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T. Vavala'



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    E03 - Chemotherapy for NSCLC (ID 3)

    • Event: WCLC 2013
    • Type: Educational Session
    • Track: Medical Oncology
    • Presentations: 1
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      E03.4 - Lung Cancer in Women (ID 385)

      14:00 - 15:30  |  Author(s): T. Vavala'

      • Abstract
      • Presentation
      • Slides

      Abstract
      At the beginning of 20th century only a few hundred cases of lung cancer were diagnosed annually, but the progressive huge spread of tobacco consumption caused a dramatic increase of the incidence of this disease among men and later on among female smokers. US data shows that the prevalence of smoking in American women peaked in 1965 at 33% and remained at that level throughout the 1970s, before beginning to slowly decrease in 1980. In contrast, more than half of American men smoked before 1965, but the prevalence dramatically decreased during the subsequent 20 years. Currently, 18% of American women smoke compared with 23% of men, reflecting the earlier and more marked decline in the prevalence of tobacco use in men. Nowadays, more women in United States die from lung cancer each year than from breast, ovarian and uterine cancer combined: lung cancer is the leading cause of cancer death with more than 110,000 new cases and more than 72,000 estimated deaths in 2013. In European countries there are more than 79,000 new cases of lung cancer in female sex per year and 82,000 is the estimated death number in 2013, that means 9,024 more than what was reported in 2009. Approximately 80% - 85% of lung cancers in women are caused by cigarette smoking. Wang et al. investigated the association of both active and passive smoking on lung cancer risk in a prospective cohort of more than 90,000 post-menopausal women: the results of the Women’s Health Initiative Observational Study (WHI-OS) have been presented at 2013 ASCO annual meeting and evidenced an higher lung cancer incidence, particularly small cell lung cancers and squamous lung cancers, in current smokers (Hazard Ratio, HR 13.44, 95%, CI 10.80-16.75) and former smokers (HR 4.20, 95% CI 3.48-5.08) compared to never smokers. In the same study, among never smoking women, passive exposure, as an adult at home for > 30 years, was associated with a trend of increased risk (HR 1.61, 95% CI 1.00-2.58) for lung cancer, confirming findings of previous prospective cohort studies. In recent times, an increased proportion of non-smoking female patients, with earlier age at diagnosis and a majority of adenocarcinoma has been observed, particularly in Asian countries. Prevalence of lung cancer in females without history of tobacco smoking is estimated to represent 19% compared with 9% of male lung carcinoma in the United States. Freedman et al. reported, on a cohort of nearly 500,000 individuals, aged from 50 to 71 years, a significant increase in the rate of lung cancer for women who did not smoke, compared with male non-smokers, whereas no increased risk was described in current and former female smokers compared with matched males. Hormonal status is one of the potential explanations for gender differences. Estrogens are involved in lung tumorigenesis and progesterone receptor expression has been described in non small cell lung cancers (NSCLC). Combination of estrogen and progesterone works synergistically in vitro to promote vascular endothelial growth factor secretion increasing tumor-associated angiogenesis. Chlebowski et al. examined estrogen plus progestin (E+P) association with lung cancer incidence and outcome evaluating more than 30,000 postmenopausal women. Results have been presented at 2013 ASCO annual meeting: in non users of E+P, lung cancer incidence and deaths from lung cancer were significantly and substantially greater in current smokers versus never smokers (p< 0.0001 for both comparisons). In current smokers, lung cancer incidence and deaths from lung cancer were significantly and substantially greater in E+P users versus non-users (p=0.0021 and 0.0005, respectively), nearly doubling a smoker’s already high risk of death from lung cancer. Conversely, the role of androgens remains unclear. Harlos et al. evaluated more than 3,000 men with lung cancer evidencing that exposure to androgen deprivation therapy (ADT) is associated with significantly better survival when compared with no exposure. Patients exposed to ADT after their diagnosis were found to have a significantly better survival than those not exposed (HR 0.36 p=0.0007). This effect was also seen in those who received ADT before and after diagnosis (HR 0.53 p<0.0001). With regard to specific gene alterations there are relevant differences in men and women. The most widely recognized is the epidermal growth factor receptor (EGFR) mutation, that is found at a much higher frequency in adenocarcinomas, women, Asians and never smokers. Mutations in HER2 gene, although much rarer, target the same subpopulations. Mutations in EGFR (and HER2) are mutually exclusive of K-ras mutations: these are primarily observed in smokers and historically associated with male sex, but there are also publications demonstrating an higher frequency in women of “non-classical” type of K-ras mutations even if these data need further validations. The echinoderm microtubule associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) translocation has been evidenced to occur more frequently in young patients, light or never smokers, while no major differences have been clearly stated between genders. B-Raf (V600) is described in 2% of patients with lung adenocarcinoma in western countries, related with worse prognosis and it is noted more frequently in women. An analysis of the p53 mutation databases indicated that the different spectra of p53 mutational patterns among smoker and never smoker cancers were almost entirely a result of differences between lung cancers in women, whereas male tumours did not show significant differences. Finally, recent studies investigated the role of telomere shortening in lung cancer. Kim et al. hypothesized that relative telomere length may be associated with recurrence in early stage NSCLC after curative resection. Longer telomeres were significantly associated with higher risk of developing recurrence in female (HR 2.25; 95% CI, 1.02-4.96, P= 0.044) and adenocarcinoma subgroups (HR 2.19; 95% CI, 1.05-4.55). All these findings provide multiple evidence for the specificities of lung cancer in women. The different expression of specific biomarkers, which could be targeted by therapy, will improve research towards personalized sex-based investigations, stimulating the development of further gender-based approaches in thoracic oncology.

