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Katrina Hueniken
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-70 - Dominant Circulating Myeloid Populations Are Associated with Poor Response in NSCLC Treated with 1st Line PD-1 Monotherapy (Now Available) (ID 2295)
09:45 - 18:00 | Author(s): Katrina Hueniken
- Abstract
Background
Immune subpopulations within the tumor microenvironment (TME) play a central role in determining response to checkpoint inhibitors. Myeloid derived suppressor cells (MDSC), a heterogeneous population of immature myeloid cells, have a predominantly immunosuppressive role by stimulating T regulatory cells. We hypothesize that elevated myeloid-to-lymphocyte measures in the peripheral blood predict for greater numbers of myeloid derived suppressor cells in the TME and worse outcomes.
Method
We identified all advanced NSCLC patients treated with immunotherapy between 2010-2019 at the Princess Margaret Cancer Center. Patients who received first line monotherapy with a PD-1 inhibitor were reviewed for clinical information including age, sex, histology, stage, smoking status, ethnicity, PD-L1 expression and tumor genotype. Myeloid cells lines analyzed included neutrophils, monocytes and platelets, expressed as ratios to peripheral lymphocytes. Multivariate analyses were conducted using the cox and logistic regression models to adjust for confounders.
Result
We identified 75 patients who were eligible for analysis. Disproportionate increases in the different myeloid cell types were highly correlated with each other (all Pearson’s rho>0.8) and the neutrophil to lymphocyte ratio (NLR) was selected as representative. A high NLR (>5) was associated with shorter time-to-treatment-failure (median TTF 9.7 vs 29.4 months) that remained significant after adjusting for confounders including PD-L1 and presence of liver metastases (p=0.004). High NLR was also an independent predictor of poor OS (median 11.3 vs 56.8 months, HR 3.02, p=0.04). Although NLR was not predictive of radiographic response, there was a trend to association with a rapidly progressive phenotype defined by primary progressive disease and a duration of therapy ≤2 months (p=0.06). Other predictive factors included the presence of liver metastases, which was associated with a worse OS (HR3.37 p=0.05) but not TTF (p=0.14). An association was also seen between NLR and liver metastases (mean NLR 6.6 vs 25.2 in the absence and presence of liver metastases respectively, p<0.001).
Conclusion
A disproportionate increase in peripheral immune myeloid populations may represent a systemic, myeloid-driven, immunosuppressive state that is significantly associated with primary refractory disease, rapid progression, and poor survival. A subset of about 50 patients with biobanked tissue are presently being analyzed using multiplex immunofluorescence to assess for MDSCs in the TME to correlate with peripheral blood findings.
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P1.07 - Nursing and Allied Professionals (ID 171)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Nursing and Allied Professionals
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.07-15 - Screening for Long Term Ototoxicity in Lung and Upper Aerodigestive Cancer Survivors Treated with Platinum Chemotherapy (ID 2011)
09:45 - 18:00 | Author(s): Katrina Hueniken
- Abstract
Background
Platinum-induced ototoxicity (PIO) is the hearing disorder that results from the temporary or permanent inner ear dysfunction after treatment with platinum based chemotherapy. Debilitating symptoms can include hearing loss, tinnitus and ear pain, affecting 40-80% of adults treated with platinum chemotherapies (up to 50% of lung cancer patients). There is no cure for PIO and the focus should be on early detection and lifestyle management. Ototoxicity negatively impacts quality of life in survivorship impacted by difficulty in speech recognition, safety concerns, social isolation and depression. At most cancer centres, hearing tests are not routinely performed in adults receiving cisplatin.
This study aims to implement screening audiometry initially through formal audiometry testing, and later through a mobile electronic tablet-based platform. Our study goals are: i) to confirm the high prevalence of ototoxicity; and ii) the feasibility of implementing an in-clinic tablet based hearing test as part of routine care for lung cancer patients.
Method
Using the CIHR Knowledge-to-Action framework, we formally assessed the clinic readiness, barriers to implementation, identification of facilitators, and initiated a pilot outpatient clinic-based study in our lung and head and neck cancer patients to determine viability and sustainability within the clinic.
Result
Prevalence of hearing loss ranged between 22-58% of cisplatin-treated patients. Barriers to implementation included: (i) difficulty contacting some survivors; (ii) coordinating testing across broad geographic areas; (iii) missing test results; (iv) allocation of physician versus nursing responsibilities in a multidisciplinary setting; (v) health care provider education; and (vii) long-term transition plan to primary care follow-up. Nursing/clinic champions improved uptake substantially. New procedures were necessary to ensure that tests are performed, results checked, and patients were triaged accordingly.
