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R. Garcia-Campelo



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    MO26 - Anatomical Pathology II (ID 129)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      MO26.08 - The concomitant presence of echinoderm microtubule associated protein like 4 - anaplastic lymphoma kinase (EML4-ALK) EML4-ALK fusion gene in EGFR-mutant non-small-cell lung cancer (NSCLC) patients treated with erlotinib or chemotherapy in the EURTAC trial</b> (ID 1109)

      11:10 - 11:15  |  Author(s): R. Garcia-Campelo

      • Abstract
      • Presentation
      • Slides

      Background
      Activating mutations in the epidermal growth factor receptor (EGFR) confer sensitivity to gefitinib and erlotinib in patients with NSCLC. However, response is often short-lived, and patients ultimately relapse, indicating that other concomitant actionable mutations could influence outcome in these patients. The EML4-ALK fusion gene has recently been identified in a subset of NSCLCs, but its specific role remains unclear. We have evaluated the frequency and impact of the concomitant presence of EML4-ALK in patients included in the randomized phase III EURTAC trial.

      Methods
      The EURTAC study enrolled 173 EGFR-mutant NSCLC patients who were randomized to receive erlotinib or standard chemotherapy with cisplatin or carboplatin plus docetaxel or gemcitabine. Tumor specimens were available from 95 of these patients for the analysis of EML4-ALK. EML4-ALK variants 1 and 3 (v1, v3) were analyzed by an independent single round of PCR followed by sequencing, using cDNA as a sample.

      Results
      EML4-ALK was detected in 15 samples (15.79%). Nine tumors contained v1 (E13;A20) and six v3 (E6;A20). No significant differences were found in baseline characteristics between patients with and without EML4-ALK. Progression-free survival was 10.4 months (m) for patients harboring the EML4-ALK fusion gene compared to 7.1 m for those without EML4-ALK. Overall survival (OS) was not reached in patients with EML4-ALK, compared to 22.9 m in those without. Complete data on outcome according to treatment arm will be presented.

      Conclusion
      Our findings indicate that the EML4-ALK rearrangement is concomitant with EGFR mutations in a considerable number of NSCLC patients and may affect outcome.

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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.11-046 - Women with lung cancer harboring epidermal growth factor (EGFR) mutations: prevalence, clinical characteristics and EGFR tyrosine kinase (TKI) treatment-related outcomes. Results from the Spanish WORLD07 database (ID 3078)

      09:30 - 09:30  |  Author(s): R. Garcia-Campelo

      • Abstract

      Background
      EGFR mutations define a distinct molecular subset of non-small-cell lung cancer patients (p). Prevalence, baseline clinical characteristics and outcomes for women with lung cancer harboring EGFR mutations would be of interest.

      Methods
      We analyzed the clinical characteristics of women with lung cancer harboring EGFR mutations included in the WORLD07, a Spanish prospective, multicenter, epidemiologic female-specific e-database.

      Results
      A total of 2081 newly-diagnosed women with lung cancer from 38 Spanish centers were included in the WORLD07 e-database from October/2007 to October/2012. Overall 915 p were evaluated for EGFR mutation status, and 342 of them were found to have EGFR mutation (16% of all p in the e-database, 37% of p tested). EGFR-mutated p characteristics: median age 64.6 years; 86% had offspring; 8.2% had used oral contraceptives; smoking habit: 72% never smokers, 14% current smokers, 13% former smokers; for those never smokers, second-hand smokers 35%; histology: 91% adenocarcinoma, 1.5% squamous cell carcinoma, 2% large-cell carcinoma, 5% other; EGFR mutation type: 60% deletions in exon 19, 32.5% L858R mutations, 8% exon 20 mutations, 1% exon 18 mutations, 14% unknown. Sixty-nine percent of p had stage IV disease. A total of 184 EGFR mutated p received an oral EGFRTKI as 1[st] line (ECOG PS: 0 in 24%, 1 in 53%, 2 in 13%, 4 in 4%, unknown in 5%) achieving a 59% response rate (RR), 20% stable disease (SD), 10% progression (PD) and 11% not evaluable (NE); with a median follow-up of 12 months, median overall survival for these p was 21 months. A total of 72 p received an EGFRTKI as 2[nd] line with 37% RR, 34% SD, 19% PD and 10% NE. Only 16 p received an EGFRTKI as 3[rd] line, achieving a 38% RR, 19% SD, 31% PD and 12.5% NE. For those EGFR mutated women receiving an EGFRTKI as 1[st] line, RR to an EGFRTKI was 70% in those women harboring deletion in exon 19, and 45% in those with L858R mutation; median overall survival was 24 months in those with deletion in exon 19, and 17 months in those with L858R mutation. Response rate to an EGFRTKI as 1[st] line treatment was 59% in never-smoker p and 53% in current-smoker/former-smoker p with a median overall survival of 23 months and 21 months, respectively.

