Comparison Between Epidermal Growth Factor Receptor (EGFR) Gene Expression in Primary Non-small Cell Lung Cancer (NSCLC) and in Fine-Needle Aspirates from Distant Metastatic Sites

Bozzetti, Cecilia; Tiseo, Marcello; Lagrasta, Costanza Annamaria; Nizzoli, Rita; Guazzi, Annamaria; Leonardi, Francesco; Gasparro, Donatello; Spiritelli, Elena; Rusca, Michele; Carbognani, Paolo; Majori, Maria; Franciosi, Vittorio; Rindi, Guido; Ardizzoni, Andrea

doi:10.1097/jto.0b013e31815e8ba2

Cited by 61 publications

(44 citation statements)

References 17 publications

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“…4). Consistent with these findings, two previous studies comparing primaries and related metastases again suggested that in non -small-cell lung cancer, the nonhomogeneous FISH patterns of EGFR GCN might yield discrepancies in 27% and 32% paired samples (25,26). Of note, according to our data, there is no evidence to claim that a systematic difference of mean EGFR GCN between primary tumors and metastatic lesions could underlie these discrepancies.…”

Section: Discussionsupporting

confidence: 75%

Clinical Usefulness of EGFR Gene Copy Number as a Predictive Marker in Colorectal Cancer Patients Treated with Cetuximab: A Fluorescent In situ Hybridization Study

Personeni¹,

Fieuws²,

Piessevaux

et al. 2008

Clinical Cancer Research

159

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Purpose: To evaluate the usefulness and the pitfalls inherent to the assessment of the epidermal growth factor receptor (EGFR) gene copy number (GCN) by fluorescence in situ hybridization (FISH) for outcome prediction to cetuximab in metastatic colorectal cancer. The value of testing KRAS mutation status, in addition to EGFR GCN, was also explored. Experimental Design: FISH analysis of 87 metastatic colorectal cancer patients treated with cetuximab was done, recording individual GCN per cell and using different samples per tumor. Performances of published cutoff points and different summaries of EGFR GCN distribution were assessed for response prediction. Results: In our data set, two published cutoff points performed less well than in their training set, yielding positive predictive values and negative predictive values between 40.0% and 48.3% and between 81.0% and 86.5%, respectively. Among summaries of GCN distribution explored, mean and right-tailed distribution of GCN yielded the highest performances. A mean EGFR GCN z2.83 provided an area under the curve of 0.71. Important heterogeneity of repeated measures of mean EGFR GCN was observed within tumors (intraclass correlation, 0.61; within-class SD, 0.40), leading to potential misclassifications of FISH status in 7 of 18 (38.8%) patients if a cutoff point were used. In multivariable analysis, EGFR GCN testing provided significant information independent of the KRAS status to predict response (P = 0.016) and overall survival (P = 0.005). Conclusions: We confirm the association between increased EGFR GCN and outcome after cetuximab. However, because of reproducibility concerns, any decision making based on published cutoff points is not warranted.Novel strategies that target the epidermal growth factor receptor (EGFR) have led to the clinical development of a variety of agents, including small inhibitory molecules and monoclonal antibodies (mAb). Two such mAbs, panitumumab and cetuximab, are active in metastatic colorectal cancer, but only subgroups of patients respond to these agents (1 -3) and reliable markers predictive of treatment benefit still need to be defined.Variations of gene copy numbers (GCN), either in terms of gains or losses, reflect the many different routes taken by individual tumors to disrupt/escape mechanisms governing normal cellular behavior. These genomic aberrations have been successfully investigated by fluorescence in situ hybridization (FISH) in a number of malignancies. Importantly, three recently published series have reported on enhanced sensitivity to anti-EGFR mAbs in colorectal cancer patients harboring an increase of mean EGFR GCN by FISH (4 -6). In most solid tumors, including non -small-cell lung cancer and colorectal cancer, the best characterized mechanisms underlying increased EGFR GCN are gene amplification and chromosome 7 polysomy (4 -7). Generally, amplification is representative of high-level genomic gain and it is readily identifiable by FISH. Conversely, polysomy mirrors variable degrees of chromosomal ga...

