Jia-Juan Hsieh

Hand‐foot skin reaction in patients treated with sorafenib: a clinicopathological study of cutaneous manifestations due to multitargeted kinase inhibitor therapy

Background  Hand‐foot skin reaction is a distinctive cutaneous side‐effect of antineoplastic kinase inhibitor‐targeted therapy. Severe hand‐foot skin reaction requires postponement of treatment or dose reduction. Histopathological studies of skin toxicity associated with kinase inhibitors are currently unavailable.

Reversed mutation rates of KRAS and EGFR genes in adenocarcinoma of the lung in Taiwan and their implications.

In western countries, the Kirsten ras oncogene homolog gene (KRAS) mutation rate is high in patients with nonsmall cell lung cancer (NSCLC), especially in those with adenocarcinoma (30%‐50%), but the epidermal growth factor receptor gene (EGFR) mutation rate is very low (3%‐8%). In addition, KRAS mutations reportedly were associated with EGFR tyrosine kinase inhibitor (EGFR‐TKI) resistance. In Taiwan, high EGFR mutation rates associated with high EGFR‐TKI response rates in patients with NSCLC have been reported; however, KRAS mutation data are limited and have not been correlated with TKI response.

Adequacy and complications of computed tomography-guided core needle biopsy on non-small cell lung cancers for epidermal growth factor receptor mutations demonstration: 18-gauge or 20-gauge biopsy needle

INTRODUCTION To compare adequacy of tissue acquisition for EGFR DNA mutation analysis and the resulting complications in CT-guided lung biopsy cases with either 18-gauge or 20-gauge core biopsy needle. METHODS Forty-seven patients with advanced staged non-small cell lung cancers who were failure-treated by conventional chemotherapy were retrospectively reviewed. All had received CT-guided core needle lung biopsy for histology diagnosis and freshly frozen for EGFR mutation analysis before targeted therapy. We compared the complications resulting from these CT-guided lung biopsies and the specimen assessment using 18-gauge (32 patients) or 20-gauge (15 patients) biopsy needle via 17-gauge or 19-gauge coaxial needle. RESULTS With an overall pneumothorax rate of 12.8%, pneumothorax occurred in 12.5% and 13.3% of patients by 17-gauge and 19-gauge coaxial needles respectively. The overall rate of hemoptysis was 6.4%, with 6.3% by 18-gauge biopsy needle and 6.6% by 20-gauge biopsy needle. Large peritumoral hemorrhage revealed only in 2 cases of those completed with 18-gauge biopsy needles. 18-gauge biopsy needle obtained larger specimens with heavier weight (average 10.15mg vs 9mg) and higher DNA concentration (average 47.13ng/ul vs 35.92ng/ul) than 20-gauge biopsy needle. Otherwise, the range of optical density (1.67-2.09) was more constant in the specimens by 20-gauge biopsy needles. Mutation demonstration was achieved for all samples. CONCLUSION CT-guided core needle biopsy is a feasible technique in acquisition of fresh cancer tissues for EGFR gene mutation analysis. The specimen is adequate for gene demonstration either using 18-gauge or 20-gauge tru-cut biopsy needles via 17-gauge or 19-gauge coaxial needles.

Increased epidermal growth factor receptor (EGFR) gene copy number is strongly associated with EGFR mutations and adenocarcinoma in non-small cell lung cancers: A chromogenic in situ hybridization study of 182 patients

SUMMARY To evaluate the association of epidermal growth factor receptor (EGFR) gene copy number with EGFR and k-ras mutation status and tyrosine kinase inhibitor (TKI) sensitivity in non-small cell lung cancer (NSCLC), EGFR gene copy number of 182 NSCLC tumor specimens were analyzed by chromogenic in situ hybridization (CISH). EGFR and k-ras mutation analyses were also performed for, respectively, 176 and 157 of the 182 patients. Additionally, 36 patients in this study had received TKI monotherapy. The tumor was considered to be CISH positive if the gene copy number was >or=5 signals per nucleus in >or=40% of tumor cells. CISH-positive tumors were strongly associated with adenocarcinoma (56.8%) compared with squamous cell carcinoma (15.9%) (p<0.0001). The CISH-positive tumors were also strongly associated with EGFR mutations (78%) compared with wild type (20.2%) (p<0.0001). Only six tumors had k-ras mutations. None had EGFR mutation and only one was CISH positive. In the patients treated with TKI, EGFR mutation was strongly associated with TKI responsiveness (22/25 responders) (p<0.0001), but the CISH-positive tumors were only marginally significant (18/25 responders) (p=0.0665). Patients with EGFR mutations or CISH-positive tumors were all associated with longer median survival, although not statistically significant. Our results suggest Increased EGFR copy number was highly correlated with EGFR mutation in adenocarcinoma. Although it is less correlated with TKI responsiveness when compared with EGFR mutations, it still could be a good alternative molecular predictive marker for TKI responsiveness, since CISH can be done on paraffin section and is much quicker than DNA sequencing.

