title: MET and PTEN gene copy numbers and Ki-67 protein expression associate with pathologic complete response in ERBB2-positive breast carcinoma patients treated with neoadjuvant trastuzumab-based therapy.
abstract: Pathologic complete response (pCR) after neoadjuvant chemotherapy for breast cancer is associated with improved prognosis in aggressive tumor subtypes, including ERBB2- positive tumors. Recent adoption of pCR as a surrogate endpoint for clinical trials in early stage breast cancer in the neoadjuvant setting highlights the need for biomarkers that, alone or in combination, help predict the likelihood of response to treatment.
  
  
  
  Biopsy specimens from 29 patients with invasive ductal carcinoma treated with trastuzumab-based therapy prior to definitive resection and pathologic staging were evaluated by dual color bright field in situ hybridization (dual ISH) using probes for MET, TOP2A, PTEN, and PIK3CA genes, each paired with centromeric probes to their respective chromosomes (chromosomes 7, 17, 10, and 3). Ki-67 expression was assessed by immunohistochemistry (IHC). Various parameters describing copy number alterations were evaluated for each gene and centromere probe to identify the optimal parameters for clinical relevance. Combinations of ISH parameters and IHC expression for Ki-67 were also evaluated.
  
  
  
  Of the four genes and their respective chromosomes evaluated by ISH, two gene copy number parameters provided statistically significant associations with pCR: MET gain or loss relative to chromosome 7 (AUC = 0.791, sensitivity = 92 % and specificity = 67 % at optimal cutoff, p = 0.0032) and gain of PTEN (AUC = 0.674, sensitivity = 38 % and specificity = 100 % at optimal cutoff, p = 0.039). Ki-67 expression was also found to associate significantly with pCR (AUC = 0.726, sensitivity = 100 % and specificity = 42 % at optimal cutoff, p = 0.0098). Combining gain or loss of MET relative to chromosome 7 with Ki-67 expression further improved the association with pCR (AUC = 0.847, sensitivity = 92 % and specificity = 83 % at optimal cutoffs, p = 0.0006).
  
  
  
  An immunogenotypic signature of low complexity comprising MET relative copy number and Ki-67 expression generated by dual ISH and IHC may help predict pCR in ERBB2-positive breast cancer treated with neoadjuvant chemotherapy and trastuzumab. These findings require validation in additional patient cohorts.
authors: Department of Pathology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA.
authors: Benjamin C
authors: BC
authors: Calhoun
authors: Department of Pathology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA.|Present Address: Ventana Medical Systems, Inc, 1910 E. Innovation Park Dr, Tucson, AZ, 85755, USA.
authors: Bryce
authors: B
authors: Portier
authors: Department of Pathology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA.
authors: Zhen
authors: Z
authors: Wang
authors: Department of Pathology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA.
authors: Eugen C
authors: EC
authors: Minca
authors: Department of Hematology and Oncology, Cleveland Clinic, Cleveland, OH, USA.
authors: G Thomas
authors: GT
authors: Budd
authors: Department of Pathology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA.
authors: Christopher
authors: C
authors: Lanigan
authors: Department of Pathology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA.
authors: Raymond R
authors: RR
authors: Tubbs
authors: Present Address: Ventana Medical Systems, Inc, 1910 E. Innovation Park Dr, Tucson, AZ, 85755, USA. Larry.morrison@roche.com.
authors: Larry E
authors: LE
authors: Morrison
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D017024:Chemotherapy, Adjuvant / Q000379:methods; D005260:Female; D018628:Gene Dosage; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods; D051059:PTEN Phosphohydrolase / Q000235:genetics; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D012372:ROC Curve; D018719:Erb-b2 Receptor Tyrosine Kinases; D012680:Sensitivity and Specificity; D000068878:Trastuzumab / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D051059:PTEN Phosphohydrolase; D019859:Proto-Oncogene Proteins c-met; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C491743:MET protein, human; C494929:PTEN protein, human
keywords: Biomarkers; Breast cancer; ERBB2; HER2; In situ hybridization (ISH); Neoadjuvant; Pathologic complete response (pCR)