title: Relationship between Tumor Biomarkers and Efficacy in EMILIA, a Phase III Study of Trastuzumab Emtansine in HER2-Positive Metastatic Breast Cancer.
abstract: HER2-positive breast cancer is heterogeneous. Some tumors express mutations, like activating PIK3CA mutations or reduced PTEN expression, that negatively correlate with response to HER2-targeted therapies. In this exploratory analysis, we investigated whether the efficacy of trastuzumab emtansine (T-DM1), an antibody-drug conjugate comprised of the cytotoxic agent DM1 linked to the HER2-targeted antibody trastuzumab, was correlated with the expression of specific biomarkers in the phase III EMILIA study.
  
  
  
  Tumors were evaluated for HER2 (n = 866), EGFR (n = 832), and HER3 (n = 860) mRNA expression by quantitative reverse transcriptase PCR; for PTEN protein expression (n = 271) by IHC; and for PIK3CA mutations (n = 259) using a mutation detection kit. Survival outcomes were analyzed by biomarker subgroups. T-DM1 was also tested on cell lines and in breast cancer xenograft models containing PIK3CA mutations.
  
  
  
  Longer progression-free survival (PFS) and overall survival (OS) were observed with T-DM1 compared with capecitabine plus lapatinib in all biomarker subgroups. PIK3CA mutations were associated with shorter median PFS (mutant vs. wild type: 4.3 vs. 6.4 months) and OS (17.3 vs. 27.8 months) in capecitabine plus lapatinib-treated patients, but not in T-DM1-treated patients (PFS, 10.9 vs. 9.8 months; OS, not reached in mutant or wild type). T-DM1 showed potent activity in cell lines and xenograft models with PIK3CA mutations.
  
  
  
  Although other standard HER2-directed therapies are less effective in tumors with PI3KCA mutations, T-DM1 appears to be effective in both PI3KCA-mutated and wild-type tumors. Clin Cancer Res; 22(15); 3755-63. ©2016 AACR.
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York. baselgaj@mskcc.org.
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Gail D
authors.initials: GD
authors.lastname: Lewis Phillips
authors.affiliation: Sunnybrook Odette Cancer Centre, Toronto, Canada.
authors.forename: Sunil
authors.initials: S
authors.lastname: Verma
authors.affiliation: National Cancer Center, Goyang, Korea.
authors.forename: Jungsil
authors.initials: J
authors.lastname: Ro
authors.affiliation: Breast Center, Kantonsspital St. Gallen, St. Gallen, Switzerland.
authors.forename: Jens
authors.initials: J
authors.lastname: Huober
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Alice E
authors.initials: AE
authors.lastname: Guardino
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Meghna K
authors.initials: MK
authors.lastname: Samant
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Steve
authors.initials: S
authors.lastname: Olsen
authors.affiliation: F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Sanne L
authors.initials: SL
authors.lastname: de Haas
authors.affiliation: Stanford Cancer Institute, Palo Alto, California.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Pegram
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D000818:Animals; D000074322:Antineoplastic Agents, Immunological / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D008453:Maytansine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051379:Mice; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D019869:Phosphatidylinositol 3-Kinases; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D019233:Retreatment; D000068878:Trastuzumab / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D000074322:Antineoplastic Agents, Immunological; D014408:Biomarkers, Tumor; D008453:Maytansine; D019869:Phosphatidylinositol 3-Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab