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L. Priest



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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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      P1.06-053 - Clinical utility of circulating serum and plasma biomarkers for personalised radiotherapy treatment of non-small cell lung cancer (NSCLC) (ID 3098)

      09:30 - 09:30  |  Author(s): L. Priest

      • Abstract

      Background
      Personalised strategies that tailor radiotherapy (RT) dose and schedule according to clinical and molecular factors, novel drug-RT combinations and/or advanced RT techniques are needed to optimise outcomes from RT for NSCLC. Development of such approaches would benefit from objective measures to inform on survival, chance of response and/or toxicity. We evaluated 26 circulating proteins and cytokines implicated in angiogenesis, metastasis, apoptosis, hypoxia and inflammation for prognostic (survival), predictive (RT response/toxicity) and/or pharmacodynamic significance in the context of RT for stage I-III NSCLC.

      Methods
      NSCLC patients donated blood prior to, serially and on completion of RT treatment. Samples were analysed for cell death (M30, M65, CYFRA), hypoxia (osteopontin, CA-IX), angiogenesis (Ang2, FGFb, HGF, VEGFA, VEGFC, PDGF, IL8, PlGF, KGF, VEGFR1, VEGFR2, Ang1, Tie2), metastatic (EGF, E-Selectin, VCAM1) and inflammatory (IL1b, IL10, IL12, TNFa, IL6) cytokines using single- or multi-plex ELISAs (SearchLight multiplex Aushon BioSystems, Peviva, R&D Systems). Clinical data were collected for age, gender, performance and smoking status, ace27 co-morbidity score, weight loss, TNM stage, haemoglobin, treatment received, various lung function and RT treatment parameters, histology, treatment received, toxicity, response and survival. Standard statistical methods were used to explore for associations and prognostic significance (Stata version 10).

      Results
      Seventy-eight patients were enrolled from March 2010 to August 2011: 61% male; majority (44%) squamous histology; 82% PS 0 or 1; 72% ex-smoker; 9% stage I/II, 44% stage IIIA, 47% IIIB; median age 66 years (range 31-86), 42% age > 70; 20% weight loss of 5-10%, 11% weight loss >10%; 62% prior chemotherapy/sequential RT, 20% concurrent chemoradiotherapy, 18% radiotherapy alone. RT treatment doses administered ranged from 50-55Gy in 20 fractions to 60-66 Gy in 33 fractions. Significant associations (p<0.05) were observed for EGF levels with gender and age, for FGFb with co-morbidity score and for IL8, IL1B and KGF with smoking status. Positive correlations of biomarkers at baseline (p<0.001) were observed for TNFa with FGFb, IL1b, IL8, IL12; FGFb with IL1b, IL8, IL12 KGF; IL1b with IL8, IL12; IL8 with KGF, IL12; KGF with IL12. In the overall population, at day 8 during RT significant decreases were observed for Ang2, EGF, E Selectin, FGFb, HGF, VCAM1, VEGFC & VEGFR2. Post completion of RT Ang2, EGF, E Selectin, FGFb, HGF & VEGFC levels remained significantly lower than at baseline prior to RT, and in addition significant global decreases in Ang1 and VEGFA were observed. The median survival overall was 16.8 months at a median follow up of 12 months. In univariate analysis there were non-significant trends to worse survival for older patients, weight loss >5%, higher TNM stage, higher co-morbidity scores and current smokers. Better survival was observed for patients with higher baseline levels of IL1b (p = 0.005) and TNFa (p = 0.022).

      Conclusion
      Preliminary analysis demonstrates appreciable changes of various circulating biomarkers during RT and identifies interleukin-1 beta and tumor necrosis factor alpha as potential prognostic factors. Multivariate analyses and correlation of biomarkers with response and toxicity are ongoing and will be presented.

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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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      P2.06-016 - Expression and clinical significance of the monocarboxylate transporter MCT1 as a novel therapeutic target in Small-Cell-Lung-Cancer (SCLC) (ID 1473)

      09:30 - 09:30  |  Author(s): L. Priest

      • Abstract

      Background
      Small cell lung is a rapidly proliferating disease. Because of its high proliferation index, cancer cells rely on glycolysis, rather than oxidative phosphorylation, for ATP generation. Furthermore SCLC tumours often contain regions of hypoxia which switches tumour cells to a glycolytic phenotype. Increased glycolysis leads to increased lactate production which is effluxed from the cell in order to prevent reduced intracellular pH or inhibition of metabolic pathways via the monocarboxylate transporter (MCT) proteins MCT1 and MCT4. Inhibition of these transporters has been proposed as a method of selectively targeting highly glycolytic cancer cells. AZD3965 is an orally bioavailable MCT1 specific inhibitor currently under evaluation in phase I clinical trials. In an in vitro model of SCLC we have recently shown that in hypoxic conditions resistance to AZD3965 is associated with increased MCT4 levels (Polanski et al. submitted). Aim: To examined the expression and clinical significance of MCT1 and MCT4 in SCLC.

