Herceptin®: implications for breast cancer management

Herceptin1: implications for breast cancer management Nora Kearney,Gaye McPhail It appears that no further significant improvements in the survival of women with metastatic breast cancer are likely to result from the use of traditional chemotherapeutic agents. Research attempting to identify novel agents has focused on biological therapies, which can be used to target specific abnormalities in cancer cells. Human epidermal growth factor receptor-2 (HER2) is a cell membrane receptor with growth-regulating activity. Studies indicate that the 25^30% of women with breast cancer who overexpress HER2 have aggressive disease and a worse prognosis than those who do not overexpress HER2.Herceptin1 targets HER2 and is the first humanized monoclonal antibody approved for therapeutic use. Clinical trials have demonstrated that Herceptin1 is well tolerated, produces durable objective responses and improves survival in women with metastatic breast cancer. Its side-effects are generally mild to moderate and differ from those of traditional cytotoxic agents. Cardiotoxicity, the most significant adverse effect of Herceptin1, is manageable in most patients using standard therapy. The likely positioning of Herceptin1 in the treatment of HER2-overexpressing metastatic breast cancer is in combination with paclitaxel as first-line therapy and as second- or third-line therapy when administered alone. It is likely that the exploitation of HER2 as a target for therapy and the development of Herceptin1 will serve as a model for the development of future biological therapies. # 2000 Harcourt Publishers Ltd Keywords: human epidermal growth factor receptor-2, breast cancer, prognosis, patient selection, anti-HER2 therapy, Herceptin1

INTRODUCTION

Nora Kearney RGN, MSc, Lecturer in Cancer Nursing, Gaye McPhail MN, BSc, RGN, Macmillan Lecturer/ Practitioner in Cancer Nursing, Nursing and Midwifery School, University of Glasgow, 68 Oakf|eld Avenue, Glasgow G12 8LS, UK

Breast cancer in women accounts for 24% of cancers diagnosed and 19% of the 837000 cancer deaths annually in Europe (EsteÂve et al 1996); 4135000 new cases are reported annually. Despite the introduction of various new chemotherapeutic agents and the implementation of screening programmes, the Surveillance, Epidemiology and End Results database of the National Cancer Institute indicates that 45±50% of all patients diagnosed with breast cancer will develop refractory or metastatic disease (Chu et al 1999, Ries et al 1999). Breast cancer will be the cause of death in most of these women. These statistics indicate the extent of the burden of breast cancer. It appears likely that no further signi®cant improvements in the survival of women with metastatic breast cancer will result from the use of traditional chemotherapeutic agents, despite alterations to treatment regimens and the use of

European Journal of Oncology Nursing 4 (Suppl 1), 37^ 41 # 2000 Harcourt Publishers Ltd doi:10.1054/ejon.2000.0074, available online at http://www.idealibrary.com on

new combinations of existing drugs (Hortobagyi 1998). Furthermore, severe side-e€ects continue to present obstacles to the use of many agents (Piccart et al 1999). Therefore, there is a need for novel therapies that can signi®cantly improve symptom palliation and disease outcome. Relatively few biological therapies or immunotherapies are currently available for clinical use, although agents such as rituximab (Buske et al 1999, Onrust et al 1999), interferon-a (Haase-Statz & Smalley 1999) and interleukin-2 (Fefer 1997, Frydecka et al 1999) have a developing role in therapy for various types of cancer, including non-Hodgkin's lymphoma and haematological malignancies. However, much research involving this type of agent is currently in progress and it appears likely that the number of biological agents in clinical use will increase over the next few years (Harris et al 1999, Lopez-Beltran 1999, Staib et al 1999, Syrigos et al 1999). These developments have been stimulated, at least in part, by the recognition that traditional