Conclusion
Substantial barriers were identified for clinical implementation of the routine post-platinum audiometry screening for ototoxicity in lung cancer survivors, but a list of potential solutions has led to good uptake of this process in the clinic. In a future follow-up pilot, we will test the potential benefits (time- and labour-savings; more efficient use of resources) of an in-clinic, portable, brief, tablet-based hearing test screening program, in place of formal audiometry testing.
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P1.10 - Prevention and Tobacco Control (ID 175)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Prevention and Tobacco Control
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.10-05 - Tobacco Retail Availability and Tobacco Cessation Among Lung Cancer Survivors (ID 1089)
09:45 - 18:00 | Author(s): Katrina Hueniken
- Abstract
Background
Continued smoking after a lung cancer diagnosis is associated with poorer outcomes. Tobacco retail availability is negatively associated with cessation in non-cancer patients but this has not been explored in cancer survivors. We evaluated the impact of tobacco retail availability on tobacco cessation in lung cancer survivors.
Method
Lung cancer survivors from Princess Margaret Cancer Centre (Toronto, Canada) completed questionnaires at diagnosis and follow-up evaluating changes in tobacco use with a median of 26 months apart. Validated tobacco retail location data were obtained from Ministry of Health and patient home addresses were geocoded using ArcGIS 10.6.1, which calculated walking time/distance to nearest vendor, and vendor density within 250 meters (m) and 500m from patient residences. Multivariable logistic regression and Cox proportional hazard models evaluated the impact of vendor availability on cessation and time to quitting after diagnosis respectively, adjusting for significant clinico-demographic and tobacco covariates.
Result
242/721 lung cancer survivors smoked at diagnosis; subsequent overall quit rate after diagnosis was 66%. Mean distance and walking time to a vendor was 0.8 km (range 0-13) and 10 min (range 0-157). On average, there was one vendor (range 0-19) within 250m and five vendors (range 0-36) within 500m from pts; 40% and 64% of pts lived within 250m and 500m from at least one vendor respectively. Greater distance (aOR 1.28 per 1000m [95% CI 0.97-1.70] p = 0.08) and increased walking time (aOR 1.02 per minute [1.00-1.05] p = 0.08) to a tobacco vendor had a non-significant trend towards increased chances of quitting at one year. Living within 250m (aOR 0.43 [0.25-0.74] p = 0.003) or 500m (aOR 0.50 [0.28-0.88] p = 0.02) to at least one vendor reduced quitting at one year. Living near more vendors within 500m had a non-significant trend towards having an increasing dose effect on reducing cessation rates at one year (aOR 0.97 per vendor [0.94-1.00] p = 0.08). Living within 500m to a vendor reduced chance of quitting at any time (aHR 0.70 [0.50-1.00] p = 0.05).
Conclusion
Close proximity to tobacco retail outlets is associated with reduced cessation rates for lung cancer survivors. Reducing density of tobacco vendors is a cessation strategy that could positively impact lung cancer patient outcomes.
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P2.03 - Biology (ID 162)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 2
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.03-11 - Impact of Ethnicity on Outcome in Never Smokers with EGFR and ALK Wildtype (EGFR/ALK-Wildtype) Lung Adenocarcinomas (ID 2035)
10:15 - 18:15 | Author(s): Katrina Hueniken
- Abstract
Background
EGFR-mutations and ALK-rearrangements are frequent in lung adenocarcinoma (LUAD) samples from never smoker patients. Nevertheless, up to a quarter of all LUAD cases in never smokers are EGFR/ALK-wildtype: these patients have limited therapeutic options and few well-established clinical and molecular predictors of outcome. Our main objectives here were to investigate the prognostic impact of ethnicity in never smoker patients with EGFR/ALK-wildtype LUAD and seek for specific somatic events correlated to ethnical background in these patients.
Method
We included 85 samples from lifetime never-smoker patients with EGFR/ALK-wildtype LUAD collected from surgical resection with curative intent. Stages 1/2/3 were identified in 56 (66%)/15 (18%)/14 (16%) samples. A subset of those samples (n=46), with similar stage distribution, had snap-frozen tumor and paired-adjacent tissue available and were submitted to paired-end whole-exome sequencing. Fisher’s exact and Chi-squared tests were used to compare specific mutations between Asians vs non-Asians. Recurrence-free-survival (RFS) was calculated based on the Kaplan-Meier method; Cox modeling was used to generate hazard ratios (HR), adjusted for key clinical features.
