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Rongrong Chen
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FP01 - Early Stage/Localized Disease (ID 111)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Early Stage/Localized Disease
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP01.03 - Genetic Predisposition for Pre-Invasive Lung Adenocarcinoma Manifesting as Ground-Glass Nodules with Family History of Lung Cancer (ID 1512)
00:00 - 00:00 | Author(s): Rongrong Chen
- Abstract
Introduction
Lung cancer with family history have been increasing gradually of late years in East Asian, especially those presenting as pulmonary ground-glass nodules (GGNs). The predisposition of GGN with lung cancer family history remains baffling.
Methods
This prospective study (NCT04220268) enrolled patients with pulmonary pre-invasive or invasive adenocarcinoma, which presenting as GGN in computer tomography (CT) scans. We used extreme phenotype approach to select 50 GGN patients with a family history of lung cancer (FHLC) in one or more first-degree relatives. Blood samples were collected and sequenced by whole exome sequencing (WES) to investigate rare but potential pathogenic germline mutations with a stepwise filtering strategy including: variant quality and classification, minor allele frequency (MAF) < 0.01 in public and local database, functional prediction and family segregation.
Results
In total, 2325 single nucleotide variants (SNVs) and 238 frameshift mutations with MAF <0.01 were finally identified through the filter. The number of these rare, damaging germline mutations in non-smoking patients were significantly higher than those in smoking patients (Spearman’s ρ= -0.33, p=0.02). Fifty-nine SNVs and 10 frameshifts were not only rare and deleterious but also presented in more than two families. Importantly, twenty of them had been reported to be associated with higher risk or carcinogenesis of lung cancer. Two of them were validated in 126 nonoverlapping susceptibility loci for lung carcinogenesis identified by genome-wide association studies (GWAS).
Conclusion
Patients with GGNs and FHLC may have inheritable carcinogenesis mutations. These variants may potentially contribute to the risk of pulmonary pre-invasive adenocarcinoma susceptibility in Chinese population. Non-smoking patients with GGN probably had higher genetic predisposition than the smoking patients.
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P07 - Early Stage/Localized Disease - Imaging and Biomarkers (ID 116)
- Event: WCLC 2020
- Type: Posters
- Track: Early Stage/Localized Disease
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P07.04 - Using ctDNA to Detect Minimal Residual Disease after Surgery in Resectable Lung Cancer (ID 1775)
00:00 - 00:00 | Author(s): Rongrong Chen
- Abstract
Introduction
ctDNA is a blood-based biomarker with promising potential in lung cancer for minimal residual disease (MRD) assessment and early detection of recurrence. However, there are few studies about ctDNA in postoperative monitoring for resectable lung cancer.
Methods
We retrospectively analyzed paired surgical tissues and postoperative ctDNA next-generation sequencing (NGS) results from 49 lung cancers patients (pts) who underwent surgery. We used 1021-gene panel to assess the genetic variations. ctDNA positive defined as at least one mutation from tissue was detected in postoperative plasma. The cutoff value of TMB-H/L in tissue samples was 9.0 Muts/Mb.
Results
A total of 49 pts included in this analysis with median age 59 (range 37-76), 30 were males. Histologically contained 47 adenocarcinoma, 1 squamous cell carcinoma, 1 LCNEC, and 1 SCLC. One patient had simultaneous multiple primary lung adenocarcinoma and squamous cell carcinoma in different left lobes. Tumors were in different stages, 17 were stage I, 17 were stage II, 15 were stage III and 1 was unknown. Genetic variations were found in all tissue samples. TP53 (60%) was the most common gene, followed by EGFR (42%), LRP1B (16%), KRAS (16%), et. And a total of 63 actionable mutations were found in 84.0% (42/50) tissue samples, including EGFR, KRAS, PIK3CA, ALK, RET, ERBB2, et. Meanwhile, 11 (22.9%) were high tumor mutation burden (TMB) in 48 samples which met TMB assessment conditions. Plasma samples were collected within a few weeks after surgery. Postoperative ctDNA positive rate was 26.5% (13/49) in all patients, and 17.6% (3/17) in stage I, 29.4% (5/17) in stage Ⅱ and 33.3% (5/15) in stage Ⅲ. The ctDNA status had no relationship with collection time from surgery. The median mutation number in ctDNA was 2 (range 1-27). ctDNA positive rate was higher in TMB-H group 63.6% (7/11) than TMB-L 13.5% (5/37) (p=0.003). Considering the possible interference caused by the mutation number in tissue, we limited the top10 genes from tissues to analyze ctDNA again. And the result was the same as previous (p=0.027). Interestingly, in the patient with simultaneous adenocarcinoma and squamous cell carcinoma, we found that the six mutations in ctDNA were 100% matched to adenocarcinoma, and very different from squamous cell carcinoma.
