We found a significant association between EGFR mutation and risk of brain metastases at the time of diagnosis and follow-up after curative resection for pulmonary adenocarcinoma. This result indicates the distinct clinical features of EGFR-mutated tumors in terms of brain metastases.

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The development of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) seems almost inevitable, even in patients with lung cancer that initially respond well to EGFR-TKIs. MET amplification was recently found to be a mechanism of escape from the anticancer effect of EGFR inhibitors. In the present study, we investigated the means whereby MET affects sensitivity to EGFR-TKIs in PC-9 cells. Gefitinib-or erlotinib-resistant sublines were established by exposing the parental PC-9 cell line to chronic, repeated treatments with these drugs. These resistant sublines showed more than 100-fold more resistance to gefitinib and erlotinib and acquired cross-resistance to other EGFR-TKIs. The T790M EGFR mutation was found by pyrosequencing, and this seemed to be the cause of drug resistance. Resistant cells also showed MET activation, although gene amplification was not detected. Furthermore, the induction of MET activity was not found to be associated with sensitivity to EGFR-TKIs. Interestingly, increased passage number without exposure to gefitinib or erlotinib caused MET activation, but this did not affect sensitivity to EGFR-TKIs. In addition, hepatocyte growth factor was found to block the ability of EGFR-TKIs to inhibit MET activation. However, sustained MET activation by hepatocyte growth factor did not modulate the cellular effects of gefitinib or erlotinib. Rather, activated MET enhanced migration and invasion abilities. Summarizing, MET activation may be acquired during cancer cell proliferation and enhances migratory and invasive abilities without affecting cellular sensitivity to EGFR-TKIs. Accordingly, the present study suggests that MET activation caused by factors other than MET gene amplification is not a suitable surrogate marker of resistance to EGFR-TKIs.

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Purpose: To evaluate response and survival according to 18 F-fluoro-2-deoxy-glucose uptake at presentation in patients with gefitinib-treated non^small cell lung cancer. Experimental Design: We retrospectively analyzed 84 positron emission tomography/computed tomography findings. Patient characteristics, response rates, and survivals were evaluated according to the maximum standardized uptake value (SUV) of primary tumor. The cutoff value of SUVs was obtained from receiver operating characteristic analysis. Results: The response rate (RR) was higher for never-smokers (41%) than ever-smokers (9%; P = 0.001). Patients with adenocarcinoma showed higher RR than those with other tumor histopathology (35% versus 9%; P = 0.009). The SUV was significantly lower in patients who were never-smokers (P = 0.005), patients with adenocarcinoma (P < 0.001), and female patients (P = 0.017). Patients with a low SUV showed higher RR compared with those with a high SUV (53% versus 18%; P = 0.003). Prolonged progression-free survival was observed in patients with low SUVs compared with those with high SUVs (median, 33.1 weeks versus 8.6 weeks; P = 0.003). While controlling for performance status, smoking history, and pathology, the high SUV conferred unfavorable outcome (hazard ratio, 2.3; P = 0.012). In terms of overall survival, a low SUV was associated with favorable outcome in univariate analysis (P = 0.011). Patients with a low SUV showed prolonged survival in multivariate analysis (P = 0.043). Conclusions: These results suggest that low SUVs at presentation can predict favorable response and survival in gefitinib-treated non^small cell lung cancer patients.

Primary gastric choriocarcinoma (PGC) is a rare tumor, and its pathogenesis is still uncertain. Most PGCs have been reported to possess an adenocarcinoma component of variable extent, and pure PGC is especially rare. The diagnosis of PGC is confirmed by exhibition of choriocarcinomatous components on biopsy and exhibition of β-hCG positive cell on immunohistochemical stain and elevation of the serum β-hCG. Moreover it must be confirmed that no other site including gonads displays any tumor masses. The PGC tends to be more invasive and to have early metastasis. The median survival is known to be less than several months. We report two cases. The first case was a 62 year-old man who was diagnosed as advanced gastric cancer (AGC) by endoscopic biopsy with hepatic metasasis and received palliative chemotherapy with modified FOLFOX regimen and Genexol plus cisplatin regimen. He underwent subtotal gastrectomy due to perforation of the stomach during chemotherapy. O n post-operative biopsy, H e was re-diagnosed as PGC and received another palliative chemotherapy modified FOLFIRI, BEP, EMACO, VIP. However, multiple liver metastases were aggravated, and also serum AFP level increased. Ultimately, the paient died 10 months after initial diagnosis. Another case was a 45 year-old man. On endoscopic biopsy, he was diagnosed as AGC of adenocarcinoma. On Chest and Abdomen CT, multiple pulmonary and hepatic metastasis were also confirmed. On liver biopsy, He was diagnosed as PGC. The immunohistochemical stains were performed and the results were cytokeratin positive, EMA negative and β-hCG weak positive. The serum β-hCG level was highly elevated. BEP, VIP and EMA/CO combination therapy were administered, but he died at 12th months after the initial diagnosis.

Background: Our previous report showed an association between age and outcome in gefitinib-treated female patients with non-small cell lung cancer (NSCLC). Only limited numbers of molecular studies have been performed with respect to the presence of epidermal growth factor receptor (EGFR) mutations according to age. This retrospective study was performed to evaluate a possible association between age at the time diagnosis and the presence of EGFR mutations in female patients with NSCLC. Methods: Tumor specimens were collected retrospectively from paraffin blocks of 98 female patients with primary NSCLC who underwent surgical resection between January 1992 and December 2002 at the Korea Cancer Center Hospital. To detect EGFR mutations, a Scorpion Amplified Refractory Mutation System was used. Results: Most of the study population comprised never smokers (84%) and patients with adenocarcinoma (82%). The age at the time of diagnosis ranged from 34 to 74 years (median, 57 years). When the median age was used as a cutoff value, older patients were more likely to have EGFR mutations than younger patients (70 versus 39%; p ϭ 0.004). After controlling for the effects of histology, smoking history, and stage, age remained a significant predictor for EGFR mutations (odds ratio, 4.03; 95% confidence interval, 1.61-10.09; p ϭ 0.003). Conclusions: Our data suggest that age at the time of diagnosis in female patients with NSCLC may be associated with the frequency of EGFR mutations, a strong indicator for favorable outcomes.

A large portion of family caregivers may not know the patients' exact status. This study also suggests that the family caregivers' attitudes may differ from patients' and may be associated with patients' QOL.