Biomedical subjects

Maria Sanchez-Ronco

Publications and source records attributed to Maria Sanchez-Ronco.

5 recordsLinked to original sources

PubMed2006

Methylation patterns and chemosensitivity in NSCLC.

Survival in advanced non-small-cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy is rather variable. Methylation-dependent transcriptional silencing of 14-3-3sigma, a major G2/M checkpoint control gene, could be a predictor of longer survival. A sensitive methylation-specific polymerase chain reaction assay was used to evaluate 14-3-3sigma methylation status in pretreatment serum DNA obtained from 115 cisplatin-plus-gemcitabine-treated advanced NSCLC patients. 14-3-3sigma methylation was observed in all histologic types in 39 patients (34%). After a median follow-up of 9.8 months, median survival was significantly longer in the methylation-positive group (15.1 vs 9.8 months; P = 0.004). Median time to progression was 8 months in the methylation-positive group, and 6.3 months in the methylation-negative group (P = 0.027 by the log-rank test). A multivariate Cox regression model identified only 14-3-3sigma methylation status and ECOG performance status (PS) as independent prognostic factors for survival. In an exploratory analysis, median survival for 22 methylation-positive responders has not been reached, while it was 11.3 months for 29 methylation-negative responders (P = 0.001). Methylation of 14-3-3sigma is a new independent prognostic factor for survival in NSCLC patients receiving platinum-based chemotherapy. It can be reliably and conveniently detected in the serum, thus obviating the need for tumor tissue analysis.

Antineoplastic Agents↗

PubMed2005

14-3-3sigma methylation in pretreatment serum circulating DNA of cisplatin-plus-gemcitabine-treated advanced non-small-cell lung cancer patients predicts survival: The Spanish Lung Cancer Group.

PURPOSE: Survival in patients with advanced non-small-cell lung cancer (NSCLC) who are treated with platinum-based chemotherapy is rather variable. Methylation-dependent transcriptional silencing of 14-3-3sigma, a major G2-M checkpoint control gene, could be a predictor of longer survival. PATIENTS AND METHODS: A sensitive methylation-specific polymerase chain reaction assay was used to evaluate 14-3-3sigma methylation status in pretreatment serum DNA obtained from 115 cisplatin-plus-gemcitabine-treated advanced NSCLC patients. RESULTS: 14-3-3sigma methylation was observed in all histologic types of 39 patients (34%). After a median follow-up of 9.8 months, median survival was significantly longer in the methylation-positive group (15.1 v 9.8 months; P = .004). Median time to progression was 8 months in the methylation-positive group and 6.3 months in the methylation-negative group (log-rank test, P = .027). A multivariate Cox regression model identified only 14-3-3sigma methylation status and Eastern Cooperative Oncology Group performance status as independent prognostic factors for survival. In an exploratory analysis, median survival for 22 methylation-positive responders has not been reached, whereas survival was 11.3 months for 29 methylation-negative responders (P = .001). CONCLUSION Methylation of 14-3-3sigma is a new independent prognostic factor for survival in NSCLC patients receiving platinum-based chemotherapy. It can be reliably and conveniently detected in the serum, thus obviating the need for tumor tissue analysis.

14-3-3 Proteins↗

PubMed2005

Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor are associated with improved survival in gefitinib-treated chemorefractory lung adenocarcinomas.

