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G.R. Simon
Moderator of
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MA17 - Genetic Drivers (ID 409)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Biology/Pathology
- Presentations: 12
- Moderators:M. Satouchi, G.R. Simon
- Coordinates: 12/07/2016, 14:20 - 15:50, Lehar 1-2
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MA17.01 - Microarray Identification of Genetic Drivers of Brain Metastasis in Lung Adenocarcinoma (ID 3962)
14:20 - 14:26 | Author(s): G.A. Woodard, V. Ding, M. Rosenblum, F. Leguay, C.T. Zoon-Besselink, K.D. Jones, T. Lea, M.W. McDermott, I. Kim, D. Jablons
- Abstract
- Presentation
Background:
Brain metastasis in non-small cell lung cancer (NSCLC) develop in 20-40% of all patients and represent a major cause of NSCLC morbidity and mortality. The mechanisms driving metastatic potential across the blood-brain-barrier remain poorly understood.
Methods:
Affymetrix microarray was performed on RNA extracted from 75 pairs of snap-frozen primary lung adenocarcinoma and matched normal lung tissue. Changes in gene expression from the primary lung adenocarcinomas that did not ever metastasize to brain over up to 15 years of follow up were compared to the lung adenocarcinomas that ultimately seeded a brain metastasis. From these 75 patients, tissue from 5 paired snap-frozen brain metastases was also available and gene expression changes between the primary lung adenocarcinomas and matched brain metastases were investigated to identify genes and pathways of interest in the development of brain metastasis. Affymetrix Transcriptome Analysis Console software was used for data analysis and interpretation with fold changes >2.0 and p-value of <0.05 for significance.
Results:
From the 75 patients 20 (27%) ultimately developed a brain metastasis from their primary lung adenocarcinoma and 55 (73%) were followed long term without development of brain metastasis. Microarray identified 71 genes that were differentially expressed in lung adenocarcinomas that later produced brain metastasis. S100 calcium binding protein, RAP1GAP, GPR160, and immunoglobins were among the upregulated genes in primary lung adenocarcinomas that developed brain metastasis. Within the matched sets of brain metastasis, hierarchical clustering showed clear distinction in expression patterns comparing brain metastasis verses normal lung, as well as primary adenocarcinomas verses normal lung. 267 genes were identified to be significantly differentially expressed between paired brain metastasis and primary lung adenocarcinomas. Significant changes in focal adhesion, angiogenesis, matrix metalloproteinase pathways, and immunoglobulins were found in the brain metastasis compared with the paired primary lung tumor.
Conclusion:
This study represents the largest microarray analysis of snap frozen pairs of primary lung adenocarcinoma and brain metastasis to date. S100 calcium binding protein, RAP1GAP, GPR160 genes, immunoglobulins, and focal adhesion, angiogenesis, and matrix metalloproteinase pathways were among the upregulated genes in primary lung adenocarcinomas that developed brain metastasis.
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MA17.02 - Genome-Wide Copy Number and Mutational Analysis in Longitudinal Biopsies of Matched Primary and Metastatic Pulmonary Adenocarcinomas (ID 4702)
14:26 - 14:32 | Author(s): T. Lorber, N. Andor, T. Dietsche, V. Perrina, D. Juskevicius, A. Krause, D. Müller, D. Lardinois, M. Barrett, C. Ruiz, L. Bubendorf
- Abstract
Background:
There are still limited data on the extent of intratumoral heterogeneity of cancer gene mutations and genome-wide copy number aberrations between primary tumors and metastases in non-small cell lung cancers (NSCLC). Deconvolution of the intermixture of tumor and stromal components remains a major challenge for such analysis. To overcome these limitations, we applied a refined nuclei flow sorting approach on matched longitudinal biopsies (primary/metastasis) from pulmonary adenocarcinomas.
Methods:
Multiparameter Ploidy Profiling (MPP) comprises the isolation of nuclei from frozen or formalin-fixed and paraffin embedded (FFPE) tissues, followed by multiparameter flow sorting by DAPI for DNA content (ploidy) and TTF1 as a lineage marker to enrich for tumor cell nuclei. Homogenous TTF1 expression was ascertained by immunohistochemistry. Sorted populations were subjected to genomic profiling by high resolution aCGH and NGS with the Ion Torrent™ Comprehensive Cancer Panel. This approach allows for the detection of genome-wide copy number aberrations and provides all exon-coverage of 409 well-known cancer genes. Sequencing was performed with a mean depth of 965x.
