Refractory or Recurrent Metastatic Breast Cancer

A supplement to December 2010 A Continuing Medical Education Activity Refractory or Recurrent Metastatic Breast Cancer Treatment Paradigms on the Horizon Faculty Lee S. Schwartzberg, MD, FACP Joyce A. O Shaughnessy, MD Linda T. Vahdat, MD Medical Writer Emma Hitt, PhD Cosponsored by the University of Cincinnati Office of Continuing Medical Education and ArcMesa Educators This activity is supported by an educational grant from Eisai Inc.

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Refractory or Recurrent Metastatic Breast Cancer (MBC): Treatment Paradigms on the Horizon Contents Educational Activity 2 MBC: Oncologist Perspective 12 Posttest 14 Evaluation 16 TARGET AUDIENCE This activity is intended for medical oncologists and oncology nurses. STATEMENT OF NEED Although early detection and improved treatment have resulted in a decline in the breast cancer death rate, the 5-year survival rate for patients who later develop metastatic breast cancer (MBC) is only 23% (compared with 98% for localized breast cancer). Current National Comprehensive Cancer Network guidelines list a plethora of treatment options for MBC. With so many options, oncologists face complex challenges in deciding which treatment to recommend. Adding to the problem, many patients with MBC have a fairly extensive treatment history and data for treating heavily pretreated patients are limited. There is a significant educational need for oncologists who manage patients with refractory or recurrent MBC to be aware that new evidence-based treatment options are available or will soon be available. Oncologists need to be familiar with updated guidelines and newer agents in order to optimize the care of patients. EDUCATIONAL OBJECTIVES Upon completing this activity as designed, participants should be able to: Describe the biological mechanisms responsible for resistance to chemotherapy in patients with refractory or recurrent MBC Review the current practice guidelines regarding the treatment of patients with refractory or recurrent MBC Identify the limitations of the evidence-based guidelines for managing heavily pretreated patients with MBC Analyze the recent clinical data on emerging novel therapies and regimens in the management of patients with refractory or recurrent MBC Implement a systematic treatment plan to safely and effectively integrate new combination treatment regimens into existing protocols for patients with refractory or recurrent MBC ACCREDITATION AND CREDIT DESIGNATION The University of Cincinnati is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education (CME) for physicians. The University of Cincinnati designates this educational activity for a maximum of 2 AMA PRA Category 1 credit(s). Physicians should only claim credit commensurate with the extent of their participation in the activity. Initial release date: December 15, 2010 Expiration date: December 15, 2011 DISCLOSURE POLICY According to the disclosure policies of the University of Cincinnati Office of Continuing Medical Education, faculty, editors, managers, and other individuals who are in a position to control content are required to disclose any relevant financial relationships with relevant commercial companies related to this activity. If a potential conflict is identified, it is the responsibility of the University of Cincinnati Office of Continuing Medical Education to initiate a mechanism to resolve the conflict(s). The existence of these interests or relationships is not viewed as implying bias or decreasing the value of the presentation. All educational materials are reviewed for fair balance, scientific objectivity or studies reported, and levels of evidence. Participating Faculty Lee S. Schwartzberg, MD, FACP, clinical professor of medicine, University of Tennessee School of Medicine, and medical director, The West Clinic, Memphis, Tennessee Joyce A. O Shaughnessy, MD, chair, Breast Cancer Prevention Research, and co-chair, Breast Cancer Research, Baylor-Sammons Cancer Center, US Oncology, Dallas, Texas Linda T. Vahdat, MD, director, Breast Cancer Research Program, and associate professor, Clinical Medicine, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, New York Faculty Disclosure Declarations Lee S. Schwartzberg, MD, FACP, has served as a member of the speakers bureaus of Eisai Inc and Bristol-Myers Squibb. Joyce A. O Shaughnessy, MD, is a member of the speakers bureaus of Abraxis BioScience, Bristol-Myers Squibb, and sanofi-aventis US. She has served on the advisory boards of Biogen Idec, Bristol- Myers Squibb, Caris Diagnostics, Eisai Inc, Genentech Inc, Glaxo- SmithKline, GTx Inc, Hoffman-LaRoche Inc, Johnson & Johnson, and sanofi-aventis. Linda T. Vahdat, MD, has received research funding from Eisai Inc, Bristol-Myers Squibb, Pfizer, Novartis, Celldex Therapeutics, and ImClone Systems. She has served as an advisor to Eisai and Bristol- Myers Squibb. Medical Writer Disclosure Declaration Emma Hitt, PhD, Emma Hitt Medical Writing, LLC, has disclosed no relevant affiliations or financial relationships. Product Disclosure Declaration This report reviews investigational uses for products not yet commercially approved for the uses discussed, specifically, ixabepilone, sorafenib, sunitinib, iniparib, olaparib, veliparib, everolimus, trastuzumab DM1, and pertuzumab. Planning Committee Disclosure Declarations The staff of Oncology & Biotech News, ArcMesa Educators, and the University of Cincinnati Office of Continuing Medical Education have nothing to disclose relative to this activity. How to Receive Credits Participants must review the entire activity. Credits will be issued upon the successful completion of the examination with a grade of 70% or better, and return of the completed evaluation form. This activity is supported by an educational grant from Eisai Inc. Disclaimer This supplement includes information about the use of therapies that may be inconsistent with or outside the approved labeling for these products in the United States. Physicians should note that the use of these products outside current approved labeling is considered experimental and are advised to consult prescribing information for these products. Information in this supplement is current and accurate as of the date of publication.

Refractory or Recurrent Metastatic Breast Cancer Treatment Paradigms on the Horizon Introduction Breast cancer is second only to lung cancer as a cause of cancer death and is the most common malignancy in women in the United States. 1 The American Cancer Society estimates that in 2010 in the United States, 207,090 new cases of invasive breast cancer will be diagnosed and 43,010 people will die from it. 2 Although great strides have been made in breast cancer outcomes, about one-third of women who present with early-stage breast cancer will ultimately develop metastatic disease. Furthermore, only 15% of patients with metastatic disease are alive at 5 years, compared with nearly all patients with early-stage disease. 3 Although the systemic treatment of breast cancer recurrence or stage IV disease prolongs survival and enhances quality of life, treatment remains noncurative. 1 The lack of treatment options in anthracycline- and taxane-pretreated metastatic breast cancer (MBC) was highlighted in a recent review of controlled clinical trials of the cytotoxic agents used in Europe. 4 Among the regimens evaluated, none demonstrated any significant benefit in overall survival (OS), and median survival in trials was typically less than 16 months. Consequently, new options are clearly needed, and several novel agents are in late-stage clinical trials in this setting. The current article will describe the issue of taxane and anthracycline resistance in MBC, as well as current and emerging treatment options that are under evaluation, such as novel cytotoxics, anti-her2 agents, antiangiogenic approaches, and poly(adenosine-diphosphate-ribose) polymerase (PARP) inhibitors. Mechanisms of Resistance in MBC The development of resistance to anthracyclines and taxanes represents an important complication in the treatment of MBC. First-line chemotherapy in MBC usually includes a taxane, such as paclitaxel or docetaxel, with a single-agent response rate rang ing from 25% to 48% for patients with no prior anthracycline treatment. However, these responses are typically short-lived, with a median time to disease progression of 6 to 10 months. 5 It has been estimated that resistance occurs in as many as 90% of patients. 6 Taxane resistance can develop through multiple mechanisms (Figure 1). 7 These include changes in taxane binding and cell diffusion, altered subcellular distribution or drug metabolism, tubulin gene mutations, adenosine triphosphate (ATP)-binding cassette transporters, and inhibition of apoptotic signaling. 8 Likewise, anthracycline resistance mechanisms in tumor cells are multifactorial and include plasma membrane P-glycoproteins, which act as pumps that can eliminate a wide range of anticancer drugs, other proteins that also perform this function, and changes in the intracellular distribution of drug. 9 Several approaches that can potentially overcome multiple drug resistance (MDR) are being investigated. These include the modulation of MDR efflux pumps with chemosensitizers and the development of newer cytotoxic agents, such as eribulin and ixabepilone, which have demonstrated efficacy in heavily pretreated patients. The use of targeted agents with chemotherapies has also been explored. 10 2

Figure 1. Proposed Mechanisms of Taxane Resistance 7 Inhibition of apoptotic signaling Binding and cell diffusion Altered subcellular distribution or drug metabolism Taxane resistance ATP-binding cassette (ABC) transporters Tubulin bindingsite mutations ATP, adenosine triphosphate. This figure was published in Community Oncol. 2008;5(4 suppl 3):2-9. Perez EA. Modulating drug resistance in metastatic breast cancer. Copyright Elsevier (2008). Therapeutic Approaches in Recurrent Breast Cancer Chemotherapy According to National Comprehensive Cancer Network guidelines, chemotherapy should be given to women who have (1) hormone receptor negative tumors that are not localized to the bone or soft tissue only or that are associated with symptomatic visceral metastasis, or (2) hormone receptor positive tumors refractory to endocrine therapy. 1 Single agents recommended for the treatment of MBC include anthracyclines (doxorubicin, epirubicin, pegylated liposomal doxorubicin); taxanes (paclitaxel, docetaxel, albumin-bound paclitaxel); antimetabolites (capecitabine, gemcitabine); and other microtubular inhibitors (vinorelbine). 1 These are used either alone or in combination, depending on the patients clinical condition. Randomized clinical trials in patients with MBC indicate that the addition of bevacizumab to some first- or second-line chemotherapy improves time to progression and response rates but not OS. 11-13 Time to progression appears greatest with bevacizumab in combination with weekly paclitaxel. 1 The US Food and Drug Administration s decision on whether to keep or rescind the indication of bevacizumab for breast cancer is pending. Treatment of HER2-Positive Disease HER2-positive disease, when previously untreated, is usually treated with trastuzumab (preferred) in combination with paclitaxel (with or without carboplatin), docetaxel, vinorelbine, or capecitabine. Lapatinib plus capecitabine is approved for use in patients who have previously received trastuzumab. 1 A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that progressed on trastuzumab 14 showed that the addition of lapatinib prolonged time to progression (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.43-0.77; P <.001). There was also a trend toward improved OS (HR, 0.78; 95% CI, 0.55-1.12; P =.177), and fewer cases with central nervous system involvement at first progression (4 vs 13; P =.045). More recently, the combination of trastuzumab plus lapatinib was evaluated in patients with HER2- positive, trastuzumab-refractory MBC in a phase III study, EGF104900. 15 The combination of lapatinib with trastuzumab was superior to lapatinib alone for progression-free survival (PFS; HR, 0.73; 95% CI, 0.57-0.93; P =.008) (Figure 2), while the clinical benefit ratio was 24.7% in the combination arm versus 12.4% in the monotherapy arm (P =.01). Figure 2. Kaplan-Meier of Progression-Free Survival (PFS) in the Intent-to-Treat Population 15 Alive Without Progression (cumulative %) L L + T 100 80 60 40 20 No. of patients at risk L + T L 13 0 10 20 148 148 28 6-month PFS Time From Random Assignment (weeks) 53 73 21 42 30 40 50 60 13 27 5 8 Lapatinib n = 145 0 2 Lapatinib + Trastuzumab n = 146 Progressed or died, n 128 127 Median, weeks 8.1 12.0 HR (95% Cl) 0.73 (0.57 0.93) P.008 CI, confidence interval; HR, hazard ratio. Reprinted with permission from Blackwell KL, et al. J Clin Oncol. 2010;28(7):1124-1130. 3