Result
Most patients in the cohort were female (63/85, 74%); the median age was 68 years; median follow-up was 51 months. According to self-reports, 19/85 (22%) and 66/85 (78%) patients identified as Asians and non-Asians, respectively; no major clinical and pathologic differences were identified between these populations. Five-year recurrence free survival was significantly lower for Asians compared to non-Asians (50% vs. 78%, adjusted HR = 2.9; CI = 1.1-7.8, p=0.02), Figure 1. Among somatic events, in-frame deletions in CNPY3 (Toll-like receptor-specific co-chaperone for HSP90B1) were more frequent in Asians (30%) compared to non-Asians (18%). In contrast, DDX11 missense mutations (21% vs 0%; nucleic acid binding protein involved in genome stability), NOTCH2 multi-hits and frame-shift deletions (7% vs 1%), and KRAS missense mutations (7% vs 0%) were more frequently altered in non-Asians than in Asians.
Conclusion
In our cohort of never-smoker patients with EGFR/ALK-wildtype LUAD, Asian patients showed higher relapse rates than non-Asians. We identified differentially mutated genes by ethnicity that may partly account for these differences in outcome. (SNMF and AFF contributed equally)
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P2.03-37 - Genomic Landscape of EGFR/ALK Wild-Type Lung Adenocarcinomas in Never-Smokers and Importance of Epithelial-Mesenchymal-Transition (ID 1283)
10:15 - 18:15 | Author(s): Katrina Hueniken
- Abstract
Background
The molecular landscape of EGFR/ALK wild-type Lung Adenocarcinomas in never-smokers is poorly understood. Never-smokers usually have low PD-L1 expression and low Tumor Mutation Burden, challenging treatment strategies when no known driver-mutations are found. To identify putative driver mutations, we compared whole exome sequencing (WES) results in the EGFR/ALK wild-type Lung Adenocarcinoma in the never smokers Toronto cohort with a corresponding EGFR/ALK wild-type Lung Adenocarcinoma group of smokers from TCGA.
Method
For never-smokers with resected EGFR/ALK wild-type Lung Adenocarcinomas, frozen tumor and paired-normal-lung were evaluated by WES at a mean coverage of 238x. The paired-end reads were aligned using BWA and were further processed using the standard GATK pipeline. Somatic mutations and indels were identified using MuTect and VarScan, respectively. We compared mutations from our cohort to the TCGA smokers who had EGFR/ALK wild-type Lung Adenocarcinomas from publicly available data (TCGA) to identify genes at least 10% more frequently mutated in never smokers compared to the TCGA cohort.
Result
In our cohort with 45 never-smoker patients, 80% were females; median age was 70y; 29% were Asians; Stage I/II/III+ were 71%/15%/13%; after a median follow-up of 69 months, 24% had recurred. Median non-synonymous Tumor Mutation Burden was 1.3mut/Mb in never-smokers. We identified 39 genes that were more frequently mutated in never-smokers vs smokers, including some known tumor suppressor genes. The most prevalent genes included ADAM21 missense mutations (21% vs 1%; adj p=0.003), NOTCH2 frame-shift deletions and multi-hit mutations (40% vs 17%; adj p=0.04), MST1 missense mutations and in-frame deletions (13% vs 0%; adj p=0.008), ZMIZ2 frame-shift insertions (13% vs 0%; adj p=0.008) and FOXD4 missense mutations (10% vs 0%; adj p=0.02). Many of these differentially mutated genes have been previously associated to epithelial-mesenchymal-transition signaling pathways. Conversely and as expected, KRAS, TP53, STK11 and KEAP1 were more frequently mutated in the TCGA smokers EGFR/ALK wild-type Lung Adenocarcinomas cohort.
Conclusion
We identified multiple genes, particularly involved in the epithelial-mesenchymal-transition signaling pathways that are over-represented in never-smokers with EGFR/ALK wild-type Lung Adenocarcinomas, when compared to smokers with EGFR/ALK wild-type Lung Adenocarcinomas. This is a novel finding with potential clinical importance. Validation studies, analyzing epithelial-mesenchymal-transition signaling activation pathways on the EGFR/ALK wild-type Lung Adenocarcinomas never smokers population are needed to best identify the actual role in carcinogenesis and metastasis, guiding future treatment strategies. (AFF and SNMF contributed equally).
