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Originally published as JCO Early Release 10.1200/JCO.2009.24.8021 on November 30 2009 © 2010 American Society of Clinical Oncology.
Biomarkers of Antiangiogenic Therapy: How Do We Move From Candidate Biomarkers to Valid Biomarkers?Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA With the increasing use of antiangiogenic agents for the treatment of cancers, establishing biomarkers of response and resistance has become a priority for oncologists and pharmaceutical companies. This urgency comes from the need to select the patients most likely to benefit from these high-cost therapies. It also stems from the necessity of identifying new targets to prevent the invariable escape from these therapies, which target specifically or primarily the vascular endothelial growth factor (VEGF) pathway.1 But the much needed biomarkers remain elusive. One of the reasons is the still unclear mechanism(s) of action of these drugs. Blocking VEGF can have antivascular and normalizing effects on the tumor vasculature, which may not necessarily translate into clinical responses as evaluated by criteria based on tumor size measurements such as the Response Evaluation Criteria in Solid Tumors.2 Moreover, excessive antivascular effects (when using high doses) might induce a transient response, but could lead to severe toxicities, as well as to more aggressive tumors, as seen in mouse models.3–6 Similarly, vascular normalization alone (with no cytotoxic treatment) might not be sufficient to shrink tumors or halt their growth, as demonstrated in mice.7 Finally, some of the actions of antiangiogenic agents could be systemic. For example, antiangiogenic agents could affect trafficking and function of hematopoietic progenitor cells and effector immune cells.8,9 This could result in promotion or delay in tumor growth depending on the hematopoietic cell type involved. Given this complexity, it is most likely that for each cancer and each agent, we might need a specific set of biomarkers for good prediction, and that these biomarkers will be mechanism specific. Ideally, these biomarkers should be relatively easy to measure by imaging or in bodily fluids using standardized protocols. For plasma or serum biomarkers, this could be achieved readily, given the multiple and reliable options to measure various proteins. To date, only a few randomized trials have retrospectively integrated circulating biomarker evaluations, and unfortunately, none have yet identified a valid circulating biomarker candidate.1 In non–small-cell lung cancer (NSCLC), the anti-VEGF antibody bevacizumab was shown to be effective when combined with chemotherapy in two randomized phase III trials.10,11 In a phase II/III study of bevacizumab with chemotherapy in NSCLC patients, a high baseline circulating plasma VEGF level did not predict patient survival, despite correlating with the response evaluated by Response Evaluation Criteria in Solid Tumors.12 Similarly, baseline soluble intracellular adhesion molecule 1 (sICAM1) was an independent prognostic factor of overall survival in patients treated with chemotherapy with chemotherapy alone or with bevacizumab. No correlation was seen with other intuitive biomarker candidates, such as basic fibroblast growth factor or sE-Selectin.12 Therefore, identifying biomarker candidates for prospective evaluation in randomized antiangiogenic trials remains an outstanding challenge in NSCLC and other cancers. The comprehensive biomarker study by Hanrahan et al13 published in this issue of Journal of Clinical Oncology is a step in the right direction. These investigators explored a set of 35 plasma biomarkers in NSCLC patients at four time-points after antiangiogenic therapy alone with the VEGF receptor 2 tyrosine kinase inhibitor (TKI) vandetanib, chemotherapy alone, or a combination of the two. Vandetanib monotherapy transiently increased the levels of circulating interleukin 8 (IL-8; at day 8) and VEGF (at day 43), and decreased the levels of its soluble receptor VEGF receptor 2 (sVEGFR2; at day 43). In contrast, chemotherapy alone did not change circulating VEGF or IL-8, but transiently decreased sVEGFR2, IL–1 receptor antagonist, matrix metalloproteinase 9, and IL-12, and increased monocyte chemotactic protein-1 plasma levels at day 8. Surprisingly, vandetanib with chemotherapy did not significantly change circulating VEGF, sVEGFR2 or IL-8 levels, but transiently decreased IL-12 and matrix metalloproteinase 9, and increased monocyte chemotactic protein-1 in plasma at day 8. Hanrahan et al also explored possible correlations between the changes in these biomarkers after treatment and the outcome in individual patients. They report that lower