Jae Ho Jeong1, Jihun Kim2, Yong Sang Hong1, Dalyong Kim1, Jeong Eun Kim1, Sun Young Kim1, Kyu-Pyo Kim1, Young-Kwang Yoon3, Deokhoon Kim4, Sung-Min Chun2, Yangsoon Park2, Se Jin Jang2, Tae Won Kim5. 1. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. 2. Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. 3. Clinical Research Center, Asan Institute of Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. 4. Center for Cancer Genome Discovery, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. 5. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address: twkimmd@amc.seoul.kr.
Abstract
BACKGROUND: Cetuximab has shown clinical benefit in patients with metastatic colorectal cancer (mCRC) harboring wild-type RAS. Human epidermal growth factor receptor 2 (HER2) amplification may be a mechanism of cetuximab resistance. We evaluated the association between HER2 amplification and cetuximab efficacy in patients with mCRC harboring wild-type RAS and BRAF. PATIENTS AND METHODS: Between December 2003 and June 2013, we identified 142 patients with mCRC whose tumors harbored both wild-type exons 2, 3, and 4 in KRAS and NRAS, and wild-type exon 15 in BRAF using high throughput sequencing (OncoMap version 4.0). All patients received cetuximab after oxaliplatin, irinotecan, and fluoropyrimidine failure. HER2 status was determined using immunohistochemistry and silver in situ hybridization (SISH) and correlated with cetuximab efficacy. RESULTS: Of 142 RAS and BRAF wild-type tumors, we observed 7 cases (4.9%) of HER2 amplification by SISH. After a median follow-up of 13.2 months (range, 1.4-78.1 months), median progression-free survival (PFS) was significantly different according to HER2 status: 3.1 months in patients with HER2 amplification compared with 5.6 months in those with non-amplified HER2 (hazard ratio, 2.73; 95% confidence interval, 1.18-6.31; P = .019). Overall survival (OS) was not significantly different between groups, although there was a tendency towards shorter OS in patients with HER2-amplified tumors (hazard ratio, 1.31; 95% confidence interval, 0.61-2.82; 10.1 vs. 13.5 months; P = .488). CONCLUSIONS: HER2 amplification is predictive of shorter PFS after cetuximab treatment in patients with mCRC harboring wild-type RAS and BRAF. Further study is warranted for this patient population.
BACKGROUND:Cetuximab has shown clinical benefit in patients with metastatic colorectal cancer (mCRC) harboring wild-type RAS. Human epidermal growth factor receptor 2 (HER2) amplification may be a mechanism of cetuximab resistance. We evaluated the association between HER2 amplification and cetuximab efficacy in patients with mCRC harboring wild-type RAS and BRAF. PATIENTS AND METHODS: Between December 2003 and June 2013, we identified 142 patients with mCRC whose tumors harbored both wild-type exons 2, 3, and 4 in KRAS and NRAS, and wild-type exon 15 in BRAF using high throughput sequencing (OncoMap version 4.0). All patients received cetuximab after oxaliplatin, irinotecan, and fluoropyrimidine failure. HER2 status was determined using immunohistochemistry and silver in situ hybridization (SISH) and correlated with cetuximab efficacy. RESULTS: Of 142 RAS and BRAF wild-type tumors, we observed 7 cases (4.9%) of HER2 amplification by SISH. After a median follow-up of 13.2 months (range, 1.4-78.1 months), median progression-free survival (PFS) was significantly different according to HER2 status: 3.1 months in patients with HER2 amplification compared with 5.6 months in those with non-amplified HER2 (hazard ratio, 2.73; 95% confidence interval, 1.18-6.31; P = .019). Overall survival (OS) was not significantly different between groups, although there was a tendency towards shorter OS in patients with HER2-amplified tumors (hazard ratio, 1.31; 95% confidence interval, 0.61-2.82; 10.1 vs. 13.5 months; P = .488). CONCLUSIONS:HER2 amplification is predictive of shorter PFS after cetuximab treatment in patients with mCRC harboring wild-type RAS and BRAF. Further study is warranted for this patient population.
Authors: Daniel R Owen; Hui-Li Wong; Melika Bonakdar; Martin Jones; Christopher S Hughes; Gregg B Morin; Steven J M Jones; Daniel J Renouf; Howard Lim; Janessa Laskin; Marco Marra; Stephen Yip; David F Schaeffer Journal: Cold Spring Harb Mol Case Stud Date: 2018-04-02
Authors: Richard M Goldberg; Clara Montagut; Zev A Wainberg; Philippe Ronga; François Audhuy; Julien Taieb; Sebastian Stintzing; Salvatore Siena; Daniele Santini Journal: ESMO Open Date: 2018-05-05