Protein Expression and Gene Amplification of Epidermal Growth Factor Receptor in Non-Small Cell Lung Cancer: Correlation with the Response to Gefitinib Therapy

BACKGROUND: Gefitinib is an EGFR tyrosine kinase inhibitor that has shown dramatic effectiveness in a subset of non-small cell lung cancer (NSCLC) patients. We evaluated the response rate to gefitinib, and the significance of the EGFR and HER2/neu status as predictive markers of the tumor response. METHODS: The EGFR and HER2/neu protein expressions, as determined by immunohistochemistry (IHC) and gene amplification via chromogenic in situ hybridization (CISH), were analyzed in biopsy specimens from 46 patients with advanced NSCLC. After their failure with the first-line treatment, all the patients had received gefitinib treatment. RESULTS: A partial response (PR) was achieved in 8 patients (17.4%). An EGFR overexpression was detected in 80.4% (37/46) of the tumors, and this was observed exclusively in patients with a PR (100% vs 75.3%, respectively; p=0.076). EGFR gene amplification was present in 47.8% of the tumors (22/46). HER2/neu was overexpressed in 13%(6/46) and it was amplified in 17% (7/46). The overall survival was prolonged in the female patients (p=0.007), and in patients with T1 and T2 disease (p=0.039), adenocarcinoma (p=0.010), a PR (p=0.022), an EGFR IHC+ status (p=0.033), an EGFR IHC+/CISH+ status (p=0.010), or an EGFR+/HER2/neu+ status (p=0.030). On multivariate analysis, gender, T disease and EGFR IHC/CISH remained the significant predictors of survival. CONCLUSIONS: Gefitinib showed a modest effect for the patients with chemotherapy-refractory advanced NSCLC. A combination of EGFR IHC and CISH might be important for identifying those patients who are most likely to benefit from gefitinib therapy.

Inhibition of EGFR and HER2 in Tamoxifen-resistant T47D:A18/4-OHT Breast Cancer Cells

PURPOSE: Tamoxifen has been prescribed as a very effective hormonal agent not only for the treatment of breast cancer, but also for the prevention of the disease. The development of resistance to tamoxifen is one of the most important obstacles to hormonal therapy of breast cancer. HER2 or EGFR expression has been reported to be associated with the development of tamoxifen resistance. This study was performed to evaluate the effect of HER2 and EGFR inhibition on tamoxifen resistance using tamoxifen-resistant breast cancer cells (T47D:A18/4-OHT cells). METHODS: Tamoxifen-resistant T47D:A18/4-OHT cells were established by long-term treatment of 1micrometer 4-hydroxytamoxifen on T47D:A18 human breast cancer cells. The effect of HER2 and EGFR inhibition was investigated by the use of a cell proliferation assay with treatment of trastuzumab, a monoclonal antibody to the extracellular domain of the human HER2 receptor, and ZD1839, an ERFR tyrosine kinase inhibitor. RESULTS: In contrast to T47D:A18 cells, T47D:A18/4-OHT cells showed estrogen-independent proliferation and partial regulation by treatment with tamoxifen. With a single treatment of trastuzumab or ZD1839, T47D:A18/4-OHT cell growth was reduced to 77.8% (P=0.15) or 74.4% (P=0.034) respectively, as compared to untreated cells. Combinational treatment with 1 nM estradiol resulted in a further reduction of T47D:A17 cell proliferation by 83.6% (P=0.002) for trastuzumab and 77.7% (P=0.047) for ZD1839, as compared to the single treatments. CONCLUSION: Tamoxifen resistance could be partially regulated by inhibition of HER2 or EGFR in T47D:A18/4-OHT cells, especially in combination with a low dose of estradiol. This effect may provide an important clue to overcome tamoxifen resistance in the treatment of breast cancer.

