2019 ASCO Annual Meeting!
Session: Gastrointestinal (Colorectal) Cancer
Type: Poster Session
Time: Monday June 3, 8:00 AM to 11:00 AM
Location: Hall A
Genomic alterations after EGFR blockade in patients with RAS wild-type metastatic colorectal cancer: Combined tissue and blood-based analysis from SCRUM-Japan GI-SCREEN and GOZILA.
Gastrointestinal (Colorectal) Cancer
2019 ASCO Annual Meeting
Poster Board Number:
Poster Session (Board #20)
J Clin Oncol 37, 2019 (suppl; abstr 3528)
Author(s): Yoshiaki Nakamura, Riu Yamashita, Wataru Okamoto, Yukiya Narita, Yoshito Komatsu, Yoshinori Kagawa, Naoki Takahashi, Taito Esaki, Takeshi Kato, Yu Sunakawa, Tadamichi Denda, Tomohiro Nishina, Atsuo Takashima, Takaaki Kobayashi, Manabu Shiozawa, Eiji Oki, Taroh Satoh, Yuta Adachi, Justin Odegaard, Takayuki Yoshino; Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan; Translational Informatics, National Cancer Center Hospital East, Kashiwa, Japan; BB/TR Support Section, Clinical Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan; Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan; Department of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan; National Hospital Organization Osaka National Hospital, Osaka, Japan; Department of Gastroenterology, Saitama Cancer Center, Saitama, Japan; Department of Gastrointestinal and Medical Oncology, National Kyushu Cancer Center, Fukuoka, Japan; 6.Department of Surgery, National Hospital Organization Osaka National Hospital, Amagasaki, Japan; Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan; Division of Gastroenterology, Chiba Cancer Center, Chiba, Japan; National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan; Division of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan; Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo, Japan; Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan; Department of Surgery and Science, Kyushu University, Fukuoka, Japan; Osaka University, Osaka, Japan; Division of Medical Oncology Cancer Research Institute, Kanazawa University, Kanazawa, Japan; Lifecode, San Francisco, CA; National Cancer Center Hospital East, Kashiwa, Japan
Background: Anti-EGFR therapy (tx) in RAS wild-type (wt) metastatic colorectal cancer (mCRC) induces resistance through acquired genomic alterations. We aimed to define such alterations in Nationwide Cancer Genome Screening Project tissue and blood specimens, using next generation sequencing (NGS). Methods: Tumor specimens in patients (pts) with RAS wt mCRC were obtained from SCRUM-Japan GI-SCREEN (tissue) and GOZILA (circulating tumor DNA [ctDNA] from blood). Genomic alterations were compared using the Oncomine Comprehensive Assay (SCRUM) and Guardant360 (GOZILA), before anti-EGFR tx and after progression. Results: 373 total actionable alterations were identified in 71 pts with available matched tissue and ctDNA; 255 (68%) were acquired after anti-EGFR tx progression. Frequently seen acquired oncogenic alterations included KRAS mutations (27%) and amplifications (amps) of EGFR (41%), CDK6 (24%), BRAF (20%), MYC (17%), MET (14%), PIK3CA (11%), FGFR1 (11%), and KRAS (10%). Fusions of RET, ALK, and FGFR3 were newly acquired in 1-4%. Acquired alterations co-arose in multiple pathways, including the cell cycle, PI3K-AKT, and MAPK, although 29% of pts had none. Acquired mutations were less frequently clonal versus primary mutations (p<0.0001), but clonal acquired mutations were seen in several oncogenes, including EGFR, KRAS, and PIK3CA. A subset of acquired KRAS, MET, CCND2, and EGFR amps had high (>7) adjusted plasma copy numbers (ApCN). Acquired ERBB2 amps were identified in 3 pts (4%) with a median ApCN of 4, one of whom (ApCN=4.2), treated with dual HER2 blockade, progressed after 2 cycles. Conclusions: Our integrated analysis revealed that anti-EGFR tx of pts with RAS WT mCRC led to acquired genomic alterations in multiple oncogenic pathways. Although most acquired alterations were subclonal, a subset of oncogenic alterations had relatively high clonality and ApCN, suggesting potential targets for overcoming acquired resistance to anti-EGFR tx. Early progression in a pt with an ApCN of 4.2 suggests low-level/subclonal acquired alterations may not be effective treatment targets.
1. Randomized phase III study comparing FOLFOX + bevacizumab versus folfoxiri + bevacizumab (BEV) as 1st line treatment in patients with metastatic colorectal cancer (mCRC) with ≥3 baseline circulating tumor cells (bCTCs).