Gene expression, molecular class changes, and pathway analysis after neoadjuvant systemic therapy for breast cancer

Ana M. Gonzalez-Angulo, Takayuki Iwamoto, Shuying Liu, Huiqin Chen, Kim Anh Do, Gabriel N. Hortobagyi, Gordon Mills, Funda Meric-Bernstam, W. Fraser Symmans, Lajos Pusztai

Research output: Contribution to journalArticle

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Abstract

Purpose: To examine gene expression differences between pre- and post-neoadjuvant systemic therapy (NST) specimens of breast cancers and identify biologic changers that may lead to new therapeutic insights. Methods: Gene expression data from prechemotherapy fine needle aspiration specimens were compared with resected residual cancers in 21 patients after 4 to 6 months of NST. We removed stroma-associated genes to minimize confounding effects. PAM50 was used to assign molecular class. Paired t test and gene set analysis were used to identify differentially expressed genes and pathways. Results: The ER and HER2 status based on mRNA expression remained stable in all but two cases, and there were no changes in proliferation metrics (Ki67 and proliferating cell nuclear antigen expression). Molecular class changed in 8 cases (33.3%), usually to normal-like class, which was associated with low residual cancer cell cellularity. The expression of 200 to 600 probe sets changed between baseline and post-NST samples. In basal-like cancers, pathways driven by increased expression of phosphoinositide 3-kinase, small G proteins, and calmodulin-dependent protein kinase II and energy metabolism were enriched, whereas immune cell-derived and the sonic hedgehog pathways were depleted in residual cancer. In non-basal-like breast cancers, notch signaling and energy metabolism (e.g., fatty acid synthesis) were enriched and sonic hedgehog signaling and immune-related pathways were depleted in residual cancer. There was no increase in epithelial-mesenchymal transition or cancer stem cell signatures. Conclusions: Our data indicate that energy metabolism related processes are upregulated and immune-related signals are depleted in residual cancers. Targeting these biologic processes may represent promising adjuvant treatment strategies for patients with residual cancer.

Original languageEnglish (US)
Pages (from-to)1109-1119
Number of pages11
JournalClinical Cancer Research
Volume18
Issue number4
DOIs
StatePublished - Feb 15 2012
Externally publishedYes

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Neoadjuvant Therapy
Residual Neoplasm
Breast Neoplasms
Gene Expression
Energy Metabolism
Genes
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Epithelial-Mesenchymal Transition
1-Phosphatidylinositol 4-Kinase
Monomeric GTP-Binding Proteins
Neoplastic Stem Cells
Proliferating Cell Nuclear Antigen
Fine Needle Biopsy
Mesenchymal Stromal Cells
Fatty Acids
Messenger RNA
Therapeutics
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Gonzalez-Angulo, A. M., Iwamoto, T., Liu, S., Chen, H., Do, K. A., Hortobagyi, G. N., ... Pusztai, L. (2012). Gene expression, molecular class changes, and pathway analysis after neoadjuvant systemic therapy for breast cancer. Clinical Cancer Research, 18(4), 1109-1119. https://doi.org/10.1158/1078-0432.CCR-11-2762

Gene expression, molecular class changes, and pathway analysis after neoadjuvant systemic therapy for breast cancer. / Gonzalez-Angulo, Ana M.; Iwamoto, Takayuki; Liu, Shuying; Chen, Huiqin; Do, Kim Anh; Hortobagyi, Gabriel N.; Mills, Gordon; Meric-Bernstam, Funda; Symmans, W. Fraser; Pusztai, Lajos.

In: Clinical Cancer Research, Vol. 18, No. 4, 15.02.2012, p. 1109-1119.

Research output: Contribution to journalArticle

Gonzalez-Angulo, AM, Iwamoto, T, Liu, S, Chen, H, Do, KA, Hortobagyi, GN, Mills, G, Meric-Bernstam, F, Symmans, WF & Pusztai, L 2012, 'Gene expression, molecular class changes, and pathway analysis after neoadjuvant systemic therapy for breast cancer', Clinical Cancer Research, vol. 18, no. 4, pp. 1109-1119. https://doi.org/10.1158/1078-0432.CCR-11-2762
Gonzalez-Angulo, Ana M. ; Iwamoto, Takayuki ; Liu, Shuying ; Chen, Huiqin ; Do, Kim Anh ; Hortobagyi, Gabriel N. ; Mills, Gordon ; Meric-Bernstam, Funda ; Symmans, W. Fraser ; Pusztai, Lajos. / Gene expression, molecular class changes, and pathway analysis after neoadjuvant systemic therapy for breast cancer. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 4. pp. 1109-1119.
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abstract = "Purpose: To examine gene expression differences between pre- and post-neoadjuvant systemic therapy (NST) specimens of breast cancers and identify biologic changers that may lead to new therapeutic insights. Methods: Gene expression data from prechemotherapy fine needle aspiration specimens were compared with resected residual cancers in 21 patients after 4 to 6 months of NST. We removed stroma-associated genes to minimize confounding effects. PAM50 was used to assign molecular class. Paired t test and gene set analysis were used to identify differentially expressed genes and pathways. Results: The ER and HER2 status based on mRNA expression remained stable in all but two cases, and there were no changes in proliferation metrics (Ki67 and proliferating cell nuclear antigen expression). Molecular class changed in 8 cases (33.3{\%}), usually to normal-like class, which was associated with low residual cancer cell cellularity. The expression of 200 to 600 probe sets changed between baseline and post-NST samples. In basal-like cancers, pathways driven by increased expression of phosphoinositide 3-kinase, small G proteins, and calmodulin-dependent protein kinase II and energy metabolism were enriched, whereas immune cell-derived and the sonic hedgehog pathways were depleted in residual cancer. In non-basal-like breast cancers, notch signaling and energy metabolism (e.g., fatty acid synthesis) were enriched and sonic hedgehog signaling and immune-related pathways were depleted in residual cancer. There was no increase in epithelial-mesenchymal transition or cancer stem cell signatures. Conclusions: Our data indicate that energy metabolism related processes are upregulated and immune-related signals are depleted in residual cancers. Targeting these biologic processes may represent promising adjuvant treatment strategies for patients with residual cancer.",
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AU - Do, Kim Anh

AU - Hortobagyi, Gabriel N.

AU - Mills, Gordon

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AU - Pusztai, Lajos

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