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Journal of Clinical Oncology, Vol 22, No 15 (August 1), 2004: pp. 3080-3090 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.08.189 Evaluation of Biologic End Points and Pharmacokinetics in Patients With Metastatic Breast Cancer After Treatment With Erlotinib, an Epidermal Growth Factor Receptor Tyrosine Kinase InhibitorFrom the Cancer Therapeutics Branch, Laboratory of Pathology, Medical Oncology Clinical Research Unit, Laboratory of Cellular and Molecular Biology, and Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute; and National Institute of Dental and Craniofacial Research and the Departments of Diagnostic Radiology and Nuclear Medicine, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD Address reprint requests to Sandra M. Swain, MD, Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, 8901 Wisconsin Ave, Building 8, Room 5101, Bethesda, MD 20889; e-mail: swains{at}mail.nih.gov
PURPOSE: To evaluate changes in epidermal growth factor receptor (EGFR) phosphorylation and its downstream signaling in tumor and surrogate tissue biopsies in patients with metastatic breast cancer treated with erlotinib, an EGFR tyrosine kinase inhibitor, and to assess relationships between biomarkers in tumor and normal tissues and between biomarkers and pharmacokinetics. PATIENTS AND METHODS: Eighteen patients were treated orally with 150 mg/d of erlotinib. Ki67, EGFR, phosphorylated EGFR (pEGFR), phosphorylated mitogen-activated protein kinase (pMAPK), and phosphorylated AKT (pAKT) in 15 paired tumor, skin, and buccal mucosa biopsies (at baseline and after 1 month of therapy) were examined by immunohistochemistry and analyzed quantitatively. Pharmacokinetic sampling was also obtained. RESULTS: The stratum corneum layer and Ki67 in keratinocytes of the epidermis in 15 paired skin biopsies significantly decreased after treatment (P = .0005 and P = .0003, respectively). No significant change in Ki67 was detected in 15 tumors, and no responses were observed. One was EGFR-positive and displayed heterogeneous expression of the receptor, and 14 were EGFR-negative. In the EGFR-positive tumor, pEGFR, pMAPK, and pAKT were reduced after treatment. Paradoxically, pEGFR was increased in EGFR-negative tumors post-treatment (P = .001). Although markers were reduced in surrogate and tumor tissues in the patient with EGFR-positive tumor, no apparent associations were observed in patients with EGFR-negative tumor. CONCLUSION: Erlotinib has inhibitory biologic effects on normal surrogate tissues and on an EGFR-positive tumor. The lack of reduced tumor proliferation may be attributed to the heterogeneous expression of receptor in the EGFR-positive patient and absence of target in this cohort of heavily pretreated patients.
Epidermal growth factor receptor (EGFR) is expressed in several solid tumors, including breast cancer. Its expression in breast carcinomas is reported to be in the range of 14% to 91%1,2 and has been associated with poor prognosis, increased risk of recurrence, and poor response to hormonal therapy.3-5 EGFR tyrosine kinase (TK) inhibitors, such as erlotinib (OSI-774, Tarceva; OSI Pharmaceuticals, Melville, NY), represent a class of compounds that can prevent EGFR autophosphorylation and interrupt downstream signaling, including the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase/AKT pathways, thus inhibiting tumor cell proliferation. Erlotinib has been shown to inhibit EGFR TK in vitro with a 50% inhibitory concentration of 2 nmol/L, and to reduce EGFR autophosphorylation in intact tumor cells with a 50% inhibitory concentration of 20 nmol/L.6 In a study with mice bearing HN5 human head and neck tumor xenografts, erlotinib inhibited EGFR autophosphorylation in a dose-related manner.7 In studies with EGFR TK inhibitors, skin has been proposed as a surrogate tissue because of its EGFR expression, its ease of accessibility, and as a site of frequently occurring toxicity.8,9 EGFR has also been shown to be present in human buccal mucosa.10 The pharmacodynamic effects of erlotinib and gefitinib (ZD1839, Iressa; AstraZeneca, Wilmington, DE), another reversible EGFR TK inhibitor, have been described in pre- and post-treatment normal skin specimens.11-14 Because of limited options in the treatment of metastatic breast cancer, therapy directed at EGFR TK represents a potentially novel approach. Because erlotinib is a targeted drug against the EGFR TK, we hypothesized it would have inhibitory effects on intermediate points in the EGFR signaling pathway. In this pilot study, we evaluated Ki67, EGFR, phosphorylated EGFR (pEGFR), phosphorylated MAPK (pMAPK) and phosphorylated AKT (pAKT) as potential biologic end points, in metastatic breast tumors, skin, and buccal mucosa, as well as pharmacokinetics pre- and post-treatment with erlotinib. In addition, fluorodeoxyglucose uptake positron emission tomography (FDG-PET) was explored as a noninvasive tool to monitor response to erlotinib.