Figure 3. EMBRACE Study Design 18 Global, randomized, open-label phase III trial (Study 305) Patients (N = 762) Locally recurrent or MBC 2-5 prior chemotherapies - 2 for advanced disease - Prior anthracycline and taxane Progression 6 months of last chemotherapy Neuropathy grade 2 ECOG 2 Eribulin mesylate 1.4 mg/m 2, 2-5 min IV Day 1, 8 q21 days Randomization 2:1 Treatment of physician s choice (TPC) Any monotherapy (chemotherapy, hormonal, biological)* or supportive care only Primary endpoint Overall survival Secondary endpoints PFS ORR Safety Stratification: - Geographical region, prior capecitabine, HER2/neu status *Approved for treatment of cancer. Palliative treatment or radiotherapy administered according to local practice, if applicable. MBC, metastatic breast cancer; ECOG, Eastern Cooperative Oncology Group; IV, intravenous; PFS, progression-free survival; ORR, objective response rate; HER2/neu, human epidermal growth factor receptor 2. Reprinted with permission from Twelves C, et al. J Clin Oncol. 2010;28(18 suppl);abstract CRA1004. Novel Therapies in Recurrent MBC In a quest to improve outcomes in MBC, much attention has been given to the development of novel agents, and several new cytotoxics and targeted therapies are currently being evaluated in late-stage clinical trials. Cytotoxics Two novel cytotoxics that have demonstrated efficacy in patients pretreated with anthracyclines and taxanes are eribulin and ixabepilone. Eribulin Eribulin mesylate (E7389) is a synthetic analogue of a polyether macrolide known as halichondrin B, isolated from a Japanese sea sponge (Halichondria okadai) that inhibits microtubule dynamics. 16 The halichondrin B compound had been shown to have anticancer activity, and a synthetic version of the macrolide subsequently has been developed. 17 Results from the phase III EMBRACE trial (Figure 3) showed that eribulin mesylate versus treatment of physician s choice in patients with locally recurrent or MBC significantly improved OS by a median of 2.5 months. In addition, eribulin was well tolerated in this patient population with heavily pretreated disease (Figure 4). 18 Grade 3/4 treatment-related adverse events of interest for eribulin were asthenia/fatigue (7.6%), neutropenia (44%), and peripheral neuropathy (8.4%). Of the patients, 10% experienced treatment-related serious adverse events (12% in the eribulin arm and 7% in the treatment-of-physician s-choice arm). Ixabepilone Ixabepilone, an epothilone B analogue that targets microtubule assembly, is a new agent for treatment of recurrent or MBC as a single agent (category 2A) or in combination with capecitabine (category 2B). Ixabepilone is indicated in combination with capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated. Ixabepilone is also indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine. 4

A phase III trial of ixabepilone plus capecitabine showed improved OS with ixabepilone + capecitabine compared with capecitabine alone in patients with MBC previously treated with anthracyclines and taxanes. Median PFS was prolonged to 6.24 months (95% CI, 5.59-6.97) for ixabepilone plus capecitabine compared with 4.4 months (95% CI, 4.14-5.42) for capecitabine (HR, 0.79; 95% CI, 0.69-0.90; P =.0005) (Figure 5). 19 Treatment with ixabepilone is fairly well tolerated but caused new or increased-severity peripheral neuropathy in approximately 65% of patients treated. Grade 3 or 4 peripheral neuropathy occurred in 23% of patients treated with ixabepilone and capecitabine but was not reported in the capecitabine-only arm. Antiangiogenic Agents Angiogenesis plays a central role in tumor growth and survival and represents an important therapeutic target in many solid tumors, including breast cancer. 20 Evaluations have been performed of 2 classes of agents that target vascular endothelial growth factor (VEGF)- mediated signaling: (1) monoclonal antibodies, including bevacizumab; and (2) small molecule receptor tyrosine kinase inhibitors, including sorafenib and sunitinib. Bevacizumab Building on earlier results of the RIBBON trial, a recent subgroup analysis evaluating the combination of bevacizumab with various chemotherapies to treat MBC in the second-line setting found that the addition of bevacizumab improved PFS overall, and also in HER2-negative MBC patients with various clinical characteristics and disease histories. 21 Sorafenib Two phase IIb trials in patients with advanced breast cancer have demonstrated activity for sorafenib plus standard chemotherapy for the primary endpoint of PFS. An analysis adjusting for covariates found that capecitabine was associated with a 36% risk reduction for events that would end PFS versus placebo + capecitabine in one study and that sorafenib + paclitaxel had a 27% risk reduction versus placebo + paclitaxel in the other study. 22 Sunitinib This agent has been evaluated in MBC; however, recent data from a randomized phase III trial of capecitabine Figure 4. Eribulin Prolongs Survival In Heavily Pretreated Metastatic Breast Cancer 18 Survival Probability 1.0 0.8 0.6 0.4 Overall Survival TPC Median 10.65 months Eribulin Median 13.12 months 0.2 2.47 months 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Overall Survival (months) 1-year survival Eribulin (n = 508) 53.9% TPC (n = 254) 43.7% HR*,0.81 (95% Cl, 0.66-0.99) P = 0.041 Intent-to-Treat Population, *HR Cox model including geographic region, HER2/neu status, and prior capecitabine therapy as strata. P value from stratified log-rank test (predefined primary analysis). TPC, treatment of physician s choice; HR, hazard ratio; Cl, confidence interval. Reprinted with permission from Twelves C, et al. J Clin Oncol. 2010;28(18 suppl);abstract CRA1004. + sunitinib do not support its use to treat advanced recurrent breast cancer. 23 PARP Inhibitors PARP inhibitors have demonstrated promising activity in MBC, most notably in BRCA1/2-mutated tumors. The target, PARP1, is involved in multiple processes associated with DNA repair. 24 Inhibition of PARP1, a key DNA repair enzyme, may prevent cancer cells from repairing their DNA, thereby enhancing the effectiveness of DNA-damaging chemotherapy. Three PARP inhibitors currently under evaluation are iniparib, olaparib, and veliparib. Iniparib Iniparib has recently shown encouraging results in the treatment of triple-negative breast cancer. The final efficacy and safety results from a trial of 123 patients with triple-negative MBC were recently reported at the 35th European Society for Medical Oncology Congress in Milan, Italy. 25 Patients had received up 5

