Randomized Parallel Study of Doxorubicin Plus Paclitaxel and Doxorubicin Plus Cyclophosphamide as Neoadjuvant Treatment of Patients With Breast Cancer

ANNOTATED BIBLIOGRAPHY Randomized Parallel Study of Doxorubicin Plus Paclitaxel and Doxorubicin Plus Cyclophosphamide as Neoadjuvant Treatment of Patients With Breast Cancer Diéras V, Fumoleau P, Romieu G, et al J Clin Oncol 22:4958-4965, 2004 In this randomized, noncomparative trial, Dieras and colleagues showed that similar pathologic response rates can be achieved after preoperative treatment with doxorubicin and either cyclophosphamide or paclitaxel in women with previously untreated breast cancer who did not qualify for breast-conserving surgery. Further, patients treated with doxorubicin and paclitaxel were more likely to undergo breast-conserving surgery compared with patients given doxorubicin and cyclophosphamide. This study was well conducted, with independent reviewers providing opinions regarding true pathologic response. This hypothesis-generating work hints that including paclitaxel in preoperative therapy may be a promising option in terms of allowing early treatment and increasing the likelihood that patients can undergo breast-conserving surgery. Pathologic response rates were similar to those of a previous study in which paclitaxel was given as single-agent preoperative therapy.1 Buzdar and colleagues have shown that the addition of paclitaxel to fluorouracil, cyclophosphamide, and doxorubicin in preoperative or adjuvant therapy can reduce the likelihood of disease recurrence.1,2 Recent data from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-27 trial showed that neoadjuvant doxorubicin and cyclophosphamide followed by docetaxel was superior to neoadjuvant doxorubicin and cyclophosphamide in terms of producing clinical and pathologic responses.3 This begs the question of whether doxorubicin plus paclitaxel may fail to capture the full benefit of combining all 3 drugs. Pending data from the E2197 trial comparing doxorubicin plus cyclophosphamide with doxorubicin plus docetaxel and the NSABP B-30 trial comparing doxorubicin plus cyclophosphamide followed by docetaxel versus doxorubicin plus docetaxel versus doxorubicin plus cyclophosphamide plus docetaxel may help to further define the benefit of anthracycline and taxanes in earlystage breast cancer. C. S. Denlinger, MD L. J. Goldstein, MD

References 1. Buzdar AU, Singletary SE, Theriault RL, et al: Prospective evaluation of paclitaxel versus combination chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide as neoadjuvant therapy in patients with operable breast cancer. J Clin Oncol 17:3412-3417, 1999. 2. Buzdar AU, Singletary SE, Valero V, et al: Evaluation of paclitaxel as adjuvant chemotherapy for patients with operable breast cancer: Preliminary data of prospective randomized trial. Clin Cancer Res 8:1073-1079, 2002. 3. Bear HD, Anderson S, Brown A, et al: The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: Preliminary results

from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 21:4165-4174, 2003.

Prediction of Docetaxel Response in Human Breast Cancer by Gene Expression Profiling Iwao-Koizumi K, Matoba R, Ueno N, et al J Clin Oncol 23:422-431, 2005 In this study, the authors analyzed pretreatment samples obtained from 44 patients with breast cancer in the hopes of finding predictive markers of response to docetaxel; they used a high-throughput reverse transcriptase–polymerase chain reaction (PCR) technique, “adapter-tagged competitive PCR” (ATAC-PCR), to measure the expression of 2,453 genes. Clinical response to docetaxel treatment was graded according to the RECIST (Response Evaluation Criteria for Solid Tumors) system. The clinical response rate (including complete and partial responses) was 48.6% and the complete pathologic response rate was 4.5%. Of the 2,453 genes studied, 85 were identified as being predictive of response, and the mechanisms in the nonresponders seemed to involve redox genes. Interestingly, the accuracy of these 85 genes in a small validation study of 26 samples was found to be about 80%. These results are the second in a series in which the goal is to identify genes that can distinguish tumors that respond to docetaxel from tumors that do not. In 2003, we published a classifying list of 92 genes that could distinguish response by gene expression analysis with the Affymetrix U95A GeneChip; notably, these patterns were significantly changed after 12 weeks of neoadjuvant chemotherapy.1,2 The findings from the study reported by Iwao-Koizumi and colleagues here are provocative and imply that intrinsic patterns of gene expression may distinguish responders from nonresponders to chemotherapy. If these findings are validated, they could lead to substantial changes in case management and minimize toxicity among women undergoing chemotherapy. However, both our initial studies and the present study by Iwao-Koizumi and colleagues need to be validated with larger numbers of patients. We recently completed a 120-patient validation study, the clinical results of which were presented at the 2005 meeting of the American Society of Clinical Oncology.3 J. C. Chang, MD

References 1. Chang JC, Wooten EC, Tsimelzon A, et al: Gene expression profiling predicts therapeutic response to docetaxel (Taxotere) in breast cancer patients. Lancet 362:280-287, 2003. 2. Chang JC, Wooten EC, Tsimelzon A, et al: Patterns of resistance and incomplete response to docetaxel by gene expression profiling in breast cancer patients. J Clin Oncol 23:1169-1177, 2005. 3. Makris A, Hisenbeck SG, Yee D, et al: A prospective randomized multicenter gene expression study of docetaxel vs doxorubicin/cyclophosphamide preoperative trial in primary breast cancers (abstract 544). Presented at the American Society of Clinical Oncology, Orlando, Florida, May 16-20, 2005. Available at www.asco.org. Accessed June 2, 2005.

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