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M.V. Bluthgen
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MA11 - Novel Approaches in SCLC and Neuroendocrine Tumors (ID 391)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:P. Lara, A. Mohn-Staudner
- Coordinates: 12/06/2016, 14:20 - 15:50, Strauss 3
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MA11.02 - Mutational Burden in Pulmonary Neuroendocrine Tumors (puNETs) (ID 6099)
14:26 - 14:32 | Author(s): M.V. Bluthgen
- Abstract
- Presentation
Background:
Tumor mutational load (TML) by whole-exome sequencing (WES) is a potential determinant of response to immune checkpoint blockers. The use of PD-L1 as a predictive biomarker for use of PD-1/PD-L1 inhibitors is limited. To date, there are few data concerning TML in puNETs.
Methods:
WES was performed in fresh-frozen tumor-normal pairs from 35 typical carcinoid (TC), 4 atypical carcinoid (AC) and 9 large-cell neuroendocrine carcinoma (LCNEC) consecutively collected. Exome enriched libraries were sequenced on an Illumina HiSeq 2000 with a paired-end 2 x 100 bp protocol. Reads were aligned to the reference hg19 using an implementation of the Burrows-Wheeler Aligner, and a BAM file was produced for each tumor and normal sample using the Picard pipeline. The MuTect algorithm was used to identify SSNVs in WES data. We used a minimal allelic fraction cutoff of 0.1. Patients' characteristics and TML were described (median and interquartile for quantitative variables and frequencies for qualitative variables). To evaluate the effect of some factors on the TML, an analysis of variance was used. A log transformation was performed according to the distribution of the TML. The median follow-up was estimated using the Schemper's method. The number of relapses and deaths was reported.
Results:
Cohort included 24 male and 24 female. Median age at diagnosis was 57 [Q1= 46; Q3= 70] years, 38% of carcinoids (TC+AC) and 89% of LCNEC were smokers, 26 (54%) stage I, 16 (34%) stage II, 3 (6%) stage III and 3 (6%) stage IV. All patients underwent surgery and 5 (10%) received neoadjuvant treatment. Median follow-up was 32.6 (min= 4.4; max= 179.9) months; there were 8 (17%) relapses (6/9 LCNEC, 2/39 carcinoids) and 10 deaths. On average, 11.6 Gb of sequence were produced per sample, aiming a mean coverage of 72X. Overall median TML was 0.31/Mb [Q1= 0.22; Q3= 0.67], significantly lower in carcinoids tumors than LCNEC (0.28 [Q1= 0.20; Q3= 0.38]/Mb vs. 2.98 [Q1= 1.20; Q3= 4.84]/Mb, respectively, p<0.0001). Similar findings were observed among smoker vs. non-smoker patients (0.28 [Q1= 0.18; Q3= 0.38]/Mb vs. 0.60 [Q1= 0.28; Q3= 2.98]/Mb, respectively, p=0.04). Both variables were found to be independently correlated with TML within the ANOVA test (p=0.0016).
Conclusion:
Our findings provide a unique portrait of puNETs, revealing different histotype mutational burden. Continued work in harnessing immunological data in puNETs are needed for better understanding immunotherapy-treatment option in this orphan disease.
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OA18 - New Insights in the Treatment of Thymic Malignancies (ID 408)
- Event: WCLC 2016
- Type: Oral Session
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:N. Girard, S.B. Watzka
- Coordinates: 12/07/2016, 11:00 - 12:30, Schubert 2
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OA18.07 - Quality of Resection and Outcome in Stage III TETs: The French RYTHMIC Network Experience (ID 6173)
12:05 - 12:15 | Author(s): M.V. Bluthgen
- Abstract
- Presentation
Background:
Stage III TET represents a heterogeneous population and their optimal approach remains unclear; most of the available literature is composed of small series spanned over extended periods of time. RYTHMIC (Réseau tumeurs THYMiques et Cancer) is a French nationwide network for TET with the objective of territorial coverage by regional expert centers and systematic discussion of patients management at national tumor board. We reviewed our experience in stage III thymic tumors in order to evaluate the value of tumor board recommendations and multidisciplinary approach.
Methods:
We conducted a retrospective analysis of patients (pts) with stage III TET discussed at the RYTHMIC tumor board from January 2012 to December 2015. Clinical, pathologic and surgical data were prospectively collected in a central database. Survival rates were based on Kaplan-Meier estimation. Cox proportional hazard models were used to evaluate prognostic factors for disease free survival (DFS) and overall survival (OS).
