nach oben

Erschienen in:

21.03.2019 | Original Article

Placental growth factor is a predictive biomarker for ramucirumab treatment in advanced gastric cancer

verfasst von: Makoto Natsume, Takaya Shimura, Hiroyasu Iwasaki, Yusuke Okuda, Mika Kitagawa, Yasuyuki Okamoto, Kazuki Hayashi, Hiromi Kataoka

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 6/2019

Einloggen, um Zugang zu erhalten

Abstract

Purpose

Ramucirumab (RAM) has been used as the second-line standard chemotherapy for advanced gastric cancer (AGC) either alone or combination with paclitaxel (PTX). However, no predictive biomarkers have been identified for RAM treatment in AGC.

Methods

We retrospectively identified 26 patients who received either RAM monotherapy or RAM + PTX therapy for AGC refractory to fluoropyrimidine and platinum agents from 2015 to 2018 at Nagoya City University Hospital. First, we extracted RNA using gastric cancer (GC) tissues from two responders and two non-responders, and then analyzed 24 VEGFR-related angiogenic genes. Subsequently, we examined the relationship between the expression of each angiogenic gene and RAM clinical activity in the entire cohort. Finally, we validated using in vitro angiogenesis assays using GC cells and microvascular endothelial cells.

Results

We identified five angiogenic genes with aberrant expression between RAM responders and non-responders and placental growth factor (PlGF) was the most significant gene among them. Overall survival (P = 0.046) and progression-free survival (P = 0.016) were significantly shorter in the PlGF-high group than in the PlGF-low group. Overall response rates were 50% in the PlGF-low group and 0% in the PlGF-high group. In GC cells co-cultured with endothelial cells, PlGF gene silencing from GC cells significantly reinforced the inhibitory effect of RAM in the in vitro angiogenesis assay (tube formation assay and endothelial migration) through the inactivation of ERK, in comparison to the control GC cells.

Conclusions

PlGF gene expression in gastric cancer tissues could be a predictive indicator of AGC treatment by RAM.

Nur mit Berechtigung zugänglich

Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136(5):E359–E386. https://doi.org/10.1002/ijc.29210 CrossRefPubMed

Yamada Y, Higuchi K, Nishikawa K, Gotoh M, Fuse N, Sugimoto N, Nishina T, Amagai K, Chin K, Niwa Y, Tsuji A, Imamura H, Tsuda M, Yasui H, Fujii H, Yamaguchi K, Yasui H, Hironaka S, Shimada K, Miwa H, Hamada C, Hyodo I (2015) Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naive patients with advanced gastric cancer. Ann Oncol 26(1):141–148. https://doi.org/10.1093/annonc/mdu472 CrossRefPubMed

Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, Miyashita K, Nishizaki T, Kobayashi O, Takiyama W, Toh Y, Nagaie T, Takagi S, Yamamura Y, Yanaoka K, Orita H, Takeuchi M (2008) S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol 9(3):215–221. https://doi.org/10.1016/S1470-2045(08)70035-4 CrossRefPubMed

Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285(21):1182–1186. https://doi.org/10.1056/NEJM197111182852108 CrossRefPubMed

Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9(6):669–676. https://doi.org/10.1038/nm0603-669 CrossRefPubMed

Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350(23):2335–2342. https://doi.org/10.1056/NEJMoa032691. (350/23/2335 [pii]) CrossRefPubMed

Spratlin JL, Cohen RB, Eadens M, Gore L, Camidge DR, Diab S, Leong S, O’Bryant C, Chow LQ, Serkova NJ, Meropol NJ, Lewis NL, Chiorean EG, Fox F, Youssoufian H, Rowinsky EK, Eckhardt SG (2010) Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. J Clin Oncol 28(5):780–787. https://doi.org/10.1200/JCO.2009.23.7537 CrossRefPubMedPubMedCentral

Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Ruschoff J, Kang YK (2010) Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 376(9742):687–697. https://doi.org/10.1016/S0140-6736(10)61121-X CrossRefPubMed

Van Cutsem E, Lenz HJ, Kohne CH, Heinemann V, Tejpar S, Melezinek I, Beier F, Stroh C, Rougier P, van Krieken JH, Ciardiello F (2015) Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol 33(7):692–700. https://doi.org/10.1200/JCO.2014.59.4812 CrossRefPubMed

10.

Vandenbroucke JP, von Elm E, Altman DG, Gotzsche PC, Mulrow CD, Pocock SJ, Poole C, Schlesselman JJ, Egger M (2007) Strengthening the reporting of observational studies in epidemiology (STROBE): explanation and elaboration. Epidemiology 18(6):805–835. https://doi.org/10.1097/EDE.0b013e3181577511. (00001648-200711000-00028 [pii]) CrossRefPubMed

11.

Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov O, Kim TY, Cunningham D, Rougier P, Komatsu Y, Ajani J, Emig M, Carlesi R, Ferry D, Chandrawansa K, Schwartz JD, Ohtsu A, Group RS (2014) Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol 15(11):1224–1235. https://doi.org/10.1016/S1470-2045(14)70420-6 CrossRefPubMed

12.

Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, dos Santos LV, Aprile G, Ferry DR, Melichar B, Tehfe M, Topuzov E, Zalcberg JR, Chau I, Campbell W, Sivanandan C, Pikiel J, Koshiji M, Hsu Y, Liepa AM, Gao L, Schwartz JD, Tabernero J, Investigators RT (2014) Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 383(9911):31–39. https://doi.org/10.1016/S0140-6736(13)61719-5 CrossRefPubMed

13.

Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247. https://doi.org/10.1016/j.ejca.2008.10.026 CrossRef

14.

Shimura T, Iwasaki H, Kitagawa M, Ebi M, Yamada T, Yamada T, Katano T, Nisie H, Okamoto Y, Ozeki K, Mizoshita T, Kataoka H (2019) Urinary cysteine-rich protein 61 and trefoil factor 3 as diagnostic biomarkers for colorectal cancer. Transl Oncol 12(3):539–544. https://doi.org/10.1016/j.tranon.2018.12.006 CrossRefPubMedPubMedCentral

15.

Shimura T, Ebi M, Yamada T, Yamada T, Katano T, Nojiri Y, Iwasaki H, Nomura S, Hayashi N, Mori Y, Kataoka H, Moses MA, Joh T (2017) Urinary kallikrein 10 predicts the incurability of gastric cancer. Oncotarget 8(17):29247–29257. https://doi.org/10.18632/oncotarget.16453 CrossRefPubMedPubMedCentral

16.

Shimura T, Dagher A, Sachdev M, Ebi M, Yamada T, Yamada T, Joh T, Moses MA (2015) Urinary ADAM12 and MMP-9/NGAL complex detect the presence of gastric cancer. Cancer Prev Res (Phila) 8(3):240–248. https://doi.org/10.1158/1940-6207.CAPR-14-0229 CrossRef

17.

Fuchs CS, Tabernero J, Tomasek J, Chau I, Melichar B, Safran H, Tehfe MA, Filip D, Topuzov E, Schlittler L, Udrea AA, Campbell W, Brincat S, Emig M, Melemed SA, Hozak RR, Ferry D, Caldwell CW, Ajani JA (2016) Biomarker analyses in REGARD gastric/GEJ carcinoma patients treated with VEGFR2-targeted antibody ramucirumab. Br J Cancer 115(8):974–982. https://doi.org/10.1038/bjc.2016.293 CrossRefPubMedPubMedCentral

18.

Tabernero J, Hozak RR, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, Ciuleanu TE, Portnoy DC, Prausova J, Muro K, Siegel RW, Konrad RJ, Ouyang H, Melemed SA, Ferry D, Nasroulah F, Van Cutsem E (2018) Analysis of angiogenesis biomarkers for ramucirumab efficacy in patients with metastatic colorectal cancer from RAISE, a global, randomized, double-blind, phase III study. Ann Oncol 29(3):602–609. https://doi.org/10.1093/annonc/mdx767 CrossRefPubMed

19.

Zhu AX, Finn RS, Mulcahy M, Gurtler J, Sun W, Schwartz JD, Dalal RP, Joshi A, Hozak RR, Xu Y, Ancukiewicz M, Jain RK, Nugent FW, Duda DG, Stuart K (2013) A phase II and biomarker study of ramucirumab, a human monoclonal antibody targeting the VEGF receptor-2, as first-line monotherapy in patients with advanced hepatocellular cancer. Clin Cancer Res 19(23):6614–6623. https://doi.org/10.1158/1078-0432.CCR-13-1442 CrossRefPubMedPubMedCentral

20.

Penson RT, Moore KM, Fleming GF, Braly P, Schimp V, Nguyen H, Matulonis UA, Banerjee S, Haluska P, Gore M, Bodurka DC, Hozak RR, Joshi A, Xu Y, Schwartz JD, McGuire WP (2014) A phase II study of ramucirumab (IMC-1121B) in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma. Gynecol Oncol 134(3):478–485. https://doi.org/10.1016/j.ygyno.2014.06.029 CrossRefPubMedPubMedCentral

21.

Waltenberger J, Claesson-Welsh L, Siegbahn A, Shibuya M, Heldin CH (1994) Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J Biol Chem 269(43):26988–26995PubMed

22.

Landgren E, Schiller P, Cao Y, Claesson-Welsh L (1998) Placenta growth factor stimulates MAP kinase and mitogenicity but not phospholipase C-gamma and migration of endothelial cells expressing Flt 1. Oncogene 16(3):359–367. https://doi.org/10.1038/sj.onc.1201545 CrossRefPubMed

Titel: Placental growth factor is a predictive biomarker for ramucirumab treatment in advanced gastric cancer
verfasst von: Makoto Natsume
Takaya Shimura
Hiroyasu Iwasaki
Yusuke Okuda
Mika Kitagawa
Yasuyuki Okamoto
Kazuki Hayashi
Hiromi Kataoka
Publikationsdatum: 21.03.2019
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 6/2019
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-019-03817-2

Die Highlights vom Kongress des American College of Cardiology 2024

Springer Medizin

Placental growth factor is a predictive biomarker for ramucirumab treatment in advanced gastric cancer