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X. Zhang
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OA 10 - Liquid Biopsy for Genomic Alterations (ID 678)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Adrian G. Sacher, Pasi A Jänne
- Coordinates: 10/18/2017, 11:00 - 12:30, F201 + F202 (Annex Hall)
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OA 10.02 - Unique Genetic Profiles from Circulating Cell-Free DNA of Cerebrospinal Fluid in Leptomeningeal Metastases of EGFR Mutant NSCLC (ID 8258)
11:00 - 12:30 | Author(s): X. Zhang
- Abstract
- Presentation
Background:
Leptomeningeal metastases (LM) are more frequent in non-small cell lung cancer (NSCLC) with EGFR mutations. Resistance mechanisms of LM remained unclear due to limited access to leptomeningeal lesions.
Method:
Primary tumor, cerebrospinal fluid (CSF) and plasma in patients with suspected LM of NSCLC were tested by Next-Generation Sequencing with 168 genes panel. Thirty patients diagnosed as LM and harboring EGFR mutation were enrolled in this cohort, and CSF cfDNA and plasma of two patients and CSF precipitates of another two patients were not available
Result:
Driver genes were detected in 100% (28/28) , 85.7% (24/28) and 75% (21/28) patients of CSF cfDNA, CSF precipitates and plasma, respectively; and 92.9% (26/28) patients had much higher allele fractions in CSF cfDNA than the other two media. Unique genetic profiles were captured in CSF cfDNA when compared with those in plasma and primary tissue. Multiple copy number variations (CNVs) were privately detected in CSF cfDNA, and CNVs in patients after TKI failure were more complicated when compared to those TKI naïve before LM. MET copy number gain identified in 44.0% (11/25) patients was the most frequent one, other CNVs included ERBB2, KRAS, ALK, MYC and FGFR1. Moreover, loss of heterozygosity (LOH) of TP53 was identified in 67.9% (19/28) CSF cfDNA, which was much higher than that in plasma (2/28, 7.1%; p<0.001), and there was a trend towards higher rate of concomitant resistance mutations in patients with TP53 LOH than those without one (70.6% vs. 25%; p=0.036 ). EGFR T790M was identified in 28% (7/25) patients with progression to TKIs in CSF cfDNA.
Conclusion:
CSF cfDNA could reveal the unique genetic profiles of LM, and it should be the most representative medium of liquid biopsy for LM in NSCLC harboring EGFR mutations.
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P1.01 - Advanced NSCLC (ID 757)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.01-009 - Clinically Primary and Secondary Resistance to ALK Inhibitors in ALK-Positive Advanced Non-Small-Cell Lung Cancer (ID 8739)
09:30 - 16:00 | Author(s): X. Zhang
- Abstract
Background:
Crizotinib is a standard of care in anaplastic lymphoma kinase(ALK)-positive advanced non-small-cell lung cancers (NSCLC).Undoubtedly,the resistance to crizotinib is a current bottleneck.Hence,it is necessary to explore the resistance mechanisms to ALK inhibitors.
Method:
From October 2010 to May 2017,225 ALK-positive NSCLC patients treated with crizotinib were reviewed at the Guangdong General Hospital in China.The status of ALK rearrangement was assessed by Lysis ALK Break Apart fluorescence in situ hybridization,reverse transcription polymerase chain reaction,or Ventana ALK immunohistochemistry.Next generation sequencing(NGS) was used to test the tissue or plasma from patients with resistance to crizotinib.Primary resistance to crizotinib occurred when Progression-free survival was less than 3 months for the patients treated with crizotinib.
Result:
Among enrolled patients,72.4%(163/225) gained secondary resistance,and 8.9%(20/225) had primary resistance.Molecular mechanisms of clinically primary resistance were shown in Figure a.The variants of ALK fusion were different between primary and secondary resistance patients.There were more variants of ALK fusion appeared in the group with primary resistance except E6-A20 and E13-A20.Among secondary resistant patients，non-EML4 partners fusion,such as DMD-ALK fusion,YWHAQ&TAF1B-ALK fusion,GALNT14-ALK fusion and SLC19A3-CCL20-ALK fusion were found,which responsed to crizotinib treatment.Acquired ALK L1196M/G1269A mutations were found in both primary and secondary resistant patients,and while ALK I1171T mutation was only found in secondary resistantpatients.Wnt signaling pathway was activated significantly after the treatment of crizotinib according to Kyoto Encyclopedia of Genes and Genomes(KEGG) and GeneOntology(GO) analyses.Moreover, AMER1 aberrance was inclined to appear in the primary resistance patients, which was significant different between the two groups in KEGG and GO analyses.Figure 1
Conclusion:
ALK mutations could exist in both primary and secondary resistance to crizotinib in ALK-rearranged NSCLC. Response to crizotinib was also observed in ALK-rearranged NSCLC patients with non-EML4 partners. NGS may facilitate precision treatment for both primary and secondary resistant patients though they have a few differences in molecular mechanisms of resistance.
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P1.01-010 - Circulating Cell-Free DNA of Cerebrospinal Fluid May Function as Liquid Biopsy for Leptomeningeal Metastases of ALK Rearrangement NSCLC (ID 8754)
09:30 - 16:00 | Author(s): X. Zhang
- Abstract
Background:
Leptomeningeal metastases (LM) are more frequent in non-small cell lung cancer (NSCLC) patients with oncogenic drivers. Resistance mechanisms of LM with ALK rearrangement remained unclear due to limited access to leptomeningeal lesions.
Method:
Primary tumor, cerebrospinal fluid (CSF) and plasma in patients with suspected LM of NSCLC were tested by Next-Generation Sequencing.
