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R.K. Thomas
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MINI 13 - Genetic Alterations and Testing (ID 120)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 15
- Moderators:Y. Koh, R.K. Thomas
- Coordinates: 9/08/2015, 10:45 - 12:15, 205+207
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MINI13.01 - Clinicopathological Profiles of ROS1 Positive Patients Screened by FISH (ID 1450)
10:45 - 10:50 | Author(s): J. Sheren, D.L. Aisner, D.T. Merrick, E.M. Berge, P. Chesnut, R.C. Doebele, R. Camidge, M. Varella-Garcia
- Abstract
- Presentation
Background:
ROS1 fusion variants represent an important subset of oncogenic driver mutations in approximately 0.7 – 3.4% of non-small cell lung cancers. Since the frequency of ROS1 positive lung cancer patients is relatively low, it is unclear whether there are significant clinicopathologic associations for positive cases. Thus far, ROS1 positive patients tend to be younger and never-smokers with tumors displaying adenocarcinoma histology. This study describes a further cohort of ROS1 positive lung cancer patients in an effort to identify clinicopathologic associations.
Methods:
The data represent a retrospective analysis of the clinicopathological profiles of primary and metastatic lung cancer patients tested for ROS1 gene rearrangements by break-apart (BA) FISH at the University of Colorado School of Medicine.
Results:
The cohort consisted of 452 patients enriched for triple-negative (EGFR-, KRAS- and ALK-) non-squamous cell carcinomas screened for ROS1 rearrangements using the BA FISH assay. Nineteen cases (4.2%) were identified as positive for rearrangement, the majority (68%) of which were female, with a mean cohort age of 54.9 years (range 30-79); as compared to negative cases which included 56% female patients (P= 0.1083), and had a mean cohort age of 62.9 (range 21-90) (P= 0.0058). Seventeen out of the 19 ROS1 positive tumors were classified as adenocarcinomas, one was diagnosed as adenosquamous carcinoma, and the histology on one specimen was not otherwise specified (NOS). Among 12 individuals with information on pathologic stage at diagnosis, the majority (75%) were stage IV. The prevalent FISH pattern for rearrangement was a split 5’ and 3’ signal (68%) with the remaining specimens showing primarily single 3’ signals (21%) or a mix of split and single 3’ signals (11%).
Conclusion:
The ROS1 positive tumors in this cohort were primarily classified as adenocarcinomas, diagnosed at an advanced stage, in patients significantly younger and more likely to be women, although the sample set was biased for non-squamous lesions thereby limiting the application of this information to squamous cell lung carcinoma. The higher prevalence of ROS1 positive cases in this cohort compared to unselected cohorts is best explained by the inclusion of specimens with known negative status for EGFR and KRAS mutations and ALK fusions. As such, these data are in agreement with previous descriptions of ROS1 positive cohorts. Screening for ROS1 rearrangements in lung cancer patients displaying adenocarcinoma histology and negative for EGFR, KRAS and ALK activating events should identify a higher frequency of ROS1 rearranged tumors compared to unselected approaches and facilitate this subset of patients to be treated with targeted ROS1 inhibitors.
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- Abstract
- Presentation
Background:
Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is a rare histological type of large cell NSCLC. Histopathologically it is similar to nasopharyngeal carcinoma which is most commonly occurred in Southern China. It had close relationship with Epstein-Barr virus (EBV) infection. Over the past 28 years since it was first reported, less than 300 Primary pulmonary LELC cases have been reported in the literature. Due to its rarity, the treatment of advanced LELC is not only empirical, but controversial. Testing for EGFR mutation and ALK rearrangement are routine for NSCLC patients in clinical practice now. However, only few genotype studies have been done in pulmonary LELC, and till now no targeted therapy has been shown effective in the treatment of these patients.
Methods:
We investigated a cohort of 42 patients with primary pulmonary LELC and genotyped for ALK rearrangement and EGFR mutation. ALK rearrangement was detected by Fluorescence in situ Hybridization (FISH). EGFR mutational analysis of exons 18 through 21 was analyzed by TaqMan real-time polymerase chain reaction (PCR).
Results:
The clinicopathologic characteristics of 42 patients with pulmonary LELC are presented in Table 1. Twenty-seven of 42 patients were in stage I-IIIA (64.3%), and only 15/42 patients (35.7%) were in stage IIIB or IV. The female to male ratio was about 22:20, and the median age at diagnosis was 51 years (range, 29-67 years). Only 13 (31.0%) patients were smokers. In situ hybridization for Epstein-Barr virus-encoded RNA (EBERs) showed positive signals in all 42 patients. By immunohistiochemistry staining, all patients demonstrated positive expression of CK5/6 and P63, but almost all patients were negative for TTF-1(34/34, 100%) or CK7 (34/35, 97.1%). None of the 42 patients had ALK rearrangement. Of 42 patients tested EGFR mutation, only one patient (2.4%) harbored L858R mutation and gefitinib was applied to this case, however no objective response was observed and the progression free survival PFS time was only 1 month.Figure 1
Conclusion:
Primary pulmonary LELC is a unique histological subtype of non-small cell lung cancer. ALK rearrangement and EGFR mutation are lack and they may not be the oncogenic driver gene in pulmonary LELC. Conventional cytoxic chemotherapy is by far still a backbone treatment in advanced stage primary pulmonary LELC. Future efforts should be made to explore other oncogenic driver gene to guide targeted therapy in this rare disease to determine the optimal treatment.
