Unravelling the pharmacologic opportunities and future directions for targeted therapies in gastro-intestinal cancers part 2: Neuroendocrine tumours, hepatocellular carcinoma, and gastro-intestinal stromal tumours☆
Introduction
Until the 1990s, cytotoxic chemotherapy has been the cornerstone of medical therapy for gastrointestinal (GI) cancers. Better understanding of the molecular biology of cancer cell has led to the therapeutic revolution of targeted therapies, i.e. monoclonal antibodies (mAb) or small molecule inhibitors (multikinase inhibitors [MKI]) directed against proteins that are specifically either overexpressed or mutated in cancer cells. These drugs were expected to be more specific to cancer cells and less toxic than conventional cytotoxic agents. However, their anticipated effects have sometimes been disappointing, due to either intrinsic or acquired resistance mechanisms, or to an activity restricted to some tumour settings or molecular subgroups (Holohan, Van Schaeybroeck, Longley, & Johnston, 2013). The identification of predictive biomarkers of response to these therapies, through deeper knowledge of GI tumour biology and phenotypic and molecular subtypes, has therefore become a major issue.
In this context, it appears crucial to gather updated clinical and translational data in a comprehensive review encompassing the lessons learned from the past as well as the yet unanswered questions regarding targeted therapies across the different GI cancer types. We propose a comprehensive two-part review providing a panoramic and chronological approach of the successes and failures of targeted agents that have reached phase III trials in GI cancers, to unravel the pharmacologic opportunities and future directions for these therapies in GI oncology. In the first part, we focused on adenocarcinomas and squamous cell carcinomas, for which targeted therapies are mostly used in combination with chemotherapy. We summarised the trajectories of targeted therapy development across these GI cancer types and highlighted how the clinical development of antiangiogenics, anti-EGFR, anti-HER2 agents, or, more recently, immune therapy, have followed strikingly different paths in terms of biological hypothesis, companion biomarkers, and refinement of their respective spectrum of sensitive tumours. In this second part, we focus on neuroendocrine tumours (NET), hepatocellular carcinoma (HCC), and gastrointestinal stromal tumours (GIST), whose treatment relies primarily on targeted therapies. For these selected GI tumours that were characterized by their poor sensitivity to chemotherapy, the advent of targeted therapies has been a complete shift of paradigm. These agents demonstrated their efficacy and offered a new therapeutic base for the management of these tumours. Hence, somatostatin receptor (SSTR)-directed strategies, sorafenib, and imatinib have revolutioned the management of NET, HCC, and GIST, respectively, and many patients affected by these tumours are now treated in first intent by targeted therapies only. However, these agents have to face problems of resistances and identification of predictive biomarkers from imaging and/or biology.
Section snippets
Epidemiology and therapeutic landscape
Digestive NET are a heterogeneous group of neoplasms arising from neuroendocrine cells that are organised as endocrine glands such as pancreas or scattered throughout the digestive tract. These rare tumours account for 1% of all digestive malignancies; nevertheless, NET are one of the most prevalent GI neoplasms after colorectal cancer, since they are usually slowly growing and associated with prolonged patient survival (Frilling et al., 2012, Frilling et al., 2014, Yao et al., 2008). The most
Epidemiology and therapeutic landscape
Hepatocellular carcinoma (HCC) represents > 90% of primary liver cancers and is a major health problem. It is the sixth most frequent cancer (780,000 new cases/year, > 80% in developing countries) and the second leading cause of cancer deaths (750,000 deaths/year) worldwide (Torre et al., 2015). In 90% of cases, HCC develops on underlying chronic liver disease (cirrhosis or chronic hepatitis), which can be caused by chronic hepatitis B (HBV) or C (HCV) virus infection, alcohol, inherited
Epidemiology and therapeutic landscape
GIST are mesenchymal tumours derived from Cajal cells or one of their precursors, developing in the majority of cases in the stomach (60%) and small bowel (20–30%), and more rarely in the rectum, colon, and esophagus, or mesentery, omentum, and retroperitoneum (extra-gastrointestinal GIST) (Emile et al., 2012, Miettinen and Lasota, 2006, Nishida et al., 2016). Although they are the most frequent mesenchymal tumours of the GI tract, they are yet relatively uncommon, with an estimated incidence
Disclosure/conflict of interest
CN: Celgene, Shire; LdM: Ipsen, Novartis, Pfizer; BR: Gilead, Novartis, Bayer; OM: Amgen, Astra-Zeneca, Bayer, Blueprint, Bristol-Myers-Squibb, Eli-Lilly, Lundbeck, Novartis, Roche, Pfizer, Servier; HK: Celgene, Baxalta; PR: Novartis, Ipsen, AAA, Pfizer; CT: Roche, Bayer, Amgen, Merck, Eli-Lilly.
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Associate editor: B. Teicher