Computed Tomography-Guided Core-Needle Biopsy Specimens Demonstrate Epidermal Growth Factor Receptor Mutations in Patients with Non-Small-Cell Lung Cancer

Background: Target therapy with a new class of epidermal growth factor receptor (EGFR) inhibitors shows improved clinical response in EGFR gene-mutated lung cancers. Purpose: To evaluate the use of computed tomography (CT)-guided core-needle biopsy specimens for the assessment of EGFR gene mutation in non-small-cell lung cancer (NSCLC). Material and Methods: Seventeen (nine males, eight females) patients with advanced NSCLC were enrolled in this study. All patients underwent CT-guided core-needle biopsy of the lung tumor prior to treatment with the EGFR inhibitor gefitinib. There were no life-threatening complications of biopsy. The specimens were sent fresh-frozen for EGFR mutation analysis and histopathological study. Results: There were 12 (70.6%) EGFR gene mutants and five (29.4%) nonmutants. The objective response rate to gefitinib therapy was 73.3% (11 of 15 patients), with 91.7% (11 of 12 mutants) for the mutant group and 0% for the nonmutant group. Conclusion: CT-guided core-needle biopsy of advanced NSCLC enables the acquisition of sufficient tissue for EGFR gene mutation analysis.

Clinical Implications of High MET Gene Dosage in Non-Small Cell Lung Cancer Patients without Previous Tyrosine Kinase Inhibitor Treatment

Introduction: Recently, two studies revealed that MET amplification was associated with secondary epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer (NSCLC) patients. But it remains uncertain whether MET amplification could be related to primary TKI resistance in NSCLC because of limited data. Materials and Methods: MET gene dosage of the tumor tissues from 208 NSCLC patients was investigated by real time quantitative polymerase chain reaction and compared with molecular and clinical features, including EGFR mutations, KRAS mutations, EGFR gene copy numbers, and patient survivals. Three copies were used as the cutoff. Among them, 25 patients were also evaluable for EGFR TKI responsiveness. Results: The proportion of high MET gene dosage was 10.58% (22/208) with higher incidence in squamous cell carcinoma (11.86%) and smokers (16.18%), although the differences with adenocarcinoma and nonsmokers were nonsignificant. Coexisting EGFR mutations were identified, and the incidence (8.54%) was similar to wild type (12.0%). High MET gene dosage was significantly associated with higher tumor stage (stage I + II versus stage III + IV; p = 0.0254) and prior chemotherapy for stage III + IV adenocarcinoma patients (35.71% versus 7.41%; p = 0.0145) but not correlated with primary TKI resistance. Among the 155 surgically resectable patients (stage I to IIIA), high MET gene dosage was significantly associated with shorter median survival (21.0 months versus 47.1 months; p = 0.042) by univariate analysis. Conclusions: High MET gene dosage was not related to primary TKI resistance and the incidence was increased after chemotherapy, suggesting high MET gene dosage may also be related to chemotherapy resistance.

Bisphosphonate zoledronic acid enhances the inhibitory effects of gefitinib on EGFR-mutated non-small cell lung carcinoma cells

