Annals of Oncology
627P The nationwide cancer genome screening project in Japan, SCRUM-
Japan GI-SCREEN: Efficient identification of cancer genome alterations
in advanced esophageal cancer
K. Kato1, T. Kojima2, H. Saeki3, H. Hara4, T. Kajiwara5, S. Hironaka6, H. Nakatsumi7,
S. Kadowaki8, Y. Kagawa9, T. Esaki10, T. Moriwaki11, T. Kobayashi12, N. Izawa13,
S. Nomura14, T. Kuwata15, S. Fujii16, W. Okamoto17, K. Shitara18, A. Ohtsu18, T. Yoshino18
1
Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo,
Japan, 2Department of Gastroenterology and Gastrointestinal Oncology, National
Cancer Center Hospital East, Kashiwa-shi, Japan, 3Department of Surgery and Science,
Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan, 4Department
of Gastroenterology, Saitama Cancer Center, Ina, Japan, 5Department of
Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer
Center, Matsuyama, Japan, 6Clinical Trial Promotion Department, Chiba Cancer Center,
Chiba, Japan, 7Department of Gastroenterology and Hepatology, Hokkaido University
Hospital, Sapporo, Japan, 8Department of Clinical Oncology, Aichi Cancer Center
Hospital, Nagoya, Japan, 9Department of Colorectal Surgery, Kansai Rosai Hospital,
Amagasaki, Japan, 10Department of Gastrointestinal and Medical Oncology, National
Kyushu Cancer Center, Fukuoka, Japan, 11Division of Gastroenterology, Faculty of
Medicine, University of Tsukuba, Tsukuba, Japan, 12Department of Medical Oncology,
Kyorin University Faculty of Medicine, Mitaka, Japan, 13Department of Clinical
Oncology, St. Marianna University School of Medicine, Kawasaki, Japan, 14Clinical
Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan,
15
Department of Pathology and Clinical Laboratories, National Cancer Center Hospital
East, Kashiwa, Japan, 16Division of Pathology, Exploratory Oncology Research & Clinical
Trial Center, National Cancer Center, Kashiwa, Japan, 17Biobank Translational Research
Support Section, Translational Research Management Division, Clinical Research
Support Office, National Cancer Center Hospital East, Kashiwa, Japan, 18Department of
Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East,
Kashiwa, Japan
Background: We have conducted the Nationwide Cancer Genome Screening Project in
Japan since April 2015 using Next Generation Sequencing in advanced non-colorectal
gastrointestinal (GI) cancer (aNon-CRC), called as the SCRUM-Japan GI-SCREEN.
The objective is to evaluate the frequency of cancer genome alterations and to identify
patients who are candidate for clinical trial for corresponding targeting agents.
Methods: This study is ongoing with the participation of 23 major cancer centers.
Patients with aNon-CRC, including advanced esophageal cancer (aEC), who plan to or
receive chemotherapy were eligible. DNA and RNA were extracted from formalin-fixed
paraffin embedded (FFPE) tumor samples and were analyzed by the Oncomine Cancer
Research Panel (OCP) which allows to detect mutations, copy number variant (CNV)
and fusion genes in a CLIA certified CAP accredited lab. The detected genomic variant
data were classified according to genetic drivers of cancer, including gain- and loss-of-
function or single nucleotide variant based on the Oncomine Knowledgebase.
Results: By the end of March 2017, a total of 220 aEC samples were analyzed. The
sequence with the OCP was successfully performed in 144 (65.5%). Out of 144 patients,
the proportion of sample and histology type is followed; surgical specimen 52.1%, squ-
amous cell carcinoma 92.4%. The frequently detected mutations were TP53(76.4%),
NFE2L2 (38.2%), CDKN2A (9.7%), PIK3CA (6.3%), RB1 (5.6%), and CNVs were
CCND1 (38.2%), EGFR (7.6%), ATP11B (6.9%), SOX2 (6.9%). ERBB2 amplification
was identified in 3 cases (2.1%) and FGFR3-TACC3 fusion was identified in one case
(0.7%). Five patients with druggable genomic alterations (PIK3CA(n ¼ 2),
EGFR(n ¼ 2), FGFR3-TACC fusion(n ¼ 1)) were enrolled for clinical trials of targeting
therapies.
