title: Pathologic complete response after preoperative anti-HER2 therapy correlates with alterations in PTEN, FOXO, phosphorylated Stat5, and autophagy protein signaling.
abstract: BACKGROUND
  To define protein molecular characteristics of tumor cells prior to, and immediately following, preoperative human epidermal growth factor receptor 2 (HER2)-targeted therapy that correlate with pathologic complete response (pCR) or non response (no pCR) to preoperative HER2-directed therapy and chemotherapy.
  
  
  METHODS
  This open-label, phase II study randomized patients with HER2-positive stage II or III invasive breast cancer to trastuzumab, lapatinib, or both, 2 weeks prior to and during chemotherapy with FEC75 for 4 courses; then paclitaxel 80 mg/m2 weekly for 12 courses, then surgery. Core needle biopsies were collected at baseline and after 2 weeks of anti-HER2 therapy prior to chemotherapy. Data were correlated with pCR, defined as absence of invasive tumor in breast and lymph nodes.
  
  
  RESULTS
  Of 100 enrolled patients, the analysis population included those who had surgery and received ≥75% chemotherapy (78% [n=78]). pCRs by arm are: trastuzumab (n=26), 54% [n=14]; lapatinib (n=29), 45% [n=13]; trastuzumab plus lapatinib (n=23), 74% [n=17]). Paired biopsy specimens were available for 49 patients (63%). Tumor cells of patients with pCR in the trastuzumab or lapatinib treatment arms showed nonphosphorylated FOXO, phosphorylated Stat5, and sparse signal-transduction protein network crosstalk representing different patterns of connections with PI3K and autophagy proteins compared with no pCR.
  
  
  CONCLUSIONS
  In this exploratory study, pCR with preoperative anti-HER2 therapy and chemotherapy correlated with the levels and phosphorylation status of specific baseline signal pathway proteins in tumor cells. These data may provide candidate biomarkers to stratify initial treatment and potential combination therapies for future study. Tissue preservation technology introduced here makes this procedure widely feasible.
  
  
  BACKGROUND
  ClinicalTrials.gov: NCT00524303.
authors.affiliation: Texas Oncology-Memorial Hermann Memorial City, US Oncology Research, 925 Gessner Road #550, Houston, TX 77024-2546, USA. FrankieAnn.Holmes@USOncology.com.
authors.forename: Frankie Ann
authors.initials: FA
authors.lastname: Holmes
authors.forename: Virginia
authors.initials: V
authors.lastname: Espina
authors.forename: Lance A
authors.initials: LA
authors.lastname: Liotta
authors.forename: Yasir M
authors.initials: YM
authors.lastname: Nagarwala
authors.forename: Michael
authors.initials: M
authors.lastname: Danso
authors.forename: Kristi J
authors.initials: KJ
authors.lastname: McIntyre
authors.forename: Cynthia R C
authors.initials: CR
authors.lastname: Osborne
authors.forename: Thomas
authors.initials: T
authors.lastname: Anderson
authors.forename: Lea
authors.initials: L
authors.lastname: Krekow
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Blum
authors.forename: John
authors.initials: J
authors.lastname: Pippen
authors.forename: Allison
authors.initials: A
authors.lastname: Florance
authors.forename: Janine
authors.initials: J
authors.lastname: Mahoney
authors.forename: Joyce A
authors.initials: JA
authors.lastname: O'Shaughnessy
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols; D001343:Autophagy; D054316:Biomarkers, Pharmacological; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004334:Drug Administration Schedule; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000077341:Lapatinib; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011799:Quinazolines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D054316:Biomarkers, Pharmacological; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D000077341:Lapatinib; D051059:PTEN Phosphohydrolase; D017239:Paclitaxel; D019869:Phosphatidylinositol 3-Kinases; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D050799:STAT5 Transcription Factor; D000068878:Trastuzumab; C085126:FOXO1 protein, human; C508053:ERBB2 protein, human; C494929:PTEN protein, human