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R. Rosell



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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 - 16:30  |  Author(s): R. Rosell

      • 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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    P2.18 - Poster Session 2 - Pathology (ID 176)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P2.18-006 - HER2 and BRAF mutations in non-small-cell lung cancer (NSCLC) patients (p). (ID 1243)

      09:30 - 16:30  |  Author(s): R. Rosell

      • Abstract

      Background
      Treatment of non-small-cell lung cancer (NSCLC) has changed drastically in recent years with an increase in rates of detection of driver mutations in a subgroup of NSCLC patients (p); the most recent mutations described in NSCLC are HER2 and BRAF. Overexpression of HER-2 (insertion in exon 20) occurs in 2-6% of NSCLC patients and is more common in women, never-smokers, Asian and adenocarcinoma hystology (adc). BRAF is found in 1.6-4.9% of p, with a higher rate of V600E mutations in smokers, and non-V600E mutations in non-smokers.

      Methods
      We systematically analyzed HER2 and BRAF mutations in EGFR wild type and non-translocated ALK p and retrospectively reviewed the results. Forty six NSCLC p were included between December 2011 to June 2013. Clinical characteristics such as histological subtype, sex, age, smoking status, and mutational status were analyzed. BRAF mutation was assessed by Taqman based assay (5’ nuclease activity) in an AB 7900HT system, with specific primers and probes for V600E positions. HER2 insertion was assessed using Sanger sequencing. All samples were PCR amplified and sequenced in AB 3130, using specific primers for exon 20.

      Results
      All patients were Caucasian; 25 p (54.3%) were women and 21 p (45.7%) men. Fourteen p (30.4%) were never-smokers, 11 (23.9%) former smokers and 19 (41.3%) smokers. Median age was 58.74 years. Forty one p (89.1%) had adc, 2 had squamous cell histology and 3 had another histology (1carcinod tumour, 1 large cell lung cancer and 1 poorly differentiated NSCLC) . Two p (4.3%) had BRAF V600E mutation: 1 female and 1 male, with median age of 56.5, both smokers. One 65 year old, female, never-smoker p (2.2%) had HER-2 insertion. All mutations were found in adc.

      Conclusion
      Analysis of less common driver mutations such as BRAF and Her2 mutations is feasible for daily clinical practice and could be useful to decide treatment. In our European population, incidence of BRAF and HER-2 mutation is similar to that previously reported (4.3% and 2.2%). Both p with BRAF V600E mutation were smokers, and the p with mutation in HER-2 was a 65 year-old female never-smoker.