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Breast Cancer Chemotherapy Options for Metastatic HER2-Negative Breast Cancer after Prior Exposure to Anthracyclines and Taxanes Minetta C Liu, MD Associate Professor, Breast Cancer Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center Abstract Metastatic breast cancer (MBC) remains incurable despite the many advances in cancer treatment. While anthracycline- and/or taxane-based regimens are the preferred first-line chemotherapies for MBC, many patients develop disease that is either resistant or becomes refractory to these agents. Currently, there is no single standard of care for women who experience disease progression after treatment with anthracyclines and taxanes. A number of chemotherapeutics have been evaluated as single agents and as part of combination regimens, with varying results. The US Food and Drug Administration has approved capecitabine, ixabepilone, and eribulin as single agents for third-line therapy and beyond. Combination regimens such as capecitabine plus ixabepilone or gemcitabine plus carboplatin are also available for pre-treated MBC patients. The present article will review the options available to MBC patients following prior treatment with anthracyclines and taxanes. Keywords Metastatic breast cancer, pre-treated disease, human epidermal growth factor receptor-2 (HER2)-negative, combination regimen, capecitabine, gemcitabine, vinorelbine, eribulin, ixabepilone Disclosure: Minetta C Liu, MD, has received a consultant fee for an advisory board role from Agendia, BiPAR/Sanofi Aventis, Genetech/Roche, Myriad Genetic Laboratories, and Veridex, LLC; speakers honoraria from GlaxoSmithKline and Veridex, LLC; an honorarium for a visiting professor role from Medimmune; and research funding, as principal investigator, from Bristol-Myers Squibb, Genentech/Roche, Geron, GlaxoSmithKline, Novartis, and Veridex, LLC. Dr Liu does not receive any direct salary or royalties from, nor does she own any directly purchased stock in, any corporate organization. Acknowledgment: Editorial assistance was provided by Angela Chan at Touch Briefings and funded by Eisai. Received: April 11, 2012 Accepted: May 2, 2012 Citation: Oncology & Hematology Review, 2012;8(1):21–5 Correspondence: Minetta C Liu, MD, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007-2198. E: liumc@georgetown.edu Support: The publication of this article was funded by Eisai. The views and opinions expressed are those of the author and not necessarily those of Eisai. Breast cancer is the most commonly diagnosed malignancy and the second leading cause of cancer-related mortality among women in the US. 1,2 Improvements in the treatment of early-stage disease have led to a decline in the incidence of metastatic breast cancer (MBC). 3 Nonetheless, 20–85 % of women diagnosed with early-stage breast cancer develop recurrent and/or metastatic disease, and an estimated 10  % of patients present with metastatic disease at the time of their initial diagnosis. 4 The prognosis for these patients is relatively poor, with a median survival of approximately two years 4 and an estimated five-year survival rate of 23 %. 2 Anthracycline- and/or taxane-based regimens remain the preferred first-line chemotherapy treatments for MBC, 3 but many patients develop disease that either does not respond or becomes refractory to these agents. With the increasing use of anthracyclines (e.g., doxorubicin, epirubicin) and/or taxanes (e.g., paclitaxel, docetaxel) as adjuvant therapy, a higher proportion of treatment-resistant or treatment-refractory patients is observed in the metastatic setting. 5,6 Despite the number of available treatment options for MBC © TOUCH BRIEFINGS 2012 (see Tables 1 7 and 2 7–10 ), there remains no single standard of care for this group of patients. Various monotherapy and combination regimens have been evaluated as candidate therapies for MBC patients who experience disease progression after treatment with anthracyclines and taxanes (A/T). At present, capecitabine, ixabepilone, and eribulin are the only cytotoxics approved by the US Food and Drug Administration (FDA) as single agents in the third-line setting and beyond. Prior to the approval of eribulin in 2010, no single agent was associated with a statistically significant improvement in overall survival (OS) in this patient population. In terms of combination therapy for human epidermal growth factor receptor-2 (HER2)-negative MBC, the FDA, based on Phase III clinical trials demonstrating benefits in progression-free survival (PFS), time to progression (TTP), objective response rates (ORR), and in some cases OS, approved the following regimens: capecitabine plus docetaxel, capecitabine plus ixabepilone, and gemcitabine plus paclitaxel. 11 The superiority of combination chemotherapy over single-agent sequential therapy is debatable, however, in the absence of 21