Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2014

Open Access 01-12-2014 | Research article

VEGFR-3 and CXCR4 as predictive markers for treatment with fluorouracil, leucovorin plus either oxaliplatin or cisplatin in patients with advanced esophagogastric cancer: a comparative study of the Arbeitsgemeinschaft Internistische Onkologie (AIO)

Authors: Thomas Thomaidis, Annett Maderer, Salah-Eddin Al-Batran, Janis Kany, Claudia Pauligk, Kristina Steinmetz, Arno Schad, Ralf Hofheinz, Harald Schmalenberg, Nils Homann, Peter Robert Galle, Markus Moehler

Published in: BMC Cancer | Issue 1/2014

Login to get access

Abstract

Background

Combination of fluoropyrimidines and a platinum derivative are currently standards for systemic chemotherapy in advanced adenocarcinoma of the stomach and gastroesophageal junction (GEJ). Nevertheless, individual likelihood for response to these therapeutic regimes remains uncertain. Even more, no predictive markers are available to determine which patients may benefit more from oxaliplatin versus cisplatin or vice versa. The new invasion and stem cell markers VEGFR-3 and CXCR4 have been linked prognostically with more aggressive esophagogastric cancer types. Thus, we aimed to assess correlations of VEGFR-3 and CXCR4 expression levels with clinical outcome in a randomized phase III study of patients with oxaliplatin/leucovorin/5-FU (FLO) versus cisplatin/leucovorin/5-FU (FLP).

Methods

The patients data examined in this study (n = 72) were from the collective of the FLO vs. FLP phase III AIO trial. Tumour tissues were stained via immunohistochemistry for VEGFR-3 and CXCR4 expression and results were evaluated by two independent, blinded investigators.
Outcome parameter: Survival analysis was calculated for patients receiving FLO vs. FLP in relation to VEGFR-3 and CXCR4 expression.

Results

54% and 36% of the examined tumour tissues showed strong positive expression of VEGFR-3 and CXCR4 respectively. No superiority of each regime was detected in terms of overall survival (OS) in the whole population. Patients with strong expression of CXCR4 on their tumour tissues profited more in terms of OS under the treatment of FLP (mOS: 28 vs 15 months, p = 0.05 respectively). Patients with negative VEGFR-3 and CXCR4 expression had a trend to live longer when FLO regime was applied (mOS: 22 vs. 9 months, p = 0.099 and 20 vs. 10 months, p = 0.073 respectively). In an exploratory analysis of patients older than 60 years at diagnosis, we observed a significant benefit in overall survival for VEGFR-3 and CXCR4-positive patients when treated with FLP (p = 0.002, p = 0.021 respectively).

