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K. Kerr
Moderator of
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ORAL 24 - CT Detected Nodules - Predicting Biological Outcome (ID 122)
- Event: WCLC 2015
- Type: Oral Session
- Track: Screening and Early Detection
- Presentations: 8
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ORAL24.01 - Natural History of Pulmonary Subsolid Nodules: A Prospective Multicenter Study (ID 1245)
10:45 - 10:56 | Author(s): R. Kakinuma, K. Ashizawa, M. Noguchi, N. Koizumi, T. Kondo, K. Kuriyama, H. Matsuguma, H. Ohmatsu, J. Okami, H. Suehisa, A.M. Maeshima, T. Yamaji, Y. Matsuno, S. Murayama, K. Murata
- Abstract
- Presentation
Background:
The purpose of this prospective multicenter study was to evaluate the natural course of progression of pulmonary subsolid nodules.
Methods:
Eight facilities participated in this prospective study. This study was conducted with the approval of the institutional review board of each of the participating institutions. Written informed consent was obtained from all the patients. A total of 845 patients with 1325 pulmonary subsolid nodules were registered, of whom 795 patients (341 men, 454 women; mean age, 62 years [range, 31-88]) with 1238 subsolid nodules were selected as being eligible for this study. In this study, the pulmonary subsolid nodules were classified into three categories: pure ground-glass nodules (hereafter abbreviated as PGGNs), heterogeneous GGNs (solid component detected only in the lung window setting; hereafter abbreviated as HGGN), and part-solid nodules (solid component also detected in the mediastinal window setting). The CT images of the nodules that showed progression were reviewed by an expert radiologists’ panel. Pathological specimens of the resected nodules were reviewed by an expert pathologists’ panel.
Results:
The mean prospective follow-up period was 4.3 ± 2.5 years (range, 0.2–12.1; median, 3.5 [IQR, 2.4–6.0]). After exclusion of 9 resected nodules (2 no-lung-cancer nodules and 7 lung cancers not reviewed by the expert pathologists’ panel), the pulmonary subsolid nodules were classified as follows at the baseline: 1046 PGGNs, 81 HGGNs, and 102 part-solid nodules. Among the 1047 PGGNs, 13 (13/1046; 1.2%) developed into HGGNs, and 56 (56/1046; 5.4%) developed into part-solid nodules. Among the 81 HGGNs, 16 (16/81; 19.8%) developed into part-solid nodules. Thus, the subsolid nodules were classified as follows at the time of the final follow-up: 977 PGGNs, 78 HGGNs and 174 part-solid nodules. Of the 977 PGGNs, 35 (3.6%) were resected; from the histopathologic standpoint, the 35 resected PGGNs consisted of 9 minimally invasive adenocarcinomas (MIAs), 21 adenocarcinomas in situ (AISs), and 5 atypical adenomatous hyperplasias (AAHs). Of the 78 HGGNs, 7 (9%) were resected; from the histopathologic standpoint, the 7 HGGNs consisted of 5 MIAs and 2 AISs. Of the 174 part-solid nodules, 49 (28.2%) were resected; from the histopathologic standpoint, the 49 part-solid nodules consisted of 12 invasive adenocarcinomas, 26 MIAs, 10 AISs, and 1 AAHs. In total, 12 (12/1229, 1%) invasive adenocarcinomas, 40 (40/1229; 3.3%) MIAs, 33 (33/1229; 2.7%) AISs, and 6 (6/1229; 0.5%) AAHs were resected as of December 31, 2013; For the PGGNs, the mean period to development into part-solid nodules was 3.8 ± 2.0 years (range, 0.5-8.7; median, 3.4 [IQR, 2.0–5.2]); for the HGGNs, the mean period to development into part-solid nodules was 2.1 ± 2.3 years (range, 0.2–8.8; median, 1.0 [IQR, 0.7–3.4]) (P=0.0004).
Conclusion:
Our prospective multicenter study revealed the frequency and period of development from PGGNs and HGGNs into part-solid nodules. Invasive adenocarcinomas were only diagnosed in the part-solid nodules. The findings of the study may contribute to the development of guidelines for follow-up of pulmonary subsolid nodules.
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ORAL24.02 - Quantification of Growth Patterns of Screen-Detected Lung Cancers: The NELSON Trial (ID 1455)
10:56 - 11:07 | Author(s): M.A. Heuvelmans, R. Vliegenthart, M.J.A.M. Van Putten, P.A. De Jong, M. Oudkerk
- Abstract
Background:
A wait-and-see principle is not commonly used when lung cancer is suspected, because of the aggressiveness of the disease. In-vivo information on growth patterns of lung cancers, from small nodules barely detectable by imaging techniques to histologically proven lung cancers, is therefore scarce. In low-dose computed tomography (LDCT) lung screening, lung nodules, usually benign, are found in the majority of screenees. Follow-up CT examinations are performed to determine nodule growth, in order to differentiate between benign and malignant nodules. Growth is often defined in terms of volume-doubling time (VDT), under the assumption of exponential growth. However, this pattern has never been quantified in actual patient data. Our purpose was to evaluate and quantify growth patterns of lung cancers detected in LDCT lung cancer screening, in order to elucidate the development and progression of early lung cancer.
