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1.
Invest New Drugs ; 30(2): 695-701, 2012 Apr.
Article in English | MEDLINE | ID: mdl-20857170

ABSTRACT

BACKGROUND: To explore the activity of lapatinib with a novel trial design focused on the drug target rather than on histology. METHODS: Patients with HER2 amplified gastro-esophageal, bladder, ovarian, or uterine tumors were enrolled into a double-blinded randomized discontinuation study of lapatinib 1,500 mg PO daily. The planned sample size was 250 patients with HER2 amplified tumors, with the goal of randomizing 100 patients with stable disease (SD) at week 12 to either lapatinib or placebo. Patients responding after 12 weeks continued on lapatinib; those who progressed were discontinued from study. The primary objectives were response rate after 12 weeks and the percentage of patients who remained progression free 12 weeks after randomization to placebo versus lapatinib. Secondary objectives were duration of response and determination of the incidence of HER2 amplification in multiple tumor types. RESULTS: A total of 141 patients were screened and 32 patients with HER2 amplified tumors were enrolled. At week 12, 1 (3%) patient had a complete response, 9 (28%) had stable disease, 20 (63%) had progressive disease, and 2 (6%) were unknown. Only 7 patients with SD underwent randomization. The low response rate coupled with slow screening and enrollment led to early study closure. CONCLUSIONS: Basing trial eligibility on the presence of a genetic target, versus histologic classification, is challenging. While HER2 amplifications appear to be prevalent in select non-breast tumors, lapatinib monotherapy is associated with modest activity. The target-specific histology-independent randomized discontinuation design still merits consideration for targets clearly implicated in "oncogene addiction".


Subject(s)
Antineoplastic Agents/administration & dosage , Biomarkers, Tumor/antagonists & inhibitors , Gene Amplification , Molecular Targeted Therapy , Neoplasms/drug therapy , Protein Kinase Inhibitors/administration & dosage , Quinazolines/administration & dosage , Receptor, ErbB-2/antagonists & inhibitors , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Disease-Free Survival , Double-Blind Method , Drug Administration Schedule , Female , Humans , In Situ Hybridization, Fluorescence , Lapatinib , Male , Middle Aged , Neoplasms/enzymology , Neoplasms/genetics , Neoplasms/pathology , Patient Selection , Precision Medicine , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , Time Factors , Treatment Outcome , United States
2.
Clin Cancer Res ; 16(6): 1938-49, 2010 Mar 15.
Article in English | MEDLINE | ID: mdl-20215545

ABSTRACT

PURPOSE: This randomized phase II study was initially designed to test the activity of two dose schedules of lapatinib (GW572016H), an oral, reversible, dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human EGFR-2 (HER2/neu; HER2), in chemotherapy-naive patients with non-small cell lung cancer (NSCLC); it was later amended to target patients with bronchioloalveolar carcinoma or no smoking history. EXPERIMENTAL DESIGN: Patients with good performance status and recurrent or metastatic NSCLC were randomized to lapatinib (orally, 1,500 mg once daily or 500 mg twice daily) until progression or intolerance. Patients could have had a maximum of one prior systemic therapy (chemotherapy or biological therapy) for NSCLC. Safety and activity were assessed every 4 and 8 weeks, respectively. Tumors were analyzed for EGFR and HER2 mutations and/or amplifications. RESULTS: Of 75 patients in the nontargeted population, 1 (1.3%) had partial response and 16 (21%) had stable disease of >or=24 weeks. No complete or partial responses were observed in 56 patients in the targeted population; 14 (25%) had stable disease of >or=24 weeks. No responses were seen in three patients with EGFR mutations and five with EGFR gene amplification. No mutations in HER2 were found. One of two patients with HER2 amplification had a 51% decrease in tumor size; however, this response was unconfirmed. The most common adverse events were grade 1 or 2 diarrhea, rash, fatigue, nausea, and anorexia. Adverse events were similar across dosing regimens. CONCLUSIONS: Lapatinib was well tolerated, with no notable difference in toxicity between treatment groups. Lapatinib monotherapy did not induce a significant number of tumor regressions in NSCLC. Further studies may be warranted to determine whether lapatinib is active in combination with other agents in the treatment of NSCLC.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Neoplasm Recurrence, Local/drug therapy , Quinazolines/therapeutic use , Adenocarcinoma/drug therapy , Adenocarcinoma/pathology , Adenocarcinoma, Bronchiolo-Alveolar/drug therapy , Adenocarcinoma, Bronchiolo-Alveolar/pathology , Adult , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/pathology , Drug Resistance, Neoplasm , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , Female , Humans , Lapatinib , Lung Neoplasms/pathology , Middle Aged , Neoplasm Metastasis , Neoplasm Recurrence, Local/pathology , Receptor, ErbB-2/antagonists & inhibitors , Receptor, ErbB-2/metabolism , Salvage Therapy , Survival Rate , Treatment Outcome
3.
J Clin Oncol ; 26(7): 1066-72, 2008 Mar 01.
Article in English | MEDLINE | ID: mdl-18212337

