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Emily Roarty
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MA17 - Molecular Mechanisms and Therapies (ID 143)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Biology
- Presentations: 1
- Now Available
- Moderators:Eloisa Jantus-Lewintre, Hongbin Ji
- Coordinates: 9/09/2019, 15:45 - 17:15, Melbourne (1991)
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MA17.10 - Lactate Transporter Blockade as a Strategy to Overcome VEGF Inhibitor-Resistance in LKB1-Deficient NSCLC (Now Available) (ID 2647)
15:45 - 17:15 | Author(s): Emily Roarty
- Abstract
- Presentation
Background
STK11/LKB1 alterations are found in 20-30% of NSCLC and used to co-occur with KRAS mutations. Because LKB1 activates AMPK, many of the best known functions of LKB1 are attributed to its ability to control metabolic alterations in cells. Our laboratory have previously reported that loss of LKB1 promotes enhanced glycolysis and elevated lactate production and more recently we demonstrated that STK11/LKB1 mutations are the strongest predictors of de novo resistance to immunotherapy in NSCLC. Prior studies have revealed an association between alterations in the LKB1/AMPK pathway and worse clinical outcomes in NSCLC and in patients treated with chemotherapy and bevacizumab. Given the roles of LKB1 in the regulation of cell metabolism and resistance to immunotherapy, it is feasible that LKB1 also impacts on the response to anti-angiogenic therapies.
Method
Xenograft mouse models were established by subcutaneous injection of H460 cells (LKB1-deficient) and H460 LKB1-expressing in nude mice and LKR10 (KRASG12D) LKB1 wild-type (K) or LKB1- knockout (KL) into 129Svmice. Mice were randomized to vehicle or B20-4.1.1 anti-VEGF antibody. Glycolytic activity of LKB1-intact and -deficient NSCLC cells was measured by Seahorse assay. We analyzed gene expression of SLC16A3 (MCT4) by qPCR and Western blot. Genetic disruption of MCT4 in the K and KL cell lines was done using CRISPR-Cas9 and mouse models were established by subcutaneous injection into mice.
Result
Mice bearing LKB1-expressing H460 xenografts treated with anti-VEGF antibody showed a significant decrease in tumor volume (p<0.05) compared with their vehicle-treated counterparts. However, mice bearing LKB1-deficient H460 xenografts showed markedly reduced efficacy of anti-VEGF therapy compared with that in LKB1-expressing xenografts. Anti-VEGF therapy significantly reduced growth of LKR10 K tumors (p<0.001) but not in LKR10 KL tumors. Microvascular density was not increased in KL tumors following anti-VEGF treatment compared to K. Human isogenic LKB1-deficient cells showed a significantly increased rate of glycolysis and lactate secretion compared with cells expressing LKB1. Human and murine LKB1-deficient cells also had increased MCT4 expression compared to K cells. Immunofluorescence and RPPA analysis of tumor samples from the K and KL mouse models showed that KL tumors upregulated MCT4 protein expression compared with K tumors (p<0.0001). The genetic disruption of MCT4 KL tumors significantly improved tumor volume reduction to anti-VEGF therapies in vivo (p<0.001).
Conclusion
LKB1 loss is associated with increased lactate secretion and resistance to VEGF inhibition in NSCLC. The targeting of the lactate transporter MCT4 enhance the sensitivity of LKB1-deficient NSCLC to anti-VEGF therapy.
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MA19 - Looking at PROs in Greater Detail - What Patients Actually Want and Expect (ID 147)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Treatment in the Real World - Support, Survivorship, Systems Research
- Presentations: 1
- Now Available
- Moderators:Joaquim Bosch-Barrera, Virginia Calvo De Juan
- Coordinates: 9/10/2019, 11:30 - 13:00, Interlaken (1988)
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MA19.03 - Differences in Symptom Burden Between Responsive and Progressive Disease in Advanced Non-Small Cell Lung Cancer (aNSCLC) (Now Available) (ID 845)
11:30 - 13:00 | Author(s): Emily Roarty
- Abstract
- Presentation
Background
We have established a real-world Advanced Non-Small Cell Lung Holistic Registry (ANCHoR) to assess how immunotherapy impacts treatment choice, clinical outcomes, and patient-reported outcomes (PROs) of aNSCLC. Our aim in this analysis was to assess the ability of the MDASI-LC to differentiate between patients who are responding or who are progressing during treatment.
Method
Between May 2017 and December 2018, patients with aNSCLC at a single institution were enrolled in ANCHoR and completed the MDASI-LC prior to therapy (PTT) and at routine clinic visits. The MDASI-LC consists of 16 symptom severity and 6 interference items rated on 0-10 scales (0 = no symptom or interference, 10 = worst imaginable symptom or complete interference). MDASI-LC scores from PTT to first recorded response determination (FRD) were compared by response group using linear mixed modeling (LMM).
