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Kenneth John O’Byrne
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MA22 - Partnering with Patients to Understand Stigma, Disparities and Values Leading to Improved Lung Cancer Care (ID 154)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Advocacy
- Presentations: 1
- Now Available
- Moderators:Diego Villalón, Christina Sit
- Coordinates: 9/09/2019, 15:45 - 17:15, Amsterdam (2011)
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MA22.06 - Longer Lung Cancer Time Intervals Amongst Culturally and Linguistically Diverse Patient Than Anglo-Australian Patients (Now Available) (ID 3103)
15:45 - 17:15 | Presenting Author(s): Kenneth John O’Byrne
- Abstract
- Presentation
Background
Lung cancer is the leading cause of cancer mortality worldwide. Culturally and Linguistically Diverse (CALD) patients are especially vulnerable, with poorer outcomes than non-immigrant patients. The LEAD (Lung cancer diagnostic and treatment pathways: A comparison between CALD and Anglo-Australian patients) study aimed to measure and compare the lung cancer diagnostic and treatment pathways between CALD and Anglo-Australian patients.
Method
LEAD is a mixed-method, observational cohort study. The presentation reports findings from the quantitative arm comprising a patient questionnaire and reviews of patients’ hospital and general practice records. A total of 577 (407 Anglo-Australian and 170 CALD) patients were recruited from Melbourne, Sydney and Brisbane, and their hospital records were reviewed. The questionnaire was returned by 189 patients (135 Anglo-Australian and 54 CALD) and a record review was completed by the General Practitioners (GPs) of 99 patients (76 Anglo-Australian and 23 CALD). Survival and Cox regression analyses were conducted to examine differences in time intervals between the two groups. LEAD is funded by Cancer Council Australia with the assistance of Cancer Australia.
Result
CALD patients reported longer time intervals from referral to diagnosis (Median = 30 days, 95% CI = 26 - 34) than Anglo-Australian patients (Median = 17, 95% CI = 14 - 20), p =. 003, Exp (B) = 1.32. This difference persisted after the impact of relevant factors, such as age and stage of lung cancer, was taken into consideration. CALD patients also reported longer time in five other intervals, including from 1) symptom notification to GP presentation, 2) GP presentation to referral, 3) referral to treatment, 4) symptom notification to treatment, and 5) symptom notification to diagnosis. However, the differences in these five intervals failed to reach significance.
Conclusion
LEAD is the first Australian study to comprehensively measure and compare the time intervals along the lung cancer pathways amongst CALD and Anglo-Australian patients. It found that CALD patients have longer time intervals from referral to diagnosis than Anglo-Australian patients.
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MA23 - Preclinical Models and Genetics of Malignant Pleural Mesothelioma (ID 353)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Mesothelioma
- Presentations: 1
- Now Available
- Moderators:Ramon Palmero Sánchez, Raphael Bueno
- Coordinates: 9/10/2019, 14:30 - 16:00, Copenhagen (1980)
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MA23.12 - Discussant - MA23.09, MA23.10, MA23.11 (Now Available) (ID 3819)
14:30 - 16:00 | Presenting Author(s): Kenneth John O’Byrne
- Abstract
- Presentation
Abstract not provided
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-01 - Clinical Relevance of Targeting Proteins Required for Mitotic Progression to Improve Chemotherapy Response in Non-Small Cell Lung Cancer (ID 1565)
09:45 - 18:00 | Author(s): Kenneth John O’Byrne
- Abstract
Background
Lung cancer is the leading cause of cancer-related mortality worldwide with a ~14% 5-year survival rate. Patients with non-small cell lung cancer (NSCLC), may undergo surgery followed by platinum-based chemotherapy for resectable disease, chemoradiotherapy for locally advanced disease, systemic treatment for advanced disease and palliative care. The primary issue with chemotherapy is that only 20-40% of patients have responsive disease. Although combinations with immunotherapy can enhance drug response in advanced disease, new strategies are needed to (1) identify which patients are most likely to benefit from platinum based therapy and (2) enhance the effectiveness of the current drug strategies.
Herein we describe cell division cycle associated protein-3 (CDCA3) and CDCA8 as a novel prognostic factors and therapeutic targets to delay or prevent platinum resistance in NSCLC. Both CDCA3 and CDCA8 are key regulators of the cell cycle mediating mitotic entry and progression. CDCA3 functions to enable cell entry into mitosis through degradation of the mitosis inhibitory factor WEE1. Whereas, CDCA8 promotes mitotic progression functioning in concert with the chromosomal passenger complex to ensure accurate chromosomal segregation.