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MINI13.03 - Characterization of MET Gene and MET Protein Expression in Lung Cancer (ID 2155)
10:55 - 11:00 | Author(s): T.A. Boyle, X. Lu, L. Berry, K.E. Ellison, A.A. Kowalewski, C.J. Rivard, F. Khalil, M. Mino-Kenudson, A. Moreira, L. Sholl, G. Sica, K. Kugler, D.J. Kwiatkowski, M. Varella-Garcia, P.A. Bunn, Jr, F.R. Hirsch
- Abstract
- Presentation
Background:
Activation of the MET signaling pathway can propel the growth of cancer cells in non-small cell lung cancer (NSCLC). Increased MET gene by amplification and/or polysomy can cause MET protein overexpression; less common causes include mutations, translocations, and alternative RNA splicing. Clinical trials using MET as a biomarker for selection of lung cancer patients who might most benefit from targeted therapy have experienced variable outcomes. We aimed to characterize the relationship between MET protein overexpression and MET amplification or mean copy number alterations in patients with NSCLC.
Methods:
The Lung Cancer Mutation Consortium (LCMC) is performing an ongoing study of biomarkers with patients with NSCLC from 16 cancer center sites across the United States. For this analysis, 403 cases had complete data for MET protein expression by immunohistochemistry (IHC, monoclonal antibody SP44, Ventana) and MET gene amplification by fluorescence in-situ hybridization (FISH, MET/CEP7 ratio). Pathologists evaluated MET expression using the H-score, a semi-quantitative assessment of the percentage of tumor cells with no, faint, moderate, and/or strong staining, ranging from 0-300. Spearman's correlation was used to analyze the correlation between MET protein expression (H-scores) and FISH results (MET/CEP7 ratio (N=403) and MET copy number (N=341). Protein overexpression using 5 different cut-offs was compared with amplification defined as MET/CEP7 ≥ 2.2 and high mean copy number defined as ≥ 5 MET gene copies per cell using the Fisher’s exact test. Cox Proportional Hazards models were built to examine the associations of these different definitions of positivity with prognosis, adjusting for stage of disease.
Results:
MET protein expression was significantly correlated with MET copy numbers (r=0.17, p=0.0025), but not MET/CEP7 ratio (r=-0.013, p=0.80). No significant association was observed between protein overexpression using a commonly used definition for MET positivity (“at least moderate staining in ≥ 50% tumor cells”) and MET amplification (p=0.47) or high mean copy number (p=0.09). A definition for MET protein overexpression as “≥ 30% tumor cells with strong staining” was significantly associated with both MET amplification (p=0.03) and high mean copy number (p=0.007), but a definition of “≥ 10% tumor cells with strong staining” was not significantly associated with either. Definitions of protein overexpression based on high H-scores (≥200 or ≥250) were associated with high MET mean copy numbers (p=0.03 and 0.0008, respectively), but not amplification (p=0.46 and 0.12, respectively). All 5 definitions of MET protein overexpression demonstrated a significant association with worse prognosis by survival analyses (p-values ranged from 0.001 to 0.03). High MET copy number (p=0.045) was associated with worse prognosis, but MET amplification was not (p=0.07).
Conclusion:
Evaluation of NSCLC specimens from LCMC sites confirms that MET protein expression is correlated with high MET copy number and protein overexpression is associated with worse prognosis. Definitions of MET protein overexpression as “an H-score ≥250” and “≥30% tumor cells with strong staining” were significantly associated with high mean MET copy number. It may be worth reevaluating the performance of MET as a biomarker by different definitions of positivity to predict response to MET-targeted therapies.
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- Abstract
- Presentation
Background:
Identification of driver mutations has led to the dramatic improvement in personalized therapy for lung adenocarcinoma. However, few targeted therapeutics are approved for treatment of squamous cell lung carcinoma. The identification of druggable molecular targets in SqCLC has been becoming a top research priority. Therefore, the aim of this study was to analyze the driver mutation profiles in a large cohort of Chinese squamous cell lung carcinomas to identify potential therapeutic targets.
Methods:
Approximately 2,800 COSMIC mutations from 50 oncogenes and tumor suppressor genes were analyzed on 159 samples by using Ion Torrent semiconductor-based next-generation sequencing. The gene copy numbers of FGFR1, EGFR, HER2, PDGFRA, CCND1, SOX2, CDKN2A, and PTEN were assessed by FISH on 250 samples. In addition, the status of PTEN expression was examined by immunohistochemistry on 250 samples.
