 mg $211,446.46 89,275 640 182 Cyclophosphamide, 100 mg $206,460.82 12,810 993 306 Injection, gemcitabine hydrochloride, 200 mg $202,724.80 2,270 297 53 Intravenous infusion, for therapy, prophylaxis or diagnosis (specify substance or drug); additional sequential infusion of a new drug/substance, up to 1 hour (List separately in addition to code for primary procedure) (Use 96367 in conjunction with 96365, 96374, 96409, 96413 to identify the infusion of a new drug/substance provided as a secondary or subsequent service after a different initial service is administered through the same IV access. Report 96367 only once per sequential infusion of same infusate mix.) $201,254.76 3,731 2,683 454 Injection, carboplatin, 50 mg $160,537.81 3,640 352 84 managedcareoncology.com |7 Breast Cancer Drug Spend — Average Allowed Claims per 1M Lives for Diagnosis Codes 174 through 175 (continued) Drug Average Units per 1M Average Claims per 1M Average Members per 1M Office or other outpatient visit for the evaluation and management of an established patient, which requires at least 2 of these 3 key components: a detailed history; a detailed examination; medical decision making of moderate complexity. Counseling and/or coordination of care with other physicians, other qualified health care professionals or agencies are provided consistent with the nature of the problem(s) and the patient's and/or family's needs. Usually, the presenting problem(s) are of moderate to high severity. Typically 25 minutes are spent face-to-face with the patient and/or family. $154,848.87 1,499 1,539 512 Chemotherapy administration; intravenous, push technique, each additional substance/drug (List separately in addition to code for primary procedure) (Use 96411 in conjunction with 96409 and 96413) $113,222.39 677 632 189 Leuprolide acetate (for depot suspension), 7.5 mg $107,473.42 263 142 38 Injection, denosumab, 1 mg (Code deleted effective 12/31/11 — see J0897) $106,980.18 5,628 51 22 Injection, filgrastim (G-CSF), 480 mcg $90,262.07 195 165 34 Therapeutic, prophylactic or diagnostic injection (specify substance or drug); subcutaneous or intramuscular $79,633.66 1,673 1,681 468 Intravenous infusion, for therapy, prophylaxis or diagnosis (specify substance or drug); initial, up to 1 hour $78,604.24 643 665 273 Chemotherapy administration, subcutaneous or intramuscular; hormonal antineoplastic $75,624.71 1,052 831 170 Injection, doxorubicin hydrochloride, 10 mg $74,733.10 5,305 530 164 Chemotherapy administration, intravenous infusion technique; each additional hour (List separately in addition to code for primary procedure) (Use 96415 in conjunction with 96413) $72,140.41 1,090 848 272 Office or other outpatient visit for the evaluation and management of an established patient, which requires at least 2 of these 3 key components: an expanded problem-focused history; an expanded problem-focused examination; medical decision making of low complexity. Counseling and/ or coordination of care with other physicians, other qualified health care professionals or agencies are provided consistent with the nature of the problem(s) and the patient's and/or family's needs. Usually, the presenting problem(s) are of low to moderate severity. Typically, 15 minutes are spent face-to-face with the patient and/or family. $65,196.12 894 935 357 Chemotherapy administration; intravenous, push technique, single or initial substance/drug $63,784.99 376 378 70 Goserelin acetate implant, per 3.6 mg $56,641.53 159 105 25 Injection, doxorubicin hydrochloride, all lipid formulations, 10 mg (Not payable by Medicare effective 7/1/12) — see Q2048 or Q2049 (Code deleted effective 12/31/12) — see J9002 $56,412.89 99 18 5 Injection, darbepoetin alfa, 1 mcg (non-ESRD use) $50,067.06 10,577 29 10 $1,157,935.13 178,657 19,028 5,970 $21,219,101.35 685,763 50,139 13,029 Drugs with less than $50,000 allowed Grand total | Average Allowed per 1M 8 managedcareoncology Quarter 3 2013 In looking at claims by diagnosis code, Magellan Pharmacy Solutions found that unspecified female breast cancer carried the highest average allowed cost, units, claims and members per 1 million lives. These unspecified claims lead by a significant margin in every category over the next most commonly coded neoplasm, the upper-outer quadrant of the female breast. As would be expected, male breast cancer diagnoses trailed all diagnoses of female breast cancer in terms of average units, claims and members per 1 million lives. Male breast cancer diagnoses also featured a significantly lower average allowed cost per 1 million lives than all forms of female breast cancer except for neoplasms of the axillary tail, which registered the lowest average allowed cost per 1 million lives overall. Breast Cancer Diagnosis — Average Allowed Claims per 1M Lives for Diagnosis Codes 174 through 175* Diagnosis Diagnosis Code Malignant neoplasm of breast (female), unspecified 174.9 Malignant neoplasm of upper-outer quadrant of female breast Average Units per 1M Average Claims per 1M Average Members per 1M $13,897,100.66 442,927 31,705 8,178 174.4 $2,739,355.02 93,623 7,265 1,908 Malignant neoplasm of other specified sites of female breast 174.8 $2,356,574.40 78,608 5,859 1,579 Malignant neoplasm of lower-outer quadrant of female breast 174.5 $534,862.52 16,204 1,232 299 Malignant neoplasm of upper-inner quadrant of female breast 174.2 $475,674.42 15,579 1,141 335 Malignant neoplasm of central portion of female breast 174.1 $467,274.75 16,701 1,339 322 Malignant neoplasm of lower-inner quadrant of female breast 174.3 $411,071.32 10,559 915 200 Malignant neoplasm of other and unspecified sites of male breast 175.9 $189,698.57 5,464 350 94 Malignant neoplasm of nipple and areola of female breast 174 $136,702.41 5,585 297 95 Malignant neoplasm of male breast 175 $6,429.01 73 8 2 Malignant neoplasm of axillary tail of female breast 174.6 $4,358.27 438 28 17 685,763 50,139 13,029 Total Average Allowed per 1M $21,219,101.35 *Notes: 1. Population includes plans with commercial and Medicare members 2. Date range: October 2011 to September 2012 3. Based on primary diagnosis of 174, 175 4. Outliers excluded managedcareoncology.com |9 10 regulatory & reimbursement Disparities Remaining Evident Under the Affordable Care Act By Denise K. Pierce, president, DK Pierce & Associates, Inc. As we all well know, the intent of the Affordable Care Act (ACA) is to increase access to care, especially for those uninsured for one or more reasons, including (but not limited to): • Choice to be uninsured • Lack of employer health benefit offerings • Exceeding Medicaid eligibility and unable to afford health insurance So, with the advent of the ACA’s insurance exchanges and Medicaid expansion, we should be able to support access to care for all and ideally see a resulting impact on patient outcomes, right? Well, let’s take an example to look at impact on cancer patients, specifically targeting breast cancer, for the purpose of this article. This example may uncover | managedcareoncology Quarter 3 2013 food for thought as the ACA rolls out plan enrollment and payors consider opportunities for their involvement with the exchanges. The Devil’s in the Detail Generally, breast cancer statistics demonstrate that, from 2000 to 2009 (in the United States), incidence of breast cancer decreased by 0.9 percent per year among women, and deaths from breast cancer decreased significantly, by 2.1 percent.1 A concerted effort that includes preventive measures, early diagnosis and the utilization of novel agents and enhanced regimens has helped reverse the curve for what was once considered a much more deadly cancer for women. As we unravel the statistics, however, we can see that the results are not so positive for black women having a diagnosis of breast cancer. Breast cancer is the most commonly diagnosed cancer among black women. The Centers for Disease Control (CDC) reported in 2010 that breast cancer was the leading cause of cancer death for black women aged 45-64 years.2 What was most alarming from the CDC data was that the breast cancer death rate for these women was 60 percent higher for black women than white women (see Figure 1). This is underscored by the fact that black women also have a lower five-year survival rate, at 77 percent, compared to 90 percent for white women. Complicating the opportunity to change the survival trend is that black women tend to present with advanced disease. In fact, the CDC estimates that 45 percent of black women present with advanced-stage disease as compared to white women, at 35 percent. Education on self-examination, and the availability of mammograms and subsequent Figure 1. Breast Cancer Deaths per 2 100,000 Breastlives cancer deaths per 100,000 lives 60 56.8 50 40 30 35.6 20 10 0 White women Black women treatment options, has not affected patient outcomes for black women as it has for white women. Back to the ACA How does this align with access to care and whether the ACA will have the effect of broadening that access for black women? Well, it undoubtedly requires outreach and education, because simply having insurance may not make the difference. A more recent 2012 CDC study looking at breast cancer data from 2005 to 2009 demonstrated that, even after learning that their mammogram is not normal, 20 percent of black women delay seeing a doctor for follow-up for more than 60 days. That’s compared to 12 percent of white women.3 Under the ACA, patients have access to mammograms with no cost share. That is a great step, but one challenge is how then to ensure the continuity of follow-up on abnormal mammograms. Waiting longer for follow-up care may allow cancer to spread. For a payor, this can ultimately lead to higher costs for that patient’s treatment. The CDC also reported that only 69 percent of black women start treatment within 30 days of their diagnosis of breast cancer, compared with 83 percent of white women. This is among black women who already have insurance, as well as those who don’t. Like other types of cancer disparities, the reasons that black women have worse breast cancer survival rates are numerous. They can include poverty, lack of access to care, lack of health insurance, literacy barriers and unequal treatment by professionals in the health care system. This was documented in a March 2002 Institute of Medicine report.4 These variables are still likely in play in today’s world, as reflected by the findings in the 2012 CDC data referenced above. From a payor’s perspective, it’s not about limiting access to new drugs and therapies. Yes, there may be prior authorizations to ensure alignment with appropriate patients, or specialty pharmacy distribution oversight, but if there is data that supports a clinically relevant outcome for the patient, payors will generally cover a drug or regimen. An example that reflects this is UnitedHealthcare’s episode of care pilot for oncology (which includes a payment methodology for breast managedcareoncology.com | 11 12 cancer).5 Pertuzumab was approved by the Food and Drug Administration (FDA) in June 2012. Although the episode of care initiative was in process, and the cost of treating with pertuzumab was anticipated to be approximately $180,000, physicians and UnitedHealthcare agreed that the drug’s promising clinical trial results warranted making the treatment available in the program with payment outside the episode. It is also not about limiting access to care through different settings. There is, however, greater guidance for appropriate care through utilization of pathways that avoids burdening the health system, while not limiting cancer care to only the hospital outpatient or only the physician office setting. CareFirst’s presentation at this year’s American Society of Clinical Oncology (ASCO) meeting reflected this. CareFirst reported overall savings from its ongoing clinical pathways program for oncology, showing that CareFirst reduced its overall costs for treating breast, lung and colon cancers by 15 percent. These savings were primarily achieved through a 7 percent decline in emergency room visits, shorter lengths of stay in the hospital, increased use of generic medications and more appropriate use of chemotherapy. The ACA’s Impact? Although, on paper, the intent of the ACA may be to broaden access to care, it clearly will not end health disparities — no matter what the demographics of the patient. Regrettably, for many low-income or underinsured women, this access is not available to them today and may not be available even under terms of the ACA, influenced by such things as a woman’s contextual understanding of health care, impact of geography and required cost share — even under the ACA’s bronze plan. As an example, let’s take a nonsmoking, divorced black woman with a child who makes $35,000 in annual income, but has no employer health benefits. Table 1 outlines the Table 1. Example Silver Exchange Plan Premium Out-of-Pocket Household income Federal Poverty Level (FPL) 23% Unsubsidized premium payments required $4,935 Maximum percent of annual income outlay for premium 7.53% Final premium payment required by individual (post-subsidy) $2,788 | managedcareoncology Quarter 3 2013 impact of patient outlay of monies related to a silver exchange plan. This example does not take into account the subsequent cost share that the individual would be required to pay, remembering that the silver plan covers 70 percent of health costs, while the individual is responsible for the 30 percent component up to a maximum out-of-pocket. This is still quite a bit of money for a single mother to outlay. If she were to move to a bronze plan, the premium would decrease to $1,943 per year, but the plan itself only covers 60 percent of health costs, requiring higher upfront coinsurance and deductible payments. This article definitely does not identify ways to resolve the specific disparities for black women diagnosed with breast cancer. It is important to realize that this is only one of many disparities evident in our health care system for many ethnicities. This article does, hopefully, generate food for thought about some of the outstanding issues that will not be resolved simply through legislation such as the ACA. How those issues are prioritized and addressed will be the ongoing challenge. References 1. Jemal A, Simard EP, Dorell C, et al. Annual report to the nation on the status of cancer, 1975-2009, featuring the burden and trends in HPV-associated cancers and HPV vaccination coverage levels. J Natl Cancer Inst. 2013;105(3):175-201. doi: 10.1093/ jnci/djs491. Published online Jan. 7, 2013. 2. National Vital Statistics System page. Centers for Disease Control and Prevention website. http://www.cdc.gov/nchs/nvss.htm. Updated June 6, 2013. Accessed June 7, 2013. 3. Centers for Disease Control and Prevention. Vital signs: Racial disparities in breast cancer severity — United States, 2005-2009. MMWR. 2012;61(45):922-926. Published online Nov. 14, 2012. 4. Smedley BD, Stith AY, Nelson AR, eds. Unequal Treatment: Addressing Racial and Ethnic Disparities in Healthcare. Washington, DC: The National Academies Press; 2003. Available at http://www.nap.edu/openbook.php?record_ id=12875&page=R1. Accessed June 7, 2013. 