Excision cross-complementing group 1 (ERCC1) single nucleotide polymorphisms (SNPs) and survival in cisplatin (cis)/docetaxel (doc)-treated stage IV non-small cell lung cancer (NSCLC) patients (p): A Spanish Lung Cancer Group study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7053-7053 ◽  
Author(s):  
M. Taron ◽  
V. Alberola ◽  
G. Lopez Vivanco ◽  
C. Camps ◽  
R. De Las Peñas ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Excision Repair ◽  
Performance Status ◽  
Stage Iv ◽  
Dna Lesions ◽  
Taqman Assay ◽  
Nucleotide Polymorphisms ◽  
Cancer Group ◽  
Nucleotide Excision Repair Pathway ◽  
Nsclc Patients

7053 Background: SNPs are the result of historical errors in DNA replication or repair that have been inherited through generations and are now shared among individuals. ERCC1 belongs to the nucleotide excision repair pathway. We examined whether ERCC1 SNPs 118 C/T and C8092A affect the repair of cis DNA lesions and thereby influence survival in cis-treated NSCLC p. Methods: SNP genotyping of ERCC1 118C/T and C8092A was performed by the TaqMan assay, and results were correlated with median survival (MS) in 706 cis/doc-treated stage IV NSCLC p. Results: Characteristics: 590 male, 116 female; performance status (PS) 0: 216 p (30.6%), PS 1: 480 p (68%), PS 2: 10 p (1.4%); adenocarcinoma, 371 p (53%). Overall response rate: 30%. After a median follow-up of 7.8 months (m) (range, 1–47 m), overall MS was 8.9 m. SNP frequencies: 118 T/T, 40.2%; C/T, 45.4%; C/C, 14.4%; C8092A C/C, 57.6%; C/A, 36%; A/A, 6.4%. MS according to 118 C/T SNP: T/T, 8.9 m; C/T, 9.5 m; C/C, 10 m (P = 0.51). MS according to C8092A SNP: C/C, 9.3 m; C/A, 10.2 m; A/A, 7.2 m (P = 0.05). When stratified by PS, the association between C8092A and MS is stronger for p with PS 0: C/C, 15.9 m; C/A, 13.8 m; A/A, 8.7 m (P = 0.04). Conclusions: This is the largest study to date reporting the effect of ERCC1 C8092A SNP on MS in stage IV NSCLC p treated with a single regimen. The uncommon A/A genotype predicts poor survival in p treated with dis/doc. No significant financial relationships to disclose.

Excision repair cross complementing 6 (ERCC6) single nucleotide polymorphism (SNP) and outcome to gemcitabine (gem)/cisplatin (cis) or docetaxel (doc)/cis in stage IV non-small cell lung cancer (NSCLC) patients (pts)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7605-7605
Author(s):  
O. Etxaniz ◽  
M. Provencio ◽  
J. Terrasa ◽  
A. Carrato ◽  
P. Lianes ◽  
...  
Keyword(s):  
Chemotherapy Regimen ◽  
Excision Repair ◽  
Performance Status ◽  
Stage Iv ◽  
Gender Performance ◽  
Differential Sensitivity ◽  
Taqman Assay ◽  
Base Excision ◽  
Nsclc Patients ◽  
Base Excision Dna Repair

7605 Background: ERCC6 (alternate name CSB) is involved in both transcription coupled and base excision DNA repair, and the ERCC6 C-6530>G SNP is involved in gene regulation. Different levels of ERCC6 mRNA expression have been observed in cells according to ERCC6–6530 genotype. Methods: We investigated the ERCC6 C-6530>G SNP in 309 stage IV NSCLC pts treated with doc/cis (196 pts) and gem/cis (113 pts). DNA was extracted from peripheral lymphocytes and Taqman assay was used for SNP typing. Results: Distribution of ERCC6 genotypes was: CC 113 pts (36.6%); CG 157 pts (50.8%); GG 39 pts (12.6%). No differences in genotype were observed according to age, gender, performance status (PS), histology, chemotherapy regimen or second-line treatment. Overall time to progression (TTP) was 5.4 months (m) and median survival (MS) 9.9 m. No differences in TTP or MS were observed according to ERCC6 SNP types. However, when pts were broken down by chemotherapy regimen, TTP was 7 m for 31 CC pts treated with gem/cis and 5.4 m for 71 CC pts treated with doc/cis (P=0.04) ( Table ). MS was longer for CC pts treated with gem/cis (11 m) than for CC pts treated with doc/cis (8.9 m) (P=0.46). Differences were also observed in pts with PS 0 and in younger pts. Conclusions: ERCC6 C-6530>G SNP may confer differential sensitivity to gem or doc in combination with cis. We hypothesize that ERCC6 6350 CC is a surrogate of ERCC6 transcript, where lower ERCC6 expression levels may increase the activity of gem/cis in comparison to doc/cis. No significant financial relationships to disclose. [Table: see text]

