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Predictors of Resistance to Preoperative Trastuzumab and Vinorelbine for HER2-Positive Early Breast Cancer

Authors' Affiliations: ¹ Dana-Farber Cancer Institute; ² Beth Israel Deaconess Medical Center; ³ Biostatistics Department, Harvard School of Public Health; ⁴ Massachusetts General Hospital; ⁵ Brigham and Women's Hospital, Boston, Massachusetts and ⁶ Abbott Molecular, Des Plaines, Illinois

Requests for reprints: Lyndsay N. Harris, Department of Medical Oncology, Yale University Medical Center, 333 Cedar Street, New Haven, CT 06510. Phone: 203-785-3213; E-mail: Lyndsay.harris{at}yale.edu.

Purpose: To assess pathologic complete response (pCR), clinical response, feasibility, safety, and potential predictors of response to preoperative trastuzumab plus vinorelbine in patients with operable, human epidermal growth factor receptor 2 (HER2)–positive breast cancer.

Experimental Design: Forty-eight patients received preoperative trastuzumab and vinorelbine weekly for 12 weeks. Single and multigene biomarker studies were done in an attempt to identify predictors of response.

Results: Eight of 40 (20%) patients achieved pCR (95% confidence interval, 9-36%). Of 9 additional patients recruited for protocol-defined toxicity analysis, 8 were evaluable; 42 of 48 (88%) patients had clinical response (16 patients, clinical complete response; 26 patients, clinical partial response). T₁ tumors more frequently exhibited clinical complete response (P = 0.05) and showed a trend to exhibit pCR (P = 0.07). Five (13%) patients experienced grade 1 cardiac dysfunction during preoperative treatment. Neither HER2 nor estrogen receptor status changed significantly after exposure to trastuzumab and vinorelbine. RNA profiling identified three top-level clusters by unsupervised analysis. Tumors with extremes of response [pCR (n = 3) versus nonresponse (n = 3)] fell into separate groups by hierarchical clustering. No predictive genes were identified in pCR tumors. Nonresponding tumors were more likely to be T₄ stage (P = 0.02) and express basal markers (P < 0.00001), growth factors, and growth factor receptors. Insulin-like growth factor-I receptor membrane expression was associated with a lower response rate (50% versus 97%; P = 0.001).

Conclusions: Preoperative trastuzumab plus vinorelbine is active and well tolerated in patients with HER2-positive, operable, stage II/III breast cancer. HER2-overexpressing tumors with a basal-like phenotype, or with expression of insulin-like growth factor-I receptor and other proteins involved in growth factor pathways, are more likely to be resistant to this regimen.

Commentary

Will Single-Time Tumor Profiling and a "Guilt by Association" Approach Allow Us to Outsmart HER2-Positive Breast Cancer?

Carlos L. Arteaga
Clin. Cancer Res. 2007 13: 1071-1073. [Full Text] [PDF]

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