GIST: advances in tyrosine kinase inhibitors enhance laparoscopic resection even in advanced disease

Abstract

Gastrointestinal stromal tumors (GIST) represent a model for targeted cancer therapy and also a prime paradigm of how laparoscopic GIST surgical resection and adjuvant treatment with tyrosine kinase inhibitors (TKIs) can result in excellent short-term and long-term outcomes of these patients. The relatively simple concept of GIST development and progress by activating mutations in only two genes, either the KIT or platelet-derived growth factor A (PDGFRA) gene, and the high pathological and clinical response to tyrosine kinase inhibitors (TKIs) [1]. By contrast, multiple genes are involved in highly complex biological processes underlying tumorigenesis and metastasis for major cancer types [2]. The potential for long-term survival or even cure of GIST patients with resectable tumors treated with surgery and adjuvant targeted treatment raises the question for improving quality-of-life (QOL) of these patients through laparoscopic surgery. This question of feasibility, safety, and efficacy of laparoscopic surgery for GIST treatment is highlighted by De Vogelaere et al. [3] in the August issue of Surgical Endoscopy. The authors report on 31 consecutive patients presenting with a primary gastric GIST without metastases. The most common symptoms were melena, anemia, and abdominal pain, and in one patient a laparoscopic approach for a GIST with acute bleeding was performed. In all 31 patients, a successful laparoscopic resection was performed. Most patients (n = 26) had a tumor larger than 2 cm in size. The duration of operation (60 vs. 103 min) and duration of hospital stay (6 vs. 8 days) were lower when tumor size was less than 2 cm compared with larger tumors. Postoperative hemorrhage was occurred in only one patient. After a median follow-up of 52 months, there were no recurrences or metastases. The authors conclude that laparoscopic resection is safe and effective in treating gastric GISTs, even for tumors larger than 2 cm. Given that GIST is uncommon, this is a large series with excellent short-term and oncological outcomes associated with laparoscopic surgical resection. The size of the tumor appears to have a modest impact in clinical treatment and outcomes, although the small number of patients (n = 5) with tumors less than 2 cm in size in this study does not allow for valid comparisons. Laparoscopic and robotic surgery for tumors located at different sites of gastrointestinal tract has evolved rapidly and become popular for the surgical treatment of resectable colon rectal and gastric cancer improving QOL of these patients [4–11]. The high responsiveness of GIST to small-molecules selective TKIs, such as imatinib [1], raises the question of laparoscopic surgery also in the treatment of locally advanced or metastatic GIST. In addition, advances in biomedical research exploring the molecular mechanisms responsible for imatinib resistance have led to the development of second generation inhibitors of mutated KIT/ PDGFRA tyrosine kinase, such as nilotinib [12]. The power of whole-exome sequencing (WES) to identify not only primary causal (driver) mutations in KIT and PDGFRA genes but also acquired (secondary) mutations in these genes involved in resistance to TKI reveals a new class of biomarkers to predict responsiveness or resistance for tailoring the best drug to individual patient with GIST. Taking lessons from this simplified two-gene model of GIST, we may improve the design of future cancer genome-based studies to evaluate much more complex molecular mechanisms of resistance to targeted drugs for common cancer types, such as colorectal cancer, C. Hottenrott (&) Chirurgische Klinik, St. Elisabethenkrankenhaus, Ginnheimer Strase 3, 60487 Frankfurt, Germany e-mail: info@gastricbreastcancer.com