5. Cantlupe J. Bundled payments come to cancer care. HealthLeaders Media website. March 11, 2013. http://www.healthleadersmedia.com/page-3/HEP-289965/ Bundled-Payments-Come-to-Cancer-Care. Accessed June 7, 2013. therapy reviews Diagnosing, Staging and Treating Invasive Breast Cancer in the Context of Managed Care by Steven M. Sugarman, M.D., assistant chair, Department of Medicine, for Clinical Trials in the Regional Network, Memorial Sloan-Kettering Cancer Center Trailing only prostate cancer, breast cancer holds the distinction of being the most common non-skin cancer in the United States and the most prevalent non-skin cancer among American women.1 managedcareoncology.com | 13 14 An estimated 234,580 cases of invasive breast cancer will be diagnosed in 2013, with the overwhelming majority (an estimated 232,340 cases) being diagnosed in women.1 In addition to leading all non-skin cancer types among women in terms of prevalence, breast cancer is also the second leading cause of cancerrelated death in women.1 As such, breast cancer is expected to account for 40,030 deaths among women in 2013.1 Accompanying this remarkable incidence and mortality are significant treatment costs, giving managed care stakeholders legitimate reason to take notice. As of 2010, breast cancer was associated with the highest direct costs of all cancer sites, contributing $16.5 billion in medical expenditures to the national health care budget.2 Although breast cancer occurs rarely in men, it is approximately 100 times more likely to affect women.3 Age represents another prominent risk factor, with approximately twothirds of invasive breast cancers occurring in women aged ≥ 55 years versus only one out of every eight invasive breast cancers being detected in women aged < 45 years.3 Among the potentially modifiable risk factors for the disease are weight gain after age 18, obesity, physical inactivity, age at the time of first pregnancy and alcohol consumption.3 Certain medical findings, such as high breast tissue density, high bone mineral density and biopsy-confirmed hyperplasia, likewise predict a higher risk for breast cancer. In terms of medical interventions that have been linked to an elevated risk for the disease, the use of hormone replacement therapy (HRT; i.e., combined estrogen and progestin) was identified as being associated with an increased risk of breast cancer according to findings from the Women’s Health Initiative published in 2002.4 However, after the publication of these results, the use of HRT significantly decreased, likely resulting in the nearly 7 percent reduction in breast cancer incidence observed from 2002 to 2003.1 Approximately 5 to 10 percent of breast cancer incidence is directly attributable to the inheritance of mutated genes.3 The discovery of inherited susceptibility syndromes and the development of various assays for specific gene mutations in breast cancer has had profound implications in the screening, early detection and treatment of the disease. The implications of identifying these mutations are perhaps best | managedcareoncology Quarter 3 2013 exemplified by those in the BRCA1 and BRCA2 genes, which represent the most common cause of hereditary breast cancer. Both of these genes also portend an increased risk of ovarian cancer. The risk of breast cancer may be as high as 80 percent for members of some families with BRCA mutations, and presence of a BRCA mutation can offer prognostic information and provide an opportunity for preventive strategies such as prophylactic mastectomy and/or oophorectomy in patients identified to be at high risk.3 BRCA-positive breast cancers tend to occur in younger women and may be associated with worse prognostic factors than cancers in women without one of these gene mutations.3 In terms of treatment, the presence of a BRCA1 mutation is associated with breast cancers that tend not to respond to hormonal treatments, while cancers associated with the BRCA2 mutation tend to be hormone-responsive.5 The identification of these gene mutations and other molecular markers allows breast cancer to be categorized into a myriad of different types and subtypes, but histology remains the primary means by which the disease is differentiated. The most common types of breast cancer are adenocarcinomas. Invasive ductal carcinoma accounts for 75 to 80 percent of cases.3 Invasive lobular carcinoma is the next most prevalent type, accounting for 10 to 15 percent of cases.3 Less common adenocarcinoma subtypes include mucinous, papillary, medullary and tubular carcinomas. Very rarely, tumors of the breast can have the appearance of nonadenocarcinomas, including squamous cell carcinomas, sarcomas, lymphomas and small cell carcinomas. Together, these make up the remaining ~5 to ~10 percent of cases.3 While a single type of breast cancer usually exists exclusively in most patients, occasionally a single breast tumor can feature a combination of different types.3 Regardless of the existence of one or multiple types of breast cancer in a particular patient, the specific type(s) of breast cancer present can have a pronounced impact on the detection and diagnosis of the disease. Diagnosis and Staging Breast cancer is traditionally detected via mammography or patient selfpalpation; however, the advent of genetic testing for inherited susceptibility has revolutionized this paradigm. While recommendations from organizations such as the American Cancer Society (ACS) have long promoted regular screening by various methods among certain demographics (e.g., annual mammograms for women aged ≥ 40 years, clinical breast exams at an interval of ≤ 3 years for women in their 20s and 30s, etc.), genetic testing allows for more aggressive screening in previously unrecognized risk groups.3 For example, the ACS recommends that individuals of any age identified as having a BRCA mutation, a firstdegree relative with a BRCA mutation or other breast cancer susceptibility syndromes who have not undergone bilateral mastectomy should undergo annual breast magnetic resonance imaging (MRI) screening in addition to mammography.3 Regardless of how a tumor is detected, a definitive diagnosis is typically made with an imaging study-guided biopsy. Imaging can be performed via mammography (X-ray), ultrasound or MRI, and the biopsy can be performed with the assistance of any of the radiologic techniques in which the tumor was visualized. Ultrasound is the preferred image-guided biopsy method, followed by stereotactic (i.e., X-ray-guided) and finally MRI. Ultrasound guidance for biopsies is the most common and preferred modality because it is generally simpler and less expensive. Stereotactic biopsies are performed for those tumors that can be visualized mammographically but not sonographically. MR-guided biopsies are reserved for those tumors that can be visualized only via MRI. Pathologic analyses are used to determine the type of cancer present in a specific patient and characterize the patient’s disease for prognostic and treatment selection purposes. In doing so, the pathologist assigns a grade of 1 to 3 based on the histologic appearance of the cells and nuclei and the overall mitotic activity. Histologic appearance is based on the arrangement of cells in relation to one another, which includes the formation of tubules and their resemblance to normal cells. Nuclear grade refers to the appearance of the nuclei (i.e., normal to irregular in appearance). Mitotic activity refers to the number of cells in the process of dividing.3 Well differentiated tumors generally resemble normal cells, with few actively dividing, while poorly differentiated tumors contain abnormal-appearing cells and nuclei and are characterized by rapid growth.3 The patient’s prognosis worsens with increasing tumor grade. Because tumor grading is based on the pathologist’s assessment of the tumor, it is somewhat subjective and less consistent than other prognostic factors. Other analyses managedcareoncology.com | 15 16 are more important in determining prognosis and treatment planning. Special studies that detect receptor proteins on the cell surface are critical in the analysis of invasive breast cancers. The most important of these are estrogen receptor (ER) status, progesterone receptor (PR) status and human epidermal growth factor receptor 2 (HER2) status. ER and PR status are based on whether a patient’s tumor cells have receptors for estrogen and progesterone, respectively. Approximately two-thirds of cases feature at least one of the two hormone receptors, with a higher percentage observed in postmenopausal women.3 Those cancers that test positive for the presence of either hormone receptor are considered to be receptor-positive. They tend to be less aggressive and generally respond to hormone-based therapy.3 Similarly designated as either positive or negative, HER2 status is based on the level of the growthpromoting HER2 protein present in the tumor cells. As such, HER2-positive cancers are characterized by rapid growth and aggressive spread. Several medications that target HER2 play an important role in the management of these tumors. Multigene assays such as Oncotype DX® and MammaPrint® also provide prognostic information. The Oncotype DX analysis provides predictive information regarding the potential benefit of chemotherapy and has been widely used in determining whether chemotherapy should be administered to patients with earlystage, node-negative tumors. A crucial piece of information in determining prognosis and assessing treatment options is determining the tumor stage. Staging for breast cancer — as with virtually all solid tumors — is based on the conventions of the American Joint Committee on Cancer (AJCC) TNM system.3 In this system, “T” describes tumor characteristics, “N” represents the presence and extent of lymph node involvement, and “M” indicates the existence of metastases.3 In staging invasive breast cancer, each of these categories that can be adequately assessed is assigned a number indicating the level of disease involvement, with 0 representing no involvement | managedcareoncology Quarter 3 2013 and greater numbers representing more extensive involvement for that particular category.3 The cumulative assessment of the numbers assigned to these categories is known as stage grouping — a process that ultimately determines the stage of a patient’s breast cancer.3 Stages range from 0 to IV, with stage 0 representing carcinoma in situ (i.e., carcinoma of the breast that remains in the duct and has not invaded the surrounding tissue). Invasive disease encompasses stages I through IV. Prognosis is inversely related to stage. The five-year survival rates for each stage reflect the worsening prognosis associated with progressively higher stages (Table 1).3 Stage IV breast cancer indicates that the tumor has spread to at least one distant site (beyond the regional lymph nodes). Although stage IV disease is rarely curable, it is considered treatable. The stage of the tumor in combination with the results of various laboratory analyses ultimately drives the treatment strategy employed by clinicians. Treatment Considerations Surgery — either breast-conserving or mastectomy — is the preeminent first-line treatment option for breast cancer and is employed at some point in virtually all cases of the disease Table 1. American Joint Committee on Cancer (AJCC) TNM Staging System for Breast Cancer and Corresponding Five-Year Survival Rates3 Stage Criteria 5-year survival rate (%) 0 • Noninvasive disease (e.g., ductal carcinoma in situ [DCIS], Paget disease of the nipple); no evidence of a primary tumor; no node involvement; no metastases 93 IA •Tumor is ≤ 2 cm; no node involvement; no metastases IB •Tumor is ≤ 2 cm or not found; micrometastases in 1 to 3 axillary lymph nodes; no metastases IIA •Tumor is ≤ 2 cm or not found; spread to 1 to 3 axillary lymph nodes > 2 mm across OR found in small amounts in internal mammary lymph nodes on sentinel lymph node biopsy OR spread to 1 to 3 lymph nodes under the arm 81 and to internal mammary lymph nodes; no metastases OR •Tumor is > 2 cm across and < 5 cm; no node involvement; no metastases IIB •Tumor is > 2 cm across and < 5 cm; spread to 1 to 3 axillary lymph nodes and/or found in small amounts in internal mammary lymph nodes on sentinel lymph node biopsy; no metastases OR •Tumor is > 5 cm across but does not grow into the chest wall or skin; no node involvement; no metastases 74 IIIA •Tumor is ≥ 5 cm across (or cannot be found); spread to 4 to 9 axillary lymph nodes, or it has enlarged the internal mammary lymph nodes; no metastases OR •Tumor is > 5 cm across but does not grow into the chest wall or skin; spread to 1 to 9 axillary nodes, or to internal mammary nodes; no metastases 67 IIIB •Tumor has grown into the chest wall or skin; no node involvement OR spread to 1 to 3 axillary lymph nodes and/or tiny amounts of cancer are found in internal mammary lymph nodes on sentinel lymph node biopsy OR spread to 4 to 9 axillary lymph nodes, or it has enlarged the internal mammary lymph nodes; no metastases 41* IIIC •The tumor is any size or can’t be found; spread to 10 or more axillary lymph nodes OR spread to the lymph nodes under the clavicle OR spread to the lymph nodes above the clavicle OR involves axillary lymph nodes and has enlarged the internal mammary lymph nodes OR spread to 4 or more axillary lymph nodes, and found in small amounts in internal mammary lymph nodes on sentinel lymph node biopsy; no metastases 49* IV •Tumor can be any size; may or may not have spread to nearby lymph nodes; metastases in distant organs or to lymph nodes far from the breast; the most common sites of spread are the bone, liver, brain and lung 15 88 *These figures are correct as printed, in that stage IIIB demonstrates worse survival than stage IIIC. with the exception of stage IV (i.e., metastatic) disease. Chemotherapy and/or hormonal therapy are frequently used after surgery (i.e., adjuvant therapy) to reduce the risk of recurrence. Radiation therapy is generally indicated when a patient undergoes breast-conserving surgery (i.e., lumpectomy) and in patients with a high risk of local recurrence who undergo mastectomy. Sometimes chemotherapy is employed before surgery (i.e., neoadjuvant therapy) in order to shrink the tumor and increase the likelihood of successful surgery in patients with locally advanced disease (i.e., stage III) or in those patients who can be converted from requiring mastectomy to permitting lumpectomy (i.e., breast conservation). Hormone receptor analyses determine whether endocrine therapy should be employed. The addition of hormone therapy reduces the risk of relapse in patients with hormone receptor-positive tumors. This therapy is often used for 5 to 10 years depending on the clinical situation. The available adjuvant hormonal agents include tamoxifen and the aromatase inhibitors (e.g., anastrozole, letrozole and exemestane). Tamoxifen works by blocking the estrogen receptor. Aromatase inhibitors work by reducing estrogen production in postmenopausal patients but are not effective in premenopausal patients. This latter class of agents has shown an improvement in disease-free survival but not overall survival in postmenopausal patients. Therefore, tamoxifen is generally the treatment of choice in premenopausal patients, and aromatase inhibitor therapy or sequential therapy with tamoxifen and an aromatase inhibitor is employed in the adjuvant treatment of postmenopausal patients. Hormone therapy is also useful in patients with stage IV receptor-positive breast cancer. Generally, the longer a patient tolerates a given agent, the more likely she will do well with a subsequent anti-estrogen. Fulvestrant, a medication that degrades the estrogen receptor on receptor-positive tumors, is often used after failure of aromatase inhibitors. Interestingly, everolimus, a drug that blocks mTOR (the mammalian target of rapamycin), when combined with exemstane (a steroidal aromatase inhibitor), has been effective in treating patients whose tumors progressed while on anastrozole or letrozole (nonsteroidal aromatase inhibitors). In those with HER2-positive disease, the targeted biologic agent trastuzumab (a monoclonal antibody that targets HER2) is used in addition to chemotherapy to reduce the risk of relapse and improve survival. The two most common combinations used in this setting are cyclophosphamide and doxorubicin, followed by paclitaxel and trastuzumab or trastuzumab with docetaxel and carboplatin.5 For managedcareoncology.com | 17 18 patients with advanced disease who have not yet received chemotherapy, pertuzumab in combination with trastuzumab and docetaxel has been shown to extend time to progression compared with trastuzumab and docetaxel.5 Other targeted agents for the treatment of metastatic, HER2amplified disease include lapatinib and ado-trastuzumab emtansine. Approved in February 2013, this antibodydrug conjugate is a combination of trastuzumab and mertansine (a tubulin inhibitor). In patients with HER2positive, unresectable, locally advanced or metastatic breast cancer who had previously failed trastuzumab/taxane therapy, ado-trastuzumab emtansine improved overall survival by 5.8 months compared with combination lapatinib/capecitabine therapy.6 In the subset of patients whose disease is hormone receptor-negative and HER2-negative — so called “triple-negative” patients — traditional chemotherapeutic agents are generally indicated for adjuvant treatment as well as in the treatment of metastatic disease. While these breast cancers generally respond well to chemotherapy, as evidenced by the high complete response rates when administered as neoadjuvant therapy, they are also often associated with a poorer prognosis than other types.3,5 Eventually, virtually all patients with metastatic breast cancer will require chemotherapy regimens that have demonstrated efficacy in this setting.5 For metastatic breast cancer, however, combination chemotherapy appears to offer no advantage over sequential single-agent chemotherapy in terms of improving survival or overall quality of life.7 This premise was established in a 2003 study of doxorubicin and paclitaxel, alone and in combination, for the treatment of metastatic breast cancer