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Patterns of Resistance and Incomplete Response to Docetaxel by Gene Expression Profiling in Breast Cancer Patients

From the Breast Center and the Departments of Medicine, Pathology, and Molecular and Cellular Biology, Baylor College of Medicine; and the Methodist Hospital, Houston, TX

Address reprint requests to Jenny Chang, MD, Breast Center, Baylor College of Medicine, 1 Baylor Plaza, MS 600, Houston, TX 77030; e-mail: jcchang{at}breastcenter.tmc.edu

PURPOSE: Chemotherapy for operable breast cancer decreases the risk of death. Docetaxel is one of the most active agents in breast cancer, but resistance or incomplete response is frequent.

PATIENTS AND METHODS: Core biopsies from 24 patients were obtained before treatment with neoadjuvant docetaxel (four cycles, 100 mg/m² every 3 weeks), and response was assessed after chemotherapy. After 3 months of neoadjuvant chemotherapy, surgical specimens (n = 13) were obtained, and laser capture microdissection (LCM; n = 8) was performed to enrich for tumor cells. From each core, surgical, and LCM specimen, sufficient total RNA (3 to 6 µg) was extracted for cDNA array analysis using the Affymetrix HgU95-Av2 GeneChip (Affymetrix, Santa Clara, CA).

RESULTS: From the initial core biopsies, differential patterns of expression of 92 genes correlated with docetaxel response (P = .001). However, the molecular patterns of the residual cancers after 3 months of docetaxel treatment were strikingly similar, independent of initial sensitivity or resistance. This relative genetic homogeneity after treatment was observed in both LCM and non-LCM surgical specimens. The residual tumor after treatment in tumors that were initially sensitive indicates selection of a residual and resistant subpopulation of cells. The gene expression pattern was populated by genes involved in cell cycle arrest at G₂M (eg, mitotic cyclins and cdc2) and survival pathways involving the mammalian target of rapamycin.

CONCLUSION: A specific and consistent gene expression pattern was found in residual tumors after docetaxel treatment. These profiles provide therapeutic targets that could lead to improved treatment.

Supported in part by the US Army Medical Research and Materiel Command grant No. DAMD17-01-0132, a Grant-in-Aid (US 11115) from Aventis Pharmaceutical Inc, the Emma Jacobs Clinical Breast Cancer Fund, and the Breast Cancer Specialized Program of Organized Research Excellence grant No. P50 CA50183 from the National Cancer Institute.

Presented in part at the 39th Annual American Society of Clinical Oncology Meeting, Chicago IL, May 31-June 3, 2003.

J.C.C. and E.C.W. contributed equally to this work.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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