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A Randomized Phase II Trial Evaluating the Performance of Genomic Expression Profiles to Direct the Use of Preoperative Chemotherapy for Early Stage Breast Cancer

Phase 2
18 Years
Not Enrolling
Early-Stage Breast Cancer

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Trial Information

A Randomized Phase II Trial Evaluating the Performance of Genomic Expression Profiles to Direct the Use of Preoperative Chemotherapy for Early Stage Breast Cancer

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

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

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.

Type of Study:


Study Design:

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

Outcome Measure:

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.

Outcome Time Frame:

10 years

Safety Issue:


Principal Investigator

Paul K Marcom, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Duke University


United States: Institutional Review Board

Study ID:




Start Date:

April 2008

Completion Date:

April 2015

Related Keywords:

  • Early-Stage Breast Cancer
  • Early-Stage Breast Cancer
  • Preoperative systemic chemotherapy (PST)
  • Genomic
  • Genomic Predictor
  • Genomic Expression Profiles
  • Randomized
  • Pathologic complete response (pCR)
  • HER2 negative
  • Doxorubicin and docetaxel
  • Doxorubicin and cyclophosphamide
  • Breast Neoplasms



Duke University Medical CenterDurham, North Carolina  27710