Surrogate Markers Of Angiogenesis Research Articles

Biomarkers for Monitoring Antiangiogenic Therapy

A variety of antiangiogenic agents are currently available for the treatment of renal cell carcinoma. With these exciting new therapeutic agents comes the challenge of elucidating useful biomarkers to monitor patients receiving these therapies. Although many patients benefit from antiangiogenic therapies, it is often by achieving stability of their disease. Thus, development of noninvasive biomarkers of disease response and relapse is a crucial objective to aid in the management of patients. The current technologies being explored in this field include circulating plasma proteins, cells, and nucleic acids and novel imaging techniques. Surrogate markers of angiogenesis could help with selecting patients for therapy, determining optimal dosing of therapy, deciding whether to change therapy, and assessing appropriate salvage therapy.

Drug Targets to Pro-Angiogenetic Factors with Special Reference to Primary Peritoneal Mesothelioma

Angiogenesis is necessary for growth and the spread of human tumors. Animal studies also suggest that angiogenesis is an important interspecies biological mechanism of tumor development. Angiogenesis is a complex multistep cascade modulated by both positive soluble factors, such as vascular endothelial growth factor, thymidine phosphorylase, basic-fibroblast growth factor and negative soluble factors such as angiostatin and endostatin. From the imbalance of the above angiogenesis regulators, tumor endothelial cells may divide up to 50 times more frequently than endothelial cells of normal tissue. Published studies have suggested that the assessment of microvessel density (MVD) or endothelial area (EA) can be considered as surrogate markers of angiogenesis with biological and prognostic relevance. Literature data on angiogenesis of mesothelioma are inconclusive, with only a few studies performed in primary peritoneal mesothelioma (PPM) due to the rarity of the disease. We assessed immunohistochemically MVD and EA and their biological and clinical significance in a consecutive series of 23 PPM cases. MVD and EA were detected in "hot spots" by a computerized image analyzer. The mean value of MVD and EA was 27 +/- 14 and 26.04 +/- 8.35 x10(-2) micro(2) per field (400x), respectively. Patients with a high MVD or EA tumors showed a more clinical aggressiveness due to the presence of ascites and a shorter overall survival. Our results suggest that PPM is an angiogenesis-dependent neoplasia. Therefore, antiangiogenic compounds should be tested particularly in those patients with highly vascularized PPM.

Comparative evaluation of microvessel density determined by CD34 or CD105 in benign and malignant gastric lesions

Microvessel density (MVD) is regarded as a surrogate marker for angiogenesis and has been used for tumor prognosis. In this study, MVD was identified immunohistochemically by monoclonal antibodies against CD105 and CD34 in the tissues representing gastric carcinoma, chronic gastritis, and hyperplastic polyps, and the results were correlated with clinicopathologic features. The expression of CD105 in the microvessels within benign lesions was barely visible, and MVD was markedly lower than that determined by CD34. CD34 was strongly expressed in the microvessels within hyperplastic polyps and tissues with gastritis. In gastric carcinoma, CD105 expression in microvessels was as high as the MVD, compared with benign lesions. CD105 stained well-formed mature and newly formed immature vessels within the cancer mass. Correlation analysis showed that MVD determined by CD105 correlated with blood vessel invasion, distant metastasis, and formation of ascites. Survival analysis demonstrated an inverse correlation between MVD count and overall survival: patients with MVD counts of 32 or higher survived for a much shorter time than those with counts lower than 32. Multivariate analysis confirmed that MVD determined by CD105 was an independent prognostic factor for survival. Microvessel density determined by CD34 inversely correlated with overall survival, but it did not correlate with other clinicopathologic parameters except formation of ascites. In conclusion, CD34 was universally expressed in blood vessels within benign and malignant tissues, whereas CD105 expression was minimal in benign tissues but stronger in gastric carcinoma. These data suggest that both CD105 and CD34 could be used for quantification of angiogenesis, but preference should be given to CD105 in the evaluation of prognosis in gastric carcinoma.

Highly Efficacious Nontoxic Preclinical Treatment for Advanced Metastatic Breast Cancer Using Combination Oral UFT-Cyclophosphamide Metronomic Chemotherapy

Metronomic antiangiogenic chemotherapy, the prolonged administration of relatively low drug doses, at close regular intervals with no significant breaks, has been mainly studied at the preclinical level using single chemotherapeutic drugs, frequently in combination with a targeted antiangiogenic drug, and almost always evaluated on primary localized tumors. We tested a "doublet" combination metronomic chemotherapy treatment using two oral drugs, UFT, a 5-fluorouracil (5-FU) prodrug administered by gavage, and cyclophosphamide, for efficacy and toxicity in a new mouse model of advanced, terminal, metastatic human breast cancer. The optimal biological dose of each drug was first determined by effects on levels of circulating endothelial progenitor cells as a surrogate marker for angiogenesis, which was assessed to be 15 mg/kg for UFT and 20 mg/kg for cyclophosphamide. A combination treatment was then evaluated in mice with advanced metastatic disease using a serially selected metastatic variant of the MDA-MB-231 breast cancer-cell line, 231/LM2-4. UFT or cyclophosphamide treatment showed only very modest survival advantages whereas a combination of the two resulted in a remarkable prolongation of survival, with no evidence of overt toxicity despite 140 days of continuous therapy, such that a significant proportion of mice survived for over a year. In contrast, this striking therapeutic effect of the combination treatment was not observed when tested on primary orthotopic tumors. We conclude that combination oral low-dose daily metronomic chemotherapy, using cyclophosphamide and UFT, is superior to monotherapy and seems to be a safe and highly effective experimental antimetastatic therapy, in this case, for advanced metastatic breast cancer.

In vivo mapping of the effects of radiotherapy on neovascular permeability using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI)

3550 Background: Neoadjuvant therapy is an integral part of rectal cancer management. Prediction of response to radiotherapy (RT) is highly relevant for both further surgery and prognosis in these patients. In a rat colorectal cancer model, we studied the use of DCE-MRI with a new macromolecular rapid clearance contrast agent (P792) to visualize tumor vascular permeability as a surrogate marker for angiogenesis and evaluate the effect of RT. Methods: Male WAG/Rij rats were injected with 2x106 CC531 cells in the hind leg. Once the tumor reached a diameter of 1 cm, DCE-MRI with high temporal resolution was performed before and 5 days after 5x500 cGy of external RT. The DCE-MRI data were used to generate parametric tissue permeability maps of the endothelial transfer constant (Ktrans) according to the Tofts-Kermode two compartment mathematical model. Separate region of interest (ROI) analyses were performed of the entire tumor (T), periferal vascular rim (P) and tumor core (C). In order to differentiate permeability changes from flow and oxygenation effects of RT, fiber optic tissue pO2 and microcirculatory laser blood flow (LBF) histogram mapping was performed in each tumor before and after RT using a stepwise micromanipulator technique. Results: The biophysical properties of P792 allowed excellent discrimination between tumor and normal tissue. Mean Ktrans (ml/min/1000g tissue) value changes measured over all pixels in a ROI were as follows: T: 24.03 vs 5.47 (p<0.05); P: 29.7 vs 10.4 (p<0.05); and C: 8.65 vs 0.47 (p<0.05) before and after radiotherapy. Microcirculatory LBF (arbitrary units) decreased from 117.3 to 84.7 (p<0.001) after RT. All tumors were severely hypoxic with a mean tissue pO2 over a 4 mm trajectory of 3.5 mm Hg before and 5.6 mm Hg after RT (p<0.001). Conclusions: High temporal resolution DCE-MRI with P792 allows non-invasive imaging and quantification of neovascular permeability in this colorectal cancer model. Administration of RT significantly reduces permeability and microcirculatory flow. RT enhanced oxygenation, but all tumors remained severely hypoxic after radiotherapy. DCE-MRI could have an important role in therapy monitoring. No significant financial relationships to disclose.

Effect of bevacizumab and chemotherapy on serum levels of sVCAM-1 in patient with inflammatory and locally advanced breast cancer

611 Background: Levels of serum vascular cell adhesion molecule (sVCAM-1), a potential surrogate marker for angiogenesis, are elevated in breast cancer. This study aims to assess changes in sVCAM-1...