      Conclusion
      According to our prospective e-database of women with lung cancer, not selected for clinical trials and including all histologies, a high proportion harbor an EGFR mutation (16% of non-selected women, 37% of those tested). The vast majority of women with lung cancer harboring EGFR mutation are never smokers, have adenocarcinoma histology and outcomes similar to those previously reported in the literature. Additional epidemiologic and treatment data will be presented at the meeting.

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    P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.06-012 - Impact of EGFR T790M mutations and BIM mRNA expression on progression-free survival (PFS) and overall survival (OS) in patients with EGFR-mutant non-small-cell lung cancer (NSCLC) treated with erlotinib or chemotherapy in the randomized phase III EURTAC trial (ID 1167)

      09:30 - 09:30  |  Author(s): R. Garcia-Campelo

      • Abstract

      Background
      Activating EGFR mutations confer sensitivity to EGFR tyrosine kinase inhibitors (TKIs) in patients with NSCLC, but responses are transient, with delay in disease progression but no impact on survival. Concomitant genetic alterations could account for these incomplete clinical responses. Erlotinib-treated EGFR-mutant NSCLC patients harboring the EGFR T790M mutation had shorter PFS than those without the mutation (12 vs 18 months [m]). Low BIM levels were associated with gefitinib resistance in EGFR-mutant NSCLC.

      Methods
      The efficacy results of the EURTAC trial were updated at January 24, 2013. We have evaluated the frequency and potential impact of pretreatment EGFR T790M mutations and BIM mRNA expression in 95 patients with EGFR-mutant NSCLC included in the EURTAC trial.

      Results
      T790M mutations were detected in 65.26% of patients. PFS to erlotinib was 9.7 m for those with T790M mutations and 15.8 m for those without, while among patients receiving chemotherapy, it was 6 and 5.1 m, respectively (P<0.0001). BIM expression was successfully analyzed in 83 patients. PFS to erlotinib was 12.9 m for those with high BIM levels and 7.2 m for those with low/intermediate BIM levels, while among chemotherapy-treated patients, it was 5.8 and 5.5 m, respectively (P=0.0003). OS was 28.6 m for patients with high BIM expression and 22.1 m for those with low/intermediate BIM expression (P=0.0364). The multivariate analyses showed that erlotinib was a marker of longer PFS (HR, 0.35; P=0.0003), while high BIM expression was a marker of longer PFS (HR, 0.49; P=0.0122) and OS (HR, 0.53; P=0.0323).

      Conclusion
      BIM mRNA expression is a biomarker of PFS and OS in EGFR-mutant NSCLC. T790M mutations and BIM mRNA expression can potentially be used for designing combination therapeutic strategies for use in lieu of EGFR TKI monotherapy.

