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1.
J Thorac Cardiovasc Surg ; 135(5): 1036-41, 2008 May.
Article in English | MEDLINE | ID: mdl-18455581

ABSTRACT

OBJECTIVE: The objective of this study is to establish clinical evidence that the p53 genotype can serve as a predictive marker for response to cisplatin-based induction therapy. METHODS: Patients with advanced non-small cell lung cancer who had received neoadjuvant chemotherapy in the context of a prospective phase II trial were analyzed for the p53 genotype of their tumors. Response to induction therapy was then correlated to the p53 genotype as assessed by complete direct DNA sequencing. Patients had received 3 cycles of cisplatin and etoposide, and 1 cycle of simultaneous radiochemotherapy. All 3 treatment components mediate their cytotoxic effect through induction of apoptosis, which is suggested to require an intact p53 gene. In addition, the results from a previously published hypothesis-finding study are updated to demonstrate the consistency of clinical results and summarize currently available clinical evidence. RESULTS: In the phase II trial, 35 patients underwent resection after induction chemotherapy, allowing a pathohistologic response assessment. The presence of a mutant p53 genotype was highly indicative of resistance to induction chemotherapy (P < .002). The sensitivity of a mutant p53 genotype to identify nonresponders was 94% (71.3-99.9 confidence interval). A normal p53 gene was significantly associated with radical resection (P < .004) and survival advantage (P = .02). CONCLUSION: This is the second clinical evaluation demonstrating a significant relation between p53 genotype and response to induction therapy in non-small cell lung cancer. We conclude that the p53 genotype should be evaluated as a predictive marker for response to induction therapy in prospective randomized protocols.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/therapy , Genes, p53/genetics , Lung Neoplasms/genetics , Lung Neoplasms/therapy , Aged , Cisplatin/administration & dosage , Clinical Trials, Phase II as Topic , Combined Modality Therapy , Etoposide/administration & dosage , Genotype , Humans , Middle Aged , Neoadjuvant Therapy , Pneumonectomy , Predictive Value of Tests , Prospective Studies , Radiotherapy, Adjuvant , Treatment Outcome
2.
Wien Klin Wochenschr ; 116(1-2): 26-31, 2004 Jan 31.
Article in English | MEDLINE | ID: mdl-15030120

ABSTRACT

INTRODUCTION: The assessment of HER2/neu overexpression in tissue provides information about one of the most relevant prognostic and predictive markers in breast cancer: overexpression of HER2/neu is associated with worse prognosis in primary breast cancer. Since core needle biopsy is increasingly used for the diagnosis of breast cancer, the purpose of this study was to assess the reliability of HER2/neu evaluation using this technique in patients with primary breast cancer. PATIENTS AND METHODS: We investigated the accuracy of immunohistochemical assessment of HER2/neu in core needle biopsies compared with surgically obtained specimens in 325 patients with primary breast cancer. In patients strongly positive for HER2/neu, additional fluorescence in situ hybridization (FISH) analysis of needle biopsies was performed. RESULTS: Using immunohistochemistry alone, accuracy of HER2/neu assessment in core biopsies in relation to surgically removed specimens was 92% and increased to 96% with additional FISH analysis (weighted Kappa coefficient: 0.86). DISCUSSION: As proven with this large series of patients, the assessment of HER2/neu status by core needle biopsy in breast cancer is accurate. Notwithstanding, in order to minimize the number of false-positive results, strongly positive core needle biopsies identified using immunohistochemistry should be confirmed by FISH analysis.


Subject(s)
Breast Neoplasms/genetics , Carcinoma, Ductal/genetics , Carcinoma, Lobular/genetics , Genetic Markers/genetics , Receptor, ErbB-2/genetics , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Antineoplastic Agents/therapeutic use , Biopsy, Needle , Breast/pathology , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Breast Neoplasms/surgery , Carcinoma, Ductal/drug therapy , Carcinoma, Ductal/pathology , Carcinoma, Ductal/surgery , Carcinoma, Lobular/drug therapy , Carcinoma, Lobular/pathology , Carcinoma, Lobular/surgery , Chromosomes, Human, Pair 17 , Combined Modality Therapy , Female , Humans , In Situ Hybridization, Fluorescence , Middle Aged , Neoadjuvant Therapy , Predictive Value of Tests , Prognosis , Reagent Kits, Diagnostic , Trastuzumab
3.
Cancer ; 98(12): 2547-53, 2003 Dec 15.
Article in English | MEDLINE | ID: mdl-14669272

