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Originally published as JCO Early Release 10.1200/JCO.2005.03.6913 on December 19 2005 © 2006 American Society of Clinical Oncology.
When Does the Presence of the Target Predict Response to the Targeted Agent?University of California, San Francisco, Comprehensive Cancer Center, San Francisco, CA The last decade has been marked by major advances in the field of biologically based therapies for solid tumors and the approval of several new therapeutic strategies. Despite the rational basis for these new treatments, the identification and validation of markers of prognostic and predictive value remains a challenge. Correlative data from studies with imatinib, trastuzumab, and epidermal growth factor receptor inhibitors suggest that the presence of the target does not guarantee a response to therapy.1-5 The successful determination of accurate prognostic and predictive markers hinges on establishing reproducible, sensitive methods of marker detection and unraveling the key components of the molecular pathways affected by a specific therapy. Angiogenesis is required for tumor growth and metastasis and is an attractive target for biologically based cancer therapy.6,7 It is a complicated, multistep process regulated by the balance of endogenous stimulatory and inhibitory factors elaborated by tumor cells and other cell types. Because of its seemingly pivotal role in tumor-associated angiogenesis across a wide range of malignancies, vascular endothelial growth factor-A (VEGF-A; commonly referred to as VEGF) has emerged as a central therapeutic target in cancer.8 VEGF is a potent, direct acting regulator of angiogenesis that signals through several receptor tyrosine kinases. Its expression is upregulated in virtually all types of cancer, and tumor-associated VEGF levels frequently correlate with microvascular density and predict for disease recurrence and decreased survival.9 Multiple isoforms are coexpressed in cancers, but the relative importance of individual splice variants remains ill defined.10 Bevacizumab (BV), a recombinant humanized monoclonal antibody directed against VEGF was approved by the US Food and Drug Administration in 2004 for use in patients with previously untreated metastatic colorectal cancer (mCRC). This was on the basis of data suggesting that the addition of BV to chemotherapy improves response rate, progression-free survival, and overall survival compared with chemotherapy alone.11 BV is generally well tolerated, but is associated with hypertension and small, but clinically significant, increases in GI perforations and arterial thromboembolic events.11 Recently, data from other phase III studies have further validated VEGF as a therapeutic target in cancer.12-14 Despite the overall impact of BV on survival in mCRC, the determinants of clinical benefit on an individual level remain undefined. Given the recent advances in our understanding of VEGF biology and the strong scientific rationale underlying this therapeutic strategy, it follows that the identification of valid prognostic and predictive markers for patients treated with BV should be feasible. In the accompanying article in this issue of the Journal of Clinical Oncology, Jubb et al15 explore the impact of VEGF expression, thrombospondin-2 expression and microvessel density (MVD) on the treatment effect of BV in metastatic colorectal cancer. The choice of potential markers reflects reports suggesting that 50% to 70% of colorectal cancers express VEGF, and the level of tumor-associated VEGF expression correlates with MVD and correlates inversely with prognosis.16-18 In addition to VEGF family members, a number of other regulators of angiogenesis (both positive and negative) are upregulated in colorectal cancer, although the relative importance of individual factors is unknown.19 Thrombospondin (THBS)-1 and THBS-2 have antiangiogenic activity, and both isoforms are expressed in human CRC.20,21 THBS-2 has been implicated in the inhibition of angiogenesis, even in the setting of high VEGF expression, and mRNA levels have been reported to correlate inversely with MVD and metastases.21,22 The authors performed a retrospective subset analysis using samples available from the 813 patients with untreated metastatic CRC (mCRC) randomly assigned to receive chemotherapy (irinotecan, fluorouracil, leucovorin [IFL]) with or without BV.11 Samples were available for approximately 35% of the patients, and 90% of the samples were from primary tumors. Epithelial and stromal VEGF expression were assessed at the level of protein (overall and maximal intensity) and mRNA on tissue microarrarys and whole sections. THBS-2 mRNA expression was scored in tumor-associated stroma. MVD was assessed in "hot spots" by immunohistochemistry as a continuous variable, as well as with varying cutoffs to define high and low MVD. Although the MVD score correlated with VEGF expression, none of the markers proved to be significant prognostic or predictive factors. Thus, the addition of BV to IFL in patients with mCRC improves survival regardless of the level of VEGF expression, THBS-2 mRNA expression, or MVD; none of the markers discriminate between patients more or less likely to benefit from