Result
One hundred one patients completed the MDASI-LC PTT and at FRD. Mean patient age was 63.8 years (standard deviation = 10.29) and 55% were males. Fifty percent of patients received chemotherapy (CTX), 22% immunotherapy (IM), 19% CTX+IM or angiogenesis inhibitor, and 9% targeted therapy. Median time from PTT to FRD was 105 days (lower quartile = 63, upper quartile = 224). Forty-six percent of patients had a complete or partial response (RECIST criteria CR, PR), 14% had stable disease (RECIST SD), and 41% progressed (RECIST PD). LMM showed progressing patients had significantly more fatigue (estimated effect [est] =1.39; p = 0.031), sleep disturbance (est=1.37; p = 0.046), and drowsiness (est=1.33; p = 0.037) and reported significantly more interference with work (est=1.67; p = 0.016) over time than responding patients.
Conclusion
The MDASI-LC differentiated the symptom burden of patients with responding disease from that of patients with progressive disease. Patients with progressive disease had more fatigue, disturbed sleep, drowsiness, and greater interference with work than those with responsive disease. Further research is needed to determine if the MDASI-LC can predict response to therapy in patients and may be useful in delineating treatment benefit.
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OA15 - Targeted Agents and Immunotherapy for Small Cell Lung Cancer (ID 152)
- Event: WCLC 2019
- Type: Oral Session
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Now Available
- Moderators:Raffaele Califano, Charles M Rudin
- Coordinates: 9/10/2019, 14:30 - 16:00, Hilton Head (1978)
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OA15.04 - Genomic and TCR Intratumor Heterogeneity of Small-Cell Lung Cancer by Multiregion Sequencing: An Association with Survival (Now Available) (ID 1458)
14:30 - 16:00 | Author(s): Emily Roarty
- Abstract
- Presentation
Background
Small cell lung cancer (SCLC) is an aggressive cancer. Although sensitive to initial therapy, recurrence is almost inevitable. The molecular mechanisms underlying recurrence are unknown. We have previously demonstrated that complex genomic and T cell receptor (TCR) intratumor heterogeneity (ITH) was associated with increased risks of relapse in non-small cell lung cancers (NSCLC). Genomic ITH and TCR architecture of SCLC and its clinical impact have not been well studied, largely due to lack of tumor specimens as surgery is rarely used to treat SCLC.
Method
We performed multiregion whole-exome sequencing and TCR sequencing of 49 tumor samples from 18 resected limited-stage SCLCs to delineate the immunogenomic ITH of SCLC. We compared the results to those in NSCLC and assessed the association of genomic and TCR attributes with patient’s survival.
Result
On average, 544 mutations/sample were detected. The median proportion of trunk mutations (mutations identified in all regions within the same tumors) was 80.4% versus 70% in NSCLC (TRACERx, Jamal-Hanjani, NEJM, 2017, p=0.08) and all TP53 and RB1 mutations were trunk mutations, suggesting these mutations were early events during carcinogenesis of this cohort of SCLCs. A higher non-synonymous tumor mutational burden (TMB) was associated with a higher T cell density (infiltration) in the tumor (r=0.46, p=0.005). Compared to the TCR repertoire of NSCLC (Reuben, WCLC, 2017), these SCLC tumors demonstrated significantly lower T-cell density (0.05 versus 0.24, p<0.0001), richness (diversity, 1,043 versus 3,666, p<0.0001) and clonality (reactivity, average 0.02 versus 0.15, p<0.0001) despite similar non-synonymous TMB (average 187 in SCLC versus 176 mutations/sample in NSCLC). Only 0.2% to 14.6% of T cells were detectable across all regions from the same tumors, suggesting substantial TCR ITH. Jaccard index (JI), a parameter quantifying TCR ITH was significantly lower in SCLC than in NSCLC (0.06 versus 0.1, p<0.0001) implying higher level of TCR ITH in SCLC than NSCLC. Interestingly, higher T-cell density, richness or clonality appeared to be associated with lower risk of recurrence numerically. Furthermore, higher TCR JI (less degree of ITH) was associated with significantly longer overall survival (HR=0.15, p=0.04).
Conclusion
Limited-stage SCLC tumors have distinct TCR repertoire and genomic ITH architecture. Overall, SCLC may have a more pronounced immunosuppressive microenvironment and higher level of TCR repertoire ITH than NSCLC. Nevertheless, higher degree of T cell infiltration and clonal expansion as well as more homogeneous T cell response may be associated with more favorable clinical outcome in patients with limited-stage SCLC.
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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P1.16 - Treatment in the Real World - Support, Survivorship, Systems Research (ID 186)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Treatment in the Real World - Support, Survivorship, Systems Research
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.16-31 - Body Mass Index Relating to Patient-Reported Symptoms in First-Line Treatment of Metastatic Non-Small Cell Lung Cancer (ID 2619)
09:45 - 18:00 | Author(s): Emily Roarty
- Abstract
Background
Patient-reported outcomes (PROs) provide information on patient treatment experience. Our aim in this analysis was to assess the longitudinal relationship between body mass index (BMI) with patient-reported symptom severity and interference during treatment.
