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Andrew G Nicholson
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ES 01 - New TNM and WHO Classification (ID 510)
- Event: WCLC 2017
- Type: Educational Session
- Track: Radiology/Staging/Screening
- Presentations: 1
- Moderators:M. Noguchi, Peter Goldstraw
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 301 + 302
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ES 01.04 - Staging and Pathology of Multiple Nodules Presenting in the Lungs (ID 7586)
12:00 - 12:20 | Presenting Author(s): Andrew G Nicholson
- Abstract
- Presentation
Abstract:
Multiple tumor nodules arising in the lungs can be due either to separate primary lung cancers (SPLCs) or intrapulmonary metastases (IPM) (separate tumor nodules). The recently revised Union for International Cancer Control (UICC) and American Joint Committee on Cancer (AJCC) staging manuals (8th editions), based on proposals from work undertaken by the IASLC Staging and Prognostic Factors Committee (SPFC), include updates in T, N and M components, that reflect increased interest in staging of patients with multiple tumor nodules (1-4) due to increased frequency of presentation (1) and advances in classification of tumor subtypes (5). T categories for multiple tumor nodules are unchanged when compared to the 7[th] edition, with SPLCs continuing to be staged individually, with the recommendation that multiple lesions be grouped with the number of lesions in brackets (e.g. (2)), or (m) for multiple. Patients with IPM are staged as T3 (same lobe), T4 (different lobe in ipsilateral lung) and M1a (contralateral lung). However, although unchanged, these categories have been impacted by changes in the histologic classification of lung cancer (6), in particular adenocarcinomas (7). For the current edition, those tumors that present with multiple areas of pneumonic consolidation, these frequently corresponding to invasive mucinous adenocarcinomas, are viewed as a potential subgroup of IPM. There is also increased interest in those patients who present with multiple ground glass lesions, these typically corresponding to patients with non-mucinous adenocarcinomas with a lepidic component. These types of multiple tumor nodules are currently viewed as a potential subgroup of SPLCs. It is hoped that the next decade will see further research from within the lung cancer community that informs the 9[th] edition in relation to the staging of these types of tumor (3). In relation to pathologic staging, from 1975 until recently, distinction between SPLC and IPM was undertaken using criteria proposed by Martini and Melamed: tumors occurring in different lobes, having different major histologic types or being separated by a time interval of more than two years were to be classified as SPLCs (8). Recently, these criteria have been supplanted by the process of comprehensive histologic assessment (CHA) (9). CHA involves determination of major histologic type, assessment of predominant and minor histologic patterns according to histologic subtyping and evaluation of cytological features. CHA has been shown to significantly improve the pathologic distinction between SPLC and IPM to a level comparable to molecular analysis (9). Recent work undertaken by the IASLC Pathology Committee has also shown that usage of this methodology has good reproducibility amongst diagnostic pathologists. Furthermore, p staging status strongly correlated with nuclear pleomorphism, cell size, acinar formation, nucleolar size, and mitotic rate. In addition to the above, immunohistochemistry already has a role in refining the distinction between SPLC and IPM, and molecular techniques are also likely to be used increasingly in the situation. Studies have been published showing that comprehensive genotypic and morphological assessment is feasible, though they are not yet sufficient to establish clonal relationships between multiple tumour nodules (10). Ultimately, a multidisciplinary approach is likely to be the best methodology for distinction between SPLC and IPM, in particular the assessment of imaging data alongside histologic, immunohistochemical and molecular profiles, both in the context of biopsies and resections. 1. Detterbeck FC, Franklin WA, Nicholson AG, Girard N, Arenberg DA, Travis WD, et al. The IASLC Lung Cancer Staging Project: Background Data and Proposed Criteria to Distinguish Separate Primary Lung Cancers from Metastatic Foci in Patients with Two Lung Tumors in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. J Thorac Oncol. 2016. 2. Detterbeck FC, Bolejack V, Arenberg DA, Crowley J, Donington JS, Franklin WA, et al. The IASLC Lung Cancer Staging Project: Background Data and Proposals for the Classification of Lung Cancer with Separate Tumor Nodules in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. J Thorac Oncol. 