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    P1.10 - Poster Session 1 - Chemotherapy (ID 204)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.10-056 - The Elderly Patient Individualized Chemotherapy Trial (EPIC): A Randomized Phase III Multicenter Trial of Customized Chemotherapy versus Standard of Care for 1st Line Treatment of Elderly Patients with Advanced Non-Small-Cell Lung Cancer (ID 1117)

      09:30 - 16:30  |  Author(s): T. Vavala'

      • Abstract

      Background
      This is an ongoing phase III multicenter randomized trial comparing first line pharmacogenomic-driven chemotherapy based on Excision-Repair-Cross-Complementing-1 (ERCC1), Ribonucleotide Reductase subunit M1 (RRM1) and Thymidylate Synthase (TS) gene expression, versus standard first line treatment in elderly patients (pts) with advanced non-small-cell lung cancer (NSCLC). Chemotherapy selection based on an individual patient’s molecular profile is a potentially promising approach to optimize efficacy with the already available cytotoxic drugs. In older pts this is particularly relevant owing to their rapid deterioration of symptoms and their increased propensity to suffer therapy-induced toxicity.

      Methods
      Pts aged >70 years, with ECOG Performance Status (PS) 0 or 1, previously untreated for stage IV NSCLC will be evaluated. In a 2:1 fashion, pts will be randomized to experimental arm (A) or standard arm (B). They must have measurable disease and EGFR negative mutational status. In arm A, treatment with single or dual-agent chemotherapy will be based on histology, ERCC1 (E), RRM1 (R) and TS (T) expression at the mRNA level. Expression of E, R and T is assessed by qRT-PCR on paraffin-embedded tumor specimens in a central laboratory. The cut off for high or low expression have been previously defined. Pts with squamous NSCLC who are: E low/R high will be treated with single agent carboplatin, E high/R low with single agent gemcitabine, E low/R low with carboplatin and gemcitabine and E high/R high with docetaxel or vinorelbine. In non-squamous NSCLC pts: E low/T high will be treated with carboplatin, E high/T low with pemetrexed, E low/T low with carboplatin and pemetrexed, E high/T high/R low with gemcitabine and E high/T high/R high with docetaxel or vinorelbine. In arm B treatment will be standard of care at the discretion of the care provider. The primary endpoint is overall survival (OS). The secondary endpoints are progression-free survival (PFS), disease response according to RECIST 1.1 and tolerability (using CTCAE version 4.0). Feasibility of treatment selection based on pharmacogenomic parameters will also be assessed. Treatment will continue to a maximum of 6 cycles if tolerated or until disease progression. Switch maintenance treatment is not allowed in either arm. Continuation maintenance (one or more of the agents used in the initial regimen) is allowed at the discretion of the investigator. Treatment upon progression is at the discretion of the care provider. Assuming an exponential survival distribution for both treatment arms and a median survival time of 8 months in the control arm we anticipate to detect an improvement of 3 months in the median survival time in the experimental arm. To have 90% power to detect a three-month improvement in median survival at a significance level of 5% (2-sided) and assuming a 10% failure rate in gene analyses or loss to follow up rate, a sample size of 567 patients is planned to be enrolled.

      Results
      Not Applicable

      Conclusion
      We hypothesize that such tailored approach will improve survival decreasing the exposure to ineffective toxic agents in advanced NSCLC elderly pts. To our knowledge this is the first pharmacogenomic-driven randomized trial in this population.

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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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      P2.06-013 - Genetic profiling of lung cancer in young adults patients: early data assessment using Next-Generation Sequencing. (ID 1189)

      09:30 - 16:30  |  Author(s): T. Vavala'

      • Abstract

      Background
      In 3% of cases, lung cancer is diagnosed in patients younger than 45 years. The epidemiology, biology and clinical history of young lung cancer patients is generally different from the adult counterpart: the higher percentage of mutations has the potential to influence both tolerability and response to treatment with consequent impact on quality of life and survival. The biomolecular characterization of the disease in this subgroup will allow the design of clinical studies dedicated to young patients, that will lead to the identification of specific items that are not deducible from trials opened to the general adult population. In this study, Next-Generation Sequencing (NGS) technology has been applied to archival tissue samples to enhance tumor-specific genomic profile knowledge in this selected cohort of young patients (pts).

      Methods
      A retrospective analysis has been performed at the Thoracic Unit of San Luigi Hospital from January 2007 to March 2013, collecting 13 lung cancer-diagnosed pts (10 completely sequenced; in 3 cases the analysis is ongoing), aged between 15-39 years. Genomic DNA was extracted by microdissected formalin-fixed and paraffin embedded (FFPE) tumor samples of all pts and by lymphocytes of three healthy controls (ctrl). Amplicons NGS libraries for 46 oncogenes included in the Ion Torrent Cancer Panel were generated, following manufacture guidelines, and sequenced in Personal Genome Machine (PGM) Ion Torrent instrument. Variant Caller included in Torrent Suite Software was used to identify mutations.

      Results
      Twenty-two non-synonymous, 3 frameshifts, 3 stop-gain and 55 synonymous somatic sequence variations were found in 10 young adult patients (allelic frequency ≥ 10%). Excluding synonymous mutations, the most frequently altered genes in patients were TP53 (7 mutations; 25%), followed by EGFR and KDR (5 mutations; 18%), PI3K (3 mutations; 11%), KIT (7 mutations; 14%), FGFR3-ABL1-MET-ATM-RB1-SMO (1 mutation; 3.6%). Furthermore, 14 of these mutations are annotated in SIFT or in PolyPhen databases as “mutations that could damage affected protein”. Overall, we identified 28 mutations annotated in COSMIC database, among which the most frequent were COSM149673, COSM28026 and COSM6223-COSM22413 with 5,4 and 2 counts, respectively. We also found 93 SNPs in our cohort, including the most frequent rs7688609, rs1873778 and rs1050171 with 13 counts (10 pts; 3 ctrl) followed by rs1800861 (9 pts; 3ctrl); rs41115 (8 pts; 2ctrl); rs1870377 (4 pts; 1ctrl); rs3822214 (2 pts; 2ctrl); rs3729687 (2 pts; 1ctrl); rs2228230 (2 pts) and rs3730358-rs3135898 (1 pt; 1ctrl).