Results:
Somatic mutations were detected in 73.6% (117/159) of patients. The most commonly mutated gene detected in this study was TP53 (56.0%, 89/159), followed by CDKN2A (8.8%, 14/159), PI3KCA (8.8%, 14/159), KRAS (4.4%, 7/159), EGFR (3.1%, 5/159), FBXW7 (2.5%, 4/159), PTEN (2.5%, 4/159), FGFR3 (1.3%, 2/159), AKT1 (1.3%, 2/159) and KIT (0.6%, 1/159). Copy number alterations were present in 77.6% (191/246) of patients, including FGFR1 amplification (13.7%, 34/248), EGFR amplification (11.4%, 28/246), HER2 amplification (8.9%, 22/246), PDGFRA amplification (7.7%, 19/246), CCND1 amplification (11.0%, 27/246), SOX2 amplification (35.0%, 86/246), CDKN2A deletion (18.7%, 46/246), and PTEN deletion (29.3%, 72/246). The loss of PTEN expression was observed in 43.5% (108/248) of patients. TP53 mutations were significantly more common in men and smokers, while the frequency of EGFR mutation was significantly higher in women and never smokers. Amplification of FGFR1, CCND1 and SOX2 genes were significantly associated with smoking. The incidence of FGFR1 amplification in patients without lymph node metastasis was significantly higher than that in patients with lymph node metastasis (19.4% vs. 10.2%，P=0.043). The frequency of SOX2 amplification in tumors with moderate and poor differentiation was significantly higher than that in tumors with well differentiation (39.6% vs. 33.6% vs. 0%，P=0.036). The incidence of loss of PTEN protein expression in patients with pleural invasion was 51.2%, which was significantly higher than that in patients without pleural invasion (P=0.017). The loss of PTEN expression was significantly associated with PTEN gene deletion (P=0.001). No significant association was observed between the molecular abnormalities and disease-free survival and overall survival.
Conclusion:
Genetic alterations are common in squamous cell lung cancers. The findings of this study may facilitate the identification of molecular target candidates for precision medicine in patients with squamous cell lung cancers.
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MINI13.05 - Discussant for MINI13.01, MINI13.02, MINI13.03, MINI13.04 (ID 3338)
11:05 - 11:15 | Author(s): M. Ladanyi
- Abstract
- Presentation
Abstract not provided
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MINI13.06 - Mutation Prevalence for Oncogenic Drivers in Lung Adenocarcinoma (ID 3279)
11:15 - 11:20 | Author(s): C.J. Rivard, T.A. Boyle, Q. Ren, A.A. Kowalewski, R.R. Hozak, G. Mi, A. Kurljac-Letunic, S. Melemed, R. Kurek, D.L. Aisner, F.R. Hirsch
- Abstract
- Presentation
Background:
Identification of mutations which drive pulmonary adenocarcinomas (ADC) has rapidly moved from the research arena to clinical practice. The prevalence of these mutations has been suggested by a multitude of studies but here we describe the prevalence of mutations from a large study of patients with advanced ADC treated in the international phase III study INSPIRE (Lancet Oncology 2015) with all testing performed in one CLIA-certified laboratory under standardized conditions.
Methods:
Mutation testing was performed on 412 adenocarcinoma specimens using SNaPshot® methodology. Mutations were examined in the AKT, EGFR, KRAS, BRAF, NRAS, PIK3CA, TP53, PTEN, CTNNB1, and MEK1 genes. The relative frequencies of genetic alterations were calculated based on the total number of adequate specimens and specific consent for testing.
Results:
Of the 412 adenocarcinoma specimens tested, 372 (90.3%) had evaluable results from mutation testing. A single mutation was detected in 157 (42.2%) specimens, whereas mutations in two genes were detected in an additional 20 (5.4%). The overall prevalence of mutations for each specific gene was as follows: KRAS (34.2%), EGFR (12.2%), TP53 (4.9%), PTEN (2.8%), PIK3CA (2.2%), CTNNB1 (2.2%), NRAS (1.8%), BRAF (1.2%), MEK1 (0.3%), and AKT (0%). Figure 1 Evaluation of smoking status identified a substantially higher percentage of KRAS mutations in ex-light smokers and current smokers (38.2% and 40.5%) combined compared to never smokers (7.6%, p<0.0001) , and a lower proportion of EGFR mutations in ex-light and current smokers (10.9% and 4.9%) combined compared to never smokers (39.7%, p<0.0001). Patients ≥70 years old had a higher proportion of both NRAS (7.1% vs. 0.7%, p=0.009) and TP53 mutations (12.5% vs. 3.3%, p=0.010). In addition, males had a lower incidence of EGFR mutation (8.6% vs. 19.0%, p=0.007) as compared to females. Patients from North America, Europe, and Australia/New Zealand demonstrated lower rates of mutation in CTNNB1 (1.4% vs. 8.6%, p=0.030) and PIK3CA (1.4% vs. 8.3%, p=0.032) compared to patients from Central/South America, South Africa and India. Finally, among specimens with two mutations, combinations involving KRAS were the most prevalent (70%, 14/20) followed by TP53 (50%, 10/20).
Conclusion:
These results demonstrate the wide spectrum of mutations that can be detected in adenocarcinoma specimens, with high prevalence rates in the EGFR and KRAS genes. Most patients had only one identified driver mutation. The study revealed age and geographical associations in some mutations. The clinical relevance of the studied mutations in relation to chemotherapy and the human EGFR antibody, Necitumumab, will be studied.
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- Abstract
- Presentation
Background:
Various protein kinases have been discovered as drivers in cancer and subsequently used as therapeutic targets.
Methods:
To discover potential target driver genes, we investigated characteristics of genome wide scans of genetic lesions in kinases from 103 Korean lung adenocarcinoma patients, whose driver mutations were unknown or negative after conventional screening of EGFR and KRAS mutations as well as EML4-ALK fusion. We employed targeted, pair-end deep sequencing and screened the coding sequences of 518 protein kinase and genes that are known to be mutated with considerable frequencies in lung adenocarcinoma such as TP53 and EGFR.
