Mutant Non-small Cell Lung Cancer Patients Research Articles

EGFR mutations and response to gefitinib or erlotinib: A meta-analysis based on a comprehensive EGFR somatic mutation database (www.egfr-mutations.org)

22049 Background: Somatic EGFR mutations have been evaluated in numerous studies as potential predictive factors of response to tyrosine kinase inhibitors, such as gefitinib and erlotinib, for patients with non-small cell lung cancer (NSCLC). Methods: We used information from a comprehensive free-access online analytical database of somatic EGFR mutations in NSCLC (www.egfr-mutations.org) to identify studies reporting on the association between mutations and response to EGFR tyrosine kinase inhibitors. Studies were eligible if they reported on the treatment of unselected patients with advanced NSCLC. Between-study heterogeneity was assessed with the I2 statistic; small study effects were assessed using Begg's and Egger's tests. In the absence of large between-study inconsistency (I2 >50%), RRs were pooled using the Mantel-Haenszel method. Results: Out of a total 202 studies reporting on somatic EGFR mutations in NSCLC patients, 30 studies (1,437 patients) were considered eligible for this analysis; 28 (1,365 patients) assessed the association of mutational status with response to gefitinib and 2 (72 patients) with response to erlotinib. Overall, 482 somatic mutations were detected (33.5%). There was no evidence of large between-study inconsistency (I2 = 30.5%), but there was strong evidence of differential small study effects (p- values for Begg's and Egger's tests <0.01). The presence of any EGFR somatic mutation was highly correlated with response, RR= 6.4 (5.17–7.91). Patient ethnicity did not alter this association: non-Asians, RR= 7.92 (5.31–11.82); Asians, RR = 6.00 (4.68–7.70); interaction p-value = 0.25. Mutational status was a predictor of response both to gefitinib, RR = 6.38 (5.14–7.91) and erlotinib, RR= 7.29 (2.12–25.09); interaction p-value = 0.84. Conclusions: Our analysis provides large-scale empirical evidence that EGFR mutations are predictive of response to gefitinib and erlotinib for patients with advanced NSCLC. The effect of the mutations appears to be independent of ethnicity. A meta-analysis of patient-level data would allow more thorough evaluation of the interaction of clinico-pathological characteristics, mutational status and treatment efficacy. No significant financial relationships to disclose.

Gefitinib for non-small-cell lung cancer patients with epidermal growth factor receptor gene mutations screened by peptide nucleic acid-locked nucleic acid PCR clamp

This study was prospectively designed to evaluate a phase II study of gefitinib for non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. Clinical samples were tested for EGFR mutations by peptide nucleic acid-locked nucleic acid PCR clamp, and patients having EGFR mutations were given gefitinib 250 mg daily as the second treatment after chemotherapy. Poor PS patients omitted chemotherapy. Of 107 consecutive patients enrolled, samples from 100 patients were informative, and EGFR mutations were observed in 38 patients. Gefitinib was given to 27 patients with EGFR mutations, and the response rate was 78% (one complete response and 20 partial responses; 95% confidence interval: 58–93%). Median time to progression and median survival time (MST) from gefitinib treatment were 9.4 and 15.4 months, respectively. Grade 3 hepatic toxicity and skin toxicity were observed in one patient each. There were significant differences between EGFR mutations and wild-type patients in response rates (78 vs 14%, P=0.0017), and MST (15.4 vs 11.1 months, P=0.0135). A Cox proportional hazards model indicated that negative EGFR mutation was a secondary prognostic factor (hazards ratio: 2.259, P=0.036). This research showed the need for screening for EGFR mutations in NSCLC patients.

Mutations of the epidermal growth factor receptor (EGFR) gene in non-small cell lung cancer (NSCLC)