by Sledge et al. and has not been refuted since.7 Furthermore, combination chemotherapy is associated with increased toxicity, causing the doses of individual agents to be compromised. Combination therapy can, however, increase the likelihood of tumor shrinkage, which may be important in certain clinical situations where a rapid response to therapy is important. Some combinations have shown improved response rates compared with single-agent therapy. Still, in situations in which a rapid response to chemotherapy is not crucial (which is usually the case), the use of sequential, single-agent chemotherapy is recommended. No specific sequence of therapy has been determined to be superior, and the sequence of chemotherapy is usually based on previous therapy, anticipated | managedcareoncology Quarter 3 2013 side effects from treatment and the patient’s underlying comorbidities. The most widely prescribed firstline chemotherapy for metastatic disease is capecitabine, paclitaxel or docetaxel. Fortunately, for the patient with advanced breast cancer, many therapeutic options are available.5 Because the treatment of breast cancer remains imperfect, clinical trials should be considered the best treatment option for appropriate candidates. Future Perspectives in Managed Care The therapeutic armamentarium for breast cancer has grown significantly over the past several years, resulting in more options for clinicians as well as improved outcomes for patients in many cases. With more than 100 investigational agents in phase 2 or 3 clinical trials for breast cancer, the future looks bright.8 As our knowledge of the molecular mechanisms of the disease grows, so does our ability to target specific steps in these pathways. Included among these promising agents are small molecules that target tumor cell spread and enzymes that are very active in growing cancers, such as PI3 kinase, AKT kinase and RAF kinase. Coupled with these developments are pharmacogenetic assays that can help determine treatment response and ensure that novel targeted agents are not inappropriately used in patients unlikely to benefit from them. The introduction and exploitation of trastuzumab and other HER2-targeted agents has shown the utility of these assays, but this is merely the proverbial tip of the iceberg. Also in the discipline of genetics, testing for inherited cancer susceptibility has refined the way we identify at-risk patients and bolstered our ability to provide tailored preventive interventions for breast cancer, creating an opportunity to save lives and avoid costly treatment altogether. While these recent developments — and similar advances on the horizon — come at significant expense to payors, managed care stakeholders are generally cognizant of their value in cost avoidance and improved outcomes. As a result, payors are relatively liberal in their coverage of newer targeted biologics, pharmacogenetic testing and germline genetic testing for breast cancer, provided that these interventions are used prudently and appropriately. Furthermore, as evidence that they are savvy to the value of pharmacogenetic testing in driving appropriate use, most payors have incorporated specific analyses (e.g., HER2 testing for trastuzumab) into their utilization management initiatives by requiring certain tests prior to authorizing payment of specific therapies when available. Management interventions, such as Prior Authorization programs and consensus guideline-driven clinical pathways, are also being used nationally in an effort to promote the appropriate use of costly therapies in the treatment of breast cancer. So long as these programs are based on the consensus opinions of leaders in their respective fields (e.g., evidence-based guidelines from organizations such as the National Comprehensive Cancer Network [NCCN]), they provide a framework for determining inappropriate use. However, payors and clinicians alike must remain aware of the fact that oncology is just as much an art as it is a science, and not every patient’s disease takes the route set forth in textbooks and journals. Taking this into consideration, payors should remain flexible in their coverage policies, whether they employ Utilization Management programs or not, so that clinicians are not handcuffed and prevented from making evidence-based, common-sense decisions. A timely and responsive appeals process within the plan infrastructure can facilitate this. Providers are also accountable for ensuring that the whole process runs fluidly; that is, with new data emerging every day, it is incumbent upon physicians to know how far that data can take them and the implications of results from clinical trials on real, everyday practice. Ultimately, a spirit of collaboration between payors and providers is in the best interests of all parties involved and, given the growing array of medical interventions available, presents the optimal scenario for improved outcomes in the treatment of breast cancer. References 1. American Cancer Society. Cancer Facts & Figures 2013. http://www.cancer.org/research/cancerfactsfigures/cancerfactsfigures/ cancer-facts-figures-2013. Accessed July 24, 2013. 2. The Cost of Cancer. National Cancer Institute at the National Institutes of Health website. http://www.cancer.gov/aboutnci/ servingpeople/cancer-statistics/costofcancer. Accessed July 24, 2013. 3. American Cancer Society. Breast Cancer — Detailed Guide. http://www.cancer.org/cancer/breastcancer/detailedguide. Accessed July 24, 2013. 4. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288:321-333. 5. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Breast Cancer. http://www.nccn.org/ professionals/physician_gls/pdf/breast.pdf. 6. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367:1783-1791. 7. Sledge GW, Neuberg D, Bernardo P, et al. Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). J Clin Oncol. 2003;21:588-592. 8. Magellan Pharmacy Solutions. Medical Pharmacy & Oncology Trend ReportTM. 3rd ed. 2012. http://www.icorehealthcare.com/ media/329731/2012_trend_report.pdf. Accessed July 24, 2013. managedcareoncology.com | 19 20 industry thought leaders The Current Role and Future Potential of Genetic Testing in Oncology A Discussion with Nicoleta Voian, M.D., M.P.H. Assistant professor of oncology and director, Clinical Genetics Service, Department of Medicine, Roswell Park Cancer Institute The genesis and evolution of genetic testing technologies and their application in preventive medicine have changed the face of oncology. Despite the fact that only approximately 5 percent of all cancers are strongly hereditary, inherited cancer susceptibility can be significant to individual patients and their immediate families.1 While some degree of heredity may exist in the development of all types of cancer, breast cancer features a relatively pronounced element of inherited susceptibility for which genetic testing has been advanced in recent years. Specifically, inherited mutations in certain breast cancer susceptibility genes account for an estimated 5 to 10 percent of all female breast cancers and anywhere from 4 to 40 percent of all male breast cancers.1 As such, reputable cancer centers across the country have implemented genetic testing programs and even dedicated entire departments to the application of gene analysis in the discipline of oncology. The accuracy of the testing employed in these centers can be characterized via the concepts of analytical validity and clinical validity, which — when coupled with individual disease-specific scenarios — lend themselves to determining the clinical utility of genetic analyses for a particular patient.2 ManagedCare Oncology recently sat down with Nicoleta Voian, M.D., M.P.H., assistant professor of oncology and director, Clinical Genetics Service, Department of Medicine, Roswell Park Cancer Institute, to gain her insights on the application of genetic testing in managed care oncology and specifically in the early detection and treatment of breast cancer. | managedcareoncology Quarter 3 2013 MCO: Can you please describe the various roles of genetic testing in contemporary oncology practice? Dr. Voian: Clinical cancer genetics is a critical component of modern oncology and preventive medicine. There are three distinct categories of molecular genetic testing in oncology: germline genetic testing, somatic genetic testing and pharmacogenetic testing. Germline genetic testing for cancer susceptibility assesses patients for an inherited gene mutation in order to determine the risk for cancer in an individual. Genetic counseling is strongly recommended before and after these tests, which are sent to specialized laboratories for analysis. The key goal of germline analyses is to offer appropriate genetic tests for appropriate patients in order to prevent and/or detect cancer early. The somatic genetic tests that oncologists use in collaboration with pathologists look for mutations in the cancer tumor that were acquired in order to estimate an individual’s response to therapy as a prognostic measure. Pharmacogenetic testing, on germline as well as somatic mutations, enables oncologists to identify patients at risk for severe treatment toxicity or poor treatment response. MCO: How does genetic testing impact the quality of care and the cost of managing the cancer patient? Dr. Voian: Identifying individuals who carry a gene mutation that confers a significantly increased risk for cancer is important because preventive and/or early detection options can then be provided to these individuals, potentially helping them avoid costly treatment. Also, in families where there is a known familial gene mutation, other family members are at risk for carrying the same mutation and will benefit from the preventive/early detection measures. Conversely, identifying family members who do not carry that mutation will eliminate unnecessary costs associated with enhanced screening. MCO: How does genetic testing fit into oncology care today? Dr. Voian: Approximately 5 to 10 percent of all cancers occur due to an inherited susceptibility resulting directly from gene mutations.1 These mutations, usually inherited from a parent, confer a high risk of multiple primary cancers occurring at younger ages, and we typically see multiple family members who inherit the cancer-predisposing mutation. Early identification of hereditary cancer syndromes benefits patients through a growing number of preventive care options available to patients and blood relatives. The most common hereditary cancer syndromes known are in breast, ovarian and colorectal cancers. Awareness regarding inherited susceptibility syndromes has been increasing over the past few years. Identifying and referring the appropriate patients diagnosed with breast cancer soon after their diagnosis for genetic counseling and testing is very important. If a patient is identified as having a gene mutation associated with an increased risk for a second breast cancer and/or other cancers, it will empower that individual with the information needed to make the appropriate treatment decisions, such as the type of breast and/or ovarian surgery necessary. MCO: Can you describe the key opportunities and challenges in managing oncology genetic testing? Dr. Voian: Genetic testing introduces the concept of personalized hereditary cancer risk assessment, which offers crucial information to help make medical management decisions to reduce cancer risk. This information is important to the patient and his or her family members and often reduces the anxiety and stress associated with hereditary cancer susceptibility — a negative result from testing is welcome news when there is a known mutation in the family. Conversely, testing may introduce anxiety in individuals identified as carrying a gene mutation. Also, the sensitivity of genetic testing is not 100 percent; therefore, some undetected mutations may exist, and testing does not detect all causes of hereditary cancer. Furthermore, genetic testing for inherited cancer susceptibility syndromes is complex. There are different methods to assess for a gene mutation, including sequencing and looking for deletions or duplications. We need to carefully offer the most complete test available for a specific case. Because there are multiple cancer syndromes that increase the risk for cancer — such as hereditary cancer syndromes associated with an increased risk for breast cancer, ovarian cancer, colon cancer, etc. — it is important to establish which syndrome is the most robust in the differential. Sometimes we have several inherited cancer syndromes in the differential and we can use a next-generation sequencing panel that will assess for multiple genes in one test. In other cases, the most appropriate person to be tested first in a managedcareoncology.com | 21 22 family suggestive for an inherited cancer predisposition is not available for testing. In these situations, testing of at-risk, unaffected family members will encounter limitations. There is a need to very carefully assess the family pedigree on both sides, as there are cases, although rare, where individuals can inherit a gene mutation from each parent. We also encounter challenges when we need to recommend further medical management in individuals who tested negative for the genetic tests offered but still have an increased risk for cancer based on their family history or clinical findings. MCO: Can you describe the key challenges and opportunities in managing oncology genetic testing specifically in the area of breast cancer? Dr. Voian: As mentioned previously, there are situations when we have multiple inherited cancer syndromes associated with an increased risk for breast cancer in the differential. There are breast cancer panels that allow for testing of multiple genes in one sample. BRCA1 and BRCA2 were not historically included in those panels because one laboratory had the patent on those specific genes, but the Supreme Court ruled on June 13, 2013, that human genes cannot be patented.3 This recent development opens up the potential for more comprehensive and inclusive breast cancer panels and decreased costs for BRCA-related analyses. Still, for BRCA1 and BRCA2, there are different tests that are offered, and the most appropriate is selected on a case-by-case basis. This is often based on ethnicity, such as the Ashkenazi Jewish panel, or if there is a previously identified gene mutation or family history of breast cancer. The complete BRCA test includes full sequencing and testing for large genomic rearrangements in both BRCA1 and BRCA2 genes, which will likely now be available from a number of different laboratories after the Supreme Court’s ruling. MCO: When is a patient referred for genetic testing? What is the process that you undertake to determine if a patient qualifies for genetic testing? Dr. Voian: There are two types of patients that we see in the genetics clinic: affected patients and unaffected patients. Affected patients have cancer or a history of cancer, while unaffected patients have only a family history of cancer. For a patient who is affected with cancer, discussion with the breast surgeon, medical oncologist and/or radiation therapist will determine the impact of genetic testing on a patient’s medical care. The National Comprehensive Cancer Network has established criteria for genetic testing eligibility for both groups, and several other professional organizations, such as the American Society of Breast Surgeons and the American Society of Clinical Oncology, also provide specific guidelines and recommendations to providers for identification of individuals at increased risk for hereditary cancer syndromes.4 Common characteristics of these patients include an early onset of cancer, a rare cancer such as male breast cancer or ovarian cancer, a known familial mutation, family members with multiple primary cancers, two or more relatives with the same type of cancer on the same side of the family, ethnicity, or pathologic findings for certain types of cancers, such as triple negative breast cancer before age 60.4 Ultimately, the most vital piece of information to help determine whether genetic testing is warranted is the potential clinical utility derived from testing and the benefits for family members with regard to their cancer risk. | managedcareoncology Quarter 3 2013 MCO: What are the steps you have to consider when you see a patient who appears to qualify for genetic testing? Dr. Voian: During genetic counseling, we perform a thorough evaluation. The individual’s personal and family medical histories are reviewed, with a focus on the cancer history and benign findings that can be associated with inherited cancer predisposition. We review the medical