**6.2 MUC-1**

MUC-1 mucins are large, complex glycoproteins that have a polypeptide core with multiple oligosaccharide side chains (Mukhopadhyay et al., 2011). The mature molecule is anchored within the cell surface by a characteristic transmembrane domain, but most of the mucins are expressed extracellular. This polar distribution is lost with neoplastic transformation and increased heterogenous MUC-1 synthesis is a common feature of breast cancer. This glycoprotein is aberrantly over expressed in adenocarcinomas including 80% of breast cancers (Salouti et al., 2011). Targeting, using antibodies directed against the MUC-1 antigen has been tested in patients with breast cancer using various antibodies. BrE-3 is an IgG1 antibody directed against the peptide epitope of the MUC-1 antigen that have been evaluated for RIT (Mohammadnejad et al, 2010). The studies of the application of BrE-3 mAbs in patients with breast cancer showed minimal cross reactivity with normal breast tissues (Howell et al., 1995; Blank et al., 1992). Because the majority of the patients rapidly showed HAMA response against the murine BrE-3 mAb, a humanized version of BrE-3 (hBrE-3) was developed (Kramer et al., 1993). Kramer and colleagues investigated the pharmacokinetics and biodistribution of 111In-MX-DTPA-labeled hBrE-3 in seven patients with metastatic breast cancer (Kramer et al., 1993). hBrE-3 was proved to have a lower immunogenicity compared to murine BrE-3 (only one patient developed a HAMA response) while tumor-targeting properties were preserved (Denardo, 2005). Monoclonal antibody 170H.82 (m170) is a murine IgG1 prepared using a synthetic asialo GM1 terminal disaccharide immunogen related to the Thomsen–Friedenreich disaccharide and selected by reactivity with MUC-1 expressing cancer cell membranes (Jonathan et al., 2000). The results of experimens showed that labeled m170 was effective for imaging of primary and metastatic breast cancer and was able to detect lesions as small as 1 cm in size using SPECT with an overall clinical accuracy of 92%. In particular, mAb 170H.82 has been studied in

Breast Cancer: Radioimmunoscintigraphy and Radioimmunotherapy 177

and neck, breast, colon, lung, kidney, prostate, brain, bladder and pancreas overexpress EGFR. Such overexpression is associated with poor prognosis and this leads to several strategies to block this pathway and improve the outcome. Cetuximab is a chimeric IgG1 monoclonal antibody that competes with an endogenous ligand to bind to the extracellular domain of EGFR (Harris, 2004). On the basis of these findings and those of previous studies, Cetuximab received FDA approval in February 2004, for using in treatment of EGFR-

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

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

It is well known that mammography provides a high sensitivity at the cost of relatively low specificity. Therefore, breast cancer diagnosis requires an adjunctive test to mammography that can increase diagnostic specificity while maintaining a high positive predictive value. Although sestamibi imaging has been introduced as an adjunctive test to mammography, it fails to provide the necessary sensitivity, specificity and predictive values for nonpalpable

treating advanced breast cancer, but not other cancers (Munnink, 2009).

positive metastatic colorectal cancer (Harris, 2004).

• **HER2/Neu receptor** 

breast carcinomas (Munnink, 2009).

**7. Radioimmunoscintigraphy** 

**6.6 VEGF** 

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 and radioimmunotherapy studies in this cancer type.
