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Xinru Mao
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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: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.01-61 - Clinical Characterization of ERBB2 Exon 20 Insertions and Heterogeneity of Outcomes to Afatinib in Chinese Lung Cancers (ID 13066)
16:45 - 18:00 | Author(s): Xinru Mao
- Abstract
Background
Background: Human epidermal growth factor 2 (HER2, ERBB2) gene alterations have been identified as oncogenic drivers in 2-5% of lung cancers. ERBB2 In-frame insertions in exon 20 (20ins) lead to constitutive activation of receptor and downstream pathways. However, response heterogeneity of different exon 20 insertions to ERBB2 inhibitor afatinib exists. In vitro and structural modeling results suggested that Glycine778 may facilitate inhibitor binding to ERBB2. In this study, our aim was to improve our understanding of clinical characteristics in ERBB2-mutated Chinese lung cancer and investigate the clinical outcomes of specific ERBB2 exon 20 insertions in response to afatinib.
a9ded1e5ce5d75814730bb4caaf49419 Method
Methods: We reviewed 7520 lung cancer patients whose tissue or plasma biopsies were sequenced in a CLIA-certified sequencing laboratory between 2015 to 2018. Clinical records of 19 patients (18 adenocarcinomas and 1 squamous cell carcinoma) with several different ERBB2 20ins after afatinib treatment were collected for clinical outcomes evaluation.
4c3880bb027f159e801041b1021e88e8 Result
Results: ERBB2 20ins were identified in 2.27% (171/7,520) in this Chinese lung cancer cohort. It occurred with a high proportion in females with adenocarcinoma histology. 11.7% (20/171) ERBB2 20ins-positive patients harbored concomitant ERBB2 amplification. Y772_A775dup (119/171, 69.6%) was the most frequently occurred 20ins subtype, followed by G778_P780dup (18/171, 10.5%). For the 19 patients treated with afatinib, they had a median PFS of 4.5 months and median OS of 11.5 months. The overall response rate in this cohort was 15.8% (3/19) and disease control rate was 68.4% (13/19). Next, we interrogated the clinical outcomes of specific 20ins subtype responding to afatinib. We found that patients harboring G778_P780dup (G778) achieved longer median PFS (10 vs 3.3 months, p=0.32) and median OS (19.7 vs 7 months, p=0.16) than non-G778 patients, consisting with in vitro results. Although statistical significance was not achieved due to limited number of G778_P780dup patients, this result warranted further investigation into this phenomenon. Moreover, to the best of our knowledge, we identified the first case of a lung squamous cell carcinoma patient harboring ERBB2 20ins from this cohort. He displayed favorable response to afatinib and achieved partial response with significant tumor shrinkage.
8eea62084ca7e541d918e823422bd82e Conclusion
Conclusion: We interrogated the characteristics of ERBB2 exon 20 insertions in a large cohort from single ethnicity. It demonstrated the response heterogeneity to afatinib among different ERBB2 exon 20 insertion subtypes. It highlighted the importance to correlate drug efficacy with specific ERBB2 exon 20 insertion variants in clinical application.
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: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.01-44 - Prognostic Value of TP53 Hot Exon Mutation in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 13150)
16:45 - 18:00 | Author(s): Xinru Mao
- Abstract
Background
Numerous studies have revealed either very marginal or no prognostic value of TP53 mutation NSCLC patients. Currently, in clinical settings, all TP53 mutations have been considered equally, without any differentiation between the various types and positions of mutations. However, increasing evidence has triggered us to challenge such practice.
a9ded1e5ce5d75814730bb4caaf49419 Method
We retrospectively investigated the correlation between mutations occurring at hot exons (5-8) and overall survival (OS) in 214 previously tyrosine kinase inhibitor (TKI) treated advanced NSCLC patients. Among them, 184 had 1 line of TKI-treatment and the remaining 30 patients had more than 1 line of TKI-treatment. 115 harbored TP53 mutation; among them 105 patients had concurrent EGFR mutation; 5 had ALK rearrangements; 1 had ROS1 rearrangements; 1 had KRAS and 2 had ERBB2 mutations. 99 patients had wild type (WT) TP53; among them, 92 had EGFR mutation, 4 with ALK-rearrangements, 1 with MET and 1 with BRAF mutation. Fisher’s exact test and the Mann-Whitney test were used to determine if categorical and continuous variables, respectively, differed between TP53 WT and mutant groups.
