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Gen Lin
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P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 2
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.01-105 - Lung Cancer Patients with Concurrent EGFR and MET Mutations: A Retrospective Analysis of 29 Cases (ID 12864)
16:45 - 18:00 | Author(s): Gen Lin
- Abstract
Background
It has been reported that about 5%-20% of EGFR-TKIs resistant NSCLC patients harbors MET amplification or activating mutations. However, the extent that MET abnormal activation contributes to EGFR-TKIs resistance remains widely unknown. Here, we describe the clinical and genetic characteristics of 29 lung cancer patients harboring concurrent EGFR and MET mutations.
a9ded1e5ce5d75814730bb4caaf49419 Method
Genetic mutations were reviewed in 6000 lung cancer patients who underwent genetic testing at our institute from 2016 to 2018. Mutation profiles were analyzed using hybridization capture based next-generation sequencing (NGS), which enables the simultaneous detection of single-nucleotide variants, insertions/deletions, rearrangements, and copy-number alterations of at least 59 genes (range 59 – 1021 genes).
4c3880bb027f159e801041b1021e88e8 Result
The selected patients included 24 lung adenocarcinoma patients, 1 squamous cell lung cancer patient and 3 lung cancer patients with unspecified pathology. Both MET amplification and activating mutations were included for analysis. MET amplification was detected in 90% (27/30) of samples, while activating mutations was present in 13.3% (4/30) of samples, including H1112Y, D1228N, D1246Y and D1246H. 14% (4/29) of patients had not received EGFR-TKIs treatment before genetic testing, which were considered as primary resistance. 79% (23/29) of patients were treated with EGFR-TKIs. Surprisingly, 60% (18/30) of cases had other functional mutations which may also affect the effectiveness of EGFR-TKIs, such as EGFR T790M mutation (3 cases), rare EGFR mutations (I744M, R108K and C769S, 3 cases), EGFR amplification (7 cases), CDK4 amplification (2 cases), loss-of-function mutations of CDKN2A (2 cases) and so on. One patient had two samples tested. He was resistant to gefitinib and osimertinib, and EGFR L858R mutation and MET amplification were detected in the first sample. Later, he was treated with combined gefitinib and crizotinib and reached PR at the 2nd month. However, his disease finally progressed probably due to an additional MET mutation (D1246Y) that caused resistance to crizotinib.
8eea62084ca7e541d918e823422bd82e Conclusion
MET amplification and activating mutations may lead to primary and acquired resistance of EGFR-TKIs. Moreover, additional potentially resistant mechanisms were detected in most cases. Therefore, it is apparently requisite to provide a comprehensive genetic testing to lung cancer patients.
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P1.01-56 - Concurrent Mutations in Chinese Lung Cancer Patients Carrying HER2 Genomic Aberrations (ID 13756)
16:45 - 18:00 | Author(s): Gen Lin
- Abstract
Background
Although human epidermal growth factor receptor 2 (HER2, ERBB2) genomic aberration has been identified as therapeutic targets, clinical trials of HER2-directed therapies have disappointing results in lung cancer. We hypothesize that the concurrent alterations might be one of the reasons, thus the aim of this study was to describe frequent concurrent alterations in Chinese lung cancer patients harboring HER2 mutations.
a9ded1e5ce5d75814730bb4caaf49419 Method
A total of 147 cancer patients with HER2 mutations were enrolled in the study. Tumor biopsy, ctDNA and pleural effusion samples were collected for detection alterations using hybridization capture based next-generation sequencing (NGS), which enables the simultaneous detection of single-nucleotide variants, insertions/deletions, rearrangements, and copy-number alterations of at least 59 genes (59-1021).
4c3880bb027f159e801041b1021e88e8 Result
Sixty-two of 147 patients with HER2 genomic aberrations were diagnosed as lung cancer. The HER2 gene was amplified in 11 (18%) patients, whereas HER2 mutations were detected in 48 patients, co-occurrence of HER2 amplification and mutations were in 3 patients. Thirty of the 62 patients (48.39%) had concurrent actionable mutations across 18 genes, which involved in RTK-PIK3CA-mTOR signaling pathways, cell-cycle pathway, DNA repair pathway, RAS-RAF-MAPK pathway and some others (details in table). Moreover, 7 patients had more than 2 concurrent mutations besides HER2 mutation/amplification.
