Phase 2 Randomized Study of Adriamycin & Docetaxel in the First-line Treatment of Locally Advanced or Metastatic Breast Cancer Patients With Measurable Primary Breast Tumor to Validate Gene Expression & Proteomic Signatures Predictive of Treatment Response
Many chemotherapeutic agents are active in breast cancer, although response rate to any
individual drug is only 30-50%. The choice of chemotherapy is empirical, and development of
a chemosensitivity assay is desirable, to reduce costs, unnecessary toxicity, and loss of
window of opportunity to cure. Single molecular markers to predict sensitivity are not
highly accurate, as chemotherapy resistance mechanisms likely involve complex pathways.
High-throughput technologies such as gene expression microarray and Proteinchip array allow
simultaneous analysis of thousands of genes, and hundreds of proteins, and may be more
informative. We previously conducted a study on patients with measurable primary breast
tumor who received primary chemotherapy with an alternating regimen of adriamycin and
docetaxel, and generated tumor genomic and tumor and plasma proteomic signatures that
predicted for clinical and pathological response using high throughput discovery platforms.
This protocol aims to recruit 20 patients as an independent test set to validate the genomic
and proteomic signatures generated previously. Half the patients will be randomized to
receive 4 cycles of pre-operative adriamycin (Arm A) allowing validation of the
adriamycin-specific signatures, while the other half will be randomized to receive 4 cycles
of pre-operative docetaxel (Arm B) allowing validation of the docetaxel-specific signatures.
Subjects will then undergo resection of the primary breast tumor, followed by 4 cycles of
adjuvant therapy with the alternative drug (docetaxel in Arm A, adriamycin in Arm B). Serial
tumor and plasma samples will be obtained for genomic and proteomic analysis. The previously
generated genomic and proteomic signatures will be applied to this independent dataset to
categorize patients into good and poor responders, and the prediction correlated with actual
treatment responses. Secondary goals include the correlation of patient genotype with drug
pharmacokinetics, and the correlation of chemotherapy-induced peripheral blood mononuclear
cell gene expression changes with treatment response and toxicities
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Clinical and pathological response rate
Clinical and pathological response rate to four cycles of pre-operative chemotherapy.
Soo Chin LEE, MBBS, MRCP
National University Hospital, Singapore
Singapore: Domain Specific Review Boards