levels of sICAM1 at day 8 after treatment were significantly associated with poorer treatment outcome in the groups of patients who received vandetanib. Although exploratory in nature and with a relatively modest sample size, Hanrahan et al13 report data from a randomized, three-arm trial. The study has important implications. First, it confirms that pursuing mechanistic biomarkers (ie, circulating proteins with known pro- or antiangiogenic activity) shortly after treatment initiation might be a fruitful approach, as many of the biomarker changes occur rapidly after the onset of therapy. Consistent with this, we have shown that circulating biomarkers (ie, circulating collagen IV) could be combined with magnetic resonance imaging biomarkers to generate a so-called mechanistic biomarker such as the vascular normalization index. This index might predict survival in patients with brain tumor treated with another VEGFR TKI, cediranib as early as 1 day after treatment.14 Second, the study by Hanrahan et al13 further supports the hypothesis that the changes in circulating VEGF and sVEGFR2 are specific to anti-VEGF therapy and might hold pharmacodynamic biomarker value—as previously suggested by multiple single-arm phase II trials of antiangiogenic therapies. In this context, it is important to note that antiangiogenic agents also increase plasma placenta growth factor levels and that bevacizumab and anti-VEGF receptor TKIs may have opposite effects on circulating sVEGFR2.1 However, the biomarker value and the functional significance of the changes in VEGF, placenta growth factor-1, or sVEGFR2 after treatment remain unclear, and should be established by future prospective studies. Third, Hanrahan et al13 reemphasize the potential role of inflammatory chemokines in tumor resistance to antiangiogenic therapy. In particular, a greater increase in IL-8 early after treatment with vandetanib and chemotherapy correlated with inferior progression-free survival, supporting the hypothesis that IL-8–driven angiogenesis could compensate for VEGF pathway blockade.15 Increases in other chemokines such as stromal cell-derived factor 1-alpha (chemokine [C-X-C motif] ligand 12) and IL-6 have been correlated with progression through anti-VEGF therapy in other cancers, and these targets can be inhibited with drugs.16–18 Corroborated with preclinical evidence,9,19 these clinical findings warrant future studies of targeting inflammatory pathways to overcome resistance to antiangiogenic therapy. Hanrahan et al13 also raise important questions regarding the use of anti-VEGF TKIs alone or in combination with chemotherapy. Monotherapy with multitargeted TKIs that possess activity against VEGFRs—such as sorafenib or sunitinib—is now a standard of care for a number of cancers (renal cell or hepatocellular carcinomas). However, no anti-VEGFR TKI has shown efficacy when combined with chemotherapy in any of the many phase III trials published to date. This in sharp contrast with bevacizumab, which has shown efficacy only with chemotherapy in phase III trials in NSCLC and other cancers.1,11,20–22 The reasons for these contrasting effects remain elusive, but biomarker studies might shed light into this issue. Compared with other anti-VEGFR TKIs (eg, cediranib, sunitinib), vandetanib has a relatively modest TKI activity against VEGFR2. This might be reflected by the transient, inconsistent, and relatively modest changes in plasma VEGF and sVEGFR2 after vatalanib in NSCLC—as reported by Hanrahan et al13—as compared with the significant and sustained changes in these potential pharmacodynamic biomarkers after therapy with more potent anti-VEGFR inhibitors such as cediranib or sunitinib in other cancers.1 Nevertheless, vandetanib inhibits both epidermal growth factor receptor and VEGFR2—considered valid targets for therapy in NSCLC. But vandetanib alone has shown less efficacy than doublet chemotherapy in NSCLC.23 Moreover, although the risk of progression tended to be reduced for patients receiving vandetanib with chemotherapy (n = 56) versus chemotherapy alone (n = 52; hazard ratio = 0.76; one-sided P = .098), the addition of vandetanib did not significantly affect overall survival.23,24 Whether any anti-VEGFR TKIs will prove efficacious with chemotherapy in NSCLC or other cancers remains to be seen. This re-emphasizes the need to learn more about potential biomarkers that would predict treatment outcome after anti-VEGF therapy with vandetanib or other antiangiogenic agents. It also highlights the great importance of deciphering the mechanisms of resistance to inhibition of VEGFR2 or epidermal growth factor receptor. Thus, these candidate biomarkers should continue to be actively explored in trials of antiangiogenic agents in patients, to get closer to the goal of improving and individualizing cancer therapy. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Rakesh K. Jain, AstraZeneca (C), Dyax (C), Millenium (C), SynDevRx (U) Stock Ownership: Rakesh K. Jain, SynDevRx Honoraria: Rakesh K. Jain, Pfizer Research Funding: Rakesh K. Jain, AstraZeneca, Dyax Expert Testimony: None Other Remuneration: None AUTHOR CONTRIBUTIONS Manuscript writing: Dan G. Duda, Marek Ancukiewicz, Rakesh K. Jain Final approval of manuscript: Dan G. Duda, Marek Ancukiewicz, Rakesh K. Jain