38 European Journal of Oncology Nursing

chemotherapeutic agents are unlikely to produce signi®cant improvements in cancer control and survival. Furthermore, new technologies, such as the ability to produce monoclonal antibodies, have made targeting speci®c cellular components feasible (Hortobagyi et al 1999). This ability to target cellular components has in turn driven the search for novel targets on cancer cells. Simultaneously with technological developments, there has been signi®cant progress in understanding of cell cycle control, signal transmission within cells and the genes involved in the control of cell growth and di€erentiation. Genetic and molecular biological techniques allowed the identi®cation of genes and proteins that, through mutation, ampli®cation or deletion, could be involved in oncogenesis. A range of targeting methods have been used, including monoclonal antibodies, immunoconjugates, vaccines, gene therapy and anti-angiogenic agents (Hortobagyi et al 1999). To date, monoclonal antibodies have proved most successful in the treatment of cancer. Targets for biological and immunotherapies in breast cancer include the product of the MUC-1 gene (Peterson et al 1997), STn antigen (Miles et al 1996), tyrosine kinase activity (Shawver 1999) and human epidermal growth factor receptor-2 (HER2) (Disis & Cheever 1997). Clinical development of agents targeting HER2, a cell membrane receptor with growth-regulating activity, is the strategy that has progressed furthest (Slamon et al 1998, Cobleigh et al 1999, Norton et al 1999). This has resulted in the development of the drug Herceptin1, the ®rst humanized monoclonal antibody approved for clinical use (approved by the US Food and Drug Administration in October 1998). As Herceptin1 is likely to be the ®rst of a number of biological agents that will be used to treat cancer, nurses will need to become familiar with the unique characteristics of this agent and those that apply more generally to biological therapies. In this article, four main issues will be discussed: . patient selection for anti-HER2 therapy . bene®t of Herceptin1 . optimal use and positioning of Herceptin1 in metastatic breast cancer therapy . individualizing therapy for metastatic breast cancer. These issues will a€ect the way we manage and care for patients with metastatic breast cancer, and have the potential to change clinical practice for the better.

PATIENT SELECTION For e€ective targeting of breast cancer cells, antiHER2 therapy relies on the fact that 25±30% of patients with metastatic breast cancer produce European Journal of Oncology Nursing 4 (Suppl 1), 37^ 41

greater than normal quantities of the HER2 receptor (overexpression) and that this is associated with poor prognosis (Slamon et al 1987, 1989). This is important because many cell types express the HER2 receptor at levels much lower than those associated with overexpression (De Potter et al 1989), although they do not appear to be a€ected by Herceptin1 (Sarup et al 1991, Carter et al 1992). However, this also meant that a method of identifying patients whose tumours overexpress the HER2 receptor was needed. Given the prognostic and predictive implications of being HER2 positive, early identi®cation of patients overexpressing HER2 would also be useful as it will allow appropriate treatment decisions to be made.

HER2 testing A number of tests are currently available to assess HER2 status, with the main ones being immunohistochemistry (IHC) and ¯uorescence in situ hybridization (FISH) (Mitchell & Press 1999). Each of these has advantages and disadvantages, but they appear to be relatively reliable and their results appear to agree relatively well (Espinoza & Anguiano 1999, Jacobs et al 1999). Furthermore, both can be used to evaluate the HER2 status of biopsy sections from primary tumour samples. As metastases of HER2-positive primary breast tumours are also HER2 positive, IHC and FISH for HER2 could be used early in the course of disease, i.e. at initial diagnosis/ staging. This would not only provide prognostic and predictive information allowing appropriate therapeutic decisions to be made, but would also dispense with the need for further biopsy if the disease progresses.