Conclusion
CtDNA is a meaningful and feasible biomarker for postoperative monitoring in resectable lung cancer. Moreover, it can identify the source of MRD in multiple primary lung cancer.
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P47 - Small Cell Lung Cancer/NET - Biology / Translational (ID 234)
- Event: WCLC 2020
- Type: Posters
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P47.08 - Blood-Based Tumor Mutation Burden as a Predictive Biomarker for Clinical Benefit of Immunotherapy in Small-Cell Lung Cancer (ID 1697)
00:00 - 00:00 | Author(s): Rongrong Chen
- Abstract
Introduction
An exploratory analysis from the Checkmate-032 trial showed that the efficacy of nivolumab ± ipilimumab was enhanced in small-cell lung cancer (SCLC) patients (pts) with high tissue-based tumor mutational burden (tTMB). However, the availability of adequate tissue for genetic testing sometimes may be challenging. In this study, we aim to evaluate the reliability of blood-based TMB (bTMB) as a predictor for clinical benefit of immunotherapy in SCLC.
Methods
Pts with treatment-naïve, histologically or cytologically confirmed, limited- or extensive-stage SCLC were enrolled. Tumor tissue-derived DNA and plasma-derived ctDNA were obtained from these pts to perform a paired tumor-normal next-generation sequencing of 1021 cancer-related genes. TMB was determined as the number of somatic non-synonymous SNVs and Indels per Mb in the coding region (with variant allele fraction ≥0.03 for tTMB, and ≥0.005 for bTMB).
Results
Between Nov 2018 and Jan 2020, 30 pts with SCLC were enrolled. The median age at diagnosis was 61.5 years (range 43-69); 22 pts were male; 13 pts with extensive-stage SCLC, 16 pts with limited-stage SCLC, and one patient with unspecified pathology. Median tTMB was 9.6 muts/Mb (range 0-25.92), and median bTMB was 11.04 muts/Mb (range 0.96-21.12). No significant difference was observed in tTMB for pts with limited- and extensive-stage disease (median tTMB was 12.48 muts/Mb and 9.6 muts/Mb, respectively; p=0.3558). Pairwise comparison of tTMB and bTMB was shown in the Figure. A positive correlation between tTMB and bTMB was observed (Spearman rank correlation=0.7089, 95% confidence interval [CI]: 0.4594-0.8597, p<0.0001). TMB was categorized as high vs. low according to the upper quartile of two cohorts (cutoff: 14.4 muts/Mb for tTMB, and 13.33 muts/Mb for bTMB). The positive percentage agreement of bTMB was 87.5% (95% CI: 57.94%-117.06%), while the negative percentage agreement was 95.45% (95% CI: 86.00%-104.91%).
Conclusion
Our study suggested a strong correlation between bTMB and tTMB. Therefore, bTMB may be used as an attractive alternative to predict response to immunotherapy in pts with limited- or extensive-stage SCLC whose tumor tissue is not available.