Methods:
The study was based on data of the Dutch-Belgian randomized lung cancer screening trial (NELSON trial). Solid lung cancers detected at ≥3 LDCT examinations before referral and diagnosis were included. Nodule volume was calculated by semi-automated software (LungCARE, Siemens, Erlangen). We fitted lung cancer volume (V) growth curves with a single exponential, expressed as V=V~1~exp(t/τ), with t time from baseline (days), V~1~ estimated volume at baseline (mm[3]) and τ estimated time constant. Overall VDT per lung cancer for all time points combined was calculated using τ*log(2). We used R[2] coefficient of determination as a measure for goodness of fit, where a perfect fit results in R[2]=1. A normalized growth curve for all lung cancers combined was created by plotting normalized volume (V/V~1~), on a logarithmic y-axis as a function of normalized time, t*=t/τ. Statistical analyses were performed using SPSS 20.0 and Octave (www.octave.org).
Results:
Forty-seven lung cancers in 46 participants were included. Seven participants were female (13.0%); mean age 61.7 ±6.2 years. Median follow-up time before lung cancer was diagnosed, was 770 days (IQR: 383-1102 days). One cancer (2.1%) was diagnosed after six LDCTs, six (12.8%) after five LDCTs, 14 (29.8%) after four LDCTs, and 26 cancers (55.3%) after three LDCTs. Most lung cancers were stage I disease (35/47, 74.5%) at diagnosis. The majority concerned adenocarcinoma (38/48, 80.9%). Median overall VDT was 348 days (IQR: 222-492). Overall VDT for adenocarcinomas versus other histological cancer types were similar (median 338 days [IQR: 225-470 days] versus 348 days [IQR: 153-558 days], respectively [p=NS]). Good fit to exponential growth was confirmed by the high R[2] coefficient of determination for the individual cancer growth curves (median 0.98; IQR: 0.94-0.99). After normalization, we found linear growth on a logarithmic scale, according to exponential growth, for almost all nodules. Not all cancers showed an exponential growth immediately from baseline; five cancers were identified with constant (low) volume for >500 days before growth expansion occurred. However, when these dormant lung cancers started growing, they followed the exponential function with excellent fit (median 1.00; IQR: 0.98-1.00).
Conclusion:
Screen-detected lung cancers usually evolve at an exponential growth rate. This makes VDT a powerful imaging biomarker to stratify prevalent lung nodules to growth rates.
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ORAL24.03 - Increasing Incidence of Non-Smoking Lung Cancer: Presentation of Patients with Early Disease to a Tertiary Institution in the UK (ID 2717)
11:07 - 11:18 | Author(s): C. Proli, M.E. Cufari, M. Phull, H. Raubenheimer, M. Al Sahaf, N. Asadi, P. Perikleous, A. Allan, L. Shedden, H. Chavan, Z. Niwaz, A. Kubler, A.G. Nicholson, P. Viola, V. Anikin, E. Beddow, N. McGonigle, M. Dusmet, S. Jordan, G. Ladas, E. Lim
- Abstract
- Presentation
Background:
Lung cancer in never-smokers is recognised as a distinct entity. Many are expected to present late. As there are no established aetiological factors, identification of patients at risk is challenging. The aim of the study is to define the incidence and clinical features of never-smokers presenting sufficiently early for surgery to determine if it is possible to identify patients at risk.
Methods:
We retrospectively analysed data from a prospectively collected database of patients who underwent surgery at our institution. The incidence was defined as number of never-smokers versus current and ex-smokers by year. Clinical features at presentation were obtained and collated as frequency (percentage).
Results:
A total of 2170 patients underwent surgical resection for lung cancer from March 2008 to November 2014. The annual incidence of developing lung cancer in never-smokers increased from 13, 15, 18, 19, 20, 20 to 28 percent respectively, attributable to an absolute increase in number and not a change in the ratio of never smokers to current and ex-smokers. A total of 436 (20%) patients were never smokers. The mean age at presentation was 60 (16 SD) years and 295 (67%) were female. Good lung function was observed with mean predicted FEV1 of 90% (23 SD) and FVC of 97% (25 SD). The majority histological types were adenocarcinoma 54% and carcinoid 27%. The main presenting features were non-specific consisting of cough in 142 (34%), chest infections in 75 (18%) and haemoptysis in 46 (11%). Recurrent chest infections were predominantly a symptom of central carcinoid tumours (30 versus 15 percent; P=0.004). A total of 59 (14%) were detected on incidental chest film, 127 (30%) on incidental CT, 32 (7%) on incidental PET/CT and 4(1%) on incidental MRI.
Conclusion:
We observed more than double the annual incidence of never smokers presenting with non small cell lung cancer, in the last 7 years, increasing from 13 to 28 percent, and hypothesise that this is representative of the UK, as we are one of the highest surgical volume centres in our country. Patients present with non-specific symptoms and the majority were detected on incidental imaging. We conclude that imaging is likely to play a more important role and further efforts need to be expended on early detection of lung cancer in this increasing cohort without any observable risk factors.