Table 1. concurrent genetic alterations in HER2-altered lung cancer patients
Signaling pathway Concurrent
actionable
mutations
Number of
patients
RTK-PIK3CA-mTOR
EGFR 11 PIK3CA 4 STK11 2 FBXW7 1 TSC1 1 FLCN 1 C11orf30 1 Cell-cycle CDKN2A 5 CCND1 2 RB1 1 DNA repair BRCA2 1 ATM 1 RAS-RAF-MAPK BRAF 1 KRAS 1 Others MDM2 2 JAK2 2 SMARCA4 2 PTCH1 1
8eea62084ca7e541d918e823422bd82e Conclusion
Concurrent of actionable genetic alterations in HER2-altered Chinese lung cancer patients was common. The complex molecular profiles elucidate the importance of comprehensive analysis of genetic mutations when considering anti-HER2 targeted therapy.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.13-08 - Distribution, Differences in Clinical Characteristics and Resistance Mechanism of ALK Variants in Chinese Lung Cancer Patients. (ID 13678)
16:45 - 18:00 | Author(s): Gen Lin
- Abstract
Background
ALK rearrangements are established targetable drivers in NSCLC. Recent reports indicate differential progression-free survival to ALK inhibitors according to specific EML4-ALK variant.
a9ded1e5ce5d75814730bb4caaf49419 Method
A total of 172 unique Chinese lung cancer patients with tumors harboring ALK rearrangements (ALK+) were enrolled in the study from 2016 to 2018. ALK+ were detected by Ventana, FISH, or next-generation sequencing based ER-Seq method, which enables simultaneously assess single-nucleotide variants, insertions/deletions, rearrangements, and somatic copy-number alterations across at least 59 genes (59-1021). Tissue biopsy was the first choice for NGS mutation profiling, and ctDNA or pleural effusion testing was used as an alternative.
4c3880bb027f159e801041b1021e88e8 Result
Of these 172 cases, the median diagnosis age was 50 (range 24-78), 58% were female, 90% was NSCLC. Of the 147 ALK+ cases detected by NGS, we identified 65 (44%) EML4-ALK v1 (E13; A20), 18 (12%) EML4-ALK v2 (E20; A20), 43 (29%) EML4-ALK v3 (E6; A20), 13 (9%) other EML4-ALK, and 8 (5%) non-EML4-ALK rearrangements. 2 new fusion genes were found in non EML4-ALK rearrangements (SRBD1-ALK (EX20; EX20) and CLIP4-ALK (EX9; EX20)), and the CLIP4-ALK patient’s tissue was also ALK positive by Ventana. V1 found a higher proportion of pleural effusion at baseline than non-v1 (12% v.s.5%). Mutation profiling by NGS were performed after disease progression in 55 patients treated with crizotinib. mPFS was 8.1 months, no significant difference existed between v1 and v3 (P=0.69). But the presence of known ALK resistance mechanisms was significantly higher in v3 as compared to non-v3 (67% v.s. 27%, P=0.038).
8eea62084ca7e541d918e823422bd82e Conclusion
Next generation sequencing allows for detection of the specific ALK fusion partner and variants, increases the understanding of the biology of ALK+ NSCLC, and may have value to foretell potential mechanisms of resistance.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P2.01 - Advanced NSCLC (Not CME Accredited Session) (ID 950)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 2
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.01-100 - Different Genetic Mutations Enriched in Circulating Tumor DNA Predict Different Metastatic Sites in Lung Adenocarcinoma Patients (ID 13636)
16:45 - 18:00 | Author(s): Gen Lin
- Abstract
Background
The mutation map of the lung adenocarcinoma is clear. However, differences of genetic mutations related to metastatic sites have not been addressed before and remain to be explored. Identification of mutation signature may help to predict metastasis.
a9ded1e5ce5d75814730bb4caaf49419 Method
We reviewed 353 ctDNA samples from lung adenocarcinoma patients with definite metastasis at our institute. Somatic mutation profiles were analyzed using hybridization capture based next-generation sequencing (NGS), which enables the simultaneous detection of single-nucleotide variants, insertions/deletions, rearrangements, and copy-number alterations of 59 genes.
4c3880bb027f159e801041b1021e88e8 Result
All the samples were divided into 2 groups based on the distance of the metastases: 165 samples was in the distal metastasis group including bone or liver metastases; 188 samples was in the proximal group, including lung, pleural or thoracic lymph node metastasis. The gene mutation number of the distal metastasis is higher than the proximal metastasis (4.92 vs 3.85, P=0.031). Gene mutations for each group are shown in the figure below. Similar to the genetic profiling of lung adenocarcinoma in COMIC database, the most frequently mutated genes were EGFR and TP53 in two groups. But the frequency mutation of NTRK1 in proximal metastasis group is three times more than that of the distal metastasis group (11/188, 5.9% vs 3/165,1.8%). And the frequency of ALK mutation in the distal metastasis group is two times more than that of the proximal metastasis group (10/165, 6.1% vs 6/188, 3.2%). Moreover, for the top 9 frequently mutant genes, there was 78% overlap in the two groups. However, the overlap with COSMIC database was 55% for distal metastasis group and 44% for the proximal metastasis.