HER2 assay standardization The major issue in HER2 testing is the development of standard criteria for scoring test results. This is currently a controversial area, with some researchers believing that proper use of current standard criteria for IHC provides useful prognostic and predictive information as well as allowing selection of patients for Herceptin1 therapy. Others believe that FISH, being quantitative, is less subject to human error and therefore should be the technique of choice for measuring HER2 abnormalities (for a review, see Mitchell & Press 1999). However, FISH measures HER2 gene ampli®cation and not all overexpressing tumours show HER2 ampli®cation. The signi®cance of this is not well established, but it is possible that patients who could bene®t from Herceptin1 therapy could be overlooked using FISH alone and that important prognostic/ predictive information might not be available. The resolution of these issues is a priority, as

Herceptin1: implications for breast cancer management 39

evidenced by the NCI Symposium `Detection of HER2/neu (erbB2) antigen overexpression', held in Bethesda, MD, USA, 7±8 October, 1999. Undoubtedly, the general acceptance of a test for HER2 status will enable informed treatment decisions and ensure that only patients who are likely to respond to Herceptin1 are treated. This will facilitate e€ective and cost-e€ective use of the drug. Furthermore, as previously discussed, biological therapies will be used increasingly to treat cancer. Many of these therapies will target speci®c abnormalities in cancer cells. Therefore, the lessons learned from the problems encountered in standardizing HER2 testing will be useful when developing tests for the selection of patients for other targeted therapies. Finally, the use of HER2 status as a prognostic and predictive marker in clinical practice is currently hampered by the inconsistency of study results (Ross & Fletcher 1998). Part of the cause of this inconsistency is the use of di€erent tests and di€erent scoring criteria in trials to date. Hopefully, the adoption of a standardized test will allow de®nitive conclusions to be made regarding the prognostic and predictive implications of HER2 status. This can only be of bene®t to our patients. Thus, IHC is currently the test most suitable for widespread use. However, FISH may take its place as our understanding of the mechanism of action of HER2 abnormalities in oncogenesis improves.

BENEFITS OF HERCEPTIN1 The main bene®ts of Herceptin1 treatment for women with metastatic breast cancer can be summarized as follows (Slamon et al 1998, Cobleigh et al 1999, Goldenberg 1999, Norton et al 1999): . Herceptin1 signi®cantly increases overall survival in women with metastatic breast cancer . Herceptin1 is well tolerated and the sidee€ects that do occur tend to be mild and transient . Herceptin1 can be used in the outpatient setting after the initial dose. In more detail, studies published to date have demonstrated that Herceptin1 is active as a single agent, producing an objective response rate of 15% in heavily pre-treated women with metastatic breast cancer. This bene®t was not obtained at the expense of signi®cant side-e€ects: the most common events were mild to moderate chills and fever occurring mainly with the ®rst dose of Herceptin1 (Cobleigh et al 1999). In combination with anthracyclines or paclitaxel, Herceptin1 has been shown to increase survival duration by 25% in comparison with chemotherapy alone and was again well tolerated (Slamon et al 1998, Norton et al 1999). In both the single-

agent and combination studies, Herceptin1 was administered weekly in the out-patient setting. In terms of side-e€ects, 53% of all patients treated with Herceptin1 have discontinued treatment for reasons associated with Herceptin1 use and only one patient has developed anti-Herceptin1 neutralizing antibodies. This should be compared with the signi®cant rates of severe side-e€ects associated with traditional cytotoxic chemotherapy (Fornier et al 1999). Patients treated with Herceptin1 in combination with these traditional cytotoxic agents experience severe side-e€ects, but these are associated with the cytotoxic drug. Cardiotoxicity is an important consideration when comparing the bene®t of Herceptin1 use with its risk. Data indicate that any cardiotoxicity that may be associated with Herceptin1 use is usually manageable and at least partially reversible, with severe heart failure becoming asymptomatic with standard therapy (Norton et al 1999). The association of cardiotoxicity with the use of Herceptin1 in combination with anthracyclines could perhaps bias against the use of Herceptin with these agents. However, the response rate with Herceptin1 combination therapy is 450%, whereas the incidence of severe cardiac dysfunction after treatment using standard cardiac therapy is approximately 5%. Ewer et al (1999) recently discussed the cardiotoxicity associated with Herceptin1 in some detail, concluding that this association may be due to one of three reasons: observational artefact associated with the use of prior cardiotoxic therapy, i.e. anthracyclines, sequential stress or intrinsic toxicity. Resolution of which of these is the cause of Herceptin1associated cardiotoxicity will require further studies, some of which are currently ongoing. With standardized testing and agreement on scoring criteria, it is likely that patient selection will improve. This may result in an apparent increase in the bene®t of Herceptin1. However, even without these improvements, Herceptin1 bene®ts women with metastatic breast cancer: they live longer, Herceptin1 does not produce the debilitating side-e€ects of traditional cytotoxic agents, and their family and social life can continue because they are being treated as out-patients (Slamon et al 1998, Baselga et al 1999, Cobleigh et al 1999, Norton et al 1999). Thus, in comparison to the treatment we have been able to o€er in the past, Herceptin1 represents important progress.

