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BREAST CANCER SYMPOSIUM - ORIGINAL ARTICLE
Year : 2014  |  Volume : 51  |  Issue : 3  |  Page : 272-276
 

Efficacy and safety of bevacizumab in the treatment of human epidermal growth factor receptor type 2 negative metastatic breast cancer: About a large series in moroccan population


Department of Medical Oncology, National Institute of Oncology, Boulevard Allal El Fassi, Rabat, Morocco

Date of Web Publication10-Dec-2014

Correspondence Address:
N Majid
Department of Medical Oncology, National Institute of Oncology, Boulevard Allal El Fassi, Rabat
Morocco
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.146779

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 » Abstract 

Context: Randomized studies have shown different magnitude of bevacizumab (BV) benefit in the treatment of advanced breast cancer. Aims: The aim of the study is to evaluate the efficacy and safety of BV for the treatment of human epidermal growth factor receptor type 2 (HER2) negative metastatic disease. Settings and Design: A large observational institutional study in Moroccan population. Materials and Methods: From January 2009 to December 2011, 42 patients with HER2 negative metastatic breast cancer were analyzed. Results: The median age was 51 years. Approximately two-third of patients analyzed were treated at the first line with BV in association with (paclitaxel, docetaxel or capecitabine) in (40.7%; 40.7% and 18.5%) and the other third at second-line therapy with a combination of the same drugs in (46.6%, 26.6% and 266% respectively); the median number of cycles was 15. In terms of the clinical benefit rate there was a trend in favor of the combination with taxanes and among responders, median duration of objective response was longer with paclitaxel. In addition, analyses of progression-free survival (PFS) across subgroups in both first and second line therapy showed consistent improvements in PFS with the combination of BV and paclitaxel the difference was statistically significant. Concerning safety, the BV was generally well-tolerated. Conclusions: BV in HER2 negative metastatic diseases potentially improved objective response rate and PFS especially in combination with Paclitaxel, which confirm and expand on the results from published literature, with tolerable toxicity.


Keywords: Bevacizumab, human epidermal growth factor receptor type 2 negative, metastatic breast cancer, vascular endothelial growth factor


How to cite this article:
Majid N, Boutayeb S, Errihani H. Efficacy and safety of bevacizumab in the treatment of human epidermal growth factor receptor type 2 negative metastatic breast cancer: About a large series in moroccan population. Indian J Cancer 2014;51:272-6

How to cite this URL:
Majid N, Boutayeb S, Errihani H. Efficacy and safety of bevacizumab in the treatment of human epidermal growth factor receptor type 2 negative metastatic breast cancer: About a large series in moroccan population. Indian J Cancer [serial online] 2014 [cited 2019 Sep 21];51:272-6. Available from: http://www.indianjcancer.com/text.asp?2014/51/3/272/146779



 » Introduction Top


Breast cancer is the most common cancer and the leading cause of mortality in women. The prevalence of metastatic disease is high because many women live with the disease for several years. More-over approximately 4-6% of breast cancers are metastatic at diagnosis. [1] The vast majority of metastatic breast cancer (MBC) is incurable; hence, the main treatment goal is palliation, with the aim of maintaining/improving quality-of-life and possibly improving survival. [2],[3]

Tumor angiogenesis, which is necessary for breast cancer growth, invasion and metastases, is regulated by pro-angiogenic factors like vascular endothelial growth factor (VEGF). [4] Bevacizumab (BV) is a recombinant humanized monoclonal antibody that targets VEGF. [5] The addition of BV to chemotherapy has improved progression-free survival (PFS) in the first- and second-line treatment of patients with advanced-stage breast cancer.

The aim of this large observational institutional study is to describe the epidemiological and clinical data and to analyze results of BV based chemotherapy in first and second line treatment of human epidermal growth factor receptor type 2 (HER2) negative MBC in terms of efficacy and safety in Moroccan population, as complementary to a previous work performed in a small number of MBC treated in the first line situation. [6]


 » Materials and Methods Top


Study population

We included all patients with HER2 negative MBC that was treated at the Department of Clinical Oncology, in the National Institute of Oncology of Rabat, for the period from January 2009 to December 2011.

Patients with histologically confirmed locally recurrent or MBC were eligible. Those with HER2-positive breast were excluded. Previous cytotoxic therapy or hormonal therapies for MBC were allowed. All patients enrolled in the study were naïve to BV. HER2/neu oncoprotein expression negativity was assessed using the Hercept Test, scored 0 (absent) or 1+ (weak) and the negativity of the HER2/neu gene amplification was confirmed by FISH if score 2+ (moderate) in Hercep Test. Hormone receptor status was analyzed by immunohistochemistry and the cut-off for defining positivity was 1%.

The study respected the ethical rules for medical research involving human subjects as stipulated by the World Medical Association okayDeclaration of Helsinki. Informed consent was obtained and documented in writing before study entry. This study was performed after approval by local hospital committees.

Treatment plan

All patients received BV, which was administered at 15 mg/kg intravenously every 3 weeks or at 10 mg/kg at day 1 and 15 and was continued until progressive disease or unacceptable toxicity. Available chemotherapy used were capecitabine 1000 mg/m 2 oral twice a day on days 1-14 of each 21-day cycle, docetaxel 100 mg/m 2 IV every 3 weeks and Paclitaxel at 175 mg/m 2 3 weeks or at 90 mg/m 2 at day 1, 8 and 15 every 4 weeks.

Study procedures

Follow-up


Patients were followed-up until March 2012. All patients who were not reviewed in the last consultations were contacted again.

Study evaluations

All patients were assessed for tumor response every 9 weeks by clinical examination and radiographic assessments (computed tomography or magnetic resonance imaging), bone scans were repeated every 24 weeks or as clinically indicated in patients with bone metastasis. Disease status was according to Response Evaluation Criteria in Solid Tumors 1.0. Safety reporting was noted and classified throughout the study according to (common terminology criteria for adverse events [AEs] version 4.0) and including selective AEs previously associated with BV (grade ≥3 venous thromboembolic events, hypertension, bleeding, proteinuria, sensory neuropathy, wound dehiscence, neutropenia and febrile neutropenia; grade ≥2 atrial thromboembolic events or the left ventricular systolic dysfunction and any grade gastrointestinal (GI) perforation or reversible posterior leukoencephalopathy syndrome), all AEs leading to study drug discontinuation and all serious AEs.

Statistical analysis

Data was analyzed using Win-hospital, an electronic case report form.

The PFS, defined as the time from start of treatment to the first documented disease progression or death from any cause. Patients without a disease-related event were censored at the last tumor assessment or last follow-up for disease progression at which they were known to be progression free. Results are expressed as percentages or medians (range). For PFS, Kaplan-Meier curves were constructed and compared by using a log-rank test. Descriptive statistics with 95% confidence interval were calculated according to standard procedure.


 » Results Top


Patients

A total of 42 patients with HER2 negative MBC were thoroughly analyzed. The majority of patients was >40 years old with a median age of 51 years. All patients had Infiltrating ductal carcinoma (100%). More than 90% of patients had Scarff, Bloom and Richardson Grade 2 and 3 and positive hormone receptors were predominant [Table 1].
Table 1: The clinico-pathological characteristics of patients

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Among patients analyzed in this study, 9 (21.5%) had metastatic disease at diagnosis and 33 (78.5%) presented metastatic relapse, the majority of them relapsed after less than 3 years from adjuvant treatment of localized disease and third of these patients was triple negative disease. Metastasis site was variable, but the predominant in bone (63.1%), liver (47.3%) and lung (47.3%).

Efficacy

Approximately two-third (64.3%) of patients analyzed were treated at the first line with BV in association with paclitaxel, docetaxel or capecitabine in 40.7%; 40.7% and 18.5% and the other third (35.7%) at the second line therapy with a combination of same drugs in 46.6%, 26.6% and 26.6%, respectively. The median number of cycles was 15 (3-34).

In terms of the clinical benefit rate, defined as the overall objective response rate and stable disease rate, there was a trend in favor of the combination with taxanes [Figure 1] and among responders, median duration of objective response was longer with paclitaxel as resumed in [Figure 2].
Figure 1: The clinical benefit rate

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Figure 2: The median duration of response

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At the time of analysis, median survival was 8.4; 6.3 and 4.2; months at the first line and 2.1; 6.3; 7 months at the second line therapy in combination with paclitaxel, docetaxel and capecitabine respectively. Analyses of PFS across subgroups in both first and second line therapy showed consistent improvements in PFS with the combination of BV and paclitaxel compared with the combination of BV with docetaxel or capecitabine. The difference was statistically significant as demonstrated in [Figure 3] and [Figure 4].
Figure 3: Kaplan-Meier curves of survival in patients treated in first line therapy

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Figure 4: Kaplan-Meier curves of survival in patients treated in second line

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Safety

Concerning safety, the BV was generally well-tolerated; the most common AE was hypertension in (n = 4 [9.5%]) patients, but was readily managed with antihypertensive therapy. Hypertension Grade 2 was occurred in 3 cases treated with monotherapy and Grade 3 in only 1 patient, but managed with bitherapy.

The other common treatment-related AEs were proteinuria Grade 1 in (n = 2 [4.7%]) and (n = 1 [2.3%]) presented proteinuria Grade 3 leading to BV discontinuation until test normalization. In addition, slight epistaxis was reported by (n = 3 [7%]) patients [Table 2].
Table 2: The toxicity profile

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 » Discussion Top


Breast cancer is the cancer with the highest incidence in women and the major cause of death world-wide. [1] About 6% of patients with breast cancer present with advanced disease Ab initio while 40% of patients with localized disease subsequently develop distant metastases. [2] Despite numerous advances in early diagnosis and treatment in local and systemic, MBC remains an incurable disease and the main objective of therapy is both the prolongation of survival and the improvement of associated symptoms (palliative intent). [3]

Angiogenesis represents an important step in the pathogenesis, invasion, progression and development of metastatic phenotype of breast cancer and is regulated by pro-angiogenic factors such as VEGF. [7] In this context, the theoretical block of tumor neo-vascularization be realized by monoclonal antibodies to factor soluble serum VEGF to its receptor or VEGFR (in different isoforms) or small molecules directed to the tyrosine-kinase receptor that appears to be a valid rationale for setting effective therapies. [8]

BV is a recombinant humanized monoclonal immunoglobulin G1 antibody. [9] It prevents the interaction between VEGF and its receptor tyrosine kinases VEGFR1 and VEGFR2. BV has a linear pharmacokinetic profile that is not affected by concurrent chemotherapy or endocrine therapy. [10] Sustained inhibition of VEGF with BV results in the regression of existing tumor micro-vasculature and normalization of surviving tumor vasculature as well as inhibition in the formation of new vasculature. BV is currently approved for the treatment of MBC, metastatic colorectal cancer, non-small-cell lung cancer, renal cell cancer it is also approved for the treatment of recurrent glioblastoma multiforme and recently in ovarian cancer.

Three randomized phase III studies evaluating the impact of adding BV to chemotherapy in the first-line treatment of HER2-negative MBC. The E2100 study showed that the addition of biweekly BV 10 mg/kg to weekly paclitaxel doubled the PFS from 5.9 to 11.8 months (P < 0.001). [11] When compared with paclitaxel alone in the first-line treatment of 722 patients with HER2-negative MBC with a higher overall response rate (ORR) of 36.9% versus 21.2% in the single agent arm (P < 0.001) without an overall survival (OS) gain. The results of Eastern Cooperative Oncology Group 2100 led to the Food and Drug Administration (FDA) and European Medicines Agency approval of BV in combination with paclitaxel for the first-line treatment of MBC. Subsequently, the (AVADO) study randomized patients to docetaxel alone or in combination to BV (at two dose levels of 15 mg/kg or 7.5 mg/kg) and demonstrated improvement in PFS and increased ORR, but no OS benefit. [12] Another Phase III the RIBBON-1 trial in which BV 15 mg/kg was added to capecitabine, anthracycline or taxane-based chemotherapy similarly showed improved PFS and ORR without OS benefit. [13]

Two meta-analyses analyzed the effect of the addition of BV to chemotherapy in MBC in over 3,000 patients in three randomized trials. In the meta-analysis conducted by Valachis et al., improved PFS was statistically significant only in the subgroup of patients receiving taxanes (or anthracyclines in a part of the study RIBBON-1) in combination with BV this advantage not seem to get in combination with capecitabine, although the latter are grouped in heterogeneous populations with regard to the treatment line. [14] In the meta-analysis conducted by Lee et al., with populations more correctly grouped by line of treatment rather than medication, the benefit of the addition of BV in PFS is restricted to first-line treatment. [15] Moreover, this analysis shows a marginal but statistically significant benefit in OS in the first line.

More recently A meta-analysis of the three trials was presented at the American Society of Clinical Oncology annual meeting in 2010. [16] It reiterated that E2100, AVADO and RIBBON-1 all have demonstrated significantly improved PFS for BV combined with different chemotherapies as first-line treatment for MBC. It also showed BV in combination with chemotherapy improved PFS regardless of sites of metastases, hormone receptor status, disease-free interval or prior adjuvant taxane use. The median PFS was 9.2 months in patients who received BV in combination with chemotherapy versus 6.7 months in the non-BV treated population. The ORR was 49% in the BV treated patients versus 32% in the chemotherapy only patients. In the pooled population, there was no statistically significant difference in OS.

In the second line situation RIBBON-2 is an international, multicenter, randomized, placebo-controlled, phase III clinical trial evaluating BV in combination with chemotherapy for the second-line treatment of metastatic, HER2-negative breast cancer. [17] A total of 684 women were randomized to receive standard second-line chemotherapy with BV or with placebo in a 2:1 ratio. PFS was the primary endpoint of the study. There was a statistically significant improvement in PFS 7.2 months versus a PFS of 5.1 months and response rate from 29.6% to 39.5%, P = 0.0193 in the BV-treated arms compared with the chemotherapy-only arms. PFS results were consistent across each chemotherapy cohort with the exception of the small vinorelbine subgroup of 76 patients. There was no significant difference in OS, but the data are still immature.

Toxicities associated with BV across the trials have been consistent, although chemotherapy toxicities differ. They were generally mild to moderate in intensity and generally manageable. In a recent meta-analysis, summary odds ratios obtained showed a statistically significant BV -associated increased risk in four of the adverse outcomes studied: Proteinuria (OR = 27.68), hypertension (OR = 12.76), left ventricular dysfunction (OR = 2.25) and hemorrhagic events (OR = 4.07). No statistically significant differences were found for GI perforation, vascular events, fatal events or febrile neutropenia. [18]

Finally, there is an urgent need for the validation and establishment of biomarkers to select patients who will benefit from the addition of BV and to substantially reduce the cost of cancer care. Currently, the FDA recommended removing the breast cancer indication for BV. In Europe, however, BV remains approved, only as first-line therapy in combination with Paclitaxel and in combination with capecitabine only if other chemotherapy options is not considered appropriate.

Recently, an Italian single-center experience confirmed the efficacy and the acceptable toxicity profile of BV plus paclitaxel as first-line regimen for MBC. [19] Our study suggest also that the better results were obtained in combination with Paclitaxel, which confirm the previous results performed in the first line MBC [6] and expand on the results from published literature, with an acceptable safety profile.


 » Conclusion Top


Based on our results we can conclude that BV may be considered as an acceptable option for HER2 neg MBC particularly in combination with Paclitaxel.

 
 » References Top

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Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277-300.  Back to cited text no. 1
    
2.
Petrelli NJ, Winer EP, Brahmer J, Dubey S, Smith S, Thomas C, et al. Clinical cancer advances 2009: Major research advances in cancer treatment, prevention, and screening - A report from the American society of clinical oncology. J Clin Oncol 2009;27:6052-69.  Back to cited text no. 2
    
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Cardoso F, Fallowfield L, Costa A, Castiglione M, Senkus E, ESMO Guidelines Working Group. Locally recurrent or metastatic breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2011;22 Suppl 6:vi25-30.  Back to cited text no. 3
    
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Kaelin WG Jr. The von Hippel-Lindau protein, HIF hydroxylation, and oxygen sensing. Biochem Biophys Res Commun 2005;338:627-38.  Back to cited text no. 4
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Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 2004;3:391-400.  Back to cited text no. 5
    
6.
Boulaamane L, Boutayeb S, Errihani H. Bevacizumab based chemotherapy in first line treatment of HER2 negative metastatic breast cancer: Results of a Moroccan observational institutional study. BMC Res Notes 2012;5:162.  Back to cited text no. 6
    
7.
Gasparini G. Angiogenesis in breast cancer: Role in biology, tumor progression, and prognosis. In: Bowcock A, editor. Breast Cancer: Molecular Genetics, Pathogenesis, and Therapeutics. Totowa, NJ: Humana Press; 1999. p. 347-71.  Back to cited text no. 7
    
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Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003;9:669-76.  Back to cited text no. 8
    
9.
Willett CG, Boucher Y, di Tomaso E, Duda DG, Munn LL, Tong RT, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 2004;10:145-7.  Back to cited text no. 9
    
10.
Gordon MS, Margolin K, Talpaz M, Sledge GW Jr, Holmgren E, Benjamin R, et al. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol 2001;19:843-50.  Back to cited text no. 10
    
11.
Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007;357:2666-76.  Back to cited text no. 11
    
12.
Miles DW, Chan A, Dirix LY, Cortés J, Pivot X, Tomczak P, et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 2010;28:3239-47.  Back to cited text no. 12
    
13.
Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, et al. RIBBON-1: Randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol 2011;29:1252-60.  Back to cited text no. 13
    
14.
Valachis A, Polyzos NP, Patsopoulos NA, Georgoulias V, Mavroudis D, Mauri D. Bevacizumab in metastatic breast cancer: A meta-analysis of randomized controlled trials. Breast Cancer Res Treat 2010;122:1-7.  Back to cited text no. 14
    
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Lee JB, Woo OH, Park KH, Woo SU, Yang DS, Kim AR, et al. Bevacizumab for salvage treatment of metastatic breast cancer: A systemic review and meta-analysis of randomized controlled trials. Invest New Drugs 2011;29:182-8.  Back to cited text no. 15
    
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O′Shaughnessy J, Miles D, Gray RJ, Dieras V, Perez EA, Zon R, et al. A meta-analysis of overall survival data from three randomized trials of bevacizumab and first-line chemotherapy as treatment for patients with metastatic breast cancer. J Clin Oncol 2010;28 Suppl 15:1005.  Back to cited text no. 16
    
17.
Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O′Neill V, et al. RIBBON-2: A randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 2011;29:4286-93.  Back to cited text no. 17
    
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Cortes J, Calvo V, Ramírez-Merino N, O′Shaughnessy J, Brufsky A, Robert N, et al. Adverse events risk associated with bevacizumab addition to breast cancer chemotherapy: A meta-analysis. Ann Oncol 2012;23:1130-7.  Back to cited text no. 18
    
19.
Livi L, Bonomo P, Meattini I, Simontacchi G, Greto D, Desideri I, et al. Paclitaxel and bevacizumab in first-line treatment for HER2-negative metastatic breast cancer: Single-center experience. Med Oncol 2013;30:434.  Back to cited text no. 19
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2]

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1 Bevacizumab
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