- Email: [email protected]
First-Line Treatment with Bevacizumab and Paclitaxel Prolongs Progression-Free Survival in Metastatic Breast Cancer
research in
brief
First-Line Treatment with Bevacizumab and Paclitaxel Prolongs Progression-Free Survival in Metastatic Breast Cancer Rationale • Bevacizumab, a recombinant humanized monoclonal antibody, binds to vascular endothelial growth factor (VEGF), an important stimulator of angiogenesis, with a high affinity (Kd = 8 x 10–10).1-3 Overexpression of VEGF has been detected in human malignancies including lung, breast, gastrointestinal tract, kidney, bladder, ovary, and cervical cancers and is correlated with increased tumor vascularity and worse prognosis in patients with advanced cancer.4-6 • The VEGF exerts its effects on the vascular endothelial cell via 2 receptor tyrosine kinases (TKs), VEGFR1 and VEGFR2 (also known as Flt-1 and Flk1/KDR, respectively). Upon binding VEGF, the receptor undergoes homodimerization, resulting in autophosphorylation and activation of the intracellular TK domains of the receptor. Activation of the VEGF receptors leads to an increase in vascular permeability, allowing for the leakage of plasma proteins into the extracellular compartment that produces a gelatinous fibrin substrate that will support the growth and migration of endothelial cells.7 It also triggers a signaling cascade that results in upregulation of mitogenesis, chemotaxis,8 and survival signals9 in the endothelial cells. • The VEGF is a critical induction signal for angiogenesis in the embryo and in tumors; however, the survival of endothelial cells in mature vasculature is not VEGF-dependent.10 Therefore, VEGF represents an attractive molecular target for cancer therapy because disruption of VEGF signaling may Prepared by: Preeta Tyagi, PhD Reviewed by: Debu Tripathy, MD
prevent tumor-stimulated neovascularization without compromising the function of the existing vasculature. In preclinical studies, bevacizumab neutralized endothelial mitogenic and vascular permeability–enhancing activities of VEGF-α.11 • In animal models of glioblastoma multiforme, leiomyosarcoma, and rhabdomyosarcoma, treatment with bevacizumab reduced the extent of angiogenesis relative to control animals and inhibited tumor growth by 70%95%.12 The combination of anti-VEGF antibody and chemotherapy in nude mice injected with human cancer xenografts had an increased antitumor effect compared with antibody or chemotherapy alone.13 • Bevacizumab in combination with intravenous 5-fluorouracil–based chemotherapy showed the prolongation of survival by almost 5 months in metastatic colorectal cancer (CRC) and was subsequently approved by the United States Food and Drug Administration on February 26, 2004, for the first-line therapy of metastatic CRC.14 These encouraging results in CRC led to the exploration of bevacizumab in several other cancer types, including breast and lung.
• The Eastern Cooperative Oncology Group (ECOG) 4599 trial of carboplatin/paclitaxel with or without bevacizumab in advanced non–smallcell lung cancer showed a significant increase in survival from 10.2 months to 12.5 months with bevacizumab (P = 0.007).15 The clinical benefit extended to significant improvements in response rate (27% vs. 10%; P < 0.001) and progression-free survival (PFS; 6.4 months vs. 4.5 months; P < 0.0001). Grade 3/4 toxicities associated with bevacizumab treatment were hemorrhage, hemoptysis, and hypertension. • A phase III study of capecitabine with or without bevacizumab in previously treated metastatic breast cancer failed to demonstrate any significant increase in PFS (4.86 months vs. 4.17 months; P = 0.857) or overall survival (OS, 15.1 months vs. 14.5 months; P = not significant) with the addition of bevacizumab despite significant improvement in response rate (19.8% vs. 9.1%; P = 0.001) in the bevacizumab arm.16 The results from this trial suggest that bevacizumab combined with a fluoropyrimidine is an active regimen in CRC but does not seem to be as active in pretreated breast cancer.