Method
Tissue microarray (TMA), immunohistochemistry, Bioinformatics, Western blot, siRNA library, CRISPR-Cas9 knockout, cell viability, mass spectrometry.
Result
Our preliminary data point to CDCA3 and CDCA8 as novel therapeutic options in NSCLC. CDCA3 and CDCA8 protein are markedly elevated in NSCLC cases with heterogeneous staining associated with Ki67+ cases and strongly prognostic in adenocarcinoma cases. Bioinformatics analysis of clinical trial data (UT Lung SPORE cohort; observation arm vs adjunct chemotherapy arm) indicated that NSCLC patients with elevated CDCA3 and CDCA8 and treated with adjuvant chemotherapy had a poorer outcome than CDCA3low/CDCA8low patients. Accordingly, in vitro analysis of CDCA3 and CDCA8 expression in NSCLC cell lines identified a strong correlation with cisplatin sensitivity whereby CDCA3/CDCA8high cell lines have greater cisplatin IC50 values. Consistently, silencing of either CDCA3 or CDCA8 significantly enhanced cisplatin sensitivity. As a means to reduce either CDCA3 or CDCA8 levels in tumours, we identified that, for CDCA3 in particular, cisplatin induces phosphorylation of CDCA3 (Ser222) which is dependent upon casein kinase 2 (CK2). Inhibition of CK2 with the small molecule CX-4945 (Senhwa Biosciences) abrogated CDCA3 phosphorylation and consequently suppressed CDCA3 levels. CK2 inhibition also suppressed CDCA8 levels whereby CDCA8 protein stability is dependent upon CDCA3. The sensitivity of cisplatin was enhanced by CX-4945 across a panel of 11 NSCLC cell lines, particularly in CDCA3/CDCA8low cell lines. Cisplatin efficacy was further enhanced in CDCA3 or CDCA8 depleted NSCLC cells.
Conclusion
Our data highlight CDCA3 and CDCA8 as novel factors mediating NSCLC cell proliferation and sensitivity to cisplatin. Our data also suggest that novel strategies to suppress CDCA3/CDCA8 protein levels, using agents such as CX-4945, might ultimately benefit NSCLC patient outcome by delaying or preventing cisplatin resistance.
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P1.01-119 - Modified Lung Immune Prognostic Index (mLIPI) as a Predictive Tool of Nivolumab Outcomes in Advanced NSCLC Patients (ID 2531)
09:45 - 18:00 | Author(s): Kenneth John O’Byrne
- Abstract
Background
Identification of sub-populations of patients with a greater likelihood of response to anti-programmed death-1 (PD-1) inhibitors in NSCLC continues to be a focus of intense interest. A Lung Immune Prognostic Index (LIPI) has previously been proposed by Mezquita et al. JAMA 2018, based on baseline LDH and dNLR.
We have previously presented data on the association between the development of immune mediated Adverse Events (IrAE) with improved outcomes (including median PFS, OS and higher rates of clinical response) and univariate analysis of baseline clinical, biochemical and radiological factors associated with improved outcomes in advanced NSCLC patients treated with Nivolumab across seven oncology institutions in Queensland, Australia.
We now propose a modified prognostic index (mLIPI) using baseline performance status (PS), Lactate dehydrogenase (LDH), and Neutrophil to Lymphocyte Ratio (NLR) to better predict patients’ likely response to immune checkpoint inhibitors and investigate the relationship between the prognostic index and occurrence of IrAE. In addition, updated survival data for the real world 220 patient cohort, a 12 week landmark toxicity analysis and multivariate analysis will be presented for the first time.
Method
Multi-institutional retrospective cohort study of 220 patients who received Nivolumab across seven oncology institutions in Queensland, Australia. The mLIPI score was calculated by allocating 1 point for each of the three poor prognostic factors, PS 2-3, NLR >3, and LDH >1.5 x ULN, resulting in 4 groups (good, intermediate, poor and very poor) and was compared against the LIPI score for the same cohort. A multi institutional ethics approval was obtained.
Result
The occurrence of IrAE was associated with a lower number of poor prognostic factors at baseline (lower mLIPI score), P value = 0.013.
Conclusion
The mLIPI score correlated with outcomes (median PFS and OS) and was able to better identify those patients likely to obtain benefit from single agent Nivolumab therapy in this cohort when compared against published scores. Patients with a high mLIPI score, indicating a higher number of poor prognostic factors at baseline were less likely to derive a clinical benefit, or develop IrAE.