POSITIONING OF HERCEPTIN1 IN METASTATIC BREAST CANCER The likely role of Herceptin1 in the treatment of metastatic breast cancer has been considered by European Journal of Oncology Nursing 4 (Suppl 1), 37^ 41

40 European Journal of Oncology Nursing

both European (Piccart et al 1999) and US groups (Hortobagyi 1999). Both groups have developed patient treatment algorithms that incorporate HER2 status and Herceptin1 therapy into the established pattern of use of traditional chemotherapeutic agents. It is interesting to note that the traditional strati®cation of patients into low and high risk based on hormone receptor status, number of metastases and organ involvement has been maintained. However, HER2 status has been used to identify patients classi®ed as low risk using these standard parameters who warrant particularly close monitoring and to make treatment decisions. The positioning of Herceptin1 in the treatment of women with metastatic breast cancer according to these algorithms is: . ®rst-line therapy in combination with taxanes in women with metastatic breast cancer whose tumour overexpresses HER2 . second- or third-line therapy as a single agent in women with metastatic breast cancer whose tumour overexpresses HER2.

INDIVIDUALIZING THERAPY FOR METASTATIC BREAST CANCER The ®nal consideration in relation to Herceptin1 is the implications that its use has for individualizing therapy. Currently, therapy is broadly tailored based on conventional prognostic factors such as hormone receptor status, tumour size, stage and grade, and number of metastases. These factors combine to allow the aggressiveness of the disease to be estimated. However, this indicates only whether aggressive treatment, with its corresponding adverse e€ects and need for close monitoring and intensive management, is warranted. In the future, it is likely that therapy will be individualized. Knowing a patient's HER2 status allows decisions on whether speci®c anti-HER2 therapy is warranted and also allows the doses of other agents to be optimized. Further research identifying other genes and/or proteins with a role in oncogenesis and/or disease prognosis will lead to further treatment individualization. This is an exciting prospect and one that clinicians should welcome to ensure optimal patient outcomes.

CONCLUSIONS Study of the HER2 gene and receptor has led to the rational development of a speci®c, targeted therapy that has been shown to produce bene®t in women with metastatic breast cancer. Furthermore, HER2 has been shown to have value as a European Journal of Oncology Nursing 4 (Suppl 1), 37^ 41

prognostic marker and as an indicator of the outcome of cytotoxic chemotherapy. Therefore, HER2 testing should be incorporated into the routine evaluation of patients with breast cancer. The proven bene®t of Herceptin1 in terms of overall survival and quality of life o€ers hope to women with metastatic breast cancer. Furthermore, use of Herceptin1 will not add signi®cantly to the nursing workload because it is well tolerated and can be administered in the outpatient setting. With the known limitations of traditional cytotoxic anticancer agents, it appears that the development of targeted biological therapies represents an exciting avenue of research for the identi®cation of useful agents for the treatment of cancer. The successful introduction of Herceptin1 into clinical use and the resolution of issues relating to HER2 testing will act as a model for the introduction of these therapies. As Hortobagyi et al (1999) have stated, `Applied research presents us with a large number of potential tools with which to intervene in the management of metastatic disease and, more recently, in the prevention of primary breast cancer'.

