title: Lapatinib activity in premalignant lesions and HER-2-positive cancer of the breast in a randomized, placebo-controlled presurgical trial.
abstract: Dual epidermal growth factor receptor (EGFR) and HER2 targeting with the tyrosine kinase inhibitor lapatinib is approved for treating advanced HER2-positive breast cancer and can prevent estrogen receptor (ER)-negative mammary tumors in HER2 transgenic mouse models. Ki-67 labeling index (LI) has prognostic and predictive value and can be used to screen drugs' therapeutic and preventive potential in a clinical model of short-term presurgical therapy of breast cancer. We conducted a randomized, placebo-controlled trial of lapatinib (1500 mg/d) administered orally for three weeks between biopsy and surgery in 60 women with HER-2-positive breast cancer to assess lapatinib biomarker (including the primary endpoint, Ki-67 LI) and clinical activity in invasive breast cancer, adjacent ductal intraepithelial neoplasia (DIN, which comprises ductal carcinoma in situ and atypical ductal hyperplasia), and distant ductal hyperplasia without atypia (DH). Ki-67 LI increased progressively in association with disease stage, increasing in the placebo arm, for example, by medians of 3% in DH to 20% in DIN to 30% in invasive cancer. Ki-67 LI in cancer tissue decreased by a mean (±SD) of 9.3% (±34.2) in the lapatinib arm and increased by 15.1% (±30.9) in the placebo arm (P = 0.008). Compared with placebo, lapatinib reduced Ki-67 significantly more in ER-negative tumors (by 34.8%; P = 0.01) but not significantly more in ER-positive tumors (by 12.3%; P = 0.2) and reduced Ki-67 more (nonsignificantly) in cytosol PTEN-overexpressing tumors (P = 0.057). The prevalence of DIN in post-treatment surgical specimens of both arms was similar (70%-76%), with a median Ki-67 of 15% (range, 5%-35%) on lapatinib versus 20% (5%-60%) on placebo (P = 0.067). The prevalence of DH also was similar in both arms (>90%), with a median Ki-67 of 1% (1%-7%) on lapatinib versus 3% (1%-5%) on placebo (P = 0.006). Other results of lapatinib versus placebo, respectively, were as follows: Median tumor diameter at surgery of 18 mm (11 mm-57 mm) versus 24 mm (10 mm-37 mm; P = 0.009); partial response of 13.6% versus 3.7%, stable disease of 59.1% versus 40.7%, and progression of 27.3% versus 55.6% (P-trend = 0.035). In conclusion, short-term lapatinib decreased cell proliferation in DIN, DH, and invasive HER-2-positive (especially ER-negative) breast cancer, thus providing the rationale for further clinical development of lapatinib for breast cancer prevention in high-risk patients, including those with HER-2-positive DIN.
authors.affiliation: Division of Cancer Prevention and Genetics, European Institute of Oncology, Milan, Italy. andrea.decensi@galliera.it
authors.forename: Andrea
authors.initials: A
authors.lastname: Decensi
authors.forename: Matteo
authors.initials: M
authors.lastname: Puntoni
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Pruneri
authors.forename: Aliana
authors.initials: A
authors.lastname: Guerrieri-Gonzaga
authors.forename: Matteo
authors.initials: M
authors.lastname: Lazzeroni
authors.forename: Davide
authors.initials: D
authors.lastname: Serrano
authors.forename: Debora
authors.initials: D
authors.lastname: Macis
authors.forename: Harriet
authors.initials: H
authors.lastname: Johansson
authors.forename: Oriana
authors.initials: O
authors.lastname: Pala
authors.forename: Alberto
authors.initials: A
authors.lastname: Luini
authors.forename: Paolo
authors.initials: P
authors.lastname: Veronesi
authors.forename: Viviana
authors.initials: V
authors.lastname: Galimberti
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Dotti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Viale
authors.forename: Bernardo
authors.initials: B
authors.lastname: Bonanni
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy*; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D006965:Hyperplasia / Q000473:pathology; D007150:Immunohistochemistry / Q000379:methods; D017404:In Situ Hybridization, Fluorescence; D019394:Ki-67 Antigen / Q000096:biosynthesis; D000077341:Lapatinib; D008875:Middle Aged; D010919:Placebos; D015995:Prevalence; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D019394:Ki-67 Antigen; D000077341:Lapatinib; D010919:Placebos; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases