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O. Juan



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    P1.06 - Poster Session 1 - Prognostic and Predictive Biomarkers (ID 161)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.06-058 - The PHALCIS Trial (PHarmacogenomic ALimta CISplatin): A clinical trial in progress by The Spanish Lung Cancer Group (ID 3425)

      09:30 - 09:30  |  Author(s): O. Juan

      • Abstract

      Background
      The inherent molecular heterogeneity prevents the efforts to improve outcomes for patients with non-small cell lung cancer (NSCLC). Platinum doublets are the standard option for the treatment of advanced NSCLC, but none of the platinum-based combinations used offer a significant advantage over the others. Pemetrexed is an antifolate antimetabolite that inhibits several key folate-dependent enzymes, mainly thymidylate synthase (TS). A phase III trial conducted in the first-line setting of advanced NSCLC demonstrated that survival was statistically superior for cisplatin plus pemetrexed in patients with adenocarcinoma (12.6 versus 10.9 months; HR 0.84, P = 0.03), and large-cell carcinoma (10.4 versus 6.7 months; HR 0.67; P = 0.0 3 compared with cisplatin plus gemcitabine (1). Preclinical data have indicated that overexpression of TS correlates with reduced sensitivity to pemetrexed (2). Baseline expression of the TS gene is superior in squamous cell carcinoma compared with adenocarcinoma (P < 0.0001) (3). BRCA1 is a component of multiple DNA repair pathways and functions as a molecular determinant of response to a range of cytotoxic chemotherapeutics agents. The analysis of BRCA expression levels in patients who had received neoadjuvant gemcitabine/cisplatin chemotherapy found that patients with low levels of BRCA1 had longer survival (P = 0.01) compared to those with high expression levels (4). RAP80 is an interacting protein that form complexes with BRCA1 and could modulate the effect of BRCA1. In patients with non-squamous lung carcinoma, survival was influenced by RAP80 expression (5). Taking into account this background, the Spanish Lung Cancer Group has started a phase IIA study of pemetrexed plus cisplatin as first line treatment for advanced/metastatic non-squamous lung carcinoma. The availability of tissue samples for analysis of expression of BRCA1, RAP80 and thymidylate synthase is mandatory. The primary objective is response rate adjusted for different expression levels of BRCA1, RAP80 and TS. Secondary objectives are OS, TTP and toxicity profile of the combination and its relationship with the biomarkers. The expected total number of patients accrued will be 90. Forty-nine patients have been included up to now. References Scagliotti GV, Parikh P, Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naïve patients with advanced-stage non–small-cell lung cancer. J Clin Oncol 2008. Sigmond J, Backus HH, Wouters D, et al. Induction of resistance to the multitarged antifolate pemetrexed in WiDr human colon cancer cells is associated with thymidylate synthase overexpression. Biochem Pharmacol 2003. Ceppi P, Volante M, Saviozzi S, et al. Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase. Cancer 2006. Taron M, Rosell R, Felip E, et al. BRCA1 mRNA expression levels as an indicator of chemoresistance in lung cancer. Hum Mol Genet 2004. Rosell R, Perez-Roca L, Sanchez JJ, et al. Customized treatment in non-small cell lung cancer based on EGFR mutations and BRCA1 expression. PLoS ONE 2009.

      Methods
      Not applicable

      Results
      Not applicable

      Conclusion
      Not applicable

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    P2.22 - Poster Session 2 - Epidemiology, Etiology (ID 167)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      P2.22-008 - Analysis of family history of cancer in women with lung cancer (WLC) from the Spanish WORLD07 database (ID 2430)

      09:30 - 09:30  |  Author(s): O. Juan

      • Abstract

      Background
      Gender differences in lung cancer (LC) have been reported, but with many unresolved issues . Family history of cancer might play an important role in lung cancer, especially in never-smoker patients. The aim of this study was to analyze potential clinical, molecular and epidemiological differences between WLC with or without family history of cancer.

      Methods
      WORLD07 is a Spanish prospective, multicenter, epidemiologic female-specific LC database sponsored by ICAPEM, a professional association committed with WLC research. Clinicopathologic data, tumor genotype, family and personal history of cancer were collected and analyzed in order to detect differences between both groups.