REFERENCES Baselga J, Kerrigan M, Burchmore M, Ash M (1999) Health-related quality of life (HRQL) in women with HER2-overexpressing metastatic breast cancer (MBC) in a phase III study of Herceptin (R) plus chemotherapy versus chemotherapy alone. European Journal of Cancer 35(Suppl 4): S318 [abstract 1276] Buske C, Feuring-Buske M, Unterhalt M, Hiddemann W (1999) Monoclonal antibody therapy for B cell nonHodgkin's lymphomas: emerging concepts of a tumour-targeted strategy. European Journal of Cancer 35: 549±557 Carter P, Presta L, Gorman CM, Ridgway JBB, Henner D, Wong WLT, Rowland AM, Kotts C, Carver ME, Shepard HM (1992) Humanization of an antip185HER2 antibody for human cancer therapy. Proceedings of the National Academy of Sciences USA 89: 4285±4289 Chu KC, Tarone RE, Brawley OW (1999) Breast cancer trends of black women compared with white women. Archives of Family Medicine 8: 521±528 Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, Wolter JM, Paton V, Shak S, Lieberman G, Slamon DJ (1999) Multinational study of the ecacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. Journal of Clinical Oncology 17: 2639±2648 De Potter CR, Quatacker J, Maertens G, Van Daele S, Pauwels C, Verhofstede C, Eechaute W, Roels H (1989) The subcellular localization of the neu protein in human normal and neoplastic cells. International Journal of Cancer 44: 969±974 Disis ML, Cheever MA (1997) HER-2/neu protein: A target for antigen-speci®c immunotherapy of human cancer. Advances in Cancer Research 71: 343±371

Herceptin1: implications for breast cancer management 41 Espinoza F, Anguiano A (1999) The HercepTest assay: Another perspective. Journal of Clinical Oncology 17: 2293b EsteÂve J, Kricker A, Ferlay J, Parkin DM in collaboration with the Steering Committee of the European Network of Cancer Registries (eds) (1996) Facts and Figures of cancer in the European Community. International Agency for Research on Cancer Ewer MS, Gibbs HR, Swa€ord J, Benjamin RS (1999) Cardiotoxicity in patients receiving trastuzumab (Herceptin): primary toxicity, synergistic or sequential stress, or surveillance artifact? Seminars in Oncology 26(Suppl 12): 96±101 Fefer A (1997) Interleukin-2 in the treatment of hematologic malignancies. Cancer Journal of the Scienti®c American 3(Suppl 1): S35±S36 Fornier M, Munster P, Seidman AD (1999) Update on the management of advanced breast cancer. Oncology 13: 647±657 Frydecka I, Kosmaczewska A, Bocko D, Ciszak L, Kaczmarek P (1999) Immunotherapy with recombinant human interleukin 2 in patients with hematological malignancies after bone marrow or peripheral blood stem cell transplantation. Archives of Immunological Therapy and Experimentation (Warszau) 47: 223±227 Goldenberg MM (1999) Trastuzumab, a recombinant DNA derived humanized monoclonal antibody, a novel agent for the treatment of metastatic breast cancer. Clinical Therapeutics 21: 309±318 Haase-Statz S, Smalley RV (1999) Role of interferon-alfa in NHL: still controversial. Oncology (Huntington) 13: 1147±1159 Harris DT, Matyas GR, Gomella LG, Talor E, Winship MD, Spitler LE, Mastrangelo MJ (1999) Immunologic approaches to the treatment of prostate cancer. Seminars in Oncology 26: 439±447 Hortobagyi (1998) Treatment of breast cancer. New England Journal of Medicine 339: 974±984. Hortobagyi GN (1999) Options for the treatment of metastatic breast cancer. American Society of Clinical Oncology 1999 Educational Book: 515±521 Hortogagyi GN, Hung M-C, Buzdar AU (1999) Recent developments in breast cancer therapy. Seminars in Oncology 26(Suppl 12): 11±20 Jacobs TW, Gown AM, Yaziji H, Barnes MJ, Schnitt SJ (1999) Comparison of ¯uorescence in situ hybridization and immunohistochemistry for the evaluation of HER-2/neu in breast cancer. Journal of Clinical Oncology 17: 1974±1982 Lopez-Beltran A (1999) Bladder treatment. Immunotherapy and chemotherapy. Urologic Clinics of North America 26: 535±554 Miles DW, Towlson KE, Graham R, Reddish M, Longenecker BM, Taylor-Papadimitriou J, Rubens RD (1996) A randomised phase II study of sialyl-Tn and DETOX-B adjuvant with or without cyclophosphamide pretreatment for the active speci®c immunotherapy of breast cancer. British Journal of Cancer 74: 1292±1296 Mitchell MS, Press MF (1999) The role of immunohistochemistry and ¯uorescence in situ hybridization for HER-2/neu in assessing the prognosis of breast cancer. Seminars in Oncology 26(Suppl 12): 108±116

