1 Division of Medical Oncology, San Filippo Neri Hospital, Rome; 2 Associazione ABO and Regional Center for the Study of Biological Markers of Malignancy, General Hospital, Venice, Italy
* Correspondence to: Professor G. Gasparini, Division of Medical Oncology San Filippo Neri Hospital, Via Martinotti 20, 00135 Rome, Italy. Tel: +39-06-33062237; Fax: +39-06-33062445; E-mail: gasparini.oncology{at}tiscalinet.it
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Abstract |
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Methods: Fifteen patients were enrolled at four sequential dose levels. Gefitinib was administered orally, at the fixed daily dose of 250 mg. The starting dose of epirubicin was 20 mg/m2. Escalating dose levels of epirubicin were planned by increments of 5 mg/m2 per level, up to the maximum tolerated dose (MTD). Pharmacodynamic studies were performed by determining serum and tissue ERBB2 and EGFR.
Results: At the first three dose levels tested no patient experienced a dose-limiting toxicity (DLT). In cohort 4, two patients experienced DLTs (grade 4 dyspnea and asthenia, grade 3 diarrhea and thrombocytopenia) identifying the MTD of epirubicin as 35 mg/m2. Of the 14 cases assessable for response, partial response was documented in two patients, and stable disease in seven, giving an overall disease control rate of 64.2%. The comparison of pre- and post-therapy ERBB2 and EGFR values was not statistically significant between the subgroups of patients regarding responsiveness to treatment.
Conclusions: The recommended dose of epirubicin for phase II studies is 30 mg/m2 in combination with gefitinib at the daily dose of 250 mg. Pharmacodynamic studies did not identify any biomarker predictive of response.
Key words: breast cancer, epirubicin, gefitinib, phase I study
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Introduction |
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ERBB2 has no soluble ligand; however, it has a pivotal role in ERBB receptors activation, since it is the preferred heterodimerization partner of the other ligand-bound family members [5]. The extracellular domain of ERBB receptors may be proteolitically cleaved and shed into extracellular fluids [6
]. The release of ERBB2 ectodomain from the cell surface is specifically processed by tumor cells and could be part of a mechanism by which the tyrosine kinase becomes activated [7
]. Shedding of ERBB2 extracellular domain could represent a marker of the activation of EGFRERBB2 heterodimers [8
].
The development of EGFR and ERBB2 antagonists represents a promising novel anticancer therapeutic approach. EGFR and ERBB2 are overexpressed or dysregulated in a variety of human solid tumors, breast cancer included, and their activation is associated with increased cell proliferation, tumor cell motility and invasiveness, angiogenesis, and inhibition of apoptosis [9, 10
]. Of importance, EGFR overexpression may predict poor prognosis and resistance to hormone therapy [11
14
]. Gefitinib (ZD1839), a quinazoline-derivative, is a low-molecular weight EGFR tyrosine kinase selective inhibitor that acts by blocking the signal transduction pathways that promote cancer cell growth [15
]. In preclinical studies gefitinib demonstrated antitumor activity against ovarian, colon and breast cancer cell lines overexpressing EGFR [16
]. Key preclinical features of this compound include good tolerability and the ability to delay growth or induce tumor regression in a wide range of xenograft models [16
, 17
]. Furthermore, gefitinib can be favorably combined with certain cytotoxic drugs or radiation therapy, leading to enhanced tumor growth inhibition in vitro [18
] and reversed drug resistance by inhibition of drug efflux in three multidrug-resistant cancer cell lines overexpressing the Breast Cancer Resistance Protein (BCRP) [19
]. In particular, the combination of gefitinib with anthracyclines demonstrated additive or synergic antitumor effects in preclinical studies [18
]. Data from a phase I study documented that the maximum tolerated dose (MTD) of gefitinib is
700 mg/day and that the recommended daily dose in non-small-cell lung cancer is 250 mg [20
22
].
Epirubicin is one of the most effective cytotoxics for the treatment of advanced breast cancer. The weekly schedule is well tolerated, with a favourable toxicologic profile as compared with conventional high single dosages given every 2128 days, without loss of efficacy [23, 24
]. Owing to the different mechanisms of action of gefitinib and epirubicin and the non-overlapping toxicity profile, their combination is of particular interest for the palliative treatment of advanced breast cancer. On this basis, we conducted a dose-finding and pharmacodynamic study aimed to identify the MTD of weekly epirubicin in combination with the fixed daily 250 mg dose of gefitinib and to identify possible predictive biomarkers of response in patients with advanced breast cancer pretreated with taxanes.