Eligibility Criteria Patients were eligible if they had histologically confirmed adenocarcinoma of the breast, metastatic tumor accessible to biopsy, were  18 years of age, had an Eastern Cooperative Oncology Group performance status of  2, and a life expectancy of 12 weeks. Requirements for adequate organ function included an absolute granulocyte count of 1,500/µL, platelets 100,000/µL, total bilirubin and creatinine within normal limits, and ALT and AST 2.5 times the upper limit of normal. Other eligibility criteria included an ejection fraction 40% and no prior chemotherapy or radiotherapy within 3 weeks of enrollment (2 weeks for prior hormonal therapy). There was no limit to the number of previous chemotherapy or hormonal treatments. Patients were excluded if they had symptomatic brain metastases, abnormalities of the cornea, or were currently using contact lenses. Patients were considered assessable if they had both pre- and post-treatment tumor biopsies collected. The protocol was approved by the institutional review board of the National Cancer Institute (NCI). All patients gave written informed consent.
Treatment Plan
Clinical Evaluation
Tissue Biopsies
Immunocytochemistry and Immunoblotting
Immunohistochemistry and Quantification by Automated Cellular Imaging System
An automated cellular imaging system (ACIS; ChromaVision Medical Systems, Inc, San Juan Capistrano, CA) was used to quantify the staining of each molecular marker.21 Each stained slide was scanned at low magnification (x10) according to either a membranous, cytoplasmic, or nuclear application in the ACIS and scored quantitatively using a free-scoring or x40 tool. Two investigators (X.Y. and S.M.H.) reviewed the images generated by ACIS independently without knowledge of any clinical data. For normal skin specimens, the thickness of the stratum corneum was measured on hematoxylin and eosin slides with a computer-generated micrometer in ACIS. The entire epidermis was outlined by a drawing tool and scored for each marker. In addition, EGFR, pEGFR, pAKT, and pMAPK in the skin were semiquantitatively assessed on a 0 (no staining), 1+ (weakly positive), 2+ (moderately positive), and 3+ (strongly positive) scale based on the relative staining intensity; Ki67 was assessed on a 0 (no staining), 1+ (few), 2+ (scattered), and 3+ (many) scale. Scoring was assessed in a blind fashion by S.M.H. For each tumor case, the hot spots feature of the ACIS was used to direct sites of staining where six fields (x40) of tumor were scored. The ACIS software calculated the average percentage and intensity of stained cells. A staining index was generated in each case by multiplying the percentage of positively stained cells and the average staining intensity after subtracting the machine readouts of the corresponding negative control for each marker. For Ki67, a labeling percentage was reported.
Pharmacokinetic Sampling and Analysis
FDG-PET Imaging Acquisition
Statistical Methods
Patient Characteristics Between January and December 2002, 18 patients were enrolled. Demographics are shown in Table 2. Fifteen patients were assessable for tissue studies. Median time on study was 28.5 days (range, 14 to 83 days). A total of 22 cycles of erlotinib were administered.