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ORAL24.04 - Discussant for ORAL24.01, ORAL24.02, ORAL24.03 (ID 3358)
11:18 - 11:28 | Author(s): G. Veronesi
- Abstract
- Presentation
Abstract not provided
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ORAL24.05 - Reclassification of Lung Cancers Detected by CT Imaging in the American College of Radiology Imaging Network National Lung Screening Trial (ID 1454)
11:28 - 11:39 | Author(s): W.A. Franklin, D.T. Merrick, R.D. Achcar, D.R. Aberle
- Abstract
- Presentation
Background:
The National Lung Screening Trial (NLST) found a 20% reduction in lung cancer-specific mortality using low dose CT vs chest radiography for screening. The magnitude of mortality benefit has been questioned given that a higher proportion of tumors in the CT arm were diagnosed as “bronchioloalveolar cell carcinoma”. Subsequent to the initiation of the NLST, the pathological classification of lung cancer was revised to take into account the reported favorable outcome for solitary in situ nodules <3 cm. The term “bronchioloalveolar carcinoma” (BAC) was eliminated in favor of the more explicit terms adenocarcinoma in situ (AIS), microinvasive adenocarcinoma (MIA), and invasive carcinoma with various predominant histological patterns. To better assess the impact of these recent changes in the Pathological classification of lung cancer on possible over-diagnosis in the NLST, we have reviewed the histology of lung tumors detected through the ACRIN-NLST trial and reclassified them according to the most recent WHO pathology classification.
Methods:
Histology was initially classified by the pathologists at sites where NLST participants were managed. Representative slides of 192 surgical resection specimens and 15 non-surgical biopsies from 207 patients were collected from 19 participating institutions. Digital images were prepared from 533 glass H&E stained slides using an Aperio digital slide imager. Digital images were examined by three pulmonary pathologists (WAF, DTM and JDH) and reclassified according to criteria and nomenclature of the recently published 2015 edition of the WHO classification.
Results:
There was 92% concordance between submitting and reference pathologists when cases were grouped into the broad categories of adenocarcinoma, squamous carcinoma, neuroendocrine and large cell lung carcinoma (LCLC). The WHO classification permitted a more detailed analysis of the tumors. Invasive adenocarcinoma was the largest tumor category comprising 61% (127) of all tumors and included 70 acinar tumors, 23 solid, 13 papillary, 8 micropapillary, 5 mixed mucinous/non-mucinous, 4 invasive mucinous, 3 lepidic and 1 adenocarcinoma that could not be further classified. There were 48 (23%) squamous tumors, 10 (5%) LCLC, 15 (7%) neuroendocrine tumors including 6 (3%) small cell lung carcinomas. Finally, one tumor had sarcomatoid histology and an additional tumor was classified at sclerosing pneumocytoma. On reclassification, only 5 of the 26 tumors originally referred to as BAC or as having BAC features by submitting pathologists met criteria for adenocarcinoma in situ or minimally invasive carcinoma. Twenty-one of these 26 tumors were reclassified as invasive adenocarcinoma, most frequently acinar pattern predominant (8 cases).
Conclusion:
Reclassification of tumors identified through low dose CT screening in the National Lung Screening Trial permitted a detailed analysis of histological features and should permit a more nuanced assessment of biology and prognosis of this important cohort than has been available to date. Reclassification of BAC mainly as invasive adenocarcinoma conflicts with the suggestion that much of the benefit in the NLST CT screening trial was derived from surgical removal presumably non-invasive low grade tumor. *ACRIN received funding from the National Cancer Institute through the grants U01 CA079778 and U01 CA080098.
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ORAL24.06 - Stratification of Lung Adenocarcinomas in the National Lung Screening Trial (ID 102)
11:39 - 11:50 | Author(s): F. Maldonado, F. Duan, S. Raghunath, S. Rajagopalan, R. Karwoski, K. Garg, E. Greco, H. Nath, R. Robb, B. Bartholmai, T. Peikert
- Abstract
- Presentation
Background:
Screening for lung cancer with low-dose computed tomography (LDCT) was shown to reduce lung cancer mortality. However, lung cancer screening also detects indolent cancers of unclear clinical significance, which generally belong to the adenocarcinoma spectrum. The individualized management of these more indolent cancers may be facilitated by non-invasive risk stratification. We present our validation study of CANARY (Computer-Aided Nodule Assessment and Risk Yield), a novel LDCT-based software, used to stratify adenocarcinoma nodules in three groups with distinct outcomes.
Methods:
All individuals in the LDCT arm of the National Lung Screening Trial (NLST) with adenocarcinoma were identified. The last LDCT data available were analyzed blinded to clinical data. Using CANARY, all lung adenocarcinoma nodules were classified as Good (G), Intermediate (I) and Poor (P) based on previously established radiologic signatures. This classification was then used for survival analysis using progression-free survival
Results:
LDCT datasets of 294 patients with resected adenocarcinomas with available outcome data were included in the blinded CANARY analysis. Kaplan-Meier analysis of all the 294 adenocarcinoma nodules stratified into G, I and P CANARY classes yielded distinct progression-free survival curves (P < 0.0001). A similar separation was seen with adjusted progression-free survival curves, after adjustment for, age, gender, race and smoking status for all pathological stage I cases.