We tested both serum and tissue ERBB2 and EGFR as possible predictive biomarkers because gefitinib can inhibit ERBB2 signaling in breast cancer cells in vitro, even at concentrations that are not capable of suppressing ERBB2 tyrosine-kinase activity [25]. Indeed, gefitinib seems to sequester ERBB3, ERBB2 and EGFR in unphosphorylated, inactive, heterodimers, resulting in suppression of heregulin-induced receptor activation in vitro [26
].
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Patients and methods |
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Schedule of administration and study design
Gefitinib was administered orally, at the fixed daily dose of 250 mg. Epirubicin was administered at the initial dose of 20 mg/m2 as a 20-min intravenous infusion weekly, for six consecutive weeks followed by a 2-week rest period. Treatment was recycled every 8 weeks for a maximum of six cycles. Escalating doses of epirubicin were planned by increments of 5 mg/m2 per level. No intrapatient dose escalation was allowed. A minimum of three patients were enrolled at each dose level. If at any dose one patient experienced dose limiting toxicities (DLT), three additional patients were treated at that dose level. If an additional patient experienced DLT at that dose level, no further dose escalation was allowed and this dose level was considered to be the MTD. DLT was defined as the occurrence of one or more of the following toxicities during the first cycle of treatment: grade 4 neutropenia lasting 4 days, febrile neutropenia, defined as absolute neutrophil count
1000/mm3 with fever (temperature of
38°C), grade 3 or 4 thrombocytopenia and any grade 3 non-hematological toxicity, except grade 3 nausea and vomiting. If a DLT occurred, the patient received the following cycles with a reduction of epirubicin dose of 5 mg/m2. The administration of gefinitib was interrupted for a maximum of 14 days in case of grade 3 or 4 non-hematological toxicity. Once the adverse event decreased in severity to grade 1, patients continued to take gefitinib.
Evaluation of toxicity and response
Toxicity was assessed using the National Cancer Institute Common Toxicity Criteria (NCI-CTC) (version 2.0). Response was evaluated, using RECIST.
Evaluation of biological markers
Serum EGFR and ERBB2 evaluation.
Serum ERBB2 and EGFR were evaluated in the basal sample (before treatment) and at the end of every cycle of treatment in each patient. Blood was drawn by forearm venipuncture and then centrifuged at 2500 g for 10 min at room temperature. The serum supernatant was collected, aliquoted and stored at 80°C until analysis.
Serum ERBB2 (HER-2/neu) was measured employing a fully automated assay two-site sandwich immunoassay (ADVIA Centaur HER-2/neu) using a direct chemiluminescent technology. The lite reagent is composed of the monoclonal mouse antibody, TA-1, labeled with acridinium ester. The fluorescin conjugate reagent is the monoclonal mouse antibody, NB-3, labeled with fluorescin. These two monoclonal antibodies are specific for unique epitopes on the external cellular domain of ERBB2. The solid phase is the purified anti-fluorescin monoclonal mousecapture antibody, which is covalently coupled to paramagnetic particles. The sample is incubated with fluorescin conjugate reagent and lite reagent simultaneously for 5.5 min. After this incubation, the solid phase is added and the mixture is incubated for an additional 2.5 min. After this final incubation, the immuno-complex formed is washed with water before beginning the chemiluminescent reaction.
Serum EGFR was measured using the Oncogene Science EGFR Microtiter ELISA by a sandwich immunoassay with a mouse monoclonal capture antibody and an alkaline phosphatase-labeled mouse monoclonal antibody as detector. Both capture and detector reagents specifically recognize the extracellular domain of EGFR. The capture antibody recognizes a protein domain on the extracellular portion of EGFR, does not inhibit EGF binding, and does not cross-react with ERBB2 oncoprotein or human blood group A antigen. The capture antibody is immobilized on the interior surface of the microtiter plate wells. To perform the test an appropriate volume of specimen is incubated in the wells to allow binding of the antigen by the capture antibody. The immobilized antigen is then exposed to the alkaline phosphatase-labeled detector antibody. Addition of the substrate to the wells allows the catalysis of a chromogen into a colored product, the intensity of which is proportional to the amount of EGFR.
ERBB2 and EGFR immunohistochemistry.