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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): R. Garcia-Campelo

      • 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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    P3.01 - Poster Session 3 - Cancer Biology (ID 147)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.01-015 - <b>Outcome in pemetrexed/cisplatin-treated non-small-cell lung cancer (NSCLC) patients according to mRNA expression levels of BRCA1, TS, AEG1 and REV3 </b> (ID 1170)

      09:30 - 09:30  |  Author(s): R. Garcia-Campelo

      • Abstract

      Background
      REV3, the catalytic subunit of the translesion synthesis (TLS) polymerase x, can continue replication past DNA adducts. Depletion of REV3 sensitizes A549 lung cancer cells to cisplatin. REV3 expression is part of a gene signature that predicted pemetrexed sensitivity in 17 NSCLC cell lines. BRCA1, TS, AEG1 and RAP80 are involved in DNA damage repair through homologous recombination. The homologous recombination and TLS pathways have non-redundant functions in response to cisplatin. We hypothesized that low mRNA expression of these genes – either alone or in combination – could confer improved outcome to cisplatin/pemetrexed in NSCLC patients.

      Methods
      REV3, BRCA1, RAP80, TS and AEG1 mRNA expression was examined by quantitative RT-PCR and categorized by terciles. Expression of each gene was correlated with outcome in 47 cisplatin/pemetrexed-treated NSCLC patients.

      Results
      63.8% male; 47% smokers; 80.9% ECOG PS 1; 80.8% adenocarcinoma. Overall response rate was 51%, with no differences according to expression levels of any of the genes. Progression-free survival (PFS) for patients with low, intermediate and high BRCA1 levels was 13.4, 5.5 and 3.9 months (m), respectively (P=0.005). Similar differences in PFS were observed according to TS (P=0.003) and AEG1 (P<0.001) expression. The hazard ratio (HR) for PFS for patients with high BRCA1 levels was 4 (P=0.002). Overall survival (OS) for patients with low, intermediate and high BRCA1 levels was 29.7, 7.4 and 6.3 m, respectively (P=0.05). Similar differences in OS were observed according to TS (P=0.005) and AEG1 (P=0.001) expression. HR for OS for patients with high BRCA1 levels was 3.6 (P=0.004). There were no differences in PFS or OS according to REV3 or RAP80 levels. However, the joint effect of BRCA1 and REV3 was significant for predictive modeling. PFS for patients with low, intermediate and high levels of both genes was 14.9, 7.2 and 2.8 m, respectively (P=0.001). OS for patients with low, intermediate and high levels of both genes was 29.7, 7.8 and 6.3 m, respectively (P=0.04).

      Conclusion
      Low BRCA1 expression predicts longer PFS and OS in pemetrexed/cisplatin-treated NSCLC p. Low TS and AEG1 levels have similar predictive value. The combination of low BRCA1 and REV3 expression confers longer PFS and OS. Analysis of these genes could be useful for customizing pemetrexed/platinum chemotherapy.

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    P3.02 - Poster Session 3 - Novel Cancer Genes and Pathways (ID 149)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.02-009 - <b>ROR1 as a novel therapeutic target for EGFR-mutant non-small-cell lung cancer (NSCLC) patients with the EGFR T790M mutation</b> (ID 1395)

      09:30 - 09:30  |  Author(s): R. Garcia-Campelo

      • Abstract

      Background
      Molecular cross-talk between EGFR and other signaling pathways creates alternative means of tumor cell proliferation and promotes resistance to single-agent erlotinib therapy in NSCLC driven by EGFR mutations. ROR1 knockdown inhibited the growth of NCI-H1975 cells (harboring EGFR L858R and T790M mutations). A pro-survival function for ROR1/MEK/ERK signaling in cooperation with AKT has been demonstrated. We have assessed ROR1 expression in 45 patients from the EURTAC trial (clinicaltrials.gov NCT00446225), 27 of whom harbored pretreatment concomitant EGFR T790M mutations, and correlated results with outcome.

      Methods
      ROR1 mRNA expression was examined by quantitative RT-PCR and categorized by terciles; patients were classified as having low/intermediate or high ROR1 expression. The T790M mutation was determined by Taqman with a PNA to inhibit amplification of the wild-type (wt) allele. Tumor samples were run in octuplicates; this method can detect 1 mutated allele among 10,000 wt alleles.

