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M. Chida
Moderator of
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OA 03 - Mediastinal and Esophageal Tumor: Insight and New Treatment (ID 654)
- Event: WCLC 2017
- Type: Oral
- Track: Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 8
- Moderators:M. Chida, Jhingook Kim
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 311 + 312
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OA 03.01 - Prevalence of Autoimmune Diseases in Thymic Epithelial Tumors (TET) Insights from RYTHMIC (ID 8745)
11:00 - 11:10 | Presenting Author(s): Marie-Eve Boucher | Author(s): E. Dansin, M. Kerjouan, Julien Mazieres, E. Pichon, F. Thillays, G. Massard, X. Quantin, O. Youssef, Virginie Westeel, L. Thiberville, C. Clement-Duchene, F. Morin, P. Thomas, Nicolas Girard, Benjamin Besse
- Abstract
- Presentation
Background:
TET have been associated with autoimmune disorders (AID) in up to 30 % of patients. However, there have been wide variations in the reported prevalence of TET associated disorders based mostly on small single center series. RYTHMIC (Réseau tumeurs THYMiques et Cancer) is a French network mandated to systematically discuss every case of TET. Using our database, we aimed to describe the prevalence of AID in a large French population with TET.
Method:
RYTHMIC database prospectively includes all consecutive patients with a diagnosis of TET discussed in our national tumor board. We calculated the prevalence and described epidemiologic, clinical and pathological characteristics of patients with TET’s related autoimmune diseases.
Result:
From January 2012 to May 2017, 1693 patients were included in the registry. Of these, 200 patients (11.8%) had autoimmune disorder. The mean age at diagnosis of TET was 54 years old and 52% were male. 149 had myasthenia gravis (75.3%), 15 Good syndrome (7.6%), 14 pure red cell aplasia (7.1%), 12 systemic erythematous lupus (6.1%) and 12 thyroiditis (6.1%). Some patients (14.5%) eventually developed more than 1 AID. Diagnosis of AID was mostly done at the same time of TET diagnosis (54.6%) but some patient had their AID diagnosed before (19.8%) or during follow up (13.4%). Masaoka Koga stages were overall well balanced with 16.5% stage III, 16% stage IIb, 13.5% stage I, 13% stage IIa and IV. Histologic subtype distribution was in order of frequency; B2 (37%), AB (14.5%), B3 (14%), B1 (10.5%), thymic carcinoma (4.5 %) and A (4%).
Conclusion:
In our registry of TET, the prevalence of autoimmune diseases was 11.8% and most diagnosis were established at the same time as TET. The extent of disease, measured by Masaoka Koga staging, does not seem correlated.
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OA 03.02 - Comprehensive Characterization of Thymic Epithelial Tumour Subtypes Through an Analysis of Somatic Mutations and Copy Number Alterations (ID 10322)
11:10 - 11:20 | Presenting Author(s): Spyridon Gennatas | Author(s): A. Mandal, Andrew G Nicholson, Sanjay Popat, A.M. Bowcock
- Abstract
- Presentation
Background:
Thymic epithelial tumours (TETs) are rare and under-researched intrathoracic cancers. So far the only significant finding is a recurrent (43%) missense mutation in GTF2I. In addition to validating this finding, we set out to expand our understanding of the molecular changes underlying TETs through whole exome sequencing (WES) and detection of copy number alterations (CNAs) following SNP genotyping.
Method:
WES was performed on 17 TETs (2AB, 1B1, 3B2, 2B3, 6CA and 3NETT) and matched normal tissue. Somatic single nucleotide variants (SNVs) were identified with the GATK HaplotypeCaller and annotated for impact prediction (SnpEff 3.6b and SnpSift 1.3.4b) and population frequency (SnpSift 1.3.4b). The frequency of the GTF2I mutation was assessed with Sanger sequencing with semi-nested primers on DNA from 144 TETs of all subtypes. SNP genotyping was performed on 100 TETs of all subtypes with matched normal tissue in most cases, to identify somatic CNAs. Analysis was performed with ASCAT (v2.4.4) and copy number segments were annotated with Bedtools (v2.26.0).