      Conclusion
      The development of new biological techniques, such as the next-generation sequencing, could allow to collect a wide number of mutations. From these preliminary results, some interesting data have been discovered concerning SNPs or mutations. This pivotal retrospective analysis is the basis for the ongoing prospective collection. A better definition of molecular-genetic pattern in this selected young population of patients could increase the knowledge about the lung cancer etiology and suggest age-related new trials design.

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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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      P3.02-013 - ATF2 contributes to Platinum resistance in Non Small Cell Lung Cancer and cJUN/ATF2 Celastrol mediated modulation restores Platinum sensitization. (ID 2275)

      09:30 - 16:30  |  Author(s): T. Vavala'

      • Abstract

      Background
      ATF2 is a member of the basic helix-loop-helix (b-ZIP) transcription factor family playing important roles in Stress and DNA damage. Several studies reported correlation between ATF2/JNK-mediated activation and resistance to damaging agents. Celastrol is an ATF2 inhibitor extracted from a Chinese plant known as “Tunder of God Vine”. Celastrol is used in traditional Chinese medicine for anti-inflammatory properties. In addition, Celastrol is a triterpene with promising anticancer activity in several cancer models both in vivo and in vitro. The purpose of the present study was to investigate whether ATF2 might play a role in inducing drug resistance in Non-Small Cell Lung Cancer (NSCLC).

      Methods
      In NSCLC cell lines ATF2 expression levels were evaluated by quantitative PCR (qPCR) and Western Blot (WB) and correlated to cisplatin (CDDP) resistance. Celastrol mediated ATF2/cJUN activity was assessed by Luminometry, qPCR and western blotting (WB). Furthermore, matched tumors and corresponding normal tissues of 88 surgically resected NSCLC specimens, were collected and both qPCR and immunohistochemical analyses for ATF2 were performed.

      Results
      NSCLC cell lines CDDP-resistant (H522 and H1395) expressed high levels of ATF2 protein. Moreover, CDDP treatment increased ATF2 phosphorylation levels leading to an enrichment within the nuclear cell compartment. In our study, Celastrol reduced ATF2 activity by decreasing the production of ATF2 mRNA and blocking the CDDP-mediated phosphorylation/mRNA expression of cJUN, a main ATF2 partner. Furthermore, ATF2/cJUN functional inhibition mediated by Celastrol restored the response to CDDP in resistant lung cell Lines. ATF2, at both protein and mRNA level, was significantly up-modulated in NSCLC tumor samples compared to the paired normal lung tissue (mRNA: p<<0.01, mean Log2(FC)=+4.7). Moreover, high expression of ATF2 mRNA was correlated with the smoking status of the patients. Relevantly, smoker or former smoker patients expressed significantly high ATF2 mRNA levels compared to non-smokers (p=0.02 and p=0.04, respectively).

      Conclusion
      This study shows that in NSCLC cell lines a correlation between ATF2 protein expression and CDDP resistance occurs. Furthermore, our results suggest a potential increase of CDDP sensitivity, following the Celastrol-mediated ATF2/cJUN inhibition. For the first time it has been shown in NSCLC an up-regulation of ATF2 mRNA/protein levels compared to normal tissues and consistent with that detected in CDDP resistant cell lines. This data suggest a possible involvement of ATF2 in NSCLC CDDP-resistance.

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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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      P3.06-026 - Thymidylate synthase (TS) mRNA and protein expression in advanced non-small cell lung cancer (NSCLC) patients treated with pemetrexed-based therapy. (ID 2355)

      09:30 - 16:30  |  Author(s): T. Vavala'

      • Abstract

      Background
      In NSCLC, higher Thymidylate Synthase (TS) levels have been reported in both squamous and large cell carcinomas compared to adenocarcinoma. In clinical practice, Pemetrexed, a potent antifolate inhibitor of TS, showed a selective benefit in patients with "non-squamous" NSCLC. Two retrospective studies have shown that low TS protein levels are associated with better clinical outcome in NSCLC patients treated with pemetrexed. Aim of this study was to explore, in a series of advanced stage IV patients receiving pemetrexed-based regimens in first line of treatment, the association between TS mRNA and protein expression with overall survival (OS) and therapeutic response.

      Methods
      Two series of histologically confirmed non squamous-NSCLC, assessed in formalin-fixed and paraffin embedded specimens from patients treated with pemetrexed-based regimens were collected: the first series at San Luigi Hospital (n=64), the second series at Regina Elena National Cancer Institute (n=8). Due to the limited amounts of tissue specimens available, total RNA extraction was possible in 52 out of 72 cases. TS protein expression was performed using immunohistochemistry (mouse monoclonal TS106 antibody) and scored through H-SCORE method, considering both staining intensity (0 no staining; +1 weak; +2 moderate; or +3 strong) and percentage of tumor cells stained, resulting in semiquantitative H-scores ranging from 0 to 300. TS nuclear and cytoplasmic staining, respectively, were separately scored. Statistical analyses were performed using the STATISTICA10 software.

      Results
      The differential H-SCORE assessment showed a strong importance of TS localisation for clinical outcome prediction: in Cox regression analysis, a statistically significant association was observed between nuclear TS expression and OS (p < 0.009) indicating that lower nuclear TS expression levels were associated with longer OS. In addition, lower nuclear TS levels were significantly associated with a better response to therapy (p<0.001). On the contrary, TS cytoplasmic staining did not affect patients’ survival or clinical response (p>0.05). Four subgroups of patients, based on the dichotomized low/high TS expression in both nucleus and cytoplasm, were obtained: both high, both low, nucleus high/cytoplasm low and nucleus low/cytoplasm high. Significant differences in overall survival among these four groups were detected (p=0.017), confirming the strong and selective influence of nuclear TS, as compared to cytoplasmic TS, expression in clinical outcome. Moreover, Chi[2] test revealed a significant association between low nuclear TS and partial response to pemetrexed treatment, independently of cytoplasmic TS expression (p<0.001). No correlation between TS protein expression data and clinico-pathological data (age, gender) were identified. TS gene expression analyses are ongoing.

      Conclusion
      This retrospective study suggests that TS protein expression, selectively assessed at nuclear level, has a potential predictive role in advanced stage IV patients, receiving pemetrexed in first line of treatment. Patients with low nuclear TS expression showed prolonged overall survival and better response to therapy. Such preliminary results define TS assessment as a potential tool which may select the most appropriate group of patients to be treated with pemetrexed.

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    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.11-041 - Treatment with crizotinib in patients with IV stage non-small cell lung cancer (NSCLC) with ALK translocation: a single institution experience. (ID 2961)

      09:30 - 16:30  |  Author(s): T. Vavala'

      • Abstract

      Background
      Crizotinibis is a MET inhibitor, having also an activity on ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) pathways. The ALK translocation is described in 4% of NSCLC and these patients (pts) benefit from crizotinib therapy with a response rate (RR) ranging from 51 to 61%.The drug is already approved by FDA and EMA; in Italy crizotinib is available in first line within controlled clinical trials and, until April 2013, within expanded access program (EAP).

      Methods
      From June 2010 to February 2013, 155 pts with advanced NSCLC were analyzed for Alk translocation using fluorescence in situ hybridization (FISH) at our institution. The selection criteria were: adenocarcinoma histology, never or ex smoker, EGFR status WT. Main pts characteristics were: 59% males, median age 57,5 years (range 26-76), 77 former smoker (76 pts for more than 15 years). Tissue samples were available from primary tumor and metastases in 78 and 22%, respectively, having 73% of cases with cytological material. In 23,2% of the specimens Alk rearrangement was not evaluable due to poor quality and/or quantity issues.

