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Gastric cancer

Robotic Gastrectomy vs Laparoscopic Gastrectomy for Gastric Cancer: Results of RCT

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Author(s)：
Toshiyasu Ojima1, Keiji Hayata1, Masahiro Katsuda1, Junya Kitadani1, Akihiro Takeuchi1, Masaki Ohi2,
Takeshi Yokoe2, Masato Kusunoki2, Masaki Nakamura1, Mikihito Nakamori1, Hiroki Yamaue1
Affiliation(s)：
1Second Department of Surgery, Wakayama Medical University, 2Department of Gastrointestinal and Pediatric Surgery, Mie University

Background: Robotic gastrectomy (RG) procedure for gastric cancer (GC) patients may be associated with decreased incidence of intra-abdominal infectious complications. Prospective randomized controlled trials (RCTs) comparing laparoscopic gastrectomy (LG) and RG are required, however. We completed an RCT to compare short-term surgical outcomes of LG and RG for GC patients. Methods: This was a randomized, two-center clinical trial. All included patients are adults with primary carcinoma of the stomach, in whom the tumor is considered surgically resectable (cStage I-III). Included in this trial were 240 patients with GC. The primary endpoint was to assess the incidence of postoperative intra-abdominal infectious complications including pancreatic fistula, intra-abdominal abscess, and anastomotic leakage. Secondary endpoints included incidence of postoperative complications, surgical results, postoperative course, and oncological outcomes. Lymphadenectomy without touching the pancreas was basically performed during robotic gastrectomy using assisting articulating forceps (Video). Results: A total of 241 patients were randomly assigned to the LG group (n = 122) or the RG group (n = 119), and 236 patients (LG119 RG117) were analyzed for ITT population. Overall incidence of intra-opereative infectious complications higher than Clavien-Dindo grade II were not significantly different (LG 8.4%, RG 6%). However, overall incidence of any complications higher than grade II were significantly lower in the RG group (19.3 vs 8.5% P = .019). In RG group, postoperative pancreatic fistula was not found. Amylase levels in drainage fluid on POD 1 were significantly lower in the RG group (893IU/L) than in the LG group (438 IU/L) (P = 0.039). Discussion: Regarding short-term surgical outcomes, RG is feasible, safe and ideal treatment procedure for GC. Our RG procedure without touching the pancreas may be associated with decreased incidence of postoperative pancreatic fistula.

Genomic alteration detection using circulating tumor DNA (ctDNA) in Japanese patients with treatment-naïve gastric cancer: GOZILA Study

Author(s)：
Hideaki Bando1, Yoshiaki Nakamura1, Takanobu Yamada2, Toshiki Masuishi3, Takeshi Kawakami4, Takashi Ohta5,
Hiroyuki Takeda6, Keiko Minashi7, Kazuhiro Yoshida8, Yoshito Komatsu9, Satoru Iwasa10, Masahiro Goto11, Yoshinori Kagawa12, Masato Yonezawa13, Yakayuki Yoshino1
Affiliation(s)：
1Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 2Department of Gastrointestinal Surgery, Kanagawa Cancer Center,3Department of Clinical Oncology, Aichi Cancer Center,4Division of Gastrointestinal Oncology, Shizuoka Cancer Center,5Department of Clinical Oncology, Kansai Rosai Hospital,6Department of Clinical Oncology, St.Marianna University,7Clinical Trial Promotion Department, Chiba Cancer Center,8Department of Surgical Oncology, Gifu University,9Department of Cancer chemotherapy, Hospital, Hokkaido University,10Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital,11Cancer Chemotherapy Center, Osaka Medical and Pharmaceutical University Hospital,12Department of Gastroenterological surgery, Osaka General Medical Center

Background: Circulating tumor DNA (ctDNA) is an emerging method for detecting genetic alterations in advanced stage cancers. The characteristics of ctDNA genomic alterations of untreated gastric cancer has not been fully elucidated.
Methods: Patients (pts) with unresectable advanced or recurrent gastrointestinal cancers were eligible for GOZILA (UMIN000029315), a nationwide screening study. Blood samples were analyzed by comprehensive next generation sequencing using a 74-gene ctDNA assay (Guardant360). Test results from pts with treatment-naïve gastric adenocarcinoma were reviewed.
Results: From Oct 28, 2018 to Jan 16, 2020, blood samples from 119 treatment-naïve gastric cancer pts (89 male, 30 female) were collected. Sequencing success rate was 100% and 104 (87%) had ctDNA detected. The median turnaround-time of ctDNA analysis was 9 days (range, 5-27 days). Frequently mutated genes included TP53 (55%), PIK3CA (13%), ARID1A (12%), KRAS (8%, G12C [0%]), APC (7%), and BRAF (3%, V600E [1%]). Synonymous alterations and variants of uncertain significance were excluded. Commonly amplified genes included CCNE1 (24%), EGFR (18%), HER2 (10%), FGFR2 (8%), and MET (5%). NTRK1 fusion was detected in one pt and MSI-High in four (3%) pts.
Conclusions: Comprehensive ctDNA analysis identified clinically relevant genomic alterations in Japanese pts with treatment-naïve advanced gastric cancer. With its ease and non-invasiveness to pts, ctDNA analysis has the potential to guide treatment decisions in advanced gastric cancer.

