NE Oncology Issue – February 2014
Overexpression of the human epidermal growth factor receptor 2 (HER2) protein is detected in the tumours of approximately 20% of patients with breast cancer, conferring an aggressive phenotype that historically resulted in poor clinical outcome.1 The landmark development of trastuzumab, a humanized monoclonal antibody targeting HER2, and other anti-HER2 agents such as lapatinib, a reversible HER2 tyrosine kinase inhibitor, have changed the course of HER2-positive disease; however, a subset of patients will still relapse.1 Given this clinical reality, new anti-HER2 agents with different mechanisms of action have been developed. Recently, the antibody-drug conjugate trastuzumab emtansine was shown to improve progression-free survival (PFS) and overall survival (OS) compared with capecitabine plus lapatinib in the phase III EMILIA study of previously treated patients with HER2-positive advanced breast cancer (ABC).2
A different approach that has also been taken has been to elucidate the molecular mechanisms mediating resistance to HER2 blockade.1 The phosphatidylinositol 3-kinase (PI3K)/mechanistic target of rapamycin (mTOR) signaling transduction pathway is commonly deregulated in breast cancer and represents a potential target. Everolimus, a mTOR kinase inhibitor, has shown some encouraging antitumour activity when used in combination with trastuzumab and chemotherapy in phase I studies of HER2-positive ABC.1 Currently, everolimus is being studied in two ongoing phase III trials in the HER2-positive ABC setting: BOLERO-1 (NCT00876395) and BOLERO-3 (NCT01007942).
The following abstracts were presented at the 2013 European Cancer Congress (ECC), some of which pertain to the ongoing development of trastuzumab emtansine and everolimus:
- Primary results from TH3RESA, a phase III study of trastuzumab emtansine versus treatment of physician’s choice in HER2-positive ABC, have demonstrated improved efficacy and favourable safety with trastuzumab emtansine.
- Patients with HER2-positive ABC in the BOLERO-3 study who have biomarkers indicative of PI3K/mTOR pathway activation may have derived greater benefit from the addition of everolimus to trastuzumab and vinorelbine.
- Preliminary results from a phase II study showed significant prolongation of PFS, with an acceptable toxicity profile, with the addition of everolimus to an aromatase inhibitor in post-menopausal women with ER+/HER2– ABC who have progressed following previous endocrine therapy.
- Results of a multicentre, phase II study have shown that bevacizumab preconditioning followed by etoposide and cisplatin (BEEP) is a highly effective treatment for brain metastases of breast cancer progressing from radiotherapy.
- The aTTom study has shown that continuing tamoxifen to year 10 rather than just to year 5 produces further reductions in breast cancer recurrence and may help reduce breast cancer mortality in women with ER-positive or ER-untested early breast cancer.
References: 1. Zardavas D, Cameron D, Krop I, et al. Beyond trastuzumab and lapatinib: new options for HER2-positive breast cancer. ASCO Educ Book 2013:2â€“11. 2. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 2012;367:1783â€“91.
Carolyn Owen, MD
Dr. Carolyn Owen completed postgraduate training in internal medicine and hematology at the University of Ottawa and the University of British Columbia, respectively, followed by a research fellowship in molecular genetics at Barts and the London School of Medicine and Dentistry in London, UK. Her research focused on familial myelodysplasia and acute myeloid leukemia. She is currently an Assistant Professor at the Foothills Medical Centre & Tom Baker Cancer Centre, and her clinical interests are low-grade lymphoma and chronic lymphocytic leukemia. She is also the local principal investigator in Calgary for several clinical trials in these areas.
Laurie H. Sehn, MD, MPH
Dr. Laurie H. Sehn is a Clinical Assistant Professor at the BC Cancer Agency and the University of British Columbia in Vancouver. She has been a medical oncologist and clinical investigator with the Lymphoma Tumour Group since 1998. Dr. Sehn has served on the Board of Directors of Lymphoma Foundation Canada (LFC) since 2002 and is currently Director of Research Fellowships for the LFC. Dr. Sehn’s research interests include all of the lymphoid cancers, with particular interest in the biology and treatment of large-cell lymphoma, the application of new imaging techniques such as PET scanning to lymphoma management, and innovative new approaches to treatment.
Matthew Seftel, MBChB, MPH, MRCP(U.K.), FRCPC
Dr. Seftel is a hematologist/oncologist based at Princess Margaret Hospital in Toronto. He is a member of the Leukemia Group and leads the Allogeneic Blood and Marrow Transplantation Program. He is an Associate Professor at the University of Toronto in the Division of Internal Medicine. He is actively involved in clinical trials and outcomes-based research related to hematological malignancies and blood and marrow transplantation.
Sunil Verma, MD, MSEd, FRCPC
Dr. Sunil Verma is a medical oncologist and the Chair of Breast Medical Oncology at the Sunnybrook Odette Cancer Centre in Toronto, Ontario. He is also an Associate Professor at the University of Toronto. Dr. Verma completed his medical degree and postgraduate training in internal medicine and medical oncology at the University of Alberta. He completed a fellowship in breast cancer at the University of Toronto and a master’s degree in medical education at the University of Southern California. Dr. Verma is internationally recognized for his educational leadership and research in breast and lung cancers. He has led and created numerous innovative educational projects in oncology and won several teaching and mentoring awards. Dr. Verma’s research interests include reducing the toxicity of systemic treatment, developing novel therapies for breast and lung cancers, and medical education. He is the principal investigator for many clinical trials in breast and lung cancers, including an international phase III trial in breast cancer, and has authored or co-authored articles appearing in publications such as the Journal of Clinical Oncology, Cancer, The Oncologist, Lancet Oncology, Lancet, and The New England Journal of Medicine.