Publication Date

2017-07-24

Availability

Open access

Embargo Period

2017-07-24

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Biochemistry and Molecular Biology (Medicine)

Date of Defense

2017-06-22

First Committee Member

Ralf Landgraf

Second Committee Member

Thomas K. Harris

Third Committee Member

Zafar Nawaz

Fourth Committee Member

William Audeh

Abstract

Death from breast cancer began a decline in the 1990’s. One widely accepted reason for this reduction was the discovery that breast cancer can be uniquely defined at the molecular level by oncogenes and tumor suppressor genes including, but not limited to, EGFR, AKT, ErbB2, PI3K, TP53, BRCA1/2, and PTEN. These genes and potential mutations within, can drive constitutive activation of aberrant signaling that can induce and sustain tumorigenesis. More importantly, these genes represent new avenues for possible markers and therapies. In the wake of this molecular biology discovery, there was an influx of new breast cancer treatments to the marketplace, most notably the launch of trastuzumab (Herceptin) in 1996. Subsequently, the incidence of death continued to decrease peaking from 2002 to 2003 when it dropped by 7% in that one year alone. However, the current challenge in oncology is how to translate the wealth of information contained in the molecular biology of cancer and translate it into patient care. While progress has been made in developing treatments, less progress has been made identifying new markers for breast cancer to get that treatment to the right patients or selecting them for treatment trials. Currently, the majority of providers and healthcare systems do not utilize molecular biology to determine risk of breast cancer recurrence and treatment decision making for breast cancer. Rather, they determine which patients require what adjuvant treatment based on some form of the breast cancer tumor–node–metastases (TNM) staging system and clinical-pathological criteria, such as lymphovascular invasion (LVI), nodal status, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2/neu) status and more. As a result, potential differences exist worldwide in the selection of patients who require adjuvant chemotherapy based on their risk of breast cancer recurrence. All of these tests and criteria are based on the anatomical extent of the tumor, with little if any insight into the patient’s breast cancer biology. A significant percentage (30 to 50%) of all early stage breast cancer patients (50,000 to 75,000 patients annually in the US alone) have clinically ambiguous or confounding clinical-pathological characteristics, making it difficult for physicians to formulate clinical risk and supports the argument for development and utilization of molecular diagnostic testing. By looking at the molecular biology of cancer, companies, such as Agendia, seek to create technologies beyond clinical screening, imaging or cell surface staining. Technologies like MammaPrint and BluePrint, reveal who is truly at risk by differentiating responders from non-responders based on genetics. By interrogating single genes or overall patterns of gene expression, it is possible to better understand the various sequences of biological events that give rise to breast cancer and in turn, better develop and guide treatments.

Keywords

Breast cancer; MammaPrint; BluePrint; Lisa Eileen Blumencranz; Agendia; genomic signature

Share

COinS