records of the patient and family members if possible, as well as the results of previous genetic tests when applicable. A physical evaluation may also be needed in some cases. Based on the findings of this workup, we establish whether genetic testing is appropriate and what specific tests should be used in those patients deemed appropriate candidates. Before any genetic test is performed, the informed consent form needs to be signed by the patients to confirm that they acknowledge the test being performed in addition to the benefits, risks and limitations of the test. They’re also informed about state and federal genetic privacy laws that protect the majority of individuals from discrimination with regard to group health insurance and employment. MCO: How do insurance regulations play into the process of genetic testing? Dr. Voian: Although payors are generally cognizant of the validity of genetic consultation and testing and relatively liberal in their related coverage policies, these services may or may not be covered by insurance. By and large, the coverage is approached on an individual case-bycase basis, meaning that many health plans routinely cover genetic counseling and testing if the test is deemed appropriate. If the genetic test is not covered, patients often choose to forgo testing due to the high out-of-pocket costs. MCO: Do you ever recommend testing as a private pay service to a patient if the test is not covered by insurance? If family history is not known, would you recommend testing? Dr. Voian: The recommendation of a genetic test is based on its clinical utility and the impact on cancer risk assessment for family members, not on the reimbursement. If the testing is performed primarily for the medical management of other family members, the patient is informed about the outof-pocket expense and given the option to pay if desired. If the family history is unknown, we base our risk assessment on personal history of cancer, such as the type of cancer and age at diagnosis. MCO: Do you have to get the testing approved by the payor before administering the test? characteristics may warrant only a single site test for a familial mutation or a full genetic panel. Dr. Voian: Many genetic laboratories will hold the sample until insurance authorization is obtained and the patient agrees with any out-of-pocket expenses that may accompany the test, after which the analysis is initiated. MCO: What are the specific types of genetic testing for breast cancer? Ovarian cancer? MCO: Are the analyses expensive? Dr. Voian: Genetic testing is often considered expensive, with costs ranging anywhere from a few hundred to a few thousand dollars, depending on the genes tested and the method of analysis. A patient’s Dr. Voian: The most common gene mutations associated with breast cancer are BRCA1 and BRCA2, which are associated with hereditary breastovarian cancer (HBOC) syndrome. Rarer gene mutations include TP53 associated with Li-Fraumeni syndrome, PTEN associated with Cowden syndrome, CDH1 associated with hereditary diffuse gastric cancer and STK11 associated with Peutz–Jeghers syndrome. For ovarian cancer, the most commonly associated hereditary syndrome is HBOC and Lynch syndrome associated with mutations in the MLH1, MSH2, MSH6, PMS2 and EPCAM genes. MCO: What does the BRCA mutation entail for both men and women? Dr. Voian: For breast cancer, the inherited risk associated with a BRCA1 and BRCA2 mutation in females is 45 to 84 percent, compared with an approximate 12 percent risk in the general population.5-7 Women who have already had breast cancer have an increased risk for a new primary contralateral breast cancer, up to a 64 percent risk in their lifetime.6 For ovarian cancer, the inherited risk is anywhere from 11 to 62 percent with the BRCA mutation, compared with approximately 2 percent in the general population.5-9 For male breast cancer, the inherited risk associated with a BRCA2 mutation is up to 8 percent, compared with a less than 1 percent risk in the general population.10,11 managedcareoncology.com | 23 24 The risk of prostate cancer is less pronounced with an inherited BRCA2 mutation at 20 percent, compared with 16 percent in the general population.12 In some families, an increased incidence of melanoma and/or pancreatic cancer may exist with an inherited BRCA mutation.13 MCO: Describe the results of genetic testing. How do the results influence further care? Dr. Voian: A positive result confirms the hereditary cancer susceptibility syndrome and the predisposition for cancer associated with a specific gene. The medical management recommendations follow the established guidelines, and the options include surveillance, chemoprevention and risk-reducing surgeries. Other family members can carry the same mutation; therefore, genetic counseling with or without genetic testing is recommended. In the event of a negative result, if there is a known mutation in the family, then the individual does not have the risks associated with that mutation and will follow the screening recommendations for the general population. For a negative result with no known mutation in the family, the result is considered uninformative. Sometimes additional genetic testing is indicated in these cases. If, after all genetic testing, the individual is still negative for a detectable mutation, the medical management recommendations are based on personal and family history of cancer and clinical symptoms. A patient may also have a variant of uncertain significance, which is when there is a change in the gene identified, but it is unknown whether that change is harmful or benign. In this latter scenario, the medical management is again based on personal and family history of cancer and clinical symptoms. MCO: Is there research being done to improve genetic testing for cancer? MCO: How do you typically present the genetic testing results to the patient? Dr. Voian: Yes, there is ongoing research to identify gene mutations in rare genes or new genes that are associated with an increased risk for cancer. For example, familial breast cancer research is being performed by Dr. Mary-Claire King at the University of Washington in Seattle, and at the Cleveland Clinic, Dr. Charis Eng is looking for mutations in the PTEN gene and at new genes associated with Cowden syndrome. Dr. Voian: We schedule an in-person follow-up consultation to disclose and discuss the genetic test results and the impact of those results on their medical management, in addition to consultation with family members tailored to each case. MCO: How are genetic tests regulated? Dr. Voian: All laboratories that do genetic testing and share results must be Clinical Laboratory Improvement Amendments (CLIA)–certified. CLIA certification provides federal standards for quality, accuracy and reliability of tests. The clinical validity for some genetic tests is required by the U.S. Food and Drug Administration. New York requires that genetic tests be performed in laboratories that hold a state permit for its residents. The clinical utility is determined by the health care providers and health insurance companies.2 MCO: Overall, do you think genetic testing and counseling is saving lives? Dr. Voian: Absolutely. Identifying individuals who carry a gene mutation that predisposes them for a significant increased risk for cancer will offer options to prevent and detect cancer at an earlier stage. Risk-reducing surgeries such as mastectomy for breast cancer, salpingo-oophorectomy for ovarian cancer and colectomy for colorectal cancer are ultimately lifesaving procedures. References 1. American Cancer Society. Cancer Facts & Figures 2013. Atlanta: American Cancer Society; 2013. http://www.cancer.org/research/cancerfactsfigures/cancerfactsfigures/cancer-facts-figures-2013. Accessed July 10, 2013. 2. U.S. National Library of Medicine. Handbook: Help Me Understand Genetics – Genetic Testing. Genetics Home Reference website. http://ghr.nlm.nih.gov/handbook/testing?show=all. Accessed July 10, 2013. 3. Association for Molecular Pathology, et al. vs. Myriad Genetics, Inc., et al., 569 U.S. ___ (2013). http://www.supremecourt.gov/opinions/12pdf/12-398_1b7d.pdf. Accessed July 10, 2013. 4. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Genetic/Familial HighRisk Assessment: Breast and Ovarian. http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf. 5. Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: A combined analysis of 22 studies. Am J Hum Genet. 2003;72(5):1117-1130. 6. Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE. Risks of cancer in BRCA1-mutation carriers: Breast Cancer Linkage Consortium. Lancet. 1994;343(8899):692-695. 7. King MC, Marks JH, Mandell JB; New York Breast Cancer Study Group. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003;302(5645):643-646. 8. Finch A, Beiner M, Lubinski J, et al. Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 mutation. JAMA. 2006;296(2):185-192. 9. Risch HA, McLaughlin JR, Cole DE, et al. Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet. 2001;68(3):700-710. 10.Thompson D, Easton D; Breast Cancer Linkage Consortium. Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am J Hum Genet. 2001;68(2):410-419. 11.Tai YC, Domchek S, Parmigiani G, Chen S. Breast cancer risk among male BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst. 2007;99(23):1811-1814. 12.Cancer risks in BRCA2 mutation carriers: The Breast Cancer Linkage Consortium. J Natl Cancer Inst. 1999;91(15):1310-1316. 13.Genetics of Breast and Ovarian Cancer (PDQ®). National Cancer Institute at the National Institutes of Health website. http://www.cancer.gov/cancertopics/pdq/genetics/breast-and-ovarian/HealthProfessional. Accessed July 10, 2013. | managedcareoncology Quarter 3 2013 pipeline report New Therapies for Breast Cancer by Howard “Skip” Burris, M.D., CMO and executive director, drug development, Sarah Cannon Research Institute Outcomes continue to improve for breast cancer patients with the study and development of new agents, including the 2012 regulatory approvals of everolimus (Novartis, Afinitor) and pertuzumab (Roche/Genentech, Perjeta), and the 2013 approval of ado-trastuzumab emtansine (Roche/ Genentech, Kadcyla). These therapies represent the advances being made with new antibodies, antibody-drug conjugates (ADCs) and small molecules targeting specific pathways. Strategies are being deployed against the various subtypes of breast cancer, such as hormone receptorpositive, HER2 amplified and triple negative disease. The use of agents inhibiting the PI3K/AKT/TOR pathway has been widely discussed in the treatment of breast cancer. The results of the BOLERO-2 phase 3 trial established the benefit of everolimus, an mTOR inhibitor, in postmenopausal metastatic breast cancer patients. In this doubleblind, placebo-controlled study of 724 patients randomized 2:1 to receive exemestane and everolimus or placebo, the investigational arm achieved sta- tistical superiority for the primary end point of progression free survival (PFS). Median PFS of 10.6 months versus 4.1 months was noted, yielding a hazard ratio (HR) of 0.36 and a p value of 10 minus 15. Median survival has not been reported, but a trend favoring the everolimus arm was noted. In addition, benefits were noted in both visceral metastases as well as bone lesions, and patients receiving everolimus maintained their quality of life for a longer period of time. All subsets of patients had superior outcomes with the everolimus plus exemestane treatment, and of particular interest, those women with multiple prior therapies had more improvement than those less heavily pretreated. The results of BOLERO-3 were reported at the American Society of Clinical Oncology 2013 annual meeting in Chicago, and once again, the investigational arm of vinorelbine, trastuzumab, everolimus was superior to vinorelbine, trastuzumab, placebo for the primary end point of progression free survival. The absolute difference was 7.0 versus 5.8 months, with HR 0.78, p < .01. The patients were heavily pretreated, including lapatinib exposure for 27 percent of the population. A total of 569 women were randomized 1:1 in the study, and received vinorelbine weekly at 25 mg/m2, trastuzumab 2 mg/kg weekly after a 4 mg/kg loading dose, and either everolimus 5 mg po qd or placebo. The BOLERO-1 study will answer the question of utilization of everolimus in the first-line setting for HER2-positive breast cancer patients. More than 700 breast cancer patients have been randomized 1:1 to receive weekly paclitaxel 80 mg/m2 weekly x 3 q 4 weeks, trastuzumab 2 mg/kg weekly after a 4 mg/kg loading dose and either everolimus 10 mg po qd or placebo. The primary end point is PFS with secondary end point evaluations of survival and clinical benefit, including quality-of-life parameters. Results are expected later this year or in early 2014. managedcareoncology.com | 25 26 Updated survival results from the phase 3 CLEOPATRA (CLinical Evaluation Of Pertuzumab And TRAstuzumab) study showed that the combination of pertuzumab (Perjeta), trastuzumab (Herceptin) and docetaxel significantly extended the overall survival of patients with previously untreated HER2-positive metastatic breast cancer (mBC), compared to trastuzumab, chemotherapy and placebo. Results showed that the risk of death was reduced by 34 percent for people who received pertuzumab, trastuzumab and chemotherapy, compared to those who received trastuzumab and chemotherapy (HR = 0.66; p = 0.0008). At the time of the analysis, median overall survival had not yet been reached in people receiving the pertuzumab triplet combination, as more than half of these people continued to survive. Median overall survival was more than three years (37.6 months) for people who received trastuzumab and chemotherapy. In June 2012, the U.S. Food and Drug Administration (FDA) approved pertuzumab (Perjeta) in combination with trastuzumab and docetaxel for the treatment of people with HER2positive mBC who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease, based on the results of the CLEOPATRA study. CLEOPATRA is an international, phase 3, randomized, double-blind, placebo-controlled study. The study evaluated the efficacy and safety profile of pertuzumab combined with trastuzumab and docetaxel, compared to trastuzumab and docetaxel plus placebo, in 808 people with previously untreated HER2-positive mBC or with HER2-positive mBC that had come back after prior therapy in the adjuvant or neoadjuvant setting. Patients receiving the combination of pertuzumab, trastuzumab and chemotherapy had a statistically significant 38 percent reduction in the risk of their | managedcareoncology Quarter 3 2013 disease worsening or death (PFS, HR = 0.62; p < 0.0001) compared to people who received trastuzumab, chemotherapy and placebo. The median PFS improved by 6.1 months from 12.4 months for people who received Herceptin and chemotherapy to 18.5 months for those who received pertuzumab, trastuzumab and chemotherapy. Perjeta is designed specifically to prevent the HER2 receptor from dimerizing or pairing with other HER receptors (EGFR/HER1, HER3 and HER4), which play a role in tumor growth and survival. The mechanisms of action of pertuzumab and trastuzumab complement each other, as both bind to the HER2 receptor, but to different places. The first antibody-drug conjugate approved for the treatment of a solid tumor occurred earlier this year with the label for ado-trastuzumab emtansine (Kadcyla, T-DM1, Roche/ Genentech) for patients with metastatic HER2-positive breast cancer, including patients previously treated with trastuzumab. The results of the EMILIA trial established the benefits of T-DM1 versus the approved combination of lapatinib and capecitabine. More than 900 patients were randomized 1:1 to receive T-DM1 3.6 mg/kg intravenously q 3 weeks or lapatinib 1,250 mg po qd plus capecitabine 1,000 mg/m2 po daily x 14 days q 21 days. Median PFS favored T-DM1 with 9.6 months versus 6.4 months (HR 0.65), with objective response rates of 44 percent versus 31 percent and two-year survival of 65 percent versus 52 percent. Followup analysis of overall survival shows a statistically significant difference favoring the T-DM1 arm at 30 months versus 25 months for lapatinib and capecitabine. These results are particularly interesting when one considers that the median survival in the registration study for lapatinib and capecitabine was 17 months a few years ago, demonstrating just how quickly the outcomes for HER2-positive patients are improving. T-DM1, or ado-trastuzumab emtansine, is composed of the parent antibody trastuzumab plus a stable thioether linker and the potent cytotoxic DM1, a maytansinoid, which inhibits tubulin with potency 20-100 times greater