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Aaron S. Mansfield
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MA 13 - New Insights of Diagnosis and Update of Treatment (ID 674)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:S. Ishikura, H. Nakayama
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 311 + 312
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MA 13.01 - Clinical and Pathological Variables Influencing Noninvasive Detection of Early Stage Lung Cancer Using Circulating Tumor DNA (ID 8686)
15:45 - 15:50 | Author(s): Aaron S. Mansfield
- Abstract
Background:
Analysis of circulating tumor DNA (ctDNA) represents a potential strategy for the early detection of lung cancer. Despite significant interest, few studies have evaluated ctDNA levels in early stage lung cancer patients and the feasibility of ctDNA-based screening remains unclear.
Method:
We applied lung cancer-focused Cancer Personalized Profiling by deep Sequencing (CAPP-Seq) to assess ctDNA levels in 55 localized lung cancer patients treated with curative intent (stage I: n=22, stage II: n=7, stage III: n=26) and 50 healthy controls. Histological subtypes included: adenocarcinoma (n=30), squamous cell carcinoma (n=19), NSCLC NOS (n=4), and small cell lung cancer (n=2). Sensitivity and specificity of ctDNA detection were evaluated in all patients and in a subset of NSCLC patients with node negative (N0) stage I-II disease. Additionally, for patients with stage I adenocarcinoma in whom ctDNA was not detectable using the standard population-based CAPP-Seq approach, we designed personalized CAPP-Seq assays covering a median of 320 mutations/patient based on tumor exome sequencing from the respective patients.
Result:
We detected ctDNA in the pre-treatment plasma of 43/55 (78%) patients at a median allele fraction (AF) of 0.48% (range: 0.004%-26.1%). ROC analysis revealed an area under curve of 0.91, with sensitivity and specificity of 78% and 98%, respectively. Among patients with non-adenocarcinoma histologies, 92% (23/25) had detectable ctDNA (median AF: 0.90%), compared to 67% of patients with adenocarcinoma (20/30; median AF: 0.23%; P=0.046). However, tumor volumes were significantly smaller in adenocarcinomas (P=0.01) and in multivariate analysis ctDNA detection was significantly associated with tumor volume (P=0.01) but not histological subtype (P=0.16). In N0 stage I-II NSCLC patients (n=22), ctDNA was detected in 64% of patients (7/14 adeno vs 7/8 non-adeno) with a specificity of 98% and median AF of 0.022% (median AF of 0.018% vs 0.030% in adeno vs non-adeno patients, respectively). Using personalized CAPP-Seq assays, we detected ctDNA in 3/4 patients with stage I adenocarcinoma in whom ctDNA was not detected using our standard lung-cancer focused CAPP-Seq assay. In these 3 patients, tumor volumes ranged from 11.6-14.7 mL and the ctDNA AF ranged from 0.0014%-0.003%. Taken together, we detected ctDNA in 17/22 (77%) N0 stage I-II tumors.
Conclusion:
These data suggest tumor volume is a stronger determinant of ctDNA levels than histology in localized lung cancers. Additionally, our findings suggest that the majority of localized lung cancers shed ctDNA and that ultra-sensitive assays will be required for early detection of lung cancer using ctDNA
Information from this presentation has been removed upon request of the author.
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MA 18 - Global Tobacco Control and Epidemiology II (ID 676)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Epidemiology/Primary Prevention/Tobacco Control and Cessation
- Presentations: 1
- Moderators:H. Kawai, Christian Klaus Manegold
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 511 + 512
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MA 18.09 - Enrollment of Minorities, the Elderly, and Women in Lung Cancer Clinical Trials (ID 8406)
16:35 - 16:40 | Author(s): Aaron S. Mansfield
- Abstract
- Presentation
Background:
Despite multiple efforts led by the National Cancer Institute (NCI) specific patient populations remained underrepresented in cancer clinical trials (CT). Therefore, we determined the representation of minorities, the elderly, and women in lung cancer CT in the past 16 years.
Method:
Clinicaltrials.gov was queried on December 31[st], 2016 for all completed therapeutic lung cancer trials from 2000 to 2016. Trials with recruitment outside of the U.S. were excluded. Enrollment fraction (EF) was defined as the number of enrollees divided by the 2013 SEER cancer prevalence. Geographic location was classified within the 5 major U.S. regions: Northeast, Southeast, Midwest, Northwest and Southwest.