NOTES See accompanying editorial on page 185 and articles on pages 193 and 207 REFERENCES 1. Jain RK, Duda DG, Willett CG, et al: Biomarkers of response and resistance to antiangiogenic therapy. Nat Rev Clin Oncol 6:327–338, 2009.[CrossRef][Medline] 2. Jain RK, Duda DG, Clark JW, et al: Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nat Clin Pract Oncol 3:24–40, 2006.[CrossRef][Medline] 3. Ebos JM, Lee CR, Cruz-Munoz W, et al: Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15:232–239, 2009.[CrossRef][Medline] 4. Loges S, Mazzone M, Hohensinner P, et al: Silencing or fueling metastasis with VEGF inhibitors: Antiangiogenesis revisited. Cancer Cell 15:167–170, 2009.[CrossRef][Medline] 5. Paez-Ribes M, Allen E, Hudock J, et al: Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15:220–231, 2009.[CrossRef][Medline] 6. Jain RK: A new target for tumor therapy. N Engl J Med 360:2669–2671, 2009. 7. Kamoun WS, Ley CD, Farrar CT, et al: Edema control by cediranib, a VEGF targeted kinase inhibitor, prolongs survival despite persistent brain tumor growth in mice. J Clin Oncol 27:2542–2552, 2009. 8. Hamzah J, Jugold M, Kiessling F, et al: Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature 453:410–414, 2008.[CrossRef][Medline] 9. Kerbel RS: Tumor angiogenesis. N Engl J Med 358:2039–2049, 2008. 10. Reck M, von Pawel J, Zatloukal P, et al: Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non–small-cell lung cancer: AVAil. J Clin Oncol 27:1227–1234, 2009. 11. Sandler A, Gray R, Perry MC, et al: Paclitaxel-carboplatin alone or with bevacizumab for non–small-cell lung cancer. N Engl J Med 355:2542–2550, 2006. 12. Dowlati A, Gray R, Johnson DH, et al: Prospective correlative assessment of biomarkers in E4599 randomized phase II/III trial of carboplatin and paclitaxel ± bevacizumab in advanced non–small-cell lung cancer (NSCLC). J Clin Oncol 24S:7027; 2006. 13. Hanrahan EO, Lin HY, Kim ES, et al: Distinct patterns of cytokine and angiogenic factor modulation and markers of benefit for vandetanib and/or chemotherapy in patients with non–small-cell lung cancer. J Clin Oncol 28:193–201, 2010. 14. Sorensen AG, Batchelor TT, Zhang WT, et al: A "vascular normalization index" as potential mechanistic biomarker to predict survival after a single dose of cediranib in recurrent glioblastoma patients. Cancer Res 69:5296–5300, 2009. 15. Mizukami Y, Jo WS, Duerr EM, et al: Induction of interleukin-8 preserves the angiogenic response in HIF-1alpha–deficient colon cancer cells. Nat Med 11:992–997, 2005.[Medline] 16. Batchelor TT, Sorensen AG, di Tomaso E, et al: AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature, and alleviates edema in glioblastoma patients. Cancer Cell 11:83–95, 2007.[CrossRef][Medline] 17. Willett CG, Duda DG, di Tomaso E, et al: Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: A multidisciplinary phase II study. J Clin Oncol 27:3020–3026, 2009. 18. Zhu AX, Sahani DV, Duda DG, et al: Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: A phase II study. J Clin Oncol 27:3027–3035, 2009. 19. Shojaei F, Wu X, Malik AK, et al: Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nat Biotechnol 25:911–920, 2007.[CrossRef][Medline] 20. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342, 2004. 21. Miller K, Wang M, Gralow J, et al: Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357:2666–2676, 2007. 22. Giantonio BJ, Catalano PJ, Meropol NJ, et al: Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: Results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25:1539–1544, 2007. 23. Heymach JV, Paz-Ares L, De Braud F, et al: Randomized phase II study of vandetanib alone or with paclitaxel and carboplatin as first-line treatment for advanced non–small-cell lung cancer. J Clin Oncol 26:5407–5415, 2008. 24. Hanrahan EO, Ryan AJ, Mann H, et al: Baseline vascular endothelial growth factor concentration as a potential predictive marker of benefit from vandetanib in non–small-cell lung cancer. Clin Cancer Res 15:3600–3609, 2009.
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Copyright © 2010 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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