Conclusions

CXCR4 positive patients profited in terms of OS from FLP, whereas FLO proved to be more effective in CXCR4 and VEGFR-3 negative patients. Our results suggest, despite the limited size of the study, a predictive value of these biomarkers concerning chemotherapy with FLP or FLO in advanced esophagogastric cancer.
Appendix
Available only for authorised users
Literature
1.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin. 2011, 61 (2): 69-90. 10.3322/caac.20107.CrossRefPubMed
2.
Wagner AD, Unverzagt S, Grothe W, Kleber G, Grothey A, Haerting J, Fleig WE: Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev. 2010, 3: CD004064
3.
Kim NK, Park YS, Heo DS, Suh C, Kim SY, Park KC, Kang YK, Shin DB, Kim HT, Kim HJ, Kang WK, Suh CI, Bang YJ: A phase III randomized study of 5-fluorouracil and cisplatin versus 5-fluorouracil, doxorubicin, and mitomycin C versus 5-fluorouracil alone in the treatment of advanced gastric cancer. Cancer. 1993, 71 (12): 3813-3818. 10.1002/1097-0142(19930615)71:12<3813::AID-CNCR2820711205>3.0.CO;2-5.CrossRefPubMed
4.
Vanhoefer U, Rougier P, Wilke H, Ducreux MP, Lacave AJ, Van Cutsem E, Planker M, Santos JG, Piedbois P, Paillot B, Bodenstein H, Schmoll HJ, Bleiberg H, Nordlinger B, Couvreur ML, Baron B, Wils JA: Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: a trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group. J Clin Oncol. 2000, 18 (14): 2648-2657.PubMed
5.
Webb A, Cunningham D, Scarffe JH, Harper P, Norman A, Joffe JK, Hughes M, Mansi J, Findlay M, Hill A, Oates J, Nicolson M, Hickish T, O'Brien M, Iveson T, Watson M, Underhill C, Wardley A, Meehan M: Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol. 1997, 15 (1): 261-267.CrossRefPubMed
6.
Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR: Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008, 358 (1): 36-46. 10.1056/NEJMoa073149.CrossRefPubMed
7.
Al-Batran SE, Hartmann JT, Probst S, Schmalenberg H, Hollerbach S, Hofheinz R, Rethwisch V, Seipelt G, Homann N, Wilhelm G, Schuch G, Stoehlmacher J, Derigs HG, Hegewisch-Becker S, Grossmann J, Pauligk C, Atmaca A, Bokemeyer C, Knuth A, Jager E: Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol. 2008, 26 (9): 1435-1442. 10.1200/JCO.2007.13.9378.CrossRefPubMed
8.
Xu W, Zhou H, Qian H, Bu X, Chen D, Gu H, Zhu W, Yan Y, Mao F: Combination of circulating CXCR4 and Bmi-1 mRNA in plasma: a potential novel tumor marker for gastric cancer. Mol Med Report. 2009, 2 (5): 765-771.CrossRef
9.
Tammela T, Zarkada G, Wallgard E, Murtomaki A, Suchting S, Wirzenius M, Waltari M, Hellstrom M, Schomber T, Peltonen R, Freitas C, Duarte A, Isoniemi H, Laakkonen P, Christofori G, Yla-Herttuala S, Shibuya M, Pytowski B, Eichmann A, Betsholtz C, Alitalo K: Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature. 2008, 454 (7204): 656-660. 10.1038/nature07083.CrossRefPubMed
10.
Laakkonen P, Waltari M, Holopainen T, Takahashi T, Pytowski B, Steiner P, Hicklin D, Persaud K, Tonra JR, Witte L, Alitalo K: Vascular endothelial growth factor receptor 3 is involved in tumor angiogenesis and growth. Cancer Res. 2007, 67 (2): 593-599. 10.1158/0008-5472.CAN-06-3567.CrossRefPubMed
11.
Han FH, Li HM, Zheng DH, He YL, Zhan WH: The effect of the expression of vascular endothelial growth factor (VEGF)-C and VEGF receptor-3 on the clinical outcome in patients with gastric carcinoma. Eur J Surg Oncol. 2010, 36 (12): 1172-1179. 10.1016/j.ejso.2010.09.002.CrossRefPubMed
12.
Choi JH, Oh YH, Park YW, Baik HK, Lee YY, Kim IS: Correlation of vascular endothelial growth factor-D expression and VEGFR-3-positive vessel density with lymph node metastasis in gastric carcinoma. J Korean Med Sci. 2008, 23 (4): 592-597. 10.3346/jkms.2008.23.4.592.CrossRefPubMedPubMedCentral
13.
Sung JY, Lee S, Kim YW, Park YK: Vascular endothelial growth factor receptor-3 is a favorable prognostic factor in advanced gastric carcinoma. Oncol Rep. 2008, 19 (4): 939-944.PubMed
14.