Figure 1. E2100 Trial: Treatment Schema17
Eligibility: • Locally recurrent or metastatic breast cancer • Chemotherapy naive • ECOG PS of 0/1
R A N D O M I Z E
Arm 1 Bevacizumab 10 mg/kg on days 1 and 15 every 4 weeks Paclitaxel 90 mg/m2 on days 1, 8, and 15 every 4 weeks Arm 2 Paclitaxel 90 mg/m2 on days 1, 8, and 15 every 4 weeks
Clinical Breast Cancer June 2005 • 105
research in
brief
Table 1. E2100 Trial: Efficacy17 Bevacizumab/ Paclitaxel
Paclitaxel
HR
P Value
Intent-to-treat
28
14
NR
< 0.0001
Measurable disease
34
16
NR
< 0.0001
10.97
6.11
0.498
< 0.001
NR
NR
0.674
0.01
Outcome Overall Response Rate (%)
PFS (Months) Overall Survival Abbreviation: NR = not reported
This randomized phase III trial of paclitaxel with or without bevacizumab was conducted in previously untreated patients with locally recurrent or metastatic breast cancer to evaluate if bevacizumab can prolong survival when given with a taxane instead of a fluropyrimidine in breast cancer.17
nervous system metastasis, significant proteinuria (> 500 mg per day) and use of anticoagulant medication. Patients were treated with paclitaxel 90 mg/m2 administered on days 1, 8, and 15 of a 4-week cycle with or without bevacizumab 10 mg/kg on days 1 and 15 (Figure 1).17 The primary endpoint was PFS.
Study Design
Results
Eligible patients were chemotherapy-naive with locally recurrent or metastatic breast cancer and were required to have an ECOG performance status (PS) of 0/1. Adjuvant taxane therapy was allowed if the disease-free interval (DFI) was > 1 year. No antitumor therapy within 3 weeks of enrollment was permitted. Other ineligibility criteria were presence of central
Seven hundred fifteen patients were accrued in this study over a period of 27 months. The results from the first planned interim analysis were presented at the 41st Annual Meeting of the American Society of Clinical Oncology in May 2005 and are summarized herein.17 Of 715 patients, 365 patients were treated with bevacizumab/paclitaxel and 350 patients were treated with pa-
ECOG 2100 Trial
Table 2. E2100 Trial: Grade 3/4 Toxicity17 Bevacizumab/ Paclitaxel (%)
Paclitaxel (%)
P Value
Hypertension
13.3
0
< 0.0001
Proteinuria
2.4
0
0.0004
Bleeding
0.9
0
NR
Neuropathy
20.5
14.2
0.01
Throboembolic Events
1.3*
1.3
NR
5
2.7*
NR
Neutropenia
5.3
3†
NR
Decrease in LVEF
0.3
0
NR
Toxicity
Fatigue
*Grade 3 only. †Grade 4 only. Abbreviations: LVEF = left ventricular ejection fraction; NR = not reported
106 • Clinical Breast Cancer June 2005
clitaxel only. Baseline patient characteristics in terms of median age (56 years in the bevacizumab/paclitaxel arm vs. 55 years in the paclitaxel-only arm), DFI ≤ 24 months (41% in each), presence of ≥ 3 metastatic sites (28% vs. 29%), adjuvant chemotherapy (65% vs. 64%), and estrogen receptor positivity (64% vs. 63%) were well balanced between treatment groups. The primary endpoint of PFS was statistically prolonged by > 4.5 months with bevacizumab combined with chemotherapy compared with chemotherapy alone (10.97 months vs. 6.11 months; hazard ratio [HR], 0.498; P < 0.001; Table 1).17 Additionally, a statistically significant relative increase in OS of 33% was reported in the bevacizumab arm (HR, 0.674; P = 0.01). The overall response rate (ORR) was significantly higher in patients in the intent-to-treat group who received treatment with bevacizumab/paclitaxel versus those who were treated with paclitaxel only (28% vs. 14%; P < 0.0001). This improvement in ORR with bevacizumab was even more prominent in the subset of patients with measurable disease (34% vs. 16%; P < 0.0001). Grade 3/4 toxicities reported in only the bevacizumab arm were hypertension (13.3%; P < 0.0001), proteinuria (2.4%; P = 0.0004), and bleeding (0.9%; P = not reported; Table 2).17 Of note, no grade 4 thromboembolic event was reported in the bevacizumab/paclitaxel arm. Grade 3/4 neuropathy was experienced by significantly more patients treated with bevacizumab/paclitaxel compared with paclitaxel only (20.5% vs. 14.2%; P = 0.01). Other grade 3/4 toxicities reported in more patients who received combination treatment relative to paclitaxel monotherapy were fatigue (5% vs. 2.7% grade 3 only), neutropenia (5.3% vs. 3% grade 4 only), and decrease in left ventricular ejection fraction (0.3% vs. zero).