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P56 - Tumor Biology and Systems Biology - Basic and Translational Science - CT DNA (ID 193)
- Event: WCLC 2020
- Type: Posters
- Track: Tumor Biology and Systems Biology - Basic and Translational Science
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P56.01 - Postoperative ctDNA Positive Presents the High-risk of Recurrence in Resectable Non-Small Cell Lung Cancers (ID 1436)
00:00 - 00:00 | Author(s): Rongrong Chen
- Abstract
Introduction
Effective biomarkers to predict the prognosis for non-small cell lung cancer (NSCLC) patients after radical resection are needed. As a potential novel maker, ctDNA help to determine which patients harbor residual disease after surgery. Here, we analyze the significance of postoperative ctDNA in this prospective cohort.
Methods
Twenty-six NSCLC surgical patients were enrolled. The paired surgical tissues and postoperative peripheral blood samples were collected. Using hybridization capture-based NGS ER-seq method, 1021-gene panel for 26 tissues and 293-gene panel for 30 ctDNA samples, which enables simultaneously assess snv/indel, cnv and rearrangement variation.
Results
Median age was 61 years (range 33-78), 9 had smoking history, and 17 were males. There were 16 lung adenocarcinoma, 6 lung squamous carcinoma, 2 sarcomatoid carcinoma, 1 adenosquamous carcinoma and 1 lymphoepithelioma-like carcinoma. Four were stage Ⅰ, 10 stage Ⅱ and 12 stage Ⅲ. Thirteen patients received adjuvant therapy.
In tissue samples, TP53 was the most common driver gene (65.4%). Followed by EGFR (30.8%), APC (19.2%), KRAS (11.5%), et. The median mutation number was 8.5 (from 3-50), and median TMB was 6.9muts/Mb (range 1-48). The mutation number had no relationship with ctDNA status. Postoperative ctDNA positive was found in 5 of 26 patients (19.2%), 3 stage Ⅲ and 2 stage Ⅱ, with a total of 10 mutations, range from 1 to 6 per-sample. The median highest mutant allele frequency (hMAF) per-sample was 0.1% (range 0.07%-6.6%). Two (7.7%) patients had actionable mutation in ctDNA.
The median follow-up time was 10 months (range 3.5-18). Only 5 (5/21, 23.8%) patients in ctDNA negative group had disease recrruence, but patients in ctDNA positive group were all relapsed (P=0.004). The disease-free survival (DFS) was significantly shorter in ctDNA positive group than ctDNA negative (mDFS 7.4 vs 16.9 mos, P﹤0.0001; HR, 9.455; 95% CI, 1.149 to 77.78). Among 12 stage Ⅲ patents, shorter DFS was also observed in ctDNA positive patients than negative (P=0.0017; HR, 7.032).
There were three patients had ctDNA monitoring results. Two persistently ctDNA negative cases did not relapse. But the patient with ctDNA changed from negative to positive relapsed within one month after transformation.
Conclusion
Postoperative ctDNA could be a promising biomarker to indicate the recurrence risk for NSCLC patients after radical surgery.
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P76 - Targeted Therapy - Clinically Focused - EGFR (ID 253)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P76.35 - Genomic Characristic and Prognosis of Concomitant with EGFR Copy Numbers Variations in EGFR Mutated Lung Cancer Patients (ID 1708)
00:00 - 00:00 | Author(s): Rongrong Chen
- Abstract
Introduction
Concomitant Genetic Alterations with EGFR could affect the response to treatment of EGFR-TKI. EGFR copy numbers variations (CNV) as a common concomitant alteration with EGFR, has been reported in several studies. However, the effect of conconmitant EGFR CNV to treatment of EGFR-TKI remained controversial. This study aims to investigate whether EGFR CNV affecting the frequency of EGFR mutation affect the treatment outcomes of EGFR-TKI.