Efficacy and pharmacogenomic correlation of the combination of oxaliplatin and paclitaxel in first line advanced non-small cell lung cancer (NSCLC). Preliminary results of the Spanish Lung Cancer Group (SLCG) 0103 phase II trial

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7122-7122 ◽  
Author(s):  
P. Garrido Lopez ◽  
D. Isla ◽  
B. Gil ◽  
M. López-Brea ◽  
P. Lianes ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Performance Status ◽  
Taqman Assay ◽  
Nucleotide Polymorphisms ◽  
Toxicity Profile ◽  
Time To Progression ◽  
First Line ◽  
Single Nucleotide ◽  
First Line Therapy ◽  
Cancer Group

7122 Background: Ox is an attractive platinum analogue that has not been fully explored in NSCLC. We tested the combination of ox/pac as first-line therapy in NSCLC. We also assessed single nucleotide polymorphisms (SNPs) in several DNA repair genes (XRCC1 Arg399Gln, XRCC3 Met241Thr, XPD Lys751Gln and XPD Asp312Asn) and correlated the results with outcome in these patients (p). Methods: 68 stage IIIB (pleural effusion) and IV NSCLC p received up to 6 cycles of p 200 mg/m2 on day 1 plus ox 130 mg/m2 on day 2 every 21 days. Response was assessed after the third and sixth cycles. SNPs were determined by TaqMan assay in peripheral blood extracted at baseline Results: p characteristics: median age 62; 82% male; performance status 0, 54.5%; adenocarcinoma 48%; CNS metastases (mets), 15%, liver mets, 17%. 259 cycles delivered. Grade (G) 3–4 toxicity profile: neutropenia 11%; febrile neutropenia 8%; neurosensory (G3) 5%; asthenia (G3) 8%; diarrhea (G3) 5%. Laryngodysesthesia was observed in 1 p. There were 2 deaths due to neutropenic fever. In 52 evaluable p, overall response rate was 48% (PR 46%, CR 2%, SD 6%, PD 21%). Median time to progression was 4.4 months (m) (95% CI, 2.9–5.9 m). Median survival was 7.9 m (95% CI, 5.5–10.3 m). Conclusions: The combination of ox/pac offers similar results to other platinum-based regimens with an acceptable different toxicity profile and without a significant increase in neurotoxicity. Final data on response, time to progression and survival according to SNPs will be presented. No significant financial relationships to disclose.

Single nucleotide polymorphisms (SNPs) of the platinum pharmacogenetic and VEGF pathways: Association with survival of platinum-treated stage IV non-small cell lung cancer (NSCLC) patients.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7586-7586
Author(s):  
Sinead Cuffe ◽  
Xiaoping Qiu ◽  
Abul Kalam Azad ◽  
Xin Qiu ◽  
Kevin Boyd ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Clinical Outcome ◽  
Systemic Therapy ◽  
Proportional Hazards ◽  
Stage Iv ◽  
Significant Snps ◽  
Cox Proportional Hazards ◽  
Nucleotide Polymorphisms ◽  
Vegf Pathway ◽  
Nsclc Patients