Adverse Events and Antitumor Activity All 18 patients were assessable for toxicity (Table 3). Grade 1 and 2 skin rash (most often acne-like or maculopapular and pustular-like) was the most commonly observed event (61%). Other frequent toxicities included grade 1 and 2 fatigue (56%) and gastrointestinal-related side effects (grades 1, 2, and 3), including nausea (50%), diarrhea (39%), and anorexia (39%). There were no grade 4 adverse events and no treatment-related deaths.
One patient developed a grade 2 rash and grade 3 diarrhea that required a dose reduction to 100 mg/d and then withdrew from study secondary to these drug-related effects. Another patient who was on verapamil experienced grade 3 diarrhea, anorexia, nausea, and stomatitis after being on study for 37 days. She required a dose reduction to 100 mg/d and then developed a grade 2 acneiform eruption and grade 3 pneumonitis, from which she recovered without the use of corticosteroids. Response was measurable in 17 patients. No clinical responses or stable disease were seen.
Specificity of Antibodies
Effect of Erlotinib on Skin and Buccal Mucosa Biopsies The effect of erlotinib on markers in 15 pairs of matched sequential skin and buccal mucosa biopsies is shown in Table 4 and Figures 2A and 2B. The height of the stratum corneum and Ki67 proliferation index in keratinocytes of the epidermis were significantly decreased by erlotinib in paired skin biopsies (P = .0005 and P = .0003, respectively; Figs 3A through 3D). In buccal mucosa, there was a trend toward a reduction in Ki67 (P = .025; Figs 3E and 3F). EGFR was expressed in the basal and parabasal layers of the epidermis in skin and in the epithelium of the buccal mucosa (data not shown). Of note, EGFR was absent in six pairs of buccal mucosa biopsies. No significant change in EGFR after treatment was observed in 15 paired skin and buccal mucosa specimens (P = .93 and P = .13, respectively). There was a decrease in pEGFR in skin and buccal mucosa that did not reach statistical significance (P = .39 and P = .20, respectively). The reduction was evident in eight (53%) of 15 paired skin and buccal mucosa samples; six pairs were concordant. There was a trend toward an increase in pMAPK (P = .04) and no significant change in pAKT in post-treatment skin samples (P = .45).
A positive correlation was observed between the change in Ki67 and change in stratum corneum height in the skin (r = 0.59; P = .02). There was also a weak to moderate correlation between the change in pEGFR and the changes in pMAPK (r = 0.31) and pAKT (r = 0.30) and a weak to moderate negative correlation between Ki67 and pMAPK in the keratinocytes (r = –0.33). A weak correlation was detected between the change in Ki67 and change in pEGFR in both skin and buccal mucosa biopsies (r = 0.15; P = .58 and r = 0.20; P = .46).
Effect of Erlotinib on EGFR-Positive and EGFR-Negative Tumor Biopsies
In the EGFR-negative tumors, pEGFR was significantly increased post-treatment (P = .001). There were no significant increases in pMAPK (P = .19) and pAKT (P = .45) or change in Ki67 (Table 5). A weak correlation was observed between the change in pEGFR in skin and buccal mucosa (r = 0.19; P = .52), with no association between pEGFR in skin and tumor biopsies (r = –0.02; P = .94) or between buccal mucosa and tumor biopsies (r = –0.08; P = .79).
Pharmacokinetics Complete concentration-time profiles were obtained from 15 patients (Table 6). The oral clearance (CL/F) varied more than seven-fold, indicating a substantial degree of interindividual variability. After correction of the CL/F for each patient’s body-surface area, a similar degree of variability was observed (57.2% v 52.2%). Erlotinib pharmacokinetic parameters were not significantly related to any common body size measure in a univariate linear regression analysis (r = 0.42; all P > .10).
