Metabolic activity on [18f]-fluorodeoxyglucose-positron emission tomography/computed tomography and glucose transporter-1 expression might predict clinical outcomes in patients with limited disease small-cell lung cancer who receive concurrent chemoradiation.

BACKGROUND: Limited disease small-cell lung cancer responds well to concurrent chemoradiation therapy (CCRT), but shows high relapse rate and short RFS. We aimed to evaluate tumor metabolic activities measured using FDG-PET as a prognostic factor and analyze its relationships with markers of tumor biologic behavior. PATIENTS AND METHODS: Forty-one LD-SCLC patients receiving 4 cycles of EP (etoposide 120 mg/m(2), days 1-3; cisplatin 60 mg/m(2), day 1), 2 cycles of EP (etoposide 130 mg/m(2), days 1-3; cisplatin 30 mg/m(2), day 1)-CCRT were enrolled. Maximum standardized uptake value (SUV; SUVmax) of primary tumor was revised with SUV of liver (SUVlivermax). Differences between pre-, posttreatment average SUV uptake of primary tumor, and intrathoracic lymph nodes were presented as ΔSUVliveravg. Thirty-one tumor biopsy specimens were immunostained for GLUT-1, Bcl-2, and HIF-1α. RESULTS: The median overall survival (OS), and RFS were 13.7 and 10.4 months, respectively. In multivariate analysis, pretreatment lactate dehydrogenase (LDH) and ΔSUVliveravg correlated with RFS (hazard ratio [HR], 2.8, P = .043; HR, 0.3, P = .004). Sex, LDH, objective tumor metabolic response, and SUVlivermax correlated with OS (HR, 12.1, P = .006; HR, 3.7, P = .037; HR, 10.1, P = .008; and HR, 0.2, P = .014, respectively). High GLUT-1 positivity (> 75%), and LDH level (> 400 U/L) correlated with better objective response rate (P = .012) and HIF-1α immunoreactivity score (P = .029). CONCLUSION: ΔSUVliveravg and GLUT-1 expression might predict RFS and ORR in patients with LD-SCLC treated with definitive CCRT.

Effects of the EGFR/HER2 kinase inhibitor GW572016 on EGFR- and HER2-overexpressing breast cancer cell line proliferation, radiosensitization, and resistance.

PURPOSE: Two members of the epidermal growth factor receptor family, EGFR and HER2, have been implicated in radioresistance in breast cancer and other malignancies. To gauge the potential clinical utility of targeting both EGFR and HER2 to control growth and radiosensitize human breast cancers, we examined the effect of a dual EGFR/HER2 inhibitor, GW572016, on the proliferation and radiation response of either EGFR- or HER2-overexpressing human breast cancer cell lines. METHODS AND MATERIALS: Primary human breast cancer cell lines that endogenously overexpress EGFR or HER2 and luminal mammary epithelial H16N2 cells stably transfected with HER2 were evaluated for the effect of GW572016 on inhibition of ligand-induced or constitutive receptor phosphorylation, proliferation, radiosensitization, and inhibition of downstream signaling. RESULTS: GW572016 inhibited constitutive and/or ligand-induced EGFR or HER2 tyrosine phosphorylation of all five cell lines, which correlated with the antiproliferative response in all but one cell line. GW572016 radiosensitized EGFR-overexpressing cell lines, but HER2-overexpressing cells were unable to form colonies after brief exposure to GW572016 even in the absence of radiation, and thus could not be evaluated for radiosensitization. One cell line was resistant to the antiproliferative and radiosensitizing effects of GW572016, despite receptor inhibition. Exploration of potential mechanisms of resistance in SUM185 cells revealed failure of GW572016 to inhibit downstream ERK and Akt activation, despite inhibition of HER2 phosphorylation. In contrast, sensitive HER2-overexpressing cell lines demonstrated inhibition of both ERK and Akt phosphorylation. CONCLUSION: GW572016 potently inhibits receptor phosphorylation in either EGFR- or HER2-overexpressing cell lines and has both antiproliferative and radiosensitizing effects. Resistance to GW572016 was not due to a lack of receptor inhibition, but rather with a lack of inhibition of ERK and Akt, suggesting that measurement of inhibition of crucial signaling pathways may better predict response than inhibition of receptor phosphorylation. The SUM185 cell line provides a valuable model for studying mechanisms of resistance of EGFR/HER2 inhibitor therapy.