Study of Clinical Features of Cutaneous Side Effects Associated with ZD 1839 / 대한피부과학회지

BACKGROUND: ZD1839 (Iressa(R)Gefitinib) is an orally active, selective epidermal growth factor (EGF) receptor tyrosine kinase inhibitor that blocks signal production pathways in cell proliferation. It is currently used in the treatment of advanced stage non-small cell lung cancer. Cutaneous side effects commonly associated with ZD 1839 treatment include acneiform eruption, dry skin and hair growth abnormalities. Cutaneous eruptions result from direct interference with functions of EGF receptor signaling in the skin. OBJECTIVE: The purpose of our study was to investigate the clinical features of cutaneous side effects of ZD 1839 in Korean with literature review. We also analysed the relationship between skin rash severity, onset and objective tumor response. METHOD: We retrospectively reviewed medical records and the histologic materials of 23 Korean patients who had been treated with ZD 1839 at Ajou University Hospital from March 2002 to September 2003 . RESULTS: The results are summarized as follows. 1. The most common cutaneous side effect was acneiform skin rash (56%) which is a well known complication of ZD 1839. 2. Acneiform eruptions were easily controlled by oral antibiotics, such as minocycline and topical retinoid ointment. 3. The second common side effect was dry scaly skin (43%). 4. We also found acute paronychia, finger tip desquamation, alopecia and intertrigo. 5. The severity of the skin rash correlated well with the treatment response of ZD 1839. 6. When the skin rash appeared within 1 week after taking ZD 1839, the skin rash was severe, and the tumor responded well to the ZD 1839. CONCLUSION: The results of this study suggest that acneiform eruption and dry skin are the most common cutaneous side effects of ZD 1839. The association between rash severity and onset of tumor response suggests that the rash may serve as a marker of response to ZD1839 therapy and may be used to guide treatment to obtain optimal response. However, further prospective studies on the potentially important association between rash severity or onset and outcome of treatment with ZD 1839 are needed.

Anti-angiogenic Effect of Selective Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor(ZD1839) against Murine Renal Cell Carcinoma Orthotopic Model / 대한비뇨기과학회지

PURPOSE: ZD1839(IressaTM) is a selective epidermal growth factor receptor tyrosine kinase inhibitor(EGFR-TKI) known to block the cell signaling pathway. However, the effect of ZD1839 in relation to renal cell carcinoma, which is highly angiogenic, has not been reported. Using an orthotopic model of murine renal cell carcinoma(Renca), we evaluated the inhibitory effect of ZD1839 on tumor growth and angiogenesis. MATERIALS AND METHODS: Renca cells (1x10(4)cells/10microliter) were first adsorbed in Gelfoam and were implanted into the balb/cj mouse kidney followed by obturation with the agarose bar. Then, tumor formation was assessed every week for 4 weeks. IC50 was obtained for ZD1839 and genistein in vitro. 7 days after the implantation, the mice were divided into three groups, and normal saline, ZD1839(40mg/kg/day), and genistein (80mg/kg/day) were subcutaneously injected for 14 days. 21 days after the implantation, the mice were sacrificed, and tumor volume measurement and analysis of microvessel density(MVD) were performed using the factor VIII-related antigen and vascular endothelial growth factor(VEGF). RESULTS: Renca tumors, which formed in the renal parenchyme and had a circular shape, reached the peak growth velocity between 14 and 21 days. MVD was the highest at 14 days of implantation. IC50 for ZD1839 and genistein were 4.68microM and 5.43microM, respectively. Tumor growth after the treatment with ZD1839 and genstein was inhibited by 86%(p<0.01) and 49%(p<0.05), respectively, compared to the control. MVD of ZD1839 and genistein-treated groups were 50%(p<0.01) and 29%(p<0.05) lower, respectively, and VEGF levels were 24%(p<0.05) and 27%(p<0.05) lower, respectively, compared to the control. CONCLUSIONS: This orthotopic implantation method of the Renca cell is an effective model for demonstrating the effect of an angiogenesis inhibitor. Our results suggest that the anti-angiogenesis effect of ZD1839 in the Renca orthotopic implantation model partially contributes to the tumor growth inhibition, and that ZD1839 may be more effective than genistein in the tumor growth regulation through the inhibition of angiogenesis.

A Case of Acneiform Skin Eruption Associated with ZD1839(Iressa(R)) / 대한피부과학회지

Epidermal growth factor (EGF) has an important role in the regulation of the proliferation and differentiation of epidermal keratinocytes, as well as in the survival, angiogenesis and metastasis of various cancer cells. There have been some reports of acneiform skin lesions that occurred in the cancer patients treated with ZD1839(Iressa(R)), an inhibitor of EGF tyrosine kinase. We report a case of acneiform eruption related to the anticancer drug, ZD1839(Iressa(R)).

The Efficacy of ZD1839 (Iressa(TM)) in Patients with Advanced Non- small Cell Lung Cancer which has Progressed After Previous Chemotherapy / 결핵및호흡기질환

BACKGROUND: The role of second-line chemotherapy in the treatment of advanced non-small cell lung cancer (NSCLC) is known to be limited. Recently, ZD1839, the small molecule epidermal growth factor receptor-tyrosine kinase inhibitor, has been developed and has shown anti-tumor activity in patients with solid malignant tumors including lung cancer. We evaluated the response rate and toxicities of ZD1839 in patients with advanced NSCLC which has progressed after previous chemotherapy. PATIENTS AND METHODS: We examined 83 patients with advanced NSCLC treated with ZD1839 for more than 1 month in Korea Cancer Center Hospital during the period from January 2002 to September 2003. All the patients were enrolled in the international expanded access program (EAP) with ZD1839 by AstraZeneca. The administered dose of ZD1839 was 250 mg once daily. Chest radiography and laboratory tests were followed-up. We evaluated the response rate, median survival, and toxicity after treatment. RESULTS: Median age of the patients was 59 years (range 33-76). The most predominant cell type was adenocarcinoma and the most stage of the patients was IV. ECOG performance status was as follows; grade 0-1 in 10, grade 2 in 42, and grade 3 in 31 patients. Partial response was achieved in 12 patients (14.5%). Median overall survival was 9.2 (range 1.3-21.6+) months and median time to progression was 3.1 (range 1-21.2+) months. The most common adverse effect of ZD1839 was skin eruption which developed in 25 patients (25.8%). Significantly higher response rate and survival was found in patients with adenocarcinoma or good performance status. CONCLUSION: ZD1839 showed modest activity and tolerable toxicity in the treatment for patients with NSCLC which has progressed after previous chemotherapy.

A Case of Hair Change and Acneiform Eruption Induced by ZD1839 (Iressa(R)) / 대한피부과학회지

ZD1839 (Iressa(R)) is a new anticancer agent, a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that blocks signal transduction pathway implicated in the proliferation and survival of cancer cells and other host-dependent process promoting cancer growth. But this agent can induce cutaneous side effects including acneiform eruption, dry skin, and hair abnormality, which is related with the interruption of normal epidermal and hair follicular kinetics. We report a case of hair change and acneiform eruption induced by ZD1839 (Iressa(R)).

A Case of Paronychia, Acneiform Eruption and Dry Skin Induced by Iressa(R) / 대한피부과학회지

Iressa(R) (ZD1839) is a new anticancer agent, acting as a selective epidermal growth factor receptor tyrosine kinase inhibitor. Iressa(R) has been generally well-tolerated in cancer patients. Predominant adverse effects are an acne-like skin rash, diarrhea, nausea, vomiting, dry skin, and mild to moderate myelosuppression. The side effect of paronychia or alopecia is rare. We report a case of paronychia with granulation tissue induced by Iressa(R). Our patient complained of an acneiform eruption on his face and xerosis on his left arm and both feet as well as paronychia of several finger and toe nails.