7586 Background: Two potentially important host pathways in lung cancer systemic therapy are: (i) the pharmacogenetic pathway of platinum agents (DNA repair, metabolism, and multidrug resistance genes); and (ii) the vascular endothelial growth factor (VEGF) pathway. We investigated the relationship between SNPs in these two pathways and clinical outcome in platinum-treated NSCLC patients. Methods: 188 platinum-treated Stage IV NSCLC patients underwent SNP genotyping for the platinum-related (48 SNPs in 7 genes) and VEGF (64 SNPs in 3 genes) pathways. SNPs were selected from the literature and through tagging. Association of SNPs and overall (OS) and progression free survival (PFS) were assessed using multivariate Cox proportional hazards models. Results: 72% were Caucasian; 73%, adenocarcinoma; 92%, ECOG PS 0-1; median age, 60 years; 54% received > one line of systemic therapy; 10% received anti-VEGF therapy/placebo; Median OS, 1.3 yrs; median follow up, 2.2 yrs. The top significant SNPs in the platinum-related pathway were in ABCC2 (rs8187710 and rs2756109, r2=0.68). The G variants of the top SNP, ABCC2 rs8187710 (4554G>A), were associated with worse OS (adjusted hazard ratio [aHR], 2.62; 95%CI: 1.5-4.5; p=0.0005) and PFS (aHR, 1.97; 95%CI: 1.2-3.4; p=0.01). Functionally, 4554G>A impairs ATP-ase activity and is associated with higher cellular accumulation of ABCC2 substrates [PMID: 22027652]; furthermore, ABCC2 expression is associated with cisplatin resistance and clinical outcome in other cancers [PMID: 17145840]. Within the VEGF pathway, the top significant SNPs were in the same haplotype block of VEGFR1/FLT1 (rs1324057, rs7324547, r2=1.0): for rs1324057, the aHR for OS was 1.59 (95%CI 1.2-2.1); p=0.001; and the aHR for PFS, 1.48 (95%CI 1.1-1.9); p=0.004. VEGFR1/FLT1 rs7324547 has been associated with esophageal cancer risk [PMID: 21751195], but has not been assessed in lung cancer. Conclusions: SNPS of the VEGFR1 and ABCC2 genes are strongly associated with OS and PFS in this cohort of platinum-treated advanced NSCLC patients. Future studies should assess whether these are predictive or prognostic markers.

Role of ERCC1, XRCC3, Aurora A and TGFBR1 single-nucleotide polymorphisms (SNP) and CHFR and 14–3-3σ methylation in a customized cisplatin (cis) trial based on ERCC1 mRNA levels in stage IV non-small cell lung cancer (NSCLC) patients (pts)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7687-7687
Author(s):  
M. Taron ◽  
M. Cobo ◽  
D. Isla ◽  
B. Massuti ◽  
A. Montes ◽  
...  
Keyword(s):  
Performance Status ◽  
Stage Iv ◽  
Taqman Assay ◽  
Lower Probability ◽  
Mrna Levels ◽  
Nucleotide Polymorphisms ◽  
Aurora A ◽  
Specific Pcr ◽  
Best Response

7687 Background: The primary aim of this trial was response. In both the control arm and in the genotypic arm with low tumor ERCC1 mRNA levels, pts received docetaxel (doc)/cis; in the genotypic arm with high tumor ERCC1 mRNA levels, pts received doc/gemcitabine. Response was significantly higher in the genotypic arms. We examined 324 pts for genetic markers that could influence response, including ERCC1 118 C/T, ERCC1 C8092A, XRCC3 241 (Thr to Met), Aurora A 91 T>A, Aurora A 169G>A, a SNP within intron 7 of the TGFBR1 gene (Int7G24A), and an in-frame germline deletion (TGFBR1*6A). Methylation of 14–3-3s and CHFR were also analyzed. Methods: DNA from peripheral lymphocytes was used for genotyping (Taqman assay) and methylation-specific PCR was used for 14–3- 3s and CHFR in pretreatment serum DNA. Results: There were no differences in clinical characteristics among the different SNP types, except that pts with Aurora A 91 AA had higher tumor ERCC1 mRNA levels (P=0.005). No relationship was found between ERCC1 SNPs and tumor ERCC1 mRNA levels. A strong correlation was found between the Int7G24A and XRCC3 241 SNPs (P=0.03). The Int7G24A GA type had a higher odds ratio (OR) of response (OR 2.32) than the AA type (OR 3.15) (P=0.02). XRCC3 241 MetMet had a lower probability of response (OR 0.23) (P=0.04). No other differences in response were observed according to any of the other SNPs or methylation. In the multivariate model, the best response was observed in pts with performance status (PS) 0, low ERCC1 levels, and XRCC3 241 SNP ( Table ). Conclusions: Further research is warranted to define the role of theTGFBR1 Int7G24A gene in customized treatments. No significant financial relationships to disclose. [Table: see text]

Predictive Molecular Markers: Has the Time Come for Routine Use in Lung Cancer?

