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Progress in Detecting and Managing HER2-Positive Breast Cancer: A Brief Clinical Update Based in part on data presented at ASCO 2008* CME/CE

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Please scroll through the CME/CE information before viewing the report. Program Description & Educational Objectives This program focuses on the latest evidence on detecting and managing HER2-positive breast cancer. Key recommendations from the current guidelines for HER2 testing are outlined, the latest efficacy data on HER2-targeted therapies are reviewed, and major safety concerns, particularly cardiotoxicity, are addressed. Upon completion of this activity, participants will be able to: • Discuss the challenges related to accurate determination of HER2 status and key recommendations from current guidelines for HER2 testing in breast cancer • Evaluate the latest efficacy data on HER2-targeted therapies in breast cancer in the adjuvant and metastatic settings • Assess and manage the key adverse effects, particularly cardiotoxicity, associated with therapies for HER2-positive breast cancer Target Audience This activity has been designed to meet the educational needs of nurses, physician assistants, and other clinicians treating patients with breast cancer. Requirements for Successful Completion In order to receive credit, participants must view the activity and complete the post-test and evaluation form. There are no pre-requisites and there is no fee to participate in this activity or to receive CME/CE credit. Certificates are awarded upon successful completion of the post-test and evaluation form. Media: Internet Release and Expiration Dates: October 3, 2008 - October 2, 2009 Time to Complete: 30 minutes Faculty & Disclosure CME Reviewer Melanie E. Royce, MD, PhD Associate Professor of Medicine Director, Multidisciplinary Breast Cancer Program Director, Hereditary Cancer Assessment Program UNM Cancer Research & Treatment Center University of New Mexico Health Sciences Center, School of Medicine Albuquerque, New Mexico Melanie E. Royce, MD, PhD, has a financial interest/relationship or affiliation in the form of: Grant/Research Support from AstraZeneca Pharmaceuticals LP; Roche Laboratories Inc.; and Genentech, Inc. Speakers Bureau participant with AstraZeneca Pharmaceuticals LP; Roche Laboratories Inc.; and Genentech, Inc. CE Reviewers Katie Spong, RN, LSW University of Minnesota Home Health Care St. Paul, Minnesota Kristine Kemp, RN Abbott-Northwestern Hospital Minneapolis, Minnesota Alexis Houck, RN, MA Health Partners Minneapolis, Minnesota Sponsorship, Credit & Support This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the University of New Mexico Health Sciences Center, School of Medicine and PVI, PeerView Institute for Medical Education. The University of New Mexico Health Sciences Center, School of Medicine is accredited by the ACCME to provide continuing medical education for physicians. The University of New Mexico Health Sciences Center, School of Medicine designates this educational activity for a maximum of 0.5 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity. Amedco, St. Paul, MN, is an approved provider of continuing nursing education by the Wisconsin Nurses Association Continuing Education Approval Program Committee, an accredited approver by the American Nurses Credentialing Center's Commission on Accreditation. The course is co-provided by Amedco and PVI, PeerView Institute for Medical Education. 0.5 contact hour(s). Note: Not all state nursing boards will accept programs 0.5 hours in length for credit. Please click here to find out the status of your state. This CME/CE activity is jointly sponsored by the University of New Mexico Health Sciences Center, School of Medicine, Amedco, and PVI, PeerView Institute for Medical Education. This activity is supported by an educational grant from Genentech BioOncology.

Post-Test Printable Transcript

Educational Objectives • Discuss the challenges related to accurate determination of HER2 status and key recommendations from current guidelines for HER2 testing in breast cancer • Evaluate the latest efficacy data on HER2-targeted therapies in breast cancer in the adjuvant and metastatic settings • Assess and manage the key adverse effects, particularly cardiotoxicity, associated with therapies for HER2-positive breast cancer