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P1.03 - Biology (ID 161)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 2
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.03-05 - COMMD4 in Lung Cancer: Towards a New Therapeutic Target and Diagnostic Biomarker (ID 2062)
09:45 - 18:00 | Presenting Author(s): Kenneth John O’Byrne
- Abstract
Background
Lung cancer has the highest incidence and mortality among all cancers. As resistance to the current therapies are inevitable, there is a great need to identify new therapeutic targets. In order to prevent cancer, cells possess a complex network of signalling pathways called the DNA damage response, which is involved in the detection, signalling, and subsequent repair of DNA. Failure of the DNA damage response results in cancer and tumorigenesis. The aims of this study were to investigate the therapeutic potential of COMMD4, a new protein within the DNA damage response, in lung cancer.
Method
The expression of COMMD4 in squamous and nonsquamous non-small cell lung cancer was investigated using bioinformatics, qPCR, lung cancer TMAs and immunoblotting experiments from immortalised human bronchial epithelial cell (HBEC) and lung cancer cell lines. We investigated the function of COMMD4 using in vitro assays in HBEC and lung cancer cells that were depleted of COMMD4 using siRNA.
Result
The COMMD4 gene was found to be upregulated in lung cancer cells compared with the non-malignant tissue. High levels of COMMD4 correlated with poor patient prognosis. Additionally, COMMD4 protein levels were upregulated in some lung cancer cells compared with the control HBEC cell line and COMMD4 protein was increased in NSCLC tissue. The depletion of COMMD4 markedly reduced the proliferation of NSCLC cells and not the control cell line. Furthermore, COMMD4-depleted cells were hypersensitive to DNA damaging chemotherapeutic agents which are currently used in the clinic and these agents lead to the induction of apoptosis and mitotic catastrophe in COMMD4-depleted cells.
Conclusion
Taken together, our data suggests COMMD4 as a potential therapeutic target and diagnostic biomarker in lung cancer, through the induction of cell death and inhibition of tumour growth.
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P1.03-19 - Circulating Tumour Cells in Non-Small Cell Lung Cancer (ID 1530)
09:45 - 18:00 | Presenting Author(s): Kenneth John O’Byrne
- Abstract
Background
Metastasis in cancer patients is reflected by measurable levels of circulating tumour cells (CTCs) in the blood of cancer patients. CTCs represent cancer cells from the primary and metastatic sites, thereby providing a comprehensive representation of the tumour burden of an individual patient.
Method
Our study was designed to use microfluidic devices for the capture and characterization of CTCs in non-small cell lung cancer (NSCLC) patient samples (n=105).
Result
We demonstrated a higher CTC capture efficiency using microfluidic CTC enrichment platforms. Using a novel multi-flow microfluidic device, we demonstrated label free CTC capture with high purity (>87%) and high recovery rate (>93%) with clinically relevant CTC concentrations. Molecular alterations present in the primary tissue were confirmed in the CTCs by 3D DNA FISH (ALK-translocations) and Immunohistochemistry (EGFR mutations, PD-L1). The presence of CTC clusters asssociated with poorer patient outcomes.
Conclusion
Our data suggests that PD-L1 is frequently expressed in NSCLC CTCs and an immunoscore may be able to identify patients likely to benefit from immunotherapy. The isolation and characterisation of CTCs by a simple blood draw provides a non-invasive means by which to sample the tumour dynamics prior to treatment and over the course of therapy.
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P1.09 - Pathology (ID 173)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Pathology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.09-07 - The Clinical Utility and Performance of Whole-Exome Sequencing for NSCLC Patient Care: A Comparison to Standard-of-Care (ID 2264)
09:45 - 18:00 | Presenting Author(s): Kenneth John O’Byrne
- Abstract
Background
Next-generation sequencing (NGS) has provided the technology to rapidly profile individual tumours and measure the increasing number of biomarkers particularly relevant to the treatment of NSCLC. The Australian Translational Genomics Centre (ATGC) was established as collaboration between the healthcare sector (Metro South Hospital and Health Service), higher education sector (Queensland University of Technology) and a government-run pathology service (Pathology Queensland) to provide genomic profiling of NSCLC patients at the princess Alexandria Hospital. The program was developed to integrate the ordering, processing and interpretation of large scale NGS sequencing into clinical practice.
Method
NSCLC samples derived from endobronchial ultrasound (EBUS) or from formalin-fixed, paraffin-embedded (FFPE) histological sections were used for molecular profiling with NGS technologies by the ATGC, providing the first NATA-accredited ISO15189 program for lung cancer in Australian public hospital. The genomic test utilized whole-exome sequencing (WES) in combination with a high-coverage spike-in panel of known cancer genes. The clinical reports included the calculation of tumour purity, tumour mutational burden, the assessment of copy number events and somatic mutations down to 3% allele frequency.
In addition, the performance of the genomic profiling was compared to the current standard practice performed by Pathology Queensland, based on a gene panel (and back-up IHC for EGFR and BRAF) with reporting on Tier 1-2 variants in selcted exons of EGFR, BRAF, KRAS and NRAS, and immunohistochemistry on EGFR and ALK. For this purpose, patient biopsies were processed in parallel by ATGC and Pathology Queensland.
Result
We demonstrated that samples derived from EBUS and FFPE sections routinely provides high quality diagnostic material of sufficient quality and tumour purity suitable for molecular profiling with NGS technologies. Thirty-six lung cancer samples were tested by WES/panel, and an average of 1.5 clinically significant Tier 1- 2 mutations were detected in NSCLC samples by WES/panel testing, and that 11 out of 36 cases had a high tumour mutational burden (>10 mutations/megabase).
Of the 36 cases, 17 were also tested by Pathology Queensland. In 7 of those 17 cases, WES/panel detected variants in genes other than EGFR, KRAS, NRAS, and BRAF not detected or reported by standard methods; and, based on the additional variants reported by WES/panel, an additional 7 of the 17 patients would be eligible for enrolment in a clinical trial in Australia (source: Molecular Match; www.molecularmatch.com).This did not include trials or medications based on the tumour mutational burden.
Conclusion
We demonstrate that integration of WES/panel testing into clinical practice is practical and provides significant advantages over standard testing by providing multiplexed testing of current and emerging biomarkers. Furthermore, adoption of WES/panel testing for the care of NSCLC patients is superior to standard-of-care in the stratification of lung cancer patients into appropriate Australian clinical trials.
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P1.14 - Targeted Therapy (ID 182)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.14-22 - SASH1, a Novel Prognostic and Predictive Factor for PARP Inhibitors in Lung Cancer (ID 744)
09:45 - 18:00 | Author(s): Kenneth John O’Byrne
- Abstract
Background
Genomic instability is a universal hallmark of all cancers. Many of the most commonly used chemotherapeutic agents target this genomic instability by directly damaging the DNA, which results in tumour cell death. Our previous work has revealed that loss of SASH1 is associated with impaired apoptosis and increased cellular proliferation. A new generation of drugs have been developed that target the DNA repair enzyme PARP to induce DNA damage and cell death. SASH1 (SAM and SH3 domain containing protein 1) has been described as a tumour suppressor and in support of this SASH1 mRNA levels are decreased in lung, breast, thyroid and colorectal cancers. Our data demonstrates that SASH1 functions in the repair of DNA damage and loss of SASH1 protein expression could be used as a companion diagnostic for PARP inhibitors.
Method
SASH1 IHC staining of lung cancer was correlated with patient survival. DNA damage repair was assessed following the depleted of SASH1 (siRNA). SASH1 protein levels in cell lines were correlated to PARP inhibitor sensitivity.
Result
A lung cancer tissue microarray (TMA) of 225 patients was assessed for SASH1 protein level. Low SASH1 levels were associated with an improved patient prognosis in adenocarcinoma on univariate analysis (p = 0.03). Analysis of DNA repair pathways demonstrated that SASH1 plays a role in homologous recombination (HR). Based on this observation, the impact of SASH1 expression on sensitivity to PARP inhibitors was explored. An inverse correlation between SASH1 levels and sensitivity to Olaparib was identified in lung cancer cell lines Figure 1 (R2 = 0.882). We subsequently analysed Olaparib sensitivity in a panel of SASH1 depleted lung cancer cells that demonstrated increased Olaparib sensitivity.
Conclusion
Our results indicate that SASH1 protein expression is a prognostic factor in lung cancer, high levels being associated with a worse prognosis in adenocarcinoma. Low SASH1 expression is associated with loss of HR and has the potential to be a predictive biomarker for sensitivity to PARP inhibitors in this disease.
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P2.14 - Targeted Therapy (ID 183)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 2
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.14-08 - Banf1 Predicts Lung Cancer Survival and Sensitivity to Platinum-Based Chemotherapy (ID 2146)
10:15 - 18:15 | Presenting Author(s): Kenneth John O’Byrne
- Abstract
Background
Barrier to autointegration factor 1 (BAF/Banf1) is a small, 10 kDa protein that functions as a non-specific DNA-binding homodimer and localises to the nuclear envelope during mitosis where it tethers DNA loops to the nuclear envelope.