Result:
WES confirmed a low mutation burden for TETs. No highly recurrent mutations were found. Hotspot mutations in NRAS and KRAS were seen, as was a hotspot mutation in TP53 in a NETT. A high impact frameshift MSH6 somatic mutation was noted in one of the squamous cell carcinomas (SCCs). Another SCC had a germline BAP1 mutation and a family history of other cancers, suggesting a BAP1 familial cancer predisposition syndrome in this individual. The GTF2I mutation was seen in 48 of 141 evaluable TETs (34%) and was present more commonly in type A (90%) and AB (69%) thymomas. The frequency decreased to 16%, 6% and 13% in B1, B2 and B3 thymomas respectively and was not seen in any squamous (0/12) or neuroendocrine carcinomas (0/6). Overall, the most frequent copy number gains in TETs involved chromosomes 7q (22%), 1q (17%) and 11q (17%). The commonest gain was in a gene not previously found to be amplified in solid tumours. The most frequent copy number losses were in chromosomes 6p (40%), 2q (37%) and 7q (32%). Gains and losses demonstrated distinct patterns between aggressive versus indolent subtypes.
Conclusion:
The mutation in GTF2I remains the single most frequently recurrent mutation in TETs. We are in the process of establishing a clinical use for this finding. Results from WES and CNA through SNP genotyping have provided important insight into other potential key players in the aetiology of this intriguing malignancy.
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OA 03.03 - Phase II Trial of Cetuximab and Chemotherapy Followed by Surgical Resection for Locally Advanced Thymoma (ID 10288)
11:20 - 11:30 | Presenting Author(s): James Huang | Author(s): D.J. Raz, M. Cristea, Kay See Tan, K. Deonaraine, A. Starr, William D Travis, M.S. Ginsberg, D. Jones, Valerie W Rusch, Mark G Kris, Gregory J Riely
- Abstract
- Presentation
Background:
The mainstay of treatment for thymoma is surgery with neoadjuvant chemotherapy recommended to patients with locally advanced disease. EGFR is overexpressed in thymoma. Clinical responses to single-agent cetuximab have been reported in patients with advanced cetuximab. We conducted this two-site prospective phase II trial of cetuximab combined with a standard induction chemotherapy regimen of cisplatin, doxorubicin and cyclophosphamide (PAC) in patients with locally advanced thymoma prior to surgical resection.
Method:
Patients with clinical Masaoka stage III-IVA thymoma were treated with cetuximab (250mg/m[2] weekly x 4 weeks) followed by cetuximab (250 mg/m[2] weekly) combined with cisplatin (50mg/m[2]), doxorubicin (50 mg/m[2]) and cyclophosphamide (500mg/m[2]) 3 weeks x 4 cycles). Radiographic response was assessed by CT using RECIST 1.1 and FDG-PET using PERCIST. All patients went on to surgery after completion of induction therapy. The primary endpoint was major pathologic response (MPR, >90% treatment effect). Planned enrollment was 18 patients in first stage of a two stage design. If 1 MPR was observed, then enrollment would expand to 28 patients.
Result:
Eighteen patients were enrolled: 8 women, median age 53 (range 32-73). WHO Histologic subtype A: 2, AB: 3, B1: 3, B2: 7, B3: 3. Final Masaoka stage I: 2, II: 2, III: 5, IVA: 9. There were no responses to cetuximab alone by RECIST criteria, although 1 patient had a 25% reduction in indicator lesions. Response rate (CR+PR), in evaluable patients after complete treatment course was 50% (8/16, 95% CI 28-72%). Partial responses by PERCIST criteria were seen on PET in 11/18 (61%) evaluable patients. There were no MPRs. R0 resection was obtained in 7 patients; 5 had R1 and 6 had R2 resections.
Conclusion:
The addition of cetuximab to PAC chemotherapy did not lead to pathologic complete responses in the neoadjuvant setting. Cetuximab alone appears to have little effect during 4 weeks of treatment. There was no apparent increase in radiographic response rate with the addition of cetuximab to PAC chemotherapy compared to historical series.