PURPOSE: Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) confer a strong sensitivity to gefitinib, a selective tyrosine kinase inhibitor of EGFR. EXPERIMENTAL DESIGN: We examined EGFR mutations at exons 18, 19, and 21 in tumor tissue from 68 gefitinib-treated, chemorefractory, advanced non-small cell lung cancer patients from the United States, Europe, and Asia and in a highly gefitinib-sensitive non-small cell lung cancer cell line and correlated their presence with response and survival. In addition, in a subgroup of 28 patients for whom the remaining tumor tissue was available, we examined the relationship among EGFR mutations, CA repeats in intron 1 of EGFR, EGFR and caveolin-1 mRNA levels, and increased EGFR gene copy numbers. RESULTS: Seventeen patients had EGFR mutations, all of which were in lung adenocarcinomas. Radiographic response was observed in 16 of 17 (94.1%) patients harboring EGFR mutations, in contrast with 6 of 51 (12.6%) with wild-type EGFR (P < 0.0001). Probability of response increased significantly in never smokers, patients receiving a greater number of prior chemotherapy regimens, Asians, and younger patients. Median survival was not reached for patients with EGFR mutations and was 9.9 months for those with wild-type EGFR (P = 0.001). EGFR mutations tended to be associated with increased numbers of CA repeats and increased EGFR gene copy numbers but not with EGFR and caveolin-1 mRNA overexpression (P = not significant). CONCLUSIONS: The presence of EGFR mutations is a major determinant of gefitinib response, and targeting EGFR should be considered in preference to chemotherapy as first-line treatment in lung adenocarcinomas that have demonstrable EGFR mutations.

Adenocarcinoma↗

PubMed2004

Gene expression as a predictive marker of outcome in stage IIB-IIIA-IIIB non-small cell lung cancer after induction gemcitabine-based chemotherapy followed by resectional surgery.

PURPOSE: The first suggestions of a relationship between gene mRNA expression and differential sensitivity to gemcitabine/cisplatin are now emerging. ERCC1, RRM1, and XPD are involved in the nucleotide excision repair pathways, and tumor up-regulation of these genes leads to chemotherapy failure. In the present study, we have examined the potential correlation and predictive value of ERCC1, RRM1, and XPD mRNA expression in resected specimens from 67 stage IIB, IIIA, and IIIB non-small cell lung cancer patients treated with neoadjuvant gemcitabine/platinum followed by surgery. EXPERIMENTAL DESIGN: ERCC1, RRM1, and XPD expression was quantified using real-time quantitative reverse transcription-PCR. RESULTS: A good correlation was found between mRNA expression levels of the three genes. For RRM1 levels, patients in the bottom quartile had a decreased risk of death compared with those in the top quartile (risk ratio = 0.30; P = 0.033). Median survival for the 17 patients in the bottom quartile was 52 months, whereas for the 15 in the top quartile, it was 26 months (P = 0.018). When the characteristics of these 17 patients were compared with all of the other 50 patients, no differences in initial staging were observed. However, the 17 patients in the bottom quartile had better outcomes, including more radiographic responses (65% versus 54%; P = 0.24), complete resections (94% versus 72%; P = 0.03), lobectomies (71% versus 34%; P = 0.004), and pathological complete responses (29% versus 0%; P = 0.00001). CONCLUSIONS: Patients with RRM1 levels in the bottom quartile benefited significantly from gemcitabine/cisplatin neoadjuvant chemotherapy, leading us to conclude that RRM1 mRNA levels should be additionally validated to proceed with tailored chemotherapy.

Aged↗

PubMed2004

Effect of the methylenetetrahydrofolate reductase C677T polymorphism on patients with cisplatin/gemcitabine-treated stage IV non-small-cell lung cancer.

Single nucleotide polymorphisms (SNPs) in the metabolic pathways of S-adenosylmethionine have been related to global hypomethylation and a lower number of hypermethylated CpG islands of tumor suppressor genes. Hypermethylation of checkpoint and DNA repair genes has been shown to be indicative of chemosensitivity. In the present study, we have examined the SNP of methylenetetrahydrofolate reductase (MTHFR) C677T, which affects DNA methylation patterns and is linked to elevated plasma homocysteine levels in 208 patients with gemcitabine/cisplatin-treated stage IV non-small-cell lung cancer (NSCLC). No differences in response rate were observed according to the MTHFR genotype. However, time to progression was 7.4 months for 68 patients with CC genotype, 5.5 months for 108 patients with heterozygous CT genotype, and 5.2 months for 28 patients with TT genotype. These findings can lead us to distinguish different outcome patterns among patients with stage IV NSCLC whose similar clinical prognostic factors would otherwise indicate similar outcomes. Carriers of the MTHFR 677T allele could benefit from supplementation with folic acid and vitamin B12. The Spanish Lung Cancer Group has undertaken a phase III randomized trial to elucidate this concept.

Adult↗