Molecular Oncology (Feb 2024)
NOTCH1 and CREBBP co‐mutations negatively affect the benefit of adjuvant therapy in completely resected EGFR‐mutated NSCLC: translational research of phase III IMPACT study
- Satoshi Ikeda,
- Masahiro Tsuboi,
- Kazuko Sakai,
- Toshihiro Misumi,
- Hiroaki Akamatsu,
- Hiroyasu Shoda,
- Noriaki Sakakura,
- Atsushi Nakamura,
- Yasuhisa Ohde,
- Hidetoshi Hayashi,
- Kyoichi Okishio,
- Morihito Okada,
- Ichiro Yoshino,
- Jiro Okami,
- Kazuhisa Takahashi,
- Norihiko Ikeda,
- Masayuki Tanahashi,
- Yuichi Tambo,
- Haruhiro Saito,
- Shinichi Toyooka,
- Hidetoshi Inokawa,
- Toyofumi Chen‐Yoshikawa,
- Toshihide Yokoyama,
- Tatsuro Okamoto,
- Noriko Yanagitani,
- Masahide Oki,
- Makoto Takahama,
- Kenji Sawa,
- Hirohito Tada,
- Kazuhiko Nakagawa,
- Tetsuya Mitsudomi,
- Kazuto Nishio
Affiliations
- Satoshi Ikeda
- Department of Respiratory Medicine Kanagawa Cardiovascular and Respiratory Center Yokohama Japan
- Masahiro Tsuboi
- Division of Thoracic Surgery National Cancer Center Hospital East Kashiwa Japan
- Kazuko Sakai
- Department of Genome Biology Kindai University Faculty of Medicine Osaka‐Sayama Japan
- Toshihiro Misumi
- Department of Data Science National Cancer Center Hospital East Kashiwa Japan
- Hiroaki Akamatsu
- Internal Medicine III Wakayama Medical University Japan
- Hiroyasu Shoda
- Department of Respiratory Medicine Hiroshima Citizens Hospital Japan
- Noriaki Sakakura
- Department of Thoracic Surgery Aichi Cancer Center Hospital Nagoya Japan
- Atsushi Nakamura
- Department of Pulmonary Medicine Sendai Kousei Hospital Japan
- Yasuhisa Ohde
- Division of Thoracic Surgery Shizuoka Cancer Center Sunto‐gun Japan
- Hidetoshi Hayashi
- Department of Medical Oncology Kindai University Faculty of Medicine Osaka‐Sayama Japan
- Kyoichi Okishio
- Department of Thoracic Oncology National Hospital Organization Kinki‐Chuo Chest Medical Center Sakai Japan
- Morihito Okada
- Department of Surgical Oncology Hiroshima University Japan
- Ichiro Yoshino
- Department of General Thoracic Surgery Chiba University Graduate School of Medicine Japan
- Jiro Okami
- Department of General Thoracic Surgery Osaka International Cancer Institute Japan
- Kazuhisa Takahashi
- Department of Respiratory Medicine Juntendo University Graduate School of Medicine Bunkyo‐ku Japan
- Norihiko Ikeda
- Department of Surgery Tokyo Medical University Shinjuku‐ku Japan
- Masayuki Tanahashi
- Division of Thoracic Surgery, Respiratory Disease Center Seirei Mikatahara General Hospital Hamamatsu Japan
- Yuichi Tambo
- Department of Respiratory Medicine Kanazawa University Hospital Japan
- Haruhiro Saito
- Department of Thoracic Oncology Kanagawa Cancer Center Yokohama Japan
- Shinichi Toyooka
- Department of General Thoracic Surgery Okayama University Graduate School of Medicine Japan
- Hidetoshi Inokawa
- Department of Thoracic Surgery Yamaguchi‐Ube Medical Center Japan
- Toyofumi Chen‐Yoshikawa
- Department of Thoracic Surgery Nagoya University Graduate School of Medicine Japan
- Toshihide Yokoyama
- Department of Respiratory Medicine Kurashiki Central Hospital Japan
- Tatsuro Okamoto
- Department of Thoracic Oncology National Hospital Organization Kyushu Cancer Center Fukuoka Japan
- Noriko Yanagitani
- Department of Thoracic Medical Oncology Cancer Institute Hospital of Japanese Foundation for Cancer Research Koto‐ku Japan
- Masahide Oki
- Department of Respiratory Medicine National Hospital Organization Nagoya Medical Center Japan
- Makoto Takahama
- Department of General Thoracic Surgery Osaka City General Hospital Japan
- Kenji Sawa
- Department of Clinical Oncology Osaka Metropolitan University Graduate School of Medicine Japan
- Hirohito Tada
- Department of Thoracic Surgery Suita Tokushukai Hospital Japan
- Kazuhiko Nakagawa
- Department of Medical Oncology Kindai University Faculty of Medicine Osaka‐Sayama Japan
- Tetsuya Mitsudomi
- Division of Thoracic Surgery Kindai University Faculty of Medicine Osaka‐Sayama Japan
- Kazuto Nishio
- Department of Genome Biology Kindai University Faculty of Medicine Osaka‐Sayama Japan
- DOI
- https://doi.org/10.1002/1878-0261.13542
- Journal volume & issue
-
Vol. 18,
no. 2
pp. 305 – 316
Abstract
The phase III IMPACT study (UMIN000044738) compared adjuvant gefitinib with cisplatin plus vinorelbine (cis/vin) in completely resected epidermal growth factor receptor (EGFR)‐mutated non‐small cell lung cancer (NSCLC). Although the primary endpoint of disease‐free survival (DFS) was not met, we searched for molecular predictors of adjuvant gefitinib efficacy. Of 234 patients enrolled in the IMPACT study, 202 patients were analyzed for 409 cancer‐related gene mutations and tumor mutation burden using resected lung cancer specimens. Frequent somatic mutations included tumor protein p53 (TP53; 58.4%), CUB and Sushi multiple domains 3 (CSMD3; 11.8%), and NOTCH1 (9.9%). Multivariate analysis showed that NOTCH1 co‐mutation was a significant poor prognostic factor for overall survival (OS) in the gefitinib group and cAMP response element binding protein (CREBBP) co‐mutation for DFS and OS in the cis/vin group. In patients with NOTCH1 co‐mutations, gefitinib group had a shorter OS than cis/vin group (Hazard ratio 5.49, 95% CI 1.07–28.00), with a significant interaction (P for interaction = 0.039). In patients with CREBBP co‐mutations, the gefitinib group had a longer DFS than the cis/vin group, with a significant interaction (P for interaction = 0.058). In completely resected EGFR‐mutated NSCLC, NOTCH1 and CREBBP mutations might predict poor outcome in patients treated with gefitinib and cis/vin, respectively.
Keywords
- adjuvant therapy
- early‐stage
- epidermal growth factor receptor
- non‐small cell lung cancer
- tyrosine kinase inhibitor
