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MINI 38 - Biology and Prognosis (ID 167)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 15
- Moderators:R. Tsuchiya, M. Wynes
- Coordinates: 9/09/2015, 18:30 - 20:00, 702+704+706
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MINI38.01 - FAK Inhibitor VS-6063 Targets Mesothelioma Cancer Stem Cells: Rationale for Maintenance Therapy after Conventional Chemotherapy (ID 2710)
18:30 - 18:35 | Author(s): V. Kolev, I. Shapiro, P. Baas, R. Bueno, J. Pachter, D. Weaver
- Abstract
- Presentation
Background:
Malignant pleural mesothelioma (MPM) is an aggressive tumor in the pleural lining of the lung and peritoneum with median overall survival with standard of care (SOC) chemotherapy only 12 months from diagnosis. This poor prognosis may be attributed at least in part to cancer stem cells (CSCs) that are resistant to chemotherapy and can mediate cancer recurrence and progression. Focal adhesion kinase (FAK) plays an essential role in the survival, self-renewal and tumor-initiating capability of CSCs. The FAK inhibitor VS-6063 (defactinib) is currently being tested in patients with MPM following disease control on standard pemetrexed/platinum chemotherapy (COMMAND, ClinicalTrials.gov NCT01870609).
Methods:
An Aldefluor assay, previously validated as a CSC assay (Shapiro et al., 2014), was used to assess the effects of chemotherapy or VS-6063 on CSCs in vitro. Tumor initiating potential of MPM cells after treatment with SOC agents, and VS-6063 alone or in combination with pemetrexed was measured in vivo. CSC marker expression in MPM patient tumor samples was measured by IHC, Q-PCR and RNASeq analysis. Novel CSC markers were validated in an in vivo limiting dilution assay.
Results:
Treatment of a human MPM cell line with pemetrexed or cisplatin, the SOC therapy for mesothelioma, resulted in a 6-fold enrichment of ALDH-positive CSCs. In direct contrast, the FAK inhibitor VS-6063 markedly reduced the proportion of CSCs. Control and pemetrexed-treated MPM cells showed robust tumor initiation in vivo, while cells treated with VS-6063 alone or VS-6063 plus pemetrexed had decreased tumor initiating capacity. FAK inhibitor was found to selectively induce apoptosis in CSCs, indicating that the mechanism of their elimination is cell death. In addition to ALDH, several new mesothelioma CSC markers were validated in in vivo limiting dilution assay and their clinical utility was assessed. An increase in CSC markers, including ALDH1, CD133 and CXCR2, was observed in tumor samples from 11 patients following first line pemetrexed-cisplatin chemotherapy. In tumor biopsies from MPM patients treated for 12 days with VS-6063, tumor pFAK (Y397) and expression of CSC markers was reduced. Interestingly, gene expression analysis of these samples revealed an inhibition of CSC pathways after VS-6063 administration. VS-6063 maintained the effect of chemotherapy in patient-derived xenograft (PDX) mouse model. Treatment with pemetrexed/cisplatin resulted in tumor growth inhibition followed by rapid tumor re-growth upon cessation of the treatment. Tumor re-growth was substantially delayed when FAK inhibitor was administered after chemotherapy.
Conclusion:
These data provide a strong rationale for the current clinical testing of VS-6063 following treatment with pemetrexed plus platinum to potentially prolong time to progression in patients with mesothelioma.
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MINI38.02 - BAP1 Inactivation in Mesothelioma Is Highly Prevalent (ID 657)
18:35 - 18:40 | Author(s): M.G. Zauderer, A. Cercek, A. Rimner, V. Rusch, P.S. Adusumilli, G.M. Nash, A. Moreira, J. Hmeljak, M. Ladanyi, L.M. Krug
- Abstract
- Presentation
Background:
Efforts to elucidate tumorigenic mutations in mesothelioma are essential to advance therapy. Prior efforts to characterize the molecular heterogeneity of this disease have been limited by sample condition and testing platforms. Herein, we describe efforts to prospectively test patients using next-generation sequencing with matched patient germline controls.
Methods:
Sequential mesothelioma patients were approached for consent to our IRB protocol NCT01775072 to perform MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets), a comprehensive molecular profiling platform based on solution-phase exon capture and next generation sequencing to detect somatic genetic alterations in FFPE tumor specimens. MSK-IMPACT involves hybridization capture and deep sequencing of all protein-coding exons of 341 key cancer-associated genes, including all genes that are druggable by approved therapies or are targets of experimental therapies being investigated in clinical trials at MSKCC.
Results:
51 patients with mesothelioma underwent MSK-IMPACT testing (see Table 1). 12 samples had low tumor content. Among 39 samples with reliable results, BAP1 was the most common alteration (46%). Another 3 samples had changes also thought to inactivate BAP1 (2 samples had gene copy number changes just below the cutoff for whole gene deletions and 1 had an inversion of LIMD-BAP1 thought to inactivate BAP1), making the incidence of BAP1 alterations possibly as high as 56%. In 4 samples with sufficient tumor content, no alterations were identified. Table 1N=39 (%) Gender M/F 26/13 (67/33) Primary site of disease * Pleural * Peritoneal * Testicular 32 (82) 6 (15) 1 (3) # identified alteration, average 3 Alterations present in >6% * BAP1 * NF2 * CDKN2Ap16INK4A * SETD2 * CDKN2Ap14ARF * LATS1 * CREBBP * WT1 * CDKN2B * PI3KCA * PBRM1 * TP53 18 (46) 8 (21) 5 (13) 5 (13) 4 (10) 4 (10) 4 (10) 4 (10) 3 (8) 3 (8) 3 (8) 3 (8)
Conclusion:
Using MSK-IMPACT, BAP1 inactivation is the most common alteration. Other aberrations previously reported at high frequency were identified but albeit at lower frequencies (NF2 and p16, previously reported as 40% and 75% respectively). For multiple samples with deep coverage, no alterations were identified. The high incidence of BAP1 mutations in this systematic testing makes this pathway ideal for developing and testing targeted therapies.