Tissue specimens were stained by immunohistochemistry using the EGFR pharmDxTM assay (DakoCytomation, Denmark), which utilizes a standard staining protocol (DakoCytomation EGFR kit insert) [27]. In summary, the EGFR pharmDx assay contains all the reagents required for the staining protocol: mouse anti-EGFR antibody (clone 2-18C9), EnVision+, DAB+, including proteinase K for antigen demasking and appropriate buffers. Control slides containing two FFPE human cell lines with staining intensity scores of 2+ and 0 provided with the assay were utilized to validate the staining performance of the assay. The EGFR pharmDx assay detects native EGFR as well as the vIII EGFR mutant [28
]. Further, the EGFR pharmDx assay has been shown not to cross-react with the other three members of the ErbB receptor family [27
, 28
].
The total percentage of tumor cells displaying EGFR membrane staining at any intensity level was captured. The highest membrane staining level of the EGFR-positive tumor cells was classified as: weak (1+), moderate (2+) or strong (3+) staining. The percentage of tumor cells displaying the highest EGFR membrane staining was also recorded. In each tumor sample, the pattern of membrane staining was assessed as predominantly complete (50%) or predominantly incomplete (below <50%).
Lastly, the total percentage of tumor cells displaying cytoplasmic EGFR staining at any intensity level was captured.
The determination of ERBB2 status was performed at study entry by the HercepTest, as described previously [29].
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Results |
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Hematological and non-hematological toxicities for the first and the overall cycles are summarized in Tables 3 and 4, respectively. The most frequently reported adverse events include asthenia, skin rash, nausea, dyspnea, conjunctivitis and diarrhea. Asthenia occurred in five patients (33.3%) at the fourth dose level and it was of grade 3 and 4 in three and one of these patients, respectively. Asthenia was reversible in 12 weeks after suspension of treatment. Skin rash, described as acneiform-like generalized dermatitis, was observed in five patients (33.3%) at all dose levels and it was of grade 2 in two patients, requiring a temporary interruption of gefitinib. Dyspnea occurred in six patients (40%), but it was of grade 3 in two patients at the first and the fourth dose level, respectively, and of grade 4 in one patient of the fourth dose level. Nine patients (60%) had grade 12 conjunctivitis (at all dose levels). Diarrhea occurred in eight patients (53.3%). A patient at the fourth dose level was admitted to the hospital due to grade 3 diarrhea, associated with grade 3 thrombocytopenia and grade 4 dyspnea and asthenia, during the first cycle of therapy. She was treated with intravenous hydration, antibiotic therapy, steroids and oral loperamide, with a resolution of all toxicities in 3 days. The patient stopped the treatment and she died 1 month later due to disease progression. Another patient had two episodes of grade 3 diarrhea at the fourth dose level, during the first and second cycle of treatment, respectively: she recovered after therapy with oral loperamide and temporary interruption of gefitinib. At all the dose levels tested no significant variation in LVEF was observed after the first cycle of treatment. One patient after the fourth course of therapy at the highest dose level experienced grade 2 reversible cardiotoxity, with a significant reduction of LVEF (from 60% to 39%). The patient was 68 years old, pretreated with adjuvant epirubicin (total dose 400 mg/m2) and reached a cumulative dose of epirubicin of 1140 mg/m2. She required hospitalization and was treated with diuretics and digoxin, with a rapid improvement of symptoms and of LVEF. Overall, the hematological toxicity was mild: grade 34 neutropenia was observed in two and one patients, respectively, at the fourth dose level; grade 3 anemia occurred in four patients of the second, third and fourth dose level; and grade 3 thrombocytopenia in two patients at the second and fourth dose level. There was no case of febrile neutropenia. There was no case of treatment-related death.
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Pharmacodynamics
Serum biomarkers.
Fourteen cases had determination of basal serum ERBB2 and 13 had sequential samples taken after therapy. The median values before and after the first cycle of therapy were 34.3 ng/ml (range 91213.2 ng/ml) and 29.25 ng/ml (range 5.83443.4), respectively. Among the nine patients with either PR or SD the basal and post-therapy median values were 32.1 and 19.9 ng/ml (P = 0.730), respectively.
Among the four cases with PD the basal and post-therapy median values were 34.3 and 105.95 ng/ml (P = 0.904), respectively. The comparison of post-therapy versus basal values between the two subgroups of patients (responsive versus non responsive) was not statistically significant (P = 0.939); however, there was a trend towards a drop of ERBB2 concentrations in the cases with PR or SD. On the contrary, an increase among the patients with progressive disease occurred.
Fourteen cases had determination of basal EGFR and 13 also after therapy. The median values were 35.6 ng/ml (range 38.437.1) and 38.8 ng/ml (range 28.645.3) respectively.
Among the nine subjects with a PR or SD the median basal and post-therapy values were similar (43.8 versus 41.4). Also, the four cases with PD had similar median pre- and post-therapy serum EGFR concentrations (35.6 versus 39.1 ng/l). The comparison of the pre- and post-therapy EGFR values was not statistically significant (P = 0.198) between the two subgroups of patients regarding responsiveness to treatment.
Tissue biomarkers.
Twelve patients had the determination of tissue expression of EGFR. Ten cases did not show any staining, one sample had weak staining (1% of positive cells) and another one had strong (80% of positive cells) staining. Regarding determination of ERBB2, six cases (Table 5) had a 3+ score using the HercepTest. The two patients who obtained a PR had both ERBB2- and EGFR-negative tumors.
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Discussion |
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Other two studies with gefitinib combined with cytotoxic agents have been up to now reported as abstracts [34, 35
]. Fountzilas et al. [34
] evaluated in a phase II study the activity of the combination of paclitaxel (175 mg/m2 every 3 weeks), carboplatin (AUC 6 every 3 weeks) and gefitinib as first-line chemotherapy in 68 patients with advanced breast cancer. Gefitinib was administred at 250 mg/day orally until disease progression, unacceptable toxicity or voluntary withdrawal. An objective response rate of 46% was reported and the major toxicities were severe neutropenia (16%), thrombocytopenia (6%), anemia (10.5%), peripheral neuropathy (6%), allergic reaction (6%) and diarrhea (7.5%) [34
].
Ciardiello et al. [35] investigated gefitinib (250 mg/day) and docetaxel (75 mg/m2, up to 100 mg/m2 in absence of unacceptable toxicity) as first-line combination therapy in patients with metastatic disease. The therapy was well tolerated, with grade 34 neutropenia in 51.2% and diarrhea in 12.2% of patients. Skin rash (grade 23) occurred in 12.2% of cases. In the preliminary analysis, a response rate of 57.9% was observed in the 38 evaluable patients.
Recently, Polychronis et al. [36] reported the results of a double-blind placebo-controlled phase II trial of preoperative gefitinib (250 mg/day) versus gefitinib and anastrozole in 57 post-menopausal patients with ER/EGFR-positive tumors. The primary end point of the study was the assessment of cell proliferation by Ki-67 labeling. Gefitinib, either alone or in combination with anastrozole significantly reduced tumor cell proliferation. However, the patients assigned to the combined treatment had a significant greater reduction of Ki 67 values (mean percentage reduction 98% versus 92.4%; P = 0.0054). No difference was observed regarding ultrasonography evaluation of reduction in primary tumor size between the two treatment arms, and approximately half of the patients obtained a PR.
Our dose-finding study demonstrated that the fixed 250 mg/daily oral administration of gefitinib was well tolerated up to the dosage of 30 mg/m2 of epirubicin. We did not evaluate the dose escalation of gefitinib up to 500 mg, 250 mg a day being the recommended, biologically active dosage [37], in addition because of the results that emerged from studies in advanced non-small-cell lung cancer, showing that the dose of 250 mg a day is well tolerated and it is equivalent in terms of efficacy to 500 mg, the latter dosage being associated with more side-effects [20
22
, 38
].
The MTD of the schedule was reached at the epirubicin dose of 35 mg/m2, with NCI-CTC grade 4 dyspnea, asthenia and grade 3 diarrhea and thrombocytopenia in two patients. Diarrhea and dyspnea recovered within 3 days with the use of loperamide and steroids. No other severe toxicities occurred. The recommended schedule for phase II studies in pretreated patients is weekly epirubicin 30 mg/m2 for six consecutive weeks followed by a 2 week rest plus gefitinib 250 mg/daily. We observed moderate hematological and non-hematological toxicities. The majority of patients in all the cohorts were able to complete at least the first cycle of therapy (93.3% of the enrolled patients): only one patient at the fourth dose level stopped therapy before completing the first cycle of therapy due to personal reasons.
Although tumor response was not a primary end point of the study, two patients achieved a long lasting PR (8 months) and another seven patients had stable disease lasting 3 months, for an overall disease control rate of 64.3%, suggesting that the schedule of therapy is active in patients pretreated with taxanes ± trastuzumab. However, whether gefitinib significantly enhances the efficacy of cytotoxic therapy in advanced breast cancer needs to be determined in randomized clinical trials.
