Kamila Wojas-Krawczyk

Predictive value of ERCC1 single-nucleotide polymorphism in patients receiving platinum-based chemotherapy for locally-advanced and advanced non-small cell lung cancer — a pilot study

Platinum-based chemotherapy is the main type of I-line treatment of advanced and non-operative NSCLC patients without EGFR gene mutation. The excision repair cross-complementation group 1 (ERCC1) is an enzyme that executes the incision of the damaged DNA strand and removes platinum-induced DNA adducts. We investigated whether ERCC1 gene polymorphism has an effect on the response to chemotherapy and survival in 43 patients with NSCLC treated with platinum-based chemotherapy. ERCC1 19007 T>C SNPs were assessed using a PCR-RFLP methods in DNA isolated from peripheral blood lymphocytes. Disease control occurred significantly (p = 0.045) more frequently in patients with CC or CT genotype compared to patients with TT genotype. Median PFS and OS for CC homozygous were 4 and 10.5 months, 4 and 12.5 months for CT heterozygous, but only 0.3 and 1.5 months for TT homozygous patients, respectively. The probability of PFS was significantly higher (HR = 0.438, 95% CI: 0.084–0.881, p = 0.03) and probability of OS was insignificantly higher (HR = 0.503, 95% CI: 0.129–1.137, p = 0.084) in patients with CC or CT genotype than in patients with TT genotype. Uncommon TT genotype of ERCC1 19007 T>C polymorphism could predict poor response and shortening of progression free survival in NSCLC patients treated with platinum-based I-line chemotherapy. The analysis of this polymorphism may serve as a promising tool in the qualification of advanced NSCLC patients for appropriate chemotherapy.

The Qualification of Docetaxel or Erlotinib for Second-Line Therapy Should Be Based on Clinical and Molecular Predictive Factors

Background: We evaluated the effectiveness of docetaxel or erlotinib in second-line treatment of non-small cell lung cancer (NSCLC) and focused on the impact of predictive factors on the outcome of therapy. Methods: 204 patients with progressive disease after platinum-based therapy were enrolled: 102 received an infusion of 75 mg/m2 of docetaxel and 102 received 150 mg of erlotinib orally. Results: Response rate (RR) was 6.9 and 8.8% for docetaxel and erlotinib, respectively. Progression-free survival (PFS) was 1.2 months for docetaxel and 1.6 months for erlotinib (hazard ratio, HR = 1.2, p = 0.17). Overall survival was 5.5 versus 7 months for docetaxel and erlotinib, respectively (HR = 1.35, p = 0.06). Using Cox regression, we found clinical factors (performance status and weight loss) with predictive values for RR and PFS in second-line-treated patients. Prior radiotherapy, smoking status and EGFR mutation might help to predict outcome of erlotinib treatment and βIII-tubulin mRNA expression that of docetaxel, but histopathological diagnosis did not have any predictive value. Conclusions: Erlotinib and docetaxel show similar efficacy in the treatment of NSCLC. The application of predictive factors may facilitate qualification for second-line treatment with both drugs.

Predictive value of ERCC1 and RRM1 gene single-nucleotide polymorphisms for first-line platinum- and gemcitabine-based chemotherapy in non-small cell lung cancer patients

Platinum-based chemotherapy with third generation drugs (such as gemcitabine) is an efficacious regimen of first-line treatment of patients with advanced, unresectable non-small cell lung cancer (NSCLC), without activating EGFR mutations. Mechanism of action of cytostatics are distortions in the DNA. ERCC1 and RRM1 are key proteins involved in the repair of DNA, thus, they may be responsible for the ineffectiveness of therapy. We investigated whether ERCC1 (19007C>T) and RRM1 (-37C>A) polymorphisms impact response to chemotherapy and survival in 62 patients with NSCLC treated with platinum and gemcitabine. Single nucleotide polymorphisms (SNPs) were assessed using a PCR-RFLP method in DNA isolated from PBLs. There were no statistically significant relationships between ERCC1 genotypes and response to therapy (p=0.581, χ2=1.09) as well as patient overall survival (OS). Carriers of the RRM1 AC genotype showed disease progression significantly more frequently (p=0.019, χ2=5.473) compared to carriers of the AA or CC genotypes. Carriers of the ERCC1/RRM1TT/CC genotype combination showed disease control significantly more frequently (p=0.047, χ2=3.95) compared to carriers of other genotype combinations. Patients with AA or CC genotypes of RRM1 showed significantly higher progression-free survival probability (p=0.0001, HR=0.39, 95% CI, 0.22-0.70) and OS probability (p=0.0104, HR=0.39, 95% CI, 0.18-0.82) compared to those with the AC genotype. In Cox regression model, poor performance status (p=0.0016, HR=4.78, 95% CI, 1.82-12.56), AC genotype of RRM1 gene (p=0.0414, HR=2.47, 95% CI, 1.04-5.87), lack of prior surgical treatment (p=0.0425, HR=4.71, 95% CI, 1.06-20.92) and lack of subsequent lines of treatment (p=0.0127, HR=3.23, 95% CI, 1.29-8.11) were significantly associated with shortening of patient survival. The analysis of RRM1 (-37C>A) more than ERCC1 (19007C>T) polymorphism may be a promising tool in the qualification of NSCLC patients for chemotherapy containing platinum compounds and gemcitabine.

