Predictors of resistance to preoperative trastuzumab and vinorelbine for HER2-positive early breast cancer

Lyndsay N. Harris, Fanglei You, Stuart J. Schnitt, Agnes Witkiewicz, Xin Lu, Dennis Sgroi, Paula D. Ryan, Steven E. Come, Harold J. Burstein, Beth Ann Lesnikoski, Madhavi Kamma, Paula N. Friedman, Rebecca Gelman, J. Dirk Iglehart, Eric P. Winer

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Abstract

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-1 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-1 receptor and other proteins involved in growth factor pathways, are more likely to be resistant to this regimen.

Original languageEnglish (US)
Pages (from-to)1198-1207
Number of pages10
JournalClinical Cancer Research
Volume13
Issue number4
DOIs
StatePublished - Feb 15 2007

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Breast Neoplasms
Somatomedin Receptors
Neoplasms
Cluster Analysis
Intercellular Signaling Peptides and Proteins
human ERBB2 protein
Trastuzumab
vinorelbine
Growth Factor Receptors
Estrogen Receptors
Research Design
Biomarkers
RNA
Confidence Intervals
Phenotype
Safety
Membranes
Genes
Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Predictors of resistance to preoperative trastuzumab and vinorelbine for HER2-positive early breast cancer. / Harris, Lyndsay N.; You, Fanglei; Schnitt, Stuart J.; Witkiewicz, Agnes; Lu, Xin; Sgroi, Dennis; Ryan, Paula D.; Come, Steven E.; Burstein, Harold J.; Lesnikoski, Beth Ann; Kamma, Madhavi; Friedman, Paula N.; Gelman, Rebecca; Iglehart, J. Dirk; Winer, Eric P.

In: Clinical Cancer Research, Vol. 13, No. 4, 15.02.2007, p. 1198-1207.

Research output: Contribution to journalArticle

Harris, LN, You, F, Schnitt, SJ, Witkiewicz, A, Lu, X, Sgroi, D, Ryan, PD, Come, SE, Burstein, HJ, Lesnikoski, BA, Kamma, M, Friedman, PN, Gelman, R, Iglehart, JD & Winer, EP 2007, 'Predictors of resistance to preoperative trastuzumab and vinorelbine for HER2-positive early breast cancer', Clinical Cancer Research, vol. 13, no. 4, pp. 1198-1207. https://doi.org/10.1158/1078-0432.CCR-06-1304
Harris, Lyndsay N. ; You, Fanglei ; Schnitt, Stuart J. ; Witkiewicz, Agnes ; Lu, Xin ; Sgroi, Dennis ; Ryan, Paula D. ; Come, Steven E. ; Burstein, Harold J. ; Lesnikoski, Beth Ann ; Kamma, Madhavi ; Friedman, Paula N. ; Gelman, Rebecca ; Iglehart, J. Dirk ; Winer, Eric P. / Predictors of resistance to preoperative trastuzumab and vinorelbine for HER2-positive early breast cancer. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 4. pp. 1198-1207.
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abstract = "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-1 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-1 receptor and other proteins involved in growth factor pathways, are more likely to be resistant to this regimen.",
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T1 - Predictors of resistance to preoperative trastuzumab and vinorelbine for HER2-positive early breast cancer

AU - Harris, Lyndsay N.

AU - You, Fanglei

AU - Schnitt, Stuart J.

AU - Witkiewicz, Agnes

AU - Lu, Xin

AU - Sgroi, Dennis

AU - Ryan, Paula D.

AU - Come, Steven E.

AU - Burstein, Harold J.

AU - Lesnikoski, Beth Ann

AU - Kamma, Madhavi

AU - Friedman, Paula N.

AU - Gelman, Rebecca

AU - Iglehart, J. Dirk

AU - Winer, Eric P.

PY - 2007/2/15

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N2 - 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-1 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-1 receptor and other proteins involved in growth factor pathways, are more likely to be resistant to this regimen.

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