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OA 03.04 - A Phase II Study of Pembrolizumab for Patients with Refractory or Relapsed Thymic Epithelial Tumor (ID 9689)
11:30 - 11:40 | Presenting Author(s): Jinhyun Cho | Author(s): K.H. Yoo, Hansang Lee, H.K. Kim, Y. Kim, J.H. Cho, S.W. Lim, Song Ee Park, Jong-Mu Sun, S. Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn
- Abstract
- Presentation
Background:
No standard treatment exists for patients with thymic epithelial tumor (TET) who progress after platinum-containing chemotherapy. We conducted a phase II study of pembrolizumab in patients with refractory or relapsed TET to evaluate the efficacy and safety.
Method:
Between March 2016 and June 2017, patients with histologically confirmed TET who progressed after at least one platinum-containing chemotherapy were eligible. Patients were excluded if they had an active autoimmune disease requiring systemic treatment within the past one year or documented history of clinically severe autoimmune disease. Patients received 200mg of pembrolizumab intravenously every 3 weeks until tumor progression or unacceptable toxicity. Response was assessed every 9 weeks by investigator. The trial was registered with ClinicalTrials.gov, number NCT02607631.
Result:
Thirty-three patients were enrolled, 26 with thymic carcinoma and 7 with thymoma. 19 (57.3%) patients received two or more prior lines of systemic chemotherapy. Median number of cycles was 8 (ranges, 1-22) and median follow-up was 11.8 months (ranges, 1.6-14.9 months). Of 33 patients, eight (24.2%) achieved partial responses, 17 (51.5%) stable disease, and 8 (24.2%) progressive disease as best response, resulting in overall response rate of 24.2% (7 confirmed PR). The median progression-free survival was 6.1 months for both of thymoma and thymic carcinoma. The most common adverse events of any grade include dyspnea (11 [33.3%] of 33 patients), chest wall pain (10 [30.3%]), anorexia (7 [21.2%]) and fatigue (7 [21.2%]). Treatment-related adverse events ≥ grade 3 associated with immune related adverse events (irAE) include hepatitis (4 [12.1%]), myocarditis (3 [9.1%]), myasthenia gravis (2 [6.1%]), thyroiditis (1 [3.0%]), ANCA-associated rapidly progressive glomerulonephritis (1 [3.0%]), colitis (1 [3.0%]), and subacute myoclonus (1 [3.0%]) except anemia (1 [3.0%]). Eight (24.2%) patients (5 thymoma, 3 thymic carcinoma) discontinued study treatment due to irAE, whereas irAEs were manageable with immediate administration of high dose corticosteroid and other immunosuppressive agents in most of patients (7 of 8 [87.5%]). In 18 (54.5%) patients who had tumor specimens available for correlative biomarker analysis, all of four patients achieved partial response had 50% or more proportion score of PD-L1 immunostaining and higher PD-L1 RNA expression compared with non-responders (p=0.0471).
Conclusion:
Pembrolizumab showed promising antitumor activity in patients with refractory or relapsed TET. Given the relatively high incidence of irAEs especially in thymoma, early detection and management of autoimmune toxicity is essential to ensure feasibility of pembrolizumab treatment in patients with TET.
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OA 03.05 - Discussant - OA 03.01, OA 03.02, OA 03.03, OA 03.04 (ID 10852)
11:40 - 11:55 | Presenting Author(s): Masanori Tsuchida
- Abstract
- Presentation
Abstract not provided
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OA 03.06 - Clinicopathologic, Immunophenotypic and Genetic Studies of Mediastinal Paragangliomas (ID 8339)
11:55 - 12:05 | Presenting Author(s): Anja C Roden | Author(s): Y. Hsu, B. Kipp, S. Jenkins, W. Sukov, H. Schaff, S. Cassivi, J. Torres-Mora
- Abstract
- Presentation
Background:
Paragangliomas (PGLs) are rare neuroendocrine neoplasms arising from paraganglia of the autonomic nervous system. Only about 2% of all PGLs are found in the mediastinum; therefore they are not thoroughly investigated. Our study aims to characterize the clinicopathologic, immunophenotypic and genetic features of mediastinal PGLs.
Method:
Surgical files of Mayo Clinic Rochester and an institutional database (1973-2015) were searched for mediastinal PGLs. Thirteen patients were previously reported (Brown ML et al, Ann Thorac Surg 2008). All cases were reviewed by a thoracic pathologist to confirm the diagnosis. Immunohistochemistry was performed using antibodies to SDHB, Ki-67, ATRX, p53, PD-L1 (clone SP263) and ASCL1. Ki-67 labelling index (LI) was calculated as the mean percent Ki-67-positive cells per 3 HPF. Next generation sequencing (NGS) used a 50-gene neuro-oncology panel. Clinical data were retrieved from medical records. Statistical analysis was performed.