than the available vinca alkaloids. Toxicities have been minimal, with little to no alopecia, reversible thrombocytopenia and infrequent liver function changes. The safety and toxicity profile of the ADC T-DM1 has been best demonstrated in the randomized phase 2 study comparing T-DM1 to the standard regimen of docetaxel 75-100 mg/m2 q 3 weeks plus trastuzumab. Median PFS favored T-DM1 over the standard combination, 14.2 months versus 9.2 months, and objective response rates of 64 percent versus 58 percent. The duration of response in the T-DM1 arm exceeded 9 months, largely attributable to the lack of cumulative toxicities, which may limit the benefit. Myelosuppression, GI toxicity and alopecia were substantially worse in the docetaxel plus trastuzumab arm. The MARIANNE study results will be widely anticipated, as the trial compares three arms: a standard taxane plus trastuzumab regimen, pertuzumab plus ado-trastuzumab emtansine or ado-trastuzumab emtansine plus placebo. More than 1,100 patients were randomized in this global study of first-line metastatic HER2-positive breast cancer patients, with initial results expected in 2014. These results will have a tremendous impact on the next round of adjuvant studies in this patient population. The antibody-drug conjugate CDX 011, glembatumumab, is targeting GPNMB, a biomarker overexpressed in several malignancies, including breast cancer and melanoma. Particularly exciting were the results from the EMERGE trial, which revealed that in the subset of patients with triple negative breast cancer overexpressing GPNMB, more than one third had an objective response. Additional randomized trials are under way to better understand both the subset of patients and the magnitude of benefit to be seen with this ADC. Great interest was generated at last year’s San Antonio Breast Cancer Conference with the results of the randomized study evaluating the cyclin-dependent kinase (CDK) inhibitor palbociclib (Pfizer, PD-0332991). Progression free survival favored the combination of palbociclib plus letrozole over letrozole alone, 26 months versus 7.5 months. A phase 3 study has been initiated and the promising agent has received “breakthrough therapy” status from the FDA. The list of PI3K/AKT/TOR pathway inhibitors continues to expand, with trials ranging from phase 1 to phase 3 under way, many in combination with hormonal therapies such as aromatase inhibitors or fulvestrant. A survey of www.clinicaltrials.gov indicates that MLN 0128 (Millennium); GDC 0941 (Genentech); AZD 2461 (Astra Zeneca); BEZ 235, BYL 179 and BKM 120 (Novartis); and SAR 2455409/XL147 (Sanofi), among others, are being developed. Single-agent and combination responses have been documented. Toxicities have largely centered on dermatitis and mucositis. A primary question centers on whether the benefit is confined to those patients with molecular aberrations in the pathway. The future has never been brighter for patients with breast cancer. More and more therapies that are devoid of the traditional toxicities seen with chemotherapy are in development. Survival is being measured in years versus months, with the hope that such advances will transfer quickly to the adjuvant setting, where the possibility for cures exists. managedcareoncology.com | 27 28 Magellan Corporate headline Total Drug can Solutions∞ be two lines Any Drug, Any Provider, Any Site of Service The pharmaceutical market is changing with traditional pharmaceutical costs declining and a drug pipeline rife with high cost specialty drugs. It is estimated that by 2019, specialty products will account for 50% of total drug spend in the United States.1 And, patients get their medications through a variety of channels with little coordination to ensure safe and affordable treatments. But among the changes, your critical needs remain the same: finding ways to manage the full range of prescription drug costs—while ensuring quality care. Now there’s Total Drug Solutions, an integrated system that does it all for you. The Total Drug Solutions program manages traditional pharmaceuticals, medical drug spend, and specialty drug spend to help reduce costs and improve the quality of care. • Flexible, customized solutions in specialty, medical, and traditional pharmacy • Transparency with flexible pricing models that support real cost savings • Clinical expertise in complex conditions such as oncology, psychiatry, HIV, rheumatoid arthritis, and multiple sclerosis Our Total Drug Solutions 360° approach offers: • Integrated approaches across all benefits and sites of service, including retail and specialty pharmacies, provider office, and hospital facilities • Over 40 years of PBM experience, while having processed 190M pharmacy claims per year • State-of-the-art analytics, reporting, and management to lower drug costs and measure outcomes • Knowledge from serving millions of lives in medical pharmacy management 1. ESI Drug Trend Report 2012 | managedcareoncology Quarter 3 2013 Total Drug Solutions utilizes our deep expertise in pharmacy management to provide a patient centric, 360° approach to manage all drugs ensuring the right drug at the right amount, the right benefit at the right site of service. Medical Pharmacy Solutions Our customizable, conditionspecific programs enable payors to combine and influence both medical and pharmacy systems and are proven to reduce overall medical pharmacy spend. • Utilization management and reimbursement strategies support physician buy and bill and reduce overall program costs • Backed by our clinical experts and external review boards • Documented cost savings and improved treatment compliance while often improving quality of care Specialty Pharmacy Solutions Our specialty pharmacy solutions provide formulary management and rebate programs along with complete specialty drug distribution services. • Patients receive one-on-one clinical coaching programs that are designed to improve outcomes while reducing costs • State of the art reporting, analytics and clinical support to help you target spend and bend trend Pharmacy Benefit Management • Pricing model customization from pure transparency through capitated/risk With more than 40 years of PBM experience, we bring payors, prescribers, patients, and pharmacies together around the right drugs, right doses, and right frequencies to maximize effectiveness and minimize cost. • Impeccable implementation record with CMS-certified PBM systems • Competitive national pharmacy network rates To learn more about how Total Drug Solutions offers you true cost savings and patient-centric management for any drug, any place and any benefit, visit TotalDrugSolutions.com or call 866-664-2673. We’re ready to put our customizable solutions to work for you. • Trend and formulary management • A focus on specialty drug management not just distribution • Formulary optimization programs, including supplemental rebate negotiation, optimizes manufacturer contracts for preferred, lower cost drugs ToTAlDrugSoluTionS.coM P-20rev4 (7/13) ©2012 Magellan Health Services, Inc. managedcareoncology.com | 29 Magellan Pharmacy Solutions Specialty Pharmacy • Medical Pharmacy • Pharmacy Benefit Management Driving healthier outcomes as well as a healthy return on your investment by managing the unseen components of drug spend Serving customers in 25 states and D.C. Let us put our experience to work for you 40+ years Medicaid pharmacy experience ~9 million Medical pharmacy lives covered 190 million Rx claim transactions processed annually 4.1 million Pharmacy calls handled Total Drug SolutionsSM $1.8 billion Total rebates managed Any pharmacy, any benefit, anywhere— 360° integrated approach TOTALDRUGSOLUTIONS.cOM | 30 managedcareoncology Quarter 3 2013 P-60 (7/13) ©2013 Magellan Health Services, Inc. Drug & Administration compendia Treatment of Breast Cancer With each publication, ManagedCare Oncology’s Drug & Administration Compendia highlights a single medication or a group of medications that could be utilized in the management of one of the featured oncology diseases. This section addresses such topics as: • Associated ICD-9-CM codes • Drugs that have been FDA-approved • Drugs that are compendia-listed for off-label use based on clinical studies that suggest beneficial use in some cases • Ancillary medications used in cancer treatment • Reimbursement and coding information HCPCS/CPT® codes and code description Current code price (AWP-based pricing) Most recent Medicare allowable (ASP + 6%), if applicable Possible CPT administration codes that can be utilized with each drug Associated ICD-9-CM Codes: 174 Malignant neoplasm of female breast Includes breast (female) connective tissue soft parts Paget’s disease of: breast nipple Use additional code to identify estrogen receptor status (V86.0, V86.1) Excludes skin of breast (172.5, 173.5) 174.0 Nipple and areola 174.1 Central portion 174.2 Upper-inner quadrant 174.3 Lower-inner quadrant 174.4 Upper-outer quadrant 174.5 Lower-outer quadrant 174.6 Axillary tail 174.8 Other specified sites of female breast Ectopic sites Inner breast Lower breast Malignant neoplasm of contiguous or overlapping sites of breast whose point of origin cannot be determined Midline of breast Outer breast Upper breast 174.9 Breast (female), unspecified 175 Malignant neoplasm of male breast Use additional code to identify estrogen receptor status (V86.0, V86.1) Excludes skin of breast (172.5, 173.5) 175.0 175.9 Nipple and areola Other and unspecified sites of male breast Ectopic breast tissue, male managedcareoncology.com | 31 32 FDA-Approved Medications Currently Available to Treat Breast Cancer Current Code Price (AWP-Based Pricing) Effective 7/1/13 Medicare Allowable (ASP + 6%) — Effective 7/1/13-9/30/13 Possible CPT Administration Code(s) generic (Brand) Name HCPCS Code — Code Description ado-trastuzumab emtansine (Kadcyla) C9131 — Injection, ado-trastuzumab emtansine, 1 mg (See also J9999) $33.28 $29.40 96413, 96415 ado-trastuzumab emtansine (Kadcyla) J9999* — Not otherwise classified, antineoplastic drugs NDC-level pricing NDC-level pricing 96413, 96415 anastrozole (Arimidex) J8999* — Prescription drug, oral, chemotherapeutic, Not Otherwise Specified NDC-level pricing NDC-level pricing N/A anastrozole (Arimidex) S0170 — Anastrozole, oral, 1 mg $13.48 S0170 — not payable by Medicare N/A capecitabine (Xeloda) J8520 — Capecitabine, oral, 150 mg $11.50 $9.59 N/A capecitabine (Xeloda) J8521 — Capecitabine, oral, 500 mg $38.34 $31.90 N/A cyclophosphamide (Cytoxan) J8530 — Cyclophosphamide, oral, 25 mg $2.53 $0.97 N/A cyclophosphamide (Cytoxan) J9070 — Cyclophosphamide, 100 mg $53.01 $40.38 96409, 96413, 96415 docetaxel (Taxotere) J9171 — Injection, docetaxel, 1 mg $18.26 $4.76 96413 doxorubicin HCl (Adriamycin) J9000 — Injection, doxorubicin hydrochloride, 10 mg $12.00 $3.67 96409 epirubicin (Ellence) J9178 — Injection, epirubicin hydrochloride, 2 mg $2.69 $1.34 96409, 96413 eribulin (Havalen) J9179 — Injection, eribulin mesylate, 0.1 mg $111.48 $97.92 96409 estradiol (Estrace) J8499*— Prescription drug, oral, nonchemotherapeutic, Not Otherwise Specified NDC-level pricing NDC-level pricing N/A everolimus (Afinitor) C9399* — Unclassified drugs or biological (Hospital Outpatient Use ONLY) NDC-level pricing NDC-level pricing N/A everolimus (Afinitor) J8999* — Prescription drug, oral, chemotherapeutic, Not Otherwise Specified NDC-level pricing NDC-level pricing N/A exemestane (Aromasin) J8999* — Prescription drug, oral, chemotherapeutic, Not Otherwise Specified NDC-level pricing NDC-level pricing N/A exemestane (Aromasin) S0156 — Exemestane, 25 mg $13.17 S0156 — not payable by Medicare N/A fluorouracil (Adrucil) J9190 — Injection, fluorouracil, 500 mg $3.45 $2.12 96409 fulvestrant (Faslodex) J9395 — Injection, fulvestrant, 25 mg $105.33 $89.62 96402 gemcitabine (Gemzar) J9201 — Injection, gemcitabine hydrochloride, 200 mg $48.00 $5.67 96413 goserelin acetate (Zoladex, 3.6 mg ONLY) J9202 — Goserelin acetate, implant, per 3.6 mg $451.19 $189.54 96372, 96402 ixabepilone (Ixempra) J9207 — Injection, ixabepilone, 1 mg $79.85 $67.66 96413, 96415 lapatinib (Tykerb) J8999* — Prescription drug, oral, chemotherapeutic, Not Otherwise Specified NDC-level pricing NDC-level pricing N/A letrozole (Femara) J8999* — Prescription drug, oral, chemotherapeutic, Not Otherwise Specified NDC-level pricing NDC-level pricing N/A megestrol (Megace) J8999* — Prescription drug, oral, chemotherapeutic, Not Otherwise Specified NDC-level pricing NDC-level pricing N/A | managedcareoncology Quarter 3 2013 generic (Brand) Name HCPCS Code — Code Description Current Code Price (AWP-Based Pricing) Effective 7/1/13 megestrol (Megace) S0179 — Megestrol acetate, oral, 20 mg $0.66 S0179 — not payable by Medicare N/A methotrexate (Trexall) J8610 — Methotrexate, oral, 2.5 mg $3.56 $0.52 N/A methotrexate sodium J9250 — Methotrexate sodium, 5 mg $0.29 $0.27 96372, 96374, 96401, 96409, 96450 methotrexate sodium J9260 — Methotrexate sodium, 50 mg $2.85 $2.76 96372, 96374, 96401, 96409, 96450 paclitaxel protein-bound particles (Abraxane) J9264 — Injection, paclitaxel protein-bound particles, 1 mg $11.42 $9.54 96413 paclitaxel (Taxol) J9265 — Injection, paclitaxel, 30 mg $15.54 $4.11 96413, 96415 pertuzumab (Perjeta) C9292 — Injection, pertuzumab, 10 mg $116.45 $102.09 96413 pertuzumab (Perjeta) J9999* — Not otherwise classified, antineoplastic drugs NDC-level pricing NDC-level pricing 96413 tamoxifen (Nolvadex) J8999* — Prescription drug, oral, chemotherapeutic, Not Otherwise Specified NDC-level pricing NDC-level pricing N/A tamoxifen (Nolvadex) S0187 — Tamoxifen citrate, oral, 10 mg $1.89 S0187 — not payable by Medicare N/A thiotepa (Thioplex) J9340 — Injection, thiotepa, 15 mg $714.00 $265.00 51720, 96409 toremifene citrate (Fareston) J8999* — Prescription drug, oral, chemotherapeutic, Not Otherwise Specified NDC-level pricing NDC-level pricing N/A trastuzumab (Herceptin) J9355 — Injection, trastuzumab, 10 mg $90.29 $78.70 96413, 96415 vinblastine (Velban) J9360 — Injection, vinblastine sulfate, 1 mg $3.18 $1.62 96409 Medicare Allowable (ASP + 6%) — Effective 7/1/13-9/30/13 Possible CPT Administration Code(s) *When billing a nonclassified medication using a CMS 1500 claim form, you must include both the HCPCS code (e.g., J8999 for Tamoxifen) in column 24D and the drug name, strength and NDC (National Drug Code) in box 19 or 24A in order to ensure appropriate reimbursement. Please note: Check with payor regarding correct placement of medication information. managedcareoncology.com | 33 34 Compendia-Listed Off-Label-Use Medications Currently Available to Treat Breast Cancer Current Code Price (AWP-Based Pricing) Effective 7/1/13 Medicare Allowable (ASP + 6%) — Effective 7/1/13-9/30/13 Possible CPT Administration Code(s) generic (Brand) Name HCPCS Code — Code Description bacillus Calmette-Guerin (Tice BCG, TheraCys) J9031 — Bacillus Calmette-Guerin (BCG) vaccine (intravesical), per installation $174.18 $119.30 51720 bacillus Calmette-Guerin (Tice BCG, TheraCys) 90586 — Bacillus Calmette-Guerin (BCG) vaccine for bladder cancer, live, for intravesical use $174.18 $119.30 51720 bacillus Calmette-Guerin (BCG vaccine) 90585 — Bacillus Calmette-Guerin (BCG) vaccine for tuberculosis, live, for percutaneous use $174.18 $119.30 90471, 90472 bevacizumab (Avastin) J9035 — Injection, bevacizumab, 10 mg $74.51 $64.64 96413, 96415 carboplatin (Paraplatin) J9045 — Injection, carboplatin, 50 mg $86.00 $2.97 96409, 96413, 96415 cisplatin (Platinol AQ) J9060 — Injection, cisplatin, powder or solution, per 10 mg $4.33 $1.84 96409, 96413, 96415 dexamethasone (Decadron) J1100 — Injection, dexamethasone sodium phosphate, 1 mg $0.15 $0.12 11900, 11901, 20600, 20605, 20610, 96372, 96374 dexamethasone (Decadron) J8540 — Dexamethasone, oral, 0.25 mg $0.10 $0.27 N/A doxorubicin HCI liposomal (Doxil) J9002 — Injection, doxorubicin hydrochloride, liposomal, 10 mg (Code no longer payable by Medicare effective 7/1/13) $581.41 N/A 96413 doxorubicin HCI liposomal (Doxil) Q2050 — Injection, doxorubicin hydrochloride, liposomal, 10 mg, Not Otherwise Specified $581.41 $545.44 96413 etoposide (Vepesid) J8560 — Etoposide, oral, 50 mg $66.85 $55.12 N/A etoposide (Toposar) J9181 — Injection, etoposide, 10 mg $0.91 $0.75 96413, 96415 hydrocortisone (Solu-Cortef) J1720 — Injection, hydrocortisone sodium succinate, up to 100 mg $2.40 $4.92 96365, 96366, 96372, 96374 hydroxyurea (Hydrea) J8999* — Prescription drug, oral, chemotherapeutic, Not Otherwise Specified NDC-level pricing NDC-level pricing N/A hydroxyurea (Hydrea) S0176 — Hydroxyurea, oral, 500 mg $1.28 S0176 — not payable by Medicare N/A ifosfamide (Ifex) J9208 — Injection, ifosfamide, 1 g $44.09 $30.27 96413, 96415 irinotecan (Camptosar) J9206 — Injection, irinotecan, 