Clinical results and impact on circulating endothelial cells (CEC) of treatment with combinations of interferon-α(Iα), thalidomide (T) and celecoxib (C) in patients with solid tumors

3193 Background: Iα, T and C have antiangiogenic activity in preclinical models. CEC and apoptotic CEC are promising surrogate markers of angiogenesis. Methods: We conducted a phase II study to evaluate combinations of Iα, T and C; endpoints were long-term tolerability, activity and effect on CEC. Eligible patients (pts) had slow growing advanced solid tumors, with progressive disease (PD) at recruitment. They were randomized to: A. Iα + T (19 pts), B. Iα + C (18 pts), C. T + C (19 pts), and further to add the third drug after 2 months of therapy (28 pts) or not (28 pts). Iα was given 0.5 MU/12 hrs s.c., T 100 mg/d orally, C 200 mg/12 hrs orally. CEC and apoptotic CEC were measured by flow cytometry every 2 months. Results: Of 56 pts enrolled from 01/02 to 09/04 (hepatocellular carcinoma: 18, renal: 17, other: 21), 51 are assessable. Median time to progression was 6 months (Kaplan-Meier estimate). We observed 1 (2%) partial response (PR) and 34 (61%) stable disease (SD), with 21 pts (38%, 95%CI: 25–51%) s...

Assessment of microvascular perfusion changes in a rat breast tumor model using SonoVue™ to monitor the effects of different anti-angiogenic therapies

Angiogenesis is a critical step in the progression and metastasis of tumor cells[ 1 Carmeliet P. Jain R.K. Angiogenesis in cancer and other diseases. Nature. 2000; 407: 249-257 Crossref PubMed Scopus (7203) Google Scholar ]. Considerable efforts have been directed to quantitatively detect tumor angiogenesis as well as to monitor the impact of various treatments on the angiogenesis process[ 2 Fanelli M. et al. Assessment of tumor vascularization immunohistochemical and non-invasive methods. Int J Biol Markers. 1999; 14: 218-231 PubMed Google Scholar , 3 Ruegg C. et al. The quest for surrogate markers of angiogenesis a paradigm for translational research in tumor angiogenesis and anti-angiogenesis trials. Curr Mol Med. 2003; 3: 673-691 Crossref PubMed Scopus (40) Google Scholar ]. Histology (i.e. determination of intratumoral microvessel density) is the most popular but is also the most invasive procedure. An additional limitation of this approach is that it does not provide information on the effective perfusion through the vessels. Moreover it reflects only a single point in time and cannot be used as a way of monitoring in vivo changes induced by anti-angiogenesis therapy. Importantly, while microvessel density can be used to predict disease progression, it has no value in monitoring or predicting response to anti-angiogenic therapy[ 4 Kerbel R. et al. Clinical translation of angiogenesis inhibitors. Nat Rev Cancer. 2002; 2: 727-739 Crossref PubMed Scopus (1390) Google Scholar ]. Non-invasive methods using CT or MRI techniques are increasingly being used[ 5 Choyke P.L. et al. Special techniques for imaging blood flow to tumors. The Cancer J. 2002; : 109-118 Crossref PubMed Scopus (18) Google Scholar , 6 Lee T.Y. et al. CT imaging of angiogenesis. Q J Nucl Med. 2003; 47: 171-187 PubMed Google Scholar ]. For instance, in order to study tumor perfusion, dynamic contrast enhanced MRI (DCE-MRI) is performed[ 7 Neeman M. et al. Magnetic resonance imaging applications in the evaluation of tumor angiogenesis. Seminar in Radiation Oncology. 2001; 11: 70-82 Abstract Full Text PDF PubMed Scopus (55) Google Scholar , 8 Miles K.A. Tumor angiogenesis and its relation to contrast enhancement on Computed Tomography a review. Eur. J. of Radiol. 1999; 30: 198-205 Abstract Full Text Full Text PDF PubMed Scopus (253) Google Scholar ]. Typically the contrast agent used is a conventional freely diffusible gadolinium chelate. Time intensity curves are generated involving three distinct phases: the initial rate of enhancement, the time and intensity of the peak enhancement and the subsequent clearance or accumulation of contrast over time. DCE-MRI has been extensively used to evaluate breast cancer based on the assumption that malignant breast tumors show distinctive time intensity profiles compared to benign or less aggressive tumors. Kinetic modeling using contrast pharmecokinetics acquired from MRI images provides different functional information i.e. capillary permeability and blood volume as well as an estimate of tumor perfusion by comparing the maximal rate of tissue enhancement to the peak vascular enhancement.

