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Sara Verdura
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EP1.12 - Small Cell Lung Cancer/NET (ID 202)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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EP1.12-15 - Oncologic Treatments and Outcomes for Small-Cell Lung Cancer Patients with Brain Metastases (Now Available) (ID 1877)
08:00 - 18:00 | Author(s): Sara Verdura
- Abstract
Background
Brain metastases (BM) are common in patients with small-cell lung cancer (SCLC), and are associated with short survival. Few data are available on this specific population of patients with SCLC and BM, as they are usually excluded from prospective randomized clinical trials.
Method
We present data on all patients diagnosed with BM from SCLC from the Cancer Register of the Hospital Universitari Dr. Josep Trueta during 2013–2017. Age, gender, and treatment in patients were recorded. Data cut-off for survival analysis was 28th March 2019.
Result
We identified 50 patients with SCLC and BM. Median age: 66 y (range: 48–82 y); male: 39 (78%). Synchronous BM were observed at the diagnosis of primary lung cancer in 33 (66%) patients. Impact of treatments on median overall survival (mOS) is summarized in Table 1. Only 1 patient received brain surgery (with an OS of 6.5 months). One-third of patients (34%) received best supportive treatment as unique treatment. The 1-year OS was 18% in our study.
Table 1 Treatment % mOS
(without treatment)mOS
(with treatment)p-value Brain radiotherapy 52 % 1.4 m 9.1 m < 0.000001 Chemotherapy 50 % 1.5 m 6.9 m =0.003 Brain radiotherapy and chemotherapy 34 % 1.6 m 10.7 m =0.000331
Conclusion
Our real-world data reinforce the need for better therapies to improve the prognosis of patients with SCLC and BM.
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P1.03 - Biology (ID 161)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.03-26 - Genetic and Molecular Profiling of Non-Smoking Related Lung Adenocarcinomas (ID 1701)
09:45 - 18:00 | Author(s): Sara Verdura
- Abstract
Background
The etiology and many details of the genomic profile and molecular basis of lung adenocarcinomas (LuADs) in nonsmoker patients remain elusive. Further, the scarcity of primary cultures available from non-smoking related lung adenocarcinomas (NSK-LuADs) contributes to hamper our biological understanding of these tumors.
Method
We established patient-derived cancer cell (PDCs) cultures from NSK-LuADs, and performed whole exome sequencing (WES) and RNA sequencing (RNA-seq) analysis to delineate their genomic architecture. For validations, we analyzed independent cohorts of LuADs.
Result
The analysis revealed non-smoker related alterations such as those at the growth factor receptors RET, ALK, EGFR and ERBB2. There were also mutations affecting signal transduction molecules such as AKT1, BRAF and KRAS, and mutations in tumor suppressor genes, including TP53, CDKN2A, RB1, ARID1A, ATM and STK11. We also identified new fusions and recurrent mutations in some genes, one of them, a possible regulator of gene expression, affecting ten percent of the LuADs, thus constituting a potentially relevant tumor suppressor gene. We also report a predominance of RB1-inactivation, mostly complex intragenic rearrangements (homozygous deletions or duplications) in EGFR-mutant tumors. Three EGFR-/RB1-mutant tumors, treated with EGFR-TKIs, and one EGFR-wild type tumor, treated with standard chemotherapy, developed small cell lung cancer and/or squamous cell carcinoma transformation, evident in the re-biopsies and/or PDCs. Finally, we found pathogenic germ-line mutations at genes associated to familiar-cancer syndromes, especially the TP53-associated Li Fraumeni syndrome, affecting ten percent of EGFR-mutant LuADs patients, underscoring a genetic predisposition origin for a subset of NSK-LuADs.
Conclusion
The recurrent gene inactivation found in candidate gene in LuADs heralds a tumor suppressor role which deserves further exploration. The pre-existent inactivation of RB1 predominates in EGFR-mutant tumors and may underlie an extremely ductile nature, albeit additional gene alterations are required to overcome sensitivity to the TKIs. Given their potential clinical and therapeutic implications, testing for RB1-alterations and for the Li-Fraumeni syndrome in EGFR-mutant LuADs patients may need to be incorporated in the clinical settings.
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P2.01 - Advanced NSCLC (ID 159)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.01-49 - Targeting STAT3-Positive Reactive Astrocytes with Silibinin in the Therapeutic Landscape of Non-Small-Cell Lung Cancer with Brain Metastases (Now Available) (ID 1336)
10:15 - 18:15 | Author(s): Sara Verdura
- Abstract
Background
Silibinin is a bioactive flavonolignan extracted from milk thistle (Silybum marianum) and is a direct inhibitor of STAT3 – with high affinity to both the Src homology-2 domain and the DNA-binding domain of STAT3. Pre-clinical data indicate that blocking STAT3 signaling in reactive astrocytes, a major component of the brain metastasis microenvironment, can decrease the number and size of brain metastases (BM).