      Results
      From October/2007 to November/2012, 2081 WLC were included in an e-database from 32 centers. Family history of cancer was common (49.4%, in first-degree was 77%), family history of lung cancer was present in 33%, of breast cancer in 25% and of colorectal cancer in 17%. No differences in median age of diagnosis of LC, previous hormonal therapy, number of children, menstrual status, tumor histology or stage at diagnosis were observed between WLC with or without family history of cancer. WLC with family history of cancer were ever smokers in a higher percentage (63% vs 56%, p=0.006), with no differences in passive smokers. The presence of EGFR mutations was similar in WLC with family history of cancer versus WLC without family history (38% vs 37%), although WLC patients with family history of cancer had a higher rate of exon 21 mutation (36% vs 28%), both in smokers WLC (32% vs 16%, p=0.220) and in never smokers WLC (43% vs 32%, p=0.094). The median overall survival was 25 months (CI95% 21.0-29.0) for WLC with family history of cancer and 22.0 months (CI95% 19.4-24.5) for patients without family history of cancer (p=0.027). Of note, the median overall survival was 34.8 months (CI95% 22.9-46.6) for WLC with family history of LC and 22.5 months (CI95% 20.5-24.5) for patients without family history of LC (p< 0.001).

      Conclusion
      The presence of familiar history of cancer in WLC patients included in the WORLD07 database was high (49.4%), being lung cancer the most common, followed by breast cancer. No clinical or pathologic characteristic differences were observed between patients with or without family history of cancer. The presence of EGFR mutations was similar, although WLC patients with family history of cancer had a higher rate of exon 21 mutation. The median overall survival was significantly higher in WLC patients with family history of cancer and LC. Family history of cancer, especially of LC, might have a role in LC development and deserves further studies focused in inherited genetic alterations related with an increased susceptibility to LC.

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    P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.06-035 - Study of the correlations between SNPs in angiogenic genes and treatment response/ outcome in patients with advanced NSCLC (non-squamous histology) treated in first line with carboplatin, paclitaxel and bevacizumab (CPB). The ANGIOMET study. (ID 2664)

      09:30 - 09:30  |  Author(s): O. Juan

      • Abstract

      Background
      It has been demonstrated that the addition of bevacizumab to paclitaxel plus carboplatin (CPB) in the treatment of advanced NSCLC improves survival. Even though, there is a high variability in drug efficacy between patients, leading to different response rates. ANGIOMET is an exploratory study promoted by the SLCG in advanced NSCLC, non-squamous histologies (NS-NSCLC) treated in first line with a combination scheme based in CPB, designed to investigate the relationship between angiogenic mediators and the outcome and response to treatment. The primary end-point was progression-free survival (PFS), and the secondary end-points are the follows: OS, response-rates and toxicity profiles.

      Methods
      In this multicentric study, patients with stage IIIB/IV NS-NSCLC (ECOG status 0–2) were included and treated in first line with CPB. Peripheral blood samples were collected before treatment administration and DNA was purified from the leukocyte fraction. Ten SNPs of VEGF-pathway genes were genotyped in 186 samples by RT-PCR in duplicate. SNPs were related to PFS and OS (Kaplan-Meir method, log-rank test) and to response rate.

      Results
      10 SNPs were determined in 186 DNA samples. In this preliminary analysis there were data from 108 patients valid for PFS and OS analysis. Baseline characteristics of the patients were: median age, 63 years [37-80]; 74.5% male; 94.1% ECOG PS 0-1; 14% never-smokers, 100% caucasian; 89.7% adenocarcinomas, 2.8% large cell carcinomas; median number of CPB cycles was 4. There was no response assessment in 27 patients (25%), 30.6% PR, 31.5% SD and 13.0% PD. The SNP rs833061 (CC) in VEGFA correlated with lower response rates to CPB than the other genotypes (p=0.07). SNPs in KRAS and VEGFR2 were associated with PFS and/or OS in our cohort. The KRAS SNP rs10842513 (TT+CT) was associated with shorter PFS compared with the CC genotype (median: 5.39 vs 6.81 months; p=0.04, respectively). The VEGFR2 SNP rs2071559 (AA) was significantly associated with longer PFS and OS (Table 1). No significant differences in PFS or OS were observed according to other SNPs analyzed. Table 1: PFS and OS for VEGFR2 SNPrs2071559.

