Trastuzumab has been shown to inhibit HER2/neu ectodomain cleavage in breast cancer cells.Experiments in laboratory animals indicate that antibodies, including trastuzumab, when bound to a cell, induce immune cells to kill that cell, and that such antibody-dependent cell-mediated cytotoxicity is another important mechanism of action. Predicting response
Trastuzumab inhibits the effects of overexpression of HER2. If the breast cancer does not overexpress HER2, trastuzumab will have no beneficial effect (and may cause harm). Doctors use laboratory tests to discover whether HER2 is overexpressed. In the routine clinical laboratory, the most commonly employed methods for this are immunohistochemistry (IHC) and either silver, chromogenic or fluorescent in situ hybridisation (SISH/CISH/FISH). HER2 amplification can be detected by virtual karyotyping of formalin-fixed paraffin embedded tumor. Virtual karyotyping has the added advantage of assessing copy number changes throughout the genome, in addition to detecting HER-2 amplification (but not overexpression). Numerous PCR-based methodologies have also been described in the literature. It is also possible to estimate HER2 copy number from microarray data.There are two FDA-approved commercial kits available for HER2 IHC; Dako HercepTest and Ventana Pathway. These are highly standardised, semi-quantitative assays which stratify expression levels into; 0 (<20,000 receptors per cell, no visible expression), 1+ (~100,000 receptors per cell, partial membrane staining, < 10% of cells overexpressing HER-2), 2+ (~500,000 receptors per cell, light to moderate complete membrane staining, > 10% of cells overexpressing HER-2), and 3+ (~2,000,000 receptors per cell, strong complete membrane staining, > 10% of cells overexpressing HER-2). The presence of cytoplasmic expression is disregarded.
The etiology or duration of renal failure seems not to be relevant, but NSF risk greatly depends on the residual kidney function. The majority of NSF cases have been identified in patients with stage 5 CKD, but NSF has also developed in patients with stage 4 and 3 CKD, and those with acute kidney injury, even if kidney function subsequently returned to normal following GBCA administration. Thus NSF should be considered as a differential diagnosis in any patient who has been exposed to a GBCA, regardless of the kidney function level.Three GBCAs have been principally implicated in NSF: gadodiamide, gadopentetate dimeglumine, and gadoversetamide, though cases have been reported with majority of GBCAs on the market. High doses in individual GBCA administrations and high cumulative doses of GBCA over the lifetime of patients with renal dysfunction are associated with increased risk of NSF. Mechanism
De-chelation of Gd(III) is responsible for the toxicity associated with gadolinium complexes such as GBCAs, and the toxicity appears to be a consequence of Zn2+, Cu2+, and Ca2+ transmetallation in vivo. This hypothesis is supported by acute toxicity experiments, which demonstrate that despite a 50-fold range of LDse values for four Gd(III) complexes, all become lethally toxic when they release precisely the same quantity of Gd(III). It is also supported by subchronic rodent toxicity experiments, which demonstrate a set of gross and microscopic findings similar to those known to be caused by Zn2+ deficiency.