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S. Kao
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MA 19 - Mesothelioma: Bench to Bedside (ID 680)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Mesothelioma
- Presentations: 1
- Moderators:Dean A Fennell, Hedy Lee Kindler
- Coordinates: 10/18/2017, 11:00 - 12:30, Room 315
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MA 19.06 - Multiple Mechanisms Contribute to Downregulation of Tumour Suppressor microRNAs in Malignant Pleural Mesothelioma (ID 9745)
11:35 - 11:40 | Author(s): S. Kao
- Abstract
- Presentation
Background:
Malignant pleural mesothelioma (MPM) is a disease with an almost invariably fatal diagnosis with limited therapeutic options. Characteristic patterns of deregulated microRNA expression have been demonstrated in MPM, and many downregulated microRNAs have been shown to have tumour suppressor activity. However, apart from silencing of miR-34b/c by promoter hypermethylation and co-deletion of miR-31 with the CDKN2A locus, the mechanisms responsible for downregulation of other tumour suppressor miRNAs such as miR-16 are yet to be elucidated.
Method:
Tumour samples (n=60) were from MPM patients undergoing extrapleural pneumonectomy, and samples of pleura (n=23) collected from patients undergoing cardiac surgery were used as normal controls. MPM cells lines were obtained from the ATCC. Expression levels of mature microRNAs in MPM tumour samples and cell lines, and pri-miRs and miRNA host genes in cell lines, were determined by RT-qPCR. Copy number variation (CNV) was analysed by droplet digital PCR (ddPCR), and methylation was inferred by miRNA expression following decitabine treatment. MYC was analysed by Western blot, and expression modulated by siRNAs.
Result:
Analysis of microRNA expression in tumour samples revealed a consistent and significant downregulation of miR-15a (4-fold, P<0.01), 15b (10-fold, P<0.01), 16 (22-fold, P<0.05), 34a (1.6-fold, P<0.05), 34b (1.8-fold, P<0.01), 34c (2.3-fold, P<0.0001) and 193a (3.1-fold, P<0.001) compared with normal pleura. Copy number variation analysis showed evidence of heterozygous loss for miR-193a (4 of 5 cell lines) and miR-15a/16-1 (2 of 5), but no change in miR-15b/16-2. Treating cell lines with the demethylating agent decitabine resulted in dramatic upregulation only in the case of miR-34c. RNAi-mediated knockdown of c-MYC led to upregulation of miR-15b and 16, and to a lesser extent miR-15a, as well as a consistent increase in the miR-15b/16-2 host gene SMC4 and the miR-15a/16-1 host gene DLEU2. Analysing the expression of these microRNAs in the tumour samples revealed a strong correlation between miR-15b and 16 (R[2]=0.793) and miR-34b and 34c (R[2]=0.753), but not between others.
Conclusion:
Our data suggest that a combination of deletion, hypermethylation and transcriptional regulation contribute to the downregulation of miR-15a/b, 16, 34a/b/c and 193a. In MPM, unlike other cancers, the downregulation of miR-15a/16-1, miR-15b/16-2 appears to be due to transcriptional changes rather than deletion or promoter hypermethylation. MYC appears to contribute to miR-16 downregulation primarily via control of SMC4 and the miR-15b/16-2 locus, suggesting that the transcriptional control of miR-16 expression by c-Myc contributes to the malignant phenotype of MPM.
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P1.01 - Advanced NSCLC (ID 757)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.01-011 - Pattern of Care and Survival of ALK Rearranged Non-Small Cell Lung Cancer in Two Australian Referral Centres (ID 8893)
09:30 - 09:30 | Author(s): S. Kao
- Abstract
Background:
ALK rearranged non-small cell lung cancer (ALK+NSCLC) represents a unique sub-group of lung cancer. Multiple effective treatments have been investigated and reported with the optimal strategy to treat advanced disease evolving rapidly with new data. First, second and now third generation single agent ALK inhibitors (ALKi) achieve excellent objective response rates (ORR), superior to chemotherapy; however, drug resistance is inevitable and remains under ongoing evaluation. Further studies are underway incorporating combination treatments, particularly immunotherapy with ALKi. Overall survival data from clinical trials continues to mature, as few non-trial series have been reported. We report our overall survival (OS) experience in treating ALK+NSCLC in a real-world cohort.
