title: Double-blind, placebo-controlled, multicenter, randomized, phase IIb neoadjuvant study of letrozole-lapatinib in postmenopausal hormone receptor-positive, human epidermal growth factor receptor 2-negative, operable breast cancer.
abstract: OBJECTIVE
  This is a randomized, double-blind, placebo-controlled study aimed to evaluate the clinical and biologic effects of letrozole plus lapatinib or placebo as neoadjuvant therapy in hormone receptor (HR) -positive/human epidermal growth factor receptor 2 (HER2) -negative operable breast cancer.
  
  
  METHODS
  Ninety-two postmenopausal women with stage II to IIIA primary breast cancer were randomly assigned to preoperative therapy consisting of 6 months of letrozole 2.5 mg orally daily plus lapatinib 1,500 mg orally daily or placebo. Surgery was performed within 2 weeks from the last study medication. Clinical response was assessed by ultrasonography. Pre- and post-treatment samples were evaluated for selected biomarkers. Fresh-frozen tissue samples were collected for genomic analyses.
  
  
  RESULTS
  Numerically similar clinical response rates (partial + complete response) were observed (70% for letrozole-lapatinib and 63% for letrozole-placebo). Toxicities were generally mild and manageable. A significant decrease in Ki-67 and pAKT expression from baseline to surgery was observed in both arms. Overall, 34 patients (37%) had a mutation in PIK3CA exon 9 or 20. In the letrozole-lapatinib arm, the probability of achieving a clinical response was significantly higher in the presence of PIK3CA mutation (objective response rate, 93% v 63% in PIK3CA wild type; P = .040).
  
  
  CONCLUSIONS
  The combination of letrozole-lapatinib in early breast cancer was feasible, with expected and manageable toxicities. In unselected estrogen receptor-positive/HER2-negative patients, letrozole-lapatinib and letrozole-placebo resulted in a similar overall clinical response rate and similar effect on Ki-67 and pAKT. Our secondary end point findings of a significant correlation between PIK3CA mutation and response to letrozole-lapatinib in HR-positive/HER2-negative early breast cancer must now be independently confirmed.
authors.affiliation: Valentina Guarneri and PierFranco Conte, Istituto Oncologico Veneto Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), University of Padova, Padova; Daniele Giulio Generali and Alberto Bottini, U.O. Multidisciplinare di Patologia Mammaria, Azienda Ospedaliera Istituti Ospitalieri di Cremona, Cremona; Antonio Frassoldati, University Hospital, Ferrara; Fabrizio Artioli and Katia Cagossi, Ramazzini Hospital, Carpi; Corrado Boni and Giancarlo Bisagni, Azienda Ospedaliera Arcispedale S. Maria Nuova, IRCCS, Reggio Emilia; Luigi Cavanna, Hospital of Piacenza, Piacenza; Enrico Tagliafico, Enrica Roncaglia, and Simona Nuzzo, Center for Genome Research, University of Modena and Reggio Emilia; Antonino Maiorana, Federico Piacentini, Guido Ficarra, and Stefania Bettelli, Modena University Hospital, Modena, Italy; Ramona Swaby and Catherine Ellis, GlaxoSmithKline, Upper Providence, PA; and Clare Holford, GlaxoSmithKline, Stockley Park, United Kingdom.
authors.forename: Valentina
authors.initials: V
authors.lastname: Guarneri
authors.forename: Daniele Giulio
authors.initials: DG
authors.lastname: Generali
authors.forename: Antonio
authors.initials: A
authors.lastname: Frassoldati
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Artioli
authors.forename: Corrado
authors.initials: C
authors.lastname: Boni
authors.forename: Luigi
authors.initials: L
authors.lastname: Cavanna
authors.forename: Enrico
authors.initials: E
authors.lastname: Tagliafico
authors.forename: Antonino
authors.initials: A
authors.lastname: Maiorana
authors.forename: Alberto
authors.initials: A
authors.lastname: Bottini
authors.forename: Katia
authors.initials: K
authors.lastname: Cagossi
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Bisagni
authors.forename: Federico
authors.initials: F
authors.lastname: Piacentini
authors.forename: Guido
authors.initials: G
authors.lastname: Ficarra
authors.forename: Stefania
authors.initials: S
authors.lastname: Bettelli
authors.forename: Enrica
authors.initials: E
authors.lastname: Roncaglia
authors.forename: Simona
authors.initials: S
authors.lastname: Nuzzo
authors.forename: Ramona
authors.initials: R
authors.lastname: Swaby
authors.forename: Catherine
authors.initials: C
authors.lastname: Ellis
authors.forename: Clare
authors.initials: C
authors.lastname: Holford
authors.forename: Pierfranco
authors.initials: P
authors.lastname: Conte
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000601:surgery; D058534:Class I Phosphatidylinositol 3-Kinases; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D000077341:Lapatinib; D000077289:Letrozole; D008875:Middle Aged; D009154:Mutation; D020360:Neoadjuvant Therapy; D009570:Nitriles / Q000008:administration & dosage; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D010766:Phosphorylation; D017698:Postmenopause; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D014230:Triazoles / Q000008:administration & dosage
chemical_list: D014408:Biomarkers, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D019394:Ki-67 Antigen; D000077341:Lapatinib; D000077289:Letrozole; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D014230:Triazoles; C484760:PIK3CA protein, human