      Results
      Among the 155 pts, 22 (14%) are ALK translocated: 19 were treated within PROFILE clinical trials and 3 patients in the EAP. 20 pts are currently evaluable for response and toxicity: 6 of them received crizotinib as first-line treatment, the others in subsequent lines. The response rate was equal to 70%. The total number of administered cycles is 235.The reduction of the dose (7% of cycles) was necessary in two pts: in 1 case due to bradicardia and fatigue G3 (in first line treatment) and in the other one due to neutropenia G3 (in second line).The observed toxicities were mostly grade 1-2 (fatigue 47%, bradycardia 5,8%, visual disorder 5,8%, anemia 29%, neutropenia 18% and nausea 12%); grade 3-4 was less common. The temporary cessation of treatment was required in 3 pts (range 4-15 days) for grade 3-4 toxicity (mostly neutropenia plus fatigue). No drug interruption for unacceptable toxicity was reported. The most common progression sites were brain (37%) and bone (27%).

      Conclusion
      The introduction of a selection criteria (such as negative EGFR status) leads on an increase of our cases of Alk traslocated pts compared to literature data; this selection is moreover recommended in diagnostic algorithm recently proposed by the Italian Expert Panel (Marchetti A et al, JTO 2013). Efficacy and tolerability profile are consistent with published data.

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    P3.18 - Poster Session 3 - Pathology (ID 177)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P3.18-014 - Implementing systematic histological and genotypic re-evaluation of Non Small Cell Lung Cancer (NSCLC) into routine clinical practice: a monocentric study (ID 2691)

      09:30 - 16:30  |  Author(s): T. Vavala'

      • Abstract

      Background
      Cancer is a multistep process in which tumor cells progressively harbour genetic alterations that confer growth and spread advantages. These observations are also confirmed in NSCLCs where specific genetic abnormalities are sensitive to the action of targeted drugs, even if secondary mutations could develop conferring drug resistance. Furthermore, in recent studies, histologic and immunophenotypic changes have been described in patients (pts) with a specific molecular alteration re-biopsied after receiving a targeted therapy. This finding suggest the possibility of a "clonal resistance mechanism" in which genetic-similar cell populations had or acquire selective survival features thus escaping the inhibitory drug effect. In the present study histological examination and wide genetic analyses have been performed in tumor tissue sampled both before and after treatment in an unselected NSCLC patient population in order to elucidate progressive clinic-pathological and genetic abnormalities.

      Methods
      NSCLC pts with adequate tissue samples before and after at least one treatment have been evaluated from July 2006 to March 2013, at Department of Oncology of San Luigi Hospital. All had ECOG Performance Status of 0, median age of 51,5 years and IIIA-IV stage at diagnosis. After histological examination, mutational analyses for EGFR, K-RAS, PIK3CA, B-RAF, and HER2 genes were performed using pyrosequencing or RealtimePCR. ALK and c-MET genomic rearrangement were tested by FISH.

      Results
      A total of 24 (12 males and 12 females) pts were collected. Histological diagnoses were re-confirmed in all but one (4%) case in which morphological and immunophenotypical histology of neuroendocrine small cell lung cancer (SCLC) was found. All samples were adequate for molecular analyses. At the first biopsy EGFR activating mutations were 10/24 (42%) and 3/24 (12,5%) were the exon 20 EGFR p.T790M mutation, 2/3 (66%) associated to EGFR activating mutations. At the second biopsy 6/10 (60%) EGFR activating mutations were maintained and no acquired mutations in EGFR wild type pts at first were found at second biopsy. On the other hand, 6/24 (25%) p.T790M mutation were detected at second biopsy, 5/6 (83%) de novo acquired, 1/6 (17%) maintained and only 1/5 (20%) associated to EGFR activating mutations. The patient who acquired SCLC histology, maintained the L858R EGFR activating mutation after treatment with no other acquired mutation. K-RAS mutations were found in 4/24 (16.7%) first biopsies, while 5/24 (21%) were found at the second biopsies. No mutations were found in BRAF, HER2 and PIK3CA genes. ALK rearrangement was assessed in 5/24 (20,8%) patients; otherwise MET amplification was seen in 3/24 (12.5%) cases only 1/3 (30%) in EGFR mutant cases.