Dynamic Gd‐DTPA enhanced MRI as a surrogate marker of angiogenesis in tissue‐engineered bladder constructs: A feasibility study in rabbits

To evaluate the potential of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to assess angiogenesis in tissue-engineered bladder constructs in a blinded animal study, and compare different analysis approaches and their correlation with microvessel density (MVD). Constructs fortified with vascular endothelial growth factor (VEGF) for enhanced vascularity were grafted onto the bladder in nine rabbits. DCE-MRI of Gd-DTPA uptake was performed and analyzed using Tofts' model, the area under the concentration time curve (AUC), and the uptake slope. DCE-MRI parameters were compared to MVD determined with CD31 immunohistochemistry. Significantly increased MVD was found in the high VEGF group (20 ng/g of tissue) but not at low VEGF (10 ng/g) (2.3x increase, P = 0.035 vs. 1.1x over control). Enhanced permeability at low VEGF was suggested by elevated K(trans), but overall correlation to MVD was poor. Significant correlation to MVD was obtained with AUC(8min) (r = 0.705, P = 0.034). Furthermore, AUC(8min) provided the most precise discrimination between different VEGF preparations and was the only parameter to show a significant increase (P = 0.0058) consistent with MVD changes at high VEGF. Findings support DCE-MRI for evaluating angiogenesis in bladder constructs and suggest vessel changes other than density. Future studies should incorporate larger contrast agents and permeability assessment to devise an optimal DCE-MRI strategy.

Randomized phase II trial of the anti-angiogenic potential of doxorubicin and docetaxel; primary chemotherapy as Biomarker Discovery Laboratory

Primary chemotherapy provides an ideal opportunity to correlate potential non-invasive surrogate markers of angiogenesis with tumor microvessel density (MVD) and response. Patients with newly diagnosed stages II or III breast cancer were treated with sequential doxorubicin 75 mg/M2 q2 wks x 3 and docetaxel 40 mg/M2 weekly x 6; treatment order was randomly assigned. Potential serologic and imaging markers of angiogenesis were obtained pre-treatment, at crossover and completion of chemotherapy. Non-invasive biomarkers were correlated with MVD and pathologic response. From June 1999 to October 2002, 70 patients were entered. Median pretreatment tumor diameter was 6.0 cm with clinically involved axillary nodes in 33 (47%) patients; 20% had inflammatory disease. Clinical response rate was 91%, including 46% clinical complete responses. Pathologic complete response (pCR) was confirmed in 9 (12.8%) patients. Baseline MVD did not correlate with clinical or pathologic response. Serologic markers were obtained in all patients; basic fibroblast growth factor (bFGF) was lower at baseline and increased during treatment in patients with a pCR but did not correlate with MVD. Color Doppler ultrasound (CDUS) was completed in 47 patients; no parameter reliably correlated with MVD or response. Positron emission tomography (PET) with [F-18]-fluoro-deoxyglucose, [O-15]-water and [C-11]-carbon monoxide were completed in 19 patients; uptake of all tracers decreased during treatment in virtually all patients. Sequential doxorubicin and docetaxel is generally well tolerated and highly active. Serum angiogenic factors and imaging parameters frequently varied throughout treatment but did not correlate with MVD or consistently predict response.

The quest for surrogate markers of angiogenesis: a paradigm for translational research in tumor angiogenesis and anti-angiogenesis trials

Inhibition of tumor angiogenesis suppresses tumor growth and metastatic spreading in many expérimental models, suggesting that anti-angiogenic drugs may be used to treat human cancer. During the past décade more than eighty molécules that showed anti-angiogenic activity in preclinical studies were tested in clinical cancer trials, but most of them failed to demonstrate any measurable antitum or activity and none have been approved for clinical use. Recent results stemming from trials with anti-VEGF antibodies, used alone or in combination with chemotherapy, suggest that systemic anti-angiogenic therapy may indeed have a measurable impact on cancer progression and patient survival. From the clinical studies it became nevertheless clear that the classical endpoints used in anti-cancer trials do not bring sufficient discriminative power to monitor the effects of anti-angiogenic drugs. It is therefore necessary to identify and validate molecular, cellular and functional surrogate markers of angiogenesis to monitor activity and efficacy of anti-angiogenic drugs in patients. Availability of such markers will be instrumental to re-evaluate the role of tumor angiogenesis in human cancer, to identify new molecular targets and drugs, and to improve planning, monitoring and interprétation of future studies. Future anti-angiogenesis trials integrating biological endpoints and surrogate markers or angiogenesis will require close collaboration between clinical investigators and laboratory-based researchers.

A randomised trial of carboplatin versus carboplatin and thalidomide in ovarian cancer, with evaluation of potential surrogate markers of angiogenesis

5024 Background: Thalidomide has anti-angiogenic activity and as a single agent induces responses in several tumour types. However, the activity and safety of thalidomide in combination with chemotherapy has not been assessed. In this study, we wished to evaluate if there was synergy with carboplatin in ovarian cancer. Methods: Patients with stage IC–IV ovarian cancers were randomised to receive either carboplatin (C) (AUC 7) alone every 4 weeks (6 cycles) or carboplatin and thalidomide (CT) 100 mg daily for 6 months, between 1997–2002. Ca125 and surrogate markers of angiogenesis, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), von Willebrands factor (vWF), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin were measured in the serum pre- treatment and after each cycle of chemotherapy. Sensory nerve action potentials (SNAP) were performed every 2 months in all patients. Results: 40 patients (Median age: 67.2yrs, range 39 to 83) were entered in the study [20 (C) and 20 (CT)] and 15 were alive at last follow up. There was no significant difference in clinical characteristics between the two groups. Overall response rate (CR+PR) was 90% in C group and 75% in CT group. There was no neurotoxicity (> Grade 1) in any patient due to thalidomide. No significant difference in toxicities or QoL (EORTC QLQ-C 30) was observed between the two groups. There was a significant fall in serum E-selectin and VCAM with treatment in both groups (p <0.02), similar to Ca 125. However, none of the surrogate markers differed significantly between the two groups in evaluable patients. Conclusions: Low dose oral thalidomide can be safely administered in combination with carboplatin chemotherapy. Chemotherapy alone with carboplatin can affect markers of angiogenesis, and this is due to tumour response. The addition of thalidomide did not significantly alter the markers (in comparison to carboplatin alone) which were evaluated. No significant financial relationships to disclose.

A randomised trial of carboplatin versus carboplatin and thalidomide in ovarian cancer, with evaluation of potential surrogate markers of angiogenesis

5024 Background: Thalidomide has anti-angiogenic activity and as a single agent induces responses in several tumour types. However, the activity and safety of thalidomide in combination with chemotherapy has not been assessed. In this study, we wished to evaluate if there was synergy with carboplatin in ovarian cancer. Methods: Patients with stage IC–IV ovarian cancers were randomised to receive either carboplatin (C) (AUC 7) alone every 4 weeks (6 cycles) or carboplatin and thalidomide (CT) 100 mg daily for 6 months, between 1997–2002. Ca125 and surrogate markers of angiogenesis, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), von Willebrands factor (vWF), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin were measured in the serum pre- treatment and after each cycle of chemotherapy. Sensory nerve action potentials (SNAP) were performed every 2 months in all patients. Results: 40 patients (Median age: 67.2yrs, range 39 to 83) were entered in the study [...

The quest for surrogate markers of angiogenesis: a paradigm for translational research in tumor angiogenesis and anti-angiogenesis trials.

Inhibition of tumor angiogenesis suppresses tumor growth and metastatic spreading in many experimental models, suggesting that anti-angiogenic drugs may be used to treat human cancer. During the past decade more than eighty molecules that showed anti-angiogenic activity in preclinical studies were tested in clinical cancer trials, but most of them failed to demonstrate any measurable anti-tumor activity and none have been approved for clinical use. Recent results stemming from trials with anti-VEGF antibodies, used alone or in combination with chemotherapy, suggest that systemic anti-angiogenic therapy may indeed have a measurable impact on cancer progression and patient survival. From the clinical studies it became nevertheless clear that the classical endpoints used in anti-cancer trials do not bring sufficient discriminative power to monitor the effects of anti-angiogenic drugs. It is therefore necessary to identify and validate molecular, cellular and functional surrogate markers of angiogenesis to monitor activity and efficacy of anti-angiogenic drugs in patients. Availability of such markers will be instrumental to re-evaluate the role of tumor angiogenesis in human cancer, to identify new molecular targets and drugs, and to improve planning, monitoring and interpretation of future studies. Future anti-angiogenesis trials integrating biological endpoints and surrogate markers or angiogenesis will require close collaboration between clinical investigators and laboratory-based researchers.

