Biomarkers of reactive resistance and early disease progression during chemotherapy plus bevacizumab treatment for colorectal carcinoma
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Hidetoshi Hayashi1,2,3, Tokuzo Arao1, Kazuko Matsumoto1, Hideharu Kimura1, Yosuke Togashi1, Yoshinori Hirashima4,5, Yosuke Horita4,6, Satoru Iwasa4, Natsuko Tsuda Okita4, Yoshitaka Honma4, Atsuo Takashima4, Ken Kato4, Tetsuya Hamaguchi4, Yasuhiro Shimada4, Kazuhiko Nakagawa2, Kazuto Nishio1, and Yasuhide Yamada4
1 Department of Genome Biology, Kinki University Faculty of Medicine, Osakasayama City, Osaka, Japan.
2 Department of Medical Oncology, Kinki University Faculty of Medicine, Osakasayama City, Osaka, Japan.
3 Department of Medical Oncology, Kishiwada Municipal Hospital, Kishiwada, Osaka, Japan.
4 Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.
5 Department of Medical Oncology, Oita University, Hazama-cho, Yufu, Oita, Japan.
6 Department of Chemotherapy, Toyama Prefectural Central Hospital, Toyama, Toyama, Japan.
Hidetoshi Hayashi, email:
Keywords: placental growth factor (PlGF), vascular endothelial growth factor (VEGF), colorectal carcinoma, bevacizumab, angiogenesis
Received: January 5, 2014 Accepted: March 20, 2014 Published: March 22, 2014
Molecular markers for predicting or monitoring the efficacy of bevacizumab in patients with metastatic colorectal cancer (mCRC) remain to be identified. We have now measured the serum concentrations of 25 angiogenesis-related molecules with antibody suspension bead array systems for 25 mCRC patients both before and during treatment in a previously reported phase II trial of FOLFIRI chemotherapy plus bevacizumab. The serum concentration of vascular endothelial growth factor–A (VEGF-A) decreased after the onset of treatment (P < 0.0001), whereas that of placental growth factor increased (P < 0.0001). Significant differences in the levels of several factors (such as VEGF-A, soluble VEGF receptor–2, and interleukin-8) were apparent between responders and nonresponders during treatment. The rapid and pronounced decrease in serum VEGF-A level after treatment onset was apparent in all subjects and was independent of the baseline concentration. However, four of nine nonresponders showed a subsequent early increase in the serum VEGF-A level. Our results thus suggest that an early increase in the serum VEGF-A concentration after the initial decrease is a potential predictive marker of a poor response and reactive resistance to bevacizumab plus chemotherapy.
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