20 mg $15.00 $2.25 96413, 96415 leucovorin calcium (Wellcovorin) J0640 — Injection, leucovorin calcium, per 50 mg $7.80 $4.76 96372, 96374, 96409 leuprolide (Eligard, Lupron Depot) J9217 — Leuprolide acetate (for depot suspension), 7.5 mg $493.20 $206.01 96402 leuprolide (Lupron) J9218 - Leuprolide acetate, per 1 mg $23.57 $10.50 96402 lomustine (CeeNU) J8999* — Prescription drug, oral, chemotherapeutic, Not Otherwise Specified NDC-level pricing NDC-level pricing N/A lomustine (CeeNU) S0178 — Lomustine, oral, 10 mg $10.59 S0178 — not payable by Medicare N/A medroxyprogesterone (DepoProvera) J1050 — Injection, medroxyprogesterone acetate, 1 mg $0.26 $0.22 96402 melphalan (Alkeran) J8600 — Melphalan, oral, 2 mg $10.14 $8.71 N/A | managedcareoncology Quarter 3 2013 generic (Brand) Name HCPCS Code — Code Description Current Code Price (AWP-Based Pricing) Effective 7/1/13 Medicare Allowable (ASP + 6%) — Effective 7/1/13-9/30/13 Possible CPT Administration Code(s) melphalan (Alkeran) J9245 — Injection, melphalan hydrochloride, 50 mg $1,971.72 $1,273.10 96409, 96413 methlyprednisolone (DepoMedrol) J1020 — Injection, methylprednisolone acetate, 20 mg $3.78 $3.12 11900, 11901, 20600, 20605, 20610, 96372, 96374 methlyprednisolone (DepoMedrol) J1030 — Injection, methylprednisolone acetate, 40 mg $5.84 $2.89 11900, 11901, 20600, 20605, 20610, 96372, 96374 methlyprednisolone (DepoMedrol) J1040 — Injection, methylprednisolone acetate, 80 mg $9.52 $5.54 11900, 11901, 20600, 20605, 20610, 96372, 96374 methlyprednisolone (SoluMedrol) J2920 — Injection, methylprednisolone sodium succinate, up to 40 mg $2.32 $1.85 11900, 11901, 20600, 20605, 20610, 96372, 96374 methlyprednisolone (SoluMedrol) J2930 — Injection, methylprednisolone sodium succinate, up to 125 mg $3.50 $2.64 11900, 11901, 20600, 20605, 20610, 96372, 96374 methlyprednisolone (Medrol) J7509 — Methylprednisolone, oral, per 4 mg $1.43 $0.66 N/A mitomycin (Mutamycin) J9280 — Injection, mitomycin, 5 mg $67.20 $23.99 96409 mitoxantrone (Novantrone) J9293 — Injection, mitoxantrone hydrochloride, per 5 mg $68.24 $37.17 96409, 96413 oxaliplatin (Eloxatin) J9263 — Injection, oxaliplatin, 0.5 mg $2.04 $0.88 96413, 96415 pemetrexed (Alimta) J9305 — Injection, pemetrexed, 10 mg $69.54 $59.48 96409 prednisone (e.g., Deltasone, Orasone) J7506 — Prednisone, oral, per 5 mg $0.08 $0.03 N/A prednisolone (e.g., Orapred, Millipred) J7510 — Prednisolone, oral, per 5 mg $7.88 $0.04 N/A topotecan (Hycamtin) J8705 — Topotecan, oral, 0.25 mg $104.02 $86.64 N/A topotecan (Hycamtin) J9351 — Injection, topotecan, 0.1 mg $7.66 $2.13 96413 triptorelin (Trelstar Depot, Trelstar LA) J3315 — Injection, triptorelin pamoate, 3.75 mg $975.89 $192.43 96372, 96402 vincristine (Vincasar PFS) J9370 — Vincristine sulfate, 1 mg $6.61 $4.42 96409 vinorelbine (Navelbine) J9390 — Injection, vinorelbine tartrate, per 10 mg $27.00 $10.23 96409 zoledronic acid (Zometa) J3487 — Injection, zoledronic acid, 1 mg (Code no longer payable by Medicare effective 7/1/13) $239.56 N/A 96365, 96413 zoledronic acid (Reclast) J3488 — Injection, zoledronic acid, 1 mg (Code no longer payable by Medicare effective 7/1/13) $199.85 N/A 96365, 96374 zoledronic acid (Reclast, Zometa) Q2051 — Injection, zoledronic acid, 1 mg, Not Otherwise Specified (Code becomes effective for Medicare billing 7/1/13) $239.13 $196.42 96365, 96413, 96374 *When billing a nonclassified medication using a CMS 1500 claim form, you must include both the HCPCS code (e.g., J8999 for Hydrea) in column 24D and the drug name, strength and NDC (National Drug Code) in box 19 in order to ensure appropriate reimbursement. managedcareoncology.com | 35 36 Ancillary Medications Used in Cancer Treatment generic (Brand) Name HCPCS Code — Code Description Current Code Price (AWP-Based Pricing) Effective 7/1/13 Medicare Allowable (ASP + 6%) — Effective 7/1/13-9/30/13 Possible CPT Administration Code(s) aprepitant (Emend) J8501 — Aprepitant, oral, 5 mg $8.49 $6.68 N/A granisetron (Kytril) J1626 — Injection, granisetron hydrochloride, 100 mcg $3.84 $0.68 96374 granisetron (Kytril) Q0166 — Granisetron hydrochloride, 1 mg oral, FDAapproved prescription antiemetic, for use as a complete therapeutic substitute for an IV antiemetic at time of chemotherapy treatment, not to exceed a 24-hour dosage regimen $59.01 $2.53 N/A granisetron (Kytril) S0091 — Granisetron hydrochloride, 1 mg (for circumstances falling under the Medicare statute, use HCPCS code Q0166) $59.01 S0091– not payable by Medicare N/A ondansetron (Zofran) J2405 — Injection, ondansetron hydrochloride, per 1 mg $0.45 $0.16 96372, 96374 ondansetron (Zofran) Q0162 — Ondansetron, 1 mg, oral, FDA-approved prescription antiemetic, for use as a complete therapeutic substitute for an IV antiemetic at the time of chemotherapy treatment, not to exceed a 48-hour dosage regimen $6.05 $0.04 N/A ondansetron (Zofran) S0119 — Ondansetron, oral, 4 mg (for circumstances falling under the Medicare statute, use HCPCS code Q0162) $24.20 S0119 — not payable by Medicare N/A palonosetron (Aloxi) J2469 — Injection, palonosetron hydrochloride, 25 mcg $45.96 $18.93 96374 CPT Administration Code Descriptions CPT Administration Code Code Description 51720 Bladder instillation of anticarcinogenic agent (including retention time) 96401 Chemotherapy administration, subcutaneous or intramuscular; nonhormonal antineoplastic 96402 Chemotherapy administration, subcutaneous or intramuscular; hormonal antineoplastic 96409 Chemotherapy administration, intravenous, push technique; single or initial substance/drug 96413 Chemotherapy administration, intravenous infusion technique; up to 1 hour, single or initial substance/drug 96415 Chemotherapy administration, intravenous infusion technique; each additional hour (List separately in addition to code for primary procedure.) (Use 96415 in conjunction with 96413.) 96422 Chemotherapy administration, intra-arterial; infusion technique, up to 1 hour 96423 Chemotherapy administration, intra-arterial; infusion technique, each additional hour (List separately in addition to code for primary procedure.) (Use 96423 in conjunction with 96422.) 96425 Chemotherapy administration, intra-arterial; infusion technique, initiation of prolonged infusion (more than 8 hours), requiring the use of a portable or implantable pump 96450 Chemotherapy administration, into CNS (e.g., intrathecal), requiring and including spinal puncture 96365 Intravenous infusion, for therapy, prophylaxis or diagnosis (specify substance or drug); initial, up to 1 hour 96366 Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); each additional hour (List separately in addition to code for primary procedure.) (Use 96366 in conjunction with 96365, 96367.) 96369 Subcutaneous infusion for therapy or prophylaxis (specify substance or drug); initial, up to 1 hour, including pump setup and establishment of subcutaneous infusion site(s) 96370 Subcutaneous infusion for therapy or prophylaxis (specify substance or drug); each additional hour (List separately in addition to code for primary procedure.) (use 96370 in conjunction with 96369.) 96372 Therapeutic, prophylactic or diagnostic injection (specify substance or drug); subcutaneous or intramuscular 96374 Therapeutic, prophylactic or diagnostic injection (specify substance or drug); intravenous push, single or initial substance/drug References • HCPCS Level II Expert 2013. • Current Procedural Terminology (CPT) 2013. • American Medical Association. ICD-9-CM for Professionals. Vol. 1 and 2. Chicago: AMA Press; 2013. • RJ Health Systems International, LLC. The Drug Reimbursement Coding and Pricing Guide. Vol. 11, Number 3, Third Quarter 2013. • FDA-approved indication (product prescribing information). • www.ReimbursementCodes.com. Powered by RJ Health Systems International, LLC., Rocky Hill, Conn. • CMS (Centers for Medicare & Medicaid Services) — Medicare Allowable Third Quarter 2013 — Effective Dates 7/1/13 – 9/30/13. CPT copyright 2013 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association. This information was supplied by RJ Health Systems International, LLC, located in Rocky Hill, Conn. | managedcareoncology Quarter 3 2013 Oncology-Related HCPCS Codes This reference chart will assist the oncology office (office manager, oncology nurse, physician and ancillary staff) and payor with the appropriate codes to utilize when billing or reimbursing for medication(s). generic (Brand) Name HCPCS Code — Code Description azacitidine (Vidaza) Current Code Price (AWP-Based Pricing)* Effective 7/1/13 Medicare Allowable (ASP + 6%) — Effective 7/1/139/30/13 Possible CPT Admin Code(s) FDA-Approved Uses Compendia-Listed Off-Label Uses J9025 — Injection, azacitidine, 1 mg Chronic myeloid leukemia (205.1_) Low-grade myelodysplastic syndrome lesions (238.72) High-grade myelodysplastic syndrome lesions (238.73) Myelodysplastic syndrome with 5 q deletion (238.74) Myelodysplastic syndrome, unspecified (238.75) Malignant neoplasm of specified parts of peritoneum (158.8) Malignant neoplasm of peritoneum, unspecified (158.9) Malignant neoplasm of pleura (163) Malignant neoplasm of heart (164.1) Acute myeloid leukemia (205.0_) Other thalassemia (282.49) Sickle-cell disease, unspecified (282.60) Hb-SS disease without crisis (282.61) Hb-SS disease with crisis (282.62) $6.59 $5.77 96401 96409 96413 brentuximab vedotin (Adcetris) J9042 — Injection, brentuximab vedotin, 1 mg Anaplastic large-cell lymphoma (200.6_) Hodgkin’s disease (201._) N/A $116.16 $102.74 96413 cabazitaxel (Jevtana) J9043 — Injection, cabazitaxel, 1 mg Malignant neoplasm of prostate (185) N/A $168.16 $139.73 96413 cetuximab (Erbitux) J9055 — Injection, cetuximab, 10 mg Malignant neoplasm of lip (140._) Malignant neoplasm of tongue (141._) Malignant neoplasm of major salivary glands (142._) Malignant neoplasm of gum (143._) Malignant neoplasm of floor of mouth (144._) Malignant neoplasm of other and unspecified parts of mouth (145._) Malignant neoplasm of oropharynx (146._) Malignant neoplasm of nasopharynx (147._) Malignant neoplasm of hypopharynx (148._) Malignant neoplasm of other and ill-defined sites within the lip, oral cavity and pharynx (149._) Malignant neoplasm of colon (153._) Malignant neoplasm of rectum, rectosigmoid junction and anus (154._) Malignant neoplasm of nasal cavities, middle ear and accessory sinuses (160._) Malignant neoplasm of larynx (161._) Malignant neoplasm of head, neck and face (195.0) Secondary and unspecified malignant neoplasm of lymph nodes of head, face and neck (196.0) Malignant neoplasm of trachea, bronchus and lung (162._) $61.14 $52.48 96413, 96415 managedcareoncology.com | 37 38 generic (Brand) Name HCPCS Code — Code Description dactinomycin (Cosmegen) Current Code Price (AWP-Based Pricing)* Effective 7/1/13 Medicare Allowable (ASP + 6%) — Effective 7/1/139/30/13 Possible CPT Admin Code(s) FDA-Approved Uses Compendia-Listed Off-Label Uses J9120 — Injection, dactinomycin, 0.5 mg Malignant neoplasm of retroperitoneum (158.0) Malignant neoplasm of bone and articular cartilage (170._) Malignant neoplasm of connective and other soft tissue (171._) Malignant neoplasm of placenta (181) Malignant neoplasm of testis (186._) Malignant neoplasm of kidney, except pelvis (189.0) Neoplasm of uncertain behavior of placenta (236.1) Malignant melanoma of skin (172._) Kaposi’s sarcoma (176._) Malignant neoplasm of ovary (183._) Malignant neoplasm of vagina (184._) Malignant neoplasm of penis and other male genital organs (187._) Malignant neoplasm of eye (190._) Complications of transplanted kidney (996.81) Complications of transplanted heart (996.83) $705.60 $618.79 96409 ixabepilone (Ixempra) J9207 — Injection, ixabepilone, 1 mg Malignant neoplasm of female breast (174._) Malignant neoplasm of male breast (175._) Malignant neoplasm of prostate (185) $79.85 $67.66 96413, 96415 panitumumab (Vectibix) J9303 — Injection, panitumumab, 10 mg Malignant neoplasm of colon (153._) Malignant neoplasm of rectum, rectosigmoid junction and anus (154._) Malignant neoplasm of trachea, bronchus and lung (162._) $106.90 $91.10 96413 96415 rituximab (Rituxan) J9310 — Injection, rituximab, 100 mg Reticulosarcoma (200.0_) Lymphosarcoma (200.1_) Burkitt’s tumor or lymphoma (200.2_) Marginal zone lymphoma (200.3_) Mantle cell lymphoma (200.4_) Primary central nervous system lymphoma (200.5_) Large cell lymphoma (200.7_) Other named variants of lymphosarcoma and reticulosarcoma (200.8_) Nodular lymphoma (202.0_) Leukemic reticuloendotheliosis (202.4_) Other malignant lymphomas (202.8_) Other and unspecified malignant neoplasms of lymphoid and histiocytic tissue (202.9_) Chronic lymphoid leukemia, without mention of having achieved remission (204.1_) Polyarteritis nodosa (446.0) Wegener’s granulomatosis (446.4) Rheumatoid arthritis (714.0) Felty’s syndrome (714.1) Other rheumatoid arthritis and other with visceral or systemic involvement (714.2) Hodgkin’s paragranuloma (201.0_) Hodgkin’s granuloma (201.1_) Hodgkin’s sarcoma (201.2_) Hodgkin’s disease, lymphocytic-histiocytic predominance (201.4_) Acute lymphoid leukemia (204.0_) Post-transplant lymphoproliferative disorder [PTLD] (238.77) Macroglobulinemia (273.3) Chronic graft-versus-host disease (279.52) Acute on chronic graft-versus-host disease (279.53) Autoimmune hemolytic anemias (283.0) Von Willebrand’s disease (286.4) Acquired coagulation factor deficiency (286.7) Other and unspecified coagulation defects (286.9) Immune thrombocytopenic purpura (287.31) Thrombotic microangiopathy (446.6) Pemphigus (694.4) Systemic lupus erythematosus (710.0) Enlargement of lymph nodes (785.6) Malignant ascites (789.51) $779.83 $678.87 96413 96415 * The code price is based on the HCPCS code description. HCPCS (Healthcare Common Procedure Coding System) codes are a component of CMS (Centers for Medicare & Medicaid Services). The code price is an AWP-based pricing methodology developed by RJ Health Systems International, LLC, Rocky Hill, Conn. Oncology-Related J-Code References • HCPCS Level II Expert 2013. • Current Procedural Terminology (CPT) 2013. • American Medical Association. ICD-9-CM for Professionals. Vol. 1 and 2. Chicago: AMA Press; 2013. • Full prescribing information for each drug listed. • www.ReimbursementCodes.com. Powered by RJ Health Systems International, LLC, Rocky Hill, Conn. • CMS (Centers for Medicare & Medicaid Services) — Medicare Allowable Third Quarter — Effective Dates 7/1/13 – 9/30/13. CPT copyright 2013 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association. This information was supplied by RJ Health Systems International, LLC, located in Rocky Hill, Conn. Current code prices are effective as of 7/1/13. | managedcareoncology Quarter 3 2013 clinical trial update by John W. Mucenski, B.S., Pharm.D., director of pharmacy operations, UPMC Cancer Centers New drugs, such as trastuzumab emtansine (T-DM1) may prove to be invaluable to patients with HER2 (+) disease, while oral antiangiogenic drugs like sorafenib may play a role in the treatment of patients with HER2 (-) metastatic breast cancer. Title: Trastuzumab emtansine for HER2-positive advanced breast cancer. Authors: Verma S, Miles D, Gianni L, et al. Reference: N Engl J Med. 2012;367:17831791. Purpose: Approximately 20 percent of patients diagnosed with breast cancer have amplification of human epidermal growth factor receptor 2 (HER2). This is associated with a decrease in survival. Combining monoclonal antibody therapy directed against HER2 in combination with standard chemotherapy has been effective in this patient population. Studies have shown the combination of trastuzumab (Herceptin) with standard chemotherapy in the first-line setting increases the time to progression and overall survival in patients with metastatic disease. For patients who have progressive disease and have previously been treated with trastuzumab, an anthracycline and a taxane, the combination of lapatinib (Tykerb) and capecitabine (Xeloda) has become the standard. Trastuzumab emtansine (T-DM1) combines the HER2-targeting antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1. The antibody and cyto- toxic agent are conjugated by means of a stable linker. This allows for intracellular delivery of the cytotoxic drug specifically to HER2-overexpressing cells, improves the therapeutic index and minimizes the exposure of the cytotoxic agent to normal tissue. Phase 2 studies have shown clinical activity of this combination in patients with HER2 (+) advanced breast cancer. This phase 3 trial will evaluate the efficacy and safety of T-DM1, in comparison to lapatinib and capecitabine, in patients previously treated with trastuzumab and a taxane. Methods: This randomized, open-label trial involved patients with HER2 (+), unresectable, locally advanced or metastatic breast cancer