Next-generation, genome- and mutational landscape heterogeneity-based novel biomarkers for personalized neoadjuvant treatment and laparoscopic rectal cancer resection

Abstract

Based on previous phase 3 randomized clinical trials suggesting patient’s benefits, preoperative chemoradiotherapy has become popular for selected patients with advanced (T3, T4 tumors or node-positive) rectal cancer. However, meta-analyses published this year reporting data from recent phase 3 trials raise concerns on the clinical utility of this neoadjuvant chemoradiotherapy [1, 2]. Preoperative tumor responsiveness to this treatment was approximately 40–50 %, and the overall resistance and complications rates balanced with the benefits. These latest clinical results reveal the urgent need of biomedical research for developing robust biomarkers for tailoring neoadjuvant treatment to sensitive tumors only and explain the recent focus of next-generation sequencing (NGS)-based biomarkers [3, 4]. Although ideally laparoscopic rectal surgery should follow neoadjuvant treatment in selected patients with predictable tumor responsiveness, it is important to obtain data evaluating the impact of this preoperative multimodal treatment in the safety and efficacy of subsequent laparoscopic surgery. Therefore, either using conventional or novel genome-based selection criteria this information is important for laparoscopic surgeons. This clinically crucial question is highlighted by Denost et al. [5] in the July issue of Surgical Endoscopy. Of 422 patients treated by laparoscopic rectal excision with sphincter preservation, 292 received preoperative radiotherapy, and 130 had primary surgery. There was no significant difference in mortality rate between radiotherapy group (0.3 %) and surgical group (0.8 %). No significant difference was observed with respect to the rates of conversion (19 vs. 15 %), overall morbidity (37 vs. 29 %), surgical morbidity (20 vs. 18 %), or anastomotic leakage (13 vs. 11 %). Preoperative radiotherapy had no impact on conversion or surgical morbidity. The authors conclude that long-course radiochemotherapy (45 Gy during 5 weeks) does not influence the feasibility or short-term outcome of laparoscopic sphincter-saving rectal excision for rectal cancer. This study by Denost et al. [5] is limited by its retrospective nature. But despite that that there were more advanced and lower tumors with lower anastomosis in the neoadjuvant group, there was no significant difference between the groups suggesting the safety of laparoscopic surgery after preoperative adjuvant chemoradiotherapy. Anastomotic leakage and morbidity rates reported in this study are within the ranges of current papers suggesting the task to reduce anastomotic leakage rate substantially lower than 10 %. Despite advances with minimally invasive surgery for gastrointestinal cancer [6–13], cancer biology still remains a scientific mystery explaining the failure of biomedical research to discover robust biomarkers to accurately predict responsiveness or resistance to currently used adjuvant multimodal treatment. Resistance is even today a major problem and despite initial enthusiasm with anti-EGFR antibodies, such as cetuximab or panitumumab, more recent well-designed and conducted phase 3 randomized clinical found no survival benefit for selected, wild-type KRAS metastatic, or adjuvant colorectal cancer [14, 15]. Patient-to-patient and intratumor heterogeneity has been confirmed by using NGS and represent a step forward to understand the complexity of cancer genome and the slow progress to discover robust biomarkers for driving a combination of drugs effective to individual responder patients. Indeed, whole-exome sequencing (WES), whole-genome C. Hottenrott (&) Chirurgische Klinik, St. Elisabethenkrankenhaus, Ginnheimer Strase 3, 60487 Frankfurt, Germany e-mail: info@gastricbreastcancer.com