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M. Leung
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MINI 01 - Pathology (ID 93)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:W.A. Franklin, A.G. Nicholson
- Coordinates: 9/07/2015, 10:45 - 12:15, Mile High Ballroom 2c-3c
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MINI01.02 - Is It Possible to Distinguish between Second Primary vs Metastasis in Resectable Synchronous Nodules with the Same Histotype of Lung Cancer? (ID 2122)
10:50 - 10:55 | Author(s): M. Leung
- Abstract
- Presentation
Background:
The prognostic significance of additional lung nodules in the setting of lung cancer is important as the impact on survival is often considered for the justification of surgical selection in the management of patients with synchronous nodules. TNM 7 down staged the impact on T category but did not distinguish between second primary versus metastasis. Traditional distinctions such as the Martini criteria do not take the same histological type into account and classification continues to improve (e.g. IASLC classification of adenocarcinoma). The aim of our study is to determine if it is possible to distinguish between second primary versus metastases in patients with the same histological type and quantity any difference in survival.
Methods:
We retrospectively analysed data from a prospectively collated database at our institution. We collected all the records which included two resected nodules. The detailed pathology reports of these patients were retrieved and the histology, subtype and pTNM of tumours documented. Slides were re-reviewed to determine the histological subtypes according to the current IASLC adenocarcinoma classification. Survival was calculated using Kaplan Meier methods and adjusted survival compared using Cox regression on R (statistical software).
Results:
From April 1999 to February 2013, a total of 2925 lung cancer resection were performed. Of these, 379 (14%) operations fulfilled the inclusion criteria of multiple nodules with 316 having synchronous tumours (83.3%) and 63 having metachronous tumours (16.6%). The tumours were ipsilateral in 87.3% and the vast majority were in the same lobe (70.9%). For synchronous tumours, patients with the same histological type had a poorer 5-years survival rate compared to tumours with different histology (p=0.041). The pathologist’s designation between second primary versus intra-pulmonary metastasis distinguished between overall survival (p= 0.001) and this remained statistically significant in the tumours of the same cell type (p= 0.035). Figure 1. Survival outcomes between patients with multiple nodules classified as second primary versus intra-pulmonary metastasis Figure 1
Conclusion:
Our results suggest that distinction between second primary and intra-pulmonary metastasis remains important for staging as appreciable differences in survival were observed in patients with synchronous nodules. Survival was poorer in patients with multiple nodules of the same histologic type (compared to different histology) and within the same histological subtype it is possible for pathologists to distinguish between second primary and intra-pulmonary metastasis. As this is currently confirmed only on pathologic stage in the majority, it presently does not influence the selection for surgery.
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ORAL 39 - Potential Biomarkers for CT Screening (ID 149)
- Event: WCLC 2015
- Type: Oral Session
- Track: Screening and Early Detection
- Presentations: 1
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ORAL39.03 - Clinical Utility of a Blood Based Circulating Tumour DNA Signature for the Diagnosis of Lung Cancer (ID 2457)
17:07 - 17:18 | Author(s): M. Leung
- Abstract
- Presentation
Background:
Lung cancer is conventionally diagnosed by confirmatory tissue biopsy, an invasive procedure that involves waiting time, costs and complications. The development push for a blood based liquid biopsy is a less invasive, more readily acceptable means to expedite the diagnosis and management of cancer. Circulating tumour DNA is promising in this regard as cancer specific genetic mutations are not usually found in the circulation of healthy individuals. The aim of our study is to report the performance of a three gene signature in for the diagnosis of cancer.
Methods:
Pre-operative blood samples were obtained from patients undergoing surgery for known or suspected lung cancer and 1ml aliquots of plasma were extracted from 9ml of EDTA preserved blood. DNA was extracted from the plasma using the QIAamp DNA blood mini kit. High resolution melt analysis was undertaken to identify mutations in hotspots of the TP53, KRAS and EGFR genes in the ctDNA from plasma as well as matching FFPE tissue. A positive test result was defined as a mutation identified in the plasma ctDNA and compared against the reference clinical histopathology report of the resected lung abnormality. Clinical test performance was quantified and reported conventionally using sensitivity and specificity.
Results:
Pre-operative blood was analysed in a blinded manner from 223 patients undergoing surgery at our institution, and the pathology reports were issued blinded to the blood test results. In total, 116 (52%) had primary lung cancer, 64 (29%) had secondary cancer, 6 (3%) had primary thoracic (not lung) cancer and 35 (16%) did not have any evidence of cancer. Of the 186 patients with confirmed cancer, a mutation was identified in the FFPE sections of the primary tumour of 113 (61%) and in the plasma ctDNA in 127 (68%) with substantial agreement of 85% and a kappa statistic of 0.70 (P<0.001). The clinical test performance for the blood based diagnostic signature was a sensitivity of 68% (95% CI 61-75), specificity of 91% (77 to 98), positive predictive value 98% (93-100) and a negative predictive value of 35% (25 to 46) when compared to conventional clinical histopathology reporting of the resected tissue.