Result:
Twenty-four patients with mediastinal PGLs (7 men, 29.2%) had a median age at time of surgery of 44.6 years (19.8-72.2). Twenty-one (87.5%) paragangliomas were completely resected, 3 had an incomplete resection. The median tumor size was 5.1 cm (1.6-14). The median Ki-67 LI was 4.1% (0.5-29.7). PD-L1 was expressed in 10% (n=2), 1% (n=4) or 0% (n=17) of tumor cells. ASCL1 was focally expressed in 2 of 23 (8.7%) cases. Diffuse loss of SDHB expression was seen in 17 of 22 (77.3%) cases. ATRX was expressed in all 22 cases tested, but its expression was patchy in 1 case that showed ATRX duplication by NGS. NGS, performed in 19 cases, revealed a single pathogenic mutation in 10 cases including SDHB (n=3), SDHD (n=6) and ATRX (n=1); and two or more mutations in 2 cases including SDHC+TERT (n=1) and SDHB+ATRX+TP53 (n=1). Two additional patients were found to have an SDHB mutation. Ten of 21 patients with available SDHx mutation status (47.6%) had no SDHx mutation. Median follow up, available in 21 patients, was 4.7 years (0.8-11.5). Five patients (2 of which with SDHx mutation) developed metastases and/or recurrence; 4 patients (2 without SDHx mutation, 2 with unknown SDHx mutation status) died (1 perisurgically, 3 of unknown cause at 2.3, 5.8, and 10.6 years after surgery each). Statistical analysis of clinicopathologic features based upon SDHx mutation could not be performed due to the small number of cases.
Conclusion:
Our study demonstrates that the majority of mediastinal PGLs harbors an SDHx gene mutation. Alterations in ATRX gene might represent another genetic event in mediastinal PGLs.
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- Abstract
- Presentation
Background:
Nomogram has demonstrated its capability in individualized survival estimates. Some nomogram studies on esophageal squamous cell carcinoma (ESCC) have been reported, but accuracy of those nomograms is not high enough. Also, the role of ESCC nomogram in adjuvant chemotherapy remains unclear. Therefore, clinicopathological prognostic nomogram was developed and validated for patients with ESCC in this study. Its role in personalized adjuvant chemotherapy was investigated as well.
Method:
Data were retrieved about 1042 ESCC patients undergoing right transthoracic radical esophageactomy at Sun Yat-sen University Cancer Centre from January 1997 to December 2013. Of 1042 patients, 886 without adjuvant chemotherapy were divided into training set (Group A, n=590) and validation set (Group B, n=296) in a 2:1 ratio. Group C (the remaining 156 patients with adjuvant chemotherapy plus Group B, n=452) was used to evaluate the role of nomogram in personalized adjuvant chemotherapy. Cut-off points of continuous variables were established by X-tile. Survival and univariate analyses were calculated by Kaplan–Meier method. R software and "rms" package were used to perform Cox proportional hazard (CPH) regression model, plot nomogram, compute C-index, compare models, validate model, and plot calibration curve. The "survivalROC" package was used to plot time-dependent receiver operating curve (ROC).
Result:
The 1-, 3- and 5-year overall survival (OS) for the entire cohort was 88.3%, 64.5% and 54.8%, respectively. Univariate analyses were performed for 13 potential clinicopathological factors. Significant variables were analyzed for CPH regression model using R software and “rms” package. A prognostic nomogram including 8 factors (grade, location, T, N, resected negative nodes, length, gender, drinking history) was developed. C-index of the model was 0.739 (95% CI 0.719-0.759), higher than that of the 7[th] TNM staging system (0.696, 95% CI 0.676-0.716), p < 0.001. The calibration curve and time-dependent ROC showed this nomogram was superior to the 7[th] TNM staging system. The cut-off of prognostic score was 160, by which we grouped patients into low and high prognostic risk subgroup. In Group C, 209 patients belonged to high prognostic risk subgroup. Among them, patients receiving adjuvant chemotherapy had longer OS (p = 0.035). The remaining 243 patients belonged to low prognostic risk subgroup. Adjuvant chemotherapy didn’t improve OS (p = 0.799) in this subgroup.
Conclusion:
An accuracy clinicopathological prognostic nomogram was developed and validated for ESCC patients undergoing right transthoracic radical esophagectomy. The nomogram provided individual prediction of survival. Risk group stratification based on nomogram prognostic score successfully guided personalized adjuvant chemotherapy for ESCC patients.
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OA 03.08 - Discussant - OA 03.06, OA 03.07 (ID 10853)
12:15 - 12:30 | Presenting Author(s): Nicolas Girard
- Abstract
- Presentation
Abstract not provided
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Author of
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P1.02 - Biology/Pathology (ID 614)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.02-018 - Number of Cancer Cells in Lung Adenocarcinoma Specimen – Correlation with Noguchi's Classification, WHO Pathologic Type, and Prognosis (ID 7565)
09:30 - 09:30 | Author(s): M. Chida
- Abstract
Background:
Patients with completely resected lung adenocarcinomas smaller than 2 cm have a good prognosis, though some develop recurrence. It has been shown that Noguchi’s classification and WHO pathologic type are correlated with prognosis. We examined the correlation of number of cancer cells/mm[2 ]in adenocarcinoma specimens with prognosis, Noguchi’s classification, and WHO pathologic type.
Method:
Primary tumors were obtained from 104 patients who underwent surgery from January 2006 through December 2010 and had pulmonary adenocarcinomas ≤2 cm in maximum diameter. This prognostic investigation was performed in November 2016. All specimens were stained with hematoxylin-eosin and evaluated using Noguchi’s classification and WHO pathologic type. We also determined the number of cancer cells/mm[2] in the specimens, with those findings evaluated using receiver operator characteristic (ROC) curve analysis and tumor size. Overall survival curves were produced using the Kaplan-Meier method and analyzed using a log rank test according to number of cancer cells, Noguchi’s classification, and WHO pathologic type. The relationship among those 3 parameters was investigated with Pearson’s correlation coefficient. A p-value <0.05 was considered to indicate significance.
Result:
At the time of the examination, 90 patients were alive and 14 had died due to lung cancer. The average number of cancer cells/mm[2] was 791.3 (range 129.4-1739.5) and that was strongly correlated with progression of Noguchi’s grade (correlation coefficient 0.519, p<0.001) and WHO pathologic type (correlation coefficient 0.436, p<0.001). ROC curve analysis established a cut-off of 992/mm[2]. In general, cases with cancer cells above the cut-off had worse prognosis (5-year survival 64.0% vs. 94.2%, p<0.001). Figure 1
Conclusion:
The number of cancer cells/mm[2] in lung adenocarcinoma specimens was found to be correlated with Noguchi’s classification and WHO pathologic type, and is considered useful for prognostic evaluation of affected patients.
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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-064 - Epidermal Growth Factor Receptor Gene Mutation in Pleural Lavage Cytology Findings of Primary Lung Adenocarcinoma Cases (ID 10487)
09:30 - 09:30 | Author(s): M. Chida
- Abstract
Background:
In the present study, we examined the relationship between intraoperative pleural lavage cytology findings and presence of EGFR gene mutations.
Method:
We investigated 160 patients who underwent surgical treatment for primary lung adenocarcinoma at our hospital from January 2011 to December 2013 to determine the presence of EGFR gene mutations and pleural lavage cytology.
Result:
Fifty-two subjects (31.5%) were positive EGFR gene mutations, of whom 38 were found to possess the Exon 21 L858R mutation. Intraoperative pleural lavage cytology examinations were performed in 160 subjects and 12 had positive results, of whom 6 were positive for EGFR gene mutations, which was the Exon 21 L858R mutation in all. In a comparison between subjects possessing the Exon 21 L858R mutation and those negative for EGFR gene mutations, lavage cytology-positive (p=0.02) and vascular infiltration-negative (p=0.01) were characteristics of the Exon 21 L868R mutation-positive group.
Conclusion:
Subjects positive for the EGFR Exon 21 L858R mutation had a higher positive rate of intraoperative pleural lavage cytology than those not possessing EGFR mutations.