Juttner S, Wissmann C, Jons T, Vieth M, Hertel J, Gretschel S, Schlag PM, Kemmner W, Hocker M: Vascular endothelial growth factor-D and its receptor VEGFR-3: two novel independent prognostic markers in gastric adenocarcinoma. J Clin Oncol. 2006, 24 (2): 228-240.CrossRefPubMed
15.
Zhao BC, Wang ZJ, Mao WZ, Ma HC, Han JG, Zhao B, Xu HM: CXCR4/SDF-1 axis is involved in lymph node metastasis of gastric carcinoma. World J Gastroenterol. 2011, 17 (19): 2389-2396. 10.3748/wjg.v17.i19.2389.CrossRefPubMedPubMedCentral
16.
Ying J, Xu Q, Zhang G, Liu B, Zhu L: The expression of CXCL12 and CXCR4 in gastric cancer and their correlation to lymph node metastasis. Med Oncol. 2012, 29 (3): 1716-1722. 10.1007/s12032-011-9990-0.CrossRefPubMed
17.
Gockel I, Schimanski CC, Heinrich C, Wehler T, Frerichs K, Drescher D, von Langsdorff C, Domeyer M, Biesterfeld S, Galle PR, Junginger T, Moehler M: Expression of chemokine receptor CXCR4 in esophageal squamous cell and adenocarcinoma. BMC Cancer. 2006, 6: 290-10.1186/1471-2407-6-290.CrossRefPubMedPubMedCentral
18.
Ozmen F, Ozmen MM, Ozdemir E, Moran M, Seckin S, Guc D, Karaagaoglu E, Kansu E: Relationship between LYVE-1, VEGFR-3 and CD44 gene expressions and lymphatic metastasis in gastric cancer. World J Gastroenterol. 2011, 17 (27): 3220-3228.PubMedPubMedCentral
19.
Qin XJ, Dai DJ, Gao ZG, Huan JL, Zhu L: Effect of lentivirus-mediated shRNA targeting VEGFR-3 on proliferation, apoptosis and invasion of gastric cancer cells. Int J Mol Med. 2011, 28 (5): 761-768.PubMed
20.
Shimizu K, Kubo H, Yamaguchi K, Kawashima K, Ueda Y, Matsuo K, Awane M, Shimahara Y, Takabayashi A, Yamaoka Y, Satoh S: Suppression of VEGFR-3 signaling inhibits lymph node metastasis in gastric cancer. Cancer Sci. 2004, 95 (4): 328-333. 10.1111/j.1349-7006.2004.tb03211.x.CrossRefPubMed
21.
Yonemura Y, Fushida S, Bando E, Kinoshita K, Miwa K, Endo Y, Sugiyama K, Partanen T, Yamamoto H, Sasaki T: Lymphangiogenesis and the vascular endothelial growth factor receptor (VEGFR)-3 in gastric cancer. Eur J Cancer. 2001, 37 (7): 918-923. 10.1016/S0959-8049(01)00015-6.CrossRefPubMed
22.
Koizumi K, Kato S, Sakurai H, Hashimoto I, Yasumoto K, Saiki I: Therapeutics target of CXCR4 and its downstream in peritoneal carcinomatosis of gastric cancer. Front Biosci (Schol Ed). 2012, 4: 269-276.CrossRef
23.
Iwasa S, Yanagawa T, Fan J, Katoh R: Expression of CXCR4 and its ligand SDF-1 in intestinal-type gastric cancer is associated with lymph node and liver metastasis. Anticancer Res. 2009, 29 (11): 4751-4758.PubMed
24.
Arigami T, Natsugoe S, Uenosono Y, Yanagita S, Arima H, Hirata M, Ishigami S, Aikou T: CCR7 and CXCR4 expression predicts lymph node status including micrometastasis in gastric cancer. Int J Oncol. 2009, 35 (1): 19-24.CrossRefPubMed
25.
Yasumoto K, Koizumi K, Kawashima A, Saitoh Y, Arita Y, Shinohara K, Minami T, Nakayama T, Sakurai H, Takahashi Y, Yoshie O, Saiki I: Role of the CXCL12/CXCR4 axis in peritoneal carcinomatosis of gastric cancer. Cancer Res. 2006, 66 (4): 2181-2187. 10.1158/0008-5472.CAN-05-3393.CrossRefPubMed
26.
Hashimoto I, Koizumi K, Tatematsu M, Minami T, Cho S, Takeno N, Nakashima A, Sakurai H, Saito S, Tsukada K, Saiki I: Blocking on the CXCR4/mTOR signalling pathway induces the anti-metastatic properties and autophagic cell death in peritoneal disseminated gastric cancer cells. Eur J Cancer. 2008, 44 (7): 1022-1029. 10.1016/j.ejca.2008.02.043.CrossRefPubMed
27.
Shah MA, Ramanathan RK, Ilson DH, Levnor A, D'Adamo D, O'Reilly E, Tse A, Trocola R, Schwartz L, Capanu M, Schwartz GK, Kelsen DP: Multicenter phase II study of irinotecan, cisplatin, and bevacizumab in patients with metastatic gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol. 2006, 24 (33): 5201-5206. 10.1200/JCO.2006.08.0887.CrossRefPubMed
28.