Methods
We screened 262 patients concomitant with EGFR CNV from 3449 newly diagnosed EGFR mutated lung cancer patients. All the patients were detected by hybridization capture-based NGS 1021-gene panel sequencing with tumor biopsy. We hypothesized that frequency of EGFR mutation is affected by EGFR CNV and divided 262 patients into three groups based on the frequency of EGFR mutations. The Group 1(n=69): The frequency of EGFR sensitive mutations was not the highest one in all detected mutations. Then, other patients were assigned to other two group based on the effect of EGFR CNV. And the effect was determinant by Nadeem Riaz et al reported mutation clonal classified methods (Ratio=frequency of highest non-EGFR mutations /frequency of EGFR mutation ≥ 0.5). Group 2: Ratio ≥0.5 means frequency of EGFR mutation was not significant affected by EGFR CNV (n=97); Others were assigned to Group 3(Ratio˂0.5,n=96).
Results
The mutational landscape of 262 patients was summarized. Except for EGFR, mutations in TP53 were the most prominent and significant variation (79%). Significantly more TP53 mutations, MYC CNV, and CCND1 CNV mutation were detected in group 1 than in group 2 and 3 (96% vs 81% vs 65%; 19% vs 5% vs 6%; 8% vs 1% vs 1%); And group 2 has more TP53 mutation and less MDM2 CNV mutation compared with group 3 (p=0.009,p=0.0006). The numbers of genetic characterization was also analyzed. Group 3 showed significantly higher EGFR copy numbers than group 1 (p˂0.0001) and 2 (p=0.0013; copy numbers:2.2 vs 2.3 vs 3.5). However, group 1 was detected significantly more numbers of gene of CNV mutation than group 2(p˂0.0001) and 3 (p˂0.0001; CNV numbers:2 vs 1 vs 1). Further, the survival of EGFR-TKI of three groups was compared. Group 1 showed a significantly shorter media PFS than group 2 and 3(mPFS=4.5 vs 9 vs 12; Figure 1).
Conclusion
In our study, frequency of EGFR mutation affected by copy numbers of EGFR CNV and related with treatment of EGFR-TKI, especially patients with a lower frequency of EGFR with an inferior treatment.
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P85 - Targeted Therapy - Clinically Focused - MET (ID 262)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P85.06 - Clinical and Genomic Features of Middle Intensity cMET Stain of Chinese Lung Cancer Patients (ID 1661)
00:00 - 00:00 | Author(s): Rongrong Chen
- Abstract
Introduction
Background：cMET overexpression has been identified as an oncogenic driver in Non-small cell lung cancer(NSCLC). About 25% NSCLC patients was detected cMET positive by immunohistochemistry(IHC) and has been studied for clinical and genomic features. Similarly, the clinical and genomic features of cMET negetive patients are need to be better understood.
Methods
Methods: Protein expression of cMET of 196 Chinese NSCLC patients by IHC was determined by measuring the intensity of the stain (0, 1+, 2+, 3+) and the percent staining (0-100%). We reviewed 132 of middle intensity cMET stain (cMET 1+/2+, negetive) with paired tumor-normal samples sequenced by 1021/59 gene panel.
Results
Results: In this study, 67.3% (132/196) were detected middle intensity cMET stain including 50.8% (67/132) cMET 2+. All of the patients were lung adenocarcinoma and the average age at diagnosis was 61.4 (range 33-80 years). 43.8% patients had a history of smoking. All of these characteristics were not significantly different between cMET 1+ and cMET 2+ groups. Differences was found in genomic. The common mutations were TP53(76/132), EGFR (74/132) and KRAS (23/132). 5 patients were found cMET activation mutations including 2 of cMET amplification and 3 of cMET mutation(Table 1). More non-synonymous mutation were found in cMET 2+ groups than cMET 1+ (media: 6 versus 5,p=0.02). Significantly higher number of copy numbers variations(CNV) was found in cMET 2+ groups (media: 2 versus 1, p=0.04,Fig 1). However, the gene mutations and actionable mutations were no differences in two groups except that MDM2 CNV mutation was higher in cMET 2+ groups(p=0.03).
Table1. Genetic aberrations of MET.
Patients Age Gender Smoking IHC of cMET NGS of cMET P1 61 Male NA cMET(2+) MET c.3028G>C P2 70 Femal NA cMET(1+) MET c.3028+3A>G P3 71 Male No cMET(2+) MET c.2888-19_2888-13delinsAAA P4 64 Male Yes cMET(1+) MET CNV P5 68 Femal No cMET(1+) MET CNV
Conclusion
Conclusion: Our data suggest that 3.8% middle intensity cMET stain patients had cMET activation which is a clearly therapeutic target to cMET inhibitors. cMET 2+ patients had more non-synonymous mutation and CNV than cMET 1+ patients which may be related to treatment and prognosis.
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P89 - Targeted Therapy - Clinically Focused - Translational (ID 266)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 2
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P89.01 - Clinical and Genomic Features of EGFR-KDD/EGFR Rearrangements of Chinese Lung Cancer Patients (ID 2854)
00:00 - 00:00 | Author(s): Rongrong Chen
- Abstract
Introduction
Background：The most frequent epidermal growth factor receptor (EGFR) mutations of lung cancer include exon 19 in deletion and the exon 21 L858R mutation. And EGFR-tyrosine kinase inhibitor (TKI) as the standard first line treatment show good response to classical/sensitizing EGFR mutations. With the development of detection methods, some uncommon genomic mutation events such as exon 18-25 kinase domain duplications (KDD) and EGFR rearrangements are found. EGFR-KDD/EGFR rearrangements have been identified and implicated to be oncogenic in nonsmall cell lung cancers (NSCLCs). However, its prevalence and clinical contributions in lung cancer are largely unknown.
Methods
Methods: Here, we conducted our database record review of 10,560 lung cancer patients who underwent 1021-gene panel sequencing using next-generation sequencing (NGS). The panel contains EGFR exons and the introns involved in EGFR-KDD and EGFR rearrangements.
Results
Results: EGFR-KDD/EGFR rearrangements were identified in a total of 24 patients, which is approximately 0.23% of the total population reviewed, and also consisted of 0.39% (24/6188) of EGFR mutation-positive patients. A total of 30% of patients (8/24) were identified with EGFR-KDD which were the canonical EGFR-KDD duplication of exons 18–25, and 7 patients were adenocarcinoma and 1 patients was adenosquamous carcinoma. Importantly, none of the 8 patients had other coexisting driver mutations, highlighting the potential oncogenic role of this type of alteration. The others 16 patients were identified EGFR rearrangements, in which 2 patients were identified with the previously described EGFR rearrangements (EGFR-RAD51, EGFR-SEPT14), while the remaining 14 patients harbored not reported rearrangements. Different to the EGFR-KDD, 68.75% of patients (11/16) harbored other EGFR driver mutations including 7 of L858R, 3 of 19 deletions, and 1 of 20 insertions. As reported, we also found 56.25% of patients (9/16) harbored EGFR copy numbers variations. Most of the patients (12/16) were adenocarcinoma, and 4 of patients were NSCLC. Some reports had shown that several types of EGFR rearrangements were sensitive to EGFR-TKI therapists, but EGFR rearrangements were also found in 4 EGFR-TKI resistance patients. One of the patients harbored EGFR 19deletion and had 16 months therapy of osimertinib. Then, a VOPP1-EGFR was detected in the patients’ tissue after EGFR-TKI therapy, highlighting the potential resistance role of this type of alteration.
Conclusion
Conclusion: Our findings provide valuable insight into the prevalence of EGFR-KDD/EGFR rearrangements in Chinese lung cancer, and suggested that such rearrangements are clinically important genomic alterations.
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P89.18 - Comprehensive Molecular Characterization of Chinese Patients with Oesophageal Cancer Related with Age (ID 3438)
00:00 - 00:00 | Author(s): Rongrong Chen
- Abstract
Introduction
Occurrence at a younger age has been to be associated with a distinct biology in oesophageal cancer. However, geonomics and clinnical characteristics among younger patients with oesophageal cancer remain to be determined.
Methods
We reviewed 230 Chinese oesophageal cancer patients with paired tumor-normal samples sequenced by a 1021 gene panel.
