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K. Woo
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MINI 06 - Quality/Prognosis/Survival (ID 111)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 1
- Moderators:R. Meguid, J. Yoshida
- Coordinates: 9/07/2015, 16:45 - 18:15, 605+607
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MINI06.13 - Multiple Lung Cancers: Is Their Survival Better or Worse Then Other Lung Cancers? (ID 3058)
17:55 - 18:00 | Author(s): K. Woo
- Abstract
- Presentation
Background:
Multiple lung cancers (MLCs) are determined using the Martini-Melamed clinical criteria, and comprehensive pathologic assessment. The prognosis of MLCs is not known. Herein, we evaluate the prognosis of patients with MLCs, one resected LC, and recurrent LC, to ascertain whether patients with MLCs have a distinct natural history compared to the other two groups.
Methods:
After IRB approval, we conducted a retrospective review of all patients who underwent an R0 resection for stage IA-IIIA LC from 2008-2013 in our institution. Patients with carcinoid tumors, adenocarcinoma-in-situ, multiple ground-glass opacities, intrapulmonary metastases and cancers not originating from the lung, were excluded. MLCs were defined using Martini-Melamed criteria and comprehensive pathologic assessment. Clinicopathologic data was collected. We used the Kaplan-Meier method and log-rank test to assess overall survival (OS) of patients with MLCs, one LC, or recurrent LC, from the time of surgery/pathologic confirmation of their MLC, one LC, or recurrent LC, respectively.
Results:
2352 patients were identified: one LC (n=2238), recurrent LC (n=348), MLC (n=113).Median OS and 2-year OS for patients in these subgroups stratified by stage, is depicted in Table 1. In patients with one LC, never smokers (p<0.001), adenocarcinoma histology (p<0.001), and surgery type (p<0.001) were associated with improved OS. In patients with recurrent LC, never smokers (p=0.015), and adenocarcinoma histology (p=0.009) were associated with favorable OS, compared to smokers and squamous histology respectively. In patients with MLCs, adenocarcinoma histology was associated with improved OS when compared to squamous histology (p=0.049).Pathologic Stage (n) Median Overall Survival (months, 95% CI) Two-Year Overall Survival p value One Lung Cancer (n=2238) All Not Reached (75.2-NA) 0<0.001 IA 0.914 IB 0.841 IIA 0.789 IIB 0.755 IIIA 0.691 Multiple Lung Cancers(n=113) All 55.5 (49.4-NA) 0.32 IA 0.810 IB 0.806 II/III 0.830 Recurrent Lung Cancer (n=348) All 10.4 (9.1-12.3) 0.077 IA 0.263 IB 0.180 IIA 0.273 IIB 0.351 IIA 0.083
Conclusion:
Martini-Melamed criteria and comprehensive pathologic assessments successfully identify patients with MLCs. Prognostic data for patients with MLCs, one LC and recurrent LC, highlight that these patients have a long natural history. MLCs have a long survival stage for stage, which underscores a definitive therapeutic approach where possible, based on favorable prognosis of these patients.
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MINI 38 - Biology and Prognosis (ID 167)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:R. Tsuchiya, M. Wynes
- Coordinates: 9/09/2015, 18:30 - 20:00, 702+704+706
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MINI38.08 - Contemporary Analysis of Prognostic Factors in Patients with Unresectable Malignant Pleural Mesothelioma (MPM) (ID 1745)
19:10 - 19:15 | Author(s): K. Woo
- Abstract
- Presentation
Background:
The CALGB and EORTC have previously developed prognostic scoring systems for patients with MPM, but these included patients managed surgically and predated the use of pemetrexed. We sought to identify prognostic factors in a contemporary cohort of patients with unresectable MPM.
Methods:
We retrospectively reviewed the charts of patients with histologically proven MPM managed non-surgically at MSKCC from 2000-2012. Variables analyzed and correlated with overall survival (OS) included: sex, age at diagnosis, smoking history, asbestos exposure, tumor laterality, initial performance status (PS), tumor histology, clinical TNM, initial PET maximum Standardized Uptake Value (SUVmax), hemoglobin level, platelet, lymphocyte and neutrophil counts, treatment type (chemotherapy and/or radiotherapy), and response to treatment. OS was analyzed by Kaplan-Meier method, and significance (p<0.05) of prognostic factors was analyzed by log-rank test and Cox regression.
Results:
191 patients met study criteria: median age 71 years (range 46-90), 147 (77%) male, 128 (67%) epithelioid , 20 (10.5%) biphasic, and 28 (14.6%) sarcomatoid. 34 patients were stage I-II at presentation and 157 (82%) stage III-IV. First line chemotherapy included pemetrexed in 159 (90.3%) patients. Median time from diagnosis to treatment was 1.2 months. With a median follow-up of 13.2 months, median OS for all patients was 13.4 months. By univariate analysis, histology (p<0.001), platelet count (≤450 vs. >450, p<0.001), initial PS, maximum PET SUV (> or ≤8.1, p=0.037) were significant. Clinical staging (I/II vs III/IV) did not correlate with OS (p=0.35). By multivariable analyses, only histology, platelet count and PS were independent prognostic factors. 1-year OS was 69% (95%CI 62%-78%) for epithelioid versus 30% (95%CI 15%-59%) and 29% (95%CI 16%-51%) for biphasic and sarcomatoid tumors, respectively. Patients with PS 0-1 had a 1-year OS of 64% (95%CI 56%-73%) versus 42% (95%CI 31%-57%) for PS 2 or greater. Epithelioid histology, PS 0-1 and elevated neutrophil count at diagnosis were significantly associated with response to first line chemotherapy. Patients with response or stable disease after the first two cycles of chemotherapy had significantly better OS, median OS was 16.8 (95% CI 14.8 – 20.1) versus 6.5 (95% CI 5.4-8.5) months (p<0.001). Patients receiving more than one line of chemotherapy had better OS, median OS 14.2 (95% CI 12.1 – 16.8) versus 8.7 (95% CI 6.6 – 11.0 ) months (p=0.013). There was no significant association between use of radiotherapy and OS (p=0.058), but patients who received radiotherapy showed a 1-year OS of 60.5% vs 44.0% of patients who did not receive radiotherapy.
