Targeted Therapy in the Management of Advanced Gastric Cancer: Are We Making Progress in the Era of Personalized Medicine?

Background. Gastric cancer is one of the leading causes of cancer death. With greater understanding of the molecular basis of carcinogenesis, targeted agents have led to a modest improvement in the outcome of advanced gastric cancer (AGC) patients. Methods and Results. We conducted an overview of the published evidence regarding the use of targeted therapy in AGC patients. Thus far, the human epidermal growth factor receptor (HER) pathway, angiogenic pathway, and phosphatidylinositol-3-kinase (PI3K)–Akt–mammalian target of rapamycin pathway have emerged as potential avenues for targeted therapy in AGC patients. The promising efficacy results of the Trastuzumab for Gastric Cancer trial led to the approved use of trastuzumab-based therapy as first-line treatment for patients with HER-2 AGC. On the other hand, the Avastin in Gastric Cancer trial evaluating bevacizumab in combination with chemotherapy did not meet its primary endpoint of a longer overall survival duration despite a significantly higher response rate and longer progression-free survival time in patients in the bevacizumab arm. Phase III data are awaited for other targeted agents, including cetuximab, panitumumab, lapatinib, and everolimus. Conclusion. Recent progress in targeted therapy development for AGC has been modest. Further improvement Correspondence: Thomas Yau, M.B. B.S., FHKCP (Med Onc), FHKAM, Room 405, Professorial Block, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong. Telephone: 852-2855-3111; Fax: 852-2816-2863; e-mail: the@netvigator.com Received September 12, 2011; accepted for publication December 19, 2011; first published online in The Oncologist Express on February 14, 2012. ©AlphaMed Press 1083-7159/2012/$20.00/0 http://dx.doi. org/10.1634/theoncologist.2011-0311 The Oncologist® Gastrointestinal Cancer The Oncologist 2012;17:346–358 www.TheOncologist. com in the outcome of AGC patients will depend on the identification of biomarkers in different patient populations to facilitate the understanding of gastric carcinogenesis, combining different targeted agents with chemotherapy, and unraveling new molecular targets for therapeutic intervention. The Oncologist 2012;17:346–358 INTRODUCTION Gastric cancer is one of the leading causes of cancer death [1]; although its global incidence is declining, it remains highly prevalent in Asian countries [2]. Conventional treatment modalities, including surgery, radiotherapy, and chemotherapy, play a role mainly in patients with early disease, for whom adjuvant chemotherapy and chemoirradiation have led to 20%– 35% longer overall survival (OS) times [3, 4]. These modalities, however, have modest efficacy in treating patients with advanced gastric cancer (AGC), conferring a median survival time in the range of 6 –11 months, with considerable treatment-related toxicities [5]. Despite the better response rates (RRs) and tolerability with various new-generation combination regimens using capecitabine, oxaliplatin, S1, docetaxel, and irinotecan [6–9], the OS outcome of AGC patients remains dismal. With the greater understanding of the biology and underlying molecular basis of carcinogenesis, several targeted agents have led to better outcomes for advanced lung, colon, breast, and kidney cancer patients, leading to their approval and widespread use for these entities. In this respect, the development of targeted agents for AGC is apparently making rather slow progress. Unlike other solid tumors, which are predominantly addicted to a particular signaling pathway, such as human epidermal growth factor receptor (HER)-2 breast cancer, the molecular and genetic pathogenesis of gastric cancer may be more complex [10, 11]. Many pathways may play key roles in gastric tumor carcinogenesis whereas the predominant driving pathway is difficult to delineate. Nevertheless, the release of the promising efficacy results of the Trastuzumab for Gastric Cancer (ToGA) trial [12, 13] marked the beginning of a new era. This pivotal trial led to the approval of trastuzumab as the first targeted agent in the firstline treatment of patients with HER-2 AGC. In addition, other signaling pathways have also emerged as potential avenues for future therapeutic interventions. In this review, we outline the underlying molecular basis and summarize the current clinical evidence and ongoing trials supporting the use of targeted agents in the treatment of patients with AGC. We also explore future perspectives, including predictive biomarkers and novel signaling pathways, that may potentially be exploited as strategic targets of treatment. THE HER FAMILY The HER family consists of four members: HER-1 (epidermal growth factor receptor [EGFR]), HER-2, HER-3, and HER-4. HER-1, HER-3, and HER-4 are all activated by ligand binding, whereas HER-2 does not require a ligand for activation. Activation of these receptors leads to homoor heterodimerization that in turn initiates phosphorylation cascades and subsequent activation of the phosphatidylinositol-3-kinase (PI3K)–Akt–mammalian target of rapamycin (mTOR) and Ras–Raf–mitogenactivated protein kinase/extracellular signal–related kinase (ERK) kinase (MEK)–ERK pathways, which are important in cancer cell proliferation and survival [14, 15] (Fig. 1).