the addition of BV to first-line chemotherapy. Assuming that the characteristics of the subgroup reflected those of the group as a whole, a larger sample size would probably not have changed the conclusion. At first glance, these findings appear to be at odds with previously published data related to prognostic markers in CRC and the concept that the presence of the target should predict response to therapy. However, these results are consistent with data generated from patients with chemotherapy-refractory breast cancer, suggesting that level of VEGF expression in the primary tumor does not predict response to BV in patients with metastatic disease.23 Furthermore, on closer inspection, the prognostic value of VEGF and MVD in CRC is somewhat controversial (perhaps as a result of differences in cohorts or methodology).24,25 Prognostic factors typically refer to markers that predict outcome independent of the administered treatment, and predictive markers are those that help distinguish patients who are more or less likely to respond to a specific treatment (and can be used to guide the choice of a particular therapy). Ultimately, one must have confidence in the method of measurement (including cut points), an accurate estimate of marker prevalence in the target population and an understanding of specificity of the marker to the disease of interest.26 Despite the use of high-quality reagents, optimal methodology, and the careful assessment of the stained tumor section, variability—including the storage period for cut tissue sections, the type of fixative used, the detection system and the interpretation of the samples—can be introduced at multiples steps.27 Thus, the choice of marker could be appropriate, but its value obscured by suboptimal methods of sample processing, marker detection, or scoring. Furthermore, a combination of markers or "signature" might prove to be of greater prognostic or predictive value than a single factor. For example, recent data suggest that the balance between the angioinhibitory factor THBS and the angiogenic factor VEGF may be key a determinant of prognosis in CRC.21,28 The optimal method for quantifying tumor-associated microvessels has not been established.29 MVD has historically been assessed by immunohistochemistry; however, different endothelial cell antigens (eg, CD31, CD34, CD105, and factor VIII/vWF) may select for specific endothelial cell populations such that the choice of antibody may have important implications. With respect to VEGF expression, the relative increase in tumor-associated VEGF mRNA expression throughout CRC progression is relatively small (eg, 1.4- to four-fold); presumably small changes in VEGF mRNA levels may result in biologically relevant effects that are disproportionate to the detectable level of protein.30 Furthermore, the binding of VEGF to its receptors invokes a complex series of molecular events within the cell, including direct activation of the intracellular signaling pathways and coactivation of other membrane-bound tyrosine kinase receptors.31 The location and function of the VEGF receptors vary by type. In addition to that documented on endothelial cells, receptor expression has been documented on dendritic cells, some tumor cells, hematopoietic stem cells, and lymphatic endothelial cell precursors. In addition to VEGF (VEGF-A), several other members of the VEGF family of proteins exist, and the interactions between the different ligands and their receptors are complex and overlapping. The role of other VEGF family members in malignant disease needs to be further characterized, but redundancy, cross talk and autocrine circuits appear to exist within the VEGF signaling pathways in colorectal cancer. VEGF-A, VEGF-C, and VEGF-D are expressed in human CRC samples, and VEGF receptor-2 (VEGFR-2) is expressed by some tumors cells, raising the possibility that VEGF inhibitors might have direct effects on tumor cell growth.32,33 Given the diversity of the signaling network, it is possible that the predictive value of the level of VEGF expression would increase if considered in the context of other determinants of pathway activity (such as specific isoforms, other ligands, receptors and coreceptors, and downstream signaling components) as well as the cross talk that exists with other signaling cascades. Support for this concept stems from data suggesting that VEGF bioavailability, not total expression, determines the response to ligand-based VEGF inhibition.34 To this end, the pattern of specific VEGF-A isoform expression, might also influence the response to therapy without substantial changes in total VEGF mRNA expression.35 Faced with the cellular and regional heterogeneity that exists within a tumor (eg, epithelium v stroma, leading edge v invasive edge), the subjectivity that is associated with scoring VEGF expression, and the complexity of the VEGF signaling pathway, perhaps it is unrealistic to expect that the level of VEGF expression (regardless of the method of detection) would predict response to BV.28 Ultimately, the identification of valid predictive markers is likely to hinge on elucidating the precise mechanism by which BV exerts its effect in vivo (both as a single agent and in combination with other therapies). Several potential mechanisms have been postulated, including inhibiting the survival signals for VEGF-dependent immature vessels, normalizing the vasculature so as to improve delivery of chemotherapy, inhibiting the growth of new vessels and/or the recruitment of circulating endothelial progenitors, direct effects on VEGFR-2–expressing tumor cells, and enhancing the antitumor immune response.36 Regardless of the choice of marker and method of detection, another issue of fundamental importance is the utility of archived primary tumor samples to assess the prognostic and predictive value of markers in patients with metastatic disease. A number of disparities between the characteristics of primary tumor tissue and that of metastatic disease have been described. Hepatic metastases have been documented to have a significantly higher apoptotic index, decreased MVD, lower proliferative index, and decreased VEGFR-2 compared to primary colon tumors.37,38 The level of VEGF expression may be site specific in patients with metastatic disease, with decreased expression noted in liver metastases relative to primary tumors and abdominal metastases.38,39 These data suggest that metastatic tumors are biologically distinct from the primary tumors from which they arose and call into question the value of archived primary tumor samples for assessing potential prognostic and predictive markers in patients with metastatic disease. It is also possible that the prognostic significance of VEGF or MVD is greatest in early stage CRC, such that primary tumor samples are uninformative in patients with advanced disease. Correlative studies on prospectively collected primary colon cancer samples from patients enrolled onto several of the recent cooperative group adjuvant studies (eg, Cancer and Leukemia Group B [CALGB] 89,803, CALGB 9581, and National Surgical Adjuvant Breast and Bowel Project [NSABP]-C-08) should provide key information about the prognostic or predictive value of candidate markers such as VEGF and MVD in primary CRC. Similar studies on prospectively collected samples from metastatic deposits are greatly needed. The challenges associated with identifying and validating predictive and prognostic markers in human tumor samples have led to intense interest in surrogate markers of activity (eg, markers of pharmacodynamic effect) that can be assessed over time. Markers that integrate the effects of multiple signals and/or are components of a final common pathway are particularly attractive. Since the acquisition of serial tumor biopsies is generally impractical, efforts have focused largely on the use of circulating markers (such as plasma levels of soluble VEGFR-1 and VEGF) and noninvasive imaging techniques.40-42 An emerging body of data also suggests that relative levels of circulating peripheral blood endothelial cells (CECs) and/or their putative, bone marrow–derived progenitor subset (CEPs) may serve as surrogate markers of antiangiogenic activity.43 Evidence for an antiangiogenic effect was demonstrated in a phase I trial in human rectal cancer exploring surrogate markers of activity.44 A single infusion of BV decreased tumor perfusion and vascular volume (as measured by functional computed tomography), MVD, and interstitial fluid pressure. In addition, treatment reduced the number of viable CECs/CEPs and increased the fraction of tumor-associated vessels with pericyte coverage, suggesting several candidate end points for future studies. More than ever, patients and physicians have choices regarding treatment options for mCRC. The advances in our understanding of the molecular mechanisms underlying disease progression have left us poised to individualize and optimize therapy based on the potential benefits and risks for a given patient. Despite the incremental advances that have resulted from the availability of BV, it is important to remember that the median survival for mCRC is still less than 2 years, and fewer than half of all patients experience a major radiographic response to therapy. In light of the rapidly changing landscape for the treatment for CRC, we are faced with the challenge of choosing from a variety of agents, sequences of applications, and combinations of drugs. In addition, as the indications for BV broaden (possibly even to the adjuvant setting), identification of patients at risk for important adverse effects such as GI perforation and arterial thromboembolic events will be essential. Future efforts should continue to be aimed at exploring the mechanisms of action of BV, the relationship between marker expression and outcome and the best use of accessible tumor tissue. A deeper understanding of the relationship between the signaling pathways driving tumor growth and their inhibition is required in order to optimize the use of anti-VEGF or other biologically targeted agents in the clinic, and should suggest strategies to delay or prevent resistance and identify appropriate combinations of targeted therapy. Author's Disclosures of Potential Conflicts of Interest
The author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
Author Contributions
REFERENCES
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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