SIAH and EGFR, Two RAS Pathway Biomarkers, are Highly Prognostic in Locally Advanced and Metastatic Breast Cancer

Lauren L.Siewertsz van Reesema, Vasilena Zheleva, Janet S. Winston, Rick J. Jansen, Carolyn F. O'Connor, Andrew J. Isbell, Minglei Bian, Rui Qin, Patricia T. Bassett, Virginia J. Hinson, Kimberly A. Dorsch, Brad W. Kirby, Robert E. Van Sciver, Angela M. Tang-Tan, Elizabeth A. Harden, David Z. Chang, Cynthia A. Allen, Roger R. Perry, Richard A. Hoefer, Amy H. Tang

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Background Metastatic breast cancer exhibits diverse and rapidly evolving intra- and inter-tumor heterogeneity. Patients with similar clinical presentations often display distinct tumor responses to standard of care (SOC) therapies. Genome landscape studies indicate that EGFR/HER2/RAS “pathway” activation is highly prevalent in malignant breast cancers. The identification of therapy-responsive and prognostic biomarkers is paramount important to stratify patients and guide therapies in clinical oncology and personalized medicine. Methods In this study, we analyzed matched pairs of tumor specimens collected from 182 patients who received neoadjuvant systemic therapies (NST). Statistical analyses were conducted to determine whether EGFR/HER2/RAS pathway biomarkers and clinicopathological predictors, alone and in combination, are prognostic in breast cancer. Findings SIAH and EGFR outperform ER, PR, HER2 and Ki67 as two logical, sensitive and prognostic biomarkers in metastatic breast cancer. We found that increased SIAH and EGFR expression correlated with advanced pathological stage and aggressive molecular subtypes. Both SIAH expression post-NST and NST-induced changes in EGFR expression in invasive mammary tumors are associated with tumor regression and increased survival, whereas ER, PR, and HER2 were not. These results suggest that SIAH and EGFR are two prognostic biomarkers in breast cancer with lymph node metastases. Interpretation The discovery of incorporating tumor heterogeneity-independent and growth-sensitive RAS pathway biomarkers, SIAH and EGFR, whose altered expression can be used to estimate therapeutic efficacy, detect emergence of resistant clones, forecast tumor regression, differentiate among partial responders, and predict patient survival in the neoadjuvant setting, has a clear clinical implication in personalizing breast cancer therapy. Funding This work was supported by the Dorothy G. Hoefer Foundation for Breast Cancer Research (A.H. Tang); Center for Innovative Technology (CIT)-Commonwealth Research Commercialization Fund (CRCF) (MF14S-009-LS to A.H. Tang), and National Cancer Institute (CA140550 to A.H. Tang).

Original languageEnglish (US)
Pages (from-to)183-198
Number of pages16
JournalEBioMedicine
Volume11
DOIs
StatePublished - Sep 1 2016

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Biomarkers
Tumors
Breast Neoplasms
Neoadjuvant Therapy
Neoplasms
Technology Transfer
Therapeutics
Precision Medicine
Oncology
Survival
Medical Oncology
National Cancer Institute (U.S.)
Clinical Medicine
Standard of Care
Medicine
Clone Cells
Genes
Lymph Nodes
Chemical activation
Genome

Keywords

  • And prognostic biomarkers
  • Clinicopathological predictors
  • Locally advanced and metastatic breast cancer
  • Needle biopsies
  • Neoadjuvant systemic therapies
  • SIAH E3 ligase
  • The RAS pathway activation in breast cancer

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

van Reesema, L. L. S., Zheleva, V., Winston, J. S., Jansen, R. J., O'Connor, C. F., Isbell, A. J., ... Tang, A. H. (2016). SIAH and EGFR, Two RAS Pathway Biomarkers, are Highly Prognostic in Locally Advanced and Metastatic Breast Cancer. EBioMedicine, 11, 183-198. https://doi.org/10.1016/j.ebiom.2016.08.014

SIAH and EGFR, Two RAS Pathway Biomarkers, are Highly Prognostic in Locally Advanced and Metastatic Breast Cancer. / van Reesema, Lauren L.Siewertsz; Zheleva, Vasilena; Winston, Janet S.; Jansen, Rick J.; O'Connor, Carolyn F.; Isbell, Andrew J.; Bian, Minglei; Qin, Rui; Bassett, Patricia T.; Hinson, Virginia J.; Dorsch, Kimberly A.; Kirby, Brad W.; Van Sciver, Robert E.; Tang-Tan, Angela M.; Harden, Elizabeth A.; Chang, David Z.; Allen, Cynthia A.; Perry, Roger R.; Hoefer, Richard A.; Tang, Amy H.

In: EBioMedicine, Vol. 11, 01.09.2016, p. 183-198.

Research output: Contribution to journalArticle

van Reesema, LLS, Zheleva, V, Winston, JS, Jansen, RJ, O'Connor, CF, Isbell, AJ, Bian, M, Qin, R, Bassett, PT, Hinson, VJ, Dorsch, KA, Kirby, BW, Van Sciver, RE, Tang-Tan, AM, Harden, EA, Chang, DZ, Allen, CA, Perry, RR, Hoefer, RA & Tang, AH 2016, 'SIAH and EGFR, Two RAS Pathway Biomarkers, are Highly Prognostic in Locally Advanced and Metastatic Breast Cancer', EBioMedicine, vol. 11, pp. 183-198. https://doi.org/10.1016/j.ebiom.2016.08.014
van Reesema, Lauren L.Siewertsz ; Zheleva, Vasilena ; Winston, Janet S. ; Jansen, Rick J. ; O'Connor, Carolyn F. ; Isbell, Andrew J. ; Bian, Minglei ; Qin, Rui ; Bassett, Patricia T. ; Hinson, Virginia J. ; Dorsch, Kimberly A. ; Kirby, Brad W. ; Van Sciver, Robert E. ; Tang-Tan, Angela M. ; Harden, Elizabeth A. ; Chang, David Z. ; Allen, Cynthia A. ; Perry, Roger R. ; Hoefer, Richard A. ; Tang, Amy H. / SIAH and EGFR, Two RAS Pathway Biomarkers, are Highly Prognostic in Locally Advanced and Metastatic Breast Cancer. In: EBioMedicine. 2016 ; Vol. 11. pp. 183-198.
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abstract = "Background Metastatic breast cancer exhibits diverse and rapidly evolving intra- and inter-tumor heterogeneity. Patients with similar clinical presentations often display distinct tumor responses to standard of care (SOC) therapies. Genome landscape studies indicate that EGFR/HER2/RAS “pathway” activation is highly prevalent in malignant breast cancers. The identification of therapy-responsive and prognostic biomarkers is paramount important to stratify patients and guide therapies in clinical oncology and personalized medicine. Methods In this study, we analyzed matched pairs of tumor specimens collected from 182 patients who received neoadjuvant systemic therapies (NST). Statistical analyses were conducted to determine whether EGFR/HER2/RAS pathway biomarkers and clinicopathological predictors, alone and in combination, are prognostic in breast cancer. Findings SIAH and EGFR outperform ER, PR, HER2 and Ki67 as two logical, sensitive and prognostic biomarkers in metastatic breast cancer. We found that increased SIAH and EGFR expression correlated with advanced pathological stage and aggressive molecular subtypes. Both SIAH expression post-NST and NST-induced changes in EGFR expression in invasive mammary tumors are associated with tumor regression and increased survival, whereas ER, PR, and HER2 were not. These results suggest that SIAH and EGFR are two prognostic biomarkers in breast cancer with lymph node metastases. Interpretation The discovery of incorporating tumor heterogeneity-independent and growth-sensitive RAS pathway biomarkers, SIAH and EGFR, whose altered expression can be used to estimate therapeutic efficacy, detect emergence of resistant clones, forecast tumor regression, differentiate among partial responders, and predict patient survival in the neoadjuvant setting, has a clear clinical implication in personalizing breast cancer therapy. Funding This work was supported by the Dorothy G. Hoefer Foundation for Breast Cancer Research (A.H. Tang); Center for Innovative Technology (CIT)-Commonwealth Research Commercialization Fund (CRCF) (MF14S-009-LS to A.H. Tang), and National Cancer Institute (CA140550 to A.H. Tang).",
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T1 - SIAH and EGFR, Two RAS Pathway Biomarkers, are Highly Prognostic in Locally Advanced and Metastatic Breast Cancer

AU - van Reesema, Lauren L.Siewertsz

AU - Zheleva, Vasilena

AU - Winston, Janet S.

AU - Jansen, Rick J.

AU - O'Connor, Carolyn F.

AU - Isbell, Andrew J.

AU - Bian, Minglei

AU - Qin, Rui

AU - Bassett, Patricia T.

AU - Hinson, Virginia J.

AU - Dorsch, Kimberly A.

AU - Kirby, Brad W.

AU - Van Sciver, Robert E.

AU - Tang-Tan, Angela M.

