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Dara L. Aisner
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MA02 - Improving Outcomes for Patients with Lung Cancer (ID 895)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 10:30 - 12:00, Room 201 BD
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MA02.01 - ROS1 Gene Rearrangements Are Associated with an Exaggerated Risk of Peri-Diagnosis Thromboembolic Events (ID 12442)
10:30 - 10:35 | Author(s): Dara L. Aisner
- Abstract
- Presentation
Background
Based on clinical observation, we hypothesized that ROS1 gene-rearranged non-small cell lung cancer (ROS1+ NSCLC) has a higher than expected thromboembolic event (TEE) rate. A multicenter, retrospective cohort study of TEE in advanced ROS1+, KRAS+, ALK+ and EGFR+ NSCLC was conducted.
a9ded1e5ce5d75814730bb4caaf49419 Method
Venous (DVT / PE) and arterial (MI/TIA/CVA) TEE within +/- 365 days of diagnosis of ROS1+, KRAS+, ALK+ or EGFR+ advanced NSCLC at 4 academic centers in USA and China from October 2002 to January 2018 were captured. The primary endpoint was the incidence of TEE in ROS1+ compared to KRAS+ NSCLC as a control group within +/- 90 days of diagnosis. Secondary endpoints compared TEE incidence between ROS1+ and ALK+, and ROS1+ and EGFR+. Fine-Gray Model was used to detect differences in TEE incidence while accounting for death as a competing risk.
4c3880bb027f159e801041b1021e88e8 Result
105 ROS1+, 101 ALK+, 112 EGFR+, and 114 KRAS+ NSCLC patients were enrolled. Incidence rate of TEE within +/- 90 days of diagnosis was 30.5% (32/105), 12.9% (13/101), 7.1% (8/112), and 12.3% (14/114) in the respective molecular cohorts. Compared to the ROS1+ cohort, the risk of TEE was significantly lower in the three other cohorts (KRAS+ HR 0.334, 95% CI: 0.18-0.62, p=0.001; ALK+ HR 0.357, 95% CI: 0.188-0.68, p=0.002; EGFR+ HR 0.193, 95% CI: 0.089-0.421, p<0.001) (Figure 1). First event TEEs were venous as opposed to arterial in 59.5% (22/37) ROS1+, 87.1% (27/31) ALK+, 80.6% (25/31) EGFR+, and 80% (16/20) KRAS+ cases. The median time (Interquartile Range) to TEE from the time of diagnosis for ROS1+/ALK+/EGFR+/ KRAS+ was 0 days (-6.75 to 7.0), 0 days (-20.0 to 35.0), 0.50 days (-43.7 to 21.3), and 13 days (0.49 to 32.0), respectively.
8eea62084ca7e541d918e823422bd82e Conclusion
Among common molecular subtypes of NSCLC, ROS1+ oncogene is associated with a significantly higher risk of developing TEE within +/- 90 days of advanced NSCLC diagnosis.
6f8b794f3246b0c1e1780bb4d4d5dc53
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OA12 - Novel Therapies in MET, RET and BRAF (ID 921)
- Event: WCLC 2018
- Type: Oral Abstract Session
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 15:15 - 16:45, Room 106
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OA12.06 - Mutational Landscape of BRAF V600E Positive Lung Cancer Patients Following BRAF Directed Therapy Failure (ID 13540)
16:10 - 16:20 | Author(s): Dara L. Aisner
- Abstract
- Presentation
Background
BRAF V600E mutation is identified as molecular drivers in 1-2% of lung adenocarcinomas and predicts response to combination BRAF and MEK inhibitors. Little is known about molecular mechanisms of acquired resistance to these therapies for lung cancer patients with BRAF V600E mutations, partially due to a lack of representative cancer models.
a9ded1e5ce5d75814730bb4caaf49419 Method
We identified patients with BRAF V600E mutated lung cancer who were progressing after initial response to a BRAF/MEK inhibitor combination in 5 academic institutions in the US. Potential molecular mechanisms of resistance were explored by comparing pre- and post-therapy results from comprehensive tissue and/or the Guardant360 and FoundationACT plasma-based next generation sequencing assays.
4c3880bb027f159e801041b1021e88e8 Result
We identified 6 patients. Prior to treatment with a BRAF/MEK inhibitor combination, four patients had received at least one line of chemotherapy and immune checkpoint inhibitor monotherapy, one had received chemotherapy only and one was treatment naïve. Five patients received dabrafenib/trametinib and one vemurafenib/cobimetinib combination. All 6 patients achieved a partial response. Progression free survival (PFS) ranged from 3 to 15 months (median 9.5 months). At the time of progression, all patients had the BRAF V600E mutation re-identified in their samples. Additionally, there was one patient with a new AKT1 E17K and a new KRAS G12A mutation, one patient with a new VHL R167Q mutation and one patient with a new TP53 splice site indel mutation at the time of progression. Another two patients had AKT1 E17K mutations that were present prior to BRAF/MEK inhibitor therapy. They both had oligoprogression, one in lymph nodes and one in the brain after 5.2 and 3 months, respectively; both continued on dabrafenib and trametinib combination therapy after radiation treatment to the progressing sites. Interestingly, co-occurrence of AKT1 E17K and BRAF V600E mutations is rare in the TCGA data, but was identified in three of six patients in our case series. Finally, we have established a BRAF V600E positive lung adenocarcinoma cell line from a TKI naïve patient for further functional studies of drug resistance.