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MINI38.03 - Validation of a Specific Missense GTF2I Mutation in More Indolent Thymic Epithelial Tumours (ID 3017)
18:40 - 18:45 | Author(s): S. Gennatas, H. Anbunathan, A. Montero, A.G. Nicholson, S. Popat, A.M. Bowcock
- Abstract
- Presentation
Background:
Thymic epithelial tumours (TETs) are rare intrathoracic cancers that can be invasive and very difficult to treat. There is currently a huge gap in the understanding of the basic science behind their development as well as great clinical need for development of effective treatments. Recently a missense mutation (T>A, at the same position on chromosome 7, 74146970) was identified in GTF2I at high frequency (78%) in the more indolent type A and AB thymomas. We examined the frequency of this alteration in an independent cohort of well clinically characterized patients from the UK.
Methods:
Tumour samples were collected from 94 patients from a single tertiary cardiothoracic centre in the UK, the Royal Brompton & Harefield NHS Foundation Trust (London). These were subject to histological assessment by expert Consultant Histopathologists to confirm the diagnosis and determine tumour abundance. DNA was extracted with Quiagen’s QIAamp DNA FFPE Tissue Kit (Catalogue No. 56404). PCR and Sanger sequencing was performed with semi-nested primers.
Results:
We assessed the frequency of the GTF2I mutation in a total of 94 TETs with a tumour abundance of at least 70%. The mean age for all patients was 57 and the male: female ratio was 1:1.25 The GTF2I mutation was seen in 25 of 87 evaluable TETs (29%) and was present more commonly in type A (85%) and AB (46%) thymomas. The frequency decreased to 9% in type B1 (1/11) and 5% in type B2 thymomas (1/19). In our cohort the mutation was not detected in any B3 thymomas or carcinomas, including neuroendocrine tumours or two cases of thymic hyperplasia. Interestingly all AB thymomas with the mutation had a much lower percentage of mutant alleles compared to the majority of the A thymomas. Twenty-three of the 25 patients (92%) with the mutation had Stage I – II disease at presentation and had complete resection of their thymoma.
Conclusion:
Our results confirm the presence of the GTF2I mutation at a high frequency in type A and AB thymomas in an entirely different patient cohort. Although the frequency of the mutation in type A thymomas in our cohort is very similar to what was reported originally (85% and 82% respectively) it was lower in the AB thymomas (46% and 74% respectively). Explanations for this include the smaller sample number in our cohort and a higher percentage of the lymphocytic component in our samples than that in the original series. The lower mutation frequency in the B subtypes and carcinomas compared to the original series could be due to the smaller numbers in our cohort. We aim to address these issues by expanding our validation series to over 200 samples. Whole exome and RNA sequencing of TETs is ongoing and will allow us to further confirm and extend this finding.
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MINI38.04 - BRCA1/OCT1/MAD2L1 Axis Regulates a Bifurcating Apoptotic Pathway Induced by Vinorelbine in Mesothelioma (ID 2675)
18:45 - 18:50 | Author(s): S. Busacca, A.J. Sharkey, D. Waller, A. Nakas, L. O'Regan, K. Kerr, M. Sheaff, A. Fry, D.A. Fennell
- Abstract
Background:
There is currently no licenced second line therapy for mesothelioma patients upon relapse after pemetrexed cisplatin. The vinca alkaloid spindle poison, vinorelbine, exhibits useful activity in mesothelioma, warranting evaluation in a new UK randomised clinical trial, VIM. However the molecular determinants of efficacy are unclear. We have reported that BRCA1 is an essential regulator of vinorelbine-induced apoptosis, and loss of detectable BRCA1 occurs in 39% of mesotheliomas. However the mechanisms governing BRCA1 dependent lethality has been lacking. We have utilized a functional genetic approach to uncover critical genes required for vinorelbine efficacy.
Methods:
Apoptosis was analysed by PARP cleavage and caspase 3/7 activity assay. Focused RNAi targeting Caspase 8, BAX and BAK was conducted to delineate critical death activators. Mouse embryonic fibroblasts (MEFs) wild type (WT) or double knockout (DKO) for BAX/BAK cells were also used. MAD2L1 expression was studied by western blot and qRT-PCR. Tumour explants were derived from 10 MPM patients.
Results:
Mitochondrial and caspase-8 dependent apoptosis pathways were shown by triple knockdown of BAX, BAK and Caspase 8 to be required to rescue completely from vinorelbine-induced apoptosis. Loss of BRCA1 recapitulated this apoptosis block and was associated with loss of Oct1 dependent MAD2L1 associated transcriptional upregulation. RNAi mediated silencing of MAD2L12 phenocopied BRCA1 loss. In cells selected for resistance to vinorelbine, MAD2L1 failed to upregulate, secondly to constitutive downregulation of BRCA1. Using mesothelioma explants derived at extrapleural decortication, exhibited either marked resistance or sensitivity to vinorelbine induced apoptosis; correlation with regulation of BRCA1/Oct1/MAD2L is ongoing and will be presented.
Conclusion:
BRCA1 functions through an Oct1/MAD2L1-dependent activation of both mitochondria dependent and independent pathways to induce apoptosis. This implicates a requirement for a functional spindle assembly checkpoint, with implications for expanding the biomarker repertoire governing vinorelbine efficacy in mesothelioma
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MINI38.05 - Discussant for MINI38.01, MINI38.02, MINI38.03, MINI38.04 (ID 3449)
18:50 - 19:00 | Author(s): J.P. Van Meerbeeck
- Abstract
- Presentation
Abstract not provided
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MINI38.06 - FP1039/GSK3052230 with Chemotherapy in Patients with Fibroblast Growth Factor (FGF) Pathway Deregulated Squamous NSCLC or MPM (ID 2879)
19:00 - 19:05 | Author(s): P. Garrido, I. Delgado, E. Felip, M. Domine, P. Paik, J. Trigo, J. Schellens, S. Gadgeel, H.L. Kindler, P. Lara Jr., S. Orlov, J. Vansteenkiste, E. Levchenko, U. Lassen, S. Viteri, J. Hambleton, K. Baker-Neblett, L. Yan, C. Wang, D. Sedoti, G. Kirby, I. Mitrica, J. Botbyl, D. Morgensztern
- Abstract
- Presentation
Background:
GSK3052230/FP1039 is a soluble fusion protein with the ECD of FGFR1c linked to the hinge and Fc regions of human IgG1 and acts as a ligand trap by sequestering FGFs involved in tumor growth and angiogenesis. In contrast to small molecule FGFR kinase inhibitors, GSK3052230 spares the hormonal FGF ligands, namely FGF19, 21 and 23. GSK3052230 combined with chemotherapy was efficacious in xenograft models of FGFR1-amplified NSCLC and malignant pleural mesothelioma (MPM) with FGF2 mRNA overexpression. A phase I monotherapy study determined 20mg/kg weekly as the maximum feasible dose (MFD) achieving the desired blood concentration, with no maximum tolerated dose (MTD) reached.
