Ji-Won Kim1, Debora K Kim2, Ahrum Min3, Kyung-Hun Lee4,5, Hyun-Jin Nam6, Jee Hyun Kim1, Jin-Soo Kim7, Tae-Yong Kim6,8, Seock-Ah Im6,8, In Ae Park6,9. 1. Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-ro-173-beon-gil, Seongnam, 463-707, Korea. 2. Seoul International School, 15 Seongnam-daero-1518-beon-gil, Seongnam, 461-830, Korea. 3. Cancer Research Institute, Seoul National University, 103 Daehak-ro, Jongno-gu, Seoul, 110-799, Korea. mar6716@snu.ac.kr. 4. Cancer Research Institute, Seoul National University, 103 Daehak-ro, Jongno-gu, Seoul, 110-799, Korea. kyunghunlee@snu.ac.kr. 5. Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Korea. kyunghunlee@snu.ac.kr. 6. Cancer Research Institute, Seoul National University, 103 Daehak-ro, Jongno-gu, Seoul, 110-799, Korea. 7. Department of Internal Medicine, SMG-SNU Boramae Medical Center, 20 Boramae-ro-5-gil, Seoul, 156-707, Korea. 8. Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Korea. 9. Department of Pathology, Seoul National University Hospital, 101 Daehak-ro, Seoul, 110-744, Korea.
Abstract
PURPOSE: Human epidermal growth factor receptor 2 (HER2) heterodimerizes and shares common signaling pathways with epidermal growth factor receptor (EGFR). In this study, we investigated the clinical implication of amphiregulin, a ligand for EGFR, on trastuzumab therapy in HER2-positive breast cancer. METHODS: Serum amphiregulin levels were quantified in 50 consecutive patients with HER2-positive metastatic breast cancer who received first-line trastuzumab plus taxane chemotherapy between October 2004 and July 2009. In addition, in vitro experiments were carried out to validate the results. RESULTS: The median serum amphiregulin level was 1.0 ng/mL with a maximum level of 4.4 ng/mL. Patients with high serum amphiregulin levels (≥0.5 ng/mL) had significantly shorter progression-free survival (15.1 months vs. not reached; P = 0.018). Colony-forming assays demonstrated that the addition of amphiregulin resulted in increased proliferation of cells. In addition, the anti-proliferative effect of trastuzumab was decreased in the presence of amphiregulin. Western blot analysis showed that amphiregulin activated AKT and ERK pathways. In addition, in the presence of amphiregulin, sustained phosphorylation of AKT and ERK pathways was observed after trastuzumab treatment. CONCLUSIONS: High serum amphiregulin levels were associated with early disease progression in these patients, possibly due to AKT and ERK signaling activation by amphiregulin.
PURPOSE:Human epidermal growth factor receptor 2 (HER2) heterodimerizes and shares common signaling pathways with epidermal growth factor receptor (EGFR). In this study, we investigated the clinical implication of amphiregulin, a ligand for EGFR, on trastuzumab therapy in HER2-positive breast cancer. METHODS: Serum amphiregulin levels were quantified in 50 consecutive patients with HER2-positive metastatic breast cancer who received first-line trastuzumab plus taxane chemotherapy between October 2004 and July 2009. In addition, in vitro experiments were carried out to validate the results. RESULTS: The median serum amphiregulin level was 1.0 ng/mL with a maximum level of 4.4 ng/mL. Patients with high serum amphiregulin levels (≥0.5 ng/mL) had significantly shorter progression-free survival (15.1 months vs. not reached; P = 0.018). Colony-forming assays demonstrated that the addition of amphiregulin resulted in increased proliferation of cells. In addition, the anti-proliferative effect of trastuzumab was decreased in the presence of amphiregulin. Western blot analysis showed that amphiregulin activated AKT and ERK pathways. In addition, in the presence of amphiregulin, sustained phosphorylation of AKT and ERK pathways was observed after trastuzumab treatment. CONCLUSIONS: High serum amphiregulin levels were associated with early disease progression in these patients, possibly due to AKT and ERK signaling activation by amphiregulin.
Entities:
Keywords:
Amphiregulin; Breast cancer; HER2; Resistance; Trastuzumab
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