A randomized phase III double-blind placebo-controlled trial of first line chemotherapy and trastuzumab with or without bevacizumab for patients with HER2/neu-positive metastatic breast cancer: a trial of the ECOG-ACRIN Cancer Research Group (E1105)

A randomized phase III double-blind placebo-controlled trial of first line chemotherapy and trastuzumab with or without bevacizumab for patients with HER2/neu-positive metastatic breast cancer: a trial of the ECOG-ACRIN Cancer Research Group (E1105) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Short Report A randomized phase III double-blind placebo-controlled trial of first line chemotherapy and trastuzumab with or without bevacizumab for patients with HER2/neu-positive metastatic breast cancer: a trial of the ECOG-ACRIN Cancer Research Group (E1105) Jessica Mezzanotte-Sharpe, Anne ONeill, Ingrid A. Mayer, Carlos L. Arteaga, and 18 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4295044/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Background In 2008, bevacizumab received accelerated Food and Drug Administration (FDA) approval for use in human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Based on the preclinical and preliminary clinical activity of the trastuzumab and bevacizumab combination, ECOG-ACRIN E1105 trial was developed to determine if the addition of bevacizumab to a chemotherapy and trastuzumab combination for first-line therapy would improve progression-free survival (PFS) in patients with HER2-positive MBC. Findings: 96 patients were randomized to receive standard first-line chemotherapy and trastuzumab with or without bevacizumab between November 2007 and October 2009, and 93 began protocol therapy. Induction therapy was given for 24 weeks, followed by maintenance trastuzumab with or without bevacizumab. 60% (56/93) began carboplatin and 74% (69/93) completed 6 cycles of induction therapy. Primary endpoint was PFS. Median PFS was 11.1 and 13.8 months for placebo and bevacizumab arms, respectively (hazard ratio [HR] 95%, Confidence Interval [Cl] for bevacizumab vs. placebo: 0.73 [0.43–1.23], p = 0.24), and at a median follow-up of 70.7 months, median survival was 49.1 and 63 months (HR [95% Cl] for OS: 1.09 [0.61–1.97], p = 0.75). The most common toxicities across both arms were neutropenia and hypertension, with left ventricular systolic dysfunction, fatigue, and sensory neuropathy reported more frequently with bevacizumab. Conclusions In this trial, the addition of bevacizumab did not improve outcomes in patients with metastatic HER2-positive breast cancer. Although the trial was underpowered due to smaller than anticipated sample size, these findings corroborated other clinical trials during this time. breast cancer trastuzumab chemotherapy bevacizumab Figures Figure 1 Figure 2 Introduction In 2008, bevacizumab received accelerated Food and Drug Administration (FDA) approval for use in human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). This was based off the E2100 study, which showed a combination of paclitaxel plus bevacizumab significantly prolonged progression-free survival (PFS) in treatment-naïve patients with MBC ( 1 ). By 2011, however, the FDA withdrew its approval for bevacizumab due to the lack of evidence of OS benefit and concern for unacceptable toxicity ( 2 ). During this time period, the interest in the use of bevacizumab in HER2-positive breast cancer was also high due to studies demonstrating association between HER2 amplification and increased vascular endothelial growth factor (VEGF) in breast cancer ( 3 – 5 ). Additionally, a phase II trial at the time showed combining bevacizumab with trastuzumab in the treatment of HER2-positive MBC was both clinically feasible and active in the absence of chemotherapy ( 6 ). Based on the preclinical and preliminary clinical activity of the trastuzumab and bevacizumab combination, E1105 was developed to determine if the addition of bevacizumab to first-line chemotherapy and trastuzumab would improve PFS in patients with HER2-positive MBC. Materials and Methods Participants Patients ≥ 18 years with histologically confirmed HER2-positive MBC, ECOG performance status of 0 or 1, adequate hematological, neurological, cardiac and end-organ function, and no prior systemic therapies were considered for enrollment ( 7 ). Prior taxane and trastuzumab were allowed if given > 12 months prior to recurrence. The study was coordinated by the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN), in collaboration with Radiation Therapy Oncology Group (RTOG), North Central Cancer Treatment Group (NCCTG), Cancer and Leukemia Group B (CALGB), Southwest Oncology Group (SWOG), National Surgical Adjuvant Breast and Bowel Project (NSABP), Cancer Trials Support Unit (CTSU). Written informed consent was obtained from all patients before enrolment. Treatment Patients were randomized to receive standard first-line induction chemotherapy (paclitaxel 90 mg/m2 IV weekly x3 every 4 weeks [6 cycles] or paclitaxel 80 mg/m2 IV weekly x3 every 4 weeks + carboplatin AUC 2 IV weekly x3 every 4 weeks [6 cycles]) with trastuzumab (2 mg/kg IV weekly [after initial loading dose of 4 mg/kg] for 6 cycles) and placebo (PLAC) or bevacizumab (BEV) (10mg/kg IV every 2 weeks for 24 weeks [6 cycles]), followed by maintenance trastuzumab (6 mg/kg IV every 3 weeks) and BEV or PLAC (15 mg/kg IV every 3 weeks) until disease progression, severe adverse event, pregnancy, withdrawal, or death. Participants were allowed to discontinue chemotherapy and proceed to maintenance therapy. If trastuzumab or bevacizumab was discontinued, chemotherapy could continue. A schematic of the trial is provided in Fig. 1 . Assessments Tumor (Computer tomography/ bone scan) and cardiac (echocardiogram or MUGA) assessments were performed at baseline, every 3 months, and 3 months post treatment. Tumor assessments continued until first progression. Complete blood counts were assessed prior to every cycle. Quality of life (QOL) assessments (FACIT-Fatigue Subscale, FACT/NCCN Breast Symptom Index, FACT/GOG-Ntx, FACT-G item GP5) were completed at baseline, end of cycles 3 and 6 induction, cycle 5 maintenance, 12 months post-randomization, and annually to 60 months post-randomization. Statistical Considerations and Endpoints Progression-free survival (PFS) was the primary endpoint and was defined as time from randomization to first disease progression via RECIST 1.0, new second breast primaries, or to death from any cause. Blinded treatment assignments were made in permuted blocks in a 1:1 fashion to PLAC or BEV. Randomization was stratified by prior adjuvant trastuzumab use, prior taxane use, disease-free interval (≤ 24 months, > 24 months), and planned carboplatin (yes, no). The accrual goal was 416 patients where 301 PFS events provided 86% power to detect a 30% reduction in the failure hazard rate. The trial was monitored by the ECOG-ACRIN DSMC, including a prespecified cardiac stopping rule for high rates of clinical CHF in BEV. Secondary endpoints included overall survival (OS), defined as time from randomization date to death from any cause. The Kaplan-Meier method was used to estimate time-to-event distributions. Cox proportional hazards models were used to estimate hazard ratios and test for significance. Toxicities were graded according to CTCAE version 3.0. Cardiac safety profiles included clinical congestive heart failure (symptomatic decline in LVEF to below the lower limit of normal or symptomatic diastolic dysfunction). Baseline characteristics are reported among 95 of 96 with baseline information available, specific treatment information is reported among 93 of 96 patients who began protocol therapy, and best response, PFS and OS are analyzed on an intent-to-treat basis. Results Baseline Characteristics Between November 9, 2007, and October 28, 2009, 96 of 416 patients were enrolled. Due to slow accrual, the trial was closed after October 2009. Table 1 provides a summary of baseline characteristics. Among the patients who began treatment in the PLAC (n = 47) and BEV (n = 46) arms, 64% (30/47) and 57% (26/46) began the optional carboplatin, and 72% (34/47) and 76% (35/46) completed 