Results:
Pathway analysis revealed that recurrent alterations were enriched in p53 signaling (TP53, ATM, CHEK2, CDKN2A) and ErbB signaling (EGFR, BRAF, KRAS, ERBB4) pathways. Mutations in TP53 and an EGFR exon 21 hotspot regions were found in 28% (29/103) and 13% (13/103) of cases (Fig 1). TP53 mutation was significantly more common in older group (97%) than in younger group (3%). We identified novel somatic mutations of genes, including CHEK2, NEK2 (mitotic progression) and SMG1 (nonsense-mediated mRNA decay), that have not been highlighted in lung cancer previously. Figure 1 Fig 1. Discovery of recurrent mutations with identical substitutions at the same site
Conclusion:
As the inhibitors of these protein kinases can be therapeutic candidates to eradicate cancer cells, our results provide useful information for the development of effective therapeutic target agents, by which the activity of various kinases can be modulated, in adenocarcinoma of the lung.
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MINI13.08 - Targetable Genomic Aberrations in Squamous Cell Lung Cancer (SCC): A Report from the Lung Cancer Genomics Ireland (LCGI) Study (ID 766)
11:25 - 11:30 | Author(s): S. Rafee, S. Toomey, Y. Elamin, K. Gately, S. Cuffe, A. Carr, S. Finn, S. Nicholson, R. Ryan, V. Young, J. Crown, P. Morris, O. Breathnach, E. Kay, A. O'Grady, B. Hennessy, K.J. O'Byrne
- Abstract
- Presentation
Background:
The prognosis of lung SCC continues to be poor with no molecularly targeted agents specifically developed for its treatment. LCGI aims to identify potential targetable oncogenes in lung SCC.
Methods:
The LCGI study is being carried out in 500 patients with surgically resected lung SCC, treated at St James’s University Hospital and Beaumont University Hospital, Dublin. We used the platform of Sequenom’s MassArray to perform genotyping for accustomed panel of 258 somatic hotspot mutations in 49 genes including genes in the MAPK and PI3K pathways. We also evaluated FGFR1 amplification by fluorescence in situ hybridization (FISH) and MET protein expression by immunohistochemistry (IHC).
Results:
Lung SCCs from 258 patients have been tested by Sequenom MassArray to date. Lung SCCs from 150 patients have been evaluated for MET protein expression and 89 for FGFR1 amplification. 163 (63.2%) patients were male. The median age of the cohort was 68. The majority of patients were either current (39.5%) or former (58.1%) smokers at the time of diagnosis. 138 (53.5%) were stage I, 87 (33.7%) were stage II, and 33 (12.8%) were stage III SCCs. At least one aberrant, potentially targetable oncogene was identified in the SCC of 101 (39.1%) patients (see Table). The presence of PIK3CA or KRAS mutations, or FGFR1 amplification did not have a statistically significant impact on median overall survival or recurrence-free survival. However, the presence of two or more aberrations in driver oncogenes in a tumor (patients, n=19) was associated with a worse median overall survival compared to patients with either a single driver aberration (p=0.04) or no aberrations (p<.01). Table: Frequency of driver mutations in LCGI compared to The Cancer Genome Atlas (TCGA) studyMutation LCGI (n=258) TCGA (n=178) FGFR1 amp (n=89) 13 % 16.8 % PIK3CA 15.1 % 10.1 % KRAS 6.5 % 0.6 % PTPN11 3.5 % 1.7 % STK11 3.1 % 1.7 % MYC 1.9 % 0.0 % NRAS 1.6 % 0.0 % BRAF 1.2 % 3.9 % HRAS 1.6 % 1.7 % CTNNB1 1.5 % 1.7 % FBXW7 1.5 % 3.4 % MET Overexpression (n=150) 1.3 % NA EGFR 0.9 % 2.8 % AKT1 0.4 % 0.6 % CDK4 0.4 % 0.0 % GNA11 0.4 % 0.6 % MAP2K1 0.4 % 0.6 % DDR2 0 % 1.1 %
Conclusion:
39.1% of lung SCC patients have an aberrant, potentially targetable driver oncogene in their tumor. The presence of two or more aberrant oncogenes is a poor prognostic factor in lung SCC. These findings can be used to guide clinical trials in lung SCC.
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MINI13.09 - Next-Generation Sequencing Analysis of Driver Gene Mutations in Pleomorphic Carcinoma of the Lung (ID 1145)
11:30 - 11:35 | Author(s): S. Manabe, R. Kasajima, Y. Miyagi, T. Nishii, T. Yokose, S. Murakami, T. Kondo, H. Saito, M. Hashimoto, H. Furumoto, T. Isaka, H. Ito, H. Nakayama, T. Kaneko, K. Yamada
- Abstract
- Presentation
Background:
Research into druggable driver gene mutations in non-small cell lung cancer has identified several molecule-targeting agents that are clinically prescribed to inhibit tumor growth in adenocarcinoma. However, lung cancers without targeted driver gene mutations show poorly differentiated histologies and unfavorable prognoses without medication. Pleomorphic carcinoma, a lung cancer that includes a mixed conventional histology and sarcomatoid components, is an extremely aggressive tumor and rarely responds well to anticancer treatments. However, it has recently been reported that lung cancer with a sarcomatoid component contains the ALK gene rearrangement. Therefore, we used a next-generation sequencing (NGS) analysis of the driver gene mutations in pleomorphic carcinoma (PC) of the lung to identify druggable target molecules.