Norton L, Slamon D, Leyland-Jones B, Wolter J, Fleming T, Eirmann W, Baselga J, Mendelsohn J, Bajamonde A, Ash M, Shak S, Multinational Herceptin Investigator Group (1999) Overall survival (OS) advantage to simultaneous chemotherapy (CRx) plus the humanized anti-HER2 monoclonal antibody Herceptin (H) in HER2-overexpressing (HER2+) metastatic breast cancer (MBC) Proceedings of the American Society of Clinical Oncology 18: 127a [abstract 483] Onrust SV, Lamb HM, Balfour JA (1999) Rituximab. Drugs 58: 79±88 Peterson JA, Blank EW, Ceriani RL (1997) E€ect of multiple, repeated doses of radioimmunotherapy on target antigen expression in breast carcinomas. Cancer Research 57: 1103±1108 Piccart MJ, Awada A, Hamilton A (1999) Integration of new therapies into management of metastatic breast cancer: A focus on chemotherapy, treatment selection through use of molecular markers, and newly developed biologic therapies in late clinical development. American Society of Clinical Oncology 1999 Educational Book: 526±538 Ries LAG, Kosary CL, Hankey BF, Miller BA, Clegg L, Edwards BK (eds) (1999) SEER Cancer Statistics Review, 1973±1996. Bethesda, MD: National Cancer Institute Ross JS, Fletcher JA (1998) The HER-2/neu oncogene in breast cancer: Prognostic factor, predictive factor, and target for therapy. Stem Cells 16: 413±428 Sarup JC, Johnson RM, King KL, Fendly BM, Lipari MT, Napier MA, Ullrich A, Shepard HM (1991) Characterization of an anti-p185HER2 monoclonal antibody that stimulates receptor functions and inhibits tumor cell growth. Growth Regulation 1: 72±82 Shawver LK (1999) Tyrosine kinase inhibitors: From the emergence of targets to their clinical development. American Society Clinical Oncology 1999 Educational Book: 29±47 Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with ampli®cation of the HER-2/neu oncogene. Science 235: 177±182 Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244: 707±712 Slamon D, Leyland-Jones B, Shak S, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Baselga J, Norton L (1998) Addition of HerceptinTM (humanized anti-HER2 antibody) to ®rst line chemotherapy for HER2 overexpressing metastatic breast cancer (HER2+/MBC) markedly increases anticancer activity: A randomized, multinational controlled phase III trial. Proceedings of the American Society of Clinical Oncology 17: [abstract 377] Staib L, Link KH, Beger HG (1999) Immunotherapy in pancreatic cancerÐcurrent status and future. Langenbecks Archives of Surgery 384: 396±404 Syrigos KN, Deonarian DP, Epenetos AA (1999) Use of monoclonal antibodies for the diagnosis and treatment of bladder cancer. Hybridoma 18: 219±224

European Journal of Oncology Nursing 4 (Suppl 1), 37^ 41