Methods:
This study (NCT01868022 funded by GSK) will evaluate the safety and efficacy of GSK3052230 weekly infusion in combination with paclitaxel + carboplatin in previously untreated FGFR1 amplified metastatic sqNSCLC (Arm A), in combination with docetaxel in FGFR1 amplified metastatic sqNSCLC that has progressed after at least 1 line of chemotherapy (Arm B), or in combination with pemetrexed + cisplatin in patients with untreated and unresectable MPM (Arm C). Each arm involves a dose escalation phase utilizing the 3+3 design, followed by an expansion phase up to 30 patients (pts). Key endpoints include the MTD/MFD of GSK3052230 with chemotherapy, safety, response rates and duration.
Results:
Thirty-four pts have been dosed with GSK3052230 at dose levels ranging from 5mg/kg to 20mg/kg in combination with chemotherapy across three Arms, n=15 (A), n=6 (B) and n=13 (C). Baseline characteristics: males/females 29/5; mean age 68.5 years; ECOG PS 0 (n=20), 1 (n=13), 2 (n=1). Most common AEs were: Arm A: asthenia, neutropenia; Arm B: neutropenia, diarrhea, rash; Arm C: decreased appetite, nausea, infusion reaction. Infusion reactions were seen in 8/34 (24%) pts (n=3 Grade (Gr)1, n=3 Gr2, n=2 Gr3). Serious AEs included: Arm A- neutropenia (n=4), fatigue (n=1), asthenia (n=1), fever (n=1), respiratory infection (n=1); Arm B- neutropenia (n=1), abdominal pain (n=1); Arm C-bowel perforation/ischemia (n=1), infusion reaction (n=1), elevated creatinine (n=1). No DLTs have been observed in sqNSCLC pts (Arms A and B). Three DLTs were reported in mesothelioma pts (Arm C 20mg/kg): Gr5 bowel perforation/ischemia, Gr4 elevated creatinine levels and Gr3 infusion reaction. MFD for Arm A is determined at 20mg/kg. Dose escalation is ongoing for Arms B and C. Preliminary PK results revealed no drug-drug interactions. At time of data-cutoff, 10 PR were observed among 23 patients evaluable for efficacy (ORR = 43%) and a clinical benefit rate of 78% with two ongoing subjects on study >300 days. Preliminary efficacy is as follows: Arm A (6 PR, 2 SD, 1 PD, 6= not-yet-evaluable (NE)), Arm B (4 SD, 1 PD, 1 NE), and Arm C (3 PR, 3 SD, 3 PD, 4 NE).
Conclusion:
GSK3052230 is in general well tolerated in combination with chemotherapy. The MFD for GSK3052230 is 20mg/kg in combination with paclitaxel + carboplatin in first line sqNSCLC patients. Toxicities typically associated with small-molecule FGFR inhibitors, namely hyperphosphatemia and retinal, nail, and skin changes, were not observed. The initial activity and safety profile of GSK3052230 warrant further study.
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MINI38.07 - RITA Enhances Mithramycin-Mediated Growth Arrest and Apoptosis of Malignant Pleural Mesothelioma Cells In-Vitro and In-Vivo (ID 2996)
19:05 - 19:10 | Author(s): M. Rao, V. Shukla, D. Straughan, S. Azoury, P. Feingold, S.M. Atay, Y. Hong, T. Upham, J.A. Hong, M. Zhang, X. Li, R.T. Ripley, D.S. Schrump
- Abstract
- Presentation
Background:
Malignant pleural mesotheliomas (MPM) are relatively rare tumors for which there are no effective treatment options. Previously we reported that mithramycin (MM) dramatically inhibits growth and tumorigenicity of MPM cells in part via depletion of Specificity Protein 1 (SP1) and activation of p53 signaling. We also demonstrated that 24h MM treatment induces G0/G1arrest and senescence with subsequent apoptosis of MPM cells. The present study was undertaken to examine the effects of RITA (Reactivation of p53 and Induction of Tumor cell Apoptosis- a p53 activator and MDM2 inhibitor) with or without MM in cultured MPM cells in vitro and in vivo.
Methods:
NCI-SB-MES1 and NCI-SB-MES7 (MES1 and MES7, respectively) with wild-type p53 were cultured in the presence of mithramycin (24h) and/or RITA (48h). DNA damage, senescence and autophagy were assessed by immunoblot/immunofluorescence analysis of g-H2A-X phosphorylation and foci formation, ß-gal staining, and immunoblot/immunofluorescence analysis of LC3 proteins. Propidium iodide and APO-BrdU techniques were used to determine cell cycle kinetics and quantify apoptosis. qRT-PCR and immunoblot techniques were used to examine signal transduction, cell cycle-related and apoptosis-related protein levels in MPM cells. Murine subcutaneous xenograft models were used to evaluate the combinatorial antitumor effects of RITA and MM in-vivo.
Results:
MM treatment (10-100nM x 24h) mediated dose-dependent depletion of SP1 and markedly increased p53 levels in MPM cells; these effects coincided with DNA damage, G0/G1 arrest, senescence and an autophagy phenotype as evidenced by induction of LC3 puncta/proteins and p-AMPK and inhibition of p-S6 kinase. Senescence or autophagy phenotype coincided with up-regulation of CDKN1A, MDM2/TP53INP1, MAPLC3B, and down-regulation of EZH2, SP1/MTOR. RITA (100-1000nM x48h) alone mediated low-level, dose-dependent growth inhibition in MPM cells. However treatment with subtherapeutic doses of MM for 24h followed by RITA for 48h resulted in synergistic growth inhibition and apoptosis in MPM cells, detected by flow cytometry, as well as immunoblot analysis of cleaved PARP and cleaved caspase 3. Sequential intraperitoneal treatment with MM (1mg/kg/week) followed by RITA (2 mg/kg/3d/week) significantly reduced volumes/masses of subcutaneous MES1 xenografts in athymic nude mice.
Conclusion:
Sequential mithramycin/RITA treatment significantly reduces mesothelioma tumor burden via induction of apoptosis. These findings provide preclinical rationale for evaluation of this drug regimen in MPM patients.
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MINI38.08 - Contemporary Analysis of Prognostic Factors in Patients with Unresectable Malignant Pleural Mesothelioma (MPM) (ID 1745)
19:10 - 19:15 | Author(s): A. Bille, M.G. Zauderer, K. Woo, V. Rusch, L.M. Krug
- Abstract
- Presentation
Background:
The CALGB and EORTC have previously developed prognostic scoring systems for patients with MPM, but these included patients managed surgically and predated the use of pemetrexed. We sought to identify prognostic factors in a contemporary cohort of patients with unresectable MPM.
Methods:
We retrospectively reviewed the charts of patients with histologically proven MPM managed non-surgically at MSKCC from 2000-2012. Variables analyzed and correlated with overall survival (OS) included: sex, age at diagnosis, smoking history, asbestos exposure, tumor laterality, initial performance status (PS), tumor histology, clinical TNM, initial PET maximum Standardized Uptake Value (SUVmax), hemoglobin level, platelet, lymphocyte and neutrophil counts, treatment type (chemotherapy and/or radiotherapy), and response to treatment. OS was analyzed by Kaplan-Meier method, and significance (p<0.05) of prognostic factors was analyzed by log-rank test and Cox regression.
Results:
191 patients met study criteria: median age 71 years (range 46-90), 147 (77%) male, 128 (67%) epithelioid , 20 (10.5%) biphasic, and 28 (14.6%) sarcomatoid. 34 patients were stage I-II at presentation and 157 (82%) stage III-IV. First line chemotherapy included pemetrexed in 159 (90.3%) patients. Median time from diagnosis to treatment was 1.2 months. With a median follow-up of 13.2 months, median OS for all patients was 13.4 months. By univariate analysis, histology (p<0.001), platelet count (≤450 vs. >450, p<0.001), initial PS, maximum PET SUV (> or ≤8.1, p=0.037) were significant. Clinical staging (I/II vs III/IV) did not correlate with OS (p=0.35). By multivariable analyses, only histology, platelet count and PS were independent prognostic factors. 1-year OS was 69% (95%CI 62%-78%) for epithelioid versus 30% (95%CI 15%-59%) and 29% (95%CI 16%-51%) for biphasic and sarcomatoid tumors, respectively. Patients with PS 0-1 had a 1-year OS of 64% (95%CI 56%-73%) versus 42% (95%CI 31%-57%) for PS 2 or greater. Epithelioid histology, PS 0-1 and elevated neutrophil count at diagnosis were significantly associated with response to first line chemotherapy. Patients with response or stable disease after the first two cycles of chemotherapy had significantly better OS, median OS was 16.8 (95% CI 14.8 – 20.1) versus 6.5 (95% CI 5.4-8.5) months (p<0.001). Patients receiving more than one line of chemotherapy had better OS, median OS 14.2 (95% CI 12.1 – 16.8) versus 8.7 (95% CI 6.6 – 11.0 ) months (p=0.013). There was no significant association between use of radiotherapy and OS (p=0.058), but patients who received radiotherapy showed a 1-year OS of 60.5% vs 44.0% of patients who did not receive radiotherapy.
Conclusion:
This analysis in patients with unresectable MPM confirms that some elements of the CALGB and EORTC prognostic scoring systems (platelet count, PS, histology) correlate with OS, and identifies factors (PS, elevated neutrophil count, histology) associated with response to chemotherapy. Our analysis emphasizes the impact of histology and response to first-line chemotherapy on outcomes, but also the lack of predictability with the use of clinical staging.
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MINI38.09 - The Prognostic Significance of Nodal Metastatic Burden in Survival following Radical Surgery for Malignant Pleural Mesothelioma (ID 2776)
19:15 - 19:20 | Author(s): A.J. Sharkey, A. Nakas, D. Waller
- Abstract
- Presentation
Background:
The staging of malignant pleural mesothelioma (MPM) remains undetermined. But it is still important for informing prognosis and selection for high risk surgery. The specific lymphatic drainage of the pleura implies that nodal staging based on that used in lung cancer may not be accurate for MPM. We have evaluated an alternative nodal staging strategy.
Methods:
We retrospectively analysed the pathology and outcome of 282 patients who survived for over 30 days following radical surgery for MPM: 190 extended pleurectomy decortication(EPD), 92 extrapleural pneumonectomy(EPP). All patients underwent intraoperative systematic nodal dissection. Nodal stations were assigned to all nodes, and patients were staged according to the current UICC system. The status and number of nodes in each station were recorded. Survival was calculated for the standard nodal stages (N0, N1, N2). We derived nodal groups Na, Nb, Nc based on the percentage of sampled nodes containing tumour, irrespective of nodal station: Na = N0, Nb ≤ median %, Nc > median %.
Results:
The type of surgery did not influence median survival; EPD 12.3 vs. EPP 14.5 months, p=0.46. The median survival of the standard nodal stages were: N0(113 patients), 16.5 months; N1(13 patients), 13.0 months; N2(156 patients), 11.8 months. There was no significance difference in survival between N1 and N2, p=0.65 but there was between N0 and N1/N2, p=0.04. The median percentage of nodal metastases was 43%. There were significant differences in median survival between Na, Nb and Nc, p=0.03. There were significantly more positive N2 nodes in group Nc (98%), than in group Nb (86%) p=0.001.
Figure 1Nodal stage No of patients Median survival (months) N0 113 16.5 N1 13 13.0 N2 156 11.8 Na - no metastases 113 16.5 Nb - 86 13.5 Nc - > 43% metastases 83 9.9
Conclusion:
There appears to be greater accuracy in a nodal staging system based on the nodal burden of metastases rather than an anatomically based system. There may be less accuracy in nodal staging in lung sparing radical surgery for MPM due to less extensive nodal sampling.
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MINI38.10 - Discussant for MINI38.06, MINI38.07, MINI38.08, MINI38.09 (ID 3482)
19:20 - 19:30 | Author(s): J.W. Riess
- Abstract
- Presentation
Abstract not provided
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MINI38.11 - Tumor Volume and Epithelioid Differentiation Are Independent Predictors of Survival in Malignant Pleural Mesothelioma (ID 2428)
19:30 - 19:35 | Author(s): D. Kircheva, A. Husain, S. Watson, A. Qudsia, A. Durkin Celauro, S. Armato, H.L. Kindler, W.T. Vigneswaran
- Abstract
- Presentation
Background:
Maximal cyto-reductive surgery with adjuvant therapy provides survival advantage in selected patients with malignant pleural mesothelioma (MPM). Extended pleurectomy and decortication (EPD), a lung sparing procedure, provides an opportunity to measure the tumor volume. We hypothesized that tumor volume is a better predictor of survival than the T and N, because it represents tumor burden more accurately. Currently the significance of epithelioid differentiation in the biphasic histology also remains poorly understood. We report our experience with patients undergoing EPD and the implication of tumor volume and epithelioid differentiation in overall survival.
Methods:
We evaluated 116 patients who underwent EPD for MPM. The following variables were assessed: age, gender, histology, tumor volume and pathological T and N stage. The tumor volume of resected specimens was measured using a water displacement method. All histological examinations were performed by a single pathologist, and the percent epithelioid histology was estimated in all patients. A Cox regression model was used to identify significant predictors of survival. Kaplan-Meier was used to summarize overall and subgroup survival.
Results:
There were 95 males and 21 females with a median age of 68 years (range 43-88 years). Epithelioid differentiation was 100% in 60 patients, 50-95% in 35 patients, and less than 50% in 21 patients (no patient with pure sarcomatoid histology was included in this report). Mean tumor volume was 642+/- 400ml. Tumor volume was between 100-299cc in 20 patients, between 300-599cc in 37 patients, and >600cc in 54 patients. In 5 patients the volume was not estimated. Six patients (5%) died within 30 days. Two-year survival from EPD was 28%. Median survival was 15.7 months. Percent epithelioid differentiation (p=0.0004) and tumor volume (p=0.001) were significant predictors of survival. T (p=0.05) stage, but not N stage, was a significant predictor of survival. Tumor volume was a predictor of T stage (p=0.05). No relationship between N stage and either tumor volume or histology was observed.
Conclusion:
Percent epithelioid differentiation and tumor volume are independent predictors of survival in MPM patients undergoing EPD.
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MINI38.12 - Multiplex Immunofluorescence Identifies Differences in Immune Microenvironment & Prognostic Biomarkers between Mesothelioma Subtypes (ID 3217)
19:35 - 19:40 | Author(s): T. Seiwert, S. McGregor, C. Shu, I. Feldman, T. Zi, Z. Zuo, A. Khattri, A. Husain, H. Duraid, W.T. Vigneswaran, T.N. Krausz, S. Sathyanarayanan, H.L. Kindler
- Abstract
- Presentation
Background:
Malignant mesothelioma (MM) is a universally lethal disease, which develops in the pleura, peritoneum, pericardium, and tunica vaginalis. MM is commonly associated with a prominent inflammatory reaction, including extensive macrophage infiltration. Early reports indicate presence of tumor infiltrating lymphocytes (TILs), PD-L1 expression (Kindler et al ASCO 2014), and activity of anti-PD-1 therapy (Alley et al AACR 2015). However, quantitative evaluation of multiple immune markers in a large mesothelioma cohort and evaluation of prognostic and biologic implications has not been reported.
Methods:
We performed multiplex immunofluorescence (IF) staining and automated, quantitative density assessments in a clinically annotated cohort of 109 malignant mesotheliomas (58 epithelioid, 43 biphasic, 8 sarcomatoid). Staining for PD-1, PD-L1 (immune checkpoint), FOXP3 (T-regulatory cells), and CD8 (TILs) was performed using a quantitative, multiplex IF system (TissueFax), and a multi-tumor-validated, quantitative StrataQuest analysis algorithm in order to identify specific immune cells and respective densities. Gene expression data (TCGA) was analyzed to confirm individual correlations. Staining for CD206 (macrophages) is ongoing.
Results:
PD-L1 density correlated with more aggressive histology, and was highest in sarcomatoid (median density score of 3016), and biphasic (2720) tumors compared with epithelioid tumors (1740). Using a cutoff of 5% PD-L1 density by area 19% of epithelioid, 38% of sarcomatoid, and 44% of biphasic tumors were deemed PD-L1 positive. PD-L1 expression exhibited a bimodal distribution (peaks at both high and low PD-L1 densities). Also with the biphasic tumor cohort expression of PD-L1 correlated with worse outcome (P=0.02), while PD-1 and CD8 did not have prognostic implications (and could not distinguish histologic subtypes). By contrast in epithelioid MM CD8 infiltration density showed a trend towards improved prognosis (P=0.06) (and correlated with PD-1 expression), while PD-L1 expression was not prognostic. Interestingly, PD-1/CD8 and PD-L1 expression did not correlate regardless of histology (R=0.02-0.08), suggesting macrophage-driven PD-L1 expression. Gene expression data supported this hypothesis and staining for M2-related macrophage markers is ongoing. In epithelioid tumors FOXP3 T-regulatory cell density showed a trend towards worse prognosis (P=0.07). In biphasic and sarcomatoid tumors prognosis was poor regardless of FOXP3 expression. Data on stromal versus tumor expression patterns is being processed.
Conclusion:
In mesothelioma CD8, PD-1, PD-L1 and FOXP3 are widely expressed, with 19% of epithelioid, and 38-44% of sarcomatoid and biphasic tumors showing elevated PD-L1 density. PD-L1 expression correlates with a worse prognosis by subtype and in the biphasic tumor population. In epithelioid tumors PD-1 may indicate better outcome. PD-1 and PD-L1 expression do not correlate with each other in malignant mesothelioma, which relates to pro-tumorigenic macrophages leading to potentially interferon gamma independent PD-L1 expression.
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MINI38.13 - Survival Outcomes in Malignant Pleural Mesothelioma Patients Fit for Surgery According to Type of Procedure and Completeness of Resection (ID 2786)
19:40 - 19:45 | Author(s): M. Infante, E. Bottoni, E. Morenghi, P.A. Zucali, D. Rahal, A. Morlacchi, A.M. Ascolese, P. Navarria, A. Testori, E. Voulaz, V. Errico, M. Perrino, M. Scorsetti, M. Alloisio
- Abstract
- Presentation
Background:
The value of surgical treatment for malignant pleural mesothelioma is still an open question. We analysed a surgical series of MPM patients undergoing surgery for MPM in a single institution
Methods:
A retrospective analysis was carried out of all surgical patients treated in our Department from 2000 to February 2015. Selection criteria were age<75, performance status 0-1, non-sarcomatoid histology, pretreatment stage I-III, and fit for major surgery. The procedure of choice was extrapleural pneumonectomy (EPP) until 2010 and radical pleurectomy/decortication (PD) thereafter. Patients that were found to be unresectable underwent palliative pleurectomy. The IMIG system was used for pathological staging, complications were scored based on WHO-derived criteria and the Charlson Co-morbidity Index was used to stratify patients.
Results:
Radical surgery was attempted in 163 patients: 91 received EPP, 47 underwent PD (1 with macroscopic residual disease) and 25 a palliative pleurectomy. Their main features and survival outcomes are summarized in table 1. Mean age and Charlson score were higher in PD than in EPP patients. A mixed histology was more prevalent in those who received palliative pleurectomy. Complications were equally frequent after EPP and PD but less frequent after palliative surgery. However, EPP patients had a high frequency of early- and late-occurring (30-600+ days postop) pleural sepsis (p=0.002) that had an unfavorable effect on OS (p=0.035). Induction chemotherapy was associated with better outcomes in PD but not in EPP. At multivariate analysis, epithelial histology (p=0.0419, grade 3+ complications (p=0.001) and Charlson index (p=0.001) were associated with better overall survival (OS). PD was associated with better OS compared with palliative pleurectomy (p=0.05), while EPP was not. Figure 1
Title table: Patients' features and survival outcomes in surgical MPM patients * Surgery + either chemo or RT, **induction + Surgery + Postoperative radiotherapy, IQI= Interquartile IntervalEP (%) P/D (%) R2 (%) N° 91 47 25 Mean Age (95% CI) 60 (58 - 61) 65 (62 - 67) 63 (60 - 66) Males 66 (72) 31 (66) 22 (88) Trimodal** 28 (30.77) 33 (70.21) 6 (24.00) Epithelioid 81 (89.01) 46 (97.87) 20 (80.00) p-Stage 0-II 18 (19.8) 18 (38.3) - p-Stage III 68 (74.73) 20 (42.55) 2 (8.00) p-Stage IV 5 (5.49) 9 (19.15) 21 (92.00) Grade 3+ Complications 25 (25.47) 12 (25.53) 2 (8.00) 30-Day Mortality 3 (3.30) 1 (2.13) - Median OS (IQI) 19.0 (9.3 - 35.6) 29.9 (13.7 - 35.2) 13.3 (4.7 - 31.6) Median DFS (IQI) 11.5 (7.1 - 21.8) 12.1 (6.4 - 19.2) -
Conclusion:
EPP does not offer a significant benefit while PD may offer an advantage over palliative pleurectomy. The Charlson index is a major independent prognosticator in patients undergoing surgery for MPM.
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MINI38.14 - Surgery and Not Radiation Improves Survival in Malignant Pleural Mesothelioma (ID 3168)
19:45 - 19:50 | Author(s): A. Wolf, E. Taioli, M. Camacho-Rivera, A. Kaufman, D. Lee, D. Nicastri, K. Rosenzweig, R. Flores
- Abstract
- Presentation
Background:
Surgery has a controversial role in the treatment of malignant pleural mesothelioma (MPM) as no trial has demonstrated independent survival benefit of surgery. Likewise, there is lack of consensus regarding the role of radiation in MPM. We evaluated whether cancer-directed surgery and/or radiation independently influenced MPM survival in a large population-based dataset.
Methods:
The Surveillance, Epidemiology, and End Results database was explored from 1973 to 2009 to identify all cases of pathologically-proven MPM. Age, sex, race, diagnosis year, stage, cancer-directed surgery, radiation, and vital status were analyzed (chemotherapy data not available). The association between prognostic factors and survival was estimated using a Cox proportional hazards model.
Results:
There were 14,228 patients with pathologic diagnosis of MPM. On multivariable analysis, female gender, younger age, localized stage, and cancer-directed surgery were independently associated with longer survival (Table). Survival was longer for patients who underwent surgery or surgery and radiation but not for those who underwent radiation only (Figure).
Figure 1Table. Association between Patient and Disease Characteristics and Survival Variable Category Adjusted HR (95% CI) * Sex Male 1 (Ref) Female 0.78 ( 0.75-0.82) Race White 1 (ref) Black 1.07 (0.98-1.16) Other 0.99 (0.89-1.09) Age (years) continuous 1.24 (1.22-1.26) Stage Localized 1 (ref) Regional 1.30 (1.21-1.40) Distant 1.34 (1.26-1.42) Diagnosis year 1973-1989 1 (ref) 1990-1994 0.91 (0.85-0.97) 1995-1999 0.86 (0.81-0.92) 2000-2004 0.86 (0.81-0.91) 2005-2009 0.80 (0.75-0.84) Therapy No radiation or surgery 1 (ref) Radiation only 1.17 (1.10-1.25) Surgery only 0.65 (0.62-0.68) Radiation and surgery 0.69 (0.63-0.75)
Conclusion:
In this study of 14,228 patients over 36 years, cancer-directed surgery was associated with better survival in MPM, independent of other forms of therapy, including radiation. These data support the role of surgery-based therapy as the cornerstone for treatment in this challenging disease.
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MINI38.15 - Discussant for MINI38.11, MINI38.12, MINI38.13, MINI38.14 (ID 3558)
19:50 - 20:00 | Author(s): H.I. Pass
- Abstract
- Presentation
Abstract not provided
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Author of
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MINI 04 - Clinical Care of Lung Cancer (ID 102)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:L. Gaspar, V. Westeel
- Coordinates: 9/07/2015, 16:45 - 18:15, Mile High Ballroom 2c-3c
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MINI04.03 - Real-World Patterns of Access to Cancer Specialist Care Among Patients With Lung Cancer in the United States: A Claims Database Analysis (ID 1592)
16:55 - 17:00 | Author(s): M. Wynes
- Abstract
- Presentation
Background:
Timely access to specialist care is an important first step in the care of patients with lung cancer (LC). This study describes real-world patterns of access to cancer specialist (CS) care in all LC patients and those with metastatic LC (mLC).