ABSTRACT

BACKGROUND: HER-2/neu is a valuable prognostic marker in primary breast carcinoma. Controversy surrounds the correlation between HER-2/neu expression and other prognostic markers, as has been discussed in preclinical and clinical studies. The objective of the current study was to investigate the probability, calculated using parameters that are assessed routinely in clinical practice, that patients with breast carcinoma had positive HER-2/neu status. METHODS: The authors evaluated HER-2/neu status in 923 consecutive patients with breast carcinoma by immunohistochemical methods. Correlations involving HER-2/neu status, estrogen receptor (ER) and progesterone receptor (PR) status, tumor grade, patient age, lymph node involvement, and tumor size were evaluated using the Mantel-Haenszel chi-square test and the Spearman correlation. The authors created a simple scoring system (i.e., the diagnostic instrument for validation of HER-2/neu score) to define subgroups of patients with breast carcinoma and to determine the likelihood of HER-2/neu positivity. RESULTS: HER-2/neu overexpression was correlated significantly with negative ER (P = 0.0001) and PR status (P = 0.0001), Grade 3 (G3) lesions (P = 0.0001), and young age (P = 0.006). The likelihood of HER-2/neu positivity in a patient with positive ER and PR status and G1/G2 disease was approximately 6.1%. CONCLUSIONS: The authors demonstrated in a large patient series that HER-2/neu overexpression was associated with negative hormone receptor status, G3, and young age. In a subgroup of patients presenting with hormone-responsive and G1/G2 tumors, the likelihood of HER-2/neu overexpression was very small. Therefore, the assessment of HER-2/neu status in this subgroup of patients with breast carcinoma may be considered unnecessary, unless the role of HER-2/neu status in adjuvant treatment has been proven.


Subject(s)
Biomarkers, Tumor/metabolism , Breast Neoplasms/diagnosis , Breast Neoplasms/metabolism , Receptor, ErbB-2/metabolism , Adult , Aged , Carcinoma, Ductal/diagnosis , Carcinoma, Ductal/metabolism , Carcinoma, Lobular/diagnosis , Carcinoma, Lobular/metabolism , DNA Probes , Female , Humans , Immunoenzyme Techniques , In Situ Hybridization, Fluorescence , Karyotyping , Lymph Nodes/pathology , Middle Aged , Neoplasm Staging , Prognosis , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Risk Factors
4.
Breast Cancer Res Treat ; 82(3): 207-13, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14703068

ABSTRACT

BACKGROUND: In primary breast cancer, the expression levels of biological markers relevant to the progression of the disease may be altered by administration of anticancer drugs. Since neoadjuvant chemotherapy with epirubicin and docetaxel is increasingly used in advanced breast cancer, our purpose was to assess the influence of this neoadjuvant chemotherapy on the expression of the growth factor receptor HER2/neu. PATIENTS AND METHODS: We investigated changes of HER2/neu status by immunohistochemistry (IHC) and applied additional fluorescence in situ hybridization (FISH) in patients with potential modulation of HER2/neu status after administration of neoadjuvant chemotherapy with docetaxel and epirubicin in 97 breast cancer patients. The influence of neoadjuvant chemotherapy on HER2/neu expression was calculated by correlation of HER2/neu status before and after chemotherapy. RESULTS: The accuracy of HER2/neu assessment before and after neoadjuvant chemotherapy by IHC combined with FISH analysis in selected cases was 100%. The evaluation of HER2/neu status in these patients by IHC alone yielded accuracy of 93%. Neoadjuvant chemotherapy with epirubicin and docetaxel caused no significant modulation of HER2/neu status (p = 0.66). DISCUSSION: The administration of epirubicin and docetaxel in the neoadjuvant setting is not associated with significant changes of HER2/neu status in primary breast cancer. As a consequence, drug resistance or sensitivity is not induced by modulation of HER2/neu expression. Moreover, the time of assessment of the HER2/neu status is not a critical factor under neoadjuvant therapy with epirubicin and docetaxel.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/analysis , Breast Neoplasms/drug therapy , Genes, erbB-2 , Adult , Aged , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Docetaxel , Epirubicin/administration & dosage , Female , Gene Expression Regulation, Neoplastic , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Middle Aged , Neoadjuvant Therapy , Taxoids/administration & dosage
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