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Papers by aristea kalykaki

British Journal of Cancer, 2007

Classical' mutations in the EGFR tyrosine kinase domain (exons 18, 19 and 21) have been associate... more Classical' mutations in the EGFR tyrosine kinase domain (exons 18, 19 and 21) have been associated with sensitivity to tyrosine kinase inhibitors (TKIs) in patients with NSCLC. The aim of the current study was to evaluate whether other than the classical G719X, DEL19 and L858R mutations of EGFR confer sensitivity to TKIs. Genomic DNA was extracted from microdissected formalinfixed paraffin-embedded tumour tissue from 86 patients treated with gefitinib. Exons 18, 19 and 21 were amplified and subjected to direct sequencing. Eleven (13%) patients harboured the classical exon's 18, 19 and 21 mutations, while 14 (16%) had 'other' variants. There was a significantly higher percentage of 'never-smoker' patients with 'classical' EGFR mutations (P ¼ 0.002). Among patients with 'classical' mutations 3 patients achieved PR and 7 SD, while in the 'other' mutations group 10 patients had SD as best response. In the wild-type group, there were 3 patients with PR and 25 with SD. Median TTP was 16, 64 (P ¼ 0.002) and 21 weeks and median survival was 36, 78 and 67 weeks for patients with wild-type, 'classical' and 'other' EGFR mutations, respectively. The clinical relevance of 'other' EGFR mutation variants remains uncertain and requires further assessment in a prospective study.

Clinical Lung Cancer, 2009

British journal of cancer, Jan 16, 2008

In non-small-cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR) and K-RAS mutation... more 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 o...

Proc Amer Assoc Cancer Res, Volume 47, 2006 5091 Purpose: We report ten novel EGFR mutations at e... more Proc Amer Assoc Cancer Res, Volume 47, 2006 5091 Purpose: We report ten novel EGFR mutations at exons18 and 21 from a series of NSCLC patients treated with gefitinib. Patients and Methods: Genomic DNA was extracted from microdissected formalin fixed paraffin-embedded tumor tissue and was amplified by nested PCR reactions for exons 18, 19, and 21 of EGFR. Sequencing was performed using forward and reverse nested primers with the ABI Prism 3100 DNA Analyzer. Results: Five novel mutations were identified in exon 18 and 5 in exon 21. Patient’s characteristics, treatment with gefitinib and outcome arepresented in the table: Patient 1, ex-smoker with squamous cell carcinoma carried a novel mutation in exon 21 and he is without disease progression after 160+ weeks with gefitinib. Patient 5 carried a novel mutation in exon 18 in primary tumor but no mutation could be detected in adrenal relapse; he achieved a PR for 146 weeks with gefitinib. Patient 3, smoker with squamous cell carcinoma, c...

Forum of Clinical Oncology

Introduction Several studies show that mutational profiles could influence treatment decisions in... more Introduction Several studies show that mutational profiles could influence treatment decisions in patients with metastatic CRC (mCRC). KRAS mutational status was the first step in biomarkers development in the era of molecular targeted therapies. Recently, NRAS mutational status was identified as an independent prognostic factor for the response to treatment with anti-EGFR moAbs. The aim of this observational study was to assess the feasibility of the KRAS/NRAS mutational analysis in patients with metastatic colorectal cancer in Greece and to identify any correlations with known clinical characteristics and histopathologic features. Methods From January 2014 until September 2014 all patients registered to the GIC-SG database with newly diagnosed metastatic disease from colon or rectal cancer were included and tumor samples were analyzed for kras/nras mutations in 9 different certified laboratories in Greece. Results Samples from 510 patients were analyzed. Mutations’ distribution wa...

PLoS ONE, 2013

Background: To prospectively evaluate the usefulness of the BRAFV600E mutation detection in daily... more Background: To prospectively evaluate the usefulness of the BRAFV600E mutation detection in daily clinical practice in patients with metastatic Colorectal Cancer (mCRC). Patients and Methods: 504 mCRC patients treated with systemic chemotherapy ± biologics were analyzed. Results: A statistically significant higher incidence of the BRAF mutation was observed in patients with ECOG-PS 2 (p=0.001), multiple metastatic sites (p=0.002),> 65 years old (p=0.004), primary tumors located in the colon (p<0.001), high-grade tumors (p=0.001) and in those with mucinous features (p=0.037). Patients with BRAFV600E mutated tumors had a statistically significantly reduced progression-free survival (PFS) compared to wild-type (wt) ones (4.1 and 11.6 months, respectively; p<0.001) and overall survival (OS) (14.0 vs. 34.6 months, respectively; p<0.001). In the multivariate analysis the BRAFV600E mutation emerged as an independent factor associated with reduced PFS (HR: 4.1, 95% CI 2.7-6.2; p<0.001) and OS (HR: 5.9, 95% CI 3.7-9.5; p<0.001). Among the 273 patients treated with salvage cetuximab or panitumumab, the BRAFV600E mutation was correlated with reduced PFS (2.2 vs. 6.0 months; p<0.0001) and OS (4.3 vs. 17.4 months; p<0.0001). Conclusions: The presence of BRAFV600E-mutation in mCRC characterizes a subgroup of patients with distinct biologic, clinical and pathological features and is associated with very poor patients' prognosis.