Conclusions: This nationwide screening system is efficient to detect rare gene altera-
tions in aEC. This novel knowledge provides an intriguing background to investigate
new target approaches in these patients and to progress precision medicine. Clinical
trial information: UMIN000016344 (Non-CRC).
Clinical trial identification: UMIN000016344.
Legal entity responsible for the study: SCRUM JAPAN.
Funding: 15 SCRUM-Japan collaborating pharmaceutical companies, AMED, NCC.
Disclosure: K. Kato: Other: 15 SCRUM-Japan collaborating pharmaceutical compa-
nies; Grants: AMED; Other: NCC, during the conduct of the study; Grants: Shionogi,
Ono Pharmaceuticals, Merck & Co., Merck Serono. T. Kojima: Grants: Shionogi, Ono
Pharmaceutical, MSD, Oncolys BioPharma, Astellas, Amgen, BioPharama, outside the
submitted work. H. Saeki, H. Hara, S. Kadowaki, Y. Kagawa, S. Hironaka, N. Izawa, S.
Fujii, K. Shitara, A. Ohtsu: Other: 15 SCRUM-Japan collaborating pharmaceutical
companies; Grants: AMED; Other: NCC, during the conduct of the study. T. Kajiwara:
Other: 15 SCRUM-Japan collaborating pharmaceutical companies; Grants: AMED,
other: NCC, during the conduct of the study; Grants and personal fees: Taiho
Pharmaceutical Co., Ltd.; Grants and personal fees: Chugai Pharmaceutical Co., Ltd.,
Bayer Yakuhin, Ltd., Merck Serono Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Yakult
Honsha Co.,Ltd., Medical & Biological Laboratories Co., Ltd., outside the submitted
work. H. Nakatsumi: Other: 15 SCRUM-Japan collaborating pharmaceutical compa-
nies; Grants: AMED; Other: NCC, during the conduct of the study; Personal fees: Ono
Pharmaceutical, Bayer Yakuhin, Lilly Japan, outside the submitted work. T. Esaki:
Other: 15 SCRUM-Japan collaborating pharmaceutical companies; Grants: AMED;
Other: NCC, during the conduct of the study; Grants and personal fees: Taiho; Eli Lilly,
Eisai, Daiichi-Sankyo, Merck Serono, Nihon Kayaku, Ono; Personal fees: Chugai,
Bristol-Myers Squibb, Takeda, Kyowa-Kirin; Grants: DS Pharma, Novartis,
AstraZeneca, Boehringer Ingelheim, MSD, Astellas, Bayer, Pfizer, Yakult, outside the
submitted work. T. Moriwaki: Grants: 15 SCRUM-Japan collaborating pharmaceutical
Volume 29 | Supplement 8 | October 2018
abstracts
companies; Grants: AMED, during the conduct of the study; Grants and personal fees:
Takeda, Chugai, Yakult; Personal fees: Taiho, Sanofi; Grants: MSD Oncology, outside
the submitted work. T. Kobayashi: Grants: 15 SCRUM-Japan collaborating pharma-
ceutical companies; Grants: J-Pharma, Taiho, Sumitomo Dainippon, Janssen, Daiichi
Sankyo, MSD, Yakult, Takeda, Chugai, Ono, Astellas, Zeria, Novartis, Nanocarrier,
Shionogi, Onco Therapy Science, Eli Lilly Japan, Bayer, Bristol-Myers Squibb, Merck
Serono, Kyowa Hakko Kirin, Eisai, Mochida, Baxalta, Sanofi, during the conduct of the
study. S. Nomura: Other: 15 SCRUM-Japan collaborating pharmaceutical companies;
Grants: AMED; Other: NCC, during the conduct of the study; Personal fees: Taiho,
outside the submitted work. T. Kuwata: Other: 15 SCRUM-Japan collaborating phar-
maceutical companies; Grants: AMED; Other: NCC, during the conduct of the study;
Personal fees: Chugai Pharm; Grants and personal fees: Daiichi-Sankyo, outside the
submitted work. W. Okamoto: Grants: MSD, outside the submitted work. T. Yoshino:
Grants: MSD K.K., Sumitomo Dainippon Pharma Co., Ltd., GlaxoSmithKline K.K.,
Nippon Boehringer Ingelheim Co., Ltd; Grants and personal fees: Sanofi K.K., Chugai
Pharmaceutical Co., Ltd; Personal fees: Eli Lilly Japan K.K, Merck Serono Co., Ltd.,
outside the submitted work.