Results:
150 pts were included in the analysis. Median age was 64 years [18 – 91], 56% males, thymoma A-B2/ B3-thymic carcinoma in 52% and 47% respectively; 12% presented with autoimmune disorder (76% myasthenia). Local treatment was surgery in 134 pts (90%) followed by radiotherapy (RT) in 90 pts; 26 pts received preoperative chemotherapy (CT). Complete resection rate (R0) was 53%. Among 38 pts considered non-surgical candidates at diagnosis, 26 pts became resectable after induction CT with a R0 rate of 58%; 12 pts received CT-RT and/or CT as primary treatment. Recurrence rate was 38% (n=57), first sites were pleural (n=32) and lung (n=12). The 5-year OS and DFS were 88% and 32% respectively. Gender (HR: 0.2 [95%CI 0.04 - 0.97] p=0.04), histology (HR: 0.19 [95%CI 0.05 - 0.70] p=0.02) and surgery (HR: 0.4 [95%CI 0.01 - 0.20] p<0.001) as primary treatment modality were significant prognostic factors for OS in multivariate analysis. Histology (HR: 0.5 [95%CI 0.30 - 0.90] p=0.02) and adjuvant RT (HR: 0.4 [95%CI 0.20 – 1.00] p=0.05) were significantly associated with DFS. Completeness of resection was not associated with survival in our cohort.
Conclusion:
Surgery followed by radiotherapy improves outcome irrespectively of R0. Stage III TET not candidate to surgery should be reassessed for resection after induction chemotherapy.
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P2.03b - Poster Session with Presenters Present (ID 465)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03b-050 - Prognostic Value of HLA-A2 Status in Advanced Non-Small Cell Lung Cancer (NSCLC) Patients (ID 4773)
14:30 - 14:30 | Author(s): M.V. Bluthgen
- Abstract
Background:
The class I human leucocyte antigen (HLA) molecules play a critical role as escape mechanism of antitumoral immunity. Indeed, novel immune-targeting cancer vaccines are currently developped in HLA-A2 positive patients for modulating the T cells response. The HLA-A2 status has been proposed as prognostic factor in lung cancer, but previous evidence is inconsistent. The aim of this study is to evaluate the role of HLA-A2 status as prognostic factor in a large cohort of advanced NSCLC patients.
Methods:
Advanced NSCLC patients eligible to platinum based chemotherapy (CT) were included from Oct. 2009 to July 2015 in the prospective MSN study (IDRCB A2008-A00373-52) in our institute. HLA-A2 status was analysed by flow cytometry. Clinical and pathological data were collected in a Case Report Form (CRF). Statistical analysis was performed with software SAS version 9.3.
Results:
Five hundred forty-five advanced NSCLC patients were included. Three hundred forty-four patients (63%) were male, median age was 61 years (21-84); 466 (85%) were smokers. Four hundred seven (75%) were adenocarcinoma, 69 (13%) squamous and 69 (13%) others histologies. Among 259 patients with known molecular profile, 113 (43.6%) NSCLC were KRASmut, 50 (19.3%) EGFRmut, 30 (11.6%) ALK positive, 9 (3.5%) BRAFmut and 8 (3.1%) FGFR1amp. Four hundred forty-seven (83%) patients had performance status 0-1 at diagnosis. Five hundred eight patients (93%) were stage IV, and 37 (7%) stage IIIB. All received platinum-based CT (49% cisplatine, 42% carboplatin and 9% both). No association was observed between HLA-A2 status and patient or tumor characteristics. The median progression free survival to platinum-based CT (PFS) was 5.6 months [confidence interval (CI) 95% 5.20-6.10]. In HLA-A2 positive patients, the median PFS was 5.6 months [CI 95% 5.1-6.4] vs. 5.7 months [CI 95% 4.9-6.2] in HLA-A2 negative patients (HR 1, Wald test, p=0.8).The median overall survival (OS) was 12.6 months [CI 95% 11.3-14.3]. The median OS was 12.8 months [CI 95% 11-14.6] in HLA-A2 positive vs. 12.5 months [CI 95% 10.4- 15.3] in HLA-A2 negative patients (HR 1, Wald test p=0.61). No significant differences were found between HLA-A2 status and PFS and OS in advanced NSCLC patients.