Conclusion:
CANARY allows the non-invasive risk stratification of lung adenocarcinomas into three groups with distinct post-surgical disease-free survival. Our results suggest that CANARY could facilitate individualized management of incidentally- or screen-detected lung adenocarcinomas.
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ORAL24.07 - Behavior Differences of Screen-Detected Lung Cancers in the CT Arm of the National Lung Screening Trial (NLST) (ID 587)
11:50 - 12:01 | Author(s): M.B. Schabath, P.P. Massion, Z.J. Thompson, S.A. Eschrich, Y. Balagurunathan, D. Goldof, D.R. Aberle, R.J. Gillies
- Abstract
Background:
Lung cancer screening identifies cancers with heterogeneous behaviors. In addition to screen-detected incidence lung cancers, screening also identifies prevalence cancers at the baseline screen and interval lung cancers diagnosed following a negative screen at any time point prior to the next screening round. To date, few studies have performed a comprehensive analyses comparing prevalence and interval lung cancers and screen-detected lung cancers based on sequence of screening results in the NLST.
Methods:
The entire CT arm of the NLST was reconstructed according to baseline and follow-up screening results (positive vs. negative screen). Lung cancers immediately following a positive baseline (T0), and prior to the T1 screen, formed the prevalence cancers (PC); interval cancers (IC) were defined as lung cancers diagnosed following a negative screen at any point prior to the next screening round. Two screen-detected lung cancer (SDLC) cohorts were identified based on one (SDLC1) or two (SDLC2) prior positive screens and two screen-detected lung cancer cohorts following one (SDLC3) or two (SDLC4) prior negative screens. Differences in patient characteristics, progression-free survival (PFS), and overall survival (OS) were assessed.
Results:
Since there were no differences in patient characteristics and outcomes between SDLC1 and SDLC2 and between SDLC3 and SDLC4, the four screen-detected cancer case groups were combined into two combined SDLC case groups (SDLC1/SDLC2 and SDLC3/SDLC4). The lung cancer-specific death rate was higher for SDLC3/SDLC4 compared to SDLC1/SDLC2 lung cancers (136.6/1,000 person-years vs. 71.3/1,000 person-years, P < 0.001). PFS and OS were significantly lower for SDLC3/SDLC4 than SDLC1/SDLC2 (P < 0.004; P < 0.002, respectively). Overall, PFS and OS were highest in SDLC1/SDLC2 and lowest in the interval cancers (Figure 1); PFS and OS for the prevalence cancers were intermediate between SDLC1/SDLC2 and SDLC3/SDLC4. All findings were consistent when stratified by stage and histology. Multivariable Cox proportional models revealed that the SDLC3/SDLC4 case groups were associated with significantly poorer PFS (HR=1.72; 95% CI 1.19-2.48) and OS (HR=1.62; 95% CI 1.08-2.45) compared to SDLC1/2 lung cancers (HR=1.00). Figure 1
Conclusion:
This post hoc analysis reveals novel insight to the heterogeneity of lung cancers diagnosed in a screening population. As with interval cancers diagnosed following a negative screen, lung tumors that arise in a lung environment ostensibly free of lung nodules are likely more rapidly growing and aggressive which results in significantly poorer outcomes. Additional research will be needed to understand the potential translational implications of these findings and to reveal biological differences of screen-detected tumors.
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ORAL24.08 - Discussant for ORAL24.05, ORAL24.06, ORAL24.07 (ID 3359)
12:01 - 12:11 | Author(s): M. Noguchi
- Abstract
- Presentation
Abstract not provided
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Author of
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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: 1
- Moderators:R. Tsuchiya, M. Wynes
- Coordinates: 9/09/2015, 18:30 - 20:00, 702+704+706
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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): K. Kerr
- 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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MS 05 - Tumor Heterogeneity (ID 23)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:S. Dacic, A.G. Nicholson
- Coordinates: 9/07/2015, 14:15 - 15:45, Mile High Ballroom 1a-1f
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MS05.02 - How Does Tumor Heterogeneity Affect Molecular Testing on Biopsy Samples - Diagnostic vs. Rebiopsy (Resistance) (ID 1865)
14:40 - 15:00 | Author(s): K. Kerr
- Abstract
- Presentation
Abstract:
There are many different manifestations of heterogeneity within lung tumours. The three main considerations are: Morphologically, all of the neoplastic cells in a tumour are not identical. These structural differences may be due to differential protein expression and cellular differentiation, in turn the result of either differential expression of wild type genes, post-transcriptional modification or expression of altered genes (mutation, fusion genes etc). Nuclear morphology varies at least in part due to alteration in chromosome structure and number. Genetically, tumour cell populations are heterogeneous, as mentioned above but also it can be demonstrated that there may be heterogeneity related to driver mutations and other functionally important changes which may not necessarily be deterministic of cell morphology. Compositely speaking, tumours are made up of more than just neoplastic cells; stromal cells, immune cells and vasculature for example may account for much of the tumour bulk. Potentially, all three of these may impact upon molecular testing practice in