Result:
Out of 320 CT, only 88 trials (27.5%) reported race/ethnicity comprising 11, 723 enrollees. Industry sponsored 65% of the trials. Non-Hispanic whites (NHW) were more likely to be enrolled in CT (EF 2.8%) than African Americans (AA) (EF 1.5%, p<0.001) and Hispanics (EF 2.1% p<0.03). Asian patients were well represented (EF 9.2 %). Distribution by race and sex is described on Table 1. Only 44 (50%) trials divided participants by age (<65 or ≥65 years). The representation of trial participants was heavily skewed towards the younger age group. Median age was 62 years and 8,440 (72%) participants were <65 years of age (p<0.001). Industry sponsored trials were less likely to enroll Hispanic patients than NCI sponsored trials (1.1% vs. 3.8%). African Americans were less likely to be recruited in first line trials compared to NHW (11% vs. 36%, p<0.0001). Underrepresentation of minorities was not affected by recruitment site geographic location.
Conclusion:
NHW were more likely to be enrolled in clinical trials than African American and Hispanics, independent of the recruitment site geographic location. Collaboration between investigators, NCI, industry, and the community is necessary to ensure broad access of unrepresented populations to clinical trials.Race/Ethnicity 2000-2016 Trial Participants n/% Enrollment Fraction % 2013 Lung Cancer Prevalence % Non-Hispanic White 9,350 (79.8) 2.8 82.7 African American 638 (5.4) 1.5 10.6 Hispanic 314 (2.7) 2.1 3.6 Asian/PI 1083 (9.2) 8.7 3.1 Native American 75 (0.6) N/A N/A Other 263 (2.2) Sex Female 4,571 (39) 2.0 55.2 Male 7,152 (61) 3.8 44.8
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OA 13 - Immuno-Biology (ID 677)
- Event: WCLC 2017
- Type: Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Hiroyuki Suzuki, Scott N. Gettinger
- Coordinates: 10/18/2017, 11:00 - 12:30, Room 301 + 302
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OA 13.07 - Contraction of T Cell Clonality in Lung Cancer Metastases (ID 7542)
12:05 - 12:15 | Presenting Author(s): Aaron S. Mansfield
- Abstract
- Presentation
Background:
Clonal evolution and the heterogeneity of non-small cell lung cancer (NSCLC) may affect patient outcomes through variations in treatment planning, response to therapy, and drug resistance. Even less is known about the diversity of the adaptive immune response to primary and metastatic lesions in this disease. We sought to characterize the richness, abundance and overlap of T cell clones between paired primary NSCLC lesions and brain metastases.
Method:
We identified 20 patients with NSCLC with paired, fully resected primary lesions and brain metastases with sufficient tissue available in our clinical archives. DNA was purified from formalin-fixed paraffin-embedded specimens. The complementarity determining region 3 of T-cell receptor β was profiled by next generation sequencing to identify unique T cell clones. Sample richness (including iChao1 and Efron-Thisted Estimator), and clonal abundance (Simpson’s diversity index) were compared between paired lesions with the paired t test. Overlap in clonality was measured with the Morisita index.
Result:
There was a significant contraction of T cell clonality in paired metastases compared to primary lesions (mean of differences -2803, 95% CI -4202 to -1405; p=0.0005). The decreased richness in clonality in brain metastases was also supported by significant differences in iChao1 (mean of differences -20355, 95% CI -29561 to -11149; p=0.0002) and the Efron-Thisted Estimator (95% CI -21331 to -7216; p=0.0004). Simpson’s diversity index was higher in brain metastases than primary lesions (mean of differences 0.002, 95% CI 0.001 to 0.004; p=0.05), but low overall. Only a fraction of T cell clones in primary lesions were also found in brain metastases (mean Morisita Index 0.23).
Conclusion:
There is greater richness but less abundance of T cell clones in primary NSCLC lesions compared to paired brain metastases. Although the blood brain barrier may restrict T cell trafficking to tumors, the minimal overlap in T cell clones may reflect the genetic divergence of metastatic tumor clones.
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P2.01 - Advanced NSCLC (ID 618)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:00 - 16:00, Exhibit Hall (Hall B + C)
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P2.01-054 - Inclusion of Central Nervous System Metastasis in Lung Cancer Early Phase Clinical Trials (ID 8407)
09:00 - 09:00 | Author(s): Aaron S. Mansfield
- Abstract
Background:
Central nervous system (CNS) metastases are commonly seen in lung cancer patients; up to 40% will have CNS involvement during the course of the disease. However, clinical trials often exclude this patient population due to the increased morbidity/mortality associated with CNS metastases, subsequent reduction of overall survival and poor CNS pharmacokinetics or uncertainty about CNS pharmacokinetics in humans. Therefore, we studied the effects of CNS metastases on the enrollment of lung cancer patients in early phase clinical trials.