Method:
All patients with advanced lung cancer and a diagnosis of ALK+ NSCLC treated until Jan 2017 in two tertiary referral centres in Sydney, Australia were pooled together for analysis. Baseline demographic, symptom, treatment and sequencing, ORR and central nervous system (CNS) ORR, survival, toxicity and cause of death data were collected. Data will be presented on updated survival via Kaplan-Meir plots with 95% confidence intervals and a swimmer plot of treatment sequencing and ORR via RECIST 1.1.
Result:
Between 18/2/2010 and 28/1/2017, 56 ALK-rearranged lung cancer patients were identified. Median age was 63 years, 41% were female; 62% never-smokers, 63% non-Asian and 66% managed on a clinical trial. At first data cut (March 31, 2017), 52% had died. Median OS in the whole cohort was 44.6 months (95%CI: 27.8-61.4mo). Two patients were not fit for active treatment; one did not receive CNS imaging. All current ALKi therapies, chemotherapy, brain directed therapy, treatment to oligo-progressive disease and combination ALKi/immunotherapy were represented. Sixty-one percent of patients received an ALKi first line with an ORR 87%; 85% of the 34 (61%) patients who received second line therapy received an ALKi, ORR 52%. Thirty-percent received at least two lines of ALKi; 44% who received only one line of ALKi remained on and are still responding at data cut-off. Median OS in the 59% of patients with CNS metastases was 44.6mo (95% CI 14.7-74.6 mo).
Conclusion:
Analysis of real world data from two ALK referral centres in Australia reveals an imposing survival, despite many patients being managed before next generation inhibitors were available in the early line setting. While CNS disease is common in ALK patients, with aggressive local therapy and evolving treatments, survival in this cohort was comparable to those without brain metastases.
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P3.09 - Mesothelioma (ID 725)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Mesothelioma
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.09-004 - Routine Clinical Parameters Can Stratify Survival Characteristics in Mesothelioma Patients Undergoing Surgery (ID 8318)
09:30 - 09:30 | Author(s): S. Kao
- Abstract
Background:
Malignant pleural mesothelioma (MPM) is a rare cancer with a heterogeneous prognosis. We have previously described and validated a prognostic model using a classification and regression tree (CART) model to analyse the interaction of multiple variables with survival in a broad MPM population.(1) We aimed to test the performance of our model on a population with MPM who had surgical intervention.
Method:
Cases from Australia and Japan with confirmed MPM who underwent surgery were analysed with clinical variables available at the time of referral recorded. The model uses combinations of different variables (Table 1) to stratify participants into different risk groups (1-4) and the survival characteristics were compared using the Log Rank test. Figure 1
Result:
A total of 289 cases were included (205 from Australia and 84 from Japan) who had surgery between 1991-2016. Overall median survival was 34.6 (IQR 17.5-56.1) months; median age 63.0 (IQR 57.0-67.8) years, 240/289 (83.0%) were male. Epithelioid MPM was the most common subtype (80.9%), weight loss was present in 36.6%, dyspnoea in 54.4%, chest pain in 29.0% and 91.8% had an ECOG performance status of 0. EPP was the most common operation performed (56.7%), followed by pleurectomy/decortication in 30.4%. There were no clinically meaningful differences between the cohorts; 40 patients were alive at censure. Survival across the risk groups was significantly different (Log Rank test p<0.0001). The group with the longest survival (median 78.1, IQR 28.1-152.4 months) had no weight loss, Hb >153g/L and serum albumin >43g/L at the time of referral to specialist surgical centre.
Conclusion:
The combination and interaction of simple, clinical variables available early after diagnosis of MPM is able to stratify survival and discriminate higher and lower risk of death in high performance status patients