Okines AF, Langley RE, Thompson LC, Stenning SP, Stevenson L, Falk S, Seymour M, Coxon F, Middleton GW, Smith D, Evans L, Slater S, Waters J, Ford D, Hall M, Iveson TJ, Petty RD, Plummer C, Allum WH, Blazeby JM, Griffin M, Cunningham D: Bevacizumab with peri-operative epirubicin, cisplatin and capecitabine (ECX) in localised gastro-oesophageal adenocarcinoma: a safety report. Ann Oncol. 2013, 24 (3): 702-709. 10.1093/annonc/mds533.CrossRefPubMed
29.
Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, Lim HY, Yamada Y, Wu J, Langer B, Starnawski M, Kang YK: Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011, 29 (30): 3968-3976. 10.1200/JCO.2011.36.2236.CrossRefPubMed
30.
Moehler M, Mueller A, Trarbach T, Lordick F, Seufferlein T, Kubicka S, Geissler M, Schwarz S, Galle PR, Kanzler S: Cetuximab with irinotecan, folinic acid and 5-fluorouracil as first-line treatment in advanced gastroesophageal cancer: a prospective multi-center biomarker-oriented phase II study. Ann Oncol. 2011, 22 (6): 1358-1366. 10.1093/annonc/mdq591.CrossRefPubMed
31.
Moehler M, Mueller A, Hartmann JT, Ebert MP, Al-Batran SE, Reimer P, Weihrauch M, Lordick F, Trarbach T, Biesterfeld S, Kabisch M, Wachtlin D, Galle PR: An open-label, multicentre biomarker-oriented AIO phase II trial of sunitinib for patients with chemo-refractory advanced gastric cancer. Eur J Cancer. 2011, 47 (10): 1511-1520. 10.1016/j.ejca.2011.04.006.CrossRefPubMed
32.
Wehler T, Wolfert F, Schimanski CC, Gockel I, Herr W, Biesterfeld S, Seifert JK, Adwan H, Berger MR, Junginger T, Galle PR, Moehler M: Strong expression of chemokine receptor CXCR4 by pancreatic cancer correlates with advanced disease. Oncol Rep. 2006, 16 (6): 1159-1164.PubMed
33.
Gockel I, Moehler M, Frerichs K, Drescher D, Trinh TT, Duenschede F, Borschitz T, Schimanski K, Biesterfeld S, Herzer K, Galle PR, Lang H, Junginger T, Schimanski CC: Co-expression of receptor tyrosine kinases in esophageal adenocarcinoma and squamous cell cancer. Oncol Rep. 2008, 20 (4): 845-850.PubMed
34.
Drescher D, Moehler M, Gockel I, Frerichs K, Muller A, Dunschede F, Borschitz T, Biesterfeld S, Holtmann M, Wehler T, Teufel A, Herzer K, Fischer T, Berger MR, Junginger T, Galle PR, Schimanski CC: Coexpression of receptor-tyrosine-kinases in gastric adenocarcinoma–a rationale for a molecular targeting strategy?. World J Gastroenterol. 2007, 13 (26): 3605-3609.CrossRefPubMedPubMedCentral
35.
Ni XF, Wu CP, Jiang JT: Serum VEGFR-3 and survival of advanced gastric cancer patients treated with FOLFOX. World J Gastroenterol. 2010, 16 (17): 2163-2169. 10.3748/wjg.v16.i17.2163.CrossRefPubMedPubMedCentral
36.
DePrimo SE, Bello C: Surrogate biomarkers in evaluating response to anti-angiogenic agents: focus on sunitinib. Ann Oncol. 2007, 18 (Suppl 10): 11-19.CrossRef
37.
Rini BI, Michaelson MD, Rosenberg JE, Bukowski RM, Sosman JA, Stadler WM, Hutson TE, Margolin K, Harmon CS, DePrimo SE, Kim ST, Chen I, George DJ: Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma. J Clin Oncol. 2008, 26 (22): 3743-3748. 10.1200/JCO.2007.15.5416.CrossRefPubMed
38.
Moehler M, Frings C, Mueller A, Gockel I, Schimanski CC, Biesterfeld S, Galle PR, Holtmann MH: VEGF-D expression correlates with colorectal cancer aggressiveness and is downregulated by cetuximab. World J Gastroenterol. 2008, 14 (26): 4156-4167. 10.3748/wjg.14.4156.CrossRefPubMedPubMedCentral
39.
Lyros O, Mueller A, Heidel F, Schimanski CC, Gockel I, Galle PR, Lang H, Moehler M: Analysis of anti-proliferative and chemosensitizing effects of sunitinib on human esophagogastric cancer cells: synergistic interaction with vandetanib via inhibition of multi-receptor tyrosine kinase pathways. Int J Cancer. 2010, 127 (5): 1197-1208.CrossRefPubMed
40.
Zhao B, Yang P, Yang J, Cai D: A randomized trial of somatostatin to regulate the VEGFs/VEGFRs in patients with gastric cancer. Hepatogastroenterology. 2011, 58 (109): 1425-1430. 10.5754/hge10749.CrossRefPubMed
41.
Aleksic T, Feller SM: Gamma-secretase inhibition combined with platinum compounds enhances cell death in a large subset of colorectal cancer cells. Cell Commun Signal. 2008, 6: 8-10.1186/1478-811X-6-8.CrossRefPubMedPubMedCentral