Polymorphisms in TS, MTHFR and ERCC1 genes as predictive markers in first‑line platinum and pemetrexed therapy in NSCLC patients

AbstractPurpose We presented retrospective analysis of up to five polymorphisms in TS, MTHFR and ERCC1 genes as molecular predictive markers for homogeneous Caucasian, non-squamous NSCLC patients treated with pemetrexed and platinum front-line chemotherapy.MethodsThe following polymorphisms in DNA isolated from 115 patients were analyzed: various number of 28-bp tandem repeats in 5′-UTR region of TS gene, single nucleotide polymorphism (SNP) within the second tandem repeat of TS gene (G>C); 6-bp deletion in 3′-UTR region of the TS (1494del6); 677C>T SNP in MTHFR; 19007C>T SNP in ERCC1. Molecular examinations’ results were correlated with disease control rate, progression-free survival (PFS) and overall survival.ResultsPolymorphic tandem repeat sequence (2R, 3R) in the enhancer region of TS gene and G>C SNP within the second repeat of 3R allele seem to be important for the effectiveness of platinum and pemetrexed in first-line chemotherapy. The insignificant shortening of PFS in 3R/3R homozygotes as compared to 2R/2R and 2R/3R genotypes were observed, while it was significantly shorter in patients carrying synchronous 3R allele and G nucleotide. The combined analysis of TS VNTR and MTHFR 677C>T SNP revealed shortening of PFS in synchronous carriers of 3R allele in TS and two C alleles in MTHFR. The strongest factors increased the risk of progression were poor PS, weight loss, anemia and synchronous presence of 3R allele and G nucleotide in the second repeat of 3R allele in TS. Moreover, lack of application of second-line chemotherapy, weight loss and poor performance status and above-mentioned genotype of TS gene increased risk of early mortality.ConclusionThe examined polymorphisms should be accounted as molecular predictor factors for pemetrexed- and platinum-based front-line chemotherapy in non-squamous NSCLC patients.

The polymorphism of the CHRNA5 gene and the strength of nicotine addiction in lung cancer and COPD patients.

A rare variant of chromosomal region 15q25.1, marked by rs16969968 (substitution 1354G>A in CHRNA5), was found to be associated with increased lung cancer and nicotine-dependence risk. We attempted to confirm the relationship of the polymorphism of the CHRNA5 gene and nicotine-dependence strength measured by the Fagerström test with the serum cotinine level in lung cancer and chronic obstructive pulmonary disease (COPD) patients and healthy individuals. Polymorphism of the CHRNA5 gene was analyzed using the PCR-based restriction fragment length polymorphism method in 97 lung cancer patients, 99 COPD patients, and 98 healthy individuals. The Fagerström test was used as an instrument for assessing the intensity of physical addiction. Cotinine serum level was measured using an enzyme-linked immunosorbent assay. The frequencies of AA, AG, and GG genotypes were 10.5, 47.3, and 42.2%, respectively. The polymorphism of CHRNA5 did not have a significant influence on the elevated risk of lung cancer and COPD. The percentage of smokers did not differ between groups of study participants with different genotypes. However, the presence of the GG genotype decreased the risk of nicotine addiction strength (hazard ratio=0.238; 95% confidence interval 0.066–0.857; P<0.05). Moreover, allele A was presented more frequently in participants with a high level of nicotine dependence and in participants with early addiction onset (P<0.05). Serum cotinine level was significantly correlated with the results of the Fagerström test (P<0.001). The carriers of allele A expressed significantly higher levels of cotinine when compared with the carriers of the GG genotype (P=0.05). We report for the first time the relationship between the polymorphism of the CHRNA5 gene and the strength of nicotine addiction measured by multiple factors including the Fagerström test score.