ABSTRACT

PURPOSE: Inflammatory breast cancer (IBC) is one of the most aggressive forms of breast cancer. Lapatinib, an oral reversible inhibitor of epidermal growth factor receptor (EGFR) and human EGFR 2 (HER-2), demonstrated clinical activity in four of five IBC patients in phase I trials. We conducted a phase II trial to confirm the sensitivity of IBC to lapatinib, to determine whether response is HER-2 or EGFR dependent, and to elucidate a molecular signature predictive of lapatinib sensitivity. PATIENTS AND METHODS: Our open-label multicenter phase II trial (EGF103009) assessed clinical activity and safety of lapatinib monotherapy in patients with recurrent or anthracycline-refractory IBC. Patients were assigned to cohorts A (HER-2-overexpressing [HER-2+]) or B(HER-2-/EGFR+) and fresh pretreatment tumor biopsies were collected. RESULTS: Forty-five patients (30 in cohort A; 15 in cohort B) received lapatinib 1,500 mg once daily continuously. Clinical presentation and biomarker analyses demonstrated a tumor molecular signature consistent with IBC. Lapatinib was generally well tolerated, with primarily grade 1/2 skin and GI toxicities. Fifteen patients (50%) in cohort A had clinical responses to lapatinib in skin and/or measurable disease (according to Response Evaluation Criteria in Solid Tumors) compared with one patient in cohort B. Within cohort A, phosphorylated (p) HER-3 and lack of p53 expression predicted for response to lapatinib (P < .05). Tumors coexpressing pHER-2 and pHER-3 were more likely to respond to lapatinib (nine of 10 v four of 14; P = .0045). Prior trastuzumab therapy and loss of phosphate and tensin homolog 10 (PTEN) did not preclude response to lapatinib. CONCLUSION: Lapatinib is well tolerated with clinical activity in heavily pretreated HER-2+, but not EGFR+/HER-2-, IBC. In this study, coexpression of pHER-2 and pHER-3 in tumors seems to predict for a favorable response to lapatinib. These findings warrant further investigation of lapatinib monotherapy or combination therapy in HER-2+ IBC.


Subject(s)
Antineoplastic Agents/therapeutic use , Biomarkers, Tumor/metabolism , Breast Neoplasms/drug therapy , Quinazolines/therapeutic use , Receptor, ErbB-2/antagonists & inhibitors , Adenocarcinoma/drug therapy , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Adult , Aged , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cohort Studies , Female , Humans , Immunoenzyme Techniques , Inflammation , Lapatinib , Lymphatic Metastasis/diagnosis , Maximum Tolerated Dose , Middle Aged , Neoplasm Invasiveness , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/metabolism , Receptor, ErbB-2/metabolism , Receptor, ErbB-3/metabolism , Sensitivity and Specificity , Skin Neoplasms/diagnosis
4.
Cancer Res ; 67(8): 3594-600, 2007 Apr 15.
Article in English | MEDLINE | ID: mdl-17440070

