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

This study has been terminated.
(voluntary closure of study)
Information provided by:
Duke University Identifier:
First received: March 9, 2008
Last updated: November 3, 2010
Last verified: November 2010

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.

Condition Intervention Phase
Early-Stage Breast Cancer
Drug: genomically-guided treatment: Doxorubicin/Cyclophosphamide (AC) or Docetaxel/Cyclophosphamide (TC)
Drug: non-genomically-guided treatment: Doxorubicin/Cyclophosphamide (AC) or Docetaxel/Cyclophosphamide (TC)
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized Phase II Trial Evaluating the Performance of Genomic Expression Profiles to Direct the Use of Preoperative Chemotherapy for Early Stage Breast Cancer

Resource links provided by NLM:

Further study details as provided by Duke University:

Primary Outcome Measures:
  • To determine in early stage breast cancer treated with PST whether genomic profiling for drug-sensitivity can improve the pCR rate as compared to random assignment of patients to therapy. [ Time Frame: 10 years ] [ Designated as safety issue: No ]
  • To determine in early stage breast cancer treated with PST whether genomic profiling can identify drug-sensitive and drug-resistant patients including a comparison of subgroups for the two individual regimens (i.e. AC and TC). [ Time Frame: 10 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • To determine if the 60% cutoff for the genomic profiles is optimal in predicting the response to chemotherapy regimens. [ Time Frame: 10 years ] [ Designated as safety issue: No ]
  • Describe the performance of the genomic profiles in assessing the relative responsiveness of patients predicted to be resistant to both chemotherapy regimens and patients randomly assigned to one treatment whose genomic profiles suggests other regimen [ Time Frame: 10 years ] [ Designated as safety issue: No ]
  • To compare genomically-guided and non-genomically guided treatment assignments relative to the rates of improvement in surgical outcome as defined elsewhere. [ Time Frame: 10 years ] [ Designated as safety issue: No ]
  • To correlate genomic profiles with clinical response, disease-free survival, sites of recurrence, and overall survival. [ Time Frame: 10 years ] [ Designated as safety issue: No ]
  • To develop a specimen repository with clinical annotation from the study participants. [ Time Frame: 10 years ] [ Designated as safety issue: No ]
  • To assess the economic impact of using genomic assessment to guide management. [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  • To assess patient perceptions of participating in a clinical trial evaluating cancer genomics for PST of early-stage breast cancer. [ Time Frame: 5 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 270
Study Start Date: April 2008
Estimated Study Completion Date: April 2015
Estimated Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 1
genomically-guided treatment allocation
Drug: genomically-guided treatment: Doxorubicin/Cyclophosphamide (AC) or Docetaxel/Cyclophosphamide (TC)
Doxorubicin 60 mg/m² and Cyclophosphamide 600 mg/m² (AC) or Docetaxel 75 mg/m² and Cyclophosphamide 600 mg/m² (TC) every 3 weeks for 4 cycles as neoadjuvant therapy
Other Names:
  • Adriamycin (Doxorubicin)
  • Rubex (Doxorubicin)
  • Taxotere (Docetaxel)
  • Cytoxan (Cyclophosphamide)
Active Comparator: 2
non-genomically-guided treatment allocation
Drug: non-genomically-guided treatment: Doxorubicin/Cyclophosphamide (AC) or Docetaxel/Cyclophosphamide (TC)
Doxorubicin 60 mg/m² and Cyclophosphamide 600 mg/m² (AC) or Docetaxel 75 mg/m² and Cyclophosphamide 600 mg/m² (TC) every 3 weeks for 4 cycles as neoadjuvant therapy
Other Names:
  • Adriamycin (Doxorubicin)
  • Rubex (Doxorubicin)
  • Taxotere (Docetaxel)
  • Cytoxan (Cyclophosphamide)

Detailed Description:

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.