Results:
MPP was successfully applied on 44 frozen or FFPE tissue specimens from 19 patients. Clonally unrelated secondary primaries were found in three patients, defined by the absence of both shared copy number (CN) transition and somatic mutations. The concordance rate between primary tumor and corresponding metastases was 65.2% and reached 85.5% for mutations and copy number amplifications/deletions in the top 12 affected genes (including CDKN2A, KRAS, ATM, KEAP1, EGFR and STK11). The correlation of the allele frequencies between primary tumors and metastases was linear (r=0.87, p<0.001), irrespective of the time interval between the tissue resections. Overall, ploidy was not different between primary tumors and metastases. Additionally, the metastases did not bear a higher burden of private events (CN transitions and somatic mutations) than the primary tumors.
Conclusion:
MPP is a powerful method to increase the precision of downstream analysis due to unprecedented purity of tumor DNA. Our data argue for a high concordance rate of mutations and CN transitions between primary tumors and their corresponding metastases. Intriguingly, the ploidy remains remarkably stable during progression even after long time-periods, which suggests chromosomal stability with a limited degree of macroevolutionary shifts over time and space. Taken together, our data suggest the presence of at least two evolutionary patterns: 1) early/branched and 2) late/linear progression, with a continuum from high to low genetic divergence of the primary tumor and metastases to their most recent common ancestor.
Information from this presentation has been removed upon request of the author.
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- Abstract
- Presentation
Background:
Evidence supports the existence of genomic discrepancy in multiple primary lung cancers (MPLC). This study identified genomic alterations of MPLC by targeted next-generation sequencing (NGS) and assessed whether inter-tumor heterogeneous somatic mutations could be detected in circulating tumor DNA (ctDNA).
Methods:
94 tumor samples originating from 45 clinically considered multiple primary lung cancer patients (including multiple solid tumors and multifocal tumors) were available for genomic alteration analysis (NCT02833467). DNA and RNA were extracted from fresh tumor tissue or formalin-fixed, paraffin-embedded tissue. 143 cancer-related genomic alterations including single nucleotide variations (SNVs), short insertions and deletions (InDels), copy number variations (CNVs) and gene rearrangements were identified by Oncomine Comprehensive Panel (OCP), Ion Torrent techniques. High frequency clinical relevant mutations (EGFR, KRAS, BRAF, PIK3CA) were identified in circulating tumor DNA by droplet digital PCR (ddPCR).
Results:
The median age of the patients was 61 years and 71% were female. 91% patients were stageⅠ. Molecular analysis performed with a good quality. One hundred and thirty-six mutations and twenty four fusions were detected. Alterations were found in 81 of the 94 lesions (86%), involving EGFR (50.0%), TP53(10.6%), KRAS (8.5%), BRAF (4.3%), ERBB2 (4.3%), PIK3CA(2.1%),PTEN(2.1%),ALK (2.1%),ROS1 (1.1%), RET (7.4%), NF2(2.1%), CDKN2A(2.1%), APC(5.3%), ATM(5.3%),etc. Forty-two (93.3%) patients harbored discordant gene distribution between multiple tumors. CNVs were much higher in patients with more than 2 lesions. Forty-eight lesions harbored detectable somatic mutations by ddPCR, in which 30(62.5%) lesions were identified positive in circulating tumor DNA. 76.9% (20/26) solid dominant lesions were positive, which is significantly higher than ground glass opacity(GGO) dominant lesions(45.5%, 10/22, p=0.037). Figure 1
Conclusion:
Targeted NGS by OCP is feasible to detect multiple mutations simultaneously in early stage multiple primary lung cancers. Circulating tumor DNA has the ability to detect discordant somatic mutations and may represent of the overall mutational load and inter-tumor heterogeneity in multiple solid lung tumors.
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MA17.04 - Discussant for MA17.01, MA17.02, MA17.03 (ID 6980)
14:38 - 14:50 | Author(s): J. Tímár
- Abstract
- Presentation
Abstract not provided
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- Abstract
- Presentation
Background:
Morphological and genetic heterogeneity predict prognostics, impede continuous responses to systemic regimens and foster inevitable treatment failure. But how morphological and genetic features evolve in tumorigenesis still remains controversial.
