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
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
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
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.
Paul K Marcom, MD
United States: Institutional Review Board
|Duke University Medical Center||Durham, North Carolina 27710|