Methods:
Adult patients diagnosed with primary LC or mLC were identified in a US commercial claims database (01/01/2008 - 03/31/2014). Patients’ specialist visits were assessed before and after their first biopsy (index date). All patients had ≥3 months follow-up after index date. CS was defined as oncologists or hematologists. Patients were divided in four mutually exclusive groups based on the specialists seen in the 6 weeks pre-index period: patients seen by CS (± other specialists), pulmonologists (no CS, ± other specialists), internists or family physicians (no CS/pulmonologist, ± other specialists), and other. CS visits in the 8-weeks post-index were assessed for each group. Reversed Kaplan-Meier plots were used to describe time from index date to first CS visit.
Results:
The analysis included 75,163 LC and 25,191 mLC patients, with a median age of 67 [interquartile range (IQR): 59-76)] and 63 (IQR: 57-73) years and a median follow-up of 11 and 9 months, respectively. In the 8-week post-index period, over half of LC patients (54%) and nearly two-thirds of mLC patients (66%) had their first CS visit (Figure 1), while 38% of LC patients and 28% of mLC patients never saw a CS within 1-year of biopsy (Figure 1). In both samples, patients in the CS and pulmonologist pre-index groups were more likely to see a CS in follow-up (Figure 2; p<0.001 for all groups). Figure 1 Figure 1 Figure 2 Figure 2
Conclusion:
A substantial proportion of patients diagnosed with LC and mLC did not see any CS after biopsy, which may negatively affect access to optimal and timely treatment.
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MINI 21 - Novel Targets (ID 133)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:B.P. Levy, D.S. Tan
- Coordinates: 9/08/2015, 16:45 - 18:15, Mile High Ballroom 2a-3b
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MINI21.10 - The TORK/DNA-PK Inhibitor CC-115 Shows Combination Anti-Proliferative Effects with Erlotinib in NSCLC Cells Resistant to EGFR Inhibition (ID 641)
17:40 - 17:45 | Author(s): M. Wynes
- Abstract
Background:
In non-small cell lung cancer (NSCLC), activation of the phosphoinositide-3-kinase (PI3K)/mTOR pathway is common in tumors resistant to Epidermal Growth Factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). CC-115 (Celgene Corporation), an mTOR kinase inhibitor that targets both mTORC1 and mTORC2 as well as DNA-dependent protein kinase (DNA-PK), is currently under early clinical development. We evaluated CC-115 in combination with Erlotinib to overcome resistance to EGFR tyrosine kinase inhibition in non-small cell lung cancer (NSCLC) cell lines and xenografts in nude mice.
Methods:
In the present study we investigated whether CC-115 is able to increase the therapeutic effect of the EGFR TKI Erlotinib in several different NSCLC cell lines which exhibit intermediate or high resistance to EGFR TKIs: A549, H1975, H1650, HCC95, H2122 and H23. Mechanisms of inhibition were analyzed with assays for proliferation, apoptosis, and cell cycle progression. Cell signaling activity was analyzed using phospho-specific antibodies in Western blotting. Xenograft mice studies were performed to confirm the results in vivo.
Results:
CC-115 demonstrated anti-proliferative activity in NSCLC cell lines with various degrees of sensitivity as reflected in different IC50 values, ranging from 0.07 up to 6.9 mM. The anti-proliferative efficacy of Erlotinib was increased in the NSCLC cells synergistically by combination treatment with CC-115 with combination indices down to 0.04-0.2, indicating strong synergy. The synergistic, anti-proliferative effect of the combination treatment could be explained by increased cell cycle arrest and inhibition of signaling components in the mTOR pathway, especially 4E-BP1. In vivo studies in mice xenografts demonstrated a strong synergistic effect of the combination treatment of Erlotinib and CC-115.
Conclusion:
We demonstrate that the therapeutic effect of the EGFR tyrosine kinase inhibitor Erlotinib can be increased by simultaneous treatment with the mTOR kinase/DNA-PK inhibitor CC-115, justifying further clinical studies in lung cancer patients with primary or acquired resistance to EGFR TKIs.
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ORAL 30 - Community Practice (ID 141)
- Event: WCLC 2015
- Type: Oral Session
- Track: Community Practice
- Presentations: 1
- Moderators:P.S.S. Kho, R. Jotte
- Coordinates: 9/08/2015, 16:45 - 18:15, Mile High Ballroom 2c-3c
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ORAL30.03 - Access to Cancer Directed Therapies and Cancer Specialists in Patients with Metastatic Lung Cancer (ID 2899)
17:07 - 17:18 | Author(s): M. Wynes
- Abstract
- Presentation
Background:
Access to cancer specialists and directed therapies is critical in the management of patients with metastatic lung cancer (mLC). This study aims to assess treatment patterns overall and stratified based on whether patients were seen or not by a cancer specialist in patients with de novo mLC.
Methods:
Adult patients diagnosed with de novo mLC between January 1, 2008 and March 31, 2014 were selected from a US commercial health claims database. All patients were followed for a minimum 3 months after the index date, defined as their first biopsy date. Patients who saw an oncologist/hematologist from 6 weeks before index date until the end of follow-up (end of data availability or health plan eligibility) were included in the cohort of patients who saw a cancer specialist. The remaining patients were included in the cohort of patients who did not see a cancer specialist. In both cohorts, the use of systemic antineoplastic therapy (Table 1) and radiation therapy was assessed following the index date.
