Effect of Bevacizumab in Metastatic Triple Negative Breast Cancer
Condition: Metastatic Triple Negative Breast Cancer; Safety Issues; Efficacy
MeSH terms: Breast Neoplasms; Triple Negative Breast Neoplasms
Study type: Interventional
Phase: Phase 2

Summary: 
      Evaluating efficacy and safety of bevacizumab when combined with chemotherapy (carboplatin
      and Paclitaxel ) in treatment of patient with metastatic triple negative breast cancer
    

Detailed description: 
      Breast cancer is the most common non cutaneous cancer in U.S. women, with an estimated 63,960
      cases of in situ disease and 266,120 cases of invasive disease in 2018. (American Cancer
      Society: Cancer Facts and Figures 2018). On the basis of ER, PR, and HER2/neu results, breast
      cancer is classified as one of the following types:

      Hormone receptor positive , HER2/neu positive and Triple negative (ER, PR, and HER2/neu
      negative).

      ER, PR, and HER2 status are important in determining prognosis and in predicting response to
      endocrine and HER2-directed therapy.(Harris JR, Morrow M, Lippman ME, et al . 1996)
      Metatstaic Triple-negative breast cancer (TNBC) is a diagnosis of exclusion, defined by the
      lack of expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal
      growth factor receptor 2 (HER2) .

      TNBC tends to occur in younger, often premenopausal patients, African Americans, and in
      association with hereditary syndromes, most commonly germline BRCA1 mutations. It constitutes
      up to 15% of all breast cancers but accounts for > 25% of breast cancer-related deaths as it
      has an inherent predisposition for rapid dissemination and visceral metastases with limited
      improvements in overall survival and inferior clinical outcomes . It is characterized by
      higher incidence of brain metastases and rapid progression from the onset of metastasis to
      death. Having aggressive biology more than other breast types due to high risk of early
      relapse between the first and third years after diagnosis , metastases are rarely preceded by
      local recurrence and most deaths occur in the first 5 years ( Livasy CA et al . 2006 ) Due to
      the palliative intent of treatment as in MBC and Optimal chemotherapy regimens have yet to be
      established in treatment of metastatic TNBC; however, there have been advances in the
      systemic treatment of triple-negative breast cancer in the neoadjuvant, adjuvant, and
      metastatic settings. ( J.M. Lebert , R. Lester , E. Powell et el current oncology journal
      2018 ) it is critical that an individualized approach is taken that incorporates patient,
      disease, and treatment-related factors, including an individual oncologist treatment
      preference.(Geels P, et al 2000 ).

      There have been several head-to-head chemotherapy trials performed within the metastatic
      setting, and much of what is applied in clinical practice is extrapolated from chemotherapy
      trials in the adjuvant setting, with taxanes and anthracyclines incorporated early on in the
      patient's treatment course.

      Angiogenesis is essential for the development of malignancies and plays a central role in the
      early stages of growth, invasion, and metastatic spread of breast cancer (BC), thus
      representing a reasonable therapeutic target. This evidence is a solid biological rationale
      for the use of therapeutic agents able to interfere with the VEGF (vaso endothelial growth
      factor ) function.

      Breast cancer is the most common non cutaneous cancer in U.S. women, with an estimated 63,960
      cases of in situ disease and 266,120 cases of invasive disease in 2018. (American Cancer
      Society: Cancer Facts and Figures 2018). On the basis of ER, PR, and HER2/neu results, breast
      cancer is classified as one of the following types:

      Hormone receptor positive , HER2/neu positive and Triple negative (ER, PR, and HER2/neu
      negative).

      ER, PR, and HER2 status are important in determining prognosis and in predicting response to
      endocrine and HER2-directed therapy.(Harris JR, Morrow M, Lippman ME, et al . 1996)
      Metatstaic Triple-negative breast cancer (TNBC) is a diagnosis of exclusion, defined by the
      lack of expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal
      growth factor receptor 2 (HER2) .

      TNBC tends to occur in younger, often premenopausal patients, African Americans, and in
      association with hereditary syndromes, most commonly germline BRCA1 mutations. It constitutes
      up to 15% of all breast cancers but accounts for > 25% of breast cancer-related deaths as it
      has an inherent predisposition for rapid dissemination and visceral metastases with limited
      improvements in overall survival and inferior clinical outcomes . It is characterized by
      higher incidence of brain metastases and rapid progression from the onset of metastasis to
      death. Having aggressive biology more than other breast types due to high risk of early
      relapse between the first and third years after diagnosis , metastases are rarely preceded by
      local recurrence and most deaths occur in the first 5 years ( Livasy CA et al . 2006 ) Due to
      the palliative intent of treatment as in MBC and Optimal chemotherapy regimens have yet to be
      established in treatment of metastatic TNBC; however, there have been advances in the
      systemic treatment of triple-negative breast cancer in the neoadjuvant, adjuvant, and
      metastatic settings. ( J.M. Lebert , R. Lester , E. Powell et el current oncology journal
      2018 ) it is critical that an individualized approach is taken that incorporates patient,
      disease, and treatment-related factors, including an individual oncologist treatment
      preference.(Geels P, et al 2000 ).

      There have been several head-to-head chemotherapy trials performed within the metastatic
      setting, and much of what is applied in clinical practice is extrapolated from chemotherapy
      trials in the adjuvant setting, with taxanes and anthracyclines incorporated early on in the
      patient's treatment course.

      Angiogenesis is essential for the development of malignancies and plays a central role in the
      early stages of growth, invasion, and metastatic spread of breast cancer (BC), thus
      representing a reasonable therapeutic target. This evidence is a solid biological rationale
      for the use of therapeutic agents able to interfere with the VEGF (vaso endothelial growth
      factor ) function.

      The recombinant monoclonal antibody bevacizumab is currently the most widely used and
      developed antiangiogenic drug in the treatment of breast cancer(BC) , able to recognize all
      the isoforms of VEGFA, preventing its binding to the cellular receptor, and inhibiting the
      angiogenic and proliferative signal. In vivo studies showed that bevacizumab inhibits both
      proliferation and migration of endothelial cells induced by VEGFA; besides in some models of
      human BC, the treatment with bevacizumab was associated to a reduction in microvascular
      density ( Zhang W et al. 2002. ) . The humanized, anti-VEGF monoclonal antibody bevacizumab
      has been shown to increase progression-free survival (PFS) and/ or overall survival (OS) in
      metastatic breast cancer (MBC), response rate RR . ( Brufsky A, et al 2012) ( Vrdoljak E1, et
      al 2016 ).

      In the Phase 3 RIBBON-2 study, previously treated patients with metastatic breast cancer were
      randomized to Avastin with chemotherapy (n=112 had triple-negative breast cancer) or
      chemotherapy with placebo (n=47 had triple-negative breast cancer). In an exploratory
      subgroup analysis of the patients with triple-negative breast cancer, median progression-free
      survival was 6 months vs 2.7 months (hazard ratio=0.49; p=0.0006), median overall survival
      was 17.8 months vs 13.5 months (hazard ratio=0.85; 95% CI, 0.58-1.26), and objective response
      rate was 41% vs 18% (p=0.0078). (Brufsky AM, Hurvitz S, Perez E, et al. 2012 ) In the
      RIBBON-1 study, chemotherapy with or without Avastin was evaluated in 1,237 patients as
      first-line treatment for metastatic breast cancer, 21.3% of whom had triplenegative breast
      cancer. In prespecified subgroup analyses, triple-negative patients demonstrated a hazard
      ratio for progression-free survival of 0.72 (95% CI, 0.49-1.06) and had a median
      progression-free survival of 6.1 vs. 4.2 months in the Avastin with capecitabine arm vs the
      capecitabine alone arm. In the Avastin with taxane/anthracycline cohort vs
      taxane/anthracycline alone cohort, triple-negative patients had a hazard ratio for
      progressionfree survival of 0.78 (95% CI, 0.53-1.15) with a median progression-free survival
      of 6.5 vs 6.2 months, respectively. (Robert NJ, Diéras V, Glaspy J, et al. RIBBON-1 ,2011) A
      subgroup analysis of the TURANDOT study compared first-line Avastin and paclitaxel (Arm A)
      with Avastin and capecitabine (Arm B) in human epidermal growth factor receptor 2-negative
      patients with triple-negative metastatic breast cancer (n=124). In the triplenegative breast
      cancer subgroup, the median overall survival was 24.4 months in Arm A and 17.7 months in Arm
      B (unstratified hazard ratio=1.35; 95% CI, 0.9-2.02). (Zielinski C, Lang I, Inbar M, et al.
      2016) Taxanes as part of chemotherapy have been studied as having an inhibitory action on the
      proliferation of endothelial progenitor cells, with an antiangiogenic effect at lower doses
      than those needed to inhibit the proliferation of cancer cells. The resulting hypoxia induces
      cancer cells to a kind of "reaction" through the autocrine production of proangiogenic agents
      , several evidences of their benefits on clinical outcomes, such as OS, time to progression
      (TTP), and over all response rate ( ORR.) ( Tran J. et al. 2002.) ( Ghersi D, et al. 2015 ) .
      Even if conventional taxanes demonstrated to be more active in endocrine receptor-negative
      tumors and are indicated in the first-line treatment of TNBC . ( Isakoff SJ Cancer J. 2010 )
      Because of the sensitivity of TNBC to platinum compounds and the synergistic effect of
      bevacizumab with paclitaxel we investigated the efficacy and toxicity of weekly paclitaxel
      and carboplatin in combination with bevacizumab as first-line treatment in metastatic TNBC.

      phase II study followed the Simon's 2-stage optimal design. Paclitaxel (90 mg/m2) and
      carboplatin (2 area under the curve) were administered on days 1, 8, and 15 every 4 weeks,
      preceded by bevacizumab 10 mg/kg on days 1 and 15. The primary end point was the objective
      response rate (ORR). A total of 46 patients were enrolled. Seven (15.2%) complete and 23
      (50%) partial responses were observed for an ORR of 65.2% (95% confidence interval,
      52.9%-80.4%). The median progression-free survival was 10.3 months, the median overall
      survival 25.7 months, and the median duration of response 18.2 months. Neutropenia Grade III
      and IV was experienced by 13 (28.3%) and 6 (13.04%) patients, respectively. One patient
      developed an uneventful Grade IV thrombocytopenia. There was 1 toxic death due to febrile
      neutropenia. Other Grade III toxicities included anemia (n = 2), neurotoxicity (n = 2),
      thrombocytopenia (n = 1), and diarrhea (n = 1). No serious bevacizumab-related toxicities
      were observed.( Saloustros E, Nikolaou M, Kalbakis etal 2017)
    

Intervention name(s): Bevacizumab
Intervention type(s): Drug
Intervention description(s): -bevacizumab 15m.g/ kg + carboplatin 450m.g + paclitaxel 175m.g/m2 D1 /21 Day until disease progression or un acceptable toxicity .
Other intervention name(s): avastin
Intervention MeSH terms: Bevacizumab
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: antiangiogenesis; taxanes and carboplatin; metastatic TNBC