Katsutoshi Shoda1,2, Kiyoshi Masuda2, Daisuke Ichikawa3, Tomohiro Arita1, Yuko Miyakami4, Miki Watanabe4, Hirotaka Konishi1, Issei Imoto5, Eigo Otsuji1. 1. Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramach Hirokoji Kajiicho, Kamigyo-ku, Kyoto, 602-8566, Japan. 2. Department of Human Genetics, Institute of Health Biosciences, University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan. 3. Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramach Hirokoji Kajiicho, Kamigyo-ku, Kyoto, 602-8566, Japan. ichikawa@koto.kpu-m.ac.jp. 4. Student Laboratory, Faculty of Medicine, University of Tokushima, Tokushima, Japan. 5. Department of Human Genetics, Institute of Health Biosciences, University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan. issehgen@tokushima-u.ac.jp.
Abstract
BACKGROUND: We used real-time quantitative polymerase chain reaction (rqPCR) to detect human epidermal growth factor receptor 2 (HER2) amplification in the circulating cell-free DNA (cfDNA) of patients with gastric cancer (GC), which shows the spatial and temporal intrinsic heterogeneity of HER2 expression/copy number during progression, for liquid biopsy and treatment monitoring. METHODS: We first enrolled 52 patients with advanced GC who underwent surgery and 40 healthy volunteers. For patients with GC, plasma cfDNA was obtained before surgery (43 patients) and during postoperative treatment (nine of 43 patients). After ribonuclease P RNA component H1 (RPPH1) had been selected as a reference gene for HER2 CN assessment by rqPCR in GC tumours and plasma, plasma HER2-to-RPPH1 ratios were determined retrospectively in a development cohort and an additional independent validation cohort. RESULTS: The HER2-to-RPPH1 ratio of GC tissues determined by rqPCR was concordant with routinely determined HER2 status. The plasma HER2-to-RPPH1 ratio was significantly higher for patients with HER2-positive tumours than for those with HER2-negative tumours. The sensitivity and specificity of the plasma HER2-to-RPPH1 ratio test were 0.539 and 0.967, respectively, in the development cohort, and 0.667 and 1.000, respectively, in the validation cohort. HER2 amplifications acquired and lost during tumour progression and treatment, respectively, were apparently detected by repeated assessments of plasma HER2-to-RPPH1 ratios during postoperative treatment. CONCLUSION: Our preliminary data demonstrated the potential clinical use of circulating cfDNA to detect HER2 amplification as a therapeutic marker to detect and monitor HER2 CN status for effective molecular targeted therapy in patients with GC.
BACKGROUND: We used real-time quantitative polymerase chain reaction (rqPCR) to detect humanepidermal growth factor receptor 2 (HER2) amplification in the circulating cell-free DNA (cfDNA) of patients with gastric cancer (GC), which shows the spatial and temporal intrinsic heterogeneity of HER2 expression/copy number during progression, for liquid biopsy and treatment monitoring. METHODS: We first enrolled 52 patients with advanced GC who underwent surgery and 40 healthy volunteers. For patients with GC, plasma cfDNA was obtained before surgery (43 patients) and during postoperative treatment (nine of 43 patients). After ribonuclease P RNA component H1 (RPPH1) had been selected as a reference gene for HER2 CN assessment by rqPCR in GC tumours and plasma, plasma HER2-to-RPPH1 ratios were determined retrospectively in a development cohort and an additional independent validation cohort. RESULTS: The HER2-to-RPPH1 ratio of GC tissues determined by rqPCR was concordant with routinely determined HER2 status. The plasma HER2-to-RPPH1 ratio was significantly higher for patients with HER2-positive tumours than for those with HER2-negative tumours. The sensitivity and specificity of the plasma HER2-to-RPPH1 ratio test were 0.539 and 0.967, respectively, in the development cohort, and 0.667 and 1.000, respectively, in the validation cohort. HER2 amplifications acquired and lost during tumour progression and treatment, respectively, were apparently detected by repeated assessments of plasma HER2-to-RPPH1 ratios during postoperative treatment. CONCLUSION: Our preliminary data demonstrated the potential clinical use of circulating cfDNA to detect HER2 amplification as a therapeutic marker to detect and monitor HER2 CN status for effective molecular targeted therapy in patients with GC.
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