Patients with non-small cell lung carcinoma (NSCLC) bearing epidermal growth factor receptor (EGFR) gene mutations are good responders to gefitinib (Iressa), an EGFR tyrosine kinase inhibitor (EGFR-TKI), yet these patients may eventually develop acquired resistance to all available EGFR-TKIs. Nitrogen-containing bisphosphonates (N-BPs) are inhibitors of farnesyl diphosphate (FPP) synthase as well as chelators of divalent cations. This study was undertaken to examine if the N-BP zoledronic acid (zoledronate) possessing antitumor activity could enhance the antitumor effect of gefitinib on the HCC827 NSCLC cell line expressing mutated EGFR. Both gefitinib and zoledronate were cytotoxic to HCC827 cells when treated alone. Combined treatment with gefitinib (0.025 microM) that induced G0/G1 arrest and zoledronate (50 microM) that caused S/G2/M accumulation generated an additive induction in cell cytotoxicity, sub-G1 cell population, and apoptosis. Gefitinib suppressed EGF-activated phosphorylation of ERK1/2 and Akt, while zoledronate seemed to impose its pharmacological effect independent of ERK1/2 and Akt phosphorylation. The volumes of xenografted tumors in nude mice co-administered with gefitinib (1 mg/kg/day, five days a week, p.o.) and zoledronate (10 microg/kg, twice weekly, i.p.) were significantly smaller than those of tumors in mice treated with gefitinib alone at the last stage of a 6-week in vivo study. Severe peri-tumoral fat loss frequently observed in gefitinib-treated mice disappeared in mice receiving the combined treatment. Hence, combined treatment of gefitinib with zoledronate may form a basis to develop a more effective and less toxic therapy for NSCLC with EGFR gene mutations.

Epidermal growth factor receptor mutations in patients with oral cavity cancer in a betel nut chewing–prevalent area

Epidermal growth factor receptor (EGFR) mutations exist in patients with oral cavity squamous cell carcinoma (OSCC), but few data about mutation patterns with clinical outcomes were reported.

Response to Sorafenib in a Patient with Metastatic Xp11 Translocation Renal Cell Carcinoma

Sorafenib, a multikinase inhibitor of tumour-cell proliferation and angiogenesis, has been shown to have a role in the treatment of metastatic renal cell carcinoma (RCC). Xp11 translocation carcinoma is a rare subtype of RCC. We report an 18-year-old male patient with metastatic Xp11 translocation RCC who was responsive to sorafenib treatment. Six weeks after commencement of treatment with sorafenib, a CT scan of the patient showed increased central necrosis of the kidney mass and para-aortic lymph nodes as well as regression of the lung and pleural masses. The patient had a progression-free survival of 12 months, and overall survival of 15 months. The most severe adverse effects were grade 3 dermatitis and grade 3 anaemia. This case has demonstrated for the first time that sorafenib is active against Xp11 translocation RCC.

Cytoplasmic and nuclear parathyroid hormone-related proteins are opposing prognostic factors in patients with non-small-cell lung cancer who have undergone curative resection

OBJECTIVE Parathyroid hormone-like related protein was a prognostic factor for non-small-cell lung cancer, but the results were conflicting. The present study was to examine the role of cytoplasmic and nuclear parathyroid hormone-like related protein in patients with non-small-cell lung cancer who have undergone surgical therapy. METHODS The expression of parathyroid hormone-like related protein was examined by immunohistochemical staining in 56 patients with resectable non-small-cell lung cancer. The impact of parathyroid hormone-like related protein expression on cancer recurrence and survival was assessed in combination with clinicopathologic features. RESULTS Patients with a high expression of cytoplasmic parathyroid hormone-like related protein had a significantly unfavorable prognosis in both disease-free survival (median 16.7 vs. 58.0 months, P = 0.029) and overall survival (median 31.6 months vs. not reached, P = 0.046). In contrast, the patients with high expression of nuclear parathyroid hormone-like related protein had favorable disease-free survival (median 35.1 vs. 19.9 months, P = 0.069) and a significantly better overall survival (median not reached vs. 36.9 months, P = 0.033). There was no correlation between the expression of cytoplasmic and nuclear parathyroid hormone-like related protein (P = 1.00). Furthermore, multivariate analysis using a Cox regression model confirmed that high expression of cytoplasmic parathyroid hormone-like related protein (disease-free survival, hazard ratio: 1.973, P = 0.079; overall survival, hazard ratio: 2.461, P = 0.067) and nuclear parathyroid hormone-like related protein (disease-free survival, hazard ratio: 0.436, P = 0.029; overall survival, hazard ratio: 0.375, P = 0.018) were independently prognostic factors for disease-free survival and overall survival. CONCLUSION Cytoplasmic and nuclear parathyroid hormone-like related protein play opposing prognostic roles for the disease-free survival and overall survival of patients with early non-small-cell lung cancer who have undergone curative resection.