Results
The frequencies of targetable genetic alterations in 230 patients with oesophageal cancer were analyzed by defined age categories, which unveiled a distinctive molecular profile in the younger group, aged less than 60 years (n=110). The media age of younger and older groups were 53 and 67 years (range: 27-59; 60-86 years). Male was significantly higher in younger group (87.3% versus 75.0%, p=0.018)., Squamous cell carcinoma were the common pathological subtype with similar proportion in two groups( 75.5% versus 67.5%,p=0.12). The number of non-synonymous mutations was the same in both groups (media: 6 versus 6), but the older groups had more copy numbers variation(CNV) than younger group (media: 2.5 versus 2, p=0.25). Notably, no higher frequency genetic alterations were associated with young age. However, a reverse trend was observed for TP53, CCND1, CDKN2A, SMARCA4, TERT, and POLE mutations, which were more frequently identified in the older group(Fig 1). Furthermore, CNV of CCND1 was much more prevalant in the older patients(7.3% versus 17.5%, p=0.019). Studies had reported that TP53 and CCND1 mutations might associated with poor prognosis of oesophageal cancer, our study indicated that older patients may need to pay more attention to mutations in these two genes. With the development of targeted drugs, older patients with higher frequency CCND1 and CDKN2A might benefit from CDK4/6 inhibitors.
Conclusion
Our study revealed a distinctive genetic profile in younger patients with oesophageal cancer. High frequency of TP53 and CCND1 mutations were found in the older patients, which especially warranted personalized treatment in this population.
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P92 - Mesothelioma, Thymoma and Other Thoracic Malignancies - Misc. Topics (ID 269)
- Event: WCLC 2020
- Type: Posters
- Track: Mesothelioma, Thymoma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P92.01 - Genetic Landscape and Potential Therapy Regimen of Thymic Tumor (ID 1685)
00:00 - 00:00 | Author(s): Rongrong Chen
- Abstract
Introduction
Thymomas and thymic carcinomas, which are rare epithelial tumors arising from the thymus gland, are the most common tumors of the anterior mediastinum. The National Comprehensive Cancer Network guidelines recommend resection followed by adjuvant platinum-based chemotherapy for resectable tumors. However, the outcomes for thymic tumors are poor with no regimen showing a consistent benefit. To investigate the possibility of targeted therapy for thymic tumor patients, a deeper understanding of the genetic basis is required.
Methods
We retrospectively evaluated our database and identified 36 patients of thymic tumor in which 12 of patients were thymomas . All the patients were detected by hybridization capture-based NGS 1021-gene panel sequencing with tumor tissue, peripheral blood and hydrothorax.
Results
We analyzed the genetic profiling of the 36 Chinese patients. The most frequently mutated genes were TP53 (11/36), followed by CDKN2A (6/36), BAP1 (5/36), BRD4 (4/36), and KIT (4/36). The common mutation types of TP53 and CDKN2A were single nucleic acid variation (SNV) and copy numbers variation (CNV). 16 of patients were detected targeted gene mutation. The common targeted mutation were CDKN2A(6/16), EGFR (2/16), FBXW7(2/16), KIT(2/16), and PIK3CA (2/16) as shown in Figure 1. CDK4/6 inhibitor like palbociclib may be a consideration targeted therapy regimen. Then, the genetic profiling of thymomas and thymic carcinomas was compared. The proportion of TP53 in thymic carcinomas was higher than thymomas, and proportion of CDKN2A was similar in two groups. However, no significant difference was found in two groups. The media number of nonsynonymous mutation detected was 4 of all patients, and thymomas and thymic carcinomas were 2 and 5, respectively. This may be indicated a poor survival in immunotherapy.
Conclusion
In conclusion, we identified genetic mutations comprehensively and provide predictive implications for thymic tumor patients. 44.4% thymic tumor patients of chinese were detected targeted mutation and 37.5% of them was CDKN2A mutation, which suggested that CDK4/6 inhibitors will be a consideration treatment regimen for Chinese patients.