2004 ◽  
Vol 2 (2) ◽  
pp. 125-131 ◽  
Author(s):  
Angela M. Davies ◽  
Philip C. Mack ◽  
Primo N. Lara ◽  
Derick H. Lau ◽  
Kathleen Danenberg ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Molecular Markers ◽  
Excision Repair ◽  
Performance Status ◽  
Growth Factor Receptor ◽  
Taxane Resistance ◽  
Molecularly Targeted Agents ◽  
Epidermal Growth ◽  
Pathway Inhibition ◽  
Nsclc Patients

Although some evidence exists to support the use of clinical factors such as performance status and weight loss to predict response and toxicity to therapy in non-small cell lung cancer (NSCLC) patients, researchers have shown little prospective data on the use of molecular markers to facilitate selection of specific chemotherapy or new molecularly targeted agents in this patient population. Breast cancer exemplifies the growing role that molecular markers are playing, not only as prognostic factors, but also in predicting response to targeted treatments such as hormonal therapy, and more recently, trastuzumab (Herceptin). Although several studies have examinedmolecular markers in lung cancer and have shown promising potential value, these studies were retrospective and require prospective validation. To identify molecular markers that reliably predict response and to be able to individualize cytotoxic and targeted therapy for NSCLC patients are the ultimate goals of future trials. This article focuses on a selected number of promising markers under study in lung cancer, including those thought to play roles in response to DNA damaging chemotherapy (excision repair cross-complementing [ERCC1], xeroderma pigmentosum group D [XPD]), taxane resistance (-tubulin III), antimetabolite therapy (RRM1), irinotecan metabolism (UGT1A1) and epidermal growth factor receptor (EGFR) pathway inhibition. To date, none of these markers can be recommended for routine use in clinical practice.

TGFBR1*6A germline deletion in gemcitabine (gem)/cisplatin (cis)-treated stage IV non-small cell lung cancer (NSCLC) patients (p)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18171-18171
Author(s):  
M. Domine ◽  
V. Alberola ◽  
J. Muñoz-Langa ◽  
M. A. Muñoz-Quintana ◽  
M. A. Molina ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Signal Sequence ◽  
Performance Status ◽  
Stage Iv ◽  
Small Cell ◽  
Small Cell Lung ◽  
Pcr Products ◽  
Nsclc Patients ◽  
Length Analysis ◽  
Genotype Response

18171 Background: An in-frame germline deletion variant (TGFBR1*6A) in the TGFBR1 gene results in loss of three alanines within the 9-alanine (*9A) repeat in the receptor. Compared with *9A, *6A is a less effective mediator of TGFB antiproliferative signals. Methods: We examined the germline deletion TGFBR1*6A in 107 gem/cis-treated stage IV NSCLC p. DNA was extracted from peripheral lymphocytes and deletion was analyzed by length analysis of fluorescently labeled PCR products. Results: Median age, 65 (range, 32- 81); male, 100 p (93%. Performance status (PS) 0, 39 p (37%); PS 1, 52 p (48.5%); PS 2, 26 p (24.5%). Adenocarcinoma: 56 p (52%). 71.6% of p had the *9A/*9A genotype; the remaining 28.4% had the *6A/*9A genotype. Response was observed in 37 p (34.5%). Overall median survival (MS) was 8 months (m). There were no differences in response or MS between p harboring the *9A/*9A genotype and those with the *6A/*9A genotype. There was a trend towards longer MS in p with PS 0 with *9A/*9A genotype (11 m) than in thoase with *6A/*9A (3 m) (P=0.06). Conclusions: Although the findings of this study do not identify significant differences between *6A and *9A, the fact that the shorter signal sequence could confer a tumor growth advantage merits further investigation. No significant financial relationships to disclose.

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