Methods:
We selected PCs from primary lung carcinomas by reviewing the records of 944 patients who had undergone surgical resection between 2007 and 2014. The Ion PGM™ NGS sequencer (Life Technology Inc., US) was used to identify known gene rearrangements in lung cancers by analyzing RNA with IonAmpliSeq™ RNA Lung FusionPanel® (Life Technology). With our original panel for targeted gene amplifications, the Ion PGM was also used to analyze nucleotide sequence of whole exons of 41 driver genes reported to be involved in lung cancers. The cases examined were also analyzed with ALK immunohistochemistry (ALK-IHC) using the N-Histofine® ALK Detection Kit (Nichirei Bioscience Inc., Tokyo, Japan) on sliced paraffin-embedded tumor specimens.
Results:
Twenty-one lung cancer specimens diagnosed as PC and frozen material from nine patients were available for NGS. The EML4ex6/ALKex20 fusion gene was detected in one case, which was also positive on ALK–IHC. No other fusion genes were detected. Another case, which was negative for the fusion gene, was weakly positivity on ALK–IHC, so an unbalanced 5¢/3¢-end ALK expression test is planned. Six of nine cases but not the ALK-fusion-positive cases showed driver gene mutations in TP53. We also found several somatic mutations in druggable genes in this study, which should be considered carefully to determine whether they are driver or passenger genes.
Conclusion:
Although a small number of PCs were examined in this study, the ALK fusion gene was detected, which indicates the frequency of ALK fusion might be high in PC. Other possible druggable gene mutations were also identified in PCs. Further cases must be investigated to understand the mutation status of driver genes in PC.
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MINI13.10 - Discussant for MINI13.06, MINI13.07, MINI13.08, MINI13.09 (ID 3339)
11:35 - 11:45 | Author(s): L. Chirieac
- Abstract
- Presentation
Abstract not provided
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MINI13.11 - Detection of Rare Clinically Actionable Mutations in NSCLC Metastatic to the Brain by Targeted Next Generation Sequencing (ID 1004)
11:45 - 11:50 | Author(s): L.J. Tafe, K.K. Maung, S.J. Weinstein, G.J. Tsongalis, K.H. Dragnev
- Abstract
- Presentation
Background:
Genotyping of non-small cell lung cancers (NSCLC) is important for directing patient care, particularly in adenocarcinomas (ADC) where targeted therapeutics are available. There is emerging evidence of efficacy of targeted therapy in the treatment and prevention of brain metastases. With recent adoption of next-generation sequencing technologies it is possible to test individual tumors simultaneously for somatic mutations in multiple genes. Here, we present the mutational spectrum of NSCLC brain metastases in our institution over a three year period.
Methods:
The department of pathology archives was searched to identify cases of NSCLC metastatic to brain that underwent surgical resections during 2012-2014. Clinicopathologic information was recorded from the pathology reports and the medical records. Molecular genotyping analysis was performed for EGFR/KRAS mutations using single gene analysis (prior to 2013) or by next generation sequencing (NGS) using the AmpliSeq Cancer Hotspot Panel v2. FISH was used to test for ALK rearrangements.
Results:
During 2012-2014, 31 NSCLC patients underwent surgical resection for brain metastases. Eighteen patients were female (58%) and 13 were male. The median age was 70 years (range 51-89). Tumor histology included 24 ADC and 7 squamous cell carcinomas (SCC). Twenty-three cases had molecular genotyping studies performed on the metastatic disease or the primary lung cancer. These included 3 SCC and 20 ADC. Of the ADC, 12 were tested with the NGS panel; 8 had been tested prior to 2013. The most frequently mutated genes were KRAS (8/20; 40%) and TP53 (7/12; 58%). Of the patients with KRAS mutations 7/8 were female (p = 0.085). The NGS assay detected clinically actionable mutations that would have not been detected with prior single gene assays including an EGFR exon 20 insertion, an ERBB2 exon 20 insertion, and two PIK3CA mutations. Additional mutations were detected in JAK3, FLT3, FBXW7, ATM, STK11, VHL and RB1.
Conclusion:
We found that 40% of the genotyped ADC metastases harbored KRAS mutations more frequently in females (although not significant), similar to prior reports. In addition, with NGS we were able to detect additional clinically significant targetable mutations. In summary, NSCLC genotyping can potentially help guide treatment and prevention of brain metastases.
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- Abstract
- Presentation
Background:
Incresing data show advanced non-small cell lung cancer (NSCLC) patients with EGFR activating mutant have discrepant response to EGFR-TKI. The abundance of EGFR mutations may be a powerful explanation for the uneven clinical benefit. This study was designed to investigate the influence of EGFR mutant abundance on efficacy of EGFR-TKI by a quantitative method.
Methods:
201 NSCLC patients treated with EGFR-TKI with available tissue samples for EGFR mutation test were enrolled into the study. EGFR common mutations were detected by amplification refractory mutation system (ARMS) and percentage of mutant EGFR was tested with the method of an Allele Specific Quantitative PCR with Competitive Blocker (ASB-qPCR). In this assay, the copies of all mutations and EGFR locus were calculated by standard curve respectively. The cutoff values were obtained by the receiver operating characteristics (ROC) curve in training set. Further, the cutoff values were confirmed in validation set and the whole population. The relationship between the abundance of EGFR mutations and efficacy of EGFR-TKI was statistically analyzed.