EGFR gene mutations in patients with adenosquamous lung carcinoma.

Adenosquamous (ADSQ) carcinoma accounts for 1–4% of non‐small cell lung cancer (NSCLC). The origin of ADSQ carcinoma and its genetic background is not fully understood. Most studies concerning epidermal growth factor receptor (EGFR) mutation status are performed in adenocarcinoma, while there is limited information about the prevalence of this mutation in ADSQ‐bearing Caucasian patients and the efficacy of EGFR tyrosine kinase inhibitors.

The Applicability of a Predictive Index for Second- and Third-Line Treatment of Unselected Non-Small-Cell Lung Cancer Patients

Background: Tyrosine kinase inhibitors of EGFR (TKI-EGFR) induced response in only 10% of Caucasian non-small-cell lung cancer patients in second- or third-line treatment. Independent predictive factors for qualification to TKI-EGFR treatment have not been assessed. In 2008, a prognostic index was reported for patients treated with erlotinib in the BR.21 trial, but its application for real, unselected patients is limited. Objectives: Based on clinical and molecular factors of patients treated with erlotinib, we tried to create a predictive index which could be applied in real treatment practice. Methods: In a Cox regression model, we established 6 factors which affected overall survival for erlotinib treatment: performance status, erlotinib-induced rash, time from diagnosis to treatment, gender, weight loss and LDH level. We analyzed the risk factors of early progression and survival shorter than 6 months. In addition we included: time from first-line chemotherapy to erlotinib treatment, smoking status, mutation status in EGFR and anemia. Results: Our model consisted of 10 factors that were assigned points according to HR or χ2 and p value. The score was used to separate patients into 4 risk categories of unfavorable disease course based on 10th, 50th and 90th percentiles: low risk (I), intermediate low risk (II), intermediate high risk (III) and high risk (IV). Survival probability was significantly higher for group I, intermediate for groups II and III, and significantly lower for group IV (χ2 = 49.5, p < 0.0001). Based on the previously reported index we could not qualify our patients for the low risk group. Conclusions: Our model could be useful for qualification for erlotinib treatment of patients with numerous adverse factors and limited access to genetic examination.

Mechanisms of resistance to reversible inhibitors of EGFR tyrosine kinase in non-small cell lung cancer

Abnormalities of epidermal growth factor receptor (EGFR) in non-small-cell lung cancer (NSCLC) patients consist of EGFR overexpression and EGFR (HER1) gene mutations. Structural dysfunction of the tyrosine kinase domain of EGFR is associated with the clinical response to tyrosine kinase inhibitors (TKI) in patients with NSCLC. The most common EGFR gene mutations occur as either deletions in exon 19 or as substitution L858R in exon 21 and cause a clinically beneficial response to gefinitib or erlotinib treatment. Unfortunately, the majority of patients finally develop resistance to these drugs. Acquired resistance is linked to secondary mutations localised in the EGFR gene, mainly substitution T790M in exon 20. Through intense research a few different mechanisms of resistance to reversible tyrosine kinase inhibitors have been identified: amplification of MET or IGF-1R genes, abnormalities of PTEN and mTOR proteins as well as rare mutations in EGFR and HER2 genes. Extensively investigated new drugs could be of significant efficiency in NSCLC patients with secondary resistance to reversible EGFR TKI.

Prevalence of rare EGFR gene mutations in nonsmall-cell lung cancer: a multicenter study on 3856 Polish Caucasian patients

Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Poland GENIM Ltd. Institute of Genetics and Immunology, Lublin, Poland Department of Clinical Oncology, Medical University of Poznan, Poland Department of Pathology, Specialist Pulmonary Hospital of Sokolowski, Zakopane, Poland Regional Centre of Oncology M. Kopernik Hospital, Lodz, Poland Mazovian Centre for Treatment of Lung Diseases and Tuberculosis, Otwock, Poland Department of Neurosurgery and Pediatric Neurosurgery, Medical University of Lublin, Poland E.J. Zeyland Wielkopolska Center of Pulmonology and Thoracic Surgery, Poznan, Poland Regional Oncology Centre in Gdansk, Poland Department of Clinical Patomorphology, Medical University of Lublin, Poland

Screening of Gene Mutations in Lung Cancer for Qualification to Molecularly Targeted Therapies

© 2012 Krawczyk et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Screening of Gene Mutations in Lung Cancer for Qualification to Molecularly Targeted Therapies