Clinical Relevance This groundbreaking trial has opened the doors for the addition of an
anti-VEGF agent to standard chemotherapy for improving ORR, prolonging PFS, and possibly improving the OS compared with chemotherapy alone in patients with metastatic breast cancer. After encouraging results in colorectal and lung cancer, now bevacizumab has shown promising activity in combination with standard first-line chemotherapy in metastatic breast cancer. The results from this trial suggest that bevacizumab is a reasonable option in patients suitable for first-line paclitaxel therapy or other chemotherapy, provided safety data are available for that combination and the patients fit the profile of the patient population on this bevacizumab/paclitaxel phase III trial. As a result of bevacizumab related toxicities, patient history (specifically in regard to thrombosis, bleeding, and hypertension) should be carefully evaluated before initiating treatment with bevacizumab. For example, this trial required that all patients undergo computed tomography or magnetic resonance imaging of the head to exclude brain metastases.
References
1. Fernando NH, Hurwitz HI. Inhibition of vascular endothelial growth factor in the treatment of colorectal cancer. Semin Oncol 2003; 30:39-50. 2. McMahon G. VEGF receptor signaling in tumor angiogenesis. Oncologist 2000; 5(suppl 1):3-10. 3. Ferrara N. Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: therapeutic implications. Semin Oncol 2002; 29(suppl 16):10-14. 4. Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev 1997; 18:4-25. 5. Takahashi Y, Kitadai Y, Bucana CD, et al. Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res 1995; 55:3964-3968. 6. Takahashi Y, Tucker SL, Kitadai Y, et al. Vessel counts and expression of vascular endothelial growth factor as prognostic factors in node-negative colon cancer. Arch Surg 1997; 132:541-546. 7. Dy GK, Adjei AA. Novel targets for lung cancer therapy: part II. J Clin Oncol 2002; 20:3016-3028. 8. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 1989; 246:1306-1309. 9. Nor JE, Christensen J, Mooney DJ, et al. Vascular endothelial growth factor (VEGF)-mediated angiogenesis is associated with enhanced endothelial cell survival and induction of Bcl-2 expression. Am J Pathol 1999; 154:375-384. 10. Fernando NH, Hurwitz HI. Inhibition of vascular endothelial growth factor in the treatment of colorectal cancer. Semin Oncol 2003; 30:39-50. 11. Kim KJ, Li B, Houck K, et al. The vascular endothelial growth factor proteins: identifi-
12.
13.
14.
15.
16.
17.