8eea62084ca7e541d918e823422bd82e ConclusionDistant metastasis group
Proximal metastasis group
COSMIC database
gene
Mutation frequency
gene
Mutation frequency
gene
Mutation frequency
1
EGFR
70.30%
EGFR
73.94%
EGFR
31%
2
TP53
60.61%
TP53
61.17%
TP53
31%
3
KRAS
11.52%
ERBB2
9.04%
KRAS
18%
4
RB1
10.30%
KRAS
9.04%
STK11
8%
5
NF1
9.70%
RB1
7.45%
CDKN2A
7%
6
ERBB2
7.88%
NF1
7.40%
SMARCA4
6%
7
APC
6.67%
APC
6.91%
NF1
6%
8
ALK
6.06%
PIK3CA
6.38%
ATM
5%
9
ATM
6.06%
RET
5.85%
KDR
5%
10
PIK3CA
6.06%
NTRK1
5.85%
Lung adenocarcinoma patients with ALK mutation are more likely to have distant metastasis. While the patients with NTRK1 mutation are more likely to have proximal metastasis.
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P2.01-117 - Concurrent Gene Alterations in Treatment-Naïve EGFR-Mutant Advanced Non-Small Cell Lung Cancer (ID 13102)
16:45 - 18:00 | Author(s): Gen Lin
- Abstract
Background
EGFR-TKIs is the standard first line treatment for EGFR-mutant advanced non-small-cell lung cancer (NSCLC). However, 20% to 30% of patients who receive EGFR-TKIs exhibit primary resistance. The gene alterations in treatment-naïve EGFR-mutant advanced NSCLC should be better explored.
a9ded1e5ce5d75814730bb4caaf49419 Method
We retrospectively reviewed gene test results of 980 treatment-naïve advanced NSCLC samples in our institute. Tumor biopsy, ctDNA, pleural effusion or cerebrospinal fluid samples were analyzed using hybridization capture-based NGS ER-seq method, white blood cells as control, which enables simultaneously assess single-nucleotide variants (SNV), insertions/deletions (indel), rearrangements and somatic copy-number(CNV) variation at least 59 genes (range 59-1021 genes).
4c3880bb027f159e801041b1021e88e8 Result
Three hundreds and eighty one cases with EGFR sensitive mutation were identified, 358 adenocarcinoma, 7 squamous cell carcinoma, 1 adenosquamous carcinoma and 15 NSCLC. Among the patients, 88 patients (23.1%) harbored concurrent actionable mutations with EGFR, which 43 were exon 19 deletion, 37 were L858R and 8 were uncommon EGFR mutations. One patient had co-occurring L858R, T790M and CDKN2A frameshift mutation. The actionable mutations were from 23 genes, which involved in cellular signaling pathways, and some genes had been reported associated with EGFR-TKIs resistance (details in table). Except the actionable mutations, TP53 mutations were detected in 225 samples (59.1%, 225/381), which 35.1% (79/225) in exon8. Bcl-2–like 11(BIM) deletion were detected in 31 (8.1%, 31/381) white blood cells.
Signaling Pathways
Concurrent gene alterations
Frequency(N=88)
Cell cycle*
CDKN2A
3.9%
CDK4
2.1%
CCNE1
0.8%
CCND1
0.8%
CCND3
0.3%
PI3K/AKT/mTOR*
PIK3CA
2.9%
PTEN
1.3%
TSC1/2
1.0%
AKT2
0.3%
NF1
0.3%
RTKs*
MET
0.8%
HER2
0.8%
FGFR2
0.3%
FGFR3-TACC3
0.3%
Ras/Raf/MAPK*
KRAS
0.8%
Homologous Recombination Repair pathway
BRCA2(sc+gm)
0.8%
BRCA1(sc)
0.5%
ATM
0.5%
PALB2
0.3%
Others
CTNNB1
2.9%
MDM2
2.4%
SMARCA4
0.8%
JAK2
0.5%
sc, somatic mutation;
gm, germline mutation;
*, genes had been reported associated with EGFR-TKIs resistance
8eea62084ca7e541d918e823422bd82e Conclusion
Concurrent gene alterations in treatment-naïve EGFR-mutant advanced NSCLC is common, and mutiple genes are involved. This maybe contribute to the primary resistance to EGFR-TKIs in EGFR-mutant advanced NSCLC. Indicate the importance of multiplex molecular test and further researches of target therapies.
6f8b794f3246b0c1e1780bb4d4d5dc53