The patient with the highest CL/F value of 11.3 L/h and the lowest AUC[tf] of 13.3 µg · h/mL was receiving 400 mg of oral phenytoin daily for the past 28 days, which possibly resulted in induction of proteins involved in erlotinib elimination pathways.25 The patient with the second highest AUC[tf] of 75.5 µg · h/mL was receiving verapamil, a known inhibitor of the cytochrome P450 isoenzyme CYP3A4, concomitantly with erlotinib and developed interstitial pneumonitis.26 The values of AGP ranged from 56 mg/dL to 312 mg/dL with a linear correlation between steady-state concentration (Css,ave) and AGP levels (r = 0.46; P = .08; Fig 5). There was a similar trend between the observed AUC[tf] and AGP levels (r = 0.46; P = .09). There was a negative correlation between Css,ave and change in Ki67 in skin (r = –0.37; P = .18). There was no correlation between Css,ave and Ki67 in buccal mucosa (r = 0.06; P = .82) nor in tumor (r = 0.02; P = .94).
FDG-PET Imaging A significant correlation (n = 8) was found between the CT volume changes and changes in volume of FDG uptake (r = 0.90; P = .001) and between CT volume changes and change in total FDG uptake (r = 0.89; P = .001). In addition, there was a trend for change in CT volume and change in glucose metabolism as measured either by a change in Patlak slope (r = 0.63; P = .07) or SUVmean (r = 0.60; P = .09).
In this study, we demonstrated the feasibility of obtaining sequential tumor, skin, and buccal mucosa biopsies concomitantly, as well as evaluated the pharmacokinetics of erlotinib and its pharmacodynamic effects in these paired samples. The significant decreases in keratinocyte proliferation and stratum corneum layer of the epidermis and oral epithelial cell proliferation in buccal mucosa were indicative of the inhibitory biologic effects of erlotinib. Similar changes are reported in normal skin biopsies after treatment with gefitinib.11 The association between the reduced Ki67 in keratinocytes and decreased thickness in the stratum corneum layer suggests that the normal level of proliferation in keratinocytes is critical to retain skin intactness. Although pEGFR expression in post-treatment skin and buccal mucosa biopsies overall were reduced, only a weak association was observed between pEGFR and reduced Ki67. This may imply that undefined markers or pathways relevant to cell proliferation were more likely to be inhibited and that there are other targets besides EGFR that may be relevant to skin and buccal mucosa biology. Other compounds have been shown to affect additional pathways besides their putative target. For example, imatinib mesylate (STI 571, Gleevec; Novartis Pharmaceuticals, East Hanover, NJ) inhibits more than one kinase, including Abl, KIT, and platelet-derived growth factor receptor.27,28 Similarly, farnesyltransferase inhibitors, which were developed to inhibit Ras, have been found to target other proteins, such as RhoB.29,30 In post-treatment skin samples, increased activity in pMAPK might reflect the ability of normal tissues to compensate transiently when treated with erlotinib. The weak to moderate association between the change in pEGFR and changes in pMAPK and pAKT in skin suggests that there are other pathways that can activate MAPK and AKT in addition to EGFR. The inverse weak association of pMAPK with Ki67 in keratinocytes suggests that pMAPK might have contributed little to the reduced keratinocyte proliferation, thereby implicating complex drug effects or drug-host interactions. The level of EGFR expression in tumor necessary to respond to EGFR TK inhibitors is currently not known. Breast cancer cell lines with either low or high levels of EGFR are inhibited by gefitinib.31-33 Therefore, EGFR expression was not required to enroll patients in clinical trials, including the current one. In the EGFR-positive case, expression of EGFR, pEGFR, pMAPK, and pAKT were all reduced, but not Ki67. The lack of clinical benefit in this case may due to the molecular heterogeneity in EGFR expression. It is conceivable that cells that had high to moderate levels of EGFR were successfully suppressed by erlotinib, whereas the EGFR-negative cells continued to proliferate. Alternatively, the receptor might have been downregulated by erlotinib. Other receptor tyrosine kinase inhibitors have been shown to accelerate ubiquitylation and degradation of ErbB family receptor tyrosine kinases in cancer cell lines.34 Interestingly, markers in the skin and buccal mucosa also decreased in the EGFR-positive case, suggesting that these normal tissues serve as surrogates of target inhibition and not of tumor response. However, this needs to be further addressed with more cases of tumors expressing EGFR. Recently, in a phase II and tumor pharmacodynamic study with gefitinib in patients with advanced breast