cation of biologically relevant regions by neutralizing monoclonal antibodies. Growth Factors 1992; 7:53-64. Kim KJ, Li B, Winer J, et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 1993; 362:841-844. Borgstrom P, Gold DP, Hillan KJ, Ferrara N. Importance of VEGF for breast cancer angiogenesis in vivo: implications from intravital microscopy of combination treatments with an anti-VEGF neutralizing monoclonal antibody and doxorubicin. Anticancer Res 1999; 19:4203-4214. FDA Approves First Angiogenesis Inhibitor to Treat Colorectal Cancer [press release]. February 26, 2004. Rockville, MD: FDA, 2004. Available at: http://www.fda.gov/bbs/ topics/news/2004/new01027.html. Accessed June 18, 2004. Sandler AB, Gray R, Brahmer J, et al. Randomized phase II/III Trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC # 704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): an Eastern Cooperative Oncology Group (ECOG) Trial - E4599. Presented at the 41st Annual Meeting of the American Society of Clinical Oncology; May 13-17, 2005; Orlando, FL. Abstract LBA4. Miller KD, Chap LI, Holmes FA, et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005; 23:792-799. Miller KD, Wang M, Gralow J, et al. E2100: a randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as firstline therapy for locally recurrent or metastatic breast cancer. Presented at the 41st Annual Meeting of the American Society of Clinical Oncology; May 13-17, 2005; Orlando, FL. Available at: http://www.asco .org/ac/1,1003,_12-002511-00_18-003400_19-005814-00_21-00,00.asp. Accessed June 24, 2005.
LY N N S A G E B R E A S T C A N C E R S Y M P O S I U M
Confirmed Symposium Speakers
October 6-9, 2005 Sheraton Chicago Hotel and Towers CHAIR CO-CHAIRS
Lynn Sage Distinguished Lecturer Gabriel Hortobagyi, MD President-Elect , ASCO
7
William J. Gradishar, MD V. Craig Jordan, OBE, PhD, DSc Monica Morrow, MD
Kathy Albain, MD Thomas Buchholz, MD Hal Burstein, MD, PhD Aman Buzdar, MD Rowan Chlebowski, MD, PhD Charles Clevenger, MD, PhD Carol Fabian, MD Gary Freedman, MD Armando Giuliano, MD Lori Goldstein, MD William Gradishar, MD V Craig Jordan, OBE, PhD, DSc Seema Khan, MD Terry Mamounas, MD Lavinia Middleton, MD Monica Morrow, MD Lisa Newman, MD, MPH C Kent Osborne, MD Peter Ravdin, MD, PhD Stuart Schnitt, MD Lawrence Solin, MD Sandy Swain, MD Laura van’t Veer, PhD Elizabeth Wiley, MD
For additional information, visit
cancer.northwestern.edu or call (312) 695-1392
brief
First-Line Treatment with Bevacizumab and Paclitaxel Prolongs Progression-Free Survival in Metastatic Breast Cancer Rationale • Bevacizumab, a recombinant humanized monoclonal antibody, binds to vascular endothelial growth factor (VEGF), an important stimulator of angiogenesis, with a high affinity (Kd = 8 x 10–10).1-3 Overexpression of VEGF has been detected in human malignancies including lung, breast, gastrointestinal tract, kidney, bladder, ovary, and cervical cancers and is correlated with increased tumor vascularity and worse prognosis in patients with advanced cancer.4-6 • The VEGF exerts its effects on the vascular endothelial cell via 2 receptor tyrosine kinases (TKs), VEGFR1 and VEGFR2 (also known as Flt-1 and Flk1/KDR, respectively). Upon binding VEGF, the receptor undergoes homodimerization, resulting in autophosphorylation and activation of the intracellular TK domains of the receptor. Activation of the VEGF receptors leads to an increase in vascular permeability, allowing for the leakage of plasma proteins into the extracellular compartment that produces a gelatinous fibrin substrate that will support the growth and migration of endothelial cells.7 It also triggers a signaling cascade that results in upregulation of mitogenesis, chemotaxis,8 and survival signals9 in the endothelial cells. • The VEGF is a critical induction signal for angiogenesis in the embryo and in tumors; however, the survival of endothelial cells in mature vasculature is not VEGF-dependent.10 Therefore, VEGF represents an attractive molecular target for cancer therapy because disruption of VEGF signaling may Prepared by: Preeta Tyagi, PhD Reviewed by: Debu Tripathy, MD
prevent tumor-stimulated neovascularization without compromising the function of the existing vasculature. In preclinical studies, bevacizumab neutralized endothelial mitogenic and vascular permeability–enhancing activities of VEGF-α.11 • In animal models of glioblastoma multiforme, leiomyosarcoma, and rhabdomyosarcoma, treatment with bevacizumab reduced the extent of angiogenesis relative to control animals and inhibited tumor growth by 70%95%.12 The combination of anti-VEGF antibody and chemotherapy in nude mice injected with human cancer xenografts had an increased antitumor effect compared with antibody or chemotherapy alone.13 • Bevacizumab in combination with intravenous 5-fluorouracil–based chemotherapy showed the prolongation of survival by almost 5 months in metastatic colorectal cancer (CRC) and was subsequently approved by the United States Food and Drug Administration on February 26, 2004, for the first-line therapy of metastatic CRC.14 These encouraging results in CRC led to the exploration of bevacizumab in several other cancer types, including breast and lung.