Figure 5. Progression-Free Survival (PFS) With Ixabepilone Combination Versus Capecitabine Alone 19 1.0 0.9 Median OS (95% CI) Proportion Not Progressed 0.8 0.7 0.6 0.5 0.4 0.3 Ixabepilone + Capecitabine Censored Capecitabine Censored 6.2 (5.6 6.8) 4.4 (4.1 5.4) 0.2 0.1 0 4 8 12 16 20 24 28 32 36 40 Time (months) OS, overall survival; CI, confidence interval. Reprinted with permission from Sparano JA, et al. J Clin Oncol. 2010;28(20):3256-3263. to 2 prior regimens for MBC and were randomized to receive either gemcitabine-carboplatin chemotherapy or chemotherapy plus iniparib. OS improved from 7.7 months with chemotherapy alone to 12.3 months with iniparib and chemotherapy (P=.014). In addition, 55.7% of women in the iniparib arm experienced clinical benefit (complete response [CR], partial response [PR], or stable disease [] for at least 6 months) compared with 33.9% of patients in the chemotherapy-alone arm (P =.015). Adverse events were comparable between the 2 groups. Olaparib In a phase I/II multicenter trial, olaparib was well tolerated when combined with paclitaxel in triple-negative MBC; however, neutropenia was excessive despite growth factor support. Of 19 patients, 15 had received prior taxane chemotherapy. Response measured with Response Evaluation Criteria in Solid Tumors (RECIST) included 7 patients (37%) with confirmed PR and 10 patients (53%) with confirmed or unconfirmed PR. The most frequent grade 1/2 adverse events were fatigue, nausea, and diarrhea. Neutropenia of any grade was reported in 12 patients. Alternative schedules and dosing of olaparib are being evaluated. 26 Veliparib A phase II trial of veliparib plus temozolomide in MBC showed that the combination was promising in MBC, especially for patients selected based on BRCA (Figure 6). 27 In 41 patients treated with veliparib plus temozolomide, best response for 24 patients evaluable for efficacy included 1 CR, 2 PRs, and 7 s. The most common grade 3/4 toxicities included thrombocytopenia (3 grade 3, 4 grade 4), and neutropenia (2 grade 3, 2 grade 4). mtor Inhibitors The mtor pathway is one of several critical central transduction pathways that sustain breast tumorigenesis, including HER2/neu and the estrogen receptor pathway. 28 Of the different mtor inhibitors, everolimus has demonstrated the most encouraging results in the treatment of breast cancer. 28 6

Everolimus In a phase II trial, everolimus in combination with paclitaxel and trastuzumab was found to have an acceptable safety profile and promising anticancer activity in HER2-positive MBC patients previously treated with trastuzumab and taxanes. 29 Treatment in 55 patients continued until progression or unacceptable toxicity. Of 25 patients evaluable for efficacy, there were 5 (20%) with confirmed PR, 14 (56%) with, and 6 (24%) with progressive disease (PD). Treatment was well tolerated, although about a third of patients developed grade 3/4 neutropenia. Another trial of everolimus and trastuzumab in patients with trastuzumab-resistant, HER2-overexpressing breast cancer showed that this combination is well tolerated, with promising clinical activity in a trastuzumab-resistant population. 30 Of 47 patients evaluable for efficacy, 7 (15%) had a PR, and 9 (19%) had lasting at least 24 weeks, equivalent to a clinical benefit rate of 34%. Median time to progression was 3.4 months (range, 1-14). Grade 3/4 toxicities included lymphopenia (13%), hyperglycemia (13%), and mucositis (11%). Anti-HER2 Strategies The HER family of receptors includes 4 closely related receptors: HER1 (epidermal growth factor receptor [EGFR]), HER2, HER3, and HER4, which are intricately involved in normal cell activity, and aberrant HER2 expression in breast cancer has become an important therapeutic target. Novel strategies directed against HER2 include antibody-chemotherapy conjugates and new HER tyrosine kinase inhibitors. 31 All of these approaches are currently being studied in metastatic disease and have shown substantial clinical activity in patients refractory to trastuzumab. Trastuzumab DM1 Trastuzumab DM1 (T-DM1) is an antibody-chemotherapy conjugate that has been evaluated in a phase I trial at the maximum tolerated dose of 3.6 mg/kg every 3 weeks. T-DM1 was associated with mild, reversible toxicity and substantial clinical activity in a heavily pretreated population (Figure 7). 32 Each bar represents duration of therapy for patients treated with T-DM1, beginning at day 0 (administration of first dose of T-DM1). 32 Figure 6. Progression-Free Survival (PFS) With Veliparib in BRCA Versus Non-BRCA Carriers 27 Overall PFS PFS Carriers Versus Noncarriers Probability of PFS 1.0 1.0 0.8 0.8 0.6 0.6 Median PFS = 1.9 months 0.4 0.4 Median PFS = 1.8 months 0.2 0.2 Noncarriers Carriers 0.0 0.0 0 1 2 3 4 5 6 0 1 2 3 4 5 6 Probability of PFS P = -0.0042, log rank test Median PFS = 5.5 months # of Patients at Risk Month # of Patients at Risk Month 41 37 18 12 10 6 0 Noncarrier Carrier 33 8 29 8 13 5 7 5 5 5 1 5 0 0 All patients (N = 41) Carriers (N = 8) Versus Noncarriers (N = 33) Reprinted with permission from Isakoff SJ, et al. J Clin Oncol. 2010;28(15 suppl);abstract 1019. 7

Figure 7. Duration of Trastuzumab DM1 (T-DM1) Therapy and Best Responses 32 Dose of T-DM1, mg/kg Best Response 0.3 (n = 3) PD 0.6 (n = 1) PD 1.2 (n = 1) 2.4 (n = 1) PR PR PR Patients 3.6 (n = 15) PR PR PR PD PD PD 4.8 (n = 3) PD 0 100 200 300 400 500 600 700 800 Duration of Therapy (days) Confirmed Response Patients still on study as of April 2009 Measurable Disease No Measurable Disease Each bar represents duration of therapy for patients treated with T-DM1, beginning at day 0 (administration of first dose of T-DM1)., stable disease; PD, progressive disease; PR, partial response. Reprinted with permission from Krop IE, et al. J Clin Oncol. 2010;28(16):2698-2704. 8

