Trial to Evaluate Genomic Expression Profiles to Direct Preoperative Chemotherapy in Early Stage Breast Cancer

2014-08-27 03:32:11 | BioPortfolio


This is a multi-center study employing genomic expression profiling to assign preoperative systemic therapy (Doxorubicin/Cyclophosphamide (AC) or Docetaxel/Cyclophosphamide (TC)) for HER2 negative early stage breast cancer to compare responses in genomically guided versus random assignment and validate chemosensitivity prediction signatures. This study will build on previous studies of cancer cell lines that identified genomic signatures of drug sensitivity and retrospective analyses of gene expression relative to pathological response.


Chemotherapy selection for early stage breast cancer is still largely empiric and guided by large randomized clinical trials on populations of patients. This approach is inadequate for the selection of individualized chemotherapy regimens. Estimates of benefits for individuals are extrapolations from the effects seen in these large trials, and do not necessarily apply to individual patients. The revolution in genomics promises to transform oncology care. By better defining cancer subtypes, a better understanding of breast cancer biology should help to guide treatment. Extensive work has already been performed and published using gene expression profiling to characterize breast cancer.

Preoperative systemic chemotherapy (PST), also known as neoadjuvant therapy, is an effective means for assessing the chemosensitivity of an individual's breast cancer. Multiple trials of preoperative systemic chemotherapy that have been performed over the past two decades have consistently demonstrated the safety of this approach as compared to primary surgery followed by adjuvant chemotherapy.

Gene expression profiling of breast cancers in the context of preoperative chemotherapy has been conducted, and shows great promise to provide predictive signatures or response to specific agents.

Currently, the addition of a taxane, either sequentially or in combination to a core anthracycline/cyclophosphamide regimen has been shown to improve disease-free survival in four separate randomized trials. Over the past two decades, PST for early stage breast cancer has been shown to be a safe and effective method for assessing the chemosensitivity of primary breast cancer. Sequencing systemic therapy first, with the consequent three to six month delay in surgery, has not been shown to adversely affect outcomes. Patients who obtain a complete pathologic response in the breast and lymph nodes have a greater than 95% survival at 7 years. PST therefore provides a powerful tool for in vivo assessment of chemosensitivity. However, this determination for each individual can only be made post hoc, requiring the exposure of each patient to toxic and potentially non-effective therapy. Consequently, it has been difficult to exploit the knowledge gained about tumor sensitivity and resistance to the patient's benefit. In addition, no studies have examined how response to PST should change post-operative treatment for those patients with minimal or no response.

Several studies have correlated breast cancer gene expression profiles with response to preoperative chemotherapy. While some studies have suggested that single markers predict resistance to anthracycline therapy, most have found that a multi-gene classifier is needed. Using in vitro cell line data and existing clinical data sets, we have developed expression profiles predicting sensitivity to a variety of clinical agents, including those in the common breast care regimens.

This trial is a prospective clinical trial employing gene expression profiling to assign preoperative systemic therapy for early-stage breast cancer. It will evaluate the performance of the gene expression profiles to assign patients to the most effective regimen for them and to identify individuals predicted to be non-responsive to either regimen. If successful, it will demonstrate a significant step forward in individualized patient therapy.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment


Early-Stage Breast Cancer


genomically-guided treatment: Doxorubicin/Cyclophosphamide (AC) or Docetaxel/Cyclophosphamide (TC), non-genomically-guided treatment: Doxorubicin/Cyclophosphamide (AC) or Docetaxel/Cyclophosphamide (TC)


Duke University Medical Center
North Carolina
United States




Duke University

Results (where available)

View Results


Published on BioPortfolio: 2014-08-27T03:32:11-0400

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Medical and Biotech [MESH] Definitions

Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the LIVER to form the active aldophosphamide. It has been used in the treatment of LYMPHOMA and LEUKEMIA. Its side effect, ALOPECIA, has been used for defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer.

An immunosuppressive agent used in combination with cyclophosphamide and hydroxychloroquine in the treatment of rheumatoid arthritis. According to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985), this substance has been listed as a known carcinogen. (Merck Index, 11th ed)

A sulfhydryl compound used to prevent urothelial toxicity by inactivating metabolites from ANTINEOPLASTIC AGENTS, such as IFOSFAMIDE or CYCLOPHOSPHAMIDE.

Positional isomer of CYCLOPHOSPHAMIDE which is active as an alkylating agent and an immunosuppressive agent.

A major cytochrome P-450 enzyme which is inducible by PHENOBARBITAL in both the LIVER and SMALL INTESTINE. It is active in the metabolism of compounds like pentoxyresorufin, TESTOSTERONE, and ANDROSTENEDIONE. This enzyme, encoded by CYP2B1 gene, also mediates the activation of CYCLOPHOSPHAMIDE and IFOSFAMIDE to MUTAGENS.

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