Imaging biomarkers predict response to Anti-HER2 (ErbB2) therapy in preclinical models of breast cancer

Chirayu Shah, Todd W. Miller, Shelby K. Wyatt, Eliot T. McKinley, Maria Graciela Olivares, Violeta Sanchez, Donald D. Nolting, Jason R. Buck, Ping Zhao, M. Sib Ansari, Ronald M. Baldwin, John C. Gore, Rachel Schiff, Carlos L. Arteaga, H. Charles Manning

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Abstract

Purpose: To evaluate noninvasive imaging methods as predictive biomarkers of response to trastuzumab in mouse models of HER2-overexpressing breast cancer. The correlation between tumor regression and molecular imaging of apoptosis, glucose metabolism, and cellular proliferationwas evaluatedlongitudinally in responding andnonresponding tumor-bearing cohorts. Experimental Design: Mammary tumors from MMTV/HER2 transgenic female mice were transplanted into syngeneic femalemice. BT474 human breast carcinoma cell line xenografts were grown in athymic nude mice. Tumor cell apoptosis (NIR700-Annexin V accumulation), glucose metabolism [2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography ([18F]FDG-PET)], and proliferation [3′-[ 18F]fluoro-3′-deoxythymidine-PET ([18F]FLT-PET)] were evaluated throughout a biweekly trastuzumab regimen. Imaging metrics were validated by direct measurement of tumor size and immunohistochemical analysis of cleaved caspase-3, phosphorylated AKT, and Ki67. Results: NIR700-Annexin V accumulated significantly in trastuzumab-treated MMTV/HER2 and BT474 tumors that ultimately regressed but not in nonresponding or vehicle-treated tumors. Uptake of [18F]FDG was not affected by trastuzumab treatment in MMTV/HER2 or BT474 tumors. [18F]FLT-PET imaging predicted trastuzumab response in BT474 tumors but not in MMTV/HER2 tumors, which exhibited modest uptake of [18F]FLT. Close agreement was observed between imaging metrics and immunohistochemical analysis. Conclusions: Molecular imaging of apoptosis accurately predicts trastuzumab-induced regression of HER2+ tumors and may warrant clinical exploration to predict early response to neoadjuvant trastuzumab. Trastuzumab does not seem to alter glucose metabolism substantially enough to afford [18F]FDG-PETsignificant predictive value in this setting. Although promising in one preclinical model, further studies are required to determine the overall value of [18F]FLT-PET as a biomarker of response to trastuzumab in HER2+ breast cancer.

Original languageEnglish (US)
Pages (from-to)4712-4721
Number of pages10
JournalClinical Cancer Research
Volume15
Issue number14
DOIs
StatePublished - Jul 15 2009

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Biomarkers
Breast Neoplasms
Neoplasms
Fluorodeoxyglucose F18
Therapeutics
Molecular Imaging
Annexin A5
Apoptosis
Nude Mice
Glucose
Trastuzumab
Heterografts
Caspase 3
Positron-Emission Tomography
Transgenic Mice
Research Design
Cell Line
alovudine

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Shah, C., Miller, T. W., Wyatt, S. K., McKinley, E. T., Olivares, M. G., Sanchez, V., ... Manning, H. C. (2009). Imaging biomarkers predict response to Anti-HER2 (ErbB2) therapy in preclinical models of breast cancer. Clinical Cancer Research, 15(14), 4712-4721. https://doi.org/10.1158/1078-0432.CCR-08-2635

Imaging biomarkers predict response to Anti-HER2 (ErbB2) therapy in preclinical models of breast cancer. / Shah, Chirayu; Miller, Todd W.; Wyatt, Shelby K.; McKinley, Eliot T.; Olivares, Maria Graciela; Sanchez, Violeta; Nolting, Donald D.; Buck, Jason R.; Zhao, Ping; Ansari, M. Sib; Baldwin, Ronald M.; Gore, John C.; Schiff, Rachel; Arteaga, Carlos L.; Manning, H. Charles.

In: Clinical Cancer Research, Vol. 15, No. 14, 15.07.2009, p. 4712-4721.