      Results
      Median age 65; 68.9% female; 57.8% never-smokers; 95.6% ECOG PS <2; 91.1% adenocarcinoma; 68.9% exon 19 deletion. No differences in baseline characteristics were observed according to ROR1 expression levels. 24 patients (53.3%) were treated with erlotinib and 21 (46.7%) with chemotherapy. 10 (41.7%) erlotinib-treated patients and 6 (28.6%) chemotherapy-treated patients had high ROR1 mRNA levels. Among erlotinib-treated patients, response rate (RR) was 40% for the 10 patients with high ROR1 levels vs 71.4% for the 14 with low/intermediate levels (P=0.058). Among chemotherapy-treated patients, RR for the 15 patients with low/intermediate ROR1 levels was 6.7%; the 6 patients with high ROR1 levels did not respond. Progression-free survival (PFS) was 11.8 months (m) for erlotinib-treated patients with low/intermediate ROR1 levels vs 5.8 m for those with high levels. PFS for chemotherapy-treated patients was 5.6 and 9 m, respectively (P=0.0165). 15 erlotinib-treated patients harbored concomitant T790M mutations; for these patients, PFS was10.8 m for those with low/intermediate ROR1 levels vs 2.7 m for those with high levels (P=0.0138).

      Conclusion
      ROR1 expression has a differential effect on outcome to erlotinib and chemotherapy in EGFR-mutant NSCLC patients. High ROR1 expression significantly limits PFS in erlotinib-treated patients with T790M mutations and ROR1-directed therapies can enhance the efficacy of treatment. In contrast, high ROR1 expression confers longer PFS to chemotherapy in the same group of patients. The role of chemotherapy and erlotinib in EGFR-mutant NSCLC patients with high ROR1 expression warrants further investigation.

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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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      P3.06-006 - Integrated genomic analysis of EGFR-mutant non-small cell lung cancer immediately following erlotinib initiation in patients (ID 1003)

      09:30 - 09:30  |  Author(s): R. Garcia-Campelo

      • Abstract

      Background
      Major obstacles limiting the clinical success of EGFR TKI therapy in EGFR mutant non-small cell lung cancer (NSCLC) patients are heterogeneity and variability in the initial anti-tumor response to treatment. The underlying molecular basis for this heterogeneity has not been explored in patients immediately after initiation of therapy.

      Methods
      We conducted CT-guided core needle biopsies immediately prior to erlotinib treatment initiation and at 6 days and 60 days post erlotinib initiation in a patient with histologically confirmed NSCLC harboring an established activating mutation in EGFR. DNA and RNA from each of the frozen biopsies were analyzed by whole exome sequencing and whole transcriptome sequencing, respectively. High-resolution CT images were also obtained at the time of each biopsy to assess the degree of molecular and radiographic responses observed.

      Results
      Two established activating somatic mutations were identified in EGFR (p.G719A and p. R776H). Gene expression analysis revealed that several proapoptotic genes including BID, CASP3 and several growth inhibitory genes including GADD45B, GADD45G were upregulated at 6 days post erlotinib treatment, while at 60 days their expression levels decreased to below pretreatment levels. Other proapoptotic genes such as BAD and BAX and were noted to be upregulated most significantly 60 days, as was growth inhibitory gene CDKN1A. In contrast, the growth-promoting genes CCNB1 and CCND3 exhibited a progressive decrease in expression across time points. Whole exome sequencing demonstrated the progressive evolution of global copy number abnormalities. High-resolution CT scans revealed no interval radiographic change in tumor size after 6 days of erlotinib treatment, and a decrease in tumor size 60 days into therapy. No clinical complications were encountered.

      Conclusion
      This study is the first reported longitudinal integrated genomic analysis of EGFR-mutant NSCLC in a patient treated with an EGFR TKI. We documented the feasibility, safety and utility of this strategy to establish initial drug efficacy at the molecular level prior to any radiographic evidence of response (6 days), as well as evidence that acquired resistance can emerge early in the course of TKI therapy. Serial integrated genomic analysis is ongoing in other TKI treated patients to enhance the management of NSCLC patients on targeted therapy.