Breast Cancer Misclassification: A Major Obstacle to Treatment?

ISSN 1745-5057 10.2217/WHE.11. 69 © 2011 Future Medicine Ltd Women's Health (2011) 7(6), 615–618 scale. The use of antibodies in an enzyme-linked immunoassay was an improvement and Pasic et al. showed that the assay was equivalent to the LBA, paying special attention to the cut point and noting that a value of 15 fmol/mg of cytosol protein by the immunoassay was equivalent to 10 fmol/mg by the LBA [3]. However, in the 1980s highly specific monoclonal antibodies and immunohistochemical techniques became available and the cut point was lost in the move to a semiquantitative assessment of these receptors in the nuclei of the tumor cells [4]. The classic work by Harvey et al. in the Allred group demonstrated that immunohistochemistry (IHC) was equivalent or superior to LBA in predicting response to hormonal therapy [5]. Shortly thereafter, IHC became the standard clinical approach to breast cancer diagnostics via hormone receptor ana lysis. This work also defined both a cut point (Allred score of three or higher for positivity) and the weakness of subjective scoring; the data showed a bimodal distribution of a dataset of a type that was previously proven by the LBA to be unimodal [6]. Since then several assay formats using a variety of ER and PgR antibodies have been validated against clinical benefit from endocrine therapy [5,7,8]. Some have been cleared by the US FDA as class II in vitro diagnostics devices. Despite the availability of FDA-cleared reagents and clinically validated methods, there is still significant variability between laboratories, leading to reduced test accuracy and substantial patient misclassification and false-negative results. Patients testing negative (even though their tumors really do express ER) do not receive adjuvant endocrine therapy and are thus denied the potential therapeutic benefits of one of the best breast cancer drugs. A comprehensive report from the UK National External Quality Assessment Service (NEQAS) revealed the results from an assay reproducibility study conducted in several European laboratories showing an overall agreement on the degree of expression of ER in shared Estrogen receptor (ER) and progesterone receptor (PgR) status determines the treatment options available to breast cancer patients. Since the measurement of these proteins was first described, there have been challenges to their overall accuracy. Even today, in the age of molecular tools and automation, there is still a surprisingly high rate of misclassification and, consequently, a negative impact on patient treatment and outcome. Here we examine this problem and suggest a solution. Breast cancer is one of the most common cancers among women worldwide. Surgery, radiotherapy and sometimes chemotherapy are the optimal treatment options for patients diagnosed with this disease. In addition, adjuvant therapy is available to patients with tumors expressing the ER and/or the PgR. Approximately 70–75% of breast cancers express ER and/or PgR, thus they are eligible for endocrine therapy (also referred to as estrogen-receptor modulators), using drugs such as tamoxifen, aromatase inhibitors and gonadotropin-releasing hormone agonists [1]. While only a percentage of ER/PgR-positive patients will respond to therapy, ER/PgR-negative cases do not respond. Here we examine the current status of this companion diagnostic test. The importance of ER as a molecular marker for the prognosis and response to therapy in breast cancer has been known since the late 1970s [2]. Many studies have been published since, demonstrating that ER and PgR are strongly predictive markers of response to endocrine therapy. The first methodology developed to assess the presence of ER (and subsequently of PgR) was a ligand-binding assay (LBA), which involved the competitive binding of a radiolabeled steroid to the receptor of interest. This assay reported the femtomoles of receptor protein per milligram of total cytosol protein (fmol/mg). While it represented a new paradigm for matching patients to therapy and was really the first companion diagnostic test in oncology, the main disadvantage was that the assay was labor intensive and difficult to Editorial