BIBW 2992 BIBW 2992 is a novel, oral, irreversible inhibitor of EGFR/HER1 and HER2. In a phase II trial this agent demonstrated safety and tolerability when given once daily until disease progression in patients with hormone receptor positive or triple-negative MBC. 33 Fifty patients received treatment, including 29 with HER2-negative, hormone receptor positive disease and 21 with triplenegative disease. No objective responses were observed, but 3 patients with triple-negative MBC achieved for 4 or more treatment cycles, with 1 achieving for 12 cycles. The most common side effects were gastrointestinal and skin-related adverse events. Thus, long-term oral administration of BIBW 2992 appeared to be safe and demonstrated clinical benefit in a small number of patients with triple-negative MBC. Pertuzumab Pertuzumab is a new monoclonal antibody that inhibits all 4 members of the human epidermal growth factor family, HER1 through HER4, and is currently being evaluated in clinical trials. A phase II trial of pertuzumab and trastuzumab in 66 patients with HER2-positive MBC that progressed during prior trastuzumab therapy indicated that addition of pertuzumab resulted in an objective response rate in approximately one-fourth of patients and a clinical benefit in one-half of patients. 34 Five patients (7.6%) experienced a CR, 11 (16.7%) experienced a PR, and 17 (25.8%) had lasting at least 6 months. The combination was generally well tolerated, with minimal cardiotoxicity observed. Similarly, in another trial of T-DM1 with pertuzumab for women with HER2-positive, locally advanced or MBC previously treated with trastuzumab, safety, tolerability, and preliminary efficacy of full dose T-DM1 + pertuzumab were encouraging, and no substantial increase in toxicity over single-agent T-DM1 was observed. 35 Conclusions While the prognosis in patients with early-stage, localized breast cancer is excellent, the same is not true for patients with MBC. Although multiple treatment options exist for breast cancer, they become progressively more limited as patients develop resistance to both taxanes and anthracyclines. Several novel therapeutic strategies are being explored in recurrent MBC, including new cytotoxics and targeted therapies, and clinical trials are demonstrating encouraging results with respect to diseasefree survival, overall response rates, and time to disease progression with these agents. As new agents enter into clinical practice and offer increasing options for patients, it will be important to select patients appropriately for treatment. In addition, optimal combinations, dosing, and duration of novel treatments must be clearly established. References 1. National Comprehensive Cancer Network. Practice Guidelines in Oncology. Breast cancer. v.2.2010. http:// www.nccn.org. Accessed October 11, 2010. 2. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60(5):277-300. 3. American Cancer Society. Breast Cancer Detailed Guide. http://www.cancer.org/cancer/breastcancer/detailed Guide. Accessed October 29, 2010. 4. Jassem J, Carroll C, Ward SE, Simpson E, Hind D. The clinical efficacy of cytotoxic agents in locally advanced or metastatic breast cancer patients pretreated with an anthracycline and a taxane: a systematic review. Eur J Cancer. 2009;45(16):2749-2758. 5. Bernard-Marty C, Cardoso F, Piccart MJ. Use and abuse of taxanes in the management of metastatic breast cancer. Eur J Cancer. 2003;39(14):1978-1989. 6. Longley DB, Johnston PG. Molecular mechanisms of drug resistance. J Pathol. 2005;205(2):275-292. 7. Perez EA. Modulating drug resistance in metastatic breast cancer. Community Oncol. 2008;5(4 suppl 3):2-9. 8. Chien AJ, Moasser MM. Cellular mechanisms of resistance to anthracyclines and taxanes in cancer: intrinsic and acquired. Semin Oncol. 2008;35(2 suppl 2): S1-S14; quiz S39. 9. Nielsen D, Maare C, Skovsgaard T. Cellular resistance to anthracyclines. Gen Pharmacol. 1996;27(2):251-255. 10. Lee JJ, Swain SM. Development of novel chemotherapeutic agents to evade the mechanisms of multidrug resistance (MDR). Semin Oncol. 2005;32(6 suppl 7):S22-S26. 11. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357(26):2666-2676. 12. Miles D, Chan A, Romieu G, et al. Randomized, doubleblind, placebo-controlled, phase III study of bevacizumab with docetaxel or docetaxel with placebo as first-line therapy for patients with locally recurrent or metastatic breast cancer (mbc): AVADO. Presented at: American Society of Clinical Oncologists Annual Meeting; May 30- June 3, 2010; Chicago, IL. J Clin Oncol. 2008;26(suppl): Abstract LBA1011. 9

13. Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab (B) for first-line treatment of HER2-negative locally recurrent or metastatic breast cancer (MBC). Presented at: American Society of Clinical Oncologists Annual Meeting; May 29- June 2, 2009; Orlando, FL. J Clin Oncol. 2009;27(15 suppl): Abstract 1005. 14. Cameron D, Casey M, Press M, et al. A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat. 2008;112(3):533-543. 15. Blackwell KL, Burstein HJ, Storniolo AM, et al. Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010;28(7): 1124-1130. 16. Hirata Y, Uemura D. Halichondrins antitumor polyether macrolides from a marine sponge. Pure and Applied Chemistry. 1986;58(5):701-710. 17. Seletsky BM, Wang Y, Hawkins LD, et al. Structurally simplified macrolactone analogues of halichondrin B. Bioorg Med Chem Lett. 2004;14(22):5547-5550. 18. Twelves C, Loesch D, Blum JL, et al. A phase III study (EMBRACE) of eribulin mesylate versus treatment of physician s choice in patients with locally recurrent or metastatic breast cancer previously treated with an anthracycline and a taxane. Presented at: American Society of Clinical Oncologists Annual Meeting; June 4-8, 2010; Chicago, IL. J Clin Oncol. 2010;28(18 suppl): Abstract CRA1004. 19. Sparano JA, Vrdoljak E, Rixe O, et al. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2010;28(20):3256-3263. 20. Giovannini M, Aldrighetti D, Zucchinelli P, Belli C, Villa E. Antiangiogenic strategies in breast cancer management. Crit Rev Oncol Hematol. 2010;76(1):13-35. 21. Brufsky A, Rivera RR, Hurvitz SA, et al. Progressionfree survival (PFS) in patient subgroups in RIBBON-2, a phase III trial of chemotherapy (chemo) plus or minus bevacizumab (BV) for second-line treatment of HER2- negative, locally recurrent or metastatic breast cancer (MBC). Presented at: American Society of Clinical Oncologists Annual Meeting; June 4-8, 2010; Chicago, IL. J Clin Oncol. 2010;28(15 suppl): Abstract 1021. 22. Gradishar WJ, Dalenc F, Kaklamani VG, et al. Multivariate analysis (MVA) of progression-free survival (PFS) in two phase IIb, multinational, double-blind, randomized, placebo (PL)-controlled trials evaluating sorafenib (SOR) plus standard chemotherapy in patients (pts) with HER2-negative locally advanced or metastatic breast cancer (BC). Presented at: American Society of Clinical Oncologists Annual Meeting; June 4-8, 2010; Chicago, IL. J Clin Oncol. 2010;28(15 suppl): Abstract 1073. 23. Crown J, Dieras V, Staroslawska E, et al. Phase III trial of sunitinib (SU) in combination with capecitabine (C) versus C in previously treated advanced breast cancer (ABC). Presented at: American Society of Clinical Oncologists Annual Meeting; June 4-8, 2010; Chicago, IL. J Clin Oncol. 2010;28(18 suppl): Abstract LBA1011. 24. Rouleau M, Patel A, Hendzel MJ, Kaufmann SH, Poirier GG. PARP inhibition: PARP1 and beyond. Nat Rev Cancer. 2010;10(4):293-301. 25. O Shaughnessy J. Iniparib extends overall survival in metastatic triple-negative breast cancer: final phase-ii results. Presented at: 35th European Society for Medical Oncology (ESMO) Congress; October 8-12, 2010; Milan, Italy. Abstract LBA11. 26. Dent RA, Lindeman GJ, Clemons M, et al. Safety and efficacy of the oral PARP inhibitor olaparib (AZD2281) in combination with paclitaxel for the first- or secondline treatment of patients with metastatic triple-negative breast cancer: results from the safety cohort of a phase I/II multicenter trial. Presented at: American Society of Clinical Oncologists Annual Meeting; June 4-8, 2010; Chicago, IL. J Clin Oncol. 2010;28(15 suppl): Abstract 1018. 27. Isakoff SJ, Overmoyer B, Tung NM, et al. A phase II trial of the PARP inhibitor veliparib (ABT888) and temozolomide for metastatic breast cancer. Presented at: American Society of Clinical Oncologists Annual Meeting; June 4-8, 2010; Chicago, IL. J Clin Oncol. 2010;28(15 suppl): Abstract 1019. 28. Margariti N, Fox SB, Bottini A, Generali D. Overcoming breast cancer drug resistance with mtor inhibitors. Could it be a myth or a real possibility in the short-term future? [published online ahead of print October 14, 2010]. Breast Cancer Res Treat. doi: 10.1007/s10549-010-0986-9. 29. Dalenc F, Campone M, Hupperets P, et al. Everolimus in combination with weekly paclitaxel and trastuzumab in patients (pts) with HER2-overexpressing metastatic breast cancer (MBC) with prior resistance to trastuzumab 10

and taxanes: a multicenter phase II clinical trial. Presented at: American Society of Clinical Oncologists Annual Meeting; June 4-8, 2010; Chicago, IL. J Clin Oncol. 2010;28(15 suppl): Abstract 1013. 30. Morrow PH, Wulf GM, Booser DJ, et al. Phase I/II trial of everolimus (RAD001) and trastuzumab in patients with trastuzumab-resistant, HER2-overexpressing breast cancer. Presented at: American Society of Clinical Oncologists Annual Meeting; June 4-8, 2010; Chicago, IL. J Clin Oncol. 2010;28(15 suppl): Abstract 1014. 31. Baselga J. Treatment of HER2-overexpressing breast cancer. Ann Oncol. 2010;21(suppl 7):vii36-vii40. 32. Krop IE, Beeram M, Modi S, et al. Phase I study of trastuzumab-dm1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer. J Clin Oncol. 2010;28(16):2698-2704. 33. Schuler MH, Uttenreuther-Fischer MM, Piccart-Gebhart MJ, et al. BIBW 2992, a novel irreversible EGFR/HER1 and HER2 tyrosine kinase inhibitor, for the treatment of patients with HER2-negative metastatic breast cancer after failure of no more than two prior chemotherapies. Presented at: American Society of Clinical Oncologists Annual Meeting; June 4-8, 2010; Chicago, IL. J Clin Oncol. 2010;28(15 suppl): Abstract 1065. 34. Baselga J, Gelmon KA, Verma S, et al. Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol. 2010;28(7):1138-1144. 35. Miller K, Gianni L, Andre F, et al. A phase Ib/II trial of trastuzumab-dm1 (T-DM1) with pertuzumab (P) for women with HER2-positive, locally advanced or metastatic breast cancer (BC) who were previously treated with trastuzumab (T). Presented at: American Society of Clinical Oncologists Annual Meeting; June 4-8, 2010; Chicago, IL. J Clin Oncol. 2010;28(15 suppl): Abstract 1012. 11