the initial diagnostic phase and at re-biopsy. Molecular testing may be executed in many different ways and may seek many different molecular changes, such that the potential for heterogeneity making an impact on testing is considerable. Some molecular tests involve the morphological examination of a histological or cytological slide for the presence or absence of a particular factor. Proteins are normally assessed at a morphological level using immunohistochemistry. In situ hybridisation can be used to visualise and assess the presence of specific mRNAs. The same technique is used to assess DNA; specific gene copy numbers (gene amplification, polysomy), the creation of new ‘fusion genes’ during rearrangement using break-apart probes etc. These techniques require the molecular signal to be visualised in the cells of interest (usually the tumour cells); morphological and compositional tumour heterogeneity greatly impact the ease with which these techniques are executed. In lung cancer molecular testing, most current interest is in mutation testing. Compositional heterogeneity is a significant practical issue and drives recommendations that samples are pathologically assessed before extraction and mandates steps be taken to maximize the proportion of the sample for extraction that is tumour (macro- or microdissection techniques are often used). The dilution of mutant alleles by wild type alleles from non-neoplastic tissue may lower the mutation allele frequency below the threshold for detection. Are therapeutically important mutations such as those in exons 18-21 of EGFR heterogeneously expressed in tumour cells? This remains a matter of some controversy. Some have argued that since these are addictive driver mutations, they are present from the start of tumourigenesis and therefore present in every tumour cell, as determined by clonal expansion of the neoplastic cell population. Studies which demonstrate mutations in some areas of extracted tumour but not in others, are criticized by failing to use sufficiently sensitive techniques to detect mutations which are over-diluted by non-neoplastic DNA. It is known that selective amplification of mutant alleles (MASI) is heterogeneous in tumours and this may lead to apparent heterogeneity of mutation (detectable in some areas and not in others) when the number of mutant alleles per tumour cell varies in different parts of the tumour, and those areas with fewer mutant alleles are not detected due to poor test sensitivity. This explanation for apparent mutational heterogeneity has been challenged by some studies, however, which have appeared to demonstrate heterogeneity, even when highly sensitive techniques are used. Heterogeneity appears to be associated with lower response rates to EGFR TKIs in EGFR mutant tumours. Discrepancy has been reported in mutational findings between synchronous primary tumour and metastatic deposits. These findings are not universal for EGFR mutations, but when present, tend to involve a mutated primary with wild type metastases more often than the reverse. Data are few but could influence biopsy strategies. More than one mutation may be present in a lung cancer. In the context of molecular aberrations commonly tested for (EGFR, KRAS mutation; ALK rearrangement), double mutations are described but are rare. It is rather more common, for example for double or even triple EGFR mutations to be found in the same tumour sample. For example, in the author’s laboratory, double EGFR mutations are found in 13.8% of EGFR-mutated cases; triple mutations in 0.6%. KRAS double mutations are exceptionally rare (0.8%). The presence of more than one mutation, often at different allelic frequencies (such as can be estimated in many studies), implies different clones of cells bearing different mutations, and from this comes the concept of minor clones of therapeutically resistant cells which are responsible for some, though probably not all disease recurrences on TKI therapy. The best known scenario fitting this ‘minor clone’ hypothesis is the emergence of tumour bearing the EGFR T790M resistance mutation, as well as the original sensitizing mutation, for which an EGFR TKI was given. Resistant minor clones of MET amplified cells may be an alternative source of recurrent, EGFR TKI resistant disease. Similarly with ALK mutated or KRAS mutated recurrences during ALK TKI therapy for ALK rearranged tumours. This increasingly recognised outcome in patients treated with EGFR or ALK TKIs is now driving re-biopsy of recurrent disease into standard of care. Testing approaches and strategy for recurrent disease are still evolving and are driven by this concept of minor clone heterogeneity. Another finding in the re-biopsy setting is histological subtype transformation. Whilst the initial EGFR or ALK altered tumour is almost always adenocarcinoma, recurrent disease may be small cell, sarcomatoid or even squamous cell carcinoma. Little is known about the mechanism of this transformation; emergent clones of different histology or differential stem cell differentiation? There are also emergent data demonstrating that where recurrence occurs at multiple sites, detectable resistance mechanisms may vary. In a broader sense, heterogeneity of sensitivity to particular therapies, amongst tumour cells, is a major driver of treatment resistance and/or relapse, and effectively why there are so very few instances of true cure of lung cancer as a consequence of systemic therapy. The development of effective treatment strategies to overcome recurrence will require a better understanding of how tumour heterogeneity influences this process.