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Histologic Documentation: Patients must have a histologic (i.e., not just cytologic) diagnosis of invasive breast cancer by core biopsy. Excisional biopsy or incisional biopsy is not allowed. All breast cancer histologic types are allowed.
  2. Stage: Any patient with a clinical T1c (>1.5 cm) to T3 invasive breast cancer by the revised TNM staging system (AJCC 6th edition) will be eligible. Any N stage disease is allowed. No distant metastases allowed.
  3. Tumor Site: Patients must have invasive cancer in the breast. Multifocal disease (i.e. confined to a single quadrant in the same breast) is allowed. Multicentric disease (i.e. disease in multiple breast quadrants) is not allowed. Determination of multifocal and multicentric disease status will be made by the evaluating surgeon; ambiguous cases will be reviewed by the principal investigator. Patients with synchronous contralateral invasive breast cancers are not eligible; prior contralateral breast cancer allowed as long as patient has not received prior chemotherapy or radiation therapy in the past 5 years.
  4. Measurable Disease: Patients must have measurable disease in the breast by imaging studies (mammogram, ultrasound, or MRI), and must be greater than 1.5 cm in at least one dimension by one or more of the imaging assessments.
  5. Conventional Biomarker Status: Standard clinical biomarkers for ER, PR, and HER2 must be obtained on the initial diagnostic core biopsy. The invasive cancer must be HER2 negative (i.e. immunohistochemistry score 1-2+ and/or FISH non-amplified). Any ER/PR status is allowed. Patients who are HER2 2+ on initial immunohistochemistry assessment will be further assessed by FISH. In this instance, patient will be consented and further screened for eligibility and have tissue acquired for genomic profiling. If the standard of care additional FISH testing is positive for HER2 gene amplification, the patient will not be randomized and will be treated in the same manner as screen failures.
  6. Must be deemed a surgical candidate.
  7. Fresh tissue biopsy material must be available for genomics analysis.
  8. No prior chemotherapy, radiotherapy, or biologic/targeted therapy for the currently diagnosed breast cancer, or any other malignancy in the past 5 years, is allowed. No prior anthracycline or taxane therapy.
  9. Prior malignancies are allowed if the patient is considered to be disease-free for 5 or more years and is deemed to be at low risk for recurrence. Patients with any prior diagnosis of in situ malignancies (melanoma, bladder, colon, cervical, basal cell, or squamous carcinoma) are eligible regardless of time from diagnosis.
  10. Aged at least 18 years.
  11. ECOG Performance Status 0-1.
  12. Adequate Organ Function:

    1. Total bilirubin ≤1.0 x the institutional ULN
    2. Hepatic enzymes (AST (SGOT), ALT (SGPT)) ≤1.5x the institutional ULN
    3. Alkaline Phosphatase ≤2.5 x ULN
    4. Serum creatinine ≤2.0 mg/dl
    5. Neutrophil count (ANC or AGC) ≥1000/ μL
    6. Platelets ≥100,000/ μL
    7. Cardiac Ejection Fraction ≥50% by MUGA, Echo or MRI.
  13. Significant cardiac disease that would preclude the use of anthracyclines: No myocardial infarction in the last 6 months; history of congestive heart failure, serious cardiac arrhythmia requiring medication, active coronary artery disease/angina pectoris requiring therapy, uncontrolled hypertension defined as BP >150/90 despite medication; any other unstable cardiac condition as perceived by treating physician or study PI.
  14. No other serious medical or psychiatric illness.
  15. Pregnancy: Patients may not be pregnant or nursing at the time of enrollment and other restrictions apply.
  16. Signed written informed consent including HIPAA.

Exclusion Criteria:

1. Patients who have received investigational drugs within 4 weeks prior to starting study drug and/or who have not recovered from side effects of such therapy are not eligible.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT00636441

United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
Sponsors and Collaborators
Duke University
Principal Investigator: Paul K Marcom, MD Duke University
  More Information

Responsible Party: P. Kelly Marcom, MD, Duke University Medical Center Identifier: NCT00636441     History of Changes
Other Study ID Numbers: Pro00001345, W81XWH-07-1-0394, BC060228-W81XWH-07-1-0394
Study First Received: March 9, 2008
Last Updated: November 3, 2010
Health Authority: United States: Institutional Review Board

Keywords provided by Duke University:
Early-Stage Breast Cancer
Preoperative systemic chemotherapy (PST)
Genomic Predictor
Genomic Expression Profiles
Pathologic complete response (pCR)
HER2 negative
Doxorubicin and docetaxel
Doxorubicin and cyclophosphamide

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Liposomal doxorubicin
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors processed this record on September 16, 2014