      Conclusion
      These preliminary data showed a complex scenario of basal and acquired alterations on tumor tissue before and after treatment highlighting the need of repeated histological and genotypic assessments to guide at the best treatment decisions.

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    P3.24 - Poster Session 3 - Supportive Care (ID 160)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Supportive Care
    • Presentations: 1
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      P3.24-009 - Histologic and genotypic evolution in lung cancer harboring mutations in the epidermal growth factor receptor (EGFR): a clinical case. (ID 708)

      09:30 - 16:30  |  Author(s): T. Vavala'

      • Abstract

      Background
      This is a clinical case of an EGFR-mutant Non-Small Cell Lung Cancer (NSCLC) with adenocarcinoma (ADC) histology: a subsequent diagnosis of high grade neuroendocrine small-cell lung cancer (SCLC) carrying an EGFR mutation was done at the first re-biopsy and further, a sarcomatous cancer was finally diagnosed. Recent publications were focused on drug-resistance mechanisms in patients with a specific biomolecular alteration re-biopsed after receiving the targeted therapy: in some cases morphologic and immunophenotypic changes were described. This finding suggests the possibility of "clonal resistance" with a selective pressure of some groups of cells, even if the histopathological features of these mechanisms have not yet been completely elucidated.

      Methods
      A 62-year-old caucasian man, with past smoking habit, presented with a 2-week history of cough and dyspnea. After a diagnosis of stage IV lung ADC, he received, on March 2010, 1st line treatment with cisplatin 75 mg/m2 plus pemetrexed 500 mg/m2 on Day 1 every 21 days, for 6 cycles. He achieved a partial response on computed tomography (CT) and a marked regression of his symptoms. On August 2011, a CT scan revealed a progressive disease (PD); he started treatment with Erlotinib plus ARQ-197/placebo within a clinical trial. As deemed by protocol, molecular analyses were performed on biopsy specimen at time of diagnosis, evidencing exon 21 – point mutation, p.Leu858Arg at EGFR mutational assessment. After 4 cycles, a local progressive disease was described by CT scan and a fibrobronchoscopic re-biopsy was performed in order to define the novel biomolecular profile at that time of the history of the disease. The histological evaluation highlighted a SCLC and molecular analyses confirmed the p.Leu858Arg mutation. Based on new histological diagnosis, he underwent chemotherapy with AUC6 carboplatin on Day 1 every 21 days plus etoposide 100 mg/m2 on Day 1,2,3 every 21 days, for a total of 6 cycles, until May 2012, achieving partial response at CT scan. On August 2012, because of radiological evidence of disease progression, he underwent chemotherapy with Cyclophosphamide 800 mg/m2, Doxorubicine 40mg/m2 and Vincristine 1mg/m2 on Day 1 every 21 days. After 3 cycles, he reported intense swelling in the supraclavicular right fossa and a fine needle aspiration of supraclavicular right lymphadenopathy was performed. The final pathological diagnosis was undifferentiated sarcoma cells (CK-,TTF1-, VIM+) . Patient died, on January 2013, because of worsening of clinical conditions.

      Results
      Not applicable

      Conclusion
      Many studies hypothesize that SCLC either evolved from the previously diagnosed NSCLC or that both arose from a common precursor. Further comparative molecular analysis of these histologically distinct tumors would be of value to better understand the potential role of EGFR in the evolution of lung cancer and the role of selection for an EGFR-mutant SCLC cell subclone as an unusual mechanism of acquired resistance to EGFR inhibitors in NSCLC.