Laparoscopic resections and ENCODE-guided genomics to advance surgery and oncology

Abstract

Recent evidence in western countries has confirmed the improvement in survival of open gastrectomy with D2 lymphadenectomy for resectable gastric cancer [1], which has been the standard approach over decades in Japan [2]. Laparoscopic or robotic surgery can improve short-term outcome and quality of life [3], but is laparoscopic D2 gastrectomy safe and effective when performed outside of elite surgeons and hospitals? Targeting gastric adenocarcinoma with human epidermal growth factor 2 (HER2) gene amplification with trastuzumab prolongs survival, but most patients with advanced disease develop recurrence as a consequence of therapeutic resistance and die from the disease. Mutational landscape heterogeneity [4] and highly complex transcriptional regulatory network diversity drive gene expression. This new evidence from sequencing studies and the ENCODE project now shape a much more complex and sophisticated research concept [5]. These latest advances raise for the first time rational hope for the next generation of biomarkers and drugs to improve cancer cure rates. But can enormous challenges be overcome? Using the propensity score matching method, Zhao et al. [6] reported in the August 2013 issue of Surgical Endoscopy the comparative results of D2 gastrectomy between laparoscopic (133 patients) and open (133) distal gastrectomy. There was no significant difference in the number of resected and examined lymph nodes and the postoperative short-term and long-term morbidity and mortality between the two groups. It appears that the only disadvantage of laparoscopic gastrectomy is the longer operating time. However, this report comes from a highly specialized institution with high-volume surgeons and skill in laparoscopic D2 gastrectomy. Laparoscopic D2 lymphadenectomy and laparoscopic total gastrectomy are highly demanding operations and the lack of data from nonspecialized institutions is cause for concern about the safety and efficacy of this approach by low-volume surgeons for whom such an approach cannot be recommended. In contrast to the wide clinical use of minimally invasive surgery such as laparoscopic or robotic resection for other common tumors, e.g., colorectal cancer [7–9], safe and effective laparoscopic D2 gastrectomy for advanced gastric cancer still remains an experimental approach outside of highvolume hospitals [10–13]. Progress in the successful treatment of patients with advanced gastric cancer is very slow. Genomic structural and functional heterogeneity and the complexity of the cancer genome explain the high rate of treatment resistance and the low survival rate for patients with advanced solid tumors, including gastric cancer [4]. Based on this genomic complexity with multiple and still unrecognized genomic subtypes, the disappointing results from current randomized trials using single-gene targeting drugs are not surprising. Trastuzumab for HER2-positive gastric cancer significantly prolongs survival but long-term mortality rates are high among patients with HER2-negative (80 % of all patients) or even HER2-positive disease [14]. Trastuzumab emtansine conjugate is improved treatment for breast cancer and can be similarly effective in HER2overexpressing gastric tumors, but we are still far from achieving high cure rates. We are now shifting from the ‘‘central dogma’’ of the single-gene/protein-phenotype (trait/disease) relationship established by Crick a half century ago to systems biology and genomic medicine. All currently available diagnostics and drugs have been developed based on this reductionist C. Hottenrott (&) Chirurgische Klinik, St. Elisabethenkrankenhaus, Ginnheimer Strase 3, 60487 Frankfurt, Germany e-mail: info@gastricbreastcancer.com