7070 Background: Mutations within tyrosine kinase domain of the EGFR gene have been identified as a potential predictor of EGFR inhibitor treatment for NSCLC patients. Detailed characteristics of EGFR gene mutations in NSCLC patients should be clarified, especially in correlation with their clinical and other genetic characteristics as well as EGFR-downstream signaling alternation. Methods: Mutations of EGFR, p53 and k-ras genes as well as hypermethylation of p16, RASSF1A and APC1A gene were examined on surgical specimens obtained from 230 NSCLC patients. Expression of p-AKT and p-MAPK was evaluated immunohistochemically. Results: Among all 230 cases, 82 cases (35.6%, 81 adenocarcinoma [Ad] cases and 1 large cell carcinoma [La] case) showed EGFR mutations (deletion mutations within the exon 19 in 51 and point mutations within the exon 21 in 31 cases). As EGFR mutations were observed exclusively in Ad or La cases (n=181), subsequent analyses were performed in these cases. Incidence of EGFR mutations was significantly higher in female than in male (66.7% vs. 28.0%, P<0.001), in non-smoker than in smoker (73.3% vs. 25.5%, P<0.001), and in well-to-moderately differentiated tumors than in poorly differentiated tumors (56.0% vs. 7.7%, P<0.001). The incidence of k-ras mutations within codon-12 was 6.8%, and no k-ras-mutated tumor showed EGFR mutation. EGFR mutation status was not correlated with p53 gene mutation status or hypermethylation status of any gene. There was no significant difference in expression status of p-AKT or p-MAPK according to the status of EGFR mutations. Conclusions: EGFR mutations were frequently observed in Ad patients without smoking history. EGFR mutations may play a key role in development of smoking-independent Ad. No significant financial relationships to disclose.

Arg72Pro P53 gene polymorphism: Clinical relevance and relation with P53 mutations in non-small cell lung cancer (NSCLC) patients

7158 Background: The aim of this study was to evaluate the clinical relevance of P53 gene codon 72 polymorphism (Arg72Pro) and its relation with P53 gene mutations in NSCLC patients (pts). Methods: Study group included 157 pts from the North Poland region (35 females and 122 males), aged from 34 to 78 years (mean 60) who underwent curative pulmonary resection between 1996 and 1998. Tumor types included squamous cell (95 pts), adenocarcinoma (41 pts), large cell carcinoma (9 pts), and mixed cell carcinoma (12 pts). Pathological TNM tumor stage distribution was as follows: I (70 pts), II (19 pts), IIIA (59 pts) and IIIB (9 pts). The control group matched for age and cigarette smoking consisted of 519 healthy subjects. P53 gene codon 72 polymorphism (Arg/Arg, Arg/Pro and Pro/Pro) was evaluated by PCR-RFLP and DHPLC methods. Results:The number of Pro allele vs Arg/Arg carriers was insignificantly higher in the NSCLC group than in controls (53.5% vs 46.2%, p=0.11). NSCLC odds ratio for the Pro allele carriers was 1.34 (95% CI: 0.94–1.91). In NSCLC patients polymorphic variants did not correlate with major clinical characteristics and survival. P53 mutations (evaluated by PCR/SSCP technique and sequencing) were found in 47 out of 157 tumor samples (29.9%). There was no correlation between P53 mutations and survival (p=0.87). The presence of Pro allele was associated with increased probability of P53 mutations (p=0.026). Conclusions:Arg72Pro P53 gene polymorphism may carry slightly increased risk of lung cancer and in NSCLC patients is strongly associated with ocurrence of P53 mutations. No significant financial relationships to disclose.

Arg72Pro P53 gene polymorphism: Clinical relevance and relation with P53 mutations in non-small cell lung cancer (NSCLC) patients

7158 Background: The aim of this study was to evaluate the clinical relevance of P53 gene codon 72 polymorphism (Arg72Pro) and its relation with P53 gene mutations in NSCLC patients (pts). Methods: Study group included 157 pts from the North Poland region (35 females and 122 males), aged from 34 to 78 years (mean 60) who underwent curative pulmonary resection between 1996 and 1998. Tumor types included squamous cell (95 pts), adenocarcinoma (41 pts), large cell carcinoma (9 pts), and mixed cell carcinoma (12 pts). Pathological TNM tumor stage distribution was as follows: I (70 pts), II (19 pts), IIIA (59 pts) and IIIB (9 pts). The control group matched for age and cigarette smoking consisted of 519 healthy subjects. P53 gene codon 72 polymorphism (Arg/Arg, Arg/Pro and Pro/Pro) was evaluated by PCR-RFLP and DHPLC methods. Results:The number of Pro allele vs Arg/Arg carriers was insignificantly higher in the NSCLC group than in controls (53.5% vs 46.2%, p=0.11). NSCLC odds ratio for the Pro allele carriers was 1.34 (95% CI: 0.94–1.91). In NSCLC patients polymorphic variants did not correlate with major clinical characteristics and survival. P53 mutations (evaluated by PCR/SSCP technique and sequencing) were found in 47 out of 157 tumor samples (29.9%). There was no correlation between P53 mutations and survival (p=0.87). The presence of Pro allele was associated with increased probability of P53 mutations (p=0.026). Conclusions:Arg72Pro P53 gene polymorphism may carry slightly increased risk of lung cancer and in NSCLC patients is strongly associated with ocurrence of P53 mutations. No significant financial relationships to disclose.