Result:
In patents with ALK rearrangement, driver genes were detected in 66.7%, 50.0% and 28.6% patients of CSF cfDNA, CSF precipitates and plasma, respectively; and all of them had much higher allele fractions in CSF cfDNA than the other two media. The diagnosis criteria of LM were positive in brain MRI or CSF cytology, and driver genes were identified in CSF cfDNA of all patients with positive CSF cytology while in those CSF cytology negative all genes were negative. Resistance mutations including gatekeeper genes ALK G1202R and ALK G1269A were identified in CSF cfDNA but they were absent in their plasma. Moreover, tailor therapy based on CSF cfDNA obtained surprising outcomes, and genetic profiles of CSF cfDNA showed dynamic changes, suggesting the potential role of CSF for follow-up studies. Figure 1
Conclusion:
CSF cfDNA could reveal the driver and resistant genes of LM, and it may function as the media of liquid biopsy for LM in NSCLC with ALK rearrangement.
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P2.03 - Chemotherapy/Targeted Therapy (ID 704)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.03-054 - EGFR Mutation with Acquired C-MET Positive Reveals Potential Immunotherapeutic Vulnerabilities (ID 10436)
09:30 - 16:00 | Author(s): X. Zhang
- Abstract
Background:
There are few effective strategies for C-MET positive advance non-small-cell lung cancer(NSCLC) patients with epidermal growth factor receptor(EGFR) inhibitor resistance.The efficacy of PD-1 blockade immunotherapy and even the status of PD-L1 expression in such population is unclear.
Method:
Patients diagnosed as advanced NSCLC synchronously tested for EGFR status, expression of PD-L1 and C-MET at the Guangdong Lung Cancer Institute (GLCI) from 2015 to 2017 were collected.PD-L1 expression on tumor cells and immune cell was evaluated using a three-tiered grading system. C-MET positive was define as immunohistochemistry staining (2+/3+) in ≥ 50% of tumor cells. A chi-squared test was used to assess the relationships between C-MET positive and PD-L1 expression.
Result:
A total of 487 eligible cases were selected including 166 EGFR mutant and 321 wild type patients.In the general population(n=487),the difference of PD-L1 expression were observed between C-MET positive group and C-MET negative group (65.3% vs 31.7%, P=0.001),which was in accordance with the result from the Cancer Genome Atlas (TCGA) dataset (n=512,P<0.001).Furthermore,among the EGFR mutant patients (n=166), PD-L1 expression was showed in 58.1% of C-MET positive group and 28.5% of C-MET negative group,P value <0.001. Subsequently,T790M negative was identified in 55%(47/86) of EGFR TKI resistant patients (n=86).In this subgroup,a significant increase of PD-L1 expression was demonstrated in C-MET positive group compared to C-MET negative group(66.7% vs 34.6%,P=0.027).Finally, clinical efficacy of immunotherapy was further confirmed in 2 C-MET positive advanced lung adenocarcinoma patients with remarkable response to PD-1 blockade immunotherapy who had disease progression after C-MET inhibitors.Figure 1
Conclusion:
C-MET positive maybe associated with high PD-L1 expression in advanced NSCLC providing therapeutic insight into targeting the PD-1/PD-L1 pathway in EGFR inhibitor-resistant NSCLC with C-MET positive and T790M negative.
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-063 - Concomitant EGFR Mutation and ALK Rearrangement in Non-Small-Cell Lung Cancer (ID 10058)
09:30 - 16:00 | Author(s): X. Zhang
- Abstract
Background:
The concomitance of epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement defines a new molecular subtype of non-small-cell lung cancer (NSCLC). We investigated the factors associated with the efficacy of targeted therapy and resistance mechanisms in EGFR/ALK co-altered NSCLCs.
Method:
EGFR mutation was identified with direct sequencing or Scorpion amplification refractory mutation system (ARMS). Relatively low EGFR-mutant abundance is considered as sequencing (-)/ARMS (+), while high abundance as sequencing (+). ALK-positive is assessed with any of the 3 methods: fluorescence in situ hybridization (FISH), rapid amplification of cDNA ends -coupled polymerase chain reaction and sequencing or Ventana immunohistochemistry (IHC). Next-generation sequencing was employed to analyze genetic profiles in patients with specimens before and after targeted therapy.
Result:
From December 2011 to December 2016, sixteen patients were identified with concomitant EGFR/ALK co-alterations, accounting for 0.6% (16/2632) in NSCLC patients, 1.8% (16/867) in EGFR-mutant and 8.6% (16/185) in ALK-positive patients. Five ALK-IHC (-)/FISH (+)/EGFR (+) patients with EGFR-TKIs experienced 3 PR, 1 SD and 1 waitiing for response evaluation, with median PFS of 11 months. Three with relatively low EGFR-mutant abundance achieved PR with crizotinib, while three with relatively high EGFR-mutant abundance obtained 2 PR and 1 SD with EGFR-TKIs. Spatial and inter-tumoral heterogeneity was observed in one EGFR/ALK co-altered patient. (Figure 1B) Two patients with T790M, one with Met pathway activation and two with loss of EGFR mutation were found after resistance to EGFR-TKIs. One with KRAS mutation was found pre- and post-EGFR-TKIs. ALK_F1174C mutation was observed in one patient after progression to crizotinib and ALK_G1202R mutation after resistance to ceritinib.Figure 1
Conclusion:
ALK protein expression, EGFR mutation abundance and tumor heterogeneity were associated with efficacy of targeted treatment for EGFR/ALK co-altered patients. Most mechanisms resistance to EGFR-TKIs and crizotinib were similar to those in typical EGFR mutation and ALK rearrangement respectively.