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MTE 20 - Biology and Pathology of Neuroendocrine Cancers (Ticketed Session) (ID 72)
- Event: WCLC 2015
- Type: Meet the Expert (Ticketed Session)
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 07:00 - 08:00, 708+710+712
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MTE20.01 - Biology and Pathology of Neuroendocrine Cancers (ID 2005)
07:00 - 07:30 | Author(s): K. Kerr
- Abstract
- Presentation
Abstract:
Introduction The neuroendocrine tumours of the lung are all malignant lesions, unified by a common characteristic of neuroendocrine differentiation, but diverse in terms of histological features, clinical presentation, aetiology and biology. In the new World Health Organisation classification of lung tumours, published in 2015, the four major types of neuroendocrine tumour (small cell carcinoma, large cell neuroendocrine carcinoma, carcinoid tumour and atypical carcinoid tumour) are now included under a single heading of neuroendocrine tumours. Small cell carcinoma (SCLC) SCLC is a high-grade malignant epithelial tumour comprising relatively small cells with scanty cytoplasm, fusiform to round nuclei, finely disperse granular chromatin, inconspicuous nucleoli and prominent nuclear moulding. Mitoses, apoptosis and extensive necrosis are typical. Tumours characteristically have neuroendocrine granules visible on electron microscopy and most cases express neuroendocrine markers by immunohistochemistry. An organoid architecture with rosettes and trabeculae is uncommon, but SCLC samples are often small, precluding identification. SCLC may be seen combined with other non-small cell carcinoma (NSCLC) subtypes (Combined small cell carcinoma). Here, SCLC has priority, regardless of the relative proportion of the tumour that is SCLC. SCLC accounts for between 10-15% of cases diagnosed and is strongly associated with tobacco smoking. The typical presentation of SCLC is stage IV metastatic disease with rapid progression. Radiologically a large central mass with contiguous, bulky hilar nodes is typical and mediastinal invasion is usually evident. The vast majority of SCLC present. Production of hormonal peptides accounts for several paraneoplastic complications. Ectopic hormones (or hormone-like peptides) such as ADH or ACTH, and peptides native to the pulmonary neuroendocrine cells (calcitonin and gastrin-releasing peptide) may be produced. Large cell neuroendocrine carcinoma (LCNEC) Another high grade neuroendocrine carcinoma, characterized by morphological neuroendocrine features (rosettes, trabeculae, peripheral nuclear palisading). Cells are relatively large, cytoplasm abundant/eosinophilic, and nuclei show coarse chromatin and nucleoli. Nodular tumour, a fine vascular stroma, cribriform architecture and central comedo necrosis are common. Mitoses are abundant (always >10 per 2mm[2]: rarely <30 and averages 75). Combined tumours, with SCLC or, more often NSCLC, when adenocarcinoma is the most frequent accompaniment, are not unusual. LCNEC should demonstrate neuroendocrine differentiation by immunohistochemistry [NCAM/CD56 (~100%), Chromogranin (80-85%), synaptophysin (50-60%). At least 50% express TTF1. Usually at least two stains are positive. There is a similar, strong association between LCNEC and tobacco smoking. These are relatively rare tumours, accounting for about 4% of resected cases but true prevalence across all stages, is not clear. Presentation and radiological appearances are no different from other NSCLC cases of similar stage; the vast majority of LCNEC are diagnosed in surgical resections. They are more often peripheral than centrally located tumours. The bulky nodal/mediastinal disease common in SCLC, is uncommon in LCNEC but there may be selection and diagnostic bias driving this observation. Hormonal production and paraneoplastic syndromes are rare in LCNEC, another difference with SCLC. Carcinoid tumour Carcinoid tumours are malignant tumours, divided into typical carcinoid (TC) where there is no evidence of necrosis and mitoses number less than 2 per 2mm[2] of tumour. Atypical carcinoid tumours (AC) may show punctate necrosis and/or exhibit 2 or more, but <10 mitoses per 2mm[2]. Otherwise, the lesions are very similar histologically - small regular cells, variable cytoplasm, bland round to oval nuclei. Architecture is usually insular, trabecular but rosettes or glands occur. Spindle cell carcinoids occur mostly in thee lung periphery; insular/trabecular lesions are characteristically central. Strong neuroendocrine markers expression is expected. Proliferation markers such as Ki67 mirror, to some extent, the mitotic rate, may aid distinction from high grade neuroendocrine tumours in crushed samples but are not reliable or recommended for distinguishing TC from AC. These are rare tumours, accounting for 4-6% of primary lung ‘cancers’; atypical carcinoid account for around 10% of all lung carcinoids. Typical carcinoids may show lymph node spread in 10% cases, distant metastases are rare. In AC, distant metastases are not unusual. Syndromes related to peptides (Cushing’s, Acromegaly) or secretion of 5-HT (carcinoid syndrome) are very rare. Neuroendocrine tumour development and Genetics Precursor lesions are not described for the high grade lesions and the strong link with smoking and the common combination with NSCLC elements makes it likely that origins at least, are from the same cell populations that give rise to other NSCLC. Both central and peripheral lung epithelial compartments are capable of neuroendocrine differentiation, possibly in part driven by transcription factor ASCL1. It is also notable that a proportion of EGFR-mutated adenocarcinomas recur as SCLC after initial response to EGFR tyrosine kinase inhibitors. Carcinoid tumours probably also derive from the same epithelia, but via different mechanisms. Carcinoid and SCLC or NSCLC effectively never co-exist in the same lesion and carcinoids are not associated with tobacco smoking. Rarely carcinoids are associated with MEN type 1 syndrome, and sporadic cases may show MEN1 mutations. A rare disease called diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is associated with spindle-cell carcinoid tumours, often multiple, and is considered a rare carcinoid precursor lesion. There are evolving data which show that SCLC in particular, has patterns of very frequent mutations and epigenetic changes (gene hypermethylation) reflecting tobacco carcinogenesis. SCLC and LCNEC share many features in their genetic profile and inactivating mutations of both RB and TP53 are characteristic. SCLC shares many of the characteristic deletions or losses of tumour suppressor genes seen in squamous cell carcinoma, especially in 3p loci. SCLC and LCNEC show many alterations in genes involved in cell cycle regulation. In LCNEC, some genes such as TTF1, CDKN2, STK11 and KEAP1 may be altered, akin to that seen in some squamous cell or adenocarcinomas, again, and reminiscent of the post-EGFR TKI recurrence scenario, raising the possibility of origin through divergent differentiation within ‘NSCLC precursors’. Carcinoid tumour genomics are entirely different, less well studied, and as expected, do not show a ‘tobacco signature’. As well as MEN1 mutations, alteration of genes of the methylation complex and chromatin remodelling genes are not infrequent. Carcinoid tumours are NOT precursor lesions for, and do not evolve into, SCLC or LCNEC.
