title: SIAH and EGFR, Two RAS Pathway Biomarkers, are Highly Prognostic in Locally Advanced and Metastatic Breast Cancer.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  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).
authors: Department of Microbiology and Molecular Cell Biology, Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA 23507, United States.
authors: Lauren L Siewertsz
authors: LLS
authors: van Reesema
authors: Department of Surgery, Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA 23507, United States.
authors: Vasilena
authors: V
authors: Zheleva
authors: Sentara Pathology and Pathology Sciences Medical Group, Department of Pathology, Sentara Norfolk General Hospital (SNGH), 600 Gresham Drive, Norfolk, VA 23507, United States.
authors: Janet S
authors: JS
authors: Winston
authors: Department of Public Health, North Dakota State University, Fargo, ND 58102, United States.
authors: Rick J
authors: RJ
authors: Jansen
authors: Department of Microbiology and Molecular Cell Biology, Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA 23507, United States.
authors: Carolyn F
authors: CF
authors: O'Connor
authors: Department of Microbiology and Molecular Cell Biology, Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA 23507, United States.
authors: Andrew J
authors: AJ
authors: Isbell
authors: Department of Microbiology and Molecular Cell Biology, Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA 23507, United States.
authors: Minglei
authors: M
authors: Bian
authors: Department of Health Sciences Research, Mayo Clinic Cancer Center, Mayo Clinic, Rochester, MN 55905, United States.
authors: Rui
authors: R
authors: Qin
authors: Sentara Pathology and Pathology Sciences Medical Group, Department of Pathology, Sentara Norfolk General Hospital (SNGH), 600 Gresham Drive, Norfolk, VA 23507, United States.
authors: Patricia T
authors: PT
authors: Bassett
authors: Sentara Pathology and Pathology Sciences Medical Group, Department of Pathology, Sentara Norfolk General Hospital (SNGH), 600 Gresham Drive, Norfolk, VA 23507, United States.
authors: Virginia J
authors: VJ
authors: Hinson
authors: Sentara Cancer Network, 11803 Jefferson Avenue, Suite 235, Newport News, Virginia 23606, United States.
authors: Kimberly A
authors: KA
authors: Dorsch
authors: Sentara Cancer Network, 11803 Jefferson Avenue, Suite 235, Newport News, Virginia 23606, United States.
authors: Brad W
authors: BW
authors: Kirby
authors: Department of Microbiology and Molecular Cell Biology, Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA 23507, United States.
authors: Robert E
authors: RE
authors: Van Sciver
authors: Princess Anne High School, International Baccalaureate (IB) Gifted and Talented Program, 4400 Virginia Beach Boulevard, Virginia Beach, VA 23462, United States.
authors: Angela M
authors: AM
authors: Tang-Tan
authors: Dorothy G. Hoefer Comprehensive Breast Center, 11803 Jefferson Avenue, Suite 235, Newport News, Virginia 23606, United States; Virginia Oncology Associates, 1051 Loftis Blvd, Suite 100, Newport News, VA 23606, United States.
authors: Elizabeth A
authors: EA
authors: Harden
authors: Virginia Oncology Associates, 1051 Loftis Blvd, Suite 100, Newport News, VA 23606, United States.
authors: David Z
authors: DZ
authors: Chang
authors: Sentara Cancer Network, 11803 Jefferson Avenue, Suite 235, Newport News, Virginia 23606, United States.
authors: Cynthia A
authors: CA
authors: Allen
authors: Department of Surgery, Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA 23507, United States.
authors: Roger R
authors: RR
authors: Perry
authors: Sentara Cancer Network, 11803 Jefferson Avenue, Suite 235, Newport News, Virginia 23606, United States; Dorothy G. Hoefer Comprehensive Breast Center, 11803 Jefferson Avenue, Suite 235, Newport News, Virginia 23606, United States; Sentara CarePlex Hospital, 11803 Jefferson Avenue, Suite 235, Newport News, Virginia 23606, United States.
authors: Richard A
authors: RA
authors: Hoefer
authors: Department of Microbiology and Molecular Cell Biology, Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA 23507, United States. Electronic address: TangAH@evms.edu.
authors: Amy H
authors: AH
authors: Tang
mesh_terms: D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D018450:Disease Progression; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008954:Models, Biological; D020360:Neoadjuvant Therapy; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D016016:Proportional Hazards Models; D015398:Signal Transduction; D016896:Treatment Outcome; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*; D000098563:Seven in Absentia Proteins
chemical_list: D014408:Biomarkers, Tumor; D009687:Nuclear Proteins; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; D066246:ErbB Receptors; D018631:ras Proteins
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