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G. Wright
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P1.02 - Biology/Pathology (ID 614)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 2
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.02-012 - Profiling DNA Repair in Lung Cancer (ID 10425)
09:30 - 09:30 | Author(s): G. Wright
- Abstract
Background:
We hypothesised that some lung cancers have DNA repair alterations that either are therapeutically targetable, or that result in resistance to particular DNA damaging therapies. Expression profiling of DNA repair genes may thus enable better matching of patients with the current chemotherapeutic options. Furthermore, profiling may identify tumours that will be more responsive to other DNA repair-directed therapies not normally used in treating NSCLCs e.g. PARP or CDKN4/6 inhibitors.
Method:
We tested RNA of more than 166 samples from tumour cores of 107 patients and 12 normals on the Nanostring platform. We developed a new approach to normalising Nanostring data based on the RUV (removing unwanted variation) method so that we could better identify differences between the patients.
Result:
Many interesting findings emerged indicating some new therapeutic options. The conclusions obtained from Nanostring analysis were verified by examination of the TCGA lung adenocarcinoma RNA-Seq data.
Conclusion:
This is the first systematic study of DNA repair gene deficiencies in NSCLC. There are important implications for the rational use of chemotherapy and radiotherapy. This work was funded by Cancer Australia.
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P1.02-071b - SASH1 Is a Prognostic Indicator and Future Target in NSCLC (ID 9591)
09:30 - 09:30 | Author(s): G. Wright
- Abstract
Background:
Lung cancer is the most commonly diagnosed cancer in the world and the fifth most common in Australia, where it is responsible for almost one in five cancer deaths. SASH1 (SAM and SH3 domain-containing protein 1) is a tumor suppressor functioning to control of apoptosis and cellular proliferation. Previously SASH1 has been shown to be down-regulated in approximately 90% of lung cancers, however little is known about the role of SASH1 in the pathogenesis of the disease. Cytotoxic platinum based chemotherapy two-drug regimens remain a cornerstone NSCLC patient care, however, resistance to these agents is almost inevitable. The re-sensitisation of these cancer cells to chemotherapeutics is a key to improving patient survival. We hypothesised that modulation of SASH1 expression may alter cisplatin sensitivity.
Method:
A panel of lung cancer cell lines depleted of SASH1 (siRNA) or overexpressing SASH1 were analysed for protein levels via immunoblotting, cell proliferation, and survival/death assays. Treatment of lung cancer cells with the SASH1 protein stabilising compound chloropyramine (0-50 μM) and/or cisplatin (0-10 μM) was performed followed by immunoblotting for SASH1, cell proliferation, and survival/death assays. SASH1 IHC staining of adenocarcinoma and Squamous cell carcinomas was correlated with patient survival.
Result:
We demonstrated that SASH1 depletion results in a significant increase in cellular proliferation of NSCLC cancer cells. The depletion of SASH1 within lung cancer cell lines was associated with a significant increase in cisplatin resistance. Transfection of SASH1 into NSCLC cell lines induced cell death. The treatment of cells with the SASH1 protein stabilising compound chloropyramine increased SASH1 levels, reduced proliferation and induced apoptosis. Furthermore, chloropyramine increased cisplatin sensitivity. The relationship between SASH1 protein expression with overall survival was accessed in a NSCLC TMA panel. This showed that high SASH1 protein levels were associated with a poor prognosis in adenocarcinomas but were non-prognostic in squamous cell disease. Interestingly high SASH1 mRNA levels were associated with a favourable prognosis in adenocarcinoma but were not prognostic in squamous cell cancer. In a panel of cancer cell lines we observed no correlation between mRNA and protein levels that may explain this discrepancy.
Conclusion:
Agents that upregulate SASH1, or SASH1 gene therapy, are potential novel approaches to the management of NSCLC. Further preclinical and clinical studies of chloropyramine in combination with chemotherapy are justified in NSCLC.
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P3.16 - Surgery (ID 732)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Surgery
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.16-045 - Evaluation of the Safety and Efficacy of VATS Pneumonectomy in the Treatment of Locally Advanced Lung Cancer (ID 9310)
09:30 - 09:30 | Author(s): G. Wright
- Abstract
Background:
VATS technique has been increasingly used worldwide for the management of lung cancer[1]. VATS lobectomy has been shown to be superior to traditional open lobectomy with shorter length of stay, fewer perioperative complications and improved quality of life[1]. There remain concerns regarding the use of VATS for larger oncological resections including pneumonectomy and sleeve resections. We add more confirmatory data to several retrospective cohort studies demonstrating the safety of VATS pneumonectomy in selected patients[1,2].
Method:
With ethics approval, a retrospective cohort study was performed at a single-centre in Melbourne, Australia. It included all patients who had undergone a pneumonectomy between 1999 and 2017. The primary outcome was overall survival. Secondary outcomes included: 30-day and 90-day mortality, disease free survival and length of stay.
Result:
79 patients underwent pneumonectomy between 1999 and 2017. 27 patients underwent pneumonectomy via VATS approach. There were 76 patients with NSCLC, two with carcinoid and one with melanoma. There was no difference in the tumour size between the two cohorts (VATS median 47mm versus open median 50mm, p=0.12). There was no significance difference in node positive disease between the two cohorts (p=0.14). The 30-day and 90-day mortality rate was 3.8% and 5.1% respectively, with all events occurring in the open cohort. Median overall survival for all patients was 22 months, with a median disease-free survival of 14 months. There was no statistically significant difference in overall survival depending on operative access (median survival VATS 86 months versus open 26.2 months, p=0.12). There was no difference in disease-free survival from NSCLC between the two groups (VATS median 86 months versus open median DFS 15.9 months, p=0.21). The length of stay was shorter in the VATS cohort (7 days versus 8 days, p=0.008). The number of lung cancer cases performed as VATS at our institution has increased from 41% between 2002 and 2011 to 84% since 2014. The rate of VATS pneumonectomy has increased from 18% between 2002 and 2011 to 58.6% since 2014, however this increase lagged three years behind less major resections (i.e. lobectomy).
Conclusion:
In concordance with other recent retrospective cohort studies, our study demonstrates both the safety of VATS pneumonectomy and the oncological efficacy in appropriately selected patients. References: 1. Sahai RK, Nwogu CE, Yendamuri S et al. Is thorascopic pneumonectomy safe? Ann Thorac Surg. 2009;88:1086-1092. 2. Nagai S, Imanishi N, Matsuoka et al. Video-assisted thorascopic pneumonectomy: retrospective outcome analysis of 47 consecutive patients. Ann Thorac Surg. 2014;97(6):1908-1913.