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ORAL 37 - Novel Targets (ID 146)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:S.S. Ramalingam, E. Thunnissen
- Coordinates: 9/09/2015, 16:45 - 18:15, Mile High Ballroom 4a-4f
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ORAL37.05 - Prevalence and Clinical Association of MET Gene Amplification in Patients with NSCLC: Results from the ETOP Lungscape Project (ID 444)
17:28 - 17:39 | Author(s): K. Kerr
- Abstract
Background:
The reported prevalence of MET gene amplification in non-small cell lung cancer (NSCLC) varies from 0-21% and clinical correlations are emerging slowly. In a well-defined NSCLC cohort of the ETOP Lungscape program, we explore the epidemiology, the natural history of MET amplification and its association with MET overexpression, overall survival (OS), relapse-free survival (RFS) and time to relapse (TTR).
Methods:
Resected stage I-III NSCLC, identified based on the quality of clinical data and FFPE tissue availability, were assessed for MET gene copy number (GCN) and expression analysis using silver in-situ hybridization (SISH) and immunohistochemistry (IHC), respectively, on TMAs (MET and centromere-specific probes; anti total c-MET antibody, clone SP44; Ventana immunostainer). MET amplification was defined as MET/centromere ratio ≥2 with average MET GCN ≥4, high MET GCN at two levels as ≥median CGN and ≥5 (irrespective of amplification) and MET IHC+ as 2+ or 3+ intensity in ≥50% of tumor cells. Sensitivity analysis to define the amplification’s thresholds was also performed. All cases were analysed at participating pathology laboratories using the same protocol, after successful completion of an external quality assurance (EQA) program.
Results:
Currently 2709 patients are included in the Lungscape iBiobank (median follow-up 4.8 years, 53.3% still alive). So far, 1547 (57%) have available results for MET GCN with amplification detected in 72 (4.7%; 95%CI: 3.6%, 5.7%) and high MET GCN (≥5) in 65 (4.2%; 95%CI: 3.2%, 5.2%). The median value of average MET GCN per cell is 2.3. IHC MET expression is available for 1515 (98%) of these cases, 350 (23%) of which are MET IHC positive [170 cases (49%) 3+, 180 (51%) 2+]. The median age, for the cohort of 1547 patients, is 66.2 years, with 32.8% women, and 13.5%, 29.7%, 54% never, current, former smokers, respectively. Stage distribution is: IA 23.6%, IB 24.6%, IIA 17%, IIB 12.1%, IIIA 20.9%, IIIB 1.8%, while 52.7%, are of adenocarcinoma and 40.0% of squamous histology. MET amplification and high MET GCN (≥5) are not significantly associated with any histological tumor characteristics or stage (multiplicity adjusted alpha: 0.005). High MET GCN (≥2.3) is less frequent in current smokers (38.3% vs. 55.6% for former or non-smokers, p<0.001). MET amplification and high MET GCN are significantly associated with IHC MET positivity (p<0.001 in all cases). MET amplification is present in 9.7% of IHC MET+ vs 3.1% of IHC MET- patients and high MET GCN (≥5) in 8.6% of IHC MET+ vs 2.8% of IHC MET- patients. MET amplification ranges from 0 to 16% between centers, while high MET GCN (≥5) and (≥2.3) from 0% to 12%, and 11.8% to 98.9%, respectively. MET amplification and both levels of high MET GCN are not associated with OS, RFS or TTR.
Conclusion:
The preliminary results for this large, predominantly European, multicenter cohort demonstrate that MET amplification assessed by SISH prevails in 4.7% of NSCLC, is associated with strong MET expression, and has no influence on prognosis. The large inter-laboratory variability in GCN despite EQA efforts may highlight a critical challenge of MET SISH analysis in routine practice.