Conclusion:
Our study has observed no prognostic role of HLA-A2 status in advanced NSCLC patients.
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P2.04 - Poster Session with Presenters Present (ID 466)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 3
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.04-003 - Chemotherapy in Advanced Thymic Epithelial Tumors: Insights from the RYTHMIC Prospective Cohort (ID 4275)
14:30 - 14:30 | Author(s): M.V. Bluthgen
- Abstract
Background:
Thymic Epithelial Tumors (TET) are rare intrathoracic malignancies, which may be aggressive and difficult to treat. In the advanced setting, chemotherapy may be delivered as a primary/induction therapy before subsequent surgery or definitive radiotherapy, and/or as exclusive treatment in patients for whom no focal treatment is feasible, and/or in the setting of recurrences. As no randomized trial and a limited number of prospective studies are available, there is paucity of prospective, multicentre evidence regarding response rates and survival of patients. RYTHMIC is the nationwide network for TET in France. The RYTHMIC prospective database is hosted by the French Intergroup (IFCT), and collects data for all patients diagnosed with TET, for whom management is discussed at a national multidisciplinary tumor board (MTB) based on consensual recommendations. Primary, exclusive chemotherapy, and chemotherapy for recurrence accounted for 149 (11%), 37 (3%), and 67 (5%) questions of a total of 1401 questions raised at the MTB between 2012 and 2015.
Methods:
All consecutive patients for whom chemotherapy and/or systemic treatment was discussed at the RYTHMIC MTB from 2012 to 2015 were identified from the RYTHMIC prospective database. Main endpoints were response rates and progression-free and overall survival.
Results:
At the time of analysis, data were available for 156 patients (80 thymic carcinomas, and 76 thymomas), for whom the management led to raise 283 questions at the MTB: 67 (24%) for primary chemotherapy, 35 (11%) for exclusive chemotherapy, and 181 (64%) for recurrences. For primary and exclusive chemotherapy, the most frequently administered regimen was CAP, producing response rates of 70% and 60%, respectively. A total of 104 patients received at least one line of chemotherapy for recurrence; 53 patients received second-line treatment, and 13 and 7 patients received third- and fourth line treatment. In the setting of first recurrence, carboplatine-paclitaxel combination was the most preferred regimen, administered to 54% of patients; overall response and disease control rates to systemic treatments for recurrences were 13% and 42% in thymic carcinomas, and 19% and 43% in thymomas (p=0.38 and p=0.92, respectively). Median recurrence-free survival after primary chemotherapy was 16.6 months; median progression-free survival after exclusive chemotherapy, and first-, second-, and third-line chemotherapy for recurrence were 6.0 months, and 7.6 months, 6.2 months, and 6.0 months.
Conclusion:
Our data provide with a unique insight in the efficacy of chemotherapy for advanced thymic epithelial tumors in a real-life setting; our results help the decision-making to better define the optimal therapeutic strategies.
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P2.04-006 - Updated Incidence of Thymic Epithelial Tumors (TET) in France and Clinical Presentation at Diagnosis (ID 5952)
14:30 - 14:30 | Author(s): M.V. Bluthgen
- Abstract
Background:
TETs are rare malignancies with an overall described incidence of 0.13 per 100.000 person-years. Given this, most of our knowledge is largely derived from small single-institution series. RYTHMIC (Réseau tumeurs THYMiques et Cancer) is a French network for TET with the objective of territorial coverage by 14 regional expert centers, systematic discussion of patients at national tumor board and collection of nationwide data within a centralized database. We reviewed our activity in 2015 in order to describe the epidemiology and main characteristics at diagnosis of thymic malignancies in France.
Methods:
Through RYTHMIC, we prospectively collected all patients (pts) with new diagnosis of primary TET in France in 2015. Epidemiologic, clinical, pathologic and surgical data were prospectively collected within a centralized database. Histologic subtype was centrally reviewed according to the WHO classification and stage by modified Masaoka-Koga classification.
Results:
A total of 234 cases with new diagnosis of primary thymoma (T) or thymic carcinoma (TC) have been discussed at RYTHMIC between Jan to Dec 2015. Among them, 58% were males; median age was 62 years [range 27; 86] for males and 61 years for females [range 24; 84]; 20% of the pts presented an autoimmune disorder (AI); myasthenia gravis was the most common in 76% of them. History of previous malignancies was described in 15% of the pts, being melanoma, prostate and breast cancer the most frequently observed. Any potentially relevant environmental exposure was declared for most of the pts. Histology was characterized as follows: A / AB / B1 / B2 / B3 / TC / neuroendocrine tumors and rare variants in 7% / 23% / 13% / 24% / 9% / 16% / 8% respectively. Stage I-II / III-IV tumors were observed in 63% / 37% respectively. Mediastinal pleura, mediastinal nodes and lung were the most common metastatic sites. Significant correlations were found between histologic sub-type (T vs TC) and presence of AI (p=0.01) and stage (I-II vs III-IV, p=0.004); no significant correlations were seen with gender (p=0.27).
Conclusion:
The estimated incidence of TETS in France in 2015 is 0.35 per 100.000 persons, based in our activity. The inclusion in the RYTHMIC network is mandatory but is still based on physician’s request. Although we might underestimate the incidence, it seems to be higher compared to other countries’ registries. The high occurrence of previous cancer might underlie variations in environmental or genetic risk factors.
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P2.04-007 - Role of F-18-Choline Petscan in Recurrence of Thymic Epithelial Tumors (TET) (ID 5971)
14:30 - 14:30 | Author(s): M.V. Bluthgen
- Abstract
Background:
Fluorine-18-fluorodeoxyglucose (F-18-FDG) uptake in TETs is highly variable based on histology subtype. The fluorine-18-choline (F-18-choline) PET/CT scan represents an emerging important tool in the management of tumors with low glucose metabolism. There have been few case reports describing positive choline uptakes in TETs. The aim of this study is to evaluate the clinical use of choline PET/CT in TET.
Methods:
We conducted a retrospective analysis of patients (pts) with diagnosis of TETs who underwent an F-18- choline PET/CT exam in the course of their disease from Jan 2012 to May 2016. Pathologic and clinical data were extracted from medical records. FDG exams with a mean standardize uptake value (SUV) higher than 4.5 and choline exams with uptake more than two times the physiologic value, were considered as positive.
Results:
A total of 10 pts were included for analyses. Among them, 8 pts were males; median age was 43 years [32-62], 8 pts presented an autoimmune disorder (62 % myasthenia gravis); 8 had thymoma (T) and 2 had thymic carcinoma (TC). All patients underwent choline PET/CT in order to evaluate suspected recurrence and/or progression. Positive choline scans were observed in 7 pts with a median SUV of 6.5 [4.8-7.8] with the following histology subtype distribution: B1 / B2 / TC in 2 / 3 / 2 pts respectively. Negative choline scan was observed in 3 pts with AB, B1 and B2 histology subtypes. Five patients (50%) showed disagreement between F-18-FDG and F-18-choline scans results. Among them, 3 pts with a negative FDG scan had a positive choline PET/CT, showing an isolated recurrence amenable to local treatment in two of them; disseminated progression excluded local treatment for the remaining patient. Diagnosis of mediastinal relapse was suspected for 2 pts on positive mediastinal FDG uptake but excluded based on a negative choline scan and MRI findings; both of them had history of mediastinal adjuvant radiotherapy. Agreement was seen between both modalities for 4 pts.
Conclusion:
Discordance between FDG and choline scans was observed for half of the pts. When FDG scan was negative, the addition of choline PET/CT impacted disease management in 75% of the cases. History of adjuvant mediastinal radiotherapy could constitute a frequent cause of false positive FDG scan with negative choline findings; therefore, choline scan might also represent a useful exam to exclude mediastinal relapses in this scenario.
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P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02b-102 - Osimertinib Benefit in ctDNA T790M Positive, EGFR-Mutant NSCLC Patients (ID 5472)
14:30 - 14:30 | Author(s): M.V. Bluthgen
- Abstract
Background:
The third generation tyrosine kinase inhibitors (TKIs) osimertinib is approved for patients with acquired epidermal growth factor receptor (EGFR) T790M mutations in advanced non-small cell lung cancer (NSCLC) patients. New tissue biopsy to detect T790M cannot always be performed, due to the size or location of the lesions and risk of complications to the patient. As an alternative, liquid biopsies based on circulating cell-free tumor DNA (ctDNA) analysis have been described. We assess the efficacy of osimertinib in ctDNA T790M-positive, EGFR-mutant NSCLC patients with progression under first- or second-generation EGFR TKIs ineligible for tissue biopsy at progression; and the feasibility of identifying T790M mutations in ctDNA isolated from blood samples in this cohort of patients.
