title: Predictive Biomarker Profiling of > 6000 Breast Cancer Patients Shows Heterogeneity in TNBC, With Treatment Implications.
abstract: BACKGROUND
  Triple-negative breast cancer (TNBC) is an aggressive disease without established targeted treatment options for patients with metastatic disease. This study was undertaken to evaluate potentially actionable biomarkers in a large cohort of TNBC and compare them with non-TNBCs.
  
  
  METHODS
  We evaluated 6341 (2111 TNBC and 4230 non-TNBC) breast cancer samples at a central laboratory for biomarkers of potential drug response across multiple platforms, including gene sequencing, protein expression, and gene copy number.
  
  
  RESULTS
  TNBC expresses androgen receptor (AR) in a significantly (P < .05) lower percentage of cases (17%) than hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-positive breast carcinomas (59% and 79%, respectively), and gene comutations were differentially associated with AR-positive versus AR-negative cases. Higher AR expression levels in TNBC predicted for lower Ki-67 levels. Seventy percent of TNBC harbored a phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), v-akt murine thymoma viral oncogene homolog 1 (AKT1), or phosophatase and tensin homolog (PTEN) aberration. TNBC patients had a significantly lower PIK3CA mutation rate (13%) than all other subtypes (P < .05) and a higher tumor protein p53 (TP53) mutation rate (64%) than the estrogen receptor (ER)-positive cases (approximately 30%; P < .05). Topoisomerase 2 (TOP2A) amplification was observed in 1.3% of TNBC and in 1.6% of HER2-negative, HR-positive cancers; in contrast, HER2-positive, HR-negative or HR-positive cancers exhibited TOP2A amplification in 19% and 40% of cases, respectively (P <.05).
  
  
  CONCLUSIONS
  Multi-platform molecular profiling identifies subgroups of TNBC with different biomarker profiles, suggesting numerous potentially targetable alterations in TNBC. TNBC is further characterized by different gene mutations and proliferative activity relative to AR expression, highlighting a need for comprehensive pathologic examination with potential to develop different, individualized treatment options.
authors.affiliation: Caris Life Sciences, Phoenix, AZ. Electronic address: smillis@ashionaim.com.
authors.forename: Sherri Z
authors.initials: SZ
authors.lastname: Millis
authors.affiliation: Caris Life Sciences, Phoenix, AZ.
authors.forename: Zoran
authors.initials: Z
authors.lastname: Gatalica
authors.affiliation: Caris Life Sciences, Phoenix, AZ.
authors.forename: Josiah
authors.initials: J
authors.lastname: Winkler
authors.affiliation: Department of Pathology, Clinical Center, University of Sarajevo, Sarajevo, Bosnia and Herzegovina.
authors.forename: Semir
authors.initials: S
authors.lastname: Vranic
authors.affiliation: Caris Life Sciences, Phoenix, AZ.
authors.forename: Jeffery
authors.initials: J
authors.lastname: Kimbrough
authors.affiliation: Caris Life Sciences, Phoenix, AZ.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Reddy
authors.affiliation: Baylor Sammons Cancer Center, Texas Oncology, US Oncology, Dallas TX.
authors.forename: Joyce A
authors.initials: JA
authors.lastname: O'Shaughnessy
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor
keywords: Immunohistochemistry; In situ hybridization; Molecular profiling; Sequencing; Targeted therapy; Triple-negative breast cancer