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Section: Discussionsupporting

confidence: 75%

Clinical Usefulness of EGFR Gene Copy Number as a Predictive Marker in Colorectal Cancer Patients Treated with Cetuximab: A Fluorescent In situ Hybridization Study

Personeni¹,

Fieuws²,

Piessevaux

et al. 2008

Clinical Cancer Research

159

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“…The discordance in EGFR mutation status was 28% and that in K-RAS was 24%. Similarly, two other studies in paired NSCLC tumours showed a discordance of 32 and 27% regarding the EGFR gene copy number (Italiano et al, 2006;Bozzetti et al, 2008), whereas another study including six NSCLC patients of Asian ethnicity reported a 100% concordance in regard to EGFR mutation status (Matsumoto et al, 2006). This discrepancy could be related to the different sites of the metastatic tumours analysed in this study (five different distant metastases), whereas in the Matsumoto's et al study, only tumour samples from brain metastases were included.…”

Section: Discussioncontrasting

confidence: 48%

Comparison of EGFR and K-RAS gene status between primary tumours and corresponding metastases in NSCLC

et al. 2008

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In non-small-cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR) and K-RAS mutations of the primary tumour are associated with responsiveness and resistance to tyrosine kinase inhibitors (TKIs), respectively. However, the EGFR and K-RAS mutation status in metastases is not well studied. We compared the mutation status of these genes between the primary tumours and the corresponding metastases of 25 patients. Epidermal growth factor receptor and K-RAS mutation status was different between primary tumours and corresponding metastases in 7 (28%) and 6 (24%) of the 25 patients, respectively. Among the 25 primary tumours, three 'hotspot' and two non-classical EGFR mutations were found; none of the corresponding metastases had the same mutation pattern. Among the five (20%) K-RAS mutations detected in the primary tumours, two were maintained in the corresponding metastasis. Epidermal growth factor receptor and K-RAS mutations were detected in the metastatic tumours of three (12%) and five (20%) patients, respectively. The expressions of EGFR and phosphorylated EGFR showed 10 and 50% discordance, in that order. We conclude that there is substantial discordance in EGFR and K-RAS mutational status between the primary tumours and corresponding metastases in patients with NSCLC and this might have therapeutic implications when treatment with TKIs is considered.

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“…As the number of patients was small in all of these studies, including the present study, it is difficult to interpret the differences. Tumor tissues in NSCLC can include histologically heterogeneous components and detection of positive or resistant EGFR mutant tumor cells may vary among different tumor sites [26,27]. As EGFR mutations were determined at initial diagnosis and not at initiation of erlotinib treatment, the biological features in the various sites of tumors may have changed somewhat during cytotoxic chemotherapies.…”

Section: Discussionmentioning

confidence: 99%

A phase II trial of erlotinib in patients with EGFR wild-type advanced non-small-cell lung cancer

Kobayashi

Koizumi

Agatsuma

et al. 2012

Cancer Chemother Pharmacol

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Comparison Between Epidermal Growth Factor Receptor (EGFR) Gene Expression in Primary Non-small Cell Lung Cancer (NSCLC) and in Fine-Needle Aspirates from Distant Metastatic Sites

Cited by 61 publications

References 17 publications

Clinical Usefulness of EGFR Gene Copy Number as a Predictive Marker in Colorectal Cancer Patients Treated with Cetuximab: A Fluorescent In situ Hybridization Study

Clinical Usefulness of EGFR Gene Copy Number as a Predictive Marker in Colorectal Cancer Patients Treated with Cetuximab: A Fluorescent In situ Hybridization Study

Comparison of EGFR and K-RAS gene status between primary tumours and corresponding metastases in NSCLC

A phase II trial of erlotinib in patients with EGFR wild-type advanced non-small-cell lung cancer

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