Method
We present data on all patients diagnosed with BM from non-small cell lung cancer (NSCLC) from the Cancer Register of the Hospital Universitari Dr. Josep Trueta during 2013–2017. Age, gender, histology, and treatment in patients were recorded. During this period, some patients received compassionate use of Legasil®, a commercially available silibinin-based nutraceutical, in addition to standard oncologic treatment. The data cut-off for survival analysis was 28th March 2019.
Result
We identified 221 patients with NSCLC and BM. Median age: 62 y (range: 32–88 y); male: 161 (72.9%). Synchronous BM were observed at the diagnosis of primary lung cancer in 133 (60.2%) patients. Differences in median overall survival (mOS) were detected by histology subtype: adenocarcinoma (66.1%)=4.6 m, squamous (17.6%)=1.8 m, not otherwise specified (16.3%)=2.2 m, p=0.000003. Treatment effects on mOS are summarized in Table 1. In the subgroup of patients that received brain radiotherapy in addition to systemic therapy for BM, differences were maintained between patients that received Legasil® (n=15) or not (n=64):28.5 months vs 6.3 months (p=0.000052).
Table 1 Treatment % mOS
(without)mOS
(with treatment)p-value Brain radiotherapy 53.8% 1.9 m 5.1 m < 0.000001 Systemic therapy 52% 1.6 m 6.9 m < 0.000001 Brain surgery 5% 3.2 m 15.5 m =0.000127 Silibinin supplementation 8.1% 3.5 m 22.8 m =0.000001
Conclusion
Our data indicate that silibinin supplementation could contribute to the control of BM in patients with NSCLC. Further evaluation of silibinin, or other STAT3 inhibitors, in clinical trials is warranted in this setting.
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P2.03 - Biology (ID 162)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.03-03 - Landscape of Gene Fusions in Lung Adenocarcinoma Patients with Minimal Cigarette Exposure Identified on Malignant Pleural Effusions (ID 575)
10:15 - 18:15 | Author(s): Sara Verdura
- Abstract
Background
Gene fusions in lung adenocarcinoma (LuAD) involving tyrosine kinase receptors such as ROS1, ALK or RET are recurrent oncogenic drivers (~10%), enriched in light or never-smokers. Some of them represent emerging and predictive biomarkers for targeted therapies. Here we report the fusions detected in a cohort of metastatic LuAD patients with low tobacco exposure (never or former-smokers).
Method
Patient-derived cancer cell lines (PDC) were successfully established from malignant pleural effusions from 11 patients diagnosed with LuAD. We assessed the genetic and molecular profile by whole-exome sequencing (WES) and RNA sequencing (RNA-seq) in each cell line.
Result
Patients’ characteristics: median age, 58 (39-86); 9 were female. Eight of eleven were never-smokers and three, former-smokers. Seven patients were treatment naïve when pleural effusion samples were collected. A cytological examination of pleural fluid was performed by a lung pathologist and all samples were positive for malignant cells. Known driver mutations in lung primary tumours included one ALK translocation detected by FISH and three EGFR Del19 mutations by targeted sequencing. The three EGFR-mutant LuAD patients progressed to first or second-generation EGFR-TKI and we were able to stablish paired PDC after progressing to tyrosine kinase inhibitors (TKI) in two of them. We identified an acquired FGFR3-TACC3 fusion in one paired PDC after gefitinib progression (T790M-negative), that led to overexpression of FGFR3 concurrent with an enrichment of squamous cell lineage transcripts (e.g. TP63, SOX2) and MDM2 amplification. Among EGFR wild type (wt) patients, two RET rearrangements, CCDC6-RET and KIF5B-RET, and one EML4-ALK fusion -also detected in the primary tumour- were identified in PDC models. In addition, in two of the samples we discovered novel gene fusions that will be described in detail, involving proteins that are not kinases, and thus, their potential role in cancer is still unknown.
Conclusion
In this cohort enriched with never-smoking LuAD patients presenting pleural effusions at diagnosis, the presence of known driver fusions during the disease’s course detected by RNA-Seq was 36% (4/11), including a FGFR3-TACC3 fusion as an acquired resistance mechanism to EGFR-TKI. Further study is ongoing in our PDC models to test the functional role of these fusions in order to facilitate precision medicine.