Method:
Trials were extracted from ClinicalTrials.gov on April 1[st], 2017. Completed and active trials from 2000-2016 were included in the analysis. Exclusion of CNS metastasis was treated as a binary variable and grouped as strict exclusion vs. allowed. Logistic regressions were used for statistical analysis.
Result:
598 trials were reviewed, 308 (52%) were phase 2, 164 (27%) were phase 1, and 126 (21%) were combined phase 1/2 trials. 304 (51%) trials were conducted in the U.S., 82 (14%) in Asia, 74 (12%) in Europe and 138 (23%) internationally. Most trials were funded by industry (59%), followed by investigator initiated/institutional (23%) and NIH funded (18%). Patients with CNS metastasis were strictly excluded in 130 (22%) trials, allowed if controlled/asymptomatic in 156 (26%) and allowed with no prior treatment in 42 (7%) trials. Patient requiring steroids for their CNS metastasis were excluded in 156 (26%) trials. CNS criteria were not referenced in 114 (19%) trials and these were excluded from further analysis. Of the 194 trials that included survival as one of their end points, 121 (62%) excluded patients with CNS disease. On univariate analysis, the odds of CNS metastasis exclusion were significantly higher in immunotherapy trials (OR: 1.26, 95%CI: 1.07-1.50, p<0.006) and significantly lower in NIH funded trials (OR: 0.35 95% CI: 0.17-0.73, p<0.005). In multivariate analysis, U.S. based trials had higher odds of exclusion of CNS disease (OR: 1.18, 95%CI: 1.06-1.31, p<0.001) compared to European, Asian and International trials. 58 phase 1 trials were followed by phase 2 trials, when comparing exclusion criteria, no changes were made regarding CNS metastasis.
Conclusion:
Many patients with lung cancer and brain metastases are excluded from participation in early phase clinical trials. Broader inclusion of patients with CNS metastasis, or separate clinical trials for those with CNS disease would help determine the efficacy of novel agents for those with CNS metastasis and provide clinical trial options for this patient population.
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P2.09 - Mesothelioma (ID 710)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Mesothelioma
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.09-001 - Effects of Tumor Burden Reduction on Survival in Epithelioid Pleural Mesothelioma (ID 7518)
09:30 - 09:30 | Presenting Author(s): Aaron S. Mansfield
- Abstract
Background:
Surrogate endpoints are commonly utilized in oncology clinical trials and have been adopted by regulatory agencies for the approval of many agents. To date, the effects of tumor size reduction on survival have not been determined for the only Food and Drug Administration (FDA)-approved regimen fo malignant pleural mesothelioma (MPM), but its widespread use mandates its validation. MPM is a challenging disease to assess and standard Response Evaluation Criteria for Solid Tumors (RECIST) were not optimized to measure pleural disease. Modified pleural RECIST (mRECIST) have been adopted by mesothelioma experts for the measurement of responses in MPM and mRECIST are the most commonly used response criteria in clinical trials for MPM. Although the gold standards for oncology outcomes are overall survival and quality of life, cross-over to subsequent therapies and competing risks influence survival outcomes. We sought to evaluate the relationship of response with survival in the clinical trial of the only FDA approved regimen for MPM.
Method:
We reviewed the clinical trial that randomized patients with MPM to receive cisplatin or cisplatin and pemetrexed. Patients with epithelioid MPM were categorized by whether or not they responded to cisplatin or the combination of cisplatin and pemetrexed accoring to the original study determination. Responders had >30% reduction in the thickness of the pleural rind measured at up to 3 points on 3 separate slices of the CT scan. Median progression-free (PFS) and overall survivals (OS) were determined and the hazard ratios for responders and non-responders were determined and compared by the logrank test.
Result:
We identified that patients with epithelioid MPM who responded to front-line therapy had a significantly longer overall survival (HR 0.341, 95% CI 0.239-0.486; median 20.6 months, 95% CI: 15.3-not reached) than those who did not respond (median 9.4 months, 95% CI: 8.1-11.0; p<0.001). Similarly patients who responded to front-line therapy had a significantly longer progression-free survival (HR 0.496, 95% CI: 0.385-0.639; median 7.8 months, 95% CI: 6.5-8.5) than those who did not respond (median 3.7 months, 95% CI: 2.9-4.3; p<0.001).
Conclusion:
Our findings demonstrate that a reduction in tumor burden was strongly associated with OS and PFS in epithelioid MPM treated with cisplatin or cisplatin and pemetrexed.