Results:
Of the 201 samples, 72 harbored 19DEL mutation, 63 carried L858R mutant, and 66 with wild-type. The cohort was randomly divided into training and validation sets. The cutoff values of 19DEL and L858R mutation abundance were 4.84% and 9.47% determined by ROC curve in training set. 9.7% of patients with 19DEL positive were low abundance (<4.84%, LA group), while 33.3% of L858R-positive patients were LA (<9.47%).High abundance (HA) group, regardless of 19DEL or L858R positive had more longer median progression free survival (PFS) compared with LA and wild-type groups in either validation set or the whole population (15.0 vs 2.0 vs 1.9, 8.0 vs 1.9 vs 1.9; 15.0 vs 4.0 vs 2.0, 12.0 vs 2.0 vs 2.0; p<0.001). COX regression analysis showed that EGFR mutation abundance, together with smoking status, were independent factors of response to EGFR-TKI.
Conclusion:
The abundance of EGFR mutation could more precisely predict EGFR-TKI efficacy. NSCLC patients with LA mutation had inferior clinical benefit with EGFR-TKI. The heterogeneity in EGFR mutant abundance partly explain the efficacy discrepancy in patients with 19DEL or L858R positive.
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MINI13.13 - Non-Small Cell Lung Cancer (NSCLC) Harboring EGFR Mutations (EGFR-m) and Breast Cancer (BC): A Retrospective Analysis (ID 2857)
11:55 - 12:00 | Author(s): T. Morán, V. Quiroga, E. Carcereny, B. Cirauqui, M. Margeli, L. Vila, M.D.L.L. Gil
- Abstract
- Presentation
Background:
EGFR-m in NSCLC and its responsiveness to TKI has proved beneficial in a subset of NSCLC patients (p) Breast cancer (BC) represents the most incident neoplasm among women. The co-existence of both EGFR-m-NSCLC and BC has been reported in p with Li-Fraumeni Syndrome. However, no systematic evaluation of the presence of both types of cancers has been performed in the general population.
Methods:
We sought to evaluate if EGFR-m-NSCLC associates higher rates of 2[nd] BC than the EGFR-wild type (WT)p. Clinical and molecular characteristics, as well as clinical outcomes of female p visited at our Institution from 2008 to 2014 and harboring both types of tumors were registered.
Results:
69/578 female p with EGFR-m were identified. Data on treatment and follow-up of 62p were available. 11/ 62p (17.7%) were diagnosed with both EGFR-m-NSCLC and BC. For EGFR-m-W-p, BC was diagnosed in 3 cases (0.52%) Regarding EGFR-m-NSCLC, age of diagnosis was 65y; 100% of p were Caucasian and never smokers. Del19, L858 and L861Q represented the 72.7%, 27.3% and 9% of EGFR-m. 36.3% had stage IV, 27.2% recurred after surgery and 36.3% initial stages never recurred. 63.6% received a TKI (42.8% erlotinib). 85.7% received TKI as 1[st] line. The overall response rate was 85.7%. 42.8% received subsequent therapies. The cause of death was related to lung cancer in all cases of death (54.5%). mOS was 29 months from the time of LC diagnosis. Regarding BC, the median age of diagnosis was 52y, BC was a prior diagnosis in 90.9%; the stage was 0, I, IIA and IIIA in 18.18%, 27.27%, 45.45% and 9.09%, respectively. After surgery (100%), 36.36% received ET, 36.36% both chemotherapy and ET and 54.54% radiotherapy (RT). 83.33% of p treated with RT developed the LC in the RT field. 90.90% of p never recurred.
Conclusion:
Diagnosis of BC appears to be higher in EGFR-m-NSCLC-p than in the general population. Evaluation of the molecular mechanism potentially related to this association is warranted.
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MINI13.14 - S768I Mutation in the EGFR Gene in Patients with Lung Cancer (ID 325)
12:00 - 12:05 | Author(s): K. Leventakos, B.R. Kipp, K.M. Rumilla, J.E. Yi, A. Mansfield
- Abstract
- Presentation
Background:
Epidermal growth factor receptor (EGFR) mutations are relatively common oncogenic drivers in non-small cell lung cancer (NSCLC). Interestingly a number of patients have more than one mutation in EGFR. In order to understand whether these patients respond to EGFR inhibition, we reviewed our experience treating these patients. Herein we describe the Mayo Clinic experience with the S768I mutation of exon 20 of the EGFR gene.
Methods:
Relevant clinical and laboratory data were abstracted for selected cases, including evaluation of response after treatment with TKIs using the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Inclusion criteria were cases including EGFR S768I mutation performed at Mayo Clinic or elsewhere until December 2014. EGFR testing was performed following microscopic examination by a pathologist to identify and select areas of tumor for macrodissection and confirm sufficient tumor percent. The EGFR test is a PCR based assay employing allele specific amplification and is used to test for mutations within exons 18-21 of the EGFR gene, most recently using the FDA approved platform. When testing was performed elsewhere, bidirectional sequencing was used.