42.
Man CH, Wei-Man Lun S, Wai-Ying Hui J, To KF, Choy KW, Wing-Hung Chan A, Chow C, Tin-Yun Chung G, Tsao SW, Tak-Chun Yip T, Busson P, Lo KW: Inhibition of NOTCH3 signalling significantly enhances sensitivity to cisplatin in EBV-associated nasopharyngeal carcinoma. J Pathol. 2012, 226 (3): 471-481. 10.1002/path.2997.CrossRefPubMed
43.
Xie L, Wei J, Qian X, Chen G, Yu L, Ding Y, Liu B: CXCR4, a potential predictive marker for docetaxel sensitivity in gastric cancer. Anticancer Res. 2010, 30 (6): 2209-2216.PubMed
44.
Persons DL, Yazlovitskaya EM, Pelling JC: Effect of extracellular signal-regulated kinase on p53 accumulation in response to cisplatin. J Biol Chem. 2000, 275 (46): 35778-35785. 10.1074/jbc.M004267200.CrossRefPubMed
45.
Makinen T, Veikkola T, Mustjoki S, Karpanen T, Catimel B, Nice EC, Wise L, Mercer A, Kowalski H, Kerjaschki D, Stacker SA, Achen MG, Alitalo K: Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J. 2001, 20 (17): 4762-4773. 10.1093/emboj/20.17.4762.CrossRefPubMedPubMedCentral
46.
Roland J, Murphy BJ, Ahr B, Robert-Hebmann V, Delauzun V, Nye KE, Devaux C, Biard-Piechaczyk M: Role of the intracellular domains of CXCR4 in SDF-1-mediated signaling. Blood. 2003, 101 (2): 399-406. 10.1182/blood-2002-03-0978.CrossRefPubMed
47.
Ganju RK, Brubaker SA, Meyer J, Dutt P, Yang Y, Qin S, Newman W, Groopman JE: The alpha-chemokine, stromal cell-derived factor-1alpha, binds to the transmembrane G-protein-coupled CXCR-4 receptor and activates multiple signal transduction pathways. J Biol Chem. 1998, 273 (36): 23169-23175. 10.1074/jbc.273.36.23169.CrossRefPubMed
48.
Wang JF, Park IW, Groopman JE: Stromal cell-derived factor-1alpha stimulates tyrosine phosphorylation of multiple focal adhesion proteins and induces migration of hematopoietic progenitor cells: roles of phosphoinositide-3 kinase and protein kinase C. Blood. 2000, 95 (8): 2505-2513.PubMed
49.
Vila-Coro AJ, Rodriguez-Frade JM, Martin De Ana A, Moreno-Ortiz MC, Martinez AC, Mellado M: The chemokine SDF-1alpha triggers CXCR4 receptor dimerization and activates the JAK/STAT pathway. FASEB J. 1999, 13 (13): 1699-1710.PubMed
50.
Rakitina TV, Vasilevskaya IA, O'Dwyer PJ: Additive interaction of oxaliplatin and 17-allylamino-17-demethoxygeldanamycin in colon cancer cell lines results from inhibition of nuclear factor kappaB signaling. Cancer Res. 2003, 63 (24): 8600-8605.PubMed
Metadata
Title
VEGFR-3 and CXCR4 as predictive markers for treatment with fluorouracil, leucovorin plus either oxaliplatin or cisplatin in patients with advanced esophagogastric cancer: a comparative study of the Arbeitsgemeinschaft Internistische Onkologie (AIO)
Authors
Thomas Thomaidis
Annett Maderer
Salah-Eddin Al-Batran
Janis Kany
Claudia Pauligk
Kristina Steinmetz
Arno Schad
Ralf Hofheinz
Harald Schmalenberg
Nils Homann
Peter Robert Galle
Markus Moehler
Publication date
01-12-2014
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2014
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-14-476

Other articles of this Issue 1/2014

BMC Cancer 1/2014 Go to the issue

Research article

Systemic neutralization of IL-17A significantly reduces breast cancer associated metastasis in arthritic mice by reducing CXCL12/SDF-1 expression in the metastatic niches

Research article

COUP-TFI modifies CXCL12 and CXCR4 expression by activating EGF signaling and stimulates breast cancer cell migration

Research article

Prognostic implication of intratumoral metabolic heterogeneity in invasive ductal carcinoma of the breast

Research article

Men’s knowledge and attitudes towards dietary prevention of a prostate cancer diagnosis: a qualitative study

Study protocol

Study design and methods for the Breast Cancer and Exercise Trial in Alberta (BETA)

Research article

Mutational profiling of kinases in glioblastoma
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits