Material and methods
- Kaufman B.
- Mackey J.R.
- Clemens M.R.
- et al.
- Marty M.
- Cognetti F.
- Maraninchi D.
- et al.
the HER family receptors
|Mechanism of action||Pathway||Description|
|Impaired access of trastuzumab to the binding site||p95HER [|
|Cleavage of HER2 results in a truncated p95 protein (also called p95 HER2) that lacks the receptor site for trastuzumab. p95 HER2 may further add to resistance by independently phosphorylating HER3 and initiating signaling via the PI3K/Akt pathway|
|Membrane masking proteins [|
|MUC 4 is a membrane-associated mucin that can conceal surface proteins on HER2, making it difficult for trastuzumab to identify the appropriate binding site|
|HER2 shedding||Shedding of the HER2 receptor with high levels of serum HER2 binds trastuzumab, reducing the amount of therapeutic trastuzumab|
|Alternate signaling||Cross-talk [|
|HER3 receptor has more specific direct binding sites than HER2 for the activation of the PI3K/Akt pathway|
|IGF-1R activation [|
|Insulin-like growth factor 1 receptor (IGF-1R) is a tyrosine kinase receptor that can very efficiently activate the PI3K/Akt pathway independently of HER2. IGF-1R decreases G1/S cell-cycle arrest via p27. Evidence of increased expression of IGF-1R in resistant clones|
|MET activation [|
|MET is a tyrosine kinase implicated in resistance to EGFR inhibitors gefitinib and erlotinib and may play a part in trastuzumab resistance via increased levels of MET and its ligand, HRG. Trastuzumab exposure can increase the expression of MET|
|HER2-independent activation of downstream signaling||PTEN [|
|PTEN is a negative regulator of the PI3K/Akt pathway. The absence of PTEN may lead to trastuzumab resistance|
|PI3K/Akt activating mutations [|
|Most frequent are E542K or E545K and H1047R on exon 9 and 20, occurring in up to 40% of breast cancers. They represent gain-of-function mutations|
|Reduced p27 expression [|
|p27 interacts with the cell cycle to produce G1/S cell-cycle arrest. Reduced expression of p27 in trastuzumab-resistant cell lines|
differences between trastuzumab and pertuzumab
|Structure||Recombinant humanized monoclonal antibody, IgG1 (κ)||Fully humanized monoclonal antibody, human IgG1 (κ)|
|Two heavy chains (451 residues) and two light chains (214 residues)||Two heavy chains (449 residues) and 2 light chains (214 residues)|
|Produced in CHO cell culture||Produced in CHO cell culture|
|Epitope-binding region||Extracellular domain of HER2 (domain IV)||Extracellular domain of HER2 (domain II)|
|Half-life||25.5 days||10 days|
|Route of administration||Intravenous||Intravenous|
|Type of inhibitor||–||Dimerization|
|Inhibitor of HER2–HER3 dimer formation in a ligand-induced fashion||No||Yes|
|Inhibitor of HER2–HER3 dimer formation in a ligand-independent fashion||Yes||No|
|Prevents HER2 extracellular domain shedding||Yes||No|
|Efficacy affected by formation of p95HER2||Yes||No|
|Reduces cross-talk, resistance||No||Yes|
mechanism of action
- Gianni L.
- Llado A.
- Bianchi G.
- et al.
the metastatic setting
- Supplement Table S1
|Baselga et al. [|
|Portera et al. [|
|Gianni et al. [|
Open-label, phase II, multicenter, randomized study of the efficacy and safety of two dose levels of pertuzumab, a human epidermal growth factor receptor 2 dimerization inhibitor, in patients with human epidermal growth factor receptor 2-negative metastatic breast cancer.
J Clin Oncol. 2010; 28: 1131-1137
|Treatment||Trastuzumab + pertuzumab|
|Trastuzumab + pertuzumab|
|Patient population||Progression on trastuzumab||Progression on trastuzumab||HER2-negative and HER2 treatment naïve|
|CR (%)||5 (7.6%)||0||0|
|PR (%)||11 (16.7%)||2 (18%)||2 (2.5%)|
|SD (%)||17 (25.8%), >6 months||3 (27%), >4.5 months||4 (5.1%), >6 months|
|ORR (%)||16 (24.2%)||2 (18%)||2 (2.5%)|
|CBR (%)||33 (50%), >24 weeks||5 (45.5%), >18 weeks||6 (7.7%)|
|PD (%) <6 weeks||11 (16.7%)||6 (55%)||43 (55.1%)|
|TTP (weeks)||15.6 weeks (3.6–68.0)||1.5 (3–4)||6.3 weeks (2.0–37.0)|
- Gianni L.
- Llado A.
- Bianchi G.
- et al.
- Supplement Figure S1
the neoadjuvant setting
- Supplement Figure S2
- Supplement Figure S3
the adjuvant setting
- Gianni L.
- Llado A.
- Bianchi G.
- et al.
|Adverse events grade ≥ 3 (%)||Neoadjuvant phase II||Metastatic phase III|
21] (n = 225)
22] (n = 417)
20] (n = 808)
|FEC + P + T → D + P + T (n = 75), %||FEC → D + T + P (n = 75), %||C + D + P + T (n = 75), %||T + D (n = 107), %||P + T + D (n = 107), %||P + T (n = 108), %||P + D (n = 94), %||T + Pla + D (n = 397), %||T + P + D (n = 407), %|
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