628P Signal transduction pathway activity during neoadjuvant treatment in
esophageal adenocarcinomas
A. Creemers1, S.L. Meijer2, M. Stoffels3, G.K.J. Hooijer2, L. Holtzer3, H. van Ooijen3, A. Van
Brussel3, E.M.G. Aussems-Custers3, M. van Berge Henegouwen4, M.C.C.M. Hulshof5,
K.K. Krishnadath6, A. van de Stolpe7, M.F. Bijlsma8, H.W.M. van Laarhoven1
1
Medical Oncology, Academic Medical Center (AMC), Amsterdam, Netherlands,
2
Pathology, Academic Medical Center (AMC), Amsterdam, Netherlands, 3Precision and
Decentralized Diagnostics, Philips Research, Eindhoven, Netherlands, 4Surgery,
Academic Medical Center, Amsterdam, Netherlands, 5Radiotherapy, Academic Medical
Center (AMC), Amsterdam, Netherlands, 6Gastroenterology, Academic Medical Center
(AMC), Amsterdam, Netherlands, 7Research, Philips, Eindhoven, Netherlands, 8LEXOR,
Academic Medical Center (AMC), Amsterdam, Netherlands
Background: Little is known about signaling pathway activity in esophageal adenocar-
cinomas. Using a new methodology we have delineated the activity of key pathways
involved in tumor growth during neoadjuvant treatment. The aim is to use this knowl-
edge to personalize, and thereby improve, treatment strategies.
Methods: We included all patients with esophageal adenocarcinomas between 2004
and May 2013 in the AMC. Paired tumor samples were obtained before start of neoad-
juvant chemoradiation therapy according to the CROSS regimen and at surgical resec-
tion of the esophagus. Using a custom-built device, digital annotations of whole slide
H&E scans were transferred to a hematoxylin-stained slide, which was subsequently
deparaffinized. Marked tumor areas were scraped for RNA extraction and qPCR. qPCR
data were subjected to stringent QC prior to determining the signaling pathway activity
scores of the AR-, ER-, FOXO/PI3K-, HH-, TGF-b- and WNT pathway, using a com-
bined mRNA-Bayesian model-based method (Verhaegh et al, Cancer Res, 2014).
Pathway activity scores were correlated to pathological response to treatment
(Mandard score).
Results: Based on a test set of esophageal tumor tissue samples, we determined that
tumor areas of  2mm2 were eligible for RNA isolation and pathway activity analysis.
We provide a analysis of 288 currently processed samples. FOXO activity was signifi-
cantly higher in post-treatment resection specimen compared to matched pre-treat-
ment biopsies (p < 0.001). Patients with high FOXO activity in post-treatment
resection specimen showed better response to treatment (p ¼ 0.019).
Conclusions: The assessment of pathway activity is feasible on small amounts of tumor.
Marked dynamics in FOXO activity are observed during nCRT in esophageal adenocar-
cinomas. Patients with high FOXO activity post-nCRT show better response to treat-
ment. An active PI3K pathway blocks FOXO transcriptional activity. To increase
FOXO transcriptional activity, patients might benefit from the addition of PI3K-inhib-
itors to the nCRT regimen.
Legal entity responsible for the study: AMC.
Funding: Royal Philips.
Disclosure: M. Stoffels, L. Holtzer, A. Van Brussel: Employee: Royal Philips; Research
funding: Royal Philips. H. van Ooijen: Employee: Royal Philips; Patents, royalties or
other intellectual property: Royal Philips. E.M.G. Aussems-Custers. A. van de Stolpe:
Employee, Funded: Royal Philips. M. van Berge Henegouwen: Research funding:
Olympus. M.F. Bijlsma: Research funding: Celgene. H.W.M. van Laarhoven:
Consultant: Philips, Celgene, Lilly, Nordic; Unrestricted research funding: Philips,
Bayer, BMS, Celgene, Lilly, Merck Serono, MSD, Nordic, Roche. All other authors have
declared no conflicts of interest.
doi:10.1093/annonc/mdy282 | viii211