Cancer Investigation, 2015

Polymorphisms in ERCC1, XPD, and XRCC1 were examined for (a) association with the clinical outcom... more Polymorphisms in ERCC1, XPD, and XRCC1 were examined for (a) association with the clinical outcome of 107 non-small cell lung cancer patients receiving front-line platinum-based chemotherapy, and (b) correlation with the ERCC1 mRNA levels of 176 chemo-naive primary tumors. The ERCC1-C8092 allele and the number of ERCC1 polymorphic variants (C8092A and Asn118Asn) were associated with progression-free survival. In non-squamous histology, tumoral ERCC1 mRNA levels were lower in patients homozygous for ERCC1-C8092 as compared with the patients carrying the A allele (p = .024). These findings merit investigation in larger cohorts of patients treated with uniform regimens.

PLoS ONE, 2014

Introduction: Circulating tumor cells (CTCs) could represent a non-invasive source of cancer cell... more Introduction: Circulating tumor cells (CTCs) could represent a non-invasive source of cancer cells used for longitudinal monitoring of the tumoral mutation status throughout the course of the disease. The aims of the present study were to investigate the detection of KRAS mutations in CTCs from patients with metastatic colorectal cancer (mCRC) and to compare their mutation status during treatment or disease progression with that of the corresponding primary tumors. Materials and Methods: Identification of the seven most common KRAS mutations on codons 12 and 13 was performed by Peptide Nucleic Acid (PNA)-based qPCR method. The sensitivity of the assay was determined after isolation of KRAS mutant cancer cells spiked into healthy donors' blood, using the CellSearch Epithelial Cell kit. Consistent detection of KRAS mutations was achieved in samples containing at least 10 tumor cells/7.5 ml of blood. Results: The clinical utility of the assay was assessed in 48 blood samples drawn from 31 patients with mCRC. All patients had PIK3CA and BRAF wild type primary tumors and 14 KRAS mutant tumors. CTCs were detected in 65% of specimens obtained from 74% of patients. KRAS mutation analysis in CTC-enriched specimens showed that 45% and 16.7% of patients with mutant and wild type primary tumors, respectively, had detectable mutations in their CTCs. Assessing KRAS mutations in serial blood samples revealed that individual patient's CTCs exhibited different mutational status of KRAS during treatment. Conclusions: The current findings support the rationale for using the CTCs as a dynamic source of tumor cells which, by reevaluating their KRAS mutation status, could predict, perhaps more accurately, the response of mCRC patients to targeted therapy.

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, 2013

Metastasis is the main cause of mortality in patients with colorectal cancer. However, most of th... more Metastasis is the main cause of mortality in patients with colorectal cancer. However, most of the targeted therapies and predictive molecular biomarkers were developed based mainly on primary tumors. The current study was conducted to determine the degree of discordance between potential predictive and/or prognostic molecular markers in primary colorectal tumors and corresponding metastases, as this could have an impact on the efficacy of targeted therapies in the advanced colorectal cancer. KRAS, PIK3CA and BRAF mutations were determined by Sanger sequencing and mutant-enriched polymerase chain reaction (PCR) assays in 83 paired samples, MET gene copy number by quantitative PCR in 59, MET expression by immunohistochemistry in 73 and nuclear and cytoplasmic expression of PTEN by immunohistochemistry in 78 and 71 pairs, respectively. A certain degree of discordance between primary tumors and corresponding metastases was demonstrated for all examined biomarkers except BRAF mutations....

Lung cancer (Amsterdam, Netherlands), 2010

Somatic mutations in EGFR and K-RAS may predict for sensitivity and resistance to EGFR tyrosine k... more Somatic mutations in EGFR and K-RAS may predict for sensitivity and resistance to EGFR tyrosine kinase inhibitors (TKIs). Whether EGFR and K-RAS mutations could also predict clinical outcome of non-small cell lung cancer (NSCLC) patients following front-line chemotherapy has not yet been established. One hundred and sixty-two chemotherapy-naïve patients with locally advanced/metastatic NSCLC who received front-line chemotherapy were included in this retrospective study and their clinical outcome data was analyzed according to EGFR and K-RAS mutation status of their tumors. Classical activating EGFR and K-RAS mutations were found in 8.2 and 22.6% of patients respectively and were not associated with patients' clinicopathological characteristics. Patients with classical EGFR mutations had a higher probability of response to front-line chemotherapy as compared to those with wild type EGFR (p=0.023). Multivariate analysis showed that the presence of activating EGFR mutations was an ...