• The Eastern Cooperative Oncology Group (ECOG) 4599 trial of carboplatin/paclitaxel with or without bevacizumab in advanced non–smallcell lung cancer showed a significant increase in survival from 10.2 months to 12.5 months with bevacizumab (P = 0.007).15 The clinical benefit extended to significant improvements in response rate (27% vs. 10%; P < 0.001) and progression-free survival (PFS; 6.4 months vs. 4.5 months; P < 0.0001). Grade 3/4 toxicities associated with bevacizumab treatment were hemorrhage, hemoptysis, and hypertension. • A phase III study of capecitabine with or without bevacizumab in previously treated metastatic breast cancer failed to demonstrate any significant increase in PFS (4.86 months vs. 4.17 months; P = 0.857) or overall survival (OS, 15.1 months vs. 14.5 months; P = not significant) with the addition of bevacizumab despite significant improvement in response rate (19.8% vs. 9.1%; P = 0.001) in the bevacizumab arm.16 The results from this trial suggest that bevacizumab combined with a fluoropyrimidine is an active regimen in CRC but does not seem to be as active in pretreated breast cancer.
Figure 1. E2100 Trial: Treatment Schema17
Eligibility: • Locally recurrent or metastatic breast cancer • Chemotherapy naive • ECOG PS of 0/1
R A N D O M I Z E
Arm 1 Bevacizumab 10 mg/kg on days 1 and 15 every 4 weeks Paclitaxel 90 mg/m2 on days 1, 8, and 15 every 4 weeks Arm 2 Paclitaxel 90 mg/m2 on days 1, 8, and 15 every 4 weeks
Clinical Breast Cancer June 2005 • 105
research in
brief
Table 1. E2100 Trial: Efficacy17 Bevacizumab/ Paclitaxel
Paclitaxel
HR
P Value
Intent-to-treat
28
14
NR
< 0.0001
Measurable disease
34
16
NR
< 0.0001
10.97
6.11
0.498
< 0.001
NR
NR
0.674
0.01
Outcome Overall Response Rate (%)
PFS (Months) Overall Survival Abbreviation: NR = not reported
This randomized phase III trial of paclitaxel with or without bevacizumab was conducted in previously untreated patients with locally recurrent or metastatic breast cancer to evaluate if bevacizumab can prolong survival when given with a taxane instead of a fluropyrimidine in breast cancer.17
nervous system metastasis, significant proteinuria (> 500 mg per day) and use of anticoagulant medication. Patients were treated with paclitaxel 90 mg/m2 administered on days 1, 8, and 15 of a 4-week cycle with or without bevacizumab 10 mg/kg on days 1 and 15 (Figure 1).17 The primary endpoint was PFS.