Results:
The study sample consisted of 25,191 mLC patients, followed for a median of 9 months. Median age was 63 years (interquartile range: 57-73). 28.4% of the patients did not see a cancer specialist. Overall, 89.9% of the mLC patients received a cancer directed therapy during the follow-up (Table 1). The proportion of patients who received a cancer directed therapy during the follow-up was larger among patients seen by a cancer specialist (91.2% vs. 86.7%, p < .0001) (Table 1). Among patients who did not see a cancer specialist, 86.7% received antineoplastic therapy and/or radiotherapy during the follow-up, 2.6% were untreated and admitted to hospice, and 10.6% were untreated and were not admitted to hospice. The majority of patients who were not seen by a cancer specialist and received treatment were seen prior to the initiation of therapy by pulmonologists, internists, family physicians, and/or radiologists. Figure 1
Conclusion:
Approximately one in ten patients with de novo mLC did not receive any cancer directed therapy and a little more than one in four patients were not seen directly by a cancer specialist. Among patients not seen by a cancer specialist many received some form of cancer directed therapy. However, the access to cancer directed therapy of these patients remained significantly lower than that of mLC patients seen by a cancer specialist. Further research should be directed towards understanding and addressing disparities in access to appropriate cancer care.
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-006 - MiRNA Signature to Assess Sensitivity to FGFR Tyrosine Kinase Inhibitors (ID 1717)
09:30 - 09:30 | Author(s): M. Wynes
- Abstract
Background:
Increased signaling through the FGF/FGFR signaling pathway has been implicated as a driver in a number of different malignancies including lymphomas, prostate cancer, breast cancer, and lung cancer. This pathway also appears to play a role in conferring de novo and acquired resistance to cancers driven by EGFR mutations. Consequently, drugs that inhibit FGFRs are being investigated as potential therapeutics for cancer. Here we screened a large panel of miRNAs as potential predictors of sensitivity to FGFR tyrosine kinase inhibitors (TKIs).
Methods:
A panel of 377 miRNAs (Megaplex Card A, Life Technologies) was screened for expression level differences between four lung cancer cell lines that are sensitive (IC~50~< 50 nM) and four lines that are resistant (IC~50~ > 100 nM) to ponatinib (non-specific FGFR TKI) and AZD4547 (FGFR-specific TKI). Expression levels were assayed by RT-qPCR and analyzed using the Statistical Analysis of Microarrays (SAM) method. Thirty-nine miRNAs having an estimated false discover rate (FDR) of zero and large median fold differences (> 8) between the sensitive and resistant lines were selected for signature development. RT-qPCR assays were incorporated into a custom microfluidics card (Life Technologies), which was used to profile the original 8 cell lines and 10 additional sensitive lines and 16 additional resistant lines (34 lines total). Logistic regression was then used to identify the best signature panel for distinguishing sensitive cell lines from resistant.
Results:
Univariate analysis indicated three miRNAs (let-7c, miR-338, and miR-218) that differed between the sensitive and resistant lines at p < .05. The best signature panel consisted of let-7c, miR-200a and miR-200b, which gave an area under the receiver operator characteristic (AUROC) curve of 0.90 (95% CI = 0.8 to 1). This performance was nearly as good as using FGFR1 mRNA alone (AUROC = 0.94). The predominant miRNA in our 3-miRNA signature was let-7c, which also exhibited a suggestive additive effect to using FGFR1 as a biomarker (p = 0.09). We also tested whether cell lines with high sensitivity to ponatinib can be made resistant by reducing the high level of let-7c in these lines. We have found that transient transfection of let-7c silencing RNA (Life Technologies) produces a decrease in FGFR1 mRNA levels for some cell lines but not others.
Conclusion:
It appears possible to predict sensitivity to an FGFR1 inhibitor using miRNA expression signatures. More studies, however, are needed to confirm the 3-marker signature developed in this study. Modulating let-7c, the predominant predictor within the signature, appears to modulate FGFR1 levels in a manner consistent with altering ponatinib sensitivity. This effect is most likely indirect as the mRNA of FGFR1 does not contain predicted binding sites for let-7c.
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P3.06 - Poster Session/ Screening and Early Detection (ID 220)
- Event: WCLC 2015
- Type: Poster
- Track: Screening and Early Detection
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.06-008 - Meta-Analysis Criteria Used to Rank Biomarkers for Validation Testing: What Works? (ID 81)
09:30 - 09:30 | Author(s): M. Wynes
- Abstract
Background:
Hundreds of biomarkers are being developed for the screening and early detection of lung cancer. The vast majority, however, even after extensive internal validation, will likely fail during external validation. For biomarkers to reach the clinic, therefore, it’s imperative that external validation studies focus on the most promising candidates. Towards this end, various strategies have been proposed to rank order and prioritize biomarker candidates. These strategies range from simple, highly intuitive ideas to highly sophisticated statistical analyses. To our knowledge, however, none of these strategies has itself been validated externally, which is an important consideration given that each strategy involves making subjective decisions. Here we conducted an independent validation test to assess the performance of the “vote-counting strategy”, a straightforward, commonly used strategy that ranks biomarkers on the basis of three highly intuitive criteria: the number of supporting studies in the literature, the combined sample size in the supporting studies, and the average fold change difference associated with the biomarker.
Methods:
We obtained vote-counting biomarker rankings from two recent meta-analyses that together surveyed over 180 miRNAs reported to distinguish lung tumor tissue from normal. We compared the rankings of 50 top candidates and 22 unranked miRNAs to our RT-qPCR results obtained from 45 tumor-normal pairs. We tested for a statistically significant Pearson correlation (r) between biomarker performance and the rankings according to each of the three ranking criteria.
Results:
We found that the number of supporting studies in the literature was indeed a statistically significant predictor of biomarker performance (r = 0.44, n = 50, p = .0006). Our results also suggested that markers supported by two studies in the literature had approximately a 50% chance of being confirmed, markers supported by 3 studies about a 67% chance, and markers supported by 6 studies about a 90% chance. Our unranked markers showed only a 5% chance of being confirmed. At the same time, we found that the combined sample size in the supporting studies was not a predictor of biomarker performance (r = 0.11, n = 50, p = 0.29). We also found that the mean fold change associated with each biomarker was not a predictor (r = 0.12, n = 47, p = 0.22) because large fold-change differences were also associated with large amounts of variability between studies.
Conclusion:
Considering that vote counting has obvious limitations (such as selection bias, not counting negative votes, and the variation in how different studies define significance) counting the number of supporting studies in the literature appears to work remarkably well for ranking biomarker candidates. On the other hand, using total sample size or mean fold change in the supporting studies to rank biomarker candidates appears to provide little, if any, added value. Our results also indicate a need for external validation testing of the current strategies being used to rank biomarkers across studies.
