title: HER2 over-expressing high grade endometrial cancer expresses high levels of p95HER2 variant.
abstract: BACKGROUND
  Subsets of high grade endometrial cancer (EnCa) over-express HER2 (ERBB2), yet clinical trials have failed to demonstrate any anti-tumor activity utilizing trastuzumab, an approved platform for HER2 positive breast cancer (BrCa). A truncated p95HER2 variant lacking the trastuzumab binding site may confer resistance. The objective of this investigation was to characterize the expression of the p95HER2 truncated variant in EnCa.
  
  
  METHODS
  With institutional approval, 86 high grade EnCa tumors were identified with tumor specimens from surgeries performed between 2000 and 2011. Clinical data were collected and all specimens underwent tumor genotyping, HER2 immunohistochemistry (IHC, HercepTest®), HER2 fluorescent in situ hybridization (FISH), along with total HER2 (H2T) and p95HER2 assessment with VeraTag® testing. Regression models were used to compare a cohort of 86 breast tumors selected for equivalent HER2 protein expression.
  
  
  RESULTS
  We identified 44 high grade endometrioid and 42 uterine serous carcinomas (USC). IHC identified high HER2 expression (2+ or 3+) in 59% of the tumors. HER2 gene amplification was observed in 16 tumors (12 USC, 4 endometrioid). Both HER2 gene amplification and protein expression correlated with H2T values. High p95HER2 expression above 2.8RF/mm2 was observed in 53% (n=54) with significant correlation with H2T levels. When matched to a cohort of 107 breast tumors based on HercepTest HER2 expression, high grade EnCa presented with higher p95 levels (p<0.001).
  
  
  CONCLUSIONS
  These data demonstrate that compared to BrCa, high grade EnCa expresses higher levels of p95HER2 possibly providing rationale for the trastuzumab resistance observed in EnCa.
authors.affiliation: Vincent Center for Reproductive Biology, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA 02114, United States; Gynecologic Oncology Division, Vincent Department of Obstetrics & Gynecology, Massachusetts General Hospital, Boston, MA 02114, United States; Harvard Medical School, Boston, MA 02115, United States. Electronic address: wgrowdon@partners.org.
authors.forename: Whitfield B
authors.initials: WB
authors.lastname: Growdon
authors.affiliation: Vincent Center for Reproductive Biology, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA 02114, United States.
authors.forename: Jolijn
authors.initials: J
authors.lastname: Groeneweg
authors.affiliation: Vincent Center for Reproductive Biology, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA 02114, United States.
authors.forename: Virginia
authors.initials: V
authors.lastname: Byron
authors.affiliation: Vincent Center for Reproductive Biology, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA 02114, United States.
authors.forename: Celeste
authors.initials: C
authors.lastname: DiGloria
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Boston, MA, United States; Harvard Medical School, Boston, MA 02115, United States.
authors.forename: Darrell R
authors.initials: DR
authors.lastname: Borger
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, United States; Harvard Medical School, Boston, MA 02115, United States.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Tambouret
authors.affiliation: Vincent Center for Reproductive Biology, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA 02114, United States; Gynecologic Oncology Division, Vincent Department of Obstetrics & Gynecology, Massachusetts General Hospital, Boston, MA 02114, United States; Harvard Medical School, Boston, MA 02115, United States.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Foster
authors.affiliation: Monogram Biosciences, San Francisco, CA 94080, United States.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Chenna
authors.affiliation: Monogram Biosciences, San Francisco, CA 94080, United States.
authors.forename: Jeff
authors.initials: J
authors.lastname: Sperinde
authors.affiliation: Monogram Biosciences, San Francisco, CA 94080, United States.
authors.forename: John
authors.initials: J
authors.lastname: Winslow
authors.affiliation: Vincent Center for Reproductive Biology, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA 02114, United States; Gynecologic Oncology Division, Vincent Department of Obstetrics & Gynecology, Massachusetts General Hospital, Boston, MA 02114, United States; Harvard Medical School, Boston, MA 02115, United States.
authors.forename: Bo R
authors.initials: BR
authors.lastname: Rueda
mesh_terms: D000368:Aged; D018269:Carcinoma, Endometrioid / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D016889:Endometrial Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D005260:Female; D005784:Gene Amplification; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D060787:Neoplasm Grading; D016612:Paraffin Embedding; D010446:Peptide Fragments / Q000096:biosynthesis / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D010446:Peptide Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
keywords: HER2 over-expression; High grade endometrial carcinoma; Trastuzumab resistance; p95HER2