Angiogenesis occurs in hairy cell leukaemia (HCL) and in NOD/SCID mice transplanted with the HCL line Bonna-12.

Microvessel density (MVD), a surrogate marker for angiogenesis, was evaluated by anti-CD34 and CD105 monoclonal antibodies (Abs), and found to be increased in the bone marrow (BM) of hairy cell leukaemia (HCL) patients and in a preclinical model of non-obese diabetic/severe combined immunodeficient mice transplanted with the HCL line Bonna-12. The anti-CD105 Ab was significantly more sensitive than anti-CD34 Ab in identifying blood vessels. The BM tumour burden significantly decreased in patients treated with interferon-alpha, but the mean value of MVD remained unchanged. These data suggest that angiogenesis may be involved in the pathogenesis of HCL.

Microvessel density, a surrogate marker of angiogenesis, is significantly related to survival in multiple myeloma patients.

We evaluated microvessel density (MVD) in bone marrow biopsies (BM) from multiple myeloma (MM) patients after staining with anti-CD34 and anti-CD105 antibodies (mAbs). The anti-CD105 mAb was significantly more sensitive than the anti-CD34 mAb in visualizing blood vessels both in controls and MM samples. MVD was significantly higher in MM than in controls with both anti-CD34 and anti-CD105 mAbs. Patients with low CD34+ MVD survived longer than patients with higher MVD (P = 0.01), whereas there was no difference in survival between patients with low and high CD105+ MVD. Multivariate analysis confirmed the independent significant association between CD34+ MVD and survival (P = 0.001).

Serum Vascular Endothelial Growth Factor and Serum Leptin in Patients with Cervical Cancer

Objective. Serum levels of vascular endothelial growth factor (VEGF) can be seen as surrogate markers of angiogenesis. Recently, leptin, which is involved in the control of satiety and energy expenditure, was also shown to modulate angiogenesis. As angiogenesis plays an abundant role in cervical carcinogenesis, we evaluated serum VEGF and leptin in patients with cervical intraepithelial neoplasia (CIN) and cervical cancer.Methods. Serum VEGF and leptin were measured in 84 patients with cervical cancer, in 28 patients with CIN I–III, and in 35 healthy women, using a commercially available enzyme-linked immunosorbent assay and radioimmunoassay, respectively.Results. Serum VEGF was significantly elevated in patients with cervical cancer and in patients with CIN I–III compared to healthy women. In patients with cervical cancer serum VEGF was significantly correlated with tumor stage, but not with lymph node involvement and histological grade. Univariate and multivariate analyses showed that elevated pretreatment serum VEGF was not associated with the duration of disease-free and overall survival. Serum leptin did not differ among patients with cervical cancer, patients with CIN I–III, and healthy women. Serum leptin was significantly correlated with body mass index (BMI). All further analyses were performed with absolute and serum leptin corrected by BMI. No differences in serum leptin could be ascertained between patients with cervical cancer and patients with CIN I–III. Serum leptin was not associated with any clinicopathological parameter and patients' survival. No correlation between serum VEGF and leptin was found.Conclusions. It can be speculated that serum VEGF might be used as a surrogate marker of angiogenesis in patients with cervical cancer. Our data support the concept that VEGF plays a role in malignant transformation and tumor growth, but not in the lymphatic spread of cervical cancer. This is the first report on leptin in a gynecological malignancy. Our results show that serum leptin falls short of being a useful marker in patients with cervical cancer.

Tumor angiogenesis of low-grade astrocytomas measured by dynamic susceptibility contrast-enhanced MRI (DSC-MRI) is predictive of local tumor control after radiation therapy