Phenotypic analysis of intraperitoneal lymphocytes and macrophages in patients with peritoneal metastasis from gastric cancer

Author(s)：
Kazuya Takahashi1, Hideyuki Ohzawa2, Rihito Kanamaru1, Kentaro Kurashina1, Shin Saito1, Hironori Yamaguchi1,
Yoshinori Hosoya1, Naohiro Sata1, Kitayama Joji1,3
Affiliation(s)：
1Department of Surgery, Hospital, Jichi Medical University, 2Department of Clinical Oncology, Hospital, Jichi Medical University,3Center for Clinical Research, Hospital, Jichi Medical University

Background: Peritoneal metastases (PM) is a common type of recurrence in patients with gastric cancer (GC). Peritoneal cavity contains many lymphocytes and macrophages (MΦ) with various phenotypes. However, it is unknown how the composition of these immune cells is altered in PM.
Methods: A total of 75 single cell suspensions derived from ascites or peritoneal lavages from patients with GC were immmunostained with monoclonal antibodies to CD45, CD326, CD11b, CD14, CD16, CD163, CD8, CD4 together with DAPI and FVS780. The ratios of each cell type were examined in DAPI(+)FVS780(-) CD45(+) live leukocytes using flow cytometry.
Results: (1) The ratios of CD8(+) T cells of patients with PM were Median (M)=17.5% (4.55-46.6%), which was significantly lower than those without PM (M=26.9%, 11.9-67.4%, p=0.0016).
(2) A few CD11b(+) CD14(+) MΦ positively expressed CD16 in all patients. However, the ratios of CD16(+) CD14(+) MΦs in PM (+) patients were M=10.2% (0.21-42.2%) which were markedly increased as compared with PM(-) patients (M=0.56%, 0.13-5.0%, p=0.0024).
(3) In flowcytometric profile, CD16(+) MΦs showed significantly higher forward (FSC) and side (SCC) scatters than CD16(-) MΦs, suggesting the cells contain rich granules with larger size. The expression levels of CD14 were significantly higher in CD16(+) than CD16(-) MΦs (mean fluorescein intensities: M=3332, 1133-16586 vs M=1666, 601-6790, p<0.0001). Moreover, CD163 was positively expressed in most of the CD16(+) MΦs (M=92.4%, 50-100%), while only in a part of CD16 (-) MΦs (M=29.9%, 4.6-76.7%, p=0.0016).
(4) In patients with PM, the ratios of CD4(+) and CD8(+) T cells showed inversed correlation with those of CD14(+) CD16(+) MΦs.
Conclusion:CD16(+) CD163(+) large granular MΦs abundantly exist in peritoneal cavity of the patients with PM, which may have suppressive role on T cell-mediated immunity and assist the development of PM.

CD44-expressing cancer stem cells target therapy to prevent peritoneal recurrence after curative gastric
cancer surgery

Author(s)：
Satoshi Murata1,2, Andreas M Sihombing2, Miyuki Shimoji2, Katsushi Takebayashi2, Hirokazu Kodama2, Sachiko Kaida2,
Tsuyoshi Yamaguchi2, Toru Miyake2, Masatsugu Kojima2, Tomoyuki Ueki2, Aya Tokuda1,2, Hiromitsu Maehira2, Hiroya Iida2, Tomoharu Shimizu2,3, Masaji Tani2
Affiliation(s)：
1Cancer Center, Faculty of Medicine, Shiga University of Medical Science, 2Department of Surgery, Faculty of Medicine, Shiga University of Medical Science,3Medical Safety Section, Faculty of Medicine, Shiga University of Medical Science

