Seyoung Seo1, Min-Hee Ryu1, Young Soo Park2, Ji Yong Ahn3, Yangsoon Park2, Sook Ryun Park1, Baek-Yeol Ryoo1, Gin Hyug Lee3, Hwoon-Young Jung3, Yoon-Koo Kang4. 1. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Republic of Korea. 2. Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. 3. Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. 4. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Republic of Korea. ykkang@amc.seoul.kr.
Abstract
BACKGROUND: Although discordance in HER2 positivity between primary and metastatic lesions is well established, changes in HER2 positivity after anti-HER2 therapy have not been well evaluated in gastric cancer. We aimed to evaluate whether HER2 expression in gastric cancer is affected by trastuzumab therapy. METHODS: We enrolled 48 HER2-positive advanced gastric cancer patients treated with trastuzumab-containing first-line chemotherapy and had paired biopsies at baseline and after progression. RESULTS: At baseline, HER2 was positive, with immunohistochemistry (IHC) 2+ and in situ hybridization (ISH)+ in five patients, and with IHC 3+ in 43 patients. Fourteen patients (29.1%) exhibited loss of HER2 positivity on post-progression biopsy: 10 with IHC 0 or 1+, and four with IHC 2+/ISH-. HER2 remained positive on second biopsy in 34 patients: four with IHC 2+/ISH+, and 30 with IHC 3+. Median H-scores decreased from 225 to 175 (p = 0.047). HER2 genetic heterogeneity was defined in one of 34 ISH-assessable patients (2.9%) at baseline and seven of 32 (21.9%) at second biopsy. Among 13 patients who received second-line trastuzumab emtansine, three showed HER2-negative conversion; they had no objective response and short progression-free survival (1.2, 1.3, and 3.4 months). Patients with stable HER2 status had a 44% response rate and median progression-free survival of 2.7 (0.4-36.8) months. CONCLUSION: A substantial portion of HER2-positive patients showed HER2-negative conversion with increased HER2 genetic heterogeneity after failure of trastuzumab-containing chemotherapy. Loss of HER2 positivity could be predictive of second-line anti-HER2 treatment, suggesting a need to reexamine HER2 status before initiating second-line anti-HER2 therapy.
BACKGROUND: Although discordance in HER2 positivity between primary and metastatic lesions is well established, changes in HER2 positivity after anti-HER2 therapy have not been well evaluated in gastric cancer. We aimed to evaluate whether HER2 expression in gastric cancer is affected by trastuzumab therapy. METHODS: We enrolled 48 HER2-positive advanced gastric cancerpatients treated with trastuzumab-containing first-line chemotherapy and had paired biopsies at baseline and after progression. RESULTS: At baseline, HER2 was positive, with immunohistochemistry (IHC) 2+ and in situ hybridization (ISH)+ in five patients, and with IHC 3+ in 43 patients. Fourteen patients (29.1%) exhibited loss of HER2 positivity on post-progression biopsy: 10 with IHC 0 or 1+, and four with IHC 2+/ISH-. HER2 remained positive on second biopsy in 34 patients: four with IHC 2+/ISH+, and 30 with IHC 3+. Median H-scores decreased from 225 to 175 (p = 0.047). HER2 genetic heterogeneity was defined in one of 34 ISH-assessable patients (2.9%) at baseline and seven of 32 (21.9%) at second biopsy. Among 13 patients who received second-line trastuzumab emtansine, three showed HER2-negative conversion; they had no objective response and short progression-free survival (1.2, 1.3, and 3.4 months). Patients with stable HER2 status had a 44% response rate and median progression-free survival of 2.7 (0.4-36.8) months. CONCLUSION: A substantial portion of HER2-positive patients showed HER2-negative conversion with increased HER2 genetic heterogeneity after failure of trastuzumab-containing chemotherapy. Loss of HER2 positivity could be predictive of second-line anti-HER2 treatment, suggesting a need to reexamine HER2 status before initiating second-line anti-HER2 therapy.
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