who had received previous therapy with trastuzumab and a taxane. Eligible patients had documented progression of disease, a left ventricular ejection fraction of at least 50 percent and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned in a 1:1 ratio to receive either T-DM1 or lapatinib and capecitabine. Those randomized to receive oral chemotherapy received lapatinib 1,250 mg per day and capecitabine 1,000 mg/m2 every 12 hours (maximum planned daily dose 2,000 mg/m2) on days one through 14 of a 21-day schedule. Patients randomly assigned to T-DM1 received 3.6 mg/kg intravenously every 21 days. Dose reductions were made secondary to toxicity in either treatment arm. Patients were stratified by number of prior therapies and disease involvement (visceral vs. nonvisceral). The primary end points were progression-free survival (PFS), overall survival (OS) and safety. Results: A total of 991 patients were enrolled, with 496 assigned to lapatinib plus capecitabine and 495 to T-DM1. PFS was significantly improved in the patients treated with T-DM1 (9.6 months vs. 6.4 months; hazard ratio [HR] 0.64; 95 percent confidence interval [CI], 0.55 to 0.77; p < 0.001). The clinical benefit was consistent across all clinically relevant subgroups, with a less definitive benefit among patients aged ≥ 75 years and those with nonvisceral or nonmeasurable disease. The median overall survival at the second interim analysis crossed the stop boundary for efficacy (30.9 vs. 25.1 months; HR for death from any cause 0.68; 95 percent CI, 0.55 to 0.85; p < 0.001). The objective response rate was higher in those patients treated with T-DM1 (43.6 vs. 30.8 percent); p < 0.001). Serious adverse events were reported in 88 (18.0 percent) of the patients treated with lapatinib plus capecitabine vs. 76 (15.5 percent) of those patients treated with T-DM1. The incidence of grade 3 or 4 adverse reactions was also higher in the oral chemotherapy group and consisted managedcareoncology.com | 39 40 primarily of diarrhea and palmarplantar erythrodysesthesia. The most common grade 3 or 4 adverse events in the T-DM1 group were thrombocytopenia and elevated liver enzymes. Conclusion: T-DM1 significantly prolonged PFS and OS with less toxicity than lapatinib plus capecitabine in patients with HER2 (+) advanced breast cancer previously treated with trastuzumab and a taxane. Managed Care Implications: Adotrastuzumab emtansine (Kadcyla) has been FDA-approved as a single agent for the treatment of patients with HER2 (+) metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. An interesting question will be the role of trastuzumab in patients who progress on this drug. Title: Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. Authors: Hurvitz SA, Dirix L, Kocsis, J, et al. Reference: J Clin Oncol. March 20, 2013;31(9):1157-1163. Purpose: HER2 overexpression occurs in approximately 20 percent of all breast cancers and is associated with increased mortality in early-stage disease, decreased time to relapse and an increased incidence of metastases when compared to HER2 (-) breast cancer. HER2-specific targeted therapies have improved clinical outcomes in patients with HER2 (+) disease. Single-agent trastuzumab (Herceptin) has shown modest activity, but trastuzumab plus taxane-based therapy has demonstrated significantly improved overall survival (OS) and progression-free survival (PFS) when compared to chemotherapy alone. Even with these advances, the majority of patients with HER2 (+) breast cancer will develop metastatic disease and progress. Chemotherapy also is associ- ated with significant toxicity, including myelosuppression and other adverse events that can negatively affect a patient’s quality of life. Trastuzumab emtansine (T-DM1; Kadcyla) is an antibody-drug conjugate developed for the treatment of HER2 (+) cancer. T-DM1 selectively delivers a cytotoxic agent intracellularly to tumor cells, and the targeting antibody, trastuzumab, is itself approved to treat metastatic breast cancer. Single-agent studies with T-DM1 reported objective response rates of 32.7 to 44.0 percent in clinical trials, with a low rate of adverse events. This study compares the response and tolerability of T-DM1 alone compared to that of trastuzumab (H) and docetaxel (Taxotere) (T), a taxane. Methods: Patients ≥ 18 years of age with histologically or cytologically confirmed HER2 (+), unresectable, locally advanced or metastatic breast cancer, without prior chemotherapy or trastuzumab for metastatic disease, were eligible. Other inclusion criteria included measurable disease, an ECOG performance status of 0 or 1 and adequate end organ function. The | managedcareoncology Quarter 3 2013 study randomly assigned patients in a 1:1 ratio to either T-DM1 3.6 mg/kg intravenously once every three weeks or trastuzumab 8 mg/kg as an intravenous (IV) loading dose followed by 6 mg/ kg IV every three weeks and docetaxel 75 or 100 mg/m2 IV every three weeks. Treatment continued until progressive disease (PD) or unacceptable toxicity. The primary end points of the study were investigator-assessed PFS and safety. Secondary end points included overall survival (OS), overall response rate (ORR) and duration of response. Results: A total of 137 patients were randomly assigned to receive either HT (n = 70, of which 68 received therapy) or T-DM1 (n = 67). The arms were wellbalanced in regard to previous anthracycline therapy and fairly well-balanced in regard to prior neoadjuvant or adjuvant trastuzumab or taxane use. The median duration of therapy was 8.1 months (range 1 to 29 months) for trastuzumab, 5.5 months (range 0 to 22 months) for docetaxel and 10.4 months (range 0 to 29 months) for T-DM1. T-DM1 provided significant improvement in PFS over HT, with a HR of 0.59 (95 percent CI, 0.36 to 0.97; p = 0.035). The median PFS was 9.2 months in the HT arm and 14.2 months in the T-DM1 arm (HR 0.59; 95 percent CI, 0.36 to 0.97). The ORR was 58 percent (95 percent CI, 45.5 to 69.2 percent) with HT and 64.2 percent (95 percent CI, 51.8 to 74.8 percent) with T-DM1. T-DM1 was also found to cause fewer ≥ grade 3 adverse events (46.4 vs. 90.9 percent), with grade 4 events occurring in 5.8 and 57.7 percent of patients, respectively. Serious events (25.8 vs. 20.3 percent) and events leading to discontinuation of therapy (40.9 vs. 7.2 percent) were also less frequent in those patients treated with T-DM1. The most common adverse events of any grade in the HT group were alopecia, neutropenia, diarrhea and fatigue. In the T-DM1 group they were fatigue, nausea, increase in serum AST and headache. Preliminary OS results were similar between the treatment arms, with a median followup of 23 months. Conclusion: First-line treatment with T-DM1 for patients with HER2 (+) metastatic breast cancer provides a significant improvement in PFS with a favorable toxicity profile, versus HT. Managed Care Implications: T-DM1 may prove to be the drug of choice for first-line therapy in patients with HER2 (+) metastatic breast cancer. Additional studies will identify its place in the treatment armamentarium. Title: A double-blind, randomized, placebo-controlled, phase 2b study evaluating sorafenib in combination with paclitaxel as a first-line therapy in patients with HER2-negative advanced breast cancer. Authors: Gradishar WJ, Kaklamani V, Sahoo TP, et al. Reference: Eur J Cancer. 2013;49:312-322. Purpose: Angiogenesis inhibitors have become important in cancer treatment. Angiogenesis is associated with disease progression, tumor growth, invasiveness, metastasis and recurrence in a number of malignancies including breast cancer. While monotherapy with antiangiogenics has shown only modest activity in patients with metastatic breast cancer (MBC), when combined with standard chemotherapy, clinical benefit has been demonstrated. The combination of bevacizumab (Avastin) and paclitaxel (Taxol) in the first-line setting for MBC showed an improved tumor response and progression-free survival (PFS) when compared to single-agent paclitaxel. Sorafenib (Nexavar) is a multikinase inhibitor with both antiproliferative and antiangiogenic activity in hepatocellular and advanced renal cell carcinomas. Studies using sorafenib in breast cancer have looked at its use with established chemotherapy or endocrine treatment in human epidermal growth factor receptor 2 (HER2)-negative patients with the primary end point being improvement in PFS. These studies led to mixed results. This study looks at the efficacy and safety of sorafenib in combination with first-line paclitaxel for HER2 (-) advanced breast cancer. Methods: Patients aged ≥ 18 years with histologically or cytologically confirmed HER2 (-) locally recurrent (inoperable) or metastatic breast cancer who had not been treated with chemotherapy for advanced disease were eligible. Other eligibility criteria included an ECOG performance status of 0 or 1, and adequate bone marrow, renal and hepatic function. Patients were randomized in a 1:1 ratio to paclitaxel 90 mg/m2 weekly intravenously on a three week on, one week off schedule in combination with placebo or to the same dosing schedule of paclitaxel in combination with sorafenib 400 mg orally twice a day, which was administered continuously. Clinical and radiologic assessment occurred every eight weeks for 24 weeks, then every 12 weeks thereafter. The primary end point was PFS in the intent-to-treat (ITT) population. Secondary end points included overall survival (OS), overall response rate (ORR), duration of response (DOR) and safety. Results: A total of 237 patients were randomized, 119 to paclitaxel plus sorafenib and 118 to paclitaxel and placebo. This was the ITT population. A total of four patients received no study treatment in the paclitaxel and sorafenib arm, leaving 115 patients to be evaluated for safety. There was a median PFS of 6.9 months noted in those patients treated with sorafenib vs. 5.6 months in the placebo arm (HR = 0.788; 95 percent CI, 0.558 to 1.112; p = 0.1715). There was no significant difference in managedcareoncology.com | 41 42 OS between the two treatment arms: 16.8 months for the sorafenib arm vs. 17.4 months for those patients treated with placebo (HR 1.022; 95 percent CI, 0.715-1.461; p = 0.904). ORR (67.2 vs. 54.2 percent; p = 0.0343) and DOR (5.6 vs. 3.7 months; p = 0.0157) favored the sorafenib-treated population and were statistically significant. Grade 3 or 4 toxicities (sorafenib vs. placebo) included hand-foot skin reactions (31 vs. 3 percent), neutropenia (13 vs. 7 percent) and anemia (11 vs. 6 percent). Two treatment-related deaths occurred in the sorafenib arm. Conclusion: The addition of sorafenib to paclitaxel in patients with MBC improved disease control but did not significantly improve PFS to support a phase 3 trial of similar design. Toxicity of the combination was manageable with dose reductions. Managed Care Implications: The activity of sorafenib with respect to disease control was encouraging, but the PFS results were inconclusive and more modest than those reported with paclitaxel and bevacizumab in advanced breast cancer. Targeting specific breast cancer populations where this combination may provide more definitive clinical benefit is warranted. Title: Docetaxel-cisplatin might be superior to docetaxel-capecitabine in first-line treatment of metastatic triplenegative breast cancer. Authors: Fan Y, Xu BH, Yuan P, et al. Reference: Ann Oncol. 2013;24:12191225. Purpose: Triple-negative breast cancer (TNBC), estrogen receptor, progesterone receptor and HER2 negative, accounts for up to 20 percent of all breast cancer cases. It has an aggressive behavior with early visceral metastases and poor outcomes. Numerous combinations of therapy have been used in an attempt to improve the prognosis for patients with TNBC. This includes optimizing choice and scheduling of drugs commonly used to treat the disease, dose intensification, and the introduction of newer, novel agents such as anti-EGFR and anti-angiogenesis agents and poly ADP ribose polymerase (PARP) inhibitors, but outcomes have been disappoint- | managedcareoncology Quarter 3 2013 ing. For now, chemotherapy remains the best therapeutic option in the adjuvant or metastatic setting in TNBC. A few retrospective or small neoadjuvant trials have suggested that TNBC may be more sensitive to DNA-damaging agents such as cisplatin (Platinol), while other studies have shown little benefit. Several phase 2 or 3 studies are presently underway looking at the use of platinumbased therapy in patients with metastatic TNBC (mTNBC). This article describes the first prospective, randomized phase 2 clinical trial comparing different regimens in the treatment of mTNBC. Methods: This prospective, open-label, randomized phase 2 trial enrolled women with locally advanced or metastatic TNBC who had not received therapy for advanced disease. Patients were at least 18 years old and had histologically confirmed TNBC, an ECOG performance status of ≤ 1 and adequate end organ function. Patients were randomized in a 1:1 ratio to receive either docetaxel (Taxotere) 75 mg/m2 and cisplatin 75 mg/m2, both intravenously on day one (TP), or docetaxel 75 mg/m2 intravenously on day one and capecitabine (Xeloda) orally at a dose of 1,000 mg/m2 twice a day on a two weeks on, one week off schedule (TX). Regimens were repeated every three weeks for up to six cycles or until disease progression, unacceptable toxicity or withdrawal of patient consent. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), overall survival (OS) and safety. Results: A total of 53 patients were randomized and evaluated, 27 to the TP arm and 26 to the TX arm. All had received previous anthracycline therapy, while over 50 percent in each arm had received previous paclitaxel (Taxol). Sixteen of 27 patients (59 percent) in the TP arm and 19 of 26 (73 percent) in the TX arm had visceral metastases. The ORR was 63.0 percent, three complete responses and 14 partial responses, in the TP arm and 15.4 percent, four partial responses in the TX arm (p = 0.001). The median PFS was 10.9 months in those patients treated with TP (95 percent CI, 2.2-19.8 months) and 4.8 months in those treated with TX (95 percent CI, 3.0-6.7 months). The hazard ratio was 0.29 with a 95 percent CI of 0.14-0.57 and a p value of < 0.001. Median overall survival also favored the patients treated with TP (32.8 vs. 21.5 months, HR 0.41; 95 percent CI, 0.18-0.92; p = 0.027). Overall, both treatment regimens were well-tolerated. Grade 3 or 4 neutropenia was similar in both arms and no grade 3 or 4 thrombocytopenia or anemia was noted. As expected, gastrointestinal toxicity such as vomiting (74.1 vs. 34.6 percent; p = 0.004) was more common in the patients receiving TP. Likewise, a higher incidence of grade 2 or 3 hand-foot syndrome was noted in patients treated in the capecitabine arm (p = 0.023). Conclusion: This study suggests that a cisplatin-based chemotherapy was superior to a capecitabine-based regimen in the first-line treatment of mTNBC, as measured by ORR, PFS and OS. Larger studies need to be completed to evaluate these findings. Managed Care Implications: With the lack of efficacy of targeted agents (e.g., PARP inhibitors) to effectively treat patients with mTNBC, other treatment strategies must be developed. DNA-damaging agents such as cisplatin may be the cornerstone for further investigations. Title: Primary results of BEATRICE, a randomized phase III trial evaluating adjuvant bevacizumab-containing therapy in triple-negative breast cancer. Authors: Cameron D, Brown J, Dent R, et al. Reference: Cancer Res. 2012;72(24 Suppl):Abstract nr S6-5. Purpose: There are no established targeted treatment options for patients with triple-negative breast cancer (TNBC), a clinically important subset of breast cancer patients. Studies in metastatic breast cancer have shown the addition of bevacizumab (Avastin), an antivascular endothelial growth factor (anti-VEGF) antibody, to standard chemotherapy significantly improves progression-free survival. Since high VEGF levels have been observed in estrogen receptor (-) and progesterone receptor (-) tumors, bevacizumab may be beneficial in TNBC based upon its ability to target the angiogenic switch before tumor vascularization and the dependency of micrometastases on angiogenesis. The objective of this study is to evaluate the addition of bevacizumab to chemotherapy in the adjuvant setting for patients with TNBC. Methods: Patients with centrally confirmed resected, early invasive TNBC were eligible for the trial. They were randomized in a 1:1 ratio to receive either standard chemotherapy (investigator’s choice between taxane-based therapy, anthracycline-based therapy or a combination of the two agents). Bevacizumab was added to half