The Effect of ZD 1839 (Iressa(R)) in the Treatment of Refractory Non Small Cell Lung Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The aim of this study was to evaluate the efficacy and the safety of ZD 1839 (Iressa(R)) as a 3rd or 4th line chemotherapy regimen in NSCLC patients who are refractory to a previous chemotherapy regimen. MATERIALS AND METHODS: Twenty-five patients who were refractory to previous chemotherapy were selected for this study. The eligible patients had an ECOG performance status of 0 to 2, and an appropriate end organ function. ZD 1839 (Iressa(R))250 mg/d was orally administered until the patients experienced disease progression or unacceptable toxicity. RESULTS: Twenty-five patients were analyzed. The median age of the patients was 57 years. The response rate was 12.0% with partial responses in 3 patients. Fourteen patients (56%) remained in the stable disease state and 8 patients progressed. The median overall survival was 9.0 months (95% CI 6.7~11.2). The median progression free survival was 3 months (95% CI 2.2~3.8). Hematological toxicities of grade 3 or 4 neutropenia, anemia and thrombocytopenia were absent. Non-hematological toxicities were grade 2 or 3 skin rashes in 10 (40.0%) patients and 1 (4.0%) patient and grade 3 nausea in 3 (12.0%) patients. No patient failed to continue chemotherapy due to any drug-related adverse events. CONCLUSION: The results suggest that ZD 1839 (Iressa(R)) monotherapy is effective and tolerable as a 3rd or 4th line salvage treatment for NSCLC patients refractory to previous chemotherapy regimens.

Antitumor Activity of Oxaliplatin, 5-FU and Paclitaxel Given Alone or in Combination with ZD1839 in Human Gastric Carcinoma Cells in vitro / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Oxaliplatin (LOHP), 5-FU, and paclitaxel (PTX) are considered highly active against advanced gastric carcinomas, and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, ZD1839 is considered as a good candidate for the treatment of gastric cancers when given alone or in combination with cytotoxic agents. The present study evaluated the antitumor effects of these agents in SNU-1 human gastric cancer cells either alone or when given as a doublet (i.e., as a cytotoxic-cytostatic combination). MATERIALS AND METHODS: We selected SNU-1 cells that showed DNA mismatch repair (MMR) deficiency and EGFR overexpression. Growth inhibition was measured by MTT and by direct cell counting and cell cycle distribution by flow cytometry. The combination index (CI) was used to describe synergistic interaction. RESULTS: The four drugs showed IC50s ranging from 1.81 nM to 13.2microM. MTT assay appeared to underestimate the cytotoxicity of PTX, which was attributed to a significant resistant fraction (32%). LOHP and PTX induced G2/M arrest, 5-FU increased in S phase, and ZD1839 in-creased in G1 in a concentration dependent manner. PTX ZD1839 showed the greatest synergism and LOHP ZD1839 showed a similar result. The cell cycle effect of PTX was potentiated by the coadministration of ZD1839. A previously developed cytostatic TPi model was used to assess the contribution of cell cycle arrest to overall growth inhibition, and 64% and 80% of the overall growth inhibition was attributed to cell cycle arrest for LOHP and PTX, when exposed to 7.55microM and 10 nM for 72 hr, respectively. CONCLUSION: This study demonstrates the antitumor activity and significant cell cycle arrest effect of ZD1839 against human gastric carcinoma cells and its synergistic interaction with LOHP and PTX. These results provide a preclinical rationale for the clinical development of ZD1839 and its use in combination with LOHP or PTX against human gastric cancers that express EGFR.

Successful treatment of pulmonary metastases of malignant fibrous histiocytoma with ZD1839: a case report / 解放军医学杂志

Malignant fibrous histiocytoma (MFH) is a common soft tissue sarcoma, which shows a strong predilection for distant metastases. Due to its limited response to radiotherapy and chemotherapy , poor prognosis is generally observed. A patient with MFH, who developed pulmonary metastases, postoperatively took ZD1839, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, because it was found that there was EGFR expression on the surface of the tumor cells. After a course of treatment (28 days), the pulmonary metastases disappeared, and the patient enjoyed a complete remission.