ABSTRACT
BACKGROUND: To investigate whether copy number gain of MET or hepatocyte growth factor (HGF) affect trastuzumab sensitivity in HER2-positive metastatic breast cancer (MBC). METHODS: We analysed 130 HER2-positive MBC treated with trastuzumab-based therapy. MET and HGF gene copy numbers (GCN) were assessed by fluorescence in situ hybridisation (FISH) in primary breast cancer samples. Receiver operating characteristic analysis was applied to find the best cutoff point for both MET and HGF GCN. RESULTS: MET FISH-positive cases (N=36, mean î¶3.72) had a significantly higher trastuzumab failure rate (44.4% vs 16.0%; P=0.001) and a significantly shorter time to progression (5.7 vs 9.9 months; HR 1.74; P=0.006) than MET FISH-negative cases (N=94, mean <3.72). Hepatocyte growth factor GCN was evaluated in 84 cases (64.6%). Receiver operating characteristic analysis identified 33 HGF FISH-positive patients (mean HGF GCN î¶3.01). HGF FISH-positive status was significantly associated with higher risk of failure (30.3% vs 7.8%; P=0.007) as compared with HGF FISH-negative cases (N=51, mean <3.01). MET and HGF FISH-positive status was highly correlated (P<0.001) and combination of both biomarkers did not increase predictive value of either considered separately. CONCLUSION: High GCNs of MET and HGF associate with an increased risk of trastuzumab-based therapy failure in HER2-positive MBC.
Subject(s)
Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Gene Dosage , Hepatocyte Growth Factor/genetics , Proto-Oncogene Proteins c-met/genetics , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Agents/administration & dosage , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Drug Resistance, Neoplasm , Female , Hepatocyte Growth Factor/metabolism , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Middle Aged , Prognosis , Proto-Oncogene Proteins c-met/metabolism , Receptor, ErbB-2/biosynthesis , Receptor, ErbB-2/metabolism , Retrospective Studies , TrastuzumabABSTRACT
PURPOSE OF INVESTIGATION: The purpose of the present study was to identify the clinical and pathologic features of ovarian cancers in patients who have a family history of breast or ovarian cancer but who do not have a mutation in the BRCA1 or BRCA2 gene. METHODS: 303 patients with ovarian cancer were reviewed for clinical features and for cancer family histories. After the exclusion of 51 patients known to carry BRCA1 or BRCA2 mutations, 24 patients with familial cancer were compared with 228 patients with non-familial cancer. RESULTS: Patients with familial cancer were more likely to have grade 2 tumors, Stage II disease and to present between ages 51 and 60 than were non-familial controls. Ten of 24 patients in the familial group presented between ages 51 and 60 with a grade 2 tumor compared to 3.0 expected (p = 0.001). CONCLUSIONS: Families of women who present with grade 2 ovarian cancer between the ages of 51 and 60 may have an unidentified ovarian cancer susceptibility gene.