2016. 3. Detterbeck FC, Nicholson AG, Franklin WA, Marom EM, Travis WD, Girard N, et al. The IASLC Lung Cancer Staging Project: Summary of Proposals for Revisions of the Classification of Lung Cancers with Multiple Pulmonary Sites of Involvement in the Forthcoming Eighth Edition of the TNM Classification. J Thorac Oncol. 2016. 4. Detterbeck FC, Marom EM, Arenberg DA, Franklin WA, Nicholson AG, Travis WD, et al. The IASLC Lung Cancer Staging Project: Background Data and Proposals for the Application of TNM Staging Rules to Lung Cancer Presenting as Multiple Nodules with Ground Glass or Lepidic Features or a Pneumonic-Type of Involvement in the Forthcoming Eighth Edition of the TNM Classification. J Thorac Oncol. 2016. 5. Travis WD, Asamura H, Bankier AA, Beasley MB, Detterbeck F, Flieder DB, et al. The IASLC Lung Cancer Staging Project: Proposals for Coding T Categories for Subsolid Nodules and Assessment of Tumor Size in Part-Solid Tumors in the Forthcoming Eighth Edition of the TNM Classification of Lung Cancer. J Thorac Oncol. 2016;11(8):1204-23. 6. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson, AG WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. IARC Press, 2015. 7. Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, et al. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 2011;6(2):244-85. 8. Martini N, Melamed MR. Multiple primary lung cancers. J Thorac Cardiovasc Surg. 1975;60:606-12. 9. Girard N, Deshpande C, Lau C, Finley D, Rusch V, Pao W, et al. Comprehensive histologic assessment helps to differentiate multiple lung primary nonsmall cell carcinomas from metastases. Am J Surg Pathol. 2009;33(12):1752-64. 10. Schneider F, Derrick V, Davison JM, Strollo D, Incharoen P, Dacic S. Morphological and molecular approach to synchronous non-small cell lung carcinomas: impact on staging. Mod Pathol. 2016;29(7):735-42.
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MA 06 - Lung Cancer Biology I (ID 660)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Biology/Pathology
- Presentations: 1
- Moderators:N. Motoi, Keith M Kerr
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 501
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MA 06.13 - Direct Metabolomic Profiling of Lung Cancers (ID 10319)
17:05 - 17:10 | Author(s): Andrew G Nicholson
- Abstract
- Presentation
Background:
Lung cancers rely on metabolites to fuel growth and to signal to surrounding tissues. Systematic study of these molecules may identify biomarkers for early diagnosis and novel pathways tractable to therapy. Previous studies of the metabolome in lung cancer have been confined to the serum and to sputum. We have therefore interrogated biochemical profiles in human lung cancers and matched adjacent normal tissues with the aim of identifying metabolites and metabolic signatures associated with lung cancer.
Method:
Global biochemical profiles were determined in human lung tumour and adjacent normal tissue. 12 tumours and 12 matched normal samples were tested from adenocarcinoma (ADC) patients, and 12 tumour/normal pairs were similarly tested from squamous cell carcinoma (SCC) patients. Samples were analysed on the Metabolon GC/MS and LC/MS/MS platforms, with the inclusion of technical replicates.
Result:
Application of PCA as a function of the tissue metabolome demonstrated that the normal, ADC and SCC groups were clearly distinguishable. We observed general metabolic changes associated with tumour tissue (q<0.10 throughout), with reductions in glucose and concomitant elevations in sorbitol and lactate indicative of Warburg metabolism in both ADC and SCC. Levels of reduced glutathione (GSH) were higher in SCC compared to ADC and normal tissue, indicating elevated antioxidant capacity in SCC. Conversely, alternative antioxidants including taurine, biliverdin, ascorbate, alpha- and gamma-tocopherol, and ergothioneine were higher in ADC than SCC. The neurotransmitters serine, NAA, GABA, and NAAG were also significantly elevated in ADC but not SCC. Finally, elevations in prostaglandin D2 and 6-keto prostaglandin F1alpha were confined to SCC and prostaglandin E2 was elevated to a much greater extent (8-fold versus 3-fold) in SCC vs. ADC, as compared respectively to normal lung tissue.
Conclusion:
Results from this pilot global profiling study confirm greater glucose utilization and lactate production, increased fatty acid synthesis, and changes in membrane biology in ADC and SCC. However, changes in glutathione metabolism, antioxidant capacity, neuroactive metabolites, and inflammation appear to vary according to tumour type. A larger scale study may identify differential therapeutic avenues and response to therapy. Profiling of matched serum/plasma from lung cancer patients may allow for identification of disease-specific biomarkers to supplement histological-based diagnostic techniques.
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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: 1
- Moderators:M. Chida, Jhingook Kim
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 311 + 312
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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 | Author(s): Andrew G Nicholson
- 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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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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P1.02-054 - The Molecular Characterisation of Lung Adenocarcinoma Subgroups (ID 9412)
09:30 - 09:30 | Author(s): Andrew G Nicholson
- Abstract
Background:
Lung adenocarcinoma is a heterogeneous disease which can be challenging to classify accurately, yet precise histological subtyping is becoming increasingly important. Subgroup patterns have been shown to confer important prognostic information. In this study, we sort to identify gene expression profiles for the six predominant subtypes within adenocarcinoma, in a sequential cohort of resected tumours, to explore whether molecular markers could enhance standard histological diagnosis.
Method:
89 paired (fresh frozen tumour and normal tissue) lung adenocarcinomas were profiled both histologically and by global gene expression and correlated with multiple clinical parameters including stage, age, gender and smoking status. The tumour samples were reviewed by a thoracic pathologist to determine the predominant subtype and assigned into lepidic, acinar, papillary, micropapillary, solid or cribriform predominant groups. Gene expression was generated using Affymetrix Human gene 1.1ST arrays and the Genetitan platform. All RINs > 6. The data was rma treated using Affymetrix Power Tools and poor quality arrays were detected and excluded using Array Quality Metrics. Low expressed probes and control probes were removed. Differential gene expression of the adenocarcinoma predominant subtypes was evaluated using Limma.
Result:
Survival analysis confirms that age and stage are the most significant predictors of outcome. Application of a highly stringent threshold (adj. P value 0.0001) identified 4805 gene transcripts that were significantly differentially expressed among the six predominant adenocarcinoma subtypes. We determined that 3887 of these transcripts are unique to one of the adenocarcinoma subgroups and therefore have the potential to contribute to a predominant subtype defining transcriptional signature. These unique transcripts include functionally interesting genes such as transcriptional factors SOX2/4/7/13/18 involved in determination of cell fate and ROR1 a receptor tyrosine kinase-like orphan receptor among others. A pairwise comparison of the individual subgroups identified that the most significant gene variation is seen between lepidic predominant and solid predominant, indicating that these subgroups are transcriptionally the most disparate to one another.
Conclusion:
In this study multiple highly significant gene transcripts that allow differentiation between the adenocarcinoma subgroups have been identified. These adenocarcinoma subtype gene signatures have the potential to augment current histological diagnosis of lung adenocarcinoma and provide valuable insights into the different biological processes underpinning the six adenocarcinoma subtypes.
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P1.17 - Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies (ID 703)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.17-019 - B7-H3 Protein Expression in Thymic Epithelial Tumour Subtypes and Its Association with PD-L1 and Clinical Characteristics (ID 10332)
09:30 - 09:30 | Author(s): Andrew G Nicholson
- Abstract
Background:
B7-H3 (CD276) belongs to the B7 immunoregulatory family that includes PD-L1. Its expression is associated with poor overall survival (OS) in a range of solid tumours but its expression in TETs is unknown. Phase II clinical trials with anti-PD-1 inhibitors are on-going and exhibit good efficacy although they are often complicated by severe autoimmune toxicities. We measured the levels of B7-H3 in TETs and associated them with PD-L1 levels, OS and GTF2I status.
Method:
TMA sections from each of 125 TET FFPEs and 18 thymic hyperplasias were stained separately with antibodies to PD-L1 (clone 28-8, Abcam) and B7-H3/ CD276 (clone 6A1, Abcam). CD45 and cytokeratin (MF116) stains were used to differentiate epithelia and lymphocytes. All sections were scored with an H-score, giving a final score range of 0-300. For each antibody scores for each TET subtype were compared to each other with the Mann-Whitney test. Positive staining was defined as any staining above 0. Associations between the antibody scores and clinicopathological variables were determined.
Result:
The histological breakdown of analyzed samples was 17 A, 4 MNT LS, 30 AB, 25 B1, 26 B2, 5 B3, 10 CA, 8 NETT and 18 hyperplasias. B7-H3 protein was detected in the epithelia of 110 of 125 TETs (88%) and in 15 of 17 hyperplasias (88%) (Subtype breakdown in Diagram 1). No link between OS and GTF2I mutations status (previously described) was found. B7-H3 and PD-L1 were co-expressed in 94 of 125 TETs (75%). Only 2 B1 TETs were negative for both. Figure 1
Conclusion:
B7-H3 protein is expressed in the large majority of TETs, being highest in A and AB thymomas followed by squamous and neuroendocrine carcinomas. Trials with anti-B7-H3 monoclonal antibodies are already underway and given these findings, patients with TETs are likely to be good subjects for these trials.