      PFS
      % Median (months) 95%CI p
      VEGFR2 (rs2071559)
      AA 25.6 9,408 5,084 - 13,732 0.01
      GG+AG 74.0 5,724 4,902 - 6,546
      OS
      % Median (months) 95%CI p
      VEGFR2 (rs2071559)
      AA 25.6 NR ---- 0.001
      GG+AG 74.0 12,270 8,760 – 15.780

      Conclusion
      These preliminary data indicate that genetic variation in VEGFR2, SNP rs2071559 variant AA, is associated with prognosis in advanced NS-NSCLC patients treated with CPB and may have predictive implications as biomarkers in patients treated with chemotherapy with bevacizumab. On behalf of the Spanish Lung Cancer Group (SLCG)

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    P3.09 - Poster Session 3 - Combined Modality (ID 214)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 1
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      P3.09-016 - A phase II study of cisplatin and oral vinorelbine concomitantly with radiotherapy in locally advanced non-small-cell lung cancer treatment: Eficacy and safety results. (ID 2687)

      09:30 - 09:30  |  Author(s): O. Juan

      • Abstract

      Background
      It has been shown an improvement in survival with concurrent chemoradiation versus the sequential administration of both treatment modalities. In patients with unresectable stage III disease, chemotherapy may best be started soon after the diagnosis of unresectable NSCLC has been made. Cisplatin (CDDP) plus oral vinorelbine (OV) as induction and concomitant regimen with radiotherapy (RT) has shown good efficacy outcomes and safety profile (Vokes, Fournel, Krzakowski). The objective of this study was to evaluate the effectiveness and toxicities of the combination of CDDP and OV given at full doses concomitantly with RT in locally advanced (LA) non-small-cell lung cancer (NSCLC).

      Methods
      Between February 2010 and December 2011, 48 chemo-naïve patients (p) with histologically confirmed unresectable stage IIIA/IIIB LA NSCLC were treated. Treatment consisted of 4 cycles (cy) of OV 60 mg/m[2] on days 1 and 8 and CDDP 80 mg/m[2] every 3 weeks plus RT 66 Gy starting on day 1, cy 2. The primary objective is the overall response rate (ORR) using RECIST 1.0. A standard Fleming two stage design was used. The sample size calculated with a type 1 error of 0.05 and type 2 error of 0.01, taking P~0~ 20% and P~1~ 40%. The study was approved by the local Ethical Committees of the participating institutions.

      Results
      Patient’s characteristics were: Median age 61 years (range 34-72); ≥ 65y 42%; males 89.6%; PS0 42% / PS1 58%; smokers 52%; adenocarcinoma 30% / squamous 64%; stage IIIA 46% / IIIB 54%. Median of days between initial diagnosis and study start was 28 days. 75% p completed the treatment as per protocol. Relative dose intensities of OV and CDDP were 97%/98%, respectively. 14.7% of cy were delayed, 11.8% due to toxicity. Dose of day 8 OV was canceled or delayed in 8.2% of cy. Hematological toxicities (% p): grade (g) 3/4 neutropenia 33.3%; g3 anemia 12.5%; g3/4 thrombocytopenia 16.6%; febrile neutropenia concomitant during CT-RT 14.6%. Non-hematological toxicities (% p): g3 esophagitis 12.5%; g3 dyspnea 4.2%, g3 vomiting 4.2%, g3-4 infection 4.2%. 2 treatment-related deaths were reported, both during cycle 1. 42 p (87.5%) received RT, 7.1% under 60 Gy, 23.8% with RT delays or interruptions due to adverse events. 44 p were evaluable for response. ORR 77.3% [CI 95%, 62.2-88.5], DCR 88.6% [CR 2 p (4.5%), PR 32 p (72.7%), SD 5 p (11.4%)]. Median follow-up was 19 months (m) (range 0.47-39.4). Median progression free survival (PFS), 12 m [CI 95%, 7.3-16.6]; 1-year PFS, 48.3% [CI 95%, 33.6-63], 2-year PFS, 30% [CI 95%, 15.8-44.2]. Median time to progression (TTP), 13.3 m [CI 95%, 9.7-16.9]; 1-year TTP, 51.7% [CI 95%, 36.9-66.6], 2-year TTP, 33.3% [18.5-48.1]. Median overall survival was not reached; 1-year and 2-year survival rates were, 72.3% [CI 95%, 59.6-85.1] and 49.4% [CI 95%, 33.8-64.9], respectively.

      Conclusion
      This prospective phase II trial shows that the schedule of cisplatin plus oral vinorelbine concomitant with radiotherapy from 2[nd] cycle obtains a good efficacy with an acceptable safety profile. Clinical trial information: EudraCT Number: 2009-010436-17