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Xiaohong Han
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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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P1.13-18 - Exploring the Resistance Mechanism of Osimertinib and Monitoring the Treatment Response Using Plasma ctDNA in Chinese NSCLC Patients (ID 13297)
16:45 - 18:00 | Author(s): Xiaohong Han
- Abstract
Background
Osimertinib (AZD9291; Tagrisso) is a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) known to be effective for patients harboring the EGFR-T790M variant, which is accounts for more than half of the acquired resistance mechanisms to the first generation EGFR-TKIs. However, limited osimertinib resistance-mechanism was reported. Study on potential osimertinib-resistance mechanisms in advanced NSCLC is necessary.
a9ded1e5ce5d75814730bb4caaf49419 Method
This study enrolled eight T790M-positive (tissue validated) patients, treated with osimertinib after first generation EGFR-TKI (Erlotinib, Gefitinib, Icotinib) resistance and progressed rapidly. Serial plasma samples were collected until disease progressed. Plasma DNA was extracted and sequenced by target-capture deep sequencing of 1021 previously annotated genes related to solid tumors. Clonal EGFR T790M mutation was defined if mutation was in the cluster with the highest mean variated allele frequency with PyClone, and otherwise subclonal EGFR T790M mutation. Molecular tumor burden index (mTBI) was calculated with the mean variant allele frequency of mutations in trunk clonal population.
4c3880bb027f159e801041b1021e88e8 Result
The median progression-free survival (PFS) of these eight rapidly-progressed patients was 3.82 months [95% CI 2.05-5.01] .Targeted capture sequencing of pretreatment ctDNA showed all of the eight patients (100%) were EGFR-positive (Exon19del [n=6] and L858R [n=2]), and seven patients (88%) harbored EGFR T790M mutation, except for the only one patient (P006) who showed an extremely low level of ctDNA. During the Osimertinib treatment, five patients (63%) had osimertinib resistance-related mutations: EGFR C797S (in cis position), G724S, KRAS G12D, PIK3CA E542K, EGFR amplification, and ERBB2 amplification. Among them, two patients had more than one resistance mechanisms: patient P034 had EGFR G724S, KRAS G12D and EGFR amplification, simultaneously; patient P013 had amplification in both EGFR and ERBB2. Other potential resistance mechanisms were identified including EGFR T751I and K754E mutations in P002 and ERBB2 S603 in P013. Notably, the only one patient (P004) who had not been detected to have any known osimertinib resistance mechanism but progressed in 3 months, was demonstrated to harbor a subclonal EGFR T790M mutation by analysis of ctDNA clonal structure. Serial ctDNA monitoring showed mTBI increased when disease progressed in 88% (7/8) patients, except P006, whose mutation were negative at second (stable disease) and third (progressed disease) therapeutic evaluations due to the extremely low level of ctDNA.
8eea62084ca7e541d918e823422bd82e Conclusion
This study presented comprehensive the resistance mechanism of osimertinib progressed rapidly in ctDNA including multiple mechanisms co-occurred in same patient. Serial monitoring of plasma ctDNA may be a promising approach to explore resistance mechanism and monitored the treatment response of third generation EGFR-TKI.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P2.17 - Treatment of Locoregional Disease - NSCLC (Not CME Accredited Session) (ID 966)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.17-13 - Genome-Wide Copy Number Alterations Profiling Predict Efficacy of Resected Stage II-IIIA Lung Adenocarcinoma (ID 13314)
16:45 - 18:00 | Presenting Author(s): Xiaohong Han
- Abstract
Background
The efficacy of platinum-based adjuvant chemotherapy(PBAC) varies for stage II-IIIA resected lung adenocarcinoma(RLUAD) patients, which necessitates the discovery of new potentially prognostic biomarkers. As a major source of genomic variations driving tumor evolution, somatic copy number alterations(CNAs) screening may identify predictive biomarkers.
a9ded1e5ce5d75814730bb4caaf49419 Method
The patterns of CNAs were analyzed by Oncoscan MIP array on formalin fixed paraffin embedded(FFPE) tumor specimens collected from 163 consecutive stage II-IIIA RLUAD patients, 145 out of which received PBAC.
4c3880bb027f159e801041b1021e88e8 Result
Among the 163 patients, 91(55.8%) relapsed within three years after surgery. The most frequent aberrations identified were 1q, 5p, 5q, 7p, 8q, 14p, 16p, 17q, 20q for copy number gains and 8p, 9p, 13p, 16q , 18q for losses. GISTIC2 analysis generated 45 amplification peaks and 40 deletion peaks, including some significantly mutated genes TERT, EGFR, MYC, CCND1, CDK4, MDM2, ERBB2, NKX2-1, CCNE1, CDKN2A, most of which were consistent with TCGA database. It was found that amplifications of 12p12.1（CMAS, GOLT1B, GYS2, LDHB, RECQL, ETNK1, IAPP, PYROXD1, KRAS）and KDM5A were associated with worse prognosis in our cohort(table), and validated in 506 LUADs from TCGA. 163 patients could be well classified into 4 groups with significantly different clinical outcomes based on thresholded copy number at reoccurring alteration peaks from GISTIC2 analysis. Among the 145 received PBAC patients, focal amplification of ERBB2 and deletion of 4q34.3 were found to be specific in relapsed patients compared with unrelapsed patients,This result was validated in an independent 183 cases corhort in Imielinski et al, indicating these two CNAs may contribute to RLUAD recurrence.
8eea62084ca7e541d918e823422bd82e ConclusionAmplifications of 12p12.1 and KDM5A associated with overall survival
Characteristics
Univariate analysis
(Amp vs Non-Amp)
Multivariate analysis
(Amp vs Non-Amp)
Genes
Location
HR (95% CI)
p
HR (95% CI)
p
CMAS
12p12.1
1.99 (1.22~3.23)
0.006
2.80 (1.60~4.88)
<0.001
GOLT1B,GYS2,LDHB,RECQL
12p12.1
1.87 (1.14~3.07)
0.014
2.48 (1.41~4.37)
0.002
ETNK1
12p12.1
1.79 (1.10~2.93)
0.020
2.26 (1.60~3.94)
0.004
IAPP,PYROXD1
12p12.1
1.78 (1.07~2.94)
0.025
2.30 (1.30~4.07)
0.004
KRAS
12p12.1
1.74 (1.06~2.84)
0.027
2.14 (1.24~3.71)
0.006
KDM5A
12p13.33
1.67 (1.02~2.74)
0.043
1.88 (1.08~3.26)
0.026
This study suggests that CNAs may be a potential prognostic classifier in RLAUD patients, amplifications of 12p12.1 and KDM5A might be prognostic biomarkers for RLUAD , and amplification of ERBB2 and deletion of 4q34.3 predicted early relapse after PBAC. These novel findings may provide implication for better clinical decision making.
6f8b794f3246b0c1e1780bb4d4d5dc53