AU - Harden, Elizabeth A.

AU - Chang, David Z.

AU - Allen, Cynthia A.

AU - Perry, Roger R.

AU - Hoefer, Richard A.

AU - Tang, Amy H.

PY - 2016/9/1

Y1 - 2016/9/1

N2 - Background Metastatic breast cancer exhibits diverse and rapidly evolving intra- and inter-tumor heterogeneity. Patients with similar clinical presentations often display distinct tumor responses to standard of care (SOC) therapies. Genome landscape studies indicate that EGFR/HER2/RAS “pathway” activation is highly prevalent in malignant breast cancers. The identification of therapy-responsive and prognostic biomarkers is paramount important to stratify patients and guide therapies in clinical oncology and personalized medicine. Methods In this study, we analyzed matched pairs of tumor specimens collected from 182 patients who received neoadjuvant systemic therapies (NST). Statistical analyses were conducted to determine whether EGFR/HER2/RAS pathway biomarkers and clinicopathological predictors, alone and in combination, are prognostic in breast cancer. Findings SIAH and EGFR outperform ER, PR, HER2 and Ki67 as two logical, sensitive and prognostic biomarkers in metastatic breast cancer. We found that increased SIAH and EGFR expression correlated with advanced pathological stage and aggressive molecular subtypes. Both SIAH expression post-NST and NST-induced changes in EGFR expression in invasive mammary tumors are associated with tumor regression and increased survival, whereas ER, PR, and HER2 were not. These results suggest that SIAH and EGFR are two prognostic biomarkers in breast cancer with lymph node metastases. Interpretation The discovery of incorporating tumor heterogeneity-independent and growth-sensitive RAS pathway biomarkers, SIAH and EGFR, whose altered expression can be used to estimate therapeutic efficacy, detect emergence of resistant clones, forecast tumor regression, differentiate among partial responders, and predict patient survival in the neoadjuvant setting, has a clear clinical implication in personalizing breast cancer therapy. Funding This work was supported by the Dorothy G. Hoefer Foundation for Breast Cancer Research (A.H. Tang); Center for Innovative Technology (CIT)-Commonwealth Research Commercialization Fund (CRCF) (MF14S-009-LS to A.H. Tang), and National Cancer Institute (CA140550 to A.H. Tang).

AB - Background Metastatic breast cancer exhibits diverse and rapidly evolving intra- and inter-tumor heterogeneity. Patients with similar clinical presentations often display distinct tumor responses to standard of care (SOC) therapies. Genome landscape studies indicate that EGFR/HER2/RAS “pathway” activation is highly prevalent in malignant breast cancers. The identification of therapy-responsive and prognostic biomarkers is paramount important to stratify patients and guide therapies in clinical oncology and personalized medicine. Methods In this study, we analyzed matched pairs of tumor specimens collected from 182 patients who received neoadjuvant systemic therapies (NST). Statistical analyses were conducted to determine whether EGFR/HER2/RAS pathway biomarkers and clinicopathological predictors, alone and in combination, are prognostic in breast cancer. Findings SIAH and EGFR outperform ER, PR, HER2 and Ki67 as two logical, sensitive and prognostic biomarkers in metastatic breast cancer. We found that increased SIAH and EGFR expression correlated with advanced pathological stage and aggressive molecular subtypes. Both SIAH expression post-NST and NST-induced changes in EGFR expression in invasive mammary tumors are associated with tumor regression and increased survival, whereas ER, PR, and HER2 were not. These results suggest that SIAH and EGFR are two prognostic biomarkers in breast cancer with lymph node metastases. Interpretation The discovery of incorporating tumor heterogeneity-independent and growth-sensitive RAS pathway biomarkers, SIAH and EGFR, whose altered expression can be used to estimate therapeutic efficacy, detect emergence of resistant clones, forecast tumor regression, differentiate among partial responders, and predict patient survival in the neoadjuvant setting, has a clear clinical implication in personalizing breast cancer therapy. Funding This work was supported by the Dorothy G. Hoefer Foundation for Breast Cancer Research (A.H. Tang); Center for Innovative Technology (CIT)-Commonwealth Research Commercialization Fund (CRCF) (MF14S-009-LS to A.H. Tang), and National Cancer Institute (CA140550 to A.H. Tang).

KW - And prognostic biomarkers

KW - Clinicopathological predictors

KW - Locally advanced and metastatic breast cancer

KW - Needle biopsies

KW - Neoadjuvant systemic therapies

KW - SIAH E3 ligase

KW - The RAS pathway activation in breast cancer

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