6 cycles of induction therapy, respectively. The median number of cycles for maintenance therapy (n = 63) was 8 and 16 for the PLAC and BEV arms. Disease progression (66% [31/47] and 50% [23/46]) and adverse events (15% [7/47] PLAC and 22% [10/46] BEV) were the most common reasons for discontinuing treatment. Table 1. Patient Demographics and Disease Characteristics (n = 95*; n(%) shown unless otherwise specified) A (Placebo; PLAC) B (Bevacizumab; BEV) Total n = 48 n = 48 n = 96 Race White 41 (85) 37 (77) 78 (81) Black 6 ( 13 ) 7 ( 15 ) 13 ( 14 ) Asian 1 ( 2 ) 2 ( 4 ) 3 ( 3 ) Native Hawaiian 0 1 ( 2 ) 1 ( 1 ) Missing 0 1 1 Age Median (min, max) 55 (27, 77) 55 (33,76) 55 (27,77) Menopausal Status Postmenopausal 33(69) 34 (71) 67 (70) Premenopausal 13 (27) 13 (27) 26 (27) Perimenopausal 1 ( 2 ) 1 ( 2 ) 2 ( 2 ) Missing 1 1 ECOG PS 0 33 (69) 31 (65) 64 (67) 1 14 (29) 17 (35) 31 (32) Missing 1 1 ER Status Negative 18 (38) 20 (42) 38 (40) Positive 29 (60) 28 (58) 57 (59) Missing 1 1 Site of Involvement Local-regional 32 (67) 31 (65) 63 (66) Ipsilateral supraclavicular 7 ( 15 ) 6 ( 13 ) 13 ( 14 ) Opposite breast 1 ( 2 ) 2 ( 4 ) 3 ( 3 ) Distant lymph nodes 13 (27) 21 (44) 34 (36) Bone 26 (54) 16 (33) 42 (44) Bone Marrow 2 ( 4 ) - 2 ( 2 ) Lung 17 (35) 17 (35) 34 ( 16 ) Liver 27 (56) 22 (46) 49 (51) Pleura 2 ( 4 ) 2 ( 4 ) 4 ( 4 ) Other 1 ( 2 ) 2 ( 4 ) 3 ( 3 ) Prior Hormonal Therapy No 34 (71) 33 (69) 67 (70) Yes 13 (27) 15 (31) 28 (29) In adjuvant setting 11 11 22 In metastatic setting 4 4 Both 2 2 Missing 1 1 Prior RT No 33 (69) 31 (66) 64 (67) Yes 14 (29) 16 (34) 30 (31) Missing 1 1 Prior Taxane in Adjuvant or Neo-adjuvant Setting No 38 (79) 35 (73) 73 (76) Yes 9 ( 19 ) 13 (27) 22 (23) Missing 1 1 Prior Doxorubicin in Adjuvant or Neo-adjuvant Setting No 30 (63) 35 (73) 65 (68) Yes 17 (35) 13 (27) 30 (31) Missing 1 1 Prior Trastuzumab in Adjuvant Setting No 41 (85) 40(83) 81 (84) Yes 6 ( 13 ) 8 ( 17 ) 14 ( 15 ) Missing 1 1 Prior Chemotherapy (other) in Adjuvant Setting No 35 (73) 39 (81) 74 (77) Yes 12 (25) 9 ( 19 ) 21 (22) Missing 1 1 *Missing On-Study Form for 1 patient. Clinical Efficacy and Secondary Endpoints The best overall response rate (CR + PR) was 54% (26/48) and 61% (29/48) in PLAC and BEV, respectively (Table 2). There was no statistically significant difference in PFS: median PFS was 11.1 and 13.8 months; hazard ratio (HR) (95% Confidence Interval [Cl]) for BEV vs. PLAC: 0.73 (0.43–1.23), p = 0.24 (Fig. 2 A). With n = 96 patients and 83 PFS events, the power to detect the original target difference between arms was only 37%. At a median follow-up of 70.7 months, median overall survival was 49.1 and 63 months; (HR [95% Cl]: 1.09 [0.61–1.97], p = 0.75) (Fig. 2 B (truncated at 60 months)). Table 2: Clinical Response and Outcomes A (Placebo; PLAC) B (Bevacizumab; BEV) Total n = 48 n = 48 n = 96 Best Overall Response n (%) n (%) n (%) CR 4( 8 ) 6( 13 ) 10( 10 ) PR 22(46) 23(48) 45(47) Stable 13(27) 9( 19 ) 22(23) PD 6( 13 ) 5( 10 ) 8( 8 ) Not evaluable 3( 6 ) 5( 10 ) 8( 8 ) Progression Free Survival # of events 44 39 83 Median in months(95% CI) 11.1(8.7–12.4) 13.8(10.6–22.5) HR* (95%CI), p-value** Univariate 0.73(0.43–1.23),0.24 Multivariable *** 1.09(0.61–1.97),0.75 Overall Survival # of events 32 27 59 Median Follow-up (months) 71.4 70.6 70.7 Median in months(95% CI) 49.1(37.2–67.4) 62.9(34.4–72.8+) HR* (95%CI), p-value** Univariate 1.09(0.61–1.97),p = 0.75 Multivariable *** 1.12(0.62–2.04),p = 0.69 *Bevacizumab vs. placebo. **P-values are two-sided and are based on stratified test using stratification factors at randomization. *** Adjusted for Age, ERPR, Primary surgery. +last censored observation as upper limit not reached. Overall Toxicity and Cardiac Safety Toxicity incidence, defined as ≥ grade 3 and experienced by ≥ 2 patients, occurred in 47% (22/47) of PLAC and 67% (30/45) of BEV patients (Table 3 ). The most frequent ≥ grade 3 toxicities across both arms were neutropenia (6.4%, 6.7%) and hypertension (10.6%, 13.3%). Left ventricular systolic dysfunction (0%, 8.9%), fatigue (2.1%, 11.1%), and sensory neuropathy (6.4%, 11.1%) occurred more frequently in the BEV arm. At Cycle 6 Induction, more BEV patients reported fatigue compared to PLAC (FACIT Fatigue Scale: mean scores: 30.2 and 37.0, p = 0.02; FACT-G item GP5 [“I am bothered by sided effects of treatment”]: mean scores: 2.5 and 3.2, p < 0.01). One patient treated with bevacizumab died from treatment-related catheter infection (Table 3 ). Clinical congestive heart failure occurred in 1 PLAC and 4 BEV patients. Table 3 Toxicity Incidence (Includes ≥Grade 3 and Experienced in ≥ 2 patients)* Toxicity Type Treatment Arm A (Placebo, n = 47) B (Bevacizumab, n = 45) Grade Grade 3 4 5 3 4 5 (n) (n) (n) (n) (n) (n) Allergic reaction 1 - - 4 - - Neutropenia - 3 - - 3 - Hypertension 5 - - 6 - - Left ventricular systolic dysfunction - - - 3 1 - Fatigue 1 - - 4 1 - Wound - non-infectious - - - 2 - - Anorexia 1 - - 2 - - Dehydration 1 1 - 2 - - Diarrhea w/o prior colostomy 4 - - 3 - - Nausea 2 - - 2 - - Vomiting 2 - - 3 - - Infection Gr0-2 neut, catheter - - - - - 1^ InfectionGr0-2 neut, skin 1 - - 1 - - Hyperglycemia 1 - - 1 1 - Proteinuria 1 - - 4 - - Nonneuropathic generalized weakness 1 - - 2 - - Neuropathy-motor 2 - - 3 - - Neuropathy-sensory 3 - - 5 - - Cough 1 - - 1 - - Renal failure 2 - - - - - Thrombosis/thrombus/embolism - 1 - 1 1 - * Only patients who began protocol treatment are included in this summary (One patient on Arm A did not begin protocol treatment, and two patients on Arm B did not begin protocol treatment.) AE reporting in the trial was limited to ≥ grade 4 hematologic events, ≥ grade 2 non-hematologic events for a select group of AEs, and ≥ grade 3 non-hematologic events otherwise. ^patient died within 30 days of ending protocol treatment. Discussion During the enrollment of the presented study, new drug approvals such as lapatinib ( 10 ), decreased metastatic recurrence with trastuzumab, and excitement regarding other HER2 targeted agents (such as pertuzumab and trastuzumab-emtansine) resulted in low patient accrual and early study closure in 2009. Due to low accrual, the study was underpowered, and no significant difference in clinical outcomes was observed between treatment arms. The safety profiles for bevacizumab and trastuzumab were consistent with prior phase I, II and III trials. Cardiac toxicity is a known side effect of trastuzumab; however, previous studies found the toxicity was reversible, unlike doxorubicin-induced cardiomyopathy ( 11 , 12 ). We saw few overall cardiac adverse events from bevacizumab in addition to the hallmark hypertension associated with anti-angiogenic drugs ( 13 ).The results from this trial corroborated the 2011 FDA decision to remove bevacizumab as a recommended therapeutic option for patients with breast cancer. Since the closure of E1105, other clinical trials have explored the combination of HER2-targeted and anti-angiogenic therapies. A phase II single-arm trial of bevacizumab, trastuzumab, and capecitabine showed clinical activity as first-line therapy for patients with HER2-positive MBC, with no unexpected toxicities, and a median time to progression of 14.5 months (95% Cl, 10.5 months to NR) ( 14 ). The AVEREL study randomized 424 first-line patients to trastuzumab/docetaxel with or without concomitant bevacizumab ( 15 ). Despite a trend favoring bevacizumab PFS (median 13.7 vs. 16.5 months; HR 0.82, log-rank P = 0.078), no difference was observed in overall survival ( 15 ). The BETH study randomized 3509 patients with HER2-positive early stage breast cancer to receive standard chemotherapy/trastuzumab with or without bevacizumab for 1 year of adjuvant therapy ( 16 ). After 38 months of follow-up, there was no statistically significant difference between treatment arms (92% IDFS rates in both groups). Currently, the majority of recent studies using bevacizumab to treat breast cancer are in the HER2-negative patient population or are in subsets of HER2-positive and -negative patients with specific types of refractory disease ( 17 , 18 ). More recently, the major focus on treating refractory HER2-positive MBC lies in developing new HER2-targeted antibody-drug conjugates, combinations of CDK4/6 or PI3K/Akt inhibitors with these agents as well as with endocrine therapies, and combinations of different immunotherapy agents with HER2-targeted therapies ( 19 ). Despite the strong pre-clinical rationale for combining HER2-targeted therapies with antiangiogenic drugs, there was no overall benefit, and there was added toxicity of combining bevacizumab with trastuzumab and chemotherapy, aligning with the 2011 FDA decision to remove the recommendation for the use of bevacizumab in all breast cancers. Despite advances in the adjuvant and metastatic setting made over the past decades, approximately 15–20% of patients with early HER2-positive breast cancer still relapse after curative therapy, and HER2-positive MBC remains incurable. Therefore, new therapeutic approaches are still necessary for this disease. Declarations Ethics approval and consent to participate Written informed consent was obtained from all patients before enrolment, in agreement with approved protocols from respective ethics committees at every site. Availability of data and materials All study data may be requested from the corresponding author and/or ECOG-ACRIN research group upon reasonable request. Competing interests JMS, AON, TJS, WJG, EAP, and ACW have no conflicts of interest related to this project. CLA has served as scientific advisor to Novartis, Lilly, Merck, Immunomedics, Daiichi Sankyo, AstraZeneca, PUMA Biotechnology, TAIHO Oncology, OrigiMed, Arvinas, Sanofi, and the Susan G. Komen Foundation. He has received grant support from Pfizer, Lilly, and Takeda. NJM is an employee of Flatiron Health, Inc. an independent member of the Roche group, and reports stock ownership in Roche. VGA has served as a scientific advisor for GuardantHealth and Astra Zeneca and has research funding support from Genetech, Bayer, and GuardantHealth. NUL declares consulting honorarium from Seagen, Daichii-Sankyo, AstraZeneca, Olema Pharmaceuticals, Janssen, Blueprint Medicines, Stemline/Menarini, Artera Inc., Eisai; travel support from Olema Pharmaceuticals; research support (to institution) from Genentech, Zion Pharmaceuticals (as part of GNE), Pfizer, Seagen, Merck, Olema Pharmaceuticals, AstraZeneca; royalties from Up To Date. SAR has served as a consultant for Daiichi-Sankyo, Astra Zeneca, Novartis, and Gilead. Funding This study was coordinated by the ECOG-ACRIN Cancer Research Group (Peter J. O'Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180820, U10CA180794, U10CA180821, U10CA180888, UG1CA189805, UG1CA189828, UG1CA189830, UG1CA189954, UG1CA189957, UG1CA190140, UG1CA232760, UG1CA233180, UG1CA233234, UG1CA233302, UG1CA233196, and UG1CA233320. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Authors contributions Conception and design: Ingrid A. Mayer, Anne ONeill, Carlos L. Arteaga, Ximing J. Yang, Lynne I. Wagner, David Cella, Neal J. Meropol, Thomas J. Saphner Provision of study materials or patients: All authors Collection and assembly of data: Ingrid A. Mayer, Anne ONeill, Ximing J. Yang, Lynne I. Wagner, David Cella, Neal J. Meropol Data analysis and interpretation/Manuscript writing/Final approval of the manuscript: All authors Acknowledgements The authors would like to acknowledge and thank the members of the Vanderbilt SWERV writing core for contributing to the editing of this manuscript. References Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA et al (2007) Paclitaxel plus Bevacizumab versus Paclitaxel Alone for Metastatic Breast Cancer. N Engl J Med 357(26):2666–2676 Rossari JR, Metzger-Filho O, Paesmans M, Saini KS, Gennari A, de Azambuja E et al (2012) Bevacizumab and Breast Cancer: A Meta-Analysis of First-Line Phase III Studies and a Critical Reappraisal of Available Evidence. J Oncol 2012:417673 Linderholm B, Andersson J, Lindh B, Beckman L, Erlanson M, Edin K et al (2004) Overexpression of c-erbB-2 is related to a higher expression of vascular endothelial growth factor (VEGF) and constitutes an independent prognostic factor in primary node-positive breast cancer after adjuvant systemic treatment. Eur J Cancer 40(1):33–42 Petit AM, Rak J, Hung MC, Rockwell P, Goldstein N, Fendly B et al (1997) Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors. Am J Pathol 151(6):1523–1530 Yang W, Klos K, Yang Y, Smith TL, Shi D, Yu D (2002) ErbB2 overexpression correlates with increased expression of vascular endothelial growth factors A, C, and D in human breast carcinoma. Cancer 94(11):2855–2861 Hurvitz S, Pegram M, Lin L, Chan D, Allen H, Dichmann R et al (2009) Final Results of a Phase II Trial Evaluating Trastuzumab and Bevacizumab as First Line Treatment of HER2-Amplified Advanced Breast Cancer. Cancer Res 69(24Supplement):6094 Wolff AC, Hammond MEH, Hicks DG, Dowsett M, McShane LM, Allison KH et al (2013) Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Update. J Clin Oncol [Internet]. Oct 7 [cited 2023 Jul 25]; https://ascopubs.org/doi/pdf/10.1200/JCO.2013.50.9984?role=tab O’Brien PC, Fleming TR (1979) A multiple testing procedure for clinical trials. Biometrics 35(3):549–556 Jennison C, Turnbull BW (1993) Group Sequential Tests for Bivariate Response: Interim Analyses of Clinical Trials with Both Efficacy and Safety Endpoints. Biometrics 49(3):741–752 Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T et al (2006) Lapatinib plus Capecitabine for HER2-Positive Advanced Breast Cancer. N Engl J Med 355(26):2733–2743 Perez EA, Suman VJ, Davidson NE, Sledge GW, Kaufman PA, Hudis CA et al (2008) Cardiac Safety Analysis of Doxorubicin and Cyclophosphamide Followed by Paclitaxel With or Without Trastuzumab in the North Central Cancer Treatment Group N9831 Adjuvant Breast Cancer Trial. J Clin Oncol 26(8):1231–1238 Ewer MS, Vooletich MT, Durand JB, Woods ML, Davis JR, Valero V et al (2005) Reversibility of trastuzumab-related cardiotoxicity: new insights based on clinical course and response to medical treatment. J Clin Oncol Off J Am Soc Clin Oncol 23(31):7820–7826 Gampenrieder SP, Romeder F, MUß C, Pircher M, Ressler S, Rinnerthaler G et al (2014) Hypertension as a Predictive Marker for Bevacizumab in Metastatic Breast Cancer: Results from a Retrospective Matched-pair Analysis. Anticancer Res 34(1):227–233 Martín M, Makhson A, Gligorov J, Lichinitser M, Lluch A, Semiglazov V et al (2012) Phase II Study of Bevacizumab in Combination with Trastuzumab and Capecitabine as First-Line Treatment for HER-2-positive Locally Recurrent or Metastatic Breast Cancer. Oncologist 17(4):469–475 Gianni L, Romieu GH, Lichinitser M, Serrano SV, Mansutti M, Pivot X et al (2013) AVEREL: a randomized phase III Trial evaluating bevacizumab in combination with docetaxel and trastuzumab as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer. J Clin Oncol Off J Am Soc Clin Oncol 31(14):1719–1725 Slamon D, Swain S, Buyse M, Martin M, Geyer C, Im YH et al (2013) Abstract S1-03: Primary results from BETH, a phase 3 controlled study of adjuvant chemotherapy and trastuzumab ± bevacizumab in patients with HER2-positive, node-positive or high risk node-negative breast cancer. Cancer Res 73(24Supplement):S1–03 Saji S, Taira N, Kitada M, Takano T, Takada M, Ohtake T et al (2022) Switch maintenance endocrine therapy plus bevacizumab after bevacizumab plus paclitaxel in advanced or metastatic oestrogen receptor-positive, HER2-negative breast cancer (BOOSTER): a randomised, open-label, phase 2 trial. Lancet Oncol 23(5):636–649 Leone JP, Emblem KE, Weitz M, Gelman RS, Schneider BP, Freedman RA et al (2020) Phase II trial of carboplatin and bevacizumab in patients with breast cancer brain metastases. Breast Cancer Res 22(1):131 Vega Cano KS, Marmolejo Castañeda DH, Escrivá-de-Romaní S, Saura C (2022) Systemic Therapy for HER2-Positive Metastatic Breast Cancer: Current and Future Trends. Cancers 15(1):51 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 17 Jun, 2024 Reviews received at journal 17 Jun, 2024 Reviewers agreed at journal 05 Jun, 2024 Reviews received at journal 12 May, 2024 Reviewers agreed at journal 28 Apr, 2024 Reviewers agreed at journal 25 Apr, 2024 Reviewers invited by journal 22 Apr, 2024 Editor assigned by journal 22 Apr, 2024 Submission checks completed at journal 22 Apr, 2024 First submitted to journal 19 Apr, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Katherine Alpaugh","email":"","orcid":"","institution":"Fox Chase Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"R.","middleName":"Katherine","lastName":"Alpaugh","suffix":""},{"id":294294594,"identity":"e6925647-7421-4235-b448-288edad4f521","order_by":9,"name":"Thomas J. Saphner","email":"","orcid":"","institution":"Aurora Health Care","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Thomas","middleName":"J.","lastName":"Saphner","suffix":""},{"id":294294596,"identity":"228894a2-2c1b-45d4-99db-57e1af13db03","order_by":10,"name":"Robert E. Swaney","email":"","orcid":"","institution":"Denver Health Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Robert","middleName":"E.","lastName":"Swaney","suffix":""},{"id":294294598,"identity":"22fac093-8331-43c4-80e7-87d6c855442d","order_by":11,"name":"Karen L Hoelzer","email":"","orcid":"","institution":"Memorial Healthcare System","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Karen","middleName":"L","lastName":"Hoelzer","suffix":""},{"id":294294600,"identity":"129c5632-1b75-40fb-b71c-f54ea1c4f8d4","order_by":12,"name":"William J. Gradishar","email":"","orcid":"","institution":"Northwestern University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"William","middleName":"J.","lastName":"Gradishar","suffix":""},{"id":294294601,"identity":"26dc21ad-c2f5-4498-b212-2faba7462bce","order_by":13,"name":"Vandana G. Abramson","email":"","orcid":"","institution":"Vanderbilt University Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Vandana","middleName":"G.","lastName":"Abramson","suffix":""},{"id":294294602,"identity":"7edc86d8-e4b9-4ac9-8234-aeebbc21cd36","order_by":14,"name":"P. Kothai Sundaram","email":"","orcid":"","institution":"Columbus NCI Community Clinical Oncology Research Program","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"P.","middleName":"Kothai","lastName":"Sundaram","suffix":""},{"id":294294603,"identity":"54346d64-4206-4efb-97cb-1dc31c011cd6","order_by":15,"name":"Shamim Z. Jilani","email":"","orcid":"","institution":"Good Samaritan Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shamim","middleName":"Z.","lastName":"Jilani","suffix":""},{"id":294294604,"identity":"85963477-afa5-4a63-bd3a-dfd9002fd6e2","order_by":16,"name":"Edith A. Perez","email":"","orcid":"","institution":"Mayo Clinic","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Edith","middleName":"A.","lastName":"Perez","suffix":""},{"id":294294605,"identity":"a9e59655-96d9-4b82-948b-00d9288f820c","order_by":17,"name":"Nancy U. Lin","email":"","orcid":"","institution":"Dana-Farber Cancer Institute","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Nancy","middleName":"U.","lastName":"Lin","suffix":""},{"id":294294606,"identity":"9adf033b-b7d9-4c61-8357-ee2a24626339","order_by":18,"name":"Mohammad Jahanzeb","email":"","orcid":"","institution":"University of Miami","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mohammad","middleName":"","lastName":"Jahanzeb","suffix":""},{"id":294294607,"identity":"2a0015ab-31f8-47ac-a900-eb9d53aebacc","order_by":19,"name":"Antonio C. Wolff","email":"","orcid":"","institution":"Johns Hopkins University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Antonio","middleName":"C.","lastName":"Wolff","suffix":""},{"id":294294608,"identity":"812184a1-44ba-409f-a266-b332994f59e3","order_by":20,"name":"George W. Sledge","email":"","orcid":"","institution":"Stanford Cancer Institute","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"George","middleName":"W.","lastName":"Sledge","suffix":""},{"id":294294609,"identity":"46e83c19-42f0-45e2-bc6d-a050408c6c99","order_by":21,"name":"Sonya A. Reid","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1klEQVRIiWNgGAWjYDADNobkAyRrSUsg2Z4cA+LUybf3HpP4wXBPjo8955s0b44dA7/08Qt4tRicOZcm2cNQbMzG83abNO+2ZAbJvpwC/FokcswkeBgSEtskcjcb8247ADSEJwG/w2bkmEn+YUiob5PIeUycFoYbOWbSQFsS2CRyGB9DtLAfIOCXM8bWMgYJhm08zwwfzt2WzCPZw4PfEvn2HsObbyoS5OXbkx8ceLvNTo6fh/0Bfj0MDCwSDEgxArSCh2AEMX9AEyBsyygYBaNgFIwsAAC6izz0z0VHKgAAAABJRU5ErkJggg==","orcid":"","institution":"Vanderbilt University Medical Center","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Sonya","middleName":"A.","lastName":"Reid","suffix":""}],"badges":[],"createdAt":"2024-04-19 21:02:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4295044/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4295044/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":55535521,"identity":"aae3d5f5-5a83-459c-9273-365bbd99abc8","added_by":"auto","created_at":"2024-04-29 16:24:51","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":229029,"visible":true,"origin":"","legend":"\u003cp\u003eStudy consort diagram.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4295044/v1/5a0973c548657334fd93ce0c.png"},{"id":55535520,"identity":"c77d9a22-c145-4585-a3b3-c4c111acbc97","added_by":"auto","created_at":"2024-04-29 16:24:51","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":161660,"visible":true,"origin":"","legend":"\u003cp\u003ePFS and OS. \u003cstrong\u003eA. \u003c/strong\u003eMedian PFS was 11.1 months in the PLAC arm and 13.8 months in the BEV arm, p=0.24, \u003cstrong\u003eB. \u003c/strong\u003eMedian OS was 49.1 months in the PLAC arm and 63 months in the BEV arm (figure truncated at 60 months), p=0.75.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4295044/v1/21341b0db66e5c17e26dccf0.jpeg"},{"id":55536300,"identity":"d1f81066-50e8-4627-bcef-5d4a942fe23e","added_by":"auto","created_at":"2024-04-29 16:32:49","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":635658,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4295044/v1/f693dec8-f3fc-4571-abe5-72d4599e833f.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A randomized phase III double-blind placebo-controlled trial of first line chemotherapy and trastuzumab with or without bevacizumab for patients with HER2/neu-positive metastatic breast cancer: a trial of the ECOG-ACRIN Cancer Research Group (E1105)","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIn 2008, bevacizumab received accelerated Food and Drug Administration (FDA) approval for use in human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). This was based off the E2100 study, which showed a combination of paclitaxel plus bevacizumab significantly prolonged progression-free survival (PFS) in treatment-na\u0026iuml;ve patients with MBC (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). By 2011, however, the FDA withdrew its approval for bevacizumab due to the lack of evidence of OS benefit and concern for unacceptable toxicity (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDuring this time period, the interest in the use of bevacizumab in HER2-positive breast cancer was also high due to studies demonstrating association between HER2 amplification and increased vascular endothelial growth factor (VEGF) in breast cancer (\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Additionally, a phase II trial at the time showed combining bevacizumab with trastuzumab in the treatment of HER2-positive MBC was both clinically feasible and active in the absence of chemotherapy (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Based on the preclinical and preliminary clinical activity of the trastuzumab and bevacizumab combination, E1105 was developed to determine if the addition of bevacizumab to first-line chemotherapy and trastuzumab would improve PFS in patients with HER2-positive MBC.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eParticipants\u003c/h2\u003e \u003cp\u003ePatients\u0026thinsp;\u0026ge;\u0026thinsp;18 years with histologically confirmed HER2-positive MBC, ECOG performance status of 0 or 1, adequate hematological, neurological, cardiac and end-organ function, and no prior systemic therapies were considered for enrollment (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Prior taxane and trastuzumab were allowed if given\u0026thinsp;\u0026gt;\u0026thinsp;12 months prior to recurrence. The study was coordinated by the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN), in collaboration with Radiation Therapy Oncology Group (RTOG), North Central Cancer Treatment Group (NCCTG), Cancer and Leukemia Group B (CALGB), Southwest Oncology Group (SWOG), National Surgical Adjuvant Breast and Bowel Project (NSABP), Cancer Trials Support Unit (CTSU). Written informed consent was obtained from all patients before enrolment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eTreatment\u003c/h2\u003e \u003cp\u003ePatients were randomized to receive standard first-line induction chemotherapy (paclitaxel 90 mg/m2 IV weekly x3 every 4 weeks [6 cycles] or paclitaxel 80 mg/m2 IV weekly x3 every 4 weeks\u0026thinsp;+\u0026thinsp;carboplatin AUC 2 IV weekly x3 every 4 weeks [6 cycles]) with trastuzumab (2 mg/kg IV weekly [after initial loading dose of 4 mg/kg] for 6 cycles) and placebo (PLAC) or bevacizumab (BEV) (10mg/kg IV every 2 weeks for 24 weeks [6 cycles]), followed by maintenance trastuzumab (6 mg/kg IV every 3 weeks) and BEV or PLAC (15 mg/kg IV every 3 weeks) until disease progression, severe adverse event, pregnancy, withdrawal, or death. Participants were allowed to discontinue chemotherapy and proceed to maintenance therapy. If trastuzumab or bevacizumab was discontinued, chemotherapy could continue. A schematic of the trial is provided in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eAssessments\u003c/h2\u003e \u003cp\u003eTumor (Computer tomography/ bone scan) and cardiac (echocardiogram or MUGA) assessments were performed at baseline, every 3 months, and 3 months post treatment. Tumor assessments continued until first progression. Complete blood counts were assessed prior to every cycle. Quality of life (QOL) assessments (FACIT-Fatigue Subscale, FACT/NCCN Breast Symptom Index, FACT/GOG-Ntx, FACT-G item GP5) were completed at baseline, end of cycles 3 and 6 induction, cycle 5 maintenance, 12 months post-randomization, and annually to 60 months post-randomization.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Considerations and Endpoints\u003c/h2\u003e \u003cp\u003eProgression-free survival (PFS) was the primary endpoint and was defined as time from randomization to first disease progression via RECIST 1.0, new second breast primaries, or to death from any cause. Blinded treatment assignments were made in permuted blocks in a 1:1 fashion to PLAC or BEV. Randomization was stratified by prior adjuvant trastuzumab use, prior taxane use, disease-free interval (\u0026le;\u0026thinsp;24 months, \u0026gt;\u0026thinsp;24 months), and planned carboplatin (yes, no). The accrual goal was 416 patients where 301 PFS events provided 86% power to detect a 30% reduction in the failure hazard rate. The trial was monitored by the ECOG-ACRIN DSMC, including a prespecified cardiac stopping rule for high rates of clinical CHF in BEV.\u003c/p\u003e \u003cp\u003eSecondary endpoints included overall survival (OS), defined as time from randomization date to death from any cause. The Kaplan-Meier method was used to estimate time-to-event distributions. Cox proportional hazards models were used to estimate hazard ratios and test for significance. Toxicities were graded according to CTCAE version 3.0. Cardiac safety profiles included clinical congestive heart failure (symptomatic decline in LVEF to below the lower limit of normal or symptomatic diastolic dysfunction). Baseline characteristics are reported among 95 of 96 with baseline information available, specific treatment information is reported among 93 of 96 patients who began protocol therapy, and best response, PFS and OS are analyzed on an intent-to-treat basis.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eBaseline Characteristics\u003c/h2\u003e \u003cp\u003eBetween November 9, 2007, and October 28, 2009, 96 of 416 patients were enrolled. Due to slow accrual, the trial was closed after October 2009. Table\u0026nbsp;1 provides a summary of baseline characteristics.\u003c/p\u003e \u003cp\u003eAmong the patients who began treatment in the PLAC (n\u0026thinsp;=\u0026thinsp;47) and BEV (n\u0026thinsp;=\u0026thinsp;46) arms, 64% (30/47) and 57% (26/46) began the optional carboplatin, and 72% (34/47) and 76% (35/46) completed 6 cycles of induction therapy, respectively. The median number of cycles for maintenance therapy (n\u0026thinsp;=\u0026thinsp;63) was 8 and 16 for the PLAC and BEV arms. Disease progression (66% [31/47] and 50% [23/46]) and adverse events (15% [7/47] PLAC and 22% [10/46] BEV) were the most common reasons for discontinuing treatment.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eTable\u0026nbsp;1. Patient Demographics and Disease Characteristics (n\u0026thinsp;=\u0026thinsp;95*; n(%) shown unless otherwise specified)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA (Placebo; PLAC)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eB (Bevacizumab; BEV)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;96\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRace\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWhite\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41 (85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37 (77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e78 (81)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlack\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAsian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNative Hawaiian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian (min, max)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55 (27, 77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55 (33,76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e55 (27,77)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMenopausal Status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePostmenopausal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33(69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34 (71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e67 (70)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePremenopausal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26 (27)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePerimenopausal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG PS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31 (65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e64 (67)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e31 (32)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eER Status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e38 (40)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28 (58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e57 (59)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSite of Involvement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocal-regional\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31 (65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e63 (66)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIpsilateral supraclavicular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOpposite breast\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDistant lymph nodes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34 (36)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e42 (44)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone Marrow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLung\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34 (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e49 (51)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePleura\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior Hormonal Therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34 (71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 (69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e67 (70)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28 (29)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIn adjuvant setting\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIn metastatic setting\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBoth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior RT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31 (66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e64 (67)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30 (31)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePrior Taxane in Adjuvant or Neo-adjuvant Setting\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38 (79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35 (73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e73 (76)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22 (23)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePrior Doxorubicin in Adjuvant or Neo-adjuvant Setting\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35 (73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e65 (68)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30 (31)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePrior Trastuzumab in Adjuvant Setting\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41 (85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40(83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e81 (84)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14 (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePrior Chemotherapy (other) in Adjuvant Setting\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39 (81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e74 (77)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21 (22)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e*Missing On-Study Form for 1 patient.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eClinical Efficacy and Secondary Endpoints\u003c/h2\u003e \u003cp\u003eThe best overall response rate (CR\u0026thinsp;+\u0026thinsp;PR) was 54% (26/48) and 61% (29/48) in PLAC and BEV, respectively (Table\u0026nbsp;2). There was no statistically significant difference in PFS: median PFS was 11.1 and 13.8 months; hazard ratio (HR) (95% Confidence Interval [Cl]) for BEV vs. PLAC: 0.73 (0.43\u0026ndash;1.23), p\u0026thinsp;=\u0026thinsp;0.24 (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). With n\u0026thinsp;=\u0026thinsp;96 patients and 83 PFS events, the power to detect the original target difference between arms was only 37%. At a median follow-up of 70.7 months, median overall survival was 49.1 and 63 months; (HR [95% Cl]: 1.09 [0.61\u0026ndash;1.97], p\u0026thinsp;=\u0026thinsp;0.75) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB (truncated at 60 months)).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabb\" border=\"1\"\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTable\u0026nbsp;2: Clinical Response and Outcomes\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA (Placebo; PLAC)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eB (Bevacizumab; BEV)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;96\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBest Overall Response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22(46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23(48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e45(47)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13(27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22(23)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNot evaluable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgression Free Survival\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e# of events\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e83\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian in months(95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.1(8.7\u0026ndash;12.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.8(10.6\u0026ndash;22.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHR* (95%CI), p-value**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnivariate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.73(0.43\u0026ndash;1.23),0.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultivariable\u003csup\u003e\u003cb\u003e***\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.09(0.61\u0026ndash;1.97),0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverall Survival\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e# of events\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian Follow-up (months)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e71.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e70.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e70.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian in months(95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49.1(37.2\u0026ndash;67.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62.9(34.4\u0026ndash;72.8+)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHR* (95%CI), p-value**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnivariate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.09(0.61\u0026ndash;1.97),p\u0026thinsp;=\u0026thinsp;0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultivariable\u003csup\u003e\u003cb\u003e***\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.12(0.62\u0026ndash;2.04),p\u0026thinsp;=\u0026thinsp;0.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e*Bevacizumab vs. placebo.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e**P-values are two-sided and are based on stratified test using stratification factors at randomization.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003csup\u003e\u003cb\u003e***\u003c/b\u003e\u003c/sup\u003eAdjusted for Age, ERPR, Primary surgery.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e+last censored observation as upper limit not reached.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eOverall Toxicity and Cardiac Safety\u003c/h2\u003e \u003cp\u003eToxicity incidence, defined as \u0026ge;\u0026thinsp;grade 3 and experienced by \u0026ge;\u0026thinsp;2 patients, occurred in 47% (22/47) of PLAC and 67% (30/45) of BEV patients (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The most frequent\u0026thinsp;\u0026ge;\u0026thinsp;grade 3 toxicities across both arms were neutropenia (6.4%, 6.7%) and hypertension (10.6%, 13.3%). Left ventricular systolic dysfunction (0%, 8.9%), fatigue (2.1%, 11.1%), and sensory neuropathy (6.4%, 11.1%) occurred more frequently in the BEV arm. At Cycle 6 Induction, more BEV patients reported fatigue compared to PLAC (FACIT Fatigue Scale: mean scores: 30.2 and 37.0, p\u0026thinsp;=\u0026thinsp;0.02; FACT-G item GP5 [\u0026ldquo;I am bothered by sided effects of treatment\u0026rdquo;]: mean scores: 2.5 and 3.2, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). One patient treated with bevacizumab died from treatment-related catheter infection (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Clinical congestive heart failure occurred in 1 PLAC and 4 BEV patients.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eToxicity Incidence (Includes \u0026ge;Grade 3 and Experienced in \u0026ge;\u0026thinsp;2 patients)*\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eToxicity Type\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"8\" nameend=\"c9\" namest=\"c2\"\u003e \u003cp\u003eTreatment Arm\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003eA (Placebo, n\u0026thinsp;=\u0026thinsp;47)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c9\" namest=\"c6\"\u003e \u003cp\u003eB (Bevacizumab, n\u0026thinsp;=\u0026thinsp;45)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003eGrade\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c9\" namest=\"c6\"\u003e \u003cp\u003eGrade\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(n)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(n)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(n)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(n)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(n)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e(n)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAllergic reaction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeft ventricular systolic dysfunction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFatigue\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWound - non-infectious\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnorexia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDehydration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiarrhea w/o prior colostomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNausea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVomiting\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfection Gr0-2 neut, catheter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1^\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfectionGr0-2 neut, skin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHyperglycemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProteinuria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNonneuropathic generalized weakness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeuropathy-motor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeuropathy-sensory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCough\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenal failure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThrombosis/thrombus/embolism\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"9\" nameend=\"c9\" namest=\"c1\"\u003e \u003cp\u003e* Only patients who began protocol treatment are included in this summary (One patient on Arm A did not begin protocol treatment, and two patients on Arm B did not begin protocol treatment.) AE reporting in the trial was limited to \u0026ge;\u0026thinsp;grade 4 hematologic events, \u0026ge; grade 2 non-hematologic events for a select group of AEs, and \u0026ge;\u0026thinsp;grade 3 non-hematologic events otherwise.\u003c/p\u003e \u003cp\u003e^patient died within 30 days of ending protocol treatment.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eDuring the enrollment of the presented study, new drug approvals such as lapatinib (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), decreased metastatic recurrence with trastuzumab, and excitement regarding other HER2 targeted agents (such as pertuzumab and trastuzumab-emtansine) resulted in low patient accrual and early study closure in 2009. Due to low accrual, the study was underpowered, and no significant difference in clinical outcomes was observed between treatment arms. The safety profiles for bevacizumab and trastuzumab were consistent with prior phase I, II and III trials. Cardiac toxicity is a known side effect of trastuzumab; however, previous studies found the toxicity was reversible, unlike doxorubicin-induced cardiomyopathy (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). We saw few overall cardiac adverse events from bevacizumab in addition to the hallmark hypertension associated with anti-angiogenic drugs (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).The results from this trial corroborated the 2011 FDA decision to remove bevacizumab as a recommended therapeutic option for patients with breast cancer.\u003c/p\u003e \u003cp\u003eSince the closure of E1105, other clinical trials have explored the combination of HER2-targeted and anti-angiogenic therapies. A phase II single-arm trial of bevacizumab, trastuzumab, and capecitabine showed clinical activity as first-line therapy for patients with HER2-positive MBC, with no unexpected toxicities, and a median time to progression of 14.5 months (95% Cl, 10.5 months to NR) (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). The AVEREL study randomized 424 first-line patients to trastuzumab/docetaxel with or without concomitant bevacizumab (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Despite a trend favoring bevacizumab PFS (median 13.7 vs. 16.5 months; HR 0.82, log-rank P\u0026thinsp;=\u0026thinsp;0.078), no difference was observed in overall survival (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). The BETH study randomized 3509 patients with HER2-positive early stage breast cancer to receive standard chemotherapy/trastuzumab with or without bevacizumab for 1 year of adjuvant therapy (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). After 38 months of follow-up, there was no statistically significant difference between treatment arms (92% IDFS rates in both groups). Currently, the majority of recent studies using bevacizumab to treat breast cancer are in the HER2-negative patient population or are in subsets of HER2-positive and -negative patients with specific types of refractory disease (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eMore recently, the major focus on treating refractory HER2-positive MBC lies in developing new HER2-targeted antibody-drug conjugates, combinations of CDK4/6 or PI3K/Akt inhibitors with these agents as well as with endocrine therapies, and combinations of different immunotherapy agents with HER2-targeted therapies (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Despite the strong pre-clinical rationale for combining HER2-targeted therapies with antiangiogenic drugs, there was no overall benefit, and there was added toxicity of combining bevacizumab with trastuzumab and chemotherapy, aligning with the 2011 FDA decision to remove the recommendation for the use of bevacizumab in all breast cancers. Despite advances in the adjuvant and metastatic setting made over the past decades, approximately 15\u0026ndash;20% of patients with early HER2-positive breast cancer still relapse after curative therapy, and HER2-positive MBC remains incurable. Therefore, new therapeutic approaches are still necessary for this disease.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from all patients before enrolment, in agreement with approved protocols from respective ethics committees at every site.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAvailability of data and materials\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll study data may be requested from the corresponding author and/or ECOG-ACRIN research group upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJMS, AON, TJS, WJG, EAP, and ACW have no conflicts of interest related to this project. CLA has served as scientific advisor to Novartis, Lilly, Merck, Immunomedics, Daiichi Sankyo, AstraZeneca, PUMA Biotechnology, TAIHO Oncology, OrigiMed, Arvinas, Sanofi, and the Susan G. Komen Foundation. He has received grant support from Pfizer, Lilly, and Takeda. NJM is an employee of Flatiron Health, Inc. an independent member of the Roche group, and reports stock ownership in Roche. VGA has served as a scientific advisor for GuardantHealth and Astra Zeneca and has research funding support from Genetech, Bayer, and GuardantHealth. NUL declares consulting honorarium from Seagen, Daichii-Sankyo, AstraZeneca, Olema Pharmaceuticals, Janssen, Blueprint Medicines, Stemline/Menarini, Artera Inc., Eisai; travel support from Olema Pharmaceuticals; research support (to institution) from Genentech, Zion Pharmaceuticals (as part of GNE), Pfizer, Seagen, Merck, Olema Pharmaceuticals, AstraZeneca; royalties from Up To Date. SAR has served as a consultant for Daiichi-Sankyo, Astra Zeneca, Novartis, and Gilead.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was coordinated by the ECOG-ACRIN Cancer Research Group (Peter J. O\u0026apos;Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180820, U10CA180794, U10CA180821, U10CA180888, UG1CA189805, UG1CA189828, UG1CA189830, UG1CA189954, UG1CA189957, UG1CA190140, UG1CA232760, UG1CA233180, UG1CA233234, UG1CA233302, UG1CA233196, and UG1CA233320. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthors contributions\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConception and design: Ingrid A. Mayer, Anne ONeill, Carlos L. Arteaga, Ximing J.