Methods:
Single(n=1112) and multiple(n=91) primary adenocarcinoma patients receiving surgeries with specific prominent subtypes were screened. Six patients with mixed ground glass opacities and maximum cross-sections of primary tumors were randomly selected. Intra-tumoral regions with different subtypes and imaging densities related to relative distributions, were resected for target region sequencing and further molecular evolutionary analyses.
Results:
Clinical data revealed certain preferences of driver gene mutations and discrepant survival benefits. Driver gene heterogeneity was higher in multiple primary lung cancers(51.7%, 15/29) than single ones(1.4%, 1/70). Copy number alterations implied more consistence within the same subtype and tended to be higher in lepidic subtype. Somatic nucleotide variants revealed highest homogeneity between different regions within the same tumor lesion. Sequencing data indicated larger fractions of geographically ubiquitous mutations than pathologically ones, and higher mutation frequencies of shared mutations in the lepidic than acinar subtype. Phylogenetic trees exhibited higher geographically private mutation burdens of lepidic than acinar region in lesions with mixed subtypes; while in lesions with the same subtype, the central region bore higher mutation burdens than in the periphery, implying a linear accumulation of genetic mutations. Functional analyses of private mutations verified that lepidic subtypes promoted intracellular organism and structure development, promoting growth and proliferation. Acinar subtypes lead to metabolic and signaling transduction pathway. Preferences of divergent pathway alterations delineated branched evolutions from low to higher grade subtypes. Figure 1
Conclusion:
We propose a model that the same morphological subtype evolves with a linear accumulation and mixed subtypes in branched evolutionary trajectories with preferences to pathway alterations. Couple with relatively geological distributions of different subtypes, tumor microenvironment might contribute more to genetic instability and thus tumor evolutions.
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MA17.06 - Landscape of Somatic Mutations Involving Lung Cancer Associated Genes in Non-Small Cell Lung Cancer (NSCLC) Patient-Derived Xenografts (ID 6084)
14:56 - 15:02 | Author(s): V. Raghavan, S. Tam, N. Pham, F. Shepherd, M. Li, M.S. Tsao, G. Liu
- Abstract
- Presentation
Background:
Patient-derived tumor xenografts (PDXs) have high fidelity to their histological origins, and maintain the molecular heterogeneity and genetic aberrations of the donor patient tumors more faithfully than established in non-small cell lung cancer (NSCLC) cell lines. This study evaluated whether our panel of PDX models recapitulate known cancer-related gene mutations.
Methods:
Whole-exome sequencing was completed on 103 NSCLC PDX models, 47 adenocarcinoma (AdC) and 56 squamous (SqCC), with a mean coverage of 84x. After filtering for contaminating mouse reads, the exome data were aligned using the Burrows-Wheeler Aligner, processed using the standard GATK pipeline, and mutations were identified using MuTect. Additional filtering using dbSNP, ExAC and ESP was performed for cases without corresponding normal adjacent lung exome data (n = 80). The identified mutations were compared to 1260 frequently mutated cancer-related genes, which were compiled from a panel of cancer-related mutated genes (555) and a panel of lung cancer-specific mutated genes (1082).
Results:
High rates of somatic mutations were observed in both AdC (mean of 12.4 mutations/megabase) and SqCC (mean of 11.7 mutations/megabase) PDX models. Compared to the rates observed in primary lung cancers in The Cancer Genome Atlas studies (mean of 8.9 mutations/megabase in AdC; 8.1 mutations/megabase in SqCC), these values appear higher, but may be inflated due to the lack of data from corresponding normal tissues. AdC models had a total of 953 mutated genes (median: 57 genes/model; range: 5-307), while SqCC models were characterized by 1007 mutated genes (median: 55 genes/model; range: 21-354). Specific mutation frequencies were compared to those determined in a recent study involving genomic alterations in human primary lung AdC and SqCC (Nature Genetics 2016; 48; 607–616). This comparison, based on mutated genes common in both studies, demonstrated significant correlation of the frequencies in 791 genes in AdC (ρ=0.78; p<2.2×10[-16]), as well as in 799 genes in SqCC (ρ=0.73; p<2.2×10[-16]). Three genes that were reported as significantly mutated in both AdC and SqCC primaries, and had higher mutation frequencies in SqCC, were also observed to be higher in our SqCC PDX models (TP53: 48.9% in AdC vs. 55.4% in SqCC; CDKN2A: 4.3% vs. 7.1% and PIK3CA: 2.1% vs. 23.2%); however, the statistical significance of these differences needs to be tested.
Conclusion:
Mutation landscapes in cancer genes are recapitulated in AdC and SqCC PDX models. The fidelity of these landscapes in matched patient primary tumour samples is being investigated.
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MA17.07 - Circulating Tumor DNA Detects Minimal Residual Disease and Predicts Outcome in Localized Lung Cancer (ID 5388)
15:02 - 15:08 | Author(s): A. Chaudhuri, A. Lovejoy, J. Chabon, A. Newman, H. Stehr, C. Say, J. Carter, L. Zhou, R. West, J.B. Shrager, J.W. Neal, H. Wakelee, B. Loo, A. Alizadeh, M. Diehn
- Abstract
Background:
CT imaging is standard-of-care for surveillance following definitive lung cancer therapy but is complicated by difficulties in distinguishing recurrence from treatment-related fibrosis and inability to detect microscopic disease. CAPP-Seq is a novel blood-based assay that uses next-generating sequencing to quantitate circulating tumor DNA (ctDNA). We performed a prospective study to compare disease surveillance by CAPP-Seq to CT imaging after definitive treatment for localized lung cancer.
Methods:
We prospectively enrolled 34 patients treated definitively for non-metastatic primary lung cancer at Stanford University between June 2010 and September 2015. Our cohort included 22 (64.7%) patients with stage III, 6 (17.6%) patients with stage II and 6 (17.6%) patients with stage I disease. All patients received pre-treatment evaluation by thoracic CT and PET/CT scans as well as ctDNA quantitation by CAPP-Seq. Twenty-one (61.8%) patients were treated with conventionally fractionated radiotherapy, 8 (23.5%) with hypofractionated radiotherapy, 3 (8.8%) with surgery, and 2 (5.9%) with both surgery and radiotherapy. Twenty-five (73.5%) patients received platinum-based doublet chemotherapy. Following treatment completion, patients underwent disease surveillance by CT scans and CAPP-Seq every 3-6 months. CT scans were evaluated using RECIST v1.1. CAPP-Seq was performed at each time point as previously described (Newman et al, Nature Medicine 2015 and Nature Biotechnology 2016).
Results:
A total of 222 scans and 107 plasma samples were analyzed. Median follow-up time was 21.1 months and median overall survival was 30.0 months. Eighteen (52.9%) patients progressed based on RECIST criteria and CAPP-Seq detected ctDNA at or before the time of RECIST progression in all patients (18 of 18; 100%) with a lead-time of 121 +/- 39 days (mean +/- SEM). For 13 of 16 (81.3%) evaluable patients who progressed, ctDNA was detected at the first time-point after completion of all treatment (median 2 months post treatment), indicating detection of minimal residual disease. Two-year overall survival for patients with detectable post-treatment ctDNA was 25.3% versus 92.9% for those with no detectable post-treatment ctDNA (p=0.0003, HR=6.8, 95% CI=2.6-17.9). This difference remained significant in multivariate models controlling for stage, age, sex, and tumor volume (P=0.01).
Conclusion:
We found that noninvasive ctDNA profiling appears to be useful for evaluating response to lung cancer treatment. Quantitation of ctDNA allowed identification of minimal residual disease, which was strongly associated with outcome. These results suggest that ctDNA assessment after definitive intent treatment could potentially be used to guide risk-adapted treatment strategies for localized lung cancer.
Information from this presentation has been removed upon request of the author.
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MA17.08 - Discussant for MA17.05, MA17.06, MA17.07 (ID 7049)
15:08 - 15:20 | Author(s): L. Müllauer
- Abstract
- Presentation
Abstract not provided
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MA17.09 - Premature Fibroblast Senescence in Large Cell Carcinoma Provides Enhanced Growth and Invasive Advantages to Cancer Cells in Culture and in vivo (ID 5352)
15:20 - 15:26 | Author(s): R. Lugo, M. Gabasa, F. Andriani, M. Puig, F. Facchinetti, J. Ramírez, A. Gómez-Caro, P. Gascón, A. Davalos, N. Reguart, L. Roz, J. Alcaraz
- Abstract
- Presentation
Background:
Tumor-associated fibroblasts (TAFs) are increasingly regarded as essential co-conspirators for tumor progression in all solid tumors including non-small cell lung cancer. While most TAFs exhibit activation markers indicative of a myofibroblast-like phenotype, senescence markers have been reported in a growing list of selected cancer types only. However, the presence of senescent TAFs in lung cancer remains undefined. Assessing senescence in lung TAFs is important because previous studies have reported that senescent TAFs enhances tumor growth, which is in marked contrast with the widely accepted tumor-suppressive role of senescence in cancer cells.