8eea62084ca7e541d918e823422bd82e Conclusion
Comprehensive molecular testing can identify potential resistance mechanisms following progression of BRAF V600E positive lung cancer to TKI therapy. AKT1 mutations were common as co-alterations in BRAF V600E mutated lung adenocarcinoma before and after targeted therapy and may contribute to drug resistance. The development of patient-derived cell line models may assist in the identification and validation of drug resistance mechanisms, and may help devise strategies to overcome drug resistance.
6f8b794f3246b0c1e1780bb4d4d5dc53Only 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 (Not CME Accredited Session) (ID 933)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.01-78 - The Incidence of Brain Metastases in ROS1-Rearranged Non-Small Cell Lung Cancer at Diagnosis and Following Progression on Crizotinib (ID 14164)
16:45 - 18:00 | Author(s): Dara L. Aisner
- Abstract
Background
Central nervous system (CNS) metastases in lung cancer are a frequent cause of morbidity and mortality. There are conflicting data on the incidence of CNS metastases in ROS1+ NSCLC at diagnosis and rate of CNS progression on crizotinib.
a9ded1e5ce5d75814730bb4caaf49419 Method
Retrospective review of 579 patients with stage IV NSCLC between June 2008 to December 2017 was performed. We captured presence of brain metastases and oncogene status. We measured progression free survival (PFS) and time to CNS progression in ROS1+ and ALK+ patients on crizotinib.
4c3880bb027f159e801041b1021e88e8 Result
We identified 33 ROS1+ and 115 ALK+ patients with advanced NSCLC. The incidence of brain metastases for treatment-naïve ROS1+ and ALK+ NSCLC was 36% (12/33) and 34% (39/115) respectively. There were no statistically significant differences in incidence of brain metastases across all oncogene sub-groups. Complete survival data was available for 19 ROS1+ and 83 ALK+ patients. Median PFS for the ROS1+ and ALK+ cohort was 11 and 8 months (p = 0.304). The CNS was the first site of progression for 52% (10/19) ROS1+ NSCLC and 43% (36/83) ALK+ NSCLC with no significant differences between the groups (p = 0.610). Among patients without CNS metastases prior to crizotinib therapy, 50% of ROS1+ and ALK+ patients developed CNS metastases as only site of progression at 24 and 21 months respectively.
8eea62084ca7e541d918e823422bd82e Conclusion
Brain metastases are common in treatment-naïve stage IV ROS1+ NSCLC, though incidence does not differ from other oncogene cohorts. The CNS is a common first site of progression in patients with ROS1+ NSCLC on crizotinib. This study reinforces the need to develop CNS-penetrant TKIs for patients with ROS1+ NSCLC, similar to ALK+ NSCLC.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P3.03 - Biology (Not CME Accredited Session) (ID 969)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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P3.03-25 - Squamous Cell Carcinoma-Associated Bronchial Dysplasias Demonstrate Altered T-helper Lymphocyte Differentiation (ID 13998)
12:00 - 13:30 | Author(s): Dara L. Aisner
- Abstract
Background
Persistent bronchial dysplasia (BD) is associated with an increased risk for development of invasive squamous cell carcinoma and demonstrates altered polarization of inflammatory cell subsets by gene expression analysis as compared to BD that regresses. We hypothesized that a decrease in the T-helper 1 (Th1) to T-helper 2 (Th2) lymphocyte ratio would be associated with progression to invasive squamous cell carcinoma (SCC).
a9ded1e5ce5d75814730bb4caaf49419 Method
VECTRA 7-color multispectral staining was applied to formalin fixed paraffin embedded (FFPE) persistent (N=12) and regressive (N=10) BD that also included four biopsies from patients that subsequently developed SCC (3 persistent and 1 regressive, 2 from the actual site of progression). inForm (Perkin-Elmer) image analysis software was used to enumerate cells that showed double positivity for Tbet-CD4 (Th1) and GATA3-CD4 (Th2) and the ratios of the percentage of Th1 and Th2 cells amongst all CD4 positive cells were calculated from multiple lesional fields for each BD (dysplastic epithelium and underlying stroma). DNA extracted from the full remaining FFPE tissue of four of these cases were sequenced employing the Oncomine Comprehensive v3 NGS panel (ThermoFisher) and the number of somatic mutations and variant allele frequencies (VAF) were determined using a threshold of at least 200 total reads and 25 variant reads per variant identified.
4c3880bb027f159e801041b1021e88e8 Result
A decreased Th1:Th2 ratio was seen in SCC-associated BD as compared to BD from patients that did not develop lung cancer (p=0.04; ratio = 0.04 vs. 0.68, respectively). No significant difference was seen in persistent versus regressive BD groups. There was an inverse correlation between Th1:Th2 ratios and mutational load (r2=0.21) and VAF (r2=0.28) although the small number of specimens precluded identification of a statistically significant relationship.
8eea62084ca7e541d918e823422bd82e Conclusion
A decreased Th1:Th2 ratio is associated with BD from subjects that progress to SCC suggesting that alterations in T-helper lymphocyte differentiation may contribute to progression. A potential inverse relationship between Th1:Th2 ratios and mutational load or mutant clonal expansion (increased VAF) will require further study.
6f8b794f3246b0c1e1780bb4d4d5dc53
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PC06 - Controversies in Immunobiomarker Testing (ID 845)
- Event: WCLC 2018
- Type: Pro-Con Session
- Track: Pathology
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 13:30 - 15:00, Room 106
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PC06.01 - Laboratory Developed Test - PRO (ID 11625)
13:30 - 13:50 | Presenting Author(s): Dara L. Aisner
- Abstract
- Presentation
Abstract not provided
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