Liquid biopsies are providing new opportunities for detection of residual disease in cell-free DNA (cfDNA) after surgery but may be confounded through identification of alterations arising from clonal hematopoiesis. Here, we identify circulating tumor-derived DNA (ctDNA) alterations through ultrasensitive targeted sequencing analyses of matched cfDNA and white blood cells from the same patient. We apply this approach to analyze samples from patients in the CRITICS trial, a phase III randomized controlled study of perioperative treatment in patients with operable gastric cancer. After filtering alterations from matched white blood cells, the presence of ctDNA predicts recurrence when analyzed within nine weeks after preoperative treatment and after surgery in patients eligible for multimodal treatment. These analyses provide a facile method for distinguishing ctDNA from other cfDNA alterations and highlight the utility of ctDNA as a predictive biomarker of patient outcome to perioperative cancer therapy and surgical resection in patients with gastric cancer.
Worldwide, gastric cancer is one of the leading causes of cancer-related death. The mainstay of curative treatment is radical surgery. But even with optimal surgical resection, the prognosis remains modest in the Western world. Numerous attempts have been undertaken to improve clinical outcome. More extensive lymph node dissection, adjuvant radiotherapy and adjuvant chemotherapy did not result in a survival benefit in randomized trials. Only postoperative chemoradiotherapy has proven to be valuable in prospective randomized trials. Questions are to be answered about optimization of surgery, radiotherapy and chemotherapy, and fine tuning of the three modalities. One of the key issues that should be addressed is whether pre- or postoperative chemoradiotherapy will benefit survival or locoregional control in the case of optimal surgery with an "over-D1" lymphadenectomy and without splenectomy. In this article the most relevant literature on locoregional treatment in operable gastric cancer will be reviewed and future strategies will be discussed.
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