Methods:
We examined common senescence markers in patient derived lung TAFs from the 3 major non-small cell lung cancer (NSCLC) subtypes: adenocarcinoma (ADC), squamous cell carcinoma (SCC) and large cell carcinoma (LCC). Given the difficulties in gathering LCC-TAFs owing to the lower prevalence of LCC compared to the other subtypes, primary fibroblasts from 2 independent fibroblast collections were used. Senescence markers included senescence-associated beta-galactosidase, permanent growth arrest and spreading.
Results:
We found an enrichment of the myofibroblast-like phenotype in TAFs regardless their histologic subtype, yet senescence was observed in LCC-TAFs only regardless their neuroendocrine status. Likewise, co-culturing normal lung fibroblasts with LCC (but not ADC or SCC) cancer cells was sufficient to induce senescence, and this induction was prevented in the presence of an antioxidant, indicating that it is mediated through oxidative stress. Remarkably, senescent fibroblasts provided growth and invasive advantages to LCC cells in culture and in vivo beyond those effects provided by control (non-senescent) fibroblasts.
Conclusion:
Our findings expand recent evidence that challenges the common assumption that lung TAFs are a heterogeneous myofibroblast-like cell population regardless their histologic subtype. Of note, because LCC often distinguishes itself in the clinic by its aggressive nature, our findings support that senescent or senescent-like TAFs may contribute to the selective aggressive behavior of LCC tumors.
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MA17.10 - YES1 Kinase is a New Therapeutic Target in Non-small Cell Lung Cancer (ID 7159)
15:26 - 15:32 | Author(s): J. Agorreta, I. Garmendia, M.J. Pajares, D. Ajona, D. Alameda, C. Behrens, I. Wistuba, R. Pio, L.M. Montuenga
- Abstract
- Presentation
Background:
Next-generation sequencing techniques have allowed the discovery of driver mutations in non-small cell lung cancer (NSCLC) that can be translated into advances in cancer diagnosis and treatment. However, specific oncogenic alterations are still unknown in a high proportion of NSCLC patients, that therefore cannot benefit from targeted therapies. The challenge is to identify new genetic alterations that allow the use of molecular-targeted therapies. In previous studies from our group (Aramburu et al. BMC Genomics 2015), the analysis of tumor molecular profiles from patients with NSCLC allowed us to identify the DNA copy number amplification of YES1 kinase (v-YES-1 Yamaguchi sarcoma viral oncogene homolog 1) as a prognostic marker in lung cancer. YES1 kinase is member of the Src family of non-receptor protein tyrosine kinases that are involved in the regulation of cell growth, apoptosis, cell-cell adhesion, cytoskeleton remodeling, and differentiation. The aim of this project is to evaluate if YES1 is a driver gene in NSCLC, and if targeting its activation may be a potential new therapeutic strategy.
Methods:
We first evaluated the prognostic role of YES1 protein expression in two independent series of 76 and 234 NSCLC patients, respectively. In both series, the multivariate analysis revealed that high YES1 expression is an independent poor prognostic factor for overall survival (CUN series HR: 3.416 [0.933-12.508]; MD Anderson series HR: 1.570 [1.032-2.391]). We next evaluated the effect of YES1 knockdown in 5 NSCLC cell lines with YES1 amplification and overexpression, and in 3 cell lines without YES1 amplification and with low protein expression. YES1 downregulation by two specific siRNAs decreased proliferation and cell survival only in those cells overexpressing YES1. Congruently, YES1 inhibition led to apoptosis only in those cells.
Results:
Consistent with these results, constitutive overexpression of YES1 in cells with low YES1 expression significantly enhanced cell proliferation. We next evaluated the effect of the multitarget Src kinase inhibitor dasatinib on the proliferation of NSCLC cell lines with high (8 cell lines) or low (4 cell lines) YES1 expression. Dasatinib dramatically inhibited proliferation in high YES1-expressing cell lines, whereas low YES1 cell lines were more resistant to dasatinib treatment (GI50s were four orders of magnitude higher in resistant cells).