The major challenge for clinical use of gefitinib is to improve the capability to select the patients responsive to therapy. In our study, pharmacodynamics evaluations did not demonstrate a significant correlation of the serum and tissue biomarkers tested with the probability of response. However, the patients with progressive disease after therapy showed a trend to increased serum ERBB2 levels.
In conclusion, the data reported here define an appropriate regimen for phase IIIII studies of gefitinib combined with weekly epirubicin. Future studies performed on larger cohorts of patients are warranted to further investigate a possible correlation of biomarkers with efficacy of gefitinib-based treatments, as well as the most appropriate combination with cytotoxic agents in advanced breast cancer.
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Acknowledgements |
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Received for publication April 19, 2005. Revision received June 30, 2005. Accepted for publication July 15, 2005.
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References |
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![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2. Winer EP, Morrow M, Osborne CK, Harris JR. Cancer of the breast. Management of patients with metastatic breast cancer. In De Vita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology. Philedelphia, PA: Lippincott 2001; 16991706.
3. Abrams JS, Vena DA, Baltz J et al. Paclitaxel activity in heavily pre-treated breast cancer: A National Cancer Institute Treatment Referral Center Trial. J Clin Oncol 1995; 13: 20562065.
4. Vogel CL. Current status of salvage chemotherapy for refractory advanced breast cancer. Oncology 1996; 10 (Suppl 6): 715.[CrossRef][Medline]
5. Graus-Porta D, Beerli R, Daly JM et al. ErbB-2 the preferred heterodimerization partner of all ErbB receptors is a mediator of lateral signaling. EMBO J 1997; 16: 16471655.
6. Garret TP, McKernan M, Lou M et al. The cristal structire of truncated ErbB2 ectodomain reveals an active conformation, poised to interact with other ErbB receptors. Mol Cell 2003; 11: 495505.[CrossRef][ISI][Medline]
7. Zabrecky JR, Lam T, McKenzie SJ et al. The extracellular domain of p185/neu is released from the surface of human breast carcinoma cells, SK-BR-3. J Biol Chem 1991; 266: 17161720.
8. Molina MA, Codony-Servat J, Albanell J et al. Trastuzumab, a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomalin cleavage in breast cancer cells. Cancer Res 2001; 61: 47444749.
9. Salomon DS, Brandt R, Fortunato C, Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 1995; 19: 183232.[CrossRef][ISI][Medline]
10. Hill CS, Treisman R. Transcriptional regulation by extracellular signals; mechanisms and specificity. Cell 1995; 80: 199211.[CrossRef][ISI][Medline]
11. Fontanini G, Vignati S, Bigini D et al. Epidermal growth factor receptor (EGFR) expression in non-small-cell lung carcinomas correlates with metastatic involvement of the hilar and mediastinal lymph nodes in the squamous subtype. Eur J Cancer 1995; 31A: 178183.[CrossRef]
12. Mukaida H, Toi M, Hirai T et al. Clinical significance of the expression of epidermal growth factor and its receptor in oesophageal cancer. Cancer 1991; 68: 142148.[ISI][Medline]
13. Neal DE, Bennett MK, Hall RR et al. Epidermal growth factor receptor in human bladder cancer. Comparison of invasive and superficial tumours. Lancet 1985; 1: 366368.[CrossRef][ISI][Medline]
14. Saisbury JRC, Farndon JR, Needham GK et al. Epidermal growth factor receptor status as predictor of early recurrence of and death from breast cancer. Lancet 1987; 1: 13981402.[ISI][Medline]
15. Wakeling AE, Guy SP, Woodburn JR et al. ZD1839 (Iressa): an orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Cancer Res 2002; 62: 57495754.
16. Woodburn JR, Barker AJ, Gibson KH et al. ZD1839, an epidermal growth factor tyrosine kinase inhibitor selected for clinical development. Proc Am Assoc Cancer Res 1997; 38: 633634.
17. Sirotnak FM, Zakowski MF, Miller VA et al. Efficacy of cytotoxics agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of tyrosine kinase. Clin Cancer Res 2000; 6: 48854892.
18. Ciardiello F, Caputo R, Bianco R et al. Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin Cancer Res 2000; 6: 20532063.
19. Nakamura Y, Oka M, Soda H et al. Gefitinib (Iressa, ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, reverses breast cancer resistance protein/ABCG2-mediated drug resistance. Cancer Res 2005; 65: 15411546.