Method
Between May 1, 2017 and December 7, 2018, patients with mNSCLC at a single institution were enrolled in a real-world Advanced Non-Small Cell Lung Holistic Registry (ANCHoR) and completed the MDASI-LC prior to start of therapy and at routine clinic visits. MDASI-LC consists of 16 symptom severity and 6 symptom interference items rated on 0-10 scales (0 = no symptom or interference, 10 = worst imaginable symptom or complete interference). BMI was measured at the same schedule as MDASI-LC. Mixed-effects models were used to examine the longitudinal association between BMI and symptom levels during treatment.
Result
103 patients completed the MDASI-LC prior to start of therapy and at least 2 follow-up assessments. Mean patient age was 64.3 years (standard deviation = 11.5) and 50% were males. 22% of patients received chemotherapy (CTX), 34% immunotherapy (IM), 23% CTX+IM or angiogenesis inhibitor, and 20% targeted therapy. The median pre-treatment BMI was 25.2 (inter quartile range, 5.2). BMI did not change during treatment and no significant difference was found among treatment groups. Compared with the obese group (BMI≥30), the overweight group (25≤BMI<30) experienced lowest levels of fatigue (estimation(est)=-1.23, standard error (SE)=0.49, p=0.016), disturbed sleep (est=-1.66, SE=0.49, p=0.002), distress (est=-0.90, SE=0.40, p=0.030) and less interference on mood (est=-1.03, SE=0.46, p=0.030) and interference with walking (est=-1.50, SE=0.51, p=0.005). The normal group (BMI<25) demonstrated lower levels of fatigue (est=-1.05, standard error (SE)=0.47, p=0.032) and disturbed sleep (est=-1.15, SE=0.47, p=0.018), compared with the obese group.
Conclusion
For patients with mNSCLC, obesity was related with higher symptom burden during active treatment. This analysis provides pilot data for future studies on balanced weight control and patients’ wellbeing during cancer treatment.
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P2.04 - Immuno-oncology (ID 167)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.04-19 - Neoadjuvant Chemotherapy Is Associated with Immunogenic Cell Death and Increased T Cell Infiltration in Early-Stage NSCLC (ID 1122)
10:15 - 18:15 | Author(s): Emily Roarty
- Abstract
Background
Recent success using immune checkpoint blockade (ICB) in the metastatic setting has raised the need to understand the immune microenvironment (IME) in early-stage disease. Moreover, pre-clinical evidence suggests that cytotoxic agents can modulate this IME. A recent study conducted by our group showed that non-small cell lung cancer (NSCLC) patients who received neoadjuvant chemotherapy followed by surgery (NCT), as compared to patients who received upfront surgery (US), had higher densities of CD3+ lymphocytes and CD68+ tumor-associated macrophages (TAMs). CD3+CD4+ lymphocytes and TAMs also correlated with better clinical outcomes. In this study, we explored the relationships between NCT and the IME by harvesting tumor samples of multiple surgical NSCLC cohorts.
Method
The PROSPECT microarray database was queried in NCT (n=45) and US (n=200) patients to investigate differentially expressed genes related to immunogenic cell death (ICD), susceptibility to CD8+ T cell and NK cell cytotoxicity, priming of antigen presenting cells, immunosuppressive enzymes and intra-tumoral cytokines. Available data from the ImmunogenomiC prOfiling of NSCLC (ICON) and other surgical NSCLC cohorts was evaluated to determine: 1) differential immune profiling using FACS (NCT=17; US=39) and multiplex IHC imaging (NCT=10; US=72); 2) plasma circulating cytokines (NCT=18; US=73); 3) tumor mutational burden (TMB) (NCT=40; US=61). Participants who received NCT or US were excluded according to these criteria: 1) concurrent treatment in addition to NCT; 2) sarcomatoid and small cell histologies; 3) clinical or pathological TNM Stage 4 disease; 4) synchronous malignancies other than lung.
Result
PROSPECT NCT patients expressed increased damage-associated molecular pattern (DAMP) genes (HSPA2, HSPA4, HSPE1, and S100A2; p<0.05) and T cell-related chemotaxis and antigen presentation genes (CXCR7, CD1A; p<0.05). Concordantly, the ICON cohort FACS results showed that NCT patients display increases in: 1) infiltration of CD8+ T cells (p=0.004); 2) proliferating Ki67+CD8+ T cells (p=0.02); 3) tissue resident memory CD8+CD103+ (p=0.02) and CD4+CD103+ non-Treg cells (p=0.01). Trends from the ICON multiplex IHC also highlighted increases in CD8+ T cells (p=0.09), CD20+ cells (p=0.08), as well as PD-L1+ malignant cells (p=0.08) and PD-L1+ TAMs (p=0.08) in NCT patients, the latter finding being supported by increased circulating MCP-1 (p=0.03). TMB was similar between NCT and US groups (p=0.912).
Conclusion
Our data provides the first evidence of ICD (i.e., increased DAMP gene expression) following NCT in human early-stage NSCLC. Furthermore, our data highlights the association of NCT with a favorable IME (i.e., increased T cell infiltration), supporting the rationale of NCT and ICB combinations in localized NSCLC.