Study Design
Results
Eligible patients were chemotherapy-naive with locally recurrent or metastatic breast cancer and were required to have an ECOG performance status (PS) of 0/1. Adjuvant taxane therapy was allowed if the disease-free interval (DFI) was > 1 year. No antitumor therapy within 3 weeks of enrollment was permitted. Other ineligibility criteria were presence of central
Seven hundred fifteen patients were accrued in this study over a period of 27 months. The results from the first planned interim analysis were presented at the 41st Annual Meeting of the American Society of Clinical Oncology in May 2005 and are summarized herein.17 Of 715 patients, 365 patients were treated with bevacizumab/paclitaxel and 350 patients were treated with pa-
ECOG 2100 Trial
Table 2. E2100 Trial: Grade 3/4 Toxicity17 Bevacizumab/ Paclitaxel (%)
Paclitaxel (%)
P Value
Hypertension
13.3
0
< 0.0001
Proteinuria
2.4
0
0.0004
Bleeding
0.9
0
NR
Neuropathy
20.5
14.2
0.01
Throboembolic Events
1.3*
1.3
NR
5
2.7*
NR
Neutropenia
5.3
3†
NR
Decrease in LVEF
0.3
0
NR
Toxicity
Fatigue
*Grade 3 only. †Grade 4 only. Abbreviations: LVEF = left ventricular ejection fraction; NR = not reported
106 • Clinical Breast Cancer June 2005
clitaxel only. Baseline patient characteristics in terms of median age (56 years in the bevacizumab/paclitaxel arm vs. 55 years in the paclitaxel-only arm), DFI ≤ 24 months (41% in each), presence of ≥ 3 metastatic sites (28% vs. 29%), adjuvant chemotherapy (65% vs. 64%), and estrogen receptor positivity (64% vs. 63%) were well balanced between treatment groups. The primary endpoint of PFS was statistically prolonged by > 4.5 months with bevacizumab combined with chemotherapy compared with chemotherapy alone (10.97 months vs. 6.11 months; hazard ratio [HR], 0.498; P < 0.001; Table 1).17 Additionally, a statistically significant relative increase in OS of 33% was reported in the bevacizumab arm (HR, 0.674; P = 0.01). The overall response rate (ORR) was significantly higher in patients in the intent-to-treat group who received treatment with bevacizumab/paclitaxel versus those who were treated with paclitaxel only (28% vs. 14%; P < 0.0001). This improvement in ORR with bevacizumab was even more prominent in the subset of patients with measurable disease (34% vs. 16%; P < 0.0001). Grade 3/4 toxicities reported in only the bevacizumab arm were hypertension (13.3%; P < 0.0001), proteinuria (2.4%; P = 0.0004), and bleeding (0.9%; P = not reported; Table 2).17 Of note, no grade 4 thromboembolic event was reported in the bevacizumab/paclitaxel arm. Grade 3/4 neuropathy was experienced by significantly more patients treated with bevacizumab/paclitaxel compared with paclitaxel only (20.5% vs. 14.2%; P = 0.01). Other grade 3/4 toxicities reported in more patients who received combination treatment relative to paclitaxel monotherapy were fatigue (5% vs. 2.7% grade 3 only), neutropenia (5.3% vs. 3% grade 4 only), and decrease in left ventricular ejection fraction (0.3% vs. zero).
Clinical Relevance This groundbreaking trial has opened the doors for the addition of an
anti-VEGF agent to standard chemotherapy for improving ORR, prolonging PFS, and possibly improving the OS compared with chemotherapy alone in patients with metastatic breast cancer. After encouraging results in colorectal and lung cancer, now bevacizumab has shown promising activity in combination with standard first-line chemotherapy in metastatic breast cancer. The results from this trial suggest that bevacizumab is a reasonable option in patients suitable for first-line paclitaxel therapy or other chemotherapy, provided safety data are available for that combination and the patients fit the profile of the patient population on this bevacizumab/paclitaxel phase III trial. As a result of bevacizumab related toxicities, patient history (specifically in regard to thrombosis, bleeding, and hypertension) should be carefully evaluated before initiating treatment with bevacizumab. For example, this trial required that all patients undergo computed tomography or magnetic resonance imaging of the head to exclude brain metastases.
