title: Relationship between tumor biomarkers and efficacy in TH3RESA, a phase III study of trastuzumab emtansine (T-DM1) vs. treatment of physician's choice in previously treated HER2-positive advanced breast cancer.
abstract: In the phase III TH3RESA study (NCT01419197), 602 patients with HER2-positive advanced breast cancer who received prior taxane therapy and ≥2 HER2-directed regimens, including trastuzumab and lapatinib (advanced setting), were randomized to trastuzumab emtansine (T-DM1) or treatment of physician's choice (TPC). A statistically significant progression-free survival (PFS) benefit favoring T-DM1 was demonstrated. Here, we examine the relationship between HER2-related biomarkers and PFS in an exploratory analysis. Biomarkers assessed included HER2 (n = 505) and HER3 (n = 505) mRNA expression, PIK3CA mutation status (n = 410) and PTEN protein expression (n = 358). For biomarkers with continuous data (HER2, HER3, PTEN), subgroups were defined using median values (>median and ≤median). For all biomarker subgroups, median PFS was longer with T-DM1 vs. TPC. The PFS benefit favoring T-DM1 vs. TPC was numerically greater in the HER2 mRNA >median subgroup (7.2 vs. 3.4 months; unstratified hazard ratio [HR], 0.40; 95% CI, 0.28-0.59; p < 0.0001) vs. ≤median subgroup (5.5 vs. 3.9 months; HR, 0.68; 95% CI, 0.49-0.92; p = 0.0131). The PFS benefit with T-DM1 was similar among HER3, PIK3CA and PTEN subgroups. Consistent with other reports, benefit was seen with T-DM1 regardless of PIK3CA mutation status. In a multivariate analysis including an interaction term (treatment group by log2-transformed HER2 mRNA), patients with higher HER2 mRNA levels benefited more from receiving T-DM1 (HR, 0.84; 95% CI, 0.75-0.94; interaction p value = 0.0027). In summary, T-DM1 prolonged median PFS in all biomarker subgroups analyzed, including activating PIK3CA mutations, with numerically greater benefit in patients with tumors expressing HER2 mRNA >median vs. ≤median.
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. sbkim3@amc.seoul.kr.
authors.forename: Sung-Bae
authors.initials: SB
authors.lastname: Kim
authors.affiliation: Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Hans
authors.initials: H
authors.lastname: Wildiers
authors.affiliation: Department of Adult Oncology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Ian E
authors.initials: IE
authors.lastname: Krop
authors.affiliation: Department of Product Development Oncology, Genentech, Inc., South San Francisco, CA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Smitt
authors.affiliation: Department of Biostatistics, Genentech, Inc, South San Francisco, CA.
authors.forename: Ron
authors.initials: R
authors.lastname: Yu
authors.affiliation: Department of Oncology Biomarker Development, F. Hoffmann-La Roche, Ltd., Basel, Switzerland.
authors.forename: Sanne
authors.initials: S
authors.lastname: Lysbet de Haas
authors.affiliation: Department of Medical Oncology, MD Anderson Cancer Center, Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Gonzalez-Martin
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D000069287:Capecitabine / Q000008:administration & dosage; D058534:Class I Phosphatidylinositol 3-Kinases; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D000077341:Lapatinib; D008453:Maytansine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011799:Quinazolines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D000068878:Trastuzumab
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D000069287:Capecitabine; D058534:Class I Phosphatidylinositol 3-Kinases; D000077341:Lapatinib; D008453:Maytansine; D019869:Phosphatidylinositol 3-Kinases; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C484760:PIK3CA protein, human; C508053:ERBB2 protein, human
keywords: HER2; T-DM1; ado-trastuzumab emtansine; biomarkers; metastatic breast cancer