Recurrent MBC: Oncologist Perspective Interviews with Dr O Shaughnessy and Dr Vahdat Joyce A. O Shaughnessy, MD Chair, Breast Cancer Prevention Research Co-Chair, Breast Cancer Research Baylor-Sammons Cancer Center US Oncology Dallas, Texas Linda T. Vahdat, MD Director, Breast Cancer Research Program Associate Professor, Clinical Medicine Weill Cornell Medical College New York-Presbyterian Hospital New York, New York 1. Please describe your approach to selecting treatment options for metastatic breast cancer (MBC) patients. Dr O Shaughnessy: It is multifactorial. It depends on the woman, the nature of the cancer, what kind of subtype of breast cancer it is, the sites of metastasis, the tempo of the disease, the symptoms or lack thereof, previous therapy, other medical problems, medications she requires, whether she needs to continue working, other family responsibilities. It can be issues such as transportation and her personal goals for therapy. That is, the acceptance or tolerance, for example, of difficult side effects, like losing the hair, etc. Dr Vahdat: Initially, there are several different levels to consider, such as how symptomatic the patient is from their breast cancer, and how symptomatic you think they are going to become within the next month or two because that is going to be your trigger for figuring out what kind of therapies to give them. There is not one approach, in terms of sequencing your treatments. You want to have a balance between efficacy, in terms of shrinking the tumor, and toxicity of the treatments. 2. How do you utilize MBC treatment guidelines in practice? Which guidelines do you use most frequently? Dr O Shaughnessy: It is basically the FDA approval guidelines that I think are most relevant to me in my practice. Otherwise, I go by the published literature or the literature that has been presented at national meetings. The issue with many of the guidelines is that they are, of course, evidencebased and the evidence to date has been done in large clinical trials that looked at all comers of breast cancer, not aimed at analysis of the biologic subtypes of breast cancer. Now we are trying to be more nuanced and targeted in our treatment and treat the various subtypes of breast cancers. Dr Vahdat: The National Comprehensive Cancer Network has very good guidelines with regard to treatments for which there is good evidence. But my approach is a summation of the published literature. The bottom line is, there is not a cookbook approach where you do treatment A first, you do treatment B second, you do treatment C third. You have to integrate everything. 3. What steps do you take to individualize treatment for each patient? Dr O Shaughnessy: Similar to my answer to question one. Family history of breast cancer is also important in trying to give you hints about what the biology of someone s cancer may be. Dr Vahdat: The first thing we think about is whether a tumor is HER2/ neu overexpressed because as part of whatever treatment you choose, you are going to give the patient an HER2/ neu-directed therapy. Right now that is Herceptin or lapatinib. If a patient has a triple-negative breast cancer, then you are going to know that hormones are not an option. If you have a patient who is hormone-receptor positive, then you will know that you will be able to use a hormonal therapy as part of their treatment. So you use these molecular subtypes as ways to guide your therapy. 4. What are your biggest challenges in selecting treatment options? Dr O Shaughnessy: Having access to the right treatments for patients. We are learning about pathways, for example, that are important in these cancers, but sometimes it can be dif- 12

ficult to access therapies. For example, there is emerging evidence that some of the irinotecan-like chemotherapy drugs are of benefit in triple-negative breast cancer, but that is an off-label use and insurance coverage is not guaranteed. Dr Vahdat: The biggest challenge of them all is you do not know, if you are going to give a treatment, whether it is going to work or not. 5. What proportion of patients do you refer to clinical trials and why? Dr O Shaughnessy: I am able to enroll 10 to 15% of my patients in a clinical trial. Dr Vahdat: I direct a research program, so clinical trials are very much on our radar. About 20% of my metastatic patients go into clinical trials. 6. What are your biggest challenges in enrolling patients in trials? Dr O Shaughnessy: We do not have clinical trials for all the different nuances of breast cancer. In many, many cases the standard of care is the best treatment for the patient. Ineligibility is another challenge, usually because of too many prior therapies, or, some clinical trials require measurable disease and the patients have evaluable disease. Dr Vahdat: The washout period. Before they go in a clinical trial, they have to stop their prior treatment for a particular amount of time. That varies from trial to trial. It is the most challenging time because for some trials they will want a 4-week washout period and sometimes that just does not work. 7. Although overall survival is obviously the ultimate goal of new therapies, what other factors do you take into consideration if you are recommending a novel therapy? Dr O Shaughnessy: The other efficacy endpoints that are very important are progression-free survival, response rate, clinical benefit rate, and then very, very importantly are side effects. You would like to be able to continue the therapy without cumulative toxicity. The other is the ease of administration how many trips to the doctor s office it is going to take for the patients. Dr Vahdat: Side effects. Of course, efficacy how good is it in terms of shrinking the tumor? Ease of administration. Do you need to give it through a port or not? Is it a whole-day infusion or is it a 3-minute infusion? 8. How does patient education fit into the treatment of MBC? Dr O Shaughnessy: The most important piece of information is telling the woman what to expect side-effectwise, and letting her know to call you 24/7 for problems earlier rather than later so that you can fix things quickly before side effects become problematic. It is very important that we work with the patients and empower them to be proactive. Dr Vahdat: Patients are educated at every juncture. You educate them about their drugs, and this happens with every new drug they are on. You educate them about the side effects. They usually sit and talk to a nurse about some of the strategies to overcome some of those side effects. There are usually separate discussions for generic side effects like febrile neutropenia, nausea, vomiting. 9. How do you approach your discussions with patients about MBC? Dr O Shaughnessy: It is very important for women to know that we do not have a cure for metastatic breast cancer, and the goal is prolonged disease control with an excellent quality of life. We are always talking about the clinical trials that we have, too. We always are looking toward the new therapies, making sure we are not overlooking something. We are trying to be very clear what the goals are to get the cancer under control, minimizing side effects, and with a good quality of life. Dr Vahdat: Upfront, straightforward from day 1, so that there is no misunderstanding about what the next few years will be like. The most important thing is to get them to understand the progressive nature of the disease, or else every time they progress it is a disaster for them emotionally. You need to get them to understand that that is just part of the landscape. 10. What do you see as the role of palliative care for MBC patients? At what point in the treatment process do you think it should be introduced? Dr O Shaughnessy: Palliative care basically means symptom management, managing side effects of therapy, and managing symptoms of cancer. We are doing that right from the beginning. Dr Vahdat: It depends on how you define palliative care. Breast cancer patients usually are doing very well until probably about 6 months before they die. Remember, they can live for a decade. Once they start having symptoms that are difficult to control, and usually those are pain symptoms, that is usually when we refer them to palliative care. 13

Refractory or Recurrent Metastatic Breast Cancer (MBC): Treatment Paradigms on the Horizon Posttest A statement of continuing education hours will be provided to those participants who successfully complete and return the answer form and program evaluation and receive a passing grade of 70% or higher. PHYSICIAN CONTINUING MEDICAL EDUCATION Accreditation Statement and Credit Designation The University of Cincinnati is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The University of Cincinnati designates this educational activity for a maximum of 2 AMA PRA Category 1 credit(s). Physicians should only claim credit commensurate with the extent of their participation in the activity. Initial release date: December 15, 2010 Expiration date: December 15, 2011 1. The 5-year survival in patients with metastatic breast cancer (MBC) is approximately which of the following? a. 15% b. 25% c. 50% d. 65% 2. Approximately what percentage of patients experiences resistance to taxanes and anthracyclines? a. 10% b. 30% c. 50% d. 90% 3. Which of the following is involved in taxane resistance? a. Tubulin gene mutations b. Adenosine triphospate-binding cassette transporters c. Inhibition of apoptotic signaling d. All of the above 4. Which of the following is true of bevacizumab? a. It targets the epidermal growth factor receptor (EGFR) b. Trials have consistently shown an overall survival (OS) benefit c. It is a small molecule receptor tyrosine kinase inhibitor that targets vascular endothelial growth factor (VEGF) signaling d. It has been well studied in combination with paclitaxel 5. When lapatinib plus trastuzumab was compared with lapatinib in trastuzumab-resistant MBC, the combination was which of the following? a. Superior to lapatinib for progression-free survival only b. Superior to lapatinib for OS only c. Comparable to lapatinib d. Inferior to lapatinib 6. From which of the following is eribulin mesylate derived? a. Halichondria okadai b. Xanthone c. Glycosylated heparin d. Apogossypol 7. Results from the EMBRACE trial showed which of the following for eribulin versus treatment of physician s choice? a. No benefit b. Unacceptable tolerability c. An OS benefit d. None of the above 14

8. The OS benefit for eribulin in the EMBRACE study of heavily pretreated patients was approximately. a. 1 month b. 2.5 months c. 4.5 months d. 6 months 9. Which of the following was the most common grade 3/4 treatment-related adverse event for eribulin? a. Peripheral neuropathy b. Neutropenia c. Mucositis d. Asthenia/fatigue 10. Ixabepilone belongs to which of the following chemical classes? a. Taxanes b. Epothilones c. Anthracyclines d. Anthraquinones 11. Ixabepilone is associated with which of the following side effects in 65% of patients? a. Peripheral neuropathy b. Renal toxicity c. Cardiotoxicity d. Mucositis 12. Which of the following does not target the VEGF signaling pathway? a. Bevacizumab b. Sorafenib c. Sunitinib d. Eribulin 13. PARP inhibitors target which of the following? a. EGFR signaling b. A key DNA repair enzyme c. VEGF signaling d. The hedgehog pathway 14. Which of the following is not a PARP inhibitor currently under evaluation? a. Iniparib b. Dexiparib c. Olaparib d. Veliparib 15. In a recent clinical trial, what was the OS benefit with iniparib added to chemotherapy? a. About 2 months b. Nearly 5 months c. Over 6 months d. None of the above 16. Which of the following mtor inhibitors has demonstrated the most encouraging results in breast cancer? a. Sirolimus b. Temsirolimus c. Everolimus d. None of the above 17. How many receptors are thought to be part of the HER family? a. 2 b. 3 c. 4 d. 5 18. Trastuzumab DM1 is which of the following? a. An albumin-bound form of trastuzumab b. A pegylated form of trastuzumab c. An antibody-chemotherapy conjugate d. An antibody-antibody conjugate 19. Which of the following describes BIBW 2992? a. An oral, irreversible inhibitor of EGFR/HER1 and HER2 b. A monoclonal antibody to HER2 only c. A monoclonal antibody to EGFR/HER1 and HER2 d. None of the above 20. A phase II trial of pertuzumab and trastuzumab showed which of the following in trastuzumabresistant patients? a. No benefit b. An objective response in approximately onefourth of patients c. Clinical benefit in nearly all patients d. An objective response in approximately half of patients 15

CME Answer Form/Evaluation (please print clearly) Name/Degree Street City/State/Zip Daytime Phone Fax E-mail Birth Date (mm/dd/yy) Last 4 Digits of Social Security No. Sponsored by the University of Cincinnati for 2 AMA PRA Category 1 credit(s). Initial release date: December 15, 2010 Expiration date: December 15, 2011 CME Test Form Refractory or Recurrent Metastatic Breast Cancer: Treatment Paradigms on the Horizon 1. a b c d 2. a b c d 3. a b c d 4. a b c d 5. a b c d 6. a b c d 7. a b c d 8. a b c d 9. a b c d 10. a b c d 11. a b c d 12. a b c d 13. a b c d 14. a b c d 15. a b c d 16. a b c d 17. a b c d 18. a b c d 19. a b c d 20. a b c d Answer Form Instructions Testing and Grading Procedures 1. Each participant achieving a passing grade of 70% or higher on any examination will receive an official computer form stating the number of CME credits earned. This form should be safeguarded and may be used as documentation of credits earned. 2. Participants receiving a failing grade on any exam will be notified and permitted to take 1 reexamination at no cost. 3. All answers should be recorded on the answer form. 4. To receive credit certification electronically, please provide your e-mail address. Detach and mail or fax the test portion of this page to: University of Cincinnati, Office of CME, PO Box 670556, Cincinnati, OH 45267-0567; phone: 513-558-7277; fax: 513-558-1708. Please print clearly to ensure receipt of CME credit. 5. To receive credit and an immediate certificate, register at http://webcentral.uc.edu/ cpd_online2/ and complete the test or reader survey. If you have previously registered, enter your user name and password to log in. Otherwise, click New User? Register! and complete the registration process (user ID and password will be e-mailed to you immediately). Once you log in, click CME Text and scroll down through the course listings to locate this supplement. O-100 CME Activity Evaluation How long did it take you to complete this activity? minutes How well did this activity achieve its educational objectives? r Very well r Well r Somewhat r Not at all What overall grade would you assign this activity? r A r B r C r D Did this activity exhibit promotional bias for any pharmaceutical agents? r Yes r No Will you make changes in your practice as a result of information presented in this lesson? r Yes r No Cut or photocopy, then mail or fax

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