of the patients at a dose of 5 mg/kg/ week equivalent. Chemotherapy was administered for four to eight cycles and bevacizumab was administered for one year. The primary end point of the study was three-year invasive disease-free survival (IDFS). Secondary end points included interim overall survival and toxicity. Results: A total of 2,591 patients were enrolled, of whom 1,290 received chemotherapy and 1,301 received chemotherapy plus bevacizumab. The three-year IDFS was 82.7 percent in those patients treated with chemotherapy alone and 83.7 percent when treated with chemotherapy and bevacizumab. This was not statistically significant, with hazard ratio of 0.87 and a p value of 0.181. The interim overall survival data also did not show a statistically significant difference between the two arms in regard to events (8.3 percent in the chemotherapy alone arm and 7.1 percent when bevacizumab was added to chemotherapy [HR 0.84 and p value of 0.2318]). As expected, grade ≥ 3 adverse events were reported at a higher frequency in those patients treated with bevacizumab and chemotherapy (11 vs. 3 percent). Hypertension and venous thrombotic events were more prevalent during the treatment phases in both arms. When bevacizumab was continued by itself following the four to eight cycles of chemotherapy for the scheduled one year, grade ≥ 3 adverse events were again higher in those patients receiving active treatment. The most common adverse events observed were congestive heart failure/left ventricular dysfunction (2 percent), hypertension (5 percent) and proteinuria (2 percent). Conclusion: The results of BEATRICE demonstrated better than anticipated three-year IDFS in this patient population with early-stage TNBC. There was no statistically significant improvement in IDFS with the addition of one year of bevacizumab to adjunct chemotherapy for TNBC. Overall, adverse events were consistent with the established safety profile of bevacizumab in metastatic breast cancer. Managed Care Implications: At first review of this study, bevacizumab does not have a role as adjuvant therapy for patients with triple-negative breast cancer. However, further followup is required to assess any potential benefit of bevacizumab on overall survival. Title: Efficacy of goserelin plus anastrozole in premenopausal women with advanced or recurrent breast cancer refractory to an LH-RH analogue with managedcareoncology.com | 43 44 tamoxifen: results of the JMTO BC08-01 phase II trial. Authors: Nishimura R, Anan K, Yamamoto Y, et al. Reference: Oncol Rep. May 2013;29(5):1707-1713. doi: 10.3892 or 2013.2312. Purpose: The majority of all cases of breast cancer are hormone-receptor (+). Endocrine therapy is used for adjuvant treatment and management of recurrence in hormone-sensitive breast cancer. Ovarian suppression induced surgically or with a luteinizing hormone-releasing hormone (LH-RH) analog as a postoperative adjunct therapy can prevent recurrence and prolong survival in this patient population. In premenopausal women, estrogen is primarily synthesized by the ovaries. After menopause, estrogen levels decline and estrogen is largely produced in peripheral adipose tissue and in cancer cells. Levels remain high enough to stimulate the proliferation of breast cancer cells. Therefore, aromatase inhibitors are used as standard treatment in postmenopausal women with breast cancer following the cessation of ovarian function. Endocrine therapy involves the sequential administration of single agents, but the combination of an LH-RH analog and tamoxifen (Nolvadex) is superior to monotherapy and thus the treatment of choice for premenopausal women with advanced or recurrent breast cancer. Should one become resistant to this combination, alternatives are few. Some have recommended that premenopausal women with advanced or recurrent breast cancer undergo ovarian ablation or suppression and then receive treatment similar to that recommended for postmenopausal women, such as an LH-RH analog and an aromatase inhibitor. However, few studies support this treatment regime for premenopausal women. A small study used goserelin (Zoladex) plus anastrozole (Arimidex) as second-line endocrine therapy in premenopausal women with advanced breast cancer who had previously received an LH-RH analog and tamoxifen. After six months of therapy, the clinical benefit rate was 75 percent, with the majority of the patients having stable disease or a biochemical response. This study evaluated the response rate to an LH-RH analog plus anastrozole in women who failed to respond to an LH-RH analog and tamoxifen. Methods: This open-label, single-arm, multicenter, phase 2 study was open to premenopausal women aged 20 to 55 with a confirmed diagnosis of metastatic or recurrent estrogen receptor (+) (ER+) and/or progesterone receptor (+) (PR+) breast cancer. Patients had to have a measurable lesion or bony lesion, be refractory to previous treatment with an LH-RH analog plus tamoxifen, and have an ECOG performance status of 0 or 1. Treatment was initiated with anastrozole 1 mg orally once a day and goserelin, a 3.6 mg depot injection administered subcutaneously into the lower abdomen every 28 days. Treatment was continued until the development of progressive disease or unacceptable adverse events. The primary end point was objective response rate (ORR), which was confirmed independently by two radiologists. Secondary end points included progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR) and safety. Results: A total of 37 patients were enrolled in the trial. The median age was 43 years (range 33 to 53). The ER/PR status was ER+/PR+ in 27 patients (73 percent), ER+/PR- in eight (21.6 percent) and ER-/PR+ in two (5.4 percent). HER2 was negative in 36 patients (97.6 percent). During previous treatment with an LH-RH analog and tamoxifen, 26 patients | managedcareoncology Quarter 3 2013 (70.3 percent) had progressive disease, six (16.2 percent) had recurrence during postoperative adjuvant therapy and five (13.5 percent) had completed the previous course of adjuvant therapy. Thirtyone patients had distant metastases and six had locally advanced disease. One patient (2.7 percent) had a complete response (CR) and an additional six (16.2 percent) had a partial response for an ORR of 18.9 percent. Sixteen patients (43.2 percent) had a prolonged stable disease for a CBR of 62.2 percent (95 percent CI, 44.8-77.5 percent). Eleven patients (29.7 percent) had progressive disease. The median PFS was 7.3 months with an OS of 35.2 months. The majority of adverse events were grade 1 and consisted of hot flashes, sweating and joint pain. Conclusion: Goserelin plus anastrozole is a safe and effective treatment for premenopausal women with hormone receptor-positive, recurrent or advanced breast cancer. The treatment may become viable in the future, particularly when tamoxifen is ineffective or contraindicated. Further studies and discussions are warranted. Managed Care Implications: The combination of subcutaneous goserelin and oral anastrozole may offer an alternative to women with recurrent or metastatic hormone receptor-positive breast cancer prior to the initiation of intravenous chemotherapy. Title: Sorafenib with gemcitabine or capecitabine in patients with HER-2 negative advanced breast cancer that progressed during or after bevacizumab. Authors: Schwartzberg LS, Tauer KW, Hermann RC, et al. Reference: Clin Cancer Res. 2013;19(10); 2745-2754. Purpose: Angiogenesis plays a critical role in the development and local progression of breast cancer and is associated with progression of metastatic disease. Targeted therapies that inhibit angiogenesis have become an important strategy for drug development. Results with single-agent angiogenesis inhibitors in metastatic breast cancer (MBC) have been less than optimal; however, preclinical studies suggest the combination of such agents with chemotherapy may be beneficial. Sorafenib (Nexavar) is an oral small molecule inhibitor of numerous tyrosine kinases and has antiproliferative and antiangiogenic activity. Information from phase 2 studies showed activity in patients with metastatic clear cell renal cell carcinoma refractory to sunitinib (Sutent) or bevacizumab (Avastin), meaning that sorafenib’s activity mechanism of action differs from those two agents. The activity of sorafenib in combination with agents effective in the treatment of MBC has been undertaken. This report assesses whether sorafenib in combination with gemcitabine (Gemzar) or capecitabine (Xeloda) could overcome clinical resistance to bevacizumab in patients with MBC. Methods: Patients ≥ 18 years of age with a histologically or cytologically confirmed HER2 (-) adenocarcinoma of the breast with locally advanced (inoperable) or metastatic disease were eligible. Other criteria included disease progression during or after treatment with bevacizumab in the adjuvant or metastatic setting, an ECOG performance status of 0 or 1, and adequate bone marrow, hepatic and renal function. This doubleblind, randomized, placebo-controlled, phase 2b study stratified patients in a 1:1 ratio to treatment with sorafenib 400 mg orally twice a day or placebo and gemcitabine 1,000 mg/m2 intravenously on days one and eight repeated every 21 days or capecitabine at a dose of 1,000 mg/m2 orally twice a day for the first 14 days of a 21-day cycle. The primary end point of the study was progression-free survival (PFS). Secondary end points included time to progression (TTP), overall response rate (ORR), overall survival (OS) and safety. Results: A total of 160 patients were randomized for treatment. The majority of patients received gemcitabine (82.5 percent, or 132 patients) with the remainder treated with capecitabine. The vast majority of patients, 95 percent, had stage IV disease, with 84.4 percent having visceral disease. The combination of sorafenib plus gemcitabine or capecitabine provided a small but statistically significant improvement in PFS compared with placebo (3.4 vs. 2.7 months; p = 0.02), with a 35 percent reduction in the risk of disease progression or death (HR = 0.65; 95 percent CI, 0.45-0.95). TTP was also increased (median 3.6 vs. 2.7 months; HR = 0.64; 95 percent CI, 0.44-0.93; p = 0.02). The ORR was 19.8 vs. 12.7 percent, again favoring sorafenib, but was not statistically significant. Median survival was 13.4 vs. 11.4 months for sorafenib versus placebo (HR = 1.01; 95 percent CI, 0.71-1.44; p = 0.95). Treatment was associated with manageable toxicity, but patients receiving combination therapy with sorafenib required more dose reductions when compared to the matched placebo controls (51.9 vs. 7.8 percent). Grade 3 toxicity occurred in 70 percent of the patients treated with sorafenib versus 47 percent in the placebo arm. The most frequent adverse events in the sorafenib arm were stomatitis (10 vs. 0 percent with placebo), fatigue (18 vs. 9 percent), anemia (5 vs. 0 percent) and hand-foot syndrome (39 vs. 5 percent). Conclusion: The addition of sorafenib to gemcitabine or capecitabine provided a small but statistically significant improvement in PFS in patients with HER2 (-) advanced MBC whose disease had progressed on bevacizumab. The combination therapy was associated with manageable toxicity but required frequent reduction in dosing. Managed Care Implications: With the use of bevacizumab in question for patients with MBC, oral sorafenib may offer an alternative. Additional studies are needed. managedcareoncology.com | 45 resources & references American Cancer Society (ACS). The ACS is a national, community-based volunteer health organization that offers programs for education, patient service, advocacy and rehabilitation. The website includes pages on breast cancer, including information about risk factors, diagnosis, staging and treatment. www.cancer.org American Society of Clinical Oncology (ASCO). This nonprofit organization is committed to conquering cancer through research, education, prevention and delivery of high-quality care. The breast cancer Web portal of ASCO’s official journal, the Journal of Clinical Oncology, is a resource for physicians to discover the latest findings in the area of breast cancer research through scientific abstracts, Virtual Meeting, guidelines and other materials. http://breast.jco.org BreastCancer.org. This nonprofit organization is dedicated to providing information and a community for those affected by breast cancer. Topics covered include lowering risk, symptoms and diagnosis, and treatment and side effects. www.breastcancer.org Breast Cancer Research Foundation (BCRF). The foundation’s mission is to achieve prevention and a cure for breast cancer in our lifetime by providing critical funding for innovative clinical and translational research at leading medical centers worldwide and increasing public awareness about good breast health. The website includes a breast health library, research information and more. www.bcrfcure.org This resource guide features links and websites on breast cancer that may be of use to the reader in daily practice.* Living Beyond Breast Cancer. This education and support organization offers specialized programs to the newly diagnosed and programs for caregivers and health care professionals to help them better meet the needs of women with breast cancer. The website features basic information about breast cancer, news, information on clinical trials and recommended resources. www.lbbc.org National Breast Cancer Coalition (NBCC). Since its founding in 1991, NBCC has changed the world of breast cancer — in public policy, science, industry and advocacy — by creating new partnerships, collaborations, research funding opportunities and avenues for access to quality care. In September 2010, NBCC launched an initiative to end the disease by the year 2020. The website features facts and figures, news and advocacy information. www.breastcancerdeadline2020.org CancerNet. This is the American Society of Clinical Oncology’s patient information website featuring peer-reviewed information on breast cancer, including male, inflammatory and metaplastic breast cancers. Statistics, staging and treatment information, medical illustrations and research information are available. www.cancer.net/cancer-types MedlinePlus. A service of the U.S. Library of Medicine and U.S. National Institutes of Health, this website offers links to peer-reviewed articles and abstracts on breast cancer, clinical trial information, glossaries, statistics and much more. www.nlm.nih.gov/medlineplus/ breastcancer.html *Note: Magellan Pharmacy Solutions does not endorse or verify the information presented. 46 | managedcareoncology Quarter 3 2013 National Breast Cancer Foundation Inc. NBCF’s mission is to increase awareness through education and provide nurturing support services to patients and survivors, as well as mammograms for patients in need. www.nationalbreastcancer.org National Cancer Institute (NCI). The NCI, part of the U.S. National Institutes of Health, conducts and supports cancer-related research, training and health information dissemination. This website provides information on treatment, screening, testing and clinical trials, research and literature related to breast cancer. www.cancer.gov/cancertopics/types/ breast National Comprehensive Cancer Network (NCCN). The NCCN publishes clinical practice guidelines that are developed through an evidence-based process, including the current practice guidelines for breast cancer. Users must register to access guidelines. www.nccn.org/professionals/ physician_gls/f_guidelines.asp#site SHARE — Self-Help for Women with Breast or Ovarian Cancer. SHARE supports, educates and empowers people affected by breast or ovarian cancer. The organization helps people face their feelings and fears, communicate effectively with their physicians and make informed decisions about their health. www.sharecancersupport.org Mage llan P ha rM acy So l ut io nS Powerful Solutions, Proven Results Magellan Pharmacy Solutions is redefining how health care manages pharmaceutical benefit spend. Our solutions can stand alone or be integrated into Total Drug Solutions∞, helping you manage the unseen components of drug spend. Any pharmacy. Any benefit. Anywhere. Our comprehensive solutions drive healthier outcomes as well as a healthy return on your investment: Specialty Pharmacy Pharmacy Benefit Management Medical Pharmacy Discover how we can partner with you to control skyrocketing pharmaceutical costs by calling 886-664-2673. Put our innovative solutions to work for you. Learn more by visiting TotalDrugSolutions.com or snap the QR code with your smart phone. ©2013 Amgen Inc. All rights reserved. 67426-R2-V1 5-13
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