Results:
1,527 cases of NSCLC that underwent EGFR testing were reviewed and the S678I mutation was present in 9 patients (0.59%), 4 of which were female. Median age at diagnosis was 61 years (range 49-68 years), 5 patients were never smokers and no subjects were current smokers at the time of diagnosis. The stage at diagnosis was I in 2, III in 3 and IV in 4 patients, respectively. All specimens were adenocarcinomas with 5 of them being grade 3. Only 3 cases had an isolated S768I mutation, 4 cases had a concurrent G719S mutation and 2 cases had a concurrent L858R mutation. The tumor responses of patients with stage IV disease are shown in the table. One patient with a concurrent S768I and L858R mutation with stage IIIa disease received curative intent lobectomy after neoadjuvant treatment with erlotinib. Erlotinib was discontinued in one case due to fatigue. Table: Response of S768I mutations to erlotinib by RECIST 1.1Mutation(s) Best response on erlotinib PFS (months) Overall survival (months) S768I alone Progressive disease 3 5 S768I + G719 Partial response 6 23 S768I + G719S Stable disease 12 33 S768I + L858R Stable disease 30 51+
Conclusion:
S768I mutations in exon 20 of the EGFR are rare and are commonly seen in conjunction with common EGFR mutations. Due to its rarity and the variability of responses of treated cases, its exact prognostic and predictive role is not fully understood. Better understanding of its function and sensitivity to newer TKIs will allow for better management of patients with this mutation.
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MINI13.15 - Discussant for MINI13.11, MINI13.12, MINI13.13, MINI13.14 (ID 3340)
12:05 - 12:15 | Author(s): L. Sholl
- Abstract
- Presentation
Abstract not provided
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Author of
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MS 07 - SCLC Biology & Models (ID 25)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:D. Carney, C.M. Rudin
- Coordinates: 9/07/2015, 14:15 - 15:45, Mile High Ballroom 4a-4f
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MS07.03 - Pre-Clinical Mouse Models of SCLC to Identify and Validate New Therapeutic Targets (ID 1874)
14:50 - 15:05 | Author(s): R.K. Thomas
- Abstract
- Presentation
Abstract:
Small cell lung cancer (SCLC) is a neuroendocrine subtype of lung cancer characterized by a fast growth rate, extensive dissemination, and rapid resistance to chemotherapy. Survival rates are dismal and have not significantly improved in the past few decades. The group of Roman Thomas and Martin Peifer sequenced the genomes of over 100 human SCLC, which demonstrates universal inactivation of p53 and RB and identified inactivating mutations in NOTCH family genes in ~25% of tumors. Accordingly, we found that activation of Notch signaling in a pre-clinical SCLC mouse model dramatically reduces the number of tumors and extends the survival of the mutant mice. In addition to suppressing proliferation, active Notch inhibits neuroendocrine gene expression in SCLC cells. Thus, Notch plays a key tumor suppressive role in SCLC and strategies to re-activate Notch in SCLC tumors may be beneficial to patients (George, Lim, et al., in press). At the histological level, SCLC tumor cells are often viewed as homogeneous. These studies and previous studies (e.g. Calbo et al., Cancer Cell, 2011 – Berns lab) have identified several levels of intra-tumor heterogeneity in SCLC, which may contribute significantly to SCLC aggressive nature and resistance to therapy. We will also discuss the existence and the role of several subpopulations of SCLC tumor cells involved in the long-term propagation of this cancer type, the rapid acquisition of chemoresistance, and metastasis. A better understanding of the molecular underpinnings of these cellular heterogeneity may help identify novel therapeutic targets in SCLC.
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ORAL 06 - Next Generation Sequencing and Testing Implications (ID 90)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:G. De Lima Lopes, V. Miller
- Coordinates: 9/07/2015, 10:45 - 12:15, Mile High Ballroom 1a-1f
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ORAL06.01 - Genomic Characterization of Large-Cell Neuroendocrine Lung Tumors (ID 1667)
11:05 - 11:16 | Author(s): R.K. Thomas
- Abstract
Background:
Neuroendocrine lung tumours account for 25% of all lung cancer cases, and they range from low-aggressive pulmonary carcinoids (PCA) to highly malignant small-cell lung cancer (SCLC) and large-cell neuroendocrine lung carcinoma (LCNEC). The last two are strongly associated with heavy smoking and are typically detected at a clinically advanced stage, having a poor survival. Comprehensive genomic analyses in lung neuroendocrine tumours are difficult because of limited availability of tissue. While more effort has been done in the context of SCLC, the detailed molecular features of LCNEC remain largely unknown.
Methods:
We conducted 6.0 SNP array analyses of 60 LCNEC tumours, exome sequencing of 55 tumor-normal pairs, genome sequencing of 11 tumour-normal pairs, transcriptome sequencing of 69 tumours, and expression arrays on 60 tumors. Data analyses were performed using in house developed and published pipelines.