cancer, pEGFR and pMAPK were reduced in EGFR-positive tumors after treatment.35 However, no significant changes in Ki67 and pAKT were described. In EGFR-negative tumors, a paradoxical increase of low to moderate levels in pEGFR activity was detected, and this warrants further study preclinically and clinically. Although there was no detectable level of EGFR in 14 pretreatment tumors, pEGFR was detected in eight of these cases, suggesting that either the EGFR antibody was not sensitive enough or the pEGFR antibody was more sensitive. In these 14 patients with EGFR-negative tumor, a weak association in the change of pEGFR between skin and buccal mucosa was found. The lack of a strong correlation could be due to the absence of EGFR expression in six pairs of buccal mucosa. Not surprisingly, there was no association in the change in pEGFR between the surrogate tissues and EGFR-negative tumors. It is predicted that after treatment with the EGFR TK inhibitors, pEGFR activity will be inhibited. In a study with gefitinib, pEGFR activity was almost absent in post-treatment skin samples.11 In our study with erlotinib, pEGFR in 15 paired skin tissues (median; pretherapy 18.5 v post-therapy 6.5) and in 15 paired buccal mucosa (pretherapy 0.8 v post-therapy 0.2) was decreased as well. Similarly, in another pharmacodynamic evaluation with erlotinib in skin, pEGFR activity was also reduced (mean ± standard deviation; pretherapy 22.91 ± 10.45 v post-therapy 16.75 ± 10.03).14 However, pEGFR activity post-treatment was still detectable in both studies with erlotinib. The discrepancy with gefitinib could be due to the fact that it is a different drug. Immunohistochemical analyses of markers in the EGFR pathway are limited by factors such as the lack of a standardized methodology and common grading criteria and interrater disagreement. To minimize potential variability in our study, all biopsies were immediately placed in formalin at the time of procurement and subsequently embedded in paraffin. Sections on slides were all freshly cut, and sequential biopsies were examined simultaneously for each marker in a blind fashion. Antibodies were chosen after serial testing and appropriate validation. For example, we have tested several pEGFR antibodies and found that the antibody, clone 9H2, was the highest in specificity and sensitivity among those tested on paraffin tissue sections for pEGFR. Finally, the immunohistochemical stains were analyzed quantitatively with assistance of ACIS, which has the advantages of providing consistency and reproducibility. A semiquantitative assessment was also performed (data not shown), and the analyses demonstrated a significant decrease in Ki67 (P = .002) and no significant changes in EGFR, pEGFR, pMAPK, and pAKT from pre- to post-treatment specimens, consistent with the automated scores. The individual and mean pharmacokinetic parameters of erlotinib were consistent with results from the phase I study.36 All of the patients achieved trough concentration values in excess of 0.5 µg/mL, which is the concentration associated with antitumor activity in xenograft models. The inverse association between Css,ave and the change in Ki67 in skin suggests that an effective drug concentration was achieved. The lack of association between Css,ave and the change in Ki67 in tumor suggests that the drug concentration achieved had no noticeable effects on tumor proliferation, consistent with the lack of clinical response. In addition, the association between Css,ave and AGP suggests that erlotinib concentrations are tightly linked to AGP levels. Decreased clearance in the presence of high AGP levels has been described for several other highly protein-bound drugs, suggesting that determination of pretreatment levels may aid in predicting systemic exposures to erlotinib.37,38 Serial FDG-PET scans were obtained to explore the utility of a noninvasive imaging tool to measure the effects of erlotinib. Correlations were detected between PET and CT parameters, which suggest that the technical aspects of PET imaging were optimal, although an obvious limitation was the small number of patients that underwent serial PET scans. To use functional imaging with EGFR-directed therapy, novel imaging probes that specifically reflect EGFR inhibition need to be designed. In summary, we have demonstrated that obtaining concomitant tumor and surrogate tissue biopsies for assessment of the drug effect in a clinical trial is feasible. Inhibitory effects of erlotinib are evident in normal tissues and on an EGFR-positive tumor. Our data suggest that in addition to EGFR signaling, other markers or pathways may also be affected by erlotinib. We hope that gene expression profiling studies will help further define these effects of erlotinib or of other EGFR TK inhibitors.