\u003c/p\u003e\n\u003cp\u003eYang, Lynne I. Wagner, David Cella, Neal J. Meropol, Thomas J. Saphner\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eProvision of study materials or patients: All authors\u003c/p\u003e\n\u003cp\u003eCollection and assembly of data: Ingrid A. Mayer, Anne ONeill, Ximing J. Yang, Lynne I. Wagner, David Cella, Neal J. Meropol\u003c/p\u003e\n\u003cp\u003eData analysis and interpretation/Manuscript writing/Final approval of the manuscript: All authors\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to acknowledge and thank the members of the Vanderbilt SWERV writing core for contributing to the editing of this manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMiller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA et al (2007) Paclitaxel plus Bevacizumab versus Paclitaxel Alone for Metastatic Breast Cancer. N Engl J Med 357(26):2666\u0026ndash;2676\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRossari JR, Metzger-Filho O, Paesmans M, Saini KS, Gennari A, de Azambuja E et al (2012) Bevacizumab and Breast Cancer: A Meta-Analysis of First-Line Phase III Studies and a Critical Reappraisal of Available Evidence. J Oncol 2012:417673\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLinderholm B, Andersson J, Lindh B, Beckman L, Erlanson M, Edin K et al (2004) Overexpression of c-erbB-2 is related to a higher expression of vascular endothelial growth factor (VEGF) and constitutes an independent prognostic factor in primary node-positive breast cancer after adjuvant systemic treatment. Eur J Cancer 40(1):33\u0026ndash;42\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePetit AM, Rak J, Hung MC, Rockwell P, Goldstein N, Fendly B et al (1997) Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors. Am J Pathol 151(6):1523\u0026ndash;1530\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang W, Klos K, Yang Y, Smith TL, Shi D, Yu D (2002) ErbB2 overexpression correlates with increased expression of vascular endothelial growth factors A, C, and D in human breast carcinoma. Cancer 94(11):2855\u0026ndash;2861\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHurvitz S, Pegram M, Lin L, Chan D, Allen H, Dichmann R et al (2009) Final Results of a Phase II Trial Evaluating Trastuzumab and Bevacizumab as First Line Treatment of HER2-Amplified Advanced Breast Cancer. Cancer Res 69(24Supplement):6094\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWolff AC, Hammond MEH, Hicks DG, Dowsett M, McShane LM, Allison KH et al (2013) Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Update. J Clin Oncol [Internet]. Oct 7 [cited 2023 Jul 25]; \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://ascopubs.org/doi/pdf/10.1200/JCO.2013.50.9984?role=tab\u003c/span\u003e\u003cspan address=\"https://ascopubs.doi/pdf/10.1200/JCO.2013.50.9984?role=tab\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eO\u0026rsquo;Brien PC, Fleming TR (1979) A multiple testing procedure for clinical trials. Biometrics 35(3):549\u0026ndash;556\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJennison C, Turnbull BW (1993) Group Sequential Tests for Bivariate Response: Interim Analyses of Clinical Trials with Both Efficacy and Safety Endpoints. Biometrics 49(3):741\u0026ndash;752\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGeyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T et al (2006) Lapatinib plus Capecitabine for HER2-Positive Advanced Breast Cancer. N Engl J Med 355(26):2733\u0026ndash;2743\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePerez EA, Suman VJ, Davidson NE, Sledge GW, Kaufman PA, Hudis CA et al (2008) Cardiac Safety Analysis of Doxorubicin and Cyclophosphamide Followed by Paclitaxel With or Without Trastuzumab in the North Central Cancer Treatment Group N9831 Adjuvant Breast Cancer Trial. J Clin Oncol 26(8):1231\u0026ndash;1238\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEwer MS, Vooletich MT, Durand JB, Woods ML, Davis JR, Valero V et al (2005) Reversibility of trastuzumab-related cardiotoxicity: new insights based on clinical course and response to medical treatment. J Clin Oncol Off J Am Soc Clin Oncol 23(31):7820\u0026ndash;7826\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGampenrieder SP, Romeder F, MU\u0026szlig; C, Pircher M, Ressler S, Rinnerthaler G et al (2014) Hypertension as a Predictive Marker for Bevacizumab in Metastatic Breast Cancer: Results from a Retrospective Matched-pair Analysis. Anticancer Res 34(1):227\u0026ndash;233\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMart\u0026iacute;n M, Makhson A, Gligorov J, Lichinitser M, Lluch A, Semiglazov V et al (2012) Phase II Study of Bevacizumab in Combination with Trastuzumab and Capecitabine as First-Line Treatment for HER-2-positive Locally Recurrent or Metastatic Breast Cancer. Oncologist 17(4):469\u0026ndash;475\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGianni L, Romieu GH, Lichinitser M, Serrano SV, Mansutti M, Pivot X et al (2013) AVEREL: a randomized phase III Trial evaluating bevacizumab in combination with docetaxel and trastuzumab as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer. J Clin Oncol Off J Am Soc Clin Oncol 31(14):1719\u0026ndash;1725\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSlamon D, Swain S, Buyse M, Martin M, Geyer C, Im YH et al (2013) Abstract S1-03: Primary results from BETH, a phase 3 controlled study of adjuvant chemotherapy and trastuzumab\u0026thinsp;\u0026plusmn;\u0026thinsp;bevacizumab in patients with HER2-positive, node-positive or high risk node-negative breast cancer. Cancer Res 73(24Supplement):S1\u0026ndash;03\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaji S, Taira N, Kitada M, Takano T, Takada M, Ohtake T et al (2022) Switch maintenance endocrine therapy plus bevacizumab after bevacizumab plus paclitaxel in advanced or metastatic oestrogen receptor-positive, HER2-negative breast cancer (BOOSTER): a randomised, open-label, phase 2 trial. Lancet Oncol 23(5):636\u0026ndash;649\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLeone JP, Emblem KE, Weitz M, Gelman RS, Schneider BP, Freedman RA et al (2020) Phase II trial of carboplatin and bevacizumab in patients with breast cancer brain metastases. Breast Cancer Res 22(1):131\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVega Cano KS, Marmolejo Casta\u0026ntilde;eda DH, Escriv\u0026aacute;-de-Roman\u0026iacute; S, Saura C (2022) Systemic Therapy for HER2-Positive Metastatic Breast Cancer: Current and Future Trends. Cancers 15(1):51\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"breast-cancer-research-and-treatment","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brea","sideBox":"Learn more about [Breast Cancer Research and Treatment](https://www.springer.com/journal/10549)","snPcode":"10549","submissionUrl":"https://submission.nature.com/new-submission/10549/3","title":"Breast Cancer Research and Treatment","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"breast cancer, trastuzumab, chemotherapy, bevacizumab","lastPublishedDoi":"10.21203/rs.3.rs-4295044/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4295044/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003e In 2008, bevacizumab received accelerated Food and Drug Administration (FDA) approval for use in human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Based on the preclinical and preliminary clinical activity of the trastuzumab and bevacizumab combination, ECOG-ACRIN E1105 trial was developed to determine if the addition of bevacizumab to a chemotherapy and trastuzumab combination for first-line therapy would improve progression-free survival (PFS) in patients with HER2-positive MBC.\u003c/p\u003e\u003ch2\u003eFindings:\u003c/h2\u003e \u003cp\u003e96 patients were randomized to receive standard first-line chemotherapy and trastuzumab with or without bevacizumab between November 2007 and October 2009, and 93 began protocol therapy. Induction therapy was given for 24 weeks, followed by maintenance trastuzumab with or without bevacizumab. 60% (56/93) began carboplatin and 74% (69/93) completed 6 cycles of induction therapy. Primary endpoint was PFS. Median PFS was 11.1 and 13.8 months for placebo and bevacizumab arms, respectively (hazard ratio [HR] 95%, Confidence Interval [Cl] for bevacizumab vs. placebo: 0.73 [0.43\u0026ndash;1.23], p\u0026thinsp;=\u0026thinsp;0.24), and at a median follow-up of 70.7 months, median survival was 49.1 and 63 months (HR [95% Cl] for OS: 1.09 [0.61\u0026ndash;1.97], p\u0026thinsp;=\u0026thinsp;0.75). The most common toxicities across both arms were neutropenia and hypertension, with left ventricular systolic dysfunction, fatigue, and sensory neuropathy reported more frequently with bevacizumab.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eIn this trial, the addition of bevacizumab did not improve outcomes in patients with metastatic HER2-positive breast cancer. 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