Conclusion:
There is substantial agreement between the detection of ctDNA and FFPE tumour tissue mutations. We postulate higher mutation levels detected in the plasma is due to heterogeneity of tumour and FFPE sections in comparison to a global (plasma based ctDNA) estimate of mutation burden. Our results suggest blood based ctDNA analysis of cancer mutations is a specific, non-invasive test for the diagnosis of cancer. A positive test strongly rules in the diagnosis but a negative test does not have sufficient discriminatory ability to exclude the diagnosis of cancer.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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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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P2.04-085 - A Comparative Analysis of Cancer Hotspot Mutation Profiles in Circulating Tumour Cells, Circulating Tumour DNA and Matched Primary Lung Tumour (ID 2451)
09:30 - 09:30 | Author(s): M. Leung
- Abstract
Background:
Blood based mutation profile analyses are becoming an increasingly important non-invasive form of mutation screening in cancer. Many have reported on single mutation comparisons between blood based and primary tumour tissue, but limited information is available on multiplex comparisons between the DNA extracted from circulating tumour cells (CTC), circulating free tumour DNA in the plasma (ctDNA) against the current standard of FFPE analysis of primary tumour.
Methods:
Pre-operative whole blood samples were collected from 30 patients who underwent thoracic surgery. CTCs were isolated using ScreenCell MB devices from 6ml of whole blood, and 1ml aliquots of plasma were removed from 9ml of EDTA samples. Matching FFPE samples were retrieved from post-resection primary tumour tissue in three 10µm PCR rolls. DNA was extracted from the CTCs, ctDNA and matched FFPE tissues using Qiagen kits (QIAamp DNA Micro kit, QIAamp DNA blood mini kit and QIAamp FFPE tissue kit, respectively). The 90 (30 matched triplicates) DNA samples were sequenced by Illumina HiSeq using Z3 cancer panel (Illumina, San Diego). Agreements of variant calls were compared between the three DNA substrates and a kappa statistic was reported using Stata 13.
Results:
Between 2011 and 2013, samples from 30 consenting patients were obtained. In total, 10 had primary lung cancer, 19 had secondary lung cancer, and 1 (intentionally included) had no evidence of cancer. From the 90 samples, a total of 18,821 variant calls were identified after the removal of known 1,048 germline variants. Within the hotspot panel alone, the mean (SD) number of variant calls per patient was 151 (44) on FFPE samples, 136 (49) on CTC samples and 463(108) on ctDNA samples. There was good agreement between CTCs and FFPE of 79.8% with a Kappa statistic of 0.42 (P<0.001). Agreement between ctDNA and FFPE was much poorer at 12.7% with a Kappa statistic of -0.40 (P=1.000). The results also suggested poor agreement between CTC and ctDNA of 16.1% with a Kappa statistic of -0.32 (P=1.000). Focusing on single gene comparisons on the multiplex platform, agreement was considerably better for KRAS and EGFR for CTCs compared to ctDNA at 44% versus 11% for KRAS and 92% versus 9% for EGFR respectively. Discordances were largely due to an increased number of variants that were identified in ctDNA and not in CTC or FFPE tissue.
Conclusion:
Our results suggest on a next generation sequencing platform that the global genetic variant profile between DNA extracted from CTC had good agreement with FFPE primary tumour tissue, and the agreement for ctDNA and FFPE was much poorer. This was observed to be an increase in the number of variants detected on single gene analysis and may be due to processing, sample or analytic difficulties with ctDNA.
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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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P3.06-015 - Is the Development of Primary Lung Adenocarcinoma Simply Due To 'Bad Luck'? (ID 2825)
09:30 - 09:30 | Author(s): M. Leung
- Abstract
Background:
Recently, Tomasetti and Vogelstein proposed that the variation in cancer risk among tissue is explained by the number of stem cell division, and this was widely interpreted as “bad luck” due to random mutations arising during DNA replication in normal non-cancerous stem cells. Smoking is widely considered as the main aetiological risk factor for the lung cancer and the aim of our study is to evaluate the hypothesis comparing the differences in proportions of the two main histological subtypes in smokers and never smokers in a patients with early stage primary lung cancer to determine the impact of smoking on the development of squamous and adenocarcinoma.
Methods:
Data were retrospectively analysed from a prospectively collated database at our institution over a 7 year period. Histological data were extracted and compared for the two main historical subtypes of squamous and adenocarcinoma (subtyped according to the new IASLC adenocarcinoma classification). Frequencies were compared using Fishers exact or Chi square tests as appropriate to the data.
Results:
A total of 2170 patients underwent surgical resection for lung cancer at our institution from March 2008 to November 2014 of which 436 (20%) patients were never smokers. The mean age (SD) was 66 (12) years and 48% were female. The relative proportion of patients with squamous carcinoma was significantly different between smokers 323 (27.0%) and never-smokers 16 (5.7%) with P <0.001 with a risk ratio of 4.70 (95% CI 2.9 to 7.6). However the relative proportions between patients with adenocarcinoma were similar between smokers 578 (48.3%) and never-smokers (54.4%) P=0.06 with a risk ratio of 0.89 (0.79 to 1.00).
Conclusion:
Our results suggest that smoking remains an important aetiological risk factor for the development of primary lung squamous cell carcinoma. For adenocarcinoma, the relative proportions between smokers and never-smokers were similar (in fact lower for smokers) supporting Tomasetti and Vogelstein hypothesis of random mutations arising during DNA replication in normal non-cancerous stem cells– or simply put as “bad luck”.