4c3880bb027f159e801041b1021e88e8 Result
The prevalence of TP53 mutation in our cohort is 53.7% (115/214); 28 had mutation on exon 5, 18 on exon 6, 22 on exon 7 and 32 on exon 8. 32 patients had loss of function mutation and 51 patients had disruptive mutation. Our data revealed a positive correlation with N and M stage. Patients harboring TP53 mutation are more likely to diagnose with more advanced N (p=0.018) and M stage (p=0.001). Furthermore, patients with TP53 mutation are more likely to have liver (p<0.001) and bone metastasis (p=0.012). In patients treated with only 1 line of TKI-treatment, although TP53 status had no effect on PFS (p=0.241) and OS (p=0.49) when they were considered collectively, we observed patients with mutation in exon 5 had shorter OS (p=0.029) and mutation in exon 8 had shorter PFS (P=0.003) after controlling for age, gender, stage and histology. Furthermore, within the osimertinib subgroup (N=101), patients harboring mutation in exon 8 had significantly shorter PFS (P=0.007). In patients treated with more than 1 line of treatment, neither TP53 mutation considered collectively, nor hot exon mutations had correlation with PFS or OS.
8eea62084ca7e541d918e823422bd82e Conclusion
Our study revealed unfavorable prognostic value of mutations in exon 5 and no prognostic value of TP53 if all mutations were considered collectively. Our study adds new dimension to the emerging picture that not all TP53 mutants are equal.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P3.12 - Small Cell Lung Cancer/NET (Not CME Accredited Session) (ID 978)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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P3.12-12 - Genomic Profiling of Pulmonary Large-Cell Neuroendocrine Carcinoma (LCNEC) Reveals Distinct Mutational Landscape (ID 13244)
12:00 - 13:30 | Author(s): Xinru Mao
- Abstract
Background
The controversial classification of lung neuroendocrine tumor has been amended a few times since recognised as a separate entity. LCNEC shares clinical features with small cell lung carcinoma (SCLC) and they were both classified as lung neuroendocrine carcinoma according to the 2015 WHO lung primary pathology classification, numerous studies have revealed barely satisfactory outcomes when it was treated as SCLC. However the underlying molecular basis for such commonalities and discrepancies are poorly understood. In this study, we interrogated the genomic landscape of LCNEC and SCLC along with their histologically related subtypes: carcinoids and atypical carcinoids to define the molecular pattern of LCNEC.
a9ded1e5ce5d75814730bb4caaf49419 Method
We performed targeted sequencing in 35 tissue samples using a panel covering 520 cancer related genes, spanning 1.6MB of human genome, with an average sequencing depth of 1,418x. Among them, 15 were diagnosed with SCLC, 9 with LCNEC, 6 with carcinoid and 5 with atypical carcinoid.
4c3880bb027f159e801041b1021e88e8 Result
On average, LCNEC exhibited 13.5 mutations per million base pairs (Mb) and a C:G>A:T transversion rate of 34%, which is indicative of tobacco exposure. LCNEC had SCLC (16.7 Mb) had comparable TMB (p=0.18), which is significantly higher than carcinoids (1.2/Mb, p<0.001) and atypical carcinoids (2.4/Mb, p<0.001). The most frequently mutated gene in LCNEC is TP53 (89%, 8/9), followed by NOTCH1 (33%), KEAP1 (22%), RB1 (22%) and a few chromatin modifiers, including KMT2D (33%), KMT2C (33%). Co-mutation in TP53 and RB1, a hallmark of SCLC, was found in 22% (2/9) of LCNEC patients; in contrast, 80% of SCLC patients harbored concurrent mutation. 67% carcinoid (4/6) and 20% (1/5) atypical carcinoid patients had no mutation identified from this panel. No classic lung adenocarcinoma driver mutations were found in any subtype. Copy number analyses revealed significantly higher copy number variation (CNV) in SCLC and LCNEC comparing with carcinoids and atypical carcinoids, which yield virtually no CNV. Our analysis revealed a comparable CNV status of SCLC and LCNEC (p=0.158), with an enrichment in amplification of chromatin modifiers.
8eea62084ca7e541d918e823422bd82e Conclusion
Our study, comprehensively characterized 4 subtypes of neuroendocrine tumors, revealed a high TMB and CG:AT transversion rate in LCNEC patients as well as a distinctive mutation landscape, with an enrichment of mutations occurring at chromatin remodelers. Furthermore, LCNEC has comparable TMB and CNV status as SCLC, which are significantly higher than carcinoid and atypical carcinoids.
6f8b794f3246b0c1e1780bb4d4d5dc53