Methods:
ctDNA analysis using enhanced eTAm-Seq™ assay (Inivata), and enhanced version of the Tam-Seq ® assay was conducted in 48 eligible patients treated in a single center between April 2015 and April 2016. Patients determined to have T790M mutation were prescribed osimertinib (80mg daily). Objective response rate (ORR) by RECIST 1.1 criteria was centrally reviewed and correlated with (A) T790M allele fraction, (B) EGFR activating mutation allele fraction, and (C) T790M by EGFR activating mutation allele fraction ratio.
Results:
T790M status in ctDNA was assessed in 48 EGFR-mutant NSCLC patients. Median age was 65 years (range 37-83); 36 (75%) patients were women and 58% were never-smoker. EGFR mutation status was Del19 in 33 (69%) and L858R in 15 (31%) NSCLC patients. The ctDNA T790M mutation was positive in 24 out of 48 (50%) patients, and 23 out of 24 T790M-positive samples maintained the original activating EGFR mutation in ctDNA analysis. Among evaluable patients (n=16), osimertinib gave a partial response rate of 62.5% and a stable disease rate of 37.5%. Neither correlation between ctDNA T790M AF and RECIST radiological response was observed, nor with the other parameters evaluated. Of the seven cases with best response (decrease of 50% or more in size), 3 cases had T790M detected at <0.25%.
Conclusion:
Osimertinib efficacy in a real-world setting among T790M-positive tumours detected in ctDNA from liquid biopsy support the use of such liquid biopsies as a surrogate marker for T790M in tumour tissue, avoiding the need for invasive tumor biopsies for personalising treatment in lung cancer patients
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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02c-031 - Immune Checkpoint Inhibitors (IC) and Paradoxical Progressive Disease (PPD) in a Subset of Non-Small Cell Lung Cancer (NSCLC) Patients (ID 5448)
14:30 - 14:30 | Author(s): M.V. Bluthgen
- Abstract
Background:
In non-squamous NSCLC PD-L1 negative patients (pts), IC might increase the risk of early death compared to docetaxel in the phase III study Checkmate 057. Tumor Growth Rate (TGR) is calculated using 2 CTscans and the time interval between the 2 exams. It integrates tumor dynamics and kinetics. We hypothesized that TGR could identify a subset of pts named PPD, in which IC could accelerate tumor progression, leading to early death.
Methods:
We performed a retrospective case study of all NSCLC pts treated by IC in a single institution between Dec. 12 and Feb. 16. CT scan were centrally reviewed by a senior radiologist and assessed according to RECIST 1.1 criteria. We calculated TGR at baseline of IC (baseline CTscan (n) vs n-1 CTscan) and TGR during IC (n+2 CTscan vs n+1 CTscan). We further estimated the difference (deltaTGR) between TGR during IC and TGR at baseline. DeltaTGR>0 means IC speeds up tumor growth. PPD was defined as deltaTGR>50%, corresponding to an absolute increase in TGR greater than 50% per month. PDL1 expression was assessed with the SP142 clone.
Results:
89 pts were eligible. 58% were male, median age 60 (41-78); 15% never smokers. 62 pts had adenocarcinoma, 21 squamous and 6 other histologies. Mutational status was unknown for 14 pts; 36% wild type, 9 pts EGFRmut, 25 pts KRASmut. PDL1 expression was positive in 25 pts, unknown in 57 pts. 52 pts (58%) received nivolumab, 25 pembrolizumab and 12 atezolizumab. Treatement was received as 1-3[rd] line in 52 pts, and as ≥ 4[th] line in 37 pts. Overall, 25 pts (28%) had a response according to RECIST 1.1 criteria, 31 (35%) a stable disease. Median OS was 14.7 months. During IC, deltaTGR was <0 in 79 pts and >0 in 20 pts. Among the 20 pts with deltaTGR>0, 9 had a PPD. Characteristics (age, sex, smoking status, pathology, number of previous line, PDL1 status) of the 9 pts were not different from other pts. None of the PPD were pseudoprogression. Median OS of PPD vs others was 3.2 and 23 months, respectively. PPD was not more frequent in tumors with high baseline TGR.
Conclusion:
Our results suggest that PPD is a new subset of response criteria in which IC may increase tumor progression, leading to a poorer survival. Rapidly growing disease at study entry nor RECIST criteria could predict the occurrence of PPD.
