• **HER2/Neu receptor**

176 12 Chapters on Nuclear Medicine

breast cancer patients, with reported a sensitivity and specificity for detecting locoregional soft tissue disease of 90% and 93%, respectively (Denardo, 2005). Because aberrant MUC-1 has provided effective target for breast cancer, gene-engineered antibody fragments (scFv) have been developed to MUC-1 antigen by phage display immunoglobulin gene libraries from mice immunized with MUC-1 peptide core and MCF-7 membranes. Numerous other monoclonal antibodies have been generated against MUC1 and have been used for breast cancer imaging such as HMFG-1 and HMFG-2, SM3, DF3, 12H12, BM2 (formerly called 2El 1), BM7, EBA-1, MA5 and PR81 (Richman & Denardo, 2001; Salouti et al., 2008). Although, not all of these antibodies necessarily react with the same MUC1 determinant, they have all shown the ability to target breast cancer either in animal xenografts or in patients. Thus, these antibodies have been shown to be suitable antibodies for radioimmunoscintigraphy

Immunohistochemical and immunocytochemical techniques have demonstrated preferential expression of TAG-72 known as tumor-associated glycoprotein in breast, gastrointestinal and ovarian adenocarcinomas compared to normal tissues (Denardo, 2005). Antibodies against the TAG-72 antigen particularly B72.3 and chB72.3 were evaluated in patients after careful study in human xenograft mouse models (Lorraine et al., 1998). The TAG-72 target antigen reactive with B72.3 pancarcinoma antibody has been used to target and image breast cancer (Denardo, 2005). CC49, a newer antibody to a different epitope of TAG-72, is a murine IgG1 monoclonal antibody that was labeled with Lutitium-177 by Milenic et al. (Milenic et al., 1991). He found that Lutitium-177 was an attractive alternative radionuclide with a lower energy beta emission and longer half life than 90Y. The images demonstrated

L6 cell surface antigen is a 24-kDa surface protein containing 3 hydrophobic transmembrane regions that are followed by a hydrophilic region (Richman & Denardo, 2001). L6 antigen is related to a number of cell surface proteins with similar predicted membrane topology that have been implicated in cell growth. L6 antigen is highly expressed in 50% of breast cancer specimens. Two mAb of this family, L6 mAb and the chimeric version (ChL6) have been studied in clinical trials (Denardo et al., 1994). 131I-Chimeric L6 antibody demonstrated

Epidermal growth factor receptor (EGFR) is a family of transmembrane growth factor receptor tyrosine kinases involved in regulation of cell proliferation and survival of epithelial cells (Cleator & Heller, 2007). EGFR family includes four receptors: EGFR/ErbB1, HER2/ErbB2, HER3/ErbB3 and HER4/ErbB4. EGFR and HER2 are over expressed in approximately 40% and 25% of breast cancers, respectively and associated with aggressive clinical behavior and poor prognosis. Due to the important roles of EGFR and HER2 receptors in diagnosis and therapy of breast cancer patients, both receptors are discussed in

EGFR (also known as ErbB1 or HER1) is a 170 kDa transmembrane protein with an intracellular tyrosine-kinase domain. Many epithelial cancers including tumors of the head

and radioimmunotherapy studies in this cancer type.

the activity uptake at the site of tumor as well as in bone marrow.

therapeutic promise for patients with breast cancer (John et al., 2009).

**6.3 TAG-72** 

**6.4 L6** 

**6.5 EGFR** 

details (Munagalaet al., 2011).

• **EGFR receptor** 

The HER2/Neu receptor is a member of the EGFR family and another important cancerrelated receptor that is over expressed in several human tumors notably on a subset of breast cancer cells (Ross et al., 2004). Trastuzumab (commonly referred to Herceptin) was the first recombinant bivalent humanized mAb targeted against extracellular domain of HER2 reported in 1998, has been approved by FDA and is frequently used clinically in "naked antibody" therapy (Rasaneh et al., 2009). Trastuzumab binds with high affinity to HER2 and leads to internalisation of HER2 receptor and blockage of signal transduction. Unlike chemotherapy, trastuzumab do not have toxic effects such as nausea, vomiting, hair loss and bone marrow toxicity (Munagala, 2011). Pertuzumab, a recombinant humanized monoclonal antibody, binds to extracellular domain II of HER2 receptor and blocks its ability to dimerize with other HER family receptors (HER1, HER2, HER3, HER4) (Untch, 2010). Pertuzumab is the first in a new class of targeted agents known as HER dimerization inhibitors (HDIs). The drug showed promising activity with trastuzumab in the treatment of metastatic breast cancer in a phase II study (Baselga et al., 2007, 2010). The patients treated with trastuzumab have an increased risk of developing cardiac dysfunction (Widakowich et al., 2007). When trastuzumab was conjugated with a radioneclide, the dose of drug was decreased that led to decrease its cardiac toxicity (Harris, 2004). Radioactive anti-HER2/neu rhumAb are considered attractive agents for RIS and RIT of aggressive HER-2/neu-positive breast carcinomas (Munnink, 2009).

### **6.6 VEGF**

Vascular-endothelial growth factor (VEGF) is a proangiogenic growth factor that regulates vascular proliferation and permeability and is an antiapoptotic factor for new blood vessels. VEGF acts via two receptors, VEGFR1 and VEGFR2, which are expressed on the vascular endothelium. VEGFR expression is commonly increased in response to hypoxia, oncogenes and cytokines and its expression is associated with poor prognosis. Bevacizumab (Avastin) is a humanised monoclonal antibody that inhibits angiogenic signaling. In February, 2004, bevacizumab received FDA approval for using in the first line treatment of metastatic colorectal cancer in combination with 5-fluorouracil-based chemotherapy (Munnink, 2009). FDA is still moving toward stripping the cancer drug bevacizumab of its indication for treating advanced breast cancer, but not other cancers (Munnink, 2009).