References
1. Fernando NH, Hurwitz HI. Inhibition of vascular endothelial growth factor in the treatment of colorectal cancer. Semin Oncol 2003; 30:39-50. 2. McMahon G. VEGF receptor signaling in tumor angiogenesis. Oncologist 2000; 5(suppl 1):3-10. 3. Ferrara N. Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: therapeutic implications. Semin Oncol 2002; 29(suppl 16):10-14. 4. Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev 1997; 18:4-25. 5. Takahashi Y, Kitadai Y, Bucana CD, et al. Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res 1995; 55:3964-3968. 6. Takahashi Y, Tucker SL, Kitadai Y, et al. Vessel counts and expression of vascular endothelial growth factor as prognostic factors in node-negative colon cancer. Arch Surg 1997; 132:541-546. 7. Dy GK, Adjei AA. Novel targets for lung cancer therapy: part II. J Clin Oncol 2002; 20:3016-3028. 8. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 1989; 246:1306-1309. 9. Nor JE, Christensen J, Mooney DJ, et al. Vascular endothelial growth factor (VEGF)-mediated angiogenesis is associated with enhanced endothelial cell survival and induction of Bcl-2 expression. Am J Pathol 1999; 154:375-384. 10. Fernando NH, Hurwitz HI. Inhibition of vascular endothelial growth factor in the treatment of colorectal cancer. Semin Oncol 2003; 30:39-50. 11. Kim KJ, Li B, Houck K, et al. The vascular endothelial growth factor proteins: identifi-
12.
13.
14.
15.
16.
17.
cation of biologically relevant regions by neutralizing monoclonal antibodies. Growth Factors 1992; 7:53-64. Kim KJ, Li B, Winer J, et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 1993; 362:841-844. Borgstrom P, Gold DP, Hillan KJ, Ferrara N. Importance of VEGF for breast cancer angiogenesis in vivo: implications from intravital microscopy of combination treatments with an anti-VEGF neutralizing monoclonal antibody and doxorubicin. Anticancer Res 1999; 19:4203-4214. FDA Approves First Angiogenesis Inhibitor to Treat Colorectal Cancer [press release]. February 26, 2004. Rockville, MD: FDA, 2004. Available at: http://www.fda.gov/bbs/ topics/news/2004/new01027.html. Accessed June 18, 2004. Sandler AB, Gray R, Brahmer J, et al. Randomized phase II/III Trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC # 704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): an Eastern Cooperative Oncology Group (ECOG) Trial - E4599. Presented at the 41st Annual Meeting of the American Society of Clinical Oncology; May 13-17, 2005; Orlando, FL. Abstract LBA4. Miller KD, Chap LI, Holmes FA, et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005; 23:792-799. Miller KD, Wang M, Gralow J, et al. E2100: a randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as firstline therapy for locally recurrent or metastatic breast cancer. Presented at the 41st Annual Meeting of the American Society of Clinical Oncology; May 13-17, 2005; Orlando, FL. Available at: http://www.asco .org/ac/1,1003,_12-002511-00_18-003400_19-005814-00_21-00,00.asp. Accessed June 24, 2005.
LY N N S A G E B R E A S T C A N C E R S Y M P O S I U M
Confirmed Symposium Speakers
October 6-9, 2005 Sheraton Chicago Hotel and Towers CHAIR CO-CHAIRS
Lynn Sage Distinguished Lecturer Gabriel Hortobagyi, MD President-Elect , ASCO
7
William J. Gradishar, MD V. Craig Jordan, OBE, PhD, DSc Monica Morrow, MD
Kathy Albain, MD Thomas Buchholz, MD Hal Burstein, MD, PhD Aman Buzdar, MD Rowan Chlebowski, MD, PhD Charles Clevenger, MD, PhD Carol Fabian, MD Gary Freedman, MD Armando Giuliano, MD Lori Goldstein, MD William Gradishar, MD V Craig Jordan, OBE, PhD, DSc Seema Khan, MD Terry Mamounas, MD Lavinia Middleton, MD Monica Morrow, MD Lisa Newman, MD, MPH C Kent Osborne, MD Peter Ravdin, MD, PhD Stuart Schnitt, MD Lawrence Solin, MD Sandy Swain, MD Laura van’t Veer, PhD Elizabeth Wiley, MD
For additional information, visit
cancer.northwestern.edu or call (312) 695-1392