ABSTRACT

Tumor-derived cell lines are used as in vitro cancer models, but their ability to accurately reflect the phenotype and genotype of the parental histology remains questionable, given the prevalence of documented cell line-specific cytogenetic changes. We have addressed the issue of whether copy number alterations seen in tumor-derived cell lines reflect those observed in studies of fresh tissue by carrying out a meta-analysis of array-based comparative genomic hybridization data that considers both copy number alteration frequencies and the occurrence of cancer gene amplifications and homozygous deletions. Pairwise correlation comparisons between the data sets of seven diagnosis-specific matched tumor and cell line groups indicate that the trends in aberration frequencies are highly correlated between tumors and cell line sets of matched cancer histology relative to unmatched pairings. Despite their similarities, cell lines showed uniformly higher locus-specific alteration frequencies (P = 0.004) and several recurring cell line-specific alterations emerged. These include the previously documented losses of 13q and 9p and gains of 20q, as well as additional undescribed cell line-specific gains of 5p, 7p, and 17q and losses of 18q and 4q. These results indicate that, on average, cell lines preserve in vitro the genetic aberrations that are unique to the parent histology from which they were derived while acquiring additional locus-specific alterations. These data may enable a more predictive understanding of individual cell lines as in vitro models of cancer biology and therapy.


Subject(s)
Cell Line, Tumor , Neoplasms/genetics , Nucleic Acid Hybridization/methods , Chromosome Aberrations , Cluster Analysis , Humans
5.
Breast Cancer Res ; 7(6): R1186-98, 2005.
Article in English | MEDLINE | ID: mdl-16457699

ABSTRACT

INTRODUCTION: Genomic aberrations in the form of subchromosomal DNA copy number changes are a hallmark of epithelial cancers, including breast cancer. The goal of the present study was to analyze such aberrations in breast cancer at high resolution. METHODS: We employed high-resolution array comparative genomic hybridization with 4,134 bacterial artificial chromosomes that cover the genome at 0.9 megabase resolution to analyze 47 primary breast tumors and 18 breast cancer cell lines. RESULTS: Common amplicons included 8q24.3 (amplified in 79% of tumors, with 5/47 exhibiting high level amplification), 1q32.1 and 16p13.3 (amplified in 66% and 57% of tumors, respectively). Moreover, we found several positive correlations between specific amplicons from different chromosomes, suggesting the existence of cooperating genetic loci. Queried by gene, the most frequently amplified kinase was PTK2 (79% of tumors), whereas the most frequently lost kinase was PTK2B (hemizygous loss in 34% of tumors). Amplification of ERBB2 as measured by comparative genomic hybridization (CGH) correlated closely with ERBB2 DNA and RNA levels measured by quantitative PCR as well as with ERBB2 protein levels. The overall frequency of recurrent losses was lower, with no region lost in more than 50% of tumors; the most frequently lost tumor suppressor gene was RB1 (hemizygous loss in 26% of tumors). Finally, we find that specific copy number changes in cell lines closely mimicked those in primary tumors, with an overall Pearson correlation coefficient of 0.843 for gains and 0.734 for losses. CONCLUSION: High resolution CGH analysis of breast cancer reveals several regions where DNA copy number is commonly gained or lost, that non-random correlations between specific amplicons exist, and that specific genetic alterations are maintained in breast cancer cell lines despite repeat passage in tissue culture. These observations suggest that genes within these regions are critical to the malignant phenotype and may thus serve as future therapeutic targets.


Subject(s)
Breast Neoplasms/genetics , DNA, Neoplasm/genetics , Gene Dosage , Cell Line, Tumor , Chromosomes, Artificial, Bacterial/genetics , Female , Focal Adhesion Kinase 1/genetics , Gene Expression Profiling , Humans , Nucleic Acid Hybridization , Oligonucleotide Array Sequence Analysis , Phenotype , Receptor, ErbB-2/genetics , Sensitivity and Specificity
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