Purpose: To assess regional cerebral blood volume (rCBV) as a surrogate marker of angiogenesis in patients with low-grade fibrillary astrocytoma before radiation therapy and to correlate measured values with clinical outcome after fractionated stereotactic radiotherapy (FSRT).Methods: Twenty-five patients with histologically proven fibrillary astrocytomas were examined using dynamic susceptibility contrast-enhanced MRI before radiotherapy. Radiotherapy was delivered to mean and median total doses of 60.9 and 60 Gy, respectively (range 55.8–66 Gy). During MRI for treatment planning, 55 T2∗-weighted gradient echo images were acquired before, during, and after i.v. contrast-bolus injection. The acquired signal-time curves were converted into concentration-time curves. By normalization to an arterial input function, absolute and relative rCBV values were calculated. Measured pretherapeutic rCBV data were correlated to outcome in terms of local control after FSRT.Results: Mean pretherapeutic rCBV for astrocytomas was 6.5 ± 3.7 ml/100 g tissue. Mean and median follow-up times were 47.8 and 52 months, respectively. Fifteen tumors recurred during the period, with a mean and median latency of 39.1 and 42 months, respectively. Tumors recurring earlier than 42 months after FSRT showed a higher pretreatment rCBV than tumors recurring later and tumors in continued local control (8.12 ± 4.48 ml/100 g vs. 6.0 ± 2.3 ml/100 g and 4.73 ± 2.47 ml/100 g; p = 0.02 and p = 0.03). The respective ratios of tumor rCBV in early recurrent tumors to gray matter and white matter rCBV were 0.98 ± 0.38 and 2.17 ± 1.36 as compared with 0.79 ± 0.14 and 1.44 ± 0.29 in locally controlled tumors (p = 0.074 and p = 0.056).Conclusions: In fibrillary low-grade astrocytomas, a noninvasive assessment of angiogenesis as indicated by rCBV measurement was feasible. The present data suggest that high pretherapeutic angiogenic activity in low-grade astrocytomas indicates a subgroup of tumors at higher risk for early local recurrence or malignant transformation after FSRT.

Serum soluble vascular cell adhesion molecule-1: role as a surrogate marker of angiogenesis.

Angiogenesis, the development of new blood vessels from pre-existing vasculature, is a prerequisite for tumor growth and metastasis. Surrogate markers for angiogenesis would be useful for studying the effectiveness of antiangiogenesis drugs. We examined the potential of three serum glycoproteins-vascular cell adhesion molecule-1 (VCAM-1), endothelial selectin (E-selectin), and von Willebrand factor (VWF)-to serve as markers for angiogenesis. Preoperative serum levels of VCAM-1, E-selectin, and VWF were measured by enzyme-linked immunosorbent assay in 93 women with early breast cancer and were compared with microvessel density in each tumor, histologic features, and recurrence after surgery. Serum samples were taken from 55 women with advanced breast cancer who were commencing hormonal therapy, both immediately before therapy and 3 months later. Changes in serum levels of VCAM-1, E-selectin, and VWF were compared with the response of the disease to hormonal therapy assessed 6 months after the start of hormone therapy or at disease progression. All P: values are two-sided. In women with early breast cancer, serum levels of VCAM-1 (but not of E-selectin or VWF) correlated closely with microvessel density in tumors (r =.65; P:<.001), and women who developed early recurrence had higher preoperative levels of serum VCAM-1 than those who remained disease free (P: =.01). Serum VCAM-1 levels rose in women with advanced breast cancer whose disease progressed (P:<.001) but remained unchanged or fell in women with advanced breast cancer whose disease remained stable or showed a partial response to hormonal therapy. Serum VCAM-1 appears to be a surrogate marker of angiogenesis in breast cancer. Its measurement may, therefore, help in the assessment of antiangiogenesis drugs currently in phase II trials.

Prognostic value of vascular endothelial growth factor in breast cancer.

Angiogenesis, the process leading to the formation of new blood vessels from a preexisting vascular network, is necessary for tumor growth, invasion, and metastasis. Data from experimental and clinical studies indicate that breast carcinoma is an angiogenesis-dependent tumor. Most retrospective studies evaluating the prognostic value of determination of intratumoral microvessel density (IMD) at the vascular "hot spot" (a surrogate marker of angiogenesis) found that IMD is a significant and independent prognostic indicator in patients with both node-negative and node-positive breast cancers. More recently, the expression of certain endothelial growth factors has been tested. Among these, vascular endothelial growth factor (VEGF), the most potent endothelial cell mitogen and also a regulator of vascular permeability, is emerging as a powerful new prognostic tool. Eight of the nine published retrospective studies reported that VEGF is significantly associated with relapse-free survival, overall survival, or both. Patients with early stage breast cancer who have tumors with elevated levels of VEGF have a higher likelihood of recurrence or death than patients with low-angiogenic tumors, even if treated with conventional adjuvant therapy. High levels of VEGF can differentiate the subgroups of patients with breast cancer with poor prognosis who benefit minimally from conventional adjuvant therapy but who may benefit from validated anti-VEGF treatments.