      Methods
      Archival SCLC biopsy specimens and clinical data from 78 patients presenting to the University Hospital of South Manchester and the Christie Hospital between 1994 and 2005 were analyzed. Nine representative cores from the tumour specimens were used to generate three TMAs. Sections were then stained for the markers MCT1, MCT4 and for the hypoxic marker CAIX. Staining was evaluated by two independent scorers and extent and intensity of the staining were estimated. A combined score for each case was calculated as the mean product of extent and intensity for all the cores in a case. The association between MCT1, MCT4 or CAIX and known prognostic factors was evaluated by Fisher’s exact test. Kaplan-Meier analysis was used to assess overall survival rates and Log Rank test was used for the comparison of the survival distributions.

      Results
      The proportion of tumours with any expression of MCT1, MCT4 or CAIX was 99%, 99%, 90% respectively. Higher levels of expression (intensity x extent) were observed for MCT1 (median=8.17) compared to MCT4 (median=2.21; p<0.001). A positive correlation was observed for CAIX expression and MCT4 expression. Tumours with CAIX expression, high MCT1 expression (>median) and low MCT4 expression ( 10 x 109/L, platelets < 150 x 109/L, Na < 135 mmol/L; LDH > 550 IU/L). However, high MCT1 expression score was associated with worse survival (14 vs. 32 months; p=0.019). Neither MCT4 nor CAIX expression was prognostic. Of the known prognostic factors assessed, extensive stage was significantly associated with shorter overall survival (6 vs. 27 months; p<0.001).

      Conclusion
      MCT1 and MCT4 are often expressed in SCLC and 21% cases in this series express a pattern associated with potential sensitivity to MCT1 inhibition. Higher expression of MCT1 is an adverse prognostic factor in univariate analysis reinforcing further evaluation of MCT1 inhibition in this disease.

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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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      P2.18-017 - Multiplexed-based mutation profiling of non small cell lung cancer small biopsy samples using the Sequenom LungCarta™ Panel and MassARRAY® System (ID 2856)

      09:30 - 09:30  |  Author(s): L. Priest

      • Abstract

      Background
      The advent of specific therapies for non small cell lung cancer (NSCLC) based on individual tumour genotype has impacted the development of high throughput genomic profiling strategies. A single platform designed for the synchronous screening of multiple mutations across different genes can potentially enable molecular profiling in samples of limited tumour tissue such as small biopsy samples.

      Methods
      Haematoxylin and eosin-stained sections and accompanying reports were reviewed from patients diagnosed with NSCLC (2008 to 2012) in Greater Manchester, U.K. Samples with less than 20% tumour cell content (TCC) were macrodissected to increase the final TCC. In each case DNA was extracted manually from 1 5µM curl/section using the cobas® DNA Sample Preparation Kit. Mutation analysis was performed with the Sequenom LungCarta™ Panel which enables screening of 214 mutations in 26 genes, and utilises multiplexed polymerase chain reactions, single base extension reactions and mass spectrometry (Sequenom MassARRAY® platform).

      Results
      Results Sixty cases comprising 47 lung biopsies, 1 wedge resection, 6 lymph node biopsies, 4 pleural biopsies, 1 brain biopsy and 1 pericardial effusion were classified as 21 adenocarcinomas (ACA), 17 squamous cell carcinomas (SCC), 8 NSCLC favour ACA, 10 NSCLC favour SCC, 1 adenosquamous carcinoma and 3 NSCLC not otherwise specified (NOS). Mutations were successfully detected at a mutant allele frequency of 10% and definite mutations were reported in 28 cases (47%). Possible mutations of low allele frequency or uncertain significance were detected in an additional 15 cases (25%) and also in 10 cases with a definite mutation. In total 32 definite and 39 equivocal mutations have been detected and are currently being validated by a combination of pyrosequencing, next-generation sequencing and immunohistochemistry (IHC).

      Table 1. Unequivocal mutations detected according to histological subtype. ([a]Includes double mutant; TP53 and MAP2K1, [b]includes triple mutant; 2 TP53 and 1 KRAS, [c]includes double mutant; KRAS and MET)
      No. of definite mutations detected No. of mutated samples ACA NSCLC favour ACA SCC NSCLC favour SCC NSCLC NOS % of mutations detected in all ACA or SCC Comment
      13 TP53 12 3[a] 2[b] 5 1 1 17 % ACA 22% SCC 1 confirmed by next generation sequencing. 7 of 8 tested cases were strongly positive for P53 IHC
      12 KRAS 12 8[c] 1[b] 3 31% ACA 11% SCC 7 confirmed by pyrosequencing
      3 MET 3 2[c] 1 10% ACA 0% SCC 1 confirmed by next generation sequencing
      2 EGFR 2 2 7% ACA 0% SCC 2 previously detected by Sanger sequencing
      1 EPHA5 1 1 0% ACA 4% SCC Moderately differentiated SCC
      1 MAP2K1 1 1 3% ACA 0% SCC Poorly differentiated ACA TTF1+

      Conclusion
      The MassARRAY® system of testing for multiple mutations is a sensitive method that facilitates the optimal use of tumour DNA present in small specimens, and can detect concurrent mutations with the potential to influence responses to targeted therapies. Unequivocal mutations were reported in 59% and 37% of cases diagnosed/favoured as ACA and SCC respectively. This may reflect the LungCarta™ panel design, which was based on mutations detected in ACA.