Abstract

Given that several targeted therapies directed towards folate receptor alpha (FRA) are in late stage clinical development, the sensitive and robust detection of FRA in tissues is of paramount importance relative to patient selection, prognosis and prediction. In the present study we undertook an immunohistochemical evaluation of expression of FRA in breast cancer samples using formalin-fixed, paraffin-embedded (FFPE) tissues, primarily invasive ductal carcinomas, using a newly described monoclonal antibody, 26B3. Samples assessed included both tissue microarrays (TMA) and whole tissue sections from archival tissue blocks. Normal breast shows a highly restricted expression of FRA to luminal membrane staining of secretory ductal cells, consistent with FRA secretion into milk. In early stage (stages I-III) invasive ductal carcinomas, FRA staining was observed in approximately 30% of all samples, independent of molecular subtype (estrogen receptor (ER)/progesterone receptor (PR)/human epidermal growth factor receptor type 2 (Her2)). However, FRA expression was shown to associate with ER/PR negative tumors relative to ER/PR positive tumors (p = 0.012) and perhaps more importantly, with triple negative breast cancers (TNBC; p < 0.0001). FRA immunoreactivity was also shown to be retained in stage IV metastatic breast cancer samples from diverse anatomic sites including lymph node and bone. In metastatic breast cancer, FRA was shown to be expressed in 86% of TNBC patients. Taken together, these data suggest that FRA expressing breast cancer represents a novel molecular subtype and, further, may represent a new therapeutic target for this devastating disease.

Highlights

  • According to Global Cancer Facts & Figures 2nd Edition, in 2008 the estimated worldwide new cases for breast cancer were 1,383,500 with a projected 458,400 deaths and a mortality rate of approximately 33%

  • As previously described (O’Shannessy et al 2011), Monoclonal antibody (MAb) 26B3 is a unique, high affinity antibody shown to be highly specific for folate receptor alpha (FRA) with no cross-reactivity to the other three members of this receptor family, namely Folate receptor beta (FRB), Folate receptor gamma (FRG) or Folate receptor delta (FRD)

  • FRA expression on the breast cancer tissue microarrays (TMA) The distribution of histologies present on the breast cancer TMA are shown in Table 1, the majority (83%) of the cases represented being identified as invasive ductal carcinoma (IDC)

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Summary

Introduction

According to Global Cancer Facts & Figures 2nd Edition, in 2008 the estimated worldwide new cases for breast cancer were 1,383,500 with a projected 458,400 deaths and a mortality rate of approximately 33%. In the U.S, 229,060 new cases of breast cancer and 39,920 deaths from this disease are expected in 2012 (Siegel & Naishadham 2012). Treatment for breast cancer is currently tailored according to cellular protein expression. Estrogen receptor/progesterone receptor (ER/PR) expressing breast cancers are treated with endocrine therapy. The treatment armamentarium of human epidermal growth factor receptor 2 (Her2) overexpressing breast cancers includes an anti-. The triple negative breast cancers (TNBC) that do not express ER, PR or Her are treated with traditional cytotoxic chemotherapy alone. New therapeutic approaches for this poor prognosis breast cancer subtype are sorely needed

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