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SECTION IV: Biological Markers, Genetic Expression

Abstract 125
Phase II Neoadjuvant Trial of Sequential Doxorubicin and Docetaxel for the Treatment of Stage III Breast Cancer Measuring Signal Transducers and Activators of Transcription (STAT) as a Predictor of Response to Therapy
Susan E. Minton, DO, H. Lee Moffitt Cancer Center and Research Institute Tampa, Florida

Neoadjuvant chemotherapy with doxorubicin (Adriamycin, Adiblastine, Adriablatina, Doxil, and others) followed by Taxotere (docetaxel) is a highly active and tolerated regimen for the treatment of stage III breast cancer, contributing to an overall response rate of 93%. The study also showed that the level of signal transducers and activators of transcription (STAT)-3 are not predictive of a response to neoadjuvant chemotherapy, even though the investigators originally hypothesized that there would be a correlation, explained Dr. Susan E. Minton during the 38^th annual ASCO meeting. However, the study did support the hypothesis that STAT-3 activation contributes to oncogenesis in breast tissue, she added.

Background: The Role of Neoadjuvant Chemotherapy with Taxotere
A number of phase II trials have demonstrated that the majority of patients with breast cancer respond to neoadjuvant therapy, but the complete response (CR) rate in those trials was less than 20%, noted Gabriel Hortobagyi, MD, of the University of Texas M.D. Anderson Cancer Center, in Houston, Texas, who moderated the Special Education Session where Dr. Minton presented her study. Pathological CR (pCR) has since been found to correlate with long-term survival following neoadjuvant therapy, Dr. Hortobagyi said.

The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-27 trial, presented at the San Antonio Breast Cancer Symposium in December 2001, showed that patients treated with neoadjuvant doxorubicin plus cyclophosphamide [Cytoxan, Cytokan, Endoxon, Neosar, Neosar For Injection] (AC) followed by Taxotere had almost a doubling in pCR compared with those treated with doxorubicin plus cyclophosphamide — 25.6% vs. 13.7% (See Dr. Mamounas's report on page 10). Long-term data on disease-free and overall survival in the NSABP B-27 trial are not yet available but are awaited with great interest, Dr. Hortobagyi told listeners.

The Aberdeen study (Smith IC. J Clin Oncol 2002;20(6):1456-1466) also showed favorable results with Taxotere in the neoadjuvant setting for breast cancer. In that study, the addition of Taxotere following chemotherapy virtually doubled the pCR compared to the same regimen without Taxotere. The pCR was 16% with eight cycles of combination chemotherapy with CVAP (cyclophosphamide, vincristine [Oncovin, Vincasar Pfs, Vincrex], doxorubicin, and prednisolone [Delta-Cortef, Adnisolone, Cortalone, Cotolone, and others]) compared with 31% after four cycles of CVAP followed by Taxotere. Improved disease-free survival and three-year overall survival was also noted in the Taxotere-containing arm — 90% and 97% for CVAP plus Taxotere and 77% and 84% for CVAP, respectively.

"Pathological CR is a late event that occurs 12 to 14 weeks after the initiation of chemotherapy. We need early markers of response to chemotherapy that can be measured a few days or a few weeks after initiating treatment," Dr. Hortobagyi said.

Dr. Minton's group wanted to determine whether STAT-3 levels could be used to predict chemotherapy response. STAT-3 proteins belong to a family of proteins involved in cell proliferation and angiogenesis. "Our underlying hypothesis was that STAT activation confers resistance to chemotherapy and that STAT-3 correlates with oncogenesis," she said.

The study enrolled 43 patients aged 31 to 69 years, who were treated with doxorubicin 80 mg/m² IV every two-weeks for three courses followed by a three-week break, then Taxotere 100 mg/m² IV every two-weeks for three courses. Granulocyte-colony stimulating factor (G-CSF; Neupogen) 5 痢/kg and levofloxacin (Levaquin) 500 mg daily was given from days 3 through 10 of each cycle, she noted.

The overall response rate to this regimen was 93%, with a CR of 23% and a partial response rate of 70%. The pCR was 26% in the breast and 27% in the lymph nodes.

STAT-3 Levels Not Predictive
STAT-3 levels were measured in biopsies of normal tissue and tumors. The majority of normal tissue had low levels of STAT-3, while higher levels were observed in tumor specimens. However, STAT-3 levels did not predict clinical response or pCR to neoadjuvant doxorubicin and Taxotere, Dr. Minton reported. STAT-3 levels did, however, correlate with expression of human epidermal growth factor receptor-2 (HER-2).

"STAT-3 represents a potential direct target for breast cancer chemotherapy," she concluded.

Key Points In Focus:

Doxorubicin followed by Taxotere is a highly active neoadjuvant regimen in patients with stage III breast cancer.
STAT-3 activation is implicated in oncogenesis in breast tissue and correlates with HER-2 expression but it is not predictive of response to neoadjuvant therapy with Taxotere and doxorubicin.

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