The appendix is included in the full-text version of this article, available online at www.jco.org. It is not included in the PDF (via Adobe® Acrobat Reader®) version.
The authors indicated no potential conflicts of interest.
We thank Richard Chang for his technical expertise.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
1. Lewis S, Locker A, Todd JH, et al: Expression of epidermal growth factor receptor in breast carcinoma. J Clin Pathol 43:385-389, 1990 2. Klijn JG, Berns PM, Schmitz PI, et al: The clinical significance of epidermal growth factor receptor (EGFR) in human breast cancer: A review on 5232 patients. Endocr Rev 13:3-17, 1992[Medline] 3. Sainsbury JR, Farndon JR, Needham GK, et al: Epidermal growth factor receptor status as predictor of early recurrence of and death from breast cancer. Lancet 1:1398-1402, 1987[Medline] 4. Nicholson S, Sainsbury JR, Halcrow P, et al: Expression of epidermal growth factor receptors associated with lack of response to endocrine therapy in recurrent breast cancer. Lancet 1:182-185, 1989[Medline] 5. Nicholson S, Richard J, Sainsbury C, et al: Epidermal growth factor receptor (EGFR): Results of a 6 year follow-up study in operable breast cancer with emphasis on the node negative subgroup. Br J Cancer 63:146-150, 1991[Medline]
6. Moyer JD, Barbacci EG, Iwata KK, et al: Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor receptor tyrosine kinase. Cancer Res 57:4838-4848, 1997
7. Pollack VA, Savage DM, Baker DA, et al: Inhibition of epidermal growth factor receptor-associated tyrosine phosphorylation in human carcinomas with CP-358,774: Dynamics of receptor inhibition in situ and antitumor effects in athymic mice. J Pharmacol Exp Ther 291:739-748, 1999 8. Nanney LB, Stoscheck CM, King LE Jr, et al: Immunolocalization of epidermal growth factor receptors in normal developing human skin. J Invest Dermatol 94:742-748, 1990[CrossRef][Medline] 9. Jost M, Kari C, Rodeck U: The EGF receptor: An essential regulator of multiple epidermal functions. Eur J Dermatol 10:505-510, 2000[Medline] 10. Wang SL, Milles M, Wu-Wang CY, et al: Identification of epidermal growth factor receptor in human buccal mucosa. Arch Oral Biol 35:823-828, 1990[CrossRef][Medline]
11. Albanell J, Rojo F, Averbuch S, et al: Pharmacodynamic studies of the epidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients: Histopathologic and molecular consequences of receptor inhibition. J Clin Oncol 20:110-124, 2002
12. Baselga J, Rischin D, Ranson M, et al: Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J Clin Oncol 20:4292-4302, 2002
13. Herbst RS, Maddox AM, Rothenberg ML, et al: Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: Results of a phase I trial. J Clin Oncol 20:3815-3825, 2002
14. Malik SN, Siu LL, Rowinksy EK, et al: Pharmacodynamic evaluation of the epidermal growth factor receptor inhibitor OSI-774 in human epidermis of cancer patients. Clin Cancer Res 9:2478-2486, 2003
15. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000
16. Soule HD, Maloney TM, Wolman SR, et al: Isolation and characterization of a spontaneously immortalized human breast epithelial cell line, MCF-10. Cancer Res 50:6075-6086, 1990 17. West KA, Brognard J, Clark AS, et al: Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells. J Clin Invest 111:81-90, 2003[CrossRef][Medline]
18. Ettenberg SA, Magnifico A, Cuello M, et al: Cbl-b-dependent coordinated degradation of the epidermal growth factor receptor signaling complex. J Biol Chem 276:27677-27684, 2001 19. Kennedy S, Merino MJ, Swain SM, et al: The effects of hormonal and chemotherapy on tumoral and nonneoplastic breast tissue. Hum Pathol 21:192-198, 1990[CrossRef][Medline]
