Schell, Michael J.

PURPOSE: The purpose of this study was to determine whether the presence of HER-2/neu gene amplification and/or overexpression in benign breast disease was associated with an increased risk of subsequent breast cancer. PATIENTS AND METHODS: We conducted a nested case-control study of a cohort of women who were diagnosed with benign breast disease at the Mayo Clinic and who were subsequently observed for the development of breast cancer. Patients who developed breast cancer formed the case group, and a matched sample from the remaining cohort served as controls. Benign tissue samples from 137 cases and 156 controls and malignant tissues from 99 cases provided DNA or tissue for evaluation of HER-2/neu amplification and protein overexpression. RESULTS: Among the controls, seven benign tissues (4.5%) demonstrated low-level HER-2/neu amplification, whereas 13 benign (9.5%) and 18 malignant (18%) tissue specimens from cases exhibited amplification. HER-2/neu amplification in benign breast biopsies was associated with an increased risk of breast cancer (odds ratio [OR] = 2.2; 95% confidence interval [CI], 0.9 to 5.8); this association approached statistical significance. The risks for breast cancer associated with benign breast histopathologic diagnoses were OR = 1.1 (95% CI, 0.6 to 1.9) for lesions exhibiting proliferation without atypia and OR = 1.5 (95% CI, 0.4 to 5.6) for the diagnosis of atypical ductal hyperplasia. For women having both HER-2/neu amplification and a proliferative histopathologic diagnosis (either typical or atypical), the risk of breast cancer was more than seven-fold (OR = 7.2; 95% CI, 0.9 to 60.8). Overexpression of the HER-2/neu protein product, defined as membrane staining in 10% or more of epithelial cells, was found in 30% of the breast tumors but was not detected in any of the benign breast tissues. Case patients who had HER-2/neu gene amplification in their malignant tumor were more likely to have had HER-2/neu amplification in their prior benign biopsy (P = .06, Fisher’s exact test). CONCLUSION: Women with benign breast biopsies demonstrating both HER-2/neu amplification and a proliferative histopathologic diagnosis may be at substantially increased risk for subsequent breast cancer.

Abstract Lessons Learned Targeted therapy options for SCLC patients are limited; no agent, thus far, has resulted in a strategy promising enough to progress to phase III trials. Linsitinib, a potent insulin growth factor-1-receptor tyrosine kinase inhibitor, may be one agent with activity against SCLC. Despite lack of a reliable predictive biomarker in this disease, which may have partly contributed to the negative outcome reported here, linsitinib, although safe, showed no clinical activity in unselected, relapsed SCLC patients. Background. Treatment of relapsed small-cell lung cancer (SCLC) remains suboptimal. Insulin growth factor-1 receptor (IGF-1R) signaling plays a role in growth, survival, and chemoresistance in SCLC. Linsitinib is a potent IGF-1R tyrosine kinase inhibitor that potentially may be active against SCLC. Methods. In this phase II study, 8 eligible patients were randomly assigned in a 1:2 ratio to topotecan (1.5 mg/m2 intravenously or 2.3 mg/m2 orally, daily for 5 days for 4 cycles) or linsitinib (150 mg orally twice daily until progression). The primary endpoint was progression-free survival. Patients with relapsed SCLC, platinum sensitive or resistant, performance status (PS) 0–2, and adequate hematologic, renal, and hepatic function were enrolled. Patients with diabetes, cirrhosis, and those taking insulinotropic agents were excluded. Crossover to linsitinib was allowed at progression. Results. Fifteen patients received topotecan (8 resistant, 3 with PS 2) and 29 received linsitinib (16 resistant, 5 with PS 2). Two partial responses were observed with topotecan. Only 4 of 15 patients with topotecan and 1 of 29 with linsitinib achieved stable disease. Median progression-free survival was 3.0 (95% confidence interval [CI], 1.5–3.6) and 1.2 (95% CI, 1.1–1.4) months for topotecan and linsitinib, respectively (p = .0001). Median survival was 5.3 (95% CI, 2.2–7.6) and 3.4 (95% CI, 1.8–5.6) months for topotecan and linsitinib, respectively (p = .71). Grade 3/4 adverse events (>5% incidence) included anemia, thrombocytopenia, neutropenia/leukopenia, diarrhea, fatigue, dehydration, and hypokalemia for topotecan; and thrombocytopenia, fatigue, and alanine aminotransferase/aspartate aminotransferase elevations for linsitinib. Conclusion. Linsitinib was safe but showed no clinical activity in unselected, relapsed SCLC patients.

Abstract Cigarette smoking is a major risk factor in the development of non–small cell lung cancer (NSCLC), which accounts for 80% of all lung cancers. Nicotine, the major addictive component of tobacco smoke, can induce proliferation, invasion, and epithelial-to-mesenchymal transition (EMT) in NSCLC cell lines and promote metastasis of NSCLC in mice. Here, we demonstrate that the scaffolding protein β-arrestin-1 is necessary for nicotine-mediated induction of mesenchymal genes vimentin and fibronectin as well as EMT regulators ZEB1 and ZEB2. Nicotine induced changes in cell morphology and ablate tight junctions consistent with EMT; β-arrestin-1, but not β-arrestin-2, was required for these changes. β-Arrestin-1 promoted the expression of the mesenchymal genes, as well as ZEB1 and ZEB2, through the mediation of the E2F1 transcription factor; this required Src kinase activity. Stimulation of multiple NSCLC cell lines with nicotine led to enhanced recruitment of β-arrestin-1 and E2F1 on vimentin, fibronectin, and ZEB1 and ZEB2 promoters. Furthermore, there was significantly more β-arrestin-1 and E2F1 associated with these promoters in human NSCLC tumors, and β-arrestin-1 levels correlated with vimentin and fibronectin levels in human NSCLC samples. A549-luciferase cells lacking β-arrestin-1 showed a significantly reduced capacity for tumor growth and metastasis when orthotopically implanted into the lungs of SCID-beige mice. Taken together, these studies reveal a novel role for β-arrestin-1 in the growth and metastasis of NSCLC. Cancer Res; 75(6); 1009–20. ©2015 AACR.