For over three decades, the Estrogen Receptor (ER) has been the most important biomarker measured during the diagnosis of breast cancer. This is due to the significant survival benefit that endocrine therapies afford a patient, whether in the adjuvant or metastatic setting, but a benefit that only applies to patients whose tumors are ER-positive. The accuracy of ER testing is critical in order to ensure patients aren't inappropriately given a costly treatment which may have harmful or fatal side-effects, but even more importantly, so that no patient is mistakenly denied a therapy which may save their life. However, current testing by immunohistochemistry (IHC) is beset by many problems, including the subjectivity and lack of standardization in scoring methods, as well as the fact that only nuclear ER is measured, when hundreds of in vitro studies have found functional presence of cytoplasmic receptor. In this dissertation, I test the hypothesis that cytoplasmic ER exists in human tumors and its measurement will improve the prognostic/predictive value of ER. I also develop a quantitative and standardized assay to measure ER, and use it to reveal the degree of, and causes for, ER misclassification currently existing in the U.S. I have documented several findings: (1) cytoplasmic ER exists in human tumors, but at an incidence of less than 2%, making it unlikely to ever serve as a useful predictive marker; (2) 10–30% of patients are misclassified as ER-negative, and potentially under-treated, depending on the lab which processes their specimen; (3) these false-negative results are primarily due to variability in the threshold of staining intensity rather than percentage of positive cells, and thus recent guidelines do not yet address this problem; (4) development of a quantitative immunofluorescent assay for ER (QIF) provides reproducible and standardized determination of the threshold for positivity, and is able to detect subtle levels of ER in patients considered negative by routine IHC, (5) the FDA-approved but less-established antibody SP1 is more sensitive in detection of ER than the current gold standard 1D5, and its use helps reduce false-negative results. These findings were the first to show clear evidence for cytoplasmic ER in human specimens, and examine over 4,200 cases to reveal its strikingly low rate of occurrence. They were also the first to develop a quantitative and standardized method for measuring ER, which addresses the issue of intensity threshold, is able to improve false-negative ER classification, and has proven applicability in the clinical setting.
|Advisor:||Rimm, David L.|
|School Location:||United States -- Connecticut|
|Source:||DAI-B 72/10, Dissertation Abstracts International|
|Subjects:||Cellular biology, Pathology, Oncology|
|Keywords:||Biomarkers, Breast cancer, Estrogen receptor, Tumors|
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