20. McCarthy NJ, Yang X, Linnoila IR, et al: Microvessel density, expression of estrogen receptor alpha, MIB-1, p53, and c-erbB-2 in inflammatory breast cancer. Clin Cancer Res 8:3857-3862, 2002
21. Bauer KD, de la Torre-Bueno J, Diel IJ, et al: Reliable and sensitive analysis of occult bone marrow metastases using automated cellular imaging. Clin Cancer Res 6:3552-3559, 2000 22. Lepper ER, Swain SM, Tan AR, et al: Liquid-chromatographic determination of erlotinib (OSI-774), an epidermal growth factor receptor tyrosine kinase inhibitor. J Chromatogr B Analyt Technol Biomed Life Sci 796:181-188, 2003[Medline] 23. Freedman NM, Sundaram SK, Kurdziel K, et al: Comparison of SUV and Patlak slope for monitoring of cancer therapy using serial PET scans. Eur J Nucl Med Mol Imaging 30:46-53, 2003[CrossRef][Medline] 24. Agresti A: Categorical Data Analysis. New York, NY, John Wiley & Sons, 1990 25. Anderson GD: A mechanistic approach to antiepileptic drug interactions. Ann Pharmacother 32:554-563, 1998[Abstract]
26. Ma B, Prueksaritanont T, Lin JH: Drug interactions with calcium channel blockers: Possible involvement of metabolite-intermediate complexation with CYP3A. Drug Metab Dispos 28:125-130, 2000
27. Heinrich MC, Griffith DJ, Druker BJ, et al: Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood 96:925-932, 2000
28. Buchdunger E, Cioffi CL, Law N, et al: Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther 295:139-145, 2000
29. Prendergast GC, Davide JP, deSolms SJ, et al: Farnesyltransferase inhibition causes morphological reversion of ras-transformed cells by a complex mechanism that involves regulation of the actin cytoskeleton. Mol Cell Biol 14:4193-4202, 1994
30. Omer CA, Chen Z, Diehl RE, et al: Mouse mammary tumor virus-Ki-rasB transgenic mice develop mammary carcinomas that can be growth-inhibited by a farnesyl:protein transferase inhibitor. Cancer Res 60:2680-2688, 2000
31. Moasser MM, Basso A, Averbuch SD, et al: The tyrosine kinase inhibitor ZD1839 ("Iressa") inhibits HER2-driven signaling and suppresses the growth of HER2-overexpressing tumor cells. Cancer Res 61:7184-7188, 2001
32. Moulder SL, Yakes FM, Muthuswamy SK, et al: Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo. Cancer Res 61:8887-8895, 2001
33. Normanno N, Campiglio M, De LA, et al: Cooperative inhibitory effect of ZD1839 (Iressa) in combination with trastuzumab (Herceptin) on human breast cancer cell growth. Ann Oncol 13:65-72, 2002 34. Citri A, Alroy I, Lavi S, et al: Drug-induced ubiquitylation and degradation of ErbB receptor tyrosine kinases: Implications for cancer therapy. EMBO J 21:2407-2417, 2002[CrossRef][Medline] 35. Baselga J, Albanell J, Ruiz A, et al: Phase II and pharmacodynamic study of gefitinib (ZD1839) in patients with advanced breast cancer. Proc Am Soc Clin Oncol 22:7, 2003 (abstr 24)
36. Hidalgo M, Siu LL, Nemunaitis J, et al: Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol 19:3267-3279, 2001
37. Bruno R, Olivares R, Berille J, et al: Alpha-1-acid glycoprotein as an independent predictor for treatment effects and a prognostic factor of survival in patients with non-small cell lung cancer treated with docetaxel. Clin Cancer Res 9:1077-1082, 2003
38. Gambacorti-Passerini C, Zucchetti M, Russo D, et al: Alpha1 acid glycoprotein binds to imatinib (STI571) and substantially alters its pharmacokinetics in chronic myeloid leukemia patients. Clin Cancer Res 9:625-632, 2003 Submitted August 27, 2003; accepted April 14, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