Research output: Contribution to journalArticle

Shah, C, Miller, TW, Wyatt, SK, McKinley, ET, Olivares, MG, Sanchez, V, Nolting, DD, Buck, JR, Zhao, P, Ansari, MS, Baldwin, RM, Gore, JC, Schiff, R, Arteaga, CL & Manning, HC 2009, 'Imaging biomarkers predict response to Anti-HER2 (ErbB2) therapy in preclinical models of breast cancer', Clinical Cancer Research, vol. 15, no. 14, pp. 4712-4721. https://doi.org/10.1158/1078-0432.CCR-08-2635
Shah, Chirayu ; Miller, Todd W. ; Wyatt, Shelby K. ; McKinley, Eliot T. ; Olivares, Maria Graciela ; Sanchez, Violeta ; Nolting, Donald D. ; Buck, Jason R. ; Zhao, Ping ; Ansari, M. Sib ; Baldwin, Ronald M. ; Gore, John C. ; Schiff, Rachel ; Arteaga, Carlos L. ; Manning, H. Charles. / Imaging biomarkers predict response to Anti-HER2 (ErbB2) therapy in preclinical models of breast cancer. In: Clinical Cancer Research. 2009 ; Vol. 15, No. 14. pp. 4712-4721.
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abstract = "Purpose: To evaluate noninvasive imaging methods as predictive biomarkers of response to trastuzumab in mouse models of HER2-overexpressing breast cancer. The correlation between tumor regression and molecular imaging of apoptosis, glucose metabolism, and cellular proliferationwas evaluatedlongitudinally in responding andnonresponding tumor-bearing cohorts. Experimental Design: Mammary tumors from MMTV/HER2 transgenic female mice were transplanted into syngeneic femalemice. BT474 human breast carcinoma cell line xenografts were grown in athymic nude mice. Tumor cell apoptosis (NIR700-Annexin V accumulation), glucose metabolism [2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography ([18F]FDG-PET)], and proliferation [3′-[ 18F]fluoro-3′-deoxythymidine-PET ([18F]FLT-PET)] were evaluated throughout a biweekly trastuzumab regimen. Imaging metrics were validated by direct measurement of tumor size and immunohistochemical analysis of cleaved caspase-3, phosphorylated AKT, and Ki67. Results: NIR700-Annexin V accumulated significantly in trastuzumab-treated MMTV/HER2 and BT474 tumors that ultimately regressed but not in nonresponding or vehicle-treated tumors. Uptake of [18F]FDG was not affected by trastuzumab treatment in MMTV/HER2 or BT474 tumors. [18F]FLT-PET imaging predicted trastuzumab response in BT474 tumors but not in MMTV/HER2 tumors, which exhibited modest uptake of [18F]FLT. Close agreement was observed between imaging metrics and immunohistochemical analysis. Conclusions: Molecular imaging of apoptosis accurately predicts trastuzumab-induced regression of HER2+ tumors and may warrant clinical exploration to predict early response to neoadjuvant trastuzumab. Trastuzumab does not seem to alter glucose metabolism substantially enough to afford [18F]FDG-PETsignificant predictive value in this setting. Although promising in one preclinical model, further studies are required to determine the overall value of [18F]FLT-PET as a biomarker of response to trastuzumab in HER2+ breast cancer.",
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AU - Shah, Chirayu

AU - Miller, Todd W.

AU - Wyatt, Shelby K.

AU - McKinley, Eliot T.

AU - Olivares, Maria Graciela

AU - Sanchez, Violeta

AU - Nolting, Donald D.

AU - Buck, Jason R.

AU - Zhao, Ping

AU - Ansari, M. Sib

AU - Baldwin, Ronald M.

AU - Gore, John C.

AU - Schiff, Rachel

AU - Arteaga, Carlos L.

AU - Manning, H. Charles

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N2 - Purpose: To evaluate noninvasive imaging methods as predictive biomarkers of response to trastuzumab in mouse models of HER2-overexpressing breast cancer. The correlation between tumor regression and molecular imaging of apoptosis, glucose metabolism, and cellular proliferationwas evaluatedlongitudinally in responding andnonresponding tumor-bearing cohorts. Experimental Design: Mammary tumors from MMTV/HER2 transgenic female mice were transplanted into syngeneic femalemice. BT474 human breast carcinoma cell line xenografts were grown in athymic nude mice. Tumor cell apoptosis (NIR700-Annexin V accumulation), glucose metabolism [2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography ([18F]FDG-PET)], and proliferation [3′-[ 18F]fluoro-3′-deoxythymidine-PET ([18F]FLT-PET)] were evaluated throughout a biweekly trastuzumab regimen. Imaging metrics were validated by direct measurement of tumor size and immunohistochemical analysis of cleaved caspase-3, phosphorylated AKT, and Ki67. Results: NIR700-Annexin V accumulated significantly in trastuzumab-treated MMTV/HER2 and BT474 tumors that ultimately regressed but not in nonresponding or vehicle-treated tumors. Uptake of [18F]FDG was not affected by trastuzumab treatment in MMTV/HER2 or BT474 tumors. [18F]FLT-PET imaging predicted trastuzumab response in BT474 tumors but not in MMTV/HER2 tumors, which exhibited modest uptake of [18F]FLT. Close agreement was observed between imaging metrics and immunohistochemical analysis. Conclusions: Molecular imaging of apoptosis accurately predicts trastuzumab-induced regression of HER2+ tumors and may warrant clinical exploration to predict early response to neoadjuvant trastuzumab. Trastuzumab does not seem to alter glucose metabolism substantially enough to afford [18F]FDG-PETsignificant predictive value in this setting. Although promising in one preclinical model, further studies are required to determine the overall value of [18F]FLT-PET as a biomarker of response to trastuzumab in HER2+ breast cancer.

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