Conclusion:
In conclusion, our results indicate that YES1 is a promising therapeutic target in NSCLC. Furthermore, amplification and high expression of YES1 may define a subset of patients who may potentially benefit from dasatinib treatment.
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- Abstract
- Presentation
Background:
Akt2 (Protein Kinase B isoform 2) is an essential protein, which is involved in tumor cell proliferation, differentiation, motility, and cell death in non small cell lung cancer (NSCLC). Raf1 is also a key protein regulating the functions in NSCLC. However, the relationships between Akt2 and Raf1 are unknown. This study aimed to investigate the influence of Akt2 knockdown and its interaction with overexpression Raf-1 in non-small cell lung cancer cells.
Methods:
Small interfering RNA was used to knockdown Akt2 and lentivirus was introduced to overexpress Raf1 in H1299, A549, Sk-mes and H460 cell lines. Western blot was performed to investigate expression levels of relevant proteins in the pathway. Cell survival, proliferation and apoptosis were evaluated in vitro and vivo. Then we examined Akt2 and Raf1 expressions via immunohistochemistry (IHC) in 65 NSCLC patients.
Results:
Knockdown of Akt2 suppressed cell proliferation, arrested tumor cells in G0/G1 phase and induced apoptosis in all cell lines distinctively. Raf1 phosphorylation was also inhibited after Akt2 knockdown in the cell lines. When Raf1 overexpression combined with Akt2 knockdown in these cell lines, cell proliferation was enhanced, and apoptosis rates was decrease compared with Akt2 knockdown alone. These trends were also observed in vivo experiments. Furthermore, the downstream proteins of Raf1, such as MEK, ERK, p-MEK and p-ERK were observed decrease in Akt2 knockdown groups. Of all NSCLC specimens, Akt2(+)/Raf1(+) patients had the worst prognosis of 5-year overall survivals. Figure 1
Conclusion:
Our study demonstrates that knockdown of Akt2 suppresses tumorigenesis by attenuating cell proliferation, increasing apoptosis and interfering cell cycle in non-small cell lung cancer. Raf1 overexpression partly offsets these effects by enhancing cell proliferation, suppressing apoptosis and affecting downstream proteins. Thus, there may be existing Akt2/Raf1 pathway in NSCLC, which plays an important role in tumorigenesis.
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MA17.12 - Discussant for MA17.09, MA17.10, MA17.11 (ID 7045)
15:38 - 15:50 | Author(s): S. Dacic
- Abstract
- Presentation
Abstract not provided
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Author of
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MA14 - Immunotherapy in Advanced NSCLC: Biomarkers and Costs (ID 394)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:M. Reck, D.R. Spigel
- Coordinates: 12/06/2016, 16:00 - 17:30, Strauss 2
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MA14.12 - Discussant for MA14.09, MA14.10, MA14.11 (ID 6944)
17:18 - 17:30 | Author(s): G.R. Simon
- Abstract
- Presentation
Abstract not provided
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OA23 - EGFR Targeted Therapies in Advanced NSCLC (ID 410)
- Event: WCLC 2016
- Type: Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:O.T. Brustugun, S. Lu
- Coordinates: 12/07/2016, 14:20 - 15:50, Stolz 2
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OA23.07 - Analysis of Outcomes in US IRESSA Clinical Access Program (ICAP) Patients on Gefitinib for More Than 10 Years (ID 3731)
15:25 - 15:35 | Author(s): G.R. Simon
- Abstract
- Presentation
Background:
In 2011, following gefitinib (IRESSA[®]) NDA voluntary withdrawal, US patients benefiting from gefitinib were eligible to continue gefitinib through the IRESSA Clinical Access Program (ICAP), an IRB-approved protocol. A subset of ICAP investigators subsequently collected additional retrospective data on their ICAP patients through another IRB-approved project (“chart-review subset”).
Methods:
For all enrolled ICAP patients, demographic and serious adverse event (SAE) reports were reviewed. All ICAP investigators were invited to participate in chart review; 47 accepted and collected data on patient/tumor characteristics and safety/tolerability of prolonged gefitinib therapy among their 79 ICAP patients.
Results:
Across 137 US sites, 191 patients enrolled in ICAP. As of September 2016, 75 (39%) remain on gefitinib; discontinuations were due to progression (36%), death (34%), AEs (13%), or other (17%). Sixty-four (34%) patients reported 162 SAEs; 5 (2.6%) patients had 12 SAEs considered to be gefitinib-related by investigators. The chart-review subset included 79 (41%) patients with median age of 69 years at ICAP enrollment, who were predominantly female (70%) and white (84%); 95% had a confirmed NSCLC diagnosis. Due to the evolving understanding of genetic mutations in NSCLC at the time of gefitinib initiation, the majority of patients (79%) never had EGFR sequencing performed. Although tissue is not available for EGFR status confirmation, we assume these patients are nearly exclusively EGFR mutation-positive. Median total length of gefitinib was 11.1 years (6.5-15.1; Table). Long-term gefitinib was well-tolerated; 5% discontinued due to a gefitinib-related AE. Ten-year survival rate from first-ever initiation of gefitinib was 86% and 15-year was 59%. Table. Gefitinib treatment patterns and tolerability among ICAP chart-review patients.Parameter n, % Observed Population (N=79) Total time on gefitinib, prior to and during ICAP Median duration, y, range 11.1 (6.5-15.1) Prior to ICAP Median duration, y, range 7.8 (5.4-10.9) Starting dose 250 mg/day 67 (84.8) No dose changes due to AEs 75 (94.9) During ICAP Median duration, y, range 3.5 (0.04-4.7) Dose: 250 mg/day 76 (96.2) Treatment-related AEs Grade 1-2 Grade ≥3 Grade unknown 13 (16.5) 1 (1.3) 2 (2.5) Dose reductions due to treatment-related AEs 1 (1.3) Discontinuations due to treatment-related AEs 4 (5.1) Discontinuations due to progressive disease 11 (28.9)
Conclusion:
The majority of this subset of patients who participated in ICAP based on long-term clinical benefit from gefitinib continue to do well with gefitinib, demonstrating good tolerance of therapy and survival for a median duration of more than 10 years.
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P2.03b - Poster Session with Presenters Present (ID 465)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03b-030 - Retrospective Review Clinical Use of a cfDNA Blood Test for Identification of Targetable Molecular Alterations in Patients with Lung Cancer (ID 5969)
14:30 - 14:30 | Author(s): G.R. Simon
- Abstract
Background:
The availability of tumor genomic information from simple, minimally invasive blood collection may lead to significant impact in patient(pt) care. We report a retrospective review the clinical utility of a CLIA-certified cell-free DNA (cfDNA) next generation sequencing (NGS) blood test in our pts with lung cancers.
Methods:
From April 2015 to May 2016, blood samples from 250 consecutive pts were collected and sent for molecular profiling at a CLIA-certified lab (Guardant360, Guardant Health, Redwood City, CA) using cfDNA NGS with a panel of 70 cancer-related genes with reported high sensitivity (able to detect mutations of < 0.1% mutant allele fraction) with high specificity (> 99.9999%) (PLoS One, 10(10), 2015).
Results:
254 Guardant360 tests were completed in 250 pts (144/F:106/M); histology: adenocarcinoma(200), squamous(7), sarcomatoid(5), small cell(4) and others(34). Rationale for blood tests: addition to tissue analysis(39%), alternative to tissue biopsy(25%), treatment evaluation/resistant(18%), insufficient tissue(11%), no documentation(7%). Based on Guardant360 results, 77 pt samples (30.3%) demonstrated targetable alterations with FDA-approved agents; concordance with at least 1 genomic alteration (targetable with FDA-approved agent) from paired tissue analysis in 21pts; and in another 29 pts, new genomic alterations provided evaluation for potential change in therapies pts: EGFR T790M(n=21), EML4-ALK fusion(n=4), MET Exon 14 Skipping (3), EGFR ex19del(n=2), EGFR L858R(n=2), other targets(n=6). Significantly, detection of EGFR T790M in cfDNA lead to change in therapy with osimertinib 19 cases and eligibility to clinical studies in 2 cases with alterations in KIF5B-RET and NOTCH1,respectively. Additional clinical outcomes are pending and will be updated.
Conclusion:
Molecular testing of cfDNA is a simple, minimally invasive test. It has utility to obviate a repeat invasive tissue biopsy when the initial tissue sample is not available or inadequate for molecular analysis. It is particularly useful in the long-term management of patients at progression for detection of emergent resistance-associated molecular alterations; such as EGFR T790M.