Results:
Analyses of chromosomal gene copy number revealed amplifications of MYCL1, FGFR1, MYC, IRS2 and TTF1. We also observed deletions of CDKN2A and PTPRD. TTF1 amplifications are characteristic of lung adenocarcinoma (AD); CDKN2A deletions are frequent alterations in both AD and squamous-cell lung carcinoma (SQ); FGFR1 amplifications are found in SQ and, less frequently, in SCLC; and MYCL1 and IRS2 amplifications are frequent events in SCLC. Similar to the copy number data, we found patterns of mutations characteristic of other lung cancer subtypes: TP53 was the most frequently mutated gene (75%) followed by RB1 (27%), and inactivation of both TP53 and RB1, which is the hallmark of SCLC, occurred in 20% of the cases. Mutations in STK11 and KEAP1-NFE2L2 (frequently seen in AD and SQ) were found in 23% and 22% of the specimens, respectively. Interestingly, mutations in RB1 and STK11/KEAP1 occurred in a mutually exclusive fashion (p-value=0.016). Despite the heterogeneity observed at the mutation level, analysis of the pattern of expression of LCNEC in comparison with the other lung cancer subtypes (AD, SQ, SCLC, and PCA) points to LCNEC as being an independent entity. An average mutation rate of 10.7 mutations per megabase was detected in LCNEC, which is in line with the rate observed in other lung tumours associated with smoking. We found that, similar to SCLC, the mutation signatures associated with APOBEC family of cytidine deaminases, smoking, and age (based on Alexandrov et al 2013) were the predominant ones in LCNEC. However, the contribution of the individual SCLC and LCNEC samples to these three signatures was quite different, and we are currently exploring it.
Conclusion:
Taking into account somatic copy number and mutation data, we distinguished two well-defined groups of LCNEC: an SCLC-like group, carrying alterations in MYCL1, ISR2, and in both RB1 and TP53; and a group resembling AD and SQ, with alterations in CDKN2A, TTF1, KEAP1-NFE2L2, and STK11. Although these results suggest that LCNEC might be a mix of different lung cancer subtypes, mutation clonality and expression analyses show that they are likely to be a separate entity, sharing molecular characteristics with the other lung cancer subtypes. Their heterogeneity suggests that LCNEC might represent an evolutionary trunk that can branch to SCLC or AD/SQ.
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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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P3.04-037 - Prevalence of NRG1 Fusions in Caucasian NSCLC Patients Determined by Fluorescence in Situ Hybridisation (ID 1553)
09:30 - 09:30 | Author(s): R.K. Thomas
- Abstract
Background:
Fusions of the gene Neuregulin1 (NRG1) have been described to activate PI3K-AKT signaling in NSCLC via NRG1 overexpression and binding to Her2/Neu-Her3. NRG1 fusions were detected in pulmonary mucinous adenocarcinoma of Asian non-smokers lacking other known oncogenic driver mutations. The incidence in such patients has been described to be between 17.6% (6/34) and 44.4% (4/9). NRG1 fusions might be targeted by Her2/Her3-inhibitors and clinical trials are planned. Here we describe for the first time the systematic analysis of NRG1 in Caucasian patients by Fluorescence in situ hybridization (FISH).
Methods:
A ZytoLight®-based FISH assay (ZytoVision, Bremerhaven, Germany) was developed and verified on nine published clinical cases with known NRG1 fusions. A total of 160 Caucasian NSCLC patients were screened. 25 of the cases were mucinous adenocarcinoma lacking a known oncogenic driver mutation as determined by deep-sequencing and FISH tests. 135 cases were pulmonary adenocarcinoma of various subtypes including 35 cases that lacked a driver mutation and 100 cases that were EGFR, ALK and ROS1 wildtype. The smoking-status was not evaluated. Statistics were calculated using R 3.1.0 .
Results:
The NRG1 fusions in the published cases were easily detected by the FISH assay. However, none of the screened cases harbored a NRG1 fusion. The result is significant compared to published reference values of 17.6% (p=0.041) and 44.4% (p<0.001). The theoretical maximum incidence of NRG1 fusions among Caucasian NSCLC patients not stratified by smoking-status was calculated to be <16.6% for mucinous adenocarcinomas lacking driver mutations, <7.5% for adenocarcinoma of all morphological subtypes lacking driver mutations and <3% for EGFR, ALK, ROS1 negative pulmonary adenocarcinoma (95% confidence intervals).
Conclusion:
FISH is a suitable technique to screen for NRG1 fusions in pulmonary adenocarcinoma. Among 160 Caucasian patients including 25 mucinous carcinomas lacking a driver mutation none were NRG1 positive. Thus, the incidence among Caucasian patients appears to be low and should be evaluated in studies of large NSCLC cohorts.
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PLEN 03 - Science Drives Lung Cancer Advances (ID 52)
- Event: WCLC 2015
- Type: Plenary
- Track: Plenary
- Presentations: 1
- Moderators:T. Mitsudomi, T. Mok
- Coordinates: 9/09/2015, 08:15 - 09:45, Plenary Hall (Bellco Theatre)
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PLEN03.02 - Lung Cancer Genomes - Squamous Cell Carcinoma/Small Cell (ID 2044)
08:35 - 08:50 | Author(s): R.K. Thomas
- Abstract
- Presentation
Abstract not provided
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PLEN 04 - Presidential Symposium Including Top 4 Abstracts (ID 86)
- Event: WCLC 2015
- Type: Plenary
- Track: Plenary
- Presentations: 1
- Moderators:T. Mok, F.R. Hirsch
- Coordinates: 9/09/2015, 10:45 - 12:15, Plenary Hall (Bellco Theatre)
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PLEN04.06 - Discussant for PLEN04.05 (ID 3569)
11:41 - 11:49 | Author(s): R.K. Thomas
- Abstract
- Presentation
Abstract not provided
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