Mutations in Banf1 are associated with the severe premature ageing syndrome, Néstor–Guillermo Progeria Syndrome. Previously, key proteins associated with other progeria syndromes have been shown to play a role in both tumourigenesis and ageing, and now more recently, Banf1 expression has been associated with poor gastric cancer survival. With lung cancers being the leading cause of cancer-related deaths worldwide, identifying markers of improved prognosis, particularly in association with specific chemotherapy treatments, is essential to maximising drug effectiveness and promoting patient survival.
Method
A variety of cell and tissue biology techniques including cellular Banf1 protein depletion and overexpression in a panel of lung cancer cell lines, drug treatments, immunofluorescence, immunoblotting and tissue microarray analysis, have been utilised in this study.
Result
Kaplan-Meier analysis of mRNA datasets from 1926 patients diagnosed with lung cancer show a statistically significant association (p=7.8e-12) between “low” Banf1 mRNA and increased median overall survival of patients at 88.7 months, compared with the 52-month median survival of the “high” Banf1 mRNA cohort.
Depletion of Banf1 in a panel of Non-Small Cell Lung Cancer (NSCLC) lines followed by cisplatin drug treatment demonstrated a heterogeneity of response, with a subset of cell lines experiencing improved survival while others displayed increased sensitivity to the drug compared with control cells.
Conclusion
Banf1 is a candidate marker of lung cancer patient prognosis with Banf1 depleted cells having altered sensitivity to cisplatin treatment. Understanding the mechanism by which Banf1 affects lung cancer cell sensitivity to this drug is an ongoing research process that may have major implications for lung cancer treatment. Identification of patient Banf1 expression levels may contribute to improved therapeutic tailoring while modulation of Banf1 expression may ultimately lead to significantly increased survival of diagnosed patients.
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P2.14-60 - Afatinib in EGFR Mutation-Positive NSCLC: Activity in Patients with Brain Metastases, and Impact on CNS Progression/Spread (ID 1664)
10:15 - 18:15 | Presenting Author(s): Kenneth John O’Byrne
- Abstract
Background
In the LUX-Lung 3 and 6 trials, first-line afatinib significantly improved progression-free survival (PFS) versus chemotherapy in patients with EGFR mutation-positive (EGFRm+) NSCLC and baseline brain metastases (hazard ratio [HR], 0.50; P=0.0297).1 In LUX-Lung 7, similar PFS improvement with afatinib versus gefitinib was observed in patients with, and without, brain metastases (HR, 0.76 and 0.74; Pint=0.93).2 The aims of this study were to assess: i) the impact of afatinib on central nervous system (CNS) progression or metastatic spread in LUX-Lung 3, 6, and 7; ii) efficacy of afatinib in patients with brain metastases in a similar setting to ‘real-world’ practice.
Method
Competing risk analysis of CNS/non-CNS progression or death was performed in patients who received afatinib in LUX-Lung 3, 6, and 7, based on the cumulative frequency of the event of interest versus the competing risk event. Separate analysis was performed of an Asian phase IIIb study, which assessed afatinib in a broad population of EGFR TKI-naïve patients with EGFRm+ NSCLC (NCT01953913).3 PFS and time-to-symptomatic progression (TTSP) in patients with baseline brain metastases were calculated by Kaplan–Meier methodology.
Result
In patients with baseline brain metastases receiving afatinib in LUX-Lung 3 and 6 (n=48; median follow-up: 10.3 months), the risk of CNS progression was 40% lower than the risk of extracranial progression; 31.3%/52.1% of patients had CNS/non-CNS progression, respectively. In patients without baseline brain metastases receiving afatinib in LUX-Lung 3, 6, and 7 (n=485; median follow-up: 13.0 months), the risk of de novo CNS/non-CNS progression was 6.4%/78.4%. Cumulative risk of CNS/non-CNS progression was 1.3%/17.2% at 6 months and 2.6%/41.2% at 12 months. In the Asian phase IIIb study, there was no difference in PFS (median 10.9 vs 12.4 months; P=0.18) or TTSP (median 14.8 vs 15.4 months; P=1.0) between patients with (n=92) or without (n=387) brain metastases.
Conclusion
Competing risk analyses of LUX-Lung 3, 6, and 7 suggest that afatinib delays the onset/progression of brain metastases. Real-world data are consistent with LUX-Lung 3, 6, and 7, and support the use of afatinib in patients with EGFRm+ NSCLC and baseline brain metastases.
1. Schuler, M. et al. J Thorac Oncol 2016;11:380‒90
2. Park, K. et al. Lancet Oncol 2016;17:577‒89
3. Wu YL, et al. J Thorac Oncol 2017;12(suppl 2):abstract P3.01-036