20. Ranson M, Hammond LA, Ferry D et al. ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial. J Clin Oncol 2002; 20: 22402250.
21. Fukuoka M, Yano S, Giaccone G et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 2003; 15; 21: 22372246.
22. Kris MG, Natale RB, Herbst RS et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 2003; 16: 21492158.[CrossRef]
23. Gasparini G, Dal Fior S, Pannizzoni GA et al. Weekly epirubicin versus doxorubicin as second line therapy in advanced breast cancer. A randomized clinical trial. Am J Clin Oncol 1991; 14: 3844.[ISI][Medline]
24. Robert J. Epirubicin: clinical pharmacology and dose-effect relationship. Drugs 1993; 45: 2029.[Medline]
25. Campiglio M, Locatelli A, Olgiati C et al. Inhibition of proliferation and induction of apoptosis in breast cancer cells by the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD 1839 (Iressa) is independent of EGFR expression level. J Cell Physiol 2004; 198: 259268.[CrossRef][ISI][Medline]
26. Anida J, Matar P, Albanell J et al. ZD 1839, a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, induces the formation of inactive EGFR/HER-2 and EGFR/HER-3 heterodimers and prevents heregulin signaling in HER-2 overexpressing breast cancer cells. Clin Cancer Res 2003; 9: 12741285.
27. Spaulding DC, Spaulding BO. Epidermal growth factor receptor expression and measurement in solid tumors. Semin Oncol 2002; 29: 4554.
28. Pii K, Andersen FG, Jensen SS, Spaulding BO. Characterization of a new monoclonal antibody, clone 2-18C9, for the measurement of Epidermal Growth Factor Receptor expression in solid tumors. Proc Am Assoc Cancer Res 2004; 45: 3709 (Abstr).
29. Hoang MP, Sahin AA, Ordone NG et al. HER-2/neu gene amplification compared with HER-2/neu protein overexpression and interobserver reproducibility in invasive breast carcinoma. Am J Clin Pathol 2000; 113: 852858.[CrossRef][ISI][Medline]
30. Baselga J, Albanell J, Ruitz A et al. Phase II and tumor pharmacodynamic study of gefitinib (ZD 1839) in patients with advanced breast cancer. Proc Am Soc Clin Oncol 2003; 22: 24 (Abstr).
31. Robertson JFR, Gutteridge E, Cheung KL et al. Gefitinib (ZD 1839) is active in acquired tamoxifen (TAM)-resistant oestrogen receptor (ER)-positive and (ER)-negative breast cancer: results from a phase II study. Proc Am Soc Clin Oncol 2003; 22: 23 (Abstr).
32. Von Minckwitz G, Jonat W, Fasching P et al. A multicentre phase II study on gefitinib in taxane- and anthracycline-pretreated metastatic breast cancer. Br Cancer Res Treat 2005; 89: 165172.[CrossRef][ISI][Medline]
33. Albain K, Elledge R, Gradishar WJ et al. Open-label, phase II multicenter trial of ZD 1839 (Iressa) in patients with advanced breast cancer. San Antonio Breast Cancer Symp 2002; (Abstr 20).
34. Fountzilas G, Pectasides D, Skarlos DV et al. Paclitaxel, carboplatin and gefitinib (Iressa, ZD 1839) as first-line chemotherapy in patients with advanced breast cancer: a phase II study. San Antonio Breast Cancer Symp 2003; 82: 375 (Abstr).
35. Ciardiello F, Troiani T, Caputo F et al. A Phase II study of gefitinib combined with docetaxel as first-line treatment in patients with advanced breast cancer. Proc Am Soc Clin Oncol 2004; 22: 725 (Abstr).
36. Polychronis A, Sinnett HD, Hadjiminas D et al. Preoperative gefitinib versus gefitinib and anastrozole in postmenopausal patients with oestrogen-receptor positive and epidermal-growth-factor-receptor-positive primary breast cancer: a double-blind placebo-controlled phase II randomized trial. Lancet Oncol 2005; 6: 383391.[CrossRef][ISI][Medline]
37. Wolf M, Swaisland H, Averbuch S. Development of the novel biologically targeted anticancer agent gefitinib: determining the optimum dose for clinical efficacy. Clin Cancer Res 2004; 10: 46074613.
38. Baselga J. The science of EGFR inhibition: a roadmap to improve outcomes? Signal 2004; 5: 48.
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