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P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-022 - A Prospective Multicenter Study for ALK IHC+ Metastasized NSCLC (ID 2566)
09:30 - 09:30 | Author(s): K. Kerr
- Abstract
Background:
Pulmonary adenocarcinomas may harbor driver mutations, that sensitize tumors to drugs that specifically target the genetic alteration. Metastasized NSCLC with an EML4-ALK translocation are sensitive to a range of tyrosine kinase inhibitors, of which crizotinib is most extensively studied. ALK-positive NSCLC was determined in a phase III trial with fluorescence in situ hybridisation (ALK FISH+). ALK immunohistochemistry (IHC) seems to run parallel with ALK FISH positivity. However discrepant cases occur, which include ALK IHC+ FISH-. The aim of this study is to collect cases with ALK IHC+ and compare within this group response to crizotinib treatment of ALK FISH+ cases with ALK FISH- cases.
Methods:
A prospective multicenter investigator initiated research study was started in Europe. This study is supported by Pfizer. Cases diagnosed with ALK IHC+ lung cancer (5A4 or D5F3) treated with crizotinib are collected centrally. Slides are submitted centrally for validation of ALK IHC (with ETOP and Ventana protocol), ALK FISH (with Vysis probes) and DNA analysis.
Results:
The study started on April 1 2014 and is still open. Currently 10 centers are actively participating. 1443 cases have been examined with ALK IHC of which 39 (2.7%) recorded positive. 24 cases have been submitted to the database. The validation process is still ongoing. The fraction of ALK IHC+ FISH- cases is low. Two cases with ALK IHC+ FISH- metastastatic NSCLC responded to crizotinib treatment. In two cases ALK positivity could not be confirmed (ALK IHC- and ALK FISH-). These patients had progressive disease following crizotinib treatment.
Conclusion:
A clinically relevant question what the effect of ALK inhibitor treatment is on metastatic NSCLC ALK IHC+ FISH- compared to ALK IHC+ FISH+ is examined. Other centers with interested collaborating physicians are invited to participate.
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-009 - Evaluation of RT-PCR Methodology for ALK Assessment in Patients with NSCLC in Europe: Results from the ETOP Lungscape Project (ID 1506)
09:30 - 09:30 | Author(s): K. Kerr
- Abstract
Background:
ALK rearrangement is documented in 2%-7% of NSCLC, depending on the population studied and detection method used. Although the reverse transcriptase-polymerase chain reaction (RT-PCR) was the first used and published method, fluorescence in situ hybridization (FISH) has become the primary standard diagnostic method. Recently, immunohistochemistry (IHC) has also proven to be a reproducible, faster and sensitive technique. This is one of the first studies concurrently comparing all three techniques in resected lung adenocarcinomas from the large ETOP Lungscape cohort.
Methods:
95 cases from the ETOP Lungscape iBiobank, selected based on any degree of IHC staining (clone 5A4 antibody, Novocastra, UK), were examined by ALK FISH (Abbott Molecular, Inc.; Blackhall, JCO 2014) and central RT-PCR. For the latter, formalin-fixed, paraffin-embedded (FFPE) unstained slides were collected from participating centers. Slides were de-paraffinized, Toluidine Blue stained, and tumors macro-dissected. Tissue digestion and RNA extraction were performed (Qiagen RNeasy FFPE Kit). Using primers described in the literature covering most of ALK known translocations, RT-PCR (Superscript One-Step RT-PCR with Platinum Taq – 40 loops) was performed, followed by capillary electrophoresis in two separate mixes. Co-amplification of B-actin was done to validate the procedure and RNA quality. All tests were duplicated.
Results:
76 of 95 RT-PCR had adequate RNA quality (B-actin co-amplification present). Among these, 18 were FISH positive, 16 were RT-PCR positive, including EML4-ALK V3a/b in 7, V1 in 5, V2 in one, and undetermined variants in 3 cases. 53 of 54 FISH negative cases were also RT-PCR negative (98%). 15 of 18 FISH positives harbored a translocation by RT-PCR (83%). Among the 4 discrepant cases, 2 FISH+/RT-PCR- cases had IHC H-scores of 180 and 260, and 98.3% and 95% of rearranged cells by FISH, probably corresponding to variants not covered by the RT-PCR. One had an IHC H-score of 5, and 16% cells rearranged on FISH, most probably corresponding to a FISH false positive case. The last had an IHC H-score of 200, 13% rearranged cells by FISH, and, thus is defined as a false negative FISH result. Provided IHC is defined as positive by an H-score above 120, all but one case (H-Score 20, FISH and RT-PCR positive) gave concordant results by a combination of FISH and RT-PCR. Overall, using as true negative or true positive the concordant result of two of the methods, the third method is characterized by high specificity and sensitivity with corresponding values of 100/98/100% and 94/94/89% for IHC/FISH/RT-PCR, respectively.
Conclusion:
RT-PCR is a very good tool for sorting discordant IHC/FISH cases, however, we do not recommend using this technique as single method due to the lower sensitivity of RT-PCR, as not all variants are covered, and also due to the limitations with RNA preservation.