Background: In gastric cancer (GC), CD44 is a putative marker for cancer stem cells (CSCs), which have an important role in tumor invasion and metastasis. We have previously shown that cancer cells spilled into the peritoneal cavity during curative GC surgery are associated with peritoneal metastasis (PM). Here, we investigated whether CD44-expressing CSCs and surgical procedures affect PM and whether CD44-targeting therapy contributes to preventing PM.
Methods: Human GC cell lines, MKN-45 (por) or KE-97 (originated from PM), were sorted into CD44-positive (+) and CD44-negative (-) cells and injected intraperitoneally (ip) into NOD/SCID mice. The effect of surgical manipulation on tumorigenicity in visceral peritoneum (omentum or mesentery) was assessed using the application of a cotton swab on the parietal peritoneum of nude mice. Before ip injection, CD44 (+) and CD44 (-) cancer cells were treated with either IM7 CD44-neutralizing antibody or rat IgG and then injected ip into NOD/SCID mice to investigate an anti-tumorigenicity effect. The tumorigenic effect was statistically assessed using In Vivo Limiting Dilution Assay.
Results: CD44 (+) cancer cells were significantly more tumorigenic on the visceral peritoneum than CD44 (-) cells (P = 0.026). Notably, tumors established by CD44 (+) cells showed CD44 expression, while the tumors originating from CD44 (+) cells contained CD44 (-) cells. Surgical manipulation of the parietal peritoneum doubled the visceral PM of CD44 (-) cells. On the other hand, the visceral PM of CD44 (+) cells was observed at a high rate (83.3%) regardless of surgical manipulation. Treatment with anti-CD44-neutralizing antibody targeting CD44 (+) cells significantly lowered the frequency of the visceral PM.
Conclusions: Intraperitoneal CD44 (+) CSCs and surgical manipulation of peritoneum suggest a cause of PM after GC surgery. Anti-CD44-targeting therapy may be a promising strategy for preventing PM just after curative GC surgery.

Trastuzumab deruxtecan in patients with HER2-positive advanced gastric or gastroesophageal junction adenocarcinoma: Final overall survival results from phase 2 study (DESTINY-Gastric01)

Author(s)：
Kensei Yamaguchi1, Yung-Jue Bang2, Satoru Iwasa3, Naotoshi Sugimoto4, Min-Hee Ryu5, Daisuke Sakai6, Hyun Cheol Chung7, Hisato Kawakami8, Hiroshi Yabusaki9, Jeeyun Lee10, Takahiro Kamio11, Akihito Kojima11, Masahiro Sugihara11, Kohei Shitara12
Affiliation(s)：
1Department of Gastroenterological Chemotherapy, The Cancer Institute Hospital, 2Seoul National University Hospital, Seoul, South Korea,3National Cancer Center Hospital,4Osaka International Cancer Institute,5Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea,6Hospital, Osaka University,7Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea,8Faculty of Medicine Hospital, Kindai University,9Niigata Cancer Center Hospital,10Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea,11Daiichi Sankyo, Co., Ltd., Tokyo, Japan,12National Cancer Center Hospital East

Background: DESTINY-Gastric01 (NCT03329690) is an open-label, multicenter, randomized, Ph2 trial of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2+ advanced gastric cancer (GC) or gastroesophageal junction (GEJ) adenocarcinoma. In the primary analysis (101 OS events; median survival follow-up: 12.3 mo), T-DXd showed statistically significant benefit vs chemotherapy in objective response rate (ORR) and overall survival (OS); here, we present the final OS analysis as well as updated efficacy and safety.
Methods: Pts with locally advanced or metastatic, centrally confirmed HER2+ (IHC3+ or IHC2+/ISH+ on archival tissue) GC or GEJ adenocarcinoma that had progressed after ≧2 previous lines of therapy including trastuzumab were randomized 2:1 (T-DXd 6.4 mg/kg Q3W or physician's choice [PC] irinotecan or paclitaxel). Primary end point was ORR by independent central review. Secondary end points were OS (key secondary), duration of response (DOR), progression-free survival (PFS), disease control rate (DCR), confirmed ORR, and safety. Final OS analysis was performed at 133 OS events.
Results: 187 pts received T-DXd (n = 125) or PC (n = 62). At data cutoff (June 3, 2020), 8% of T-DXd and 0% of PC pts remained on treatment (median survival follow-up, 18.5 mo). OS was improved with T-DXd vs PC (median OS, 12.5 vs 8.9 mo; HR 0.60 [95% CI, 0.42-0.86]); 12-month OS, 52.2% vs 29.7%. ORR was 51.3% with T-DXd vs 14.3% with PC; confirmed ORR, 42.0% vs 12.5%; DCR, 86.6% vs 62.5%; confirmed median DOR, 12.5 vs 3.9 mo; median PFS, 5.6 vs 3.5 mo. Grade ≧3 AEs occurred in 85.6% of T-DXd pts vs 56.5% with PC (details will be presented). 16 pts (12.8%) had T-DXd-related ILD (13 grade 1/2, 2 grade 3, 1 grade 4, no grade 5) vs 0 with PC.
Conclusions: With additional follow-up, T-DXd continued to demonstrate OS benefit and clinically relevant improvement in ORR compared with standard chemotherapy, and a manageable safety profile, in HER2-positive advanced GC or GEJ adenocarcinoma.

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