Cancer de mama

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antiangiogenic clinical strategies

Biomarkers of response and resistance to antiangiogenic therapy
Rakesh K. Jain, Dan G. Duda, Christopher G. Willett, Dushyant V. Sahani, Andrew X. Zhu, Jay S. Loeffler, Tracy T. Batchelor and A. Gregory Sorensen
abstract | No validated biological markers (or biomarkers) currently exist for appropriately selecting patients with cancer forantiangiogenic therapy. Nor are there biomarkers identifying escape pathways that should be targeted after tumors develop resistance to a given antiangiogenic agent. A number of potential systemic, circulating, tissue and imaging biomarkers have emerged from recently completed phase i–iii studies. some of these are measured at baseline (for example veGF polymorphisms), others are measured during treatment(such as hypertension, Mri‑measured Ktrans, circulating angiogenic molecules or collagen iv), and all are mechanistically based. some of these biomarkers might be pharmacodynamic (for example, increase in circulating veGF, placental growth factor) while others have potential for predicting clinical benefit or identifying the escape pathways (for example, stromal‑cell‑derived factor 1α,interleukin‑6). Most biomarkers are disease and/or agent specific and all of them need to be validated prospectively. we discuss the current challenges in establishing biomarkers of antiangiogenic therapy, define systemic, circulating, tissue and imaging biomarkers and their advantages and disadvantages, and comment on the future opportunities for validating biomarkers of antiangiogenic therapy.
Jain, r. K. etal. Nat. Rev. Clin. Oncol. 6, 327–338 (2009); doi:10.1038/nrclinonc.2009.63

Introduction

tumors acquire blood vessels by co-option of neighboring vessels, from sprouting or intussusceptive microvascular growth and by vasculogenesis from endothelial precursor cells.1 in most solid tumors the newly formed vessels are plagued by structural and functional abnormalities owing to the sustainedand excessive exposure to angiogenic factors produced by the growing tumor.2 Despite being abnormal, these new vessels allow tumor expansion at early stages of carcinogenesis and progression from in situ lesions to locally invasive, and eventually to metastatic tumors. the hypothesis that tumor progression can be arrested by antiangiogenesis3 has been confirmed experimentally by a large body ofevidence over the past three decades. enhanced survival of patients has yet to be achieved in phase iii clinical trials by antiangiogenic agents that only target veGF. nevertheless, the addition of bevacizumab (a veGF-specific blocking antibody) to standard chemotherapies or to interferon therapy (in metastatic renal cell
competing interests r. K. Jain declares associations with the followingcompanies: AstraZeneca, Dyax, Millenium, Pfizer, roche and synDevrx. C. G. willett declares associations with the following company: Genentech. A. X. Zhu declares associations with the following companies: Bayer and Genentech. T. T. Batchelor declares associations with the following companies: AstraZeneca, eMD‑serono, exelixis, Genentech, imClone systems, Millenium and schering‑Plough. A. G. sorensendeclares associations with the following companies: AstraZeneca, exelixis, Genentech, Millenium, Novartis and schering‑Plough. see the article online for full details of the relationships. The other authors declare no competing interests.

carcinoma [mrCC]), as well as the use of anti-veGF receptor tyrosine kinase inhibitors (tKis) with wide spectra of activity, has proven efficacious in multipleadvanced cancers such as metastatic colorectal cancer (mCrC), metastatic non-small-cell lung cancer (mnsClC), metastatic breast cancer, mrCC, hepatocellular carcinoma (HCC) and gastrointestinal stromal tumors (Gists).4–12 moreover, bevacizumab has been recently approved for recurrent glioblastoma based on phase ii trial data. these agents have changed the practice of oncology but stimulated...
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