OVERVIEW Breast cancer is not a single disease, but rather comprises several different phenotypes. Approximately 15% to 20% of patients with breast cancer have HER2-positive disease. This is important because HER2 overexpression is often correlated with a poor prognosis, and HER2 status is now an important consideration in therapeutic decision-making. However, many unanswered questions regarding the optimal way to test for HER2 status and to determine who would most benefit from HER2-targeted therapies remain. This program highlights the evolving concepts in detecting and managing HER2-positive breast cancer so that optimal care can be provided to patients by all members of the healthcare team, including oncology nurses and physician assistants. Relevant data presented at the 44th Annual Meeting of the American Society of Clinical Oncology (ASCO 2008) are briefly summarized as well. back to top HER2 Testing: Current Challenges and Latest Guideline Recommendations HER2 status is now commonly used to identify specific therapies that a patient with breast cancer should or should not receive—in particular, HER2-targeted agents including trastuzumab and lapatinib. However, considerable uncertainty surrounds the accuracy of HER2 testing as well as the methodology used. According to ASCO and the College of American Pathologists (CAP), up to 20% of current HER2 testing may be inaccurate.1 Even when tests are meticulously validated, neither fluorescent in situ hybridization (FISH) nor immunohistochemistry (IHC) demonstrates any clear superiority in accurately determining HER2 status. Thus, the laboratory standards and methods of performing either test are currently more important than the type of test used. For example, the way in which the test tissue is handled—time to fixation, method of tissue processing, time of fixation, and the type of fixative employed—affect the test outcome. The assay itself must be conducted in a standardized manner to avoid undue variation in results. Finally, variations in how results are interpreted (eg, whether or not image analysis is used, which reporting elements are selected) can vary from laboratory to laboratory and should be standardized. Updated guidelines developed through collaboration between ASCO and CAP detail recommendations for determination of HER2 status.1 The panel recommends assessing the HER2 status in all invasive breast cancers, using a testing algorithm that relies on accurate and reproducible assay performance. According to the guidelines, HER2 results should be divided into 3 categories: positive, equivocal, and negative. Using IHC techniques, a positive result is defined by 3+ cell-surface protein expression. Equivocal and negative results are defined by 2+ and 0 or 1+ cell-surface protein expression, respectively. Positive FISH results should yield more than 6 gene copies of HER2, or a HER2/CEP 17 ratio greater than 2.2. Equivocal results include the identification of 4 to 6 gene copies of HER2, or a HER2/CEP 17 ratio of 1.8 to 2.2. For equivocal results, clinicians can retry FISH or perform an IHC evaluation of the tumor sample. The guidelines also state that HER2 testing should only be performed by laboratories that can confirm that less than 5% of their testing results for HER2 conflict with a standardized assay. Therefore, only experienced personnel should conduct HER2 testing, and the competency of HER2 testing should be addressed in an ongoing fashion. Although the latest guidelines are likely to lead to improvements in the quality and accuracy of HER2 testing, much work is needed to develop diagnostic and predictive tests that could overcome the limitations of the currently used assays. Data released at ASCO 2007 and thereafter have added to the controversy related to HER2 testing and the use of HER2-targeted therapies. Namely, data from adjuvant trials evaluating chemotherapy with or without trastuzumab suggested that benefit from trastuzumab may not be limited to IHC 3+ and FISH+ patients with breast cancer.2,3 However, there is insufficient evidence to recommend the use of trastuzumab in HER2-normal or -negative patients with early-stage breast cancer. Therefore, patients whose tumors show protein overexpression (IHC 3+) and/or gene amplification, according to testing criteria prospectively used for eligibility in the reported randomized adjuvant trials, should currently be considered appropriate candidates for anti-HER2 therapy. During an educational session at ASCO 2008, Antonio C. Wolff, MD, noted that assays to select patients for and predict benefit from anti-HER2 therapy are evolving, and that the guidelines are a living document that will change if new high-quality evidence becomes available.4 back to top The Latest Data on HER2-Targeted Therapies in Breast Cancer Trastuzumab was the first HER2-targeted agent approved for breast cancer. It is currently indicated for the adjuvant treatment of HER2-overexpressing, node-positive or node-negative (ER/PR-negative, or with 1 high-risk feature) breast cancer. In the adjuvant setting, it can be used in a number of ways: as part of a treatment regimen including doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; with docetaxel and carboplatin; or as a single agent following multi-modality anthracycline-based therapy. In the metastatic setting, trastuzumab is approved for the first-line treatment of HER2-overexpressing breast cancer in combination with paclitaxel, and as a single agent in patients who have received 1 or more chemotherapy regimens for metastatic disease. Lapatinib became available in 2007 and is approved for use in combination with capecitabine for patients with HER2-positive metastatic disease that has progressed on trastuzumab. New data on the HER2-directed therapies were presented at ASCO 2008. The HERTAX trial5 compared the efficacy and toxicity of monotherapy with trastuzumab followed by docetaxel at progression and combination trastuzumab/docetaxel as first-line therapy for patients with metastatic breast cancer. Ninety-nine patients were randomized between the 2 arms. Compared with sequential therapy, combination treatment yielded a higher response rate (73% vs 50%; P = .02). The median PFS was longer with initial combination therapy compared with trastuzumab monotherapy (9.4 vs 3.9 months; P = .0001). However, there was no significant difference in PFS when sequential or combination therapy was compared. The OS was also not significantly different between the treatment arms. Additionally, grade 3 neurotoxicity was only seen in the combination arm, and there were 2 deaths due to toxicity in that arm. A current trend in the treatment of HER2-positive metastatic breast cancer is combining multiple HER-targeting agents. For example, encouraging findings have been observed with the combination of lapatinib and trastuzumab. In a trial reported at ASCO 2008, heavily pretreated patients who had received prior anthracyclines and taxanes and experienced tumor progression while on trastuzumab were randomized to ongoing trastuzumab plus lapatinib versus lapatinib alone.6 The combination of the 2 agents was found to be superior to single-agent lapatinib. The response rate with lapatinib alone was 6.9% compared with 10.3% with the combination of trastuzumab and lapatinib. The median PFS was 8.1 weeks with lapatinib versus 12 weeks with the combination (HR 0.73, P = .008). The medial OS was 39 weeks with single-agent lapatinib and 52 weeks with the combination (P = .11). Additionally, no excess toxicity was observed with the combination of the 2 agents. The study suggests that trastuzumab may potentiate the effects of lapatinib. "Total HER2 blockade with lapatinib and trastuzumab may provide a chemotherapy-free option for HER2-positive metastatic breast cancer patients," according to lead investigator Joyce O’Shaughnessy, MD, of the Baylor-Sammons Cancer Center in Dallas. Data from a study assessing the feasibility of adjuvant doxorubicin and cyclophosphamide therapy followed by trastuzumab plus lapatinib and weekly paclitaxel were also released at this year’s ASCO meeting.7 A major toxicity in the form of diarrhea was observed with the concurrent administration of trastuzumab, lapatinib, and paclitaxel. As a result, combination therapy with the 3 agents at the administered doses was deemed unfeasible. A number of novel HER2-targeted therapies are currently under evaluation. Results from a phase 2 study evaluating pertuzumab in combination with trastuzumab, in patients with HER2-positive advanced breast cancer showing evidence of tumor progression despite prior trastuzumab therapy, were presented at the recent ASCO meeting.8 Objective response was observed in 24% of the patients, and 24% were also free of progression through 6 months of treatment. Diarrhea, mucositis, and nausea or vomiting were among the adverse effects reported. Additionally, results were reported from a phase 2 study with the hsp90 inhibitor tanespimycin in combination with trastuzumab in patients who had disease progression despite prior trastuzumab therapy.9 The overall response rate among the 27/31 evaluable patients was 26%. Transaminase elevations were noted in some patients. Adverse effects commonly seen included diarrhea, nausea, and fatigue. back to top Cardiovascular Toxicity Associated With HER2-Targeted Therapies Improved long-term outcomes for patients with HER2-positive breast cancer are tempered by the risk of potentially serious treatment-related side effects, including those affecting the cardiovascular system. Trastuzumab has the potential for causing cardiotoxicity, particularly in patients receiving concurrent or prior anthracyclines, but it can be typically minimized with appropriate clinical care and drug scheduling. Cardiotoxicity associated with trastuzumab is usually treatable and at least partially reversible. In the monotherapy studies of trastuzumab in advanced breast cancer, the cardiac event rate was low. However, the pivotal phase 3 data on trastuzumab and combined chemotherapy for first-line advanced disease demonstrated an unexpectedly high number of adverse cardiac events (13% of all patients had symptomatic or asymptomatic congestive heart failure [CHF]: 27% in the combination group versus 8% with anthracycline monotherapy, and 13% in the combination paclitaxel-trastuzumab group versus 1% with paclitaxel monotherapy).10 Subsequent data confirmed these findings. In key studies of trastuzumab in the adjuvant setting, rates of asymptomatic cardiac dysfunction ranged between 3.0% and 18.0%.11,12 It is important to also consider the cardiotoxicity risk factors. Analysis of risk factors from the pivotal study in the metastatic setting10 demonstrated that age was a significant covariate while baseline left ventricular ejection fraction (LVEF) was not. According to the MD Anderson series13, baseline LVEF rather than age was a significant covariate. Other potential risk factors examined in these studies, including hypertension and prior radiotherapy, did not significantly affect outcome. In the adjuvant setting, multivariate analysis of data from the B-31 study identified age and baseline LVEF, or LVEF following anthracycline chemotherapy, as significant covariates.14 Other factors assessed were not found to significantly impact risk. Therefore, trastuzumab should not be withheld from patients who are eligible, except in cases of poor LVEF prior to therapy. In the elderly, the risk of CHF should be considered, mandatory cardiac monitoring should be performed, and consideration should be given to alternative trastuzumab scheduling.15 Monitoring of LVEF and clinical cardiac assessment should be carried out before and during adjuvant trastuzumab therapy.15 Alternative strategies are being evaluated to avoid or overcome cardiotoxicity, including trastuzumab combinations with nonanthracycline chemotherapy, short-duration trastuzumab, and the use of new small-molecule inhibitors of the tyrosine kinase domain of HER2. Cardiotoxicity seems to be less of a concern with lapatinib. A recent review of data from 44 clinical studies revealed low levels of cardiotoxicity and indicated that cardiac events were usually asymptomatic, caused reversible decreases in LVEF, and occurred at similar rates in patients who were and were not pretreated with anthracyclines or trastuzumab.16 The reversibility of cardiac events observed with trastuzumab and lapatinib suggests that the underlying mechanism is cellular dysfunction, described as type II cardiotoxicity, not cell death. Cardiotoxicity associated with anthracycline therapy is known as type I cardiotoxicity, which results in structural abnormalities of the cardiac ultrastructure and subsequent cell death. With type II cardiotoxicity, the injury results in myofibril contractile elements failing to exert coordinated activity.17,18 back to top CME/CE INFORMATION Post-Test References Wolff AC et al. J Clin Oncol. 2007;25:118-145. Paik S et al. 43rd Annual Meeting of the American Society of Clinical Oncology (ASCO 2007). Abstract 511. Perez E et al. ASCO 2007. Abstract 512. Wolff AC. Educational session from ASCO 2008: HER2-Targeted Therapy: Why Bother Testing? http://www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Virtual+Meeting?&vmview=vm_session_presentations_view&confID=55&sessionID=321. Accessed September 1, 2008. Bontenbal M et al. ASCO 2008. Abstract 1014. O’Shaughnessy J et al. ASCO 2008. Abstract 1015. Dang CT et al. ASCO 2008. Abstract 518. Gelmon KA et al. ASCO 2008. Abstract 1026. Modi S et al. ASCO 2008. Abstract 1027. Slamon DJ et al. N Engl J Med. 2001;344:783-792. Romond EH et al. N Engl J Med. 2005;353:1673-1684. Piccart-Gebhart MJ et al. N Engl J Med. 2005;353:1659-1672. Guarneri V et al. J Clin Oncol. 2006;24:4107-4115. Tan-Chiu E et al. J Clin Oncol. 2005;23:7811-7819. Popat S, Smith IE. Nat Clin Pract Oncol. 2008;5(6):324-335. Perez EA et al. Mayo Clin Proc. 2008;83(6):679-86. Ewer MS, Lippman SM. J Clin Oncol. 2005;23(13):2900-2902. Perez EA. Clin Breast Cancer. 2008;8(suppl 3):S114-S120.

*Materials are based in part on data presented at the 44th Annual Meeting of the American Society of Clinical Oncology. PeerView Press is an independent publisher of conference news and medical education programs. The materials presented here are used with the permission of the authors and/or other sources. These materials do not necessarily reflect the views of PeerView Press or any of its supporters.

This CME/CE activity is jointly sponsored by the University of New Mexico Health Sciences Center, School of Medicine, Amedco, and PVI, PeerView Institute for Medical Education. Credit Available: US Physicians – 0.5 AMA PRA Category 1 Credit(s)TM. US Nurses – 0.5 contact hour(s). This activity is supported by an educational grant from Genentech BioOncology.

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