Conclusion:
This analysis in patients with unresectable MPM confirms that some elements of the CALGB and EORTC prognostic scoring systems (platelet count, PS, histology) correlate with OS, and identifies factors (PS, elevated neutrophil count, histology) associated with response to chemotherapy. Our analysis emphasizes the impact of histology and response to first-line chemotherapy on outcomes, but also the lack of predictability with the use of clinical staging.
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ORAL 28 - T Cell Therapy for Lung Cancer (ID 132)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:P.S. Adusumilli, E. Smit
- Coordinates: 9/08/2015, 16:45 - 18:15, Four Seasons Ballroom F1+F2
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ORAL28.05 - Mesothelin and MUC16 (CA125) Are Antigen-Targets for CAR T-Cell Therapy in Primary and Metastatic Lung Adenocarcinoma (ID 3159)
17:29 - 17:40 | Author(s): K. Woo
- Abstract
Background:
Chimeric antigen receptor (CAR) T-cell therapy has shown durable remissions in hematological malignancies targeting cancer-antigen CD19. Ideal cancer-antigen targets for CAR T-cell therapy are antigens overexpressed on cancer cell-surface with limited expression in normal tissues, associated with tumor aggressiveness and expressed in a large cohort of patients. In our search for such candidate antigens in lung adenocarcinoma (ADC), we investigated the overexpression of Mesothelin (MSLN), MUC16 (CA125), and the combination of MSLN-MUC16 as the interaction of both antigens has been shown to play a role in tumor metastasis.
Methods:
In patients with stage I lung ADC (n = 912, 1995 - 2009), a tissue microarray consisting of 4 cores from each tumor and normal lung tissue was used to examine the antigen-expression characteristics, and their association with cumulative incidence of recurrence (CIR). Autologous metastatic tumor tissue was available from 36 patients. Differences in CIR between groups were tested using the Gray method (for univariate nonparametric analyses) and Fine and Gray model (for multivariate analyses).
Results:
MSLN and MUC16 were not expressed in normal lung tissue. In primary and metastatic lung ADC tumors, MSLN was expressed in 69% and 64%, MUC16 was expressed in 46% and 69%, both antigens were present in 50% and 33%, and either antigen were present in 33% and 49% respectively. On univariate analysis, patients with high MSLN expression had high risk of recurrence than low expression [5-year CIR, High: 25.1% vs Low: 17.6%, P = 0.017]. Patients with high MUC16 expression had high risk of recurrence than low expression [5-year CIR, High: 24.2% vs Low: 14.0%, P < 0.001]. Patients with high MUC16 and high MSLN had higher risk of recurrence than low expression [5-year CIR, High risk (High MUC16 and High MSLN): 27.6%, Intermediate risk (High MUC16 and Low MSLN): 24.2%, Low risk (Low MUC16): 13.6%, P < 0.001]. On multivariate analysis, increased MUC16-MSLN expression was associated with recurrence [Hazard ratio, 2.57 95% Confidence interval 1.41 – 4.68 P = 0.002], even after adjustment for currently known markers of lung ADC aggressiveness (gender, surgical procedure, stage, architectural grade and lymphatic invasion). High expression of MUC16 in the primary tumor was associated with high expression at recurrence sites.
Conclusion:
MSLN, MUC16 or a combination of expression of both antigens in patients with primary lung ADC is associated with increased risk of recurrence, a retained overexpression at metastatic sites in advanced lung ADC indicating that MUC16-MSLN expression is a marker of tumor aggressiveness. Expression in the majority of lung ADC patients imparting aggressiveness with no expression in normal lung provides the rationale to target MSLN and MUC16 for lung ADC CAR T-cell therapy.
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P1.02 - Poster Session/ Treatment of Localized Disease – NSCLC (ID 209)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.02-008 - Diagnostic Molecular Testing in Multiple Lung Cancers (ID 3149)
09:30 - 09:30 | Author(s): K. Woo
- Abstract
Background:
Multiple lung cancers (MLCs) are determined using the Martini-Melamed clinical criteria, and comprehensive pathologic assessment. The underlying biology for why MLCs develop is not known. Herein, we evaluate clinicopathologic data for patients with MLCs, and report clonality between MLC lesions using diagnostic molecular testing.
Methods:
After IRB approval, we conducted a retrospective review of all patients who underwent an R0 resection for stage IA-IIIA LC from 2008-2013 in our institution. Patients with carcinoid tumors, adenocarcinoma-in-situ, multiple ground-glass opacities, intrapulmonary metastases, and cancers not originating from the lung, were excluded. MLCs were defined using Martini-Melamed criteria, and comprehensive pathologic assessment. Clinico-pathologic data was collected for patients with MLCs, including available diagnostic molecular data from sizing assays, Sanger sequencing and mass spectrometry genotyping (Sequenom).
Results:
2352 pts were identified: one LC (n=2238), recurrent LC (n=348), MLC (n=113). In patients with MLCs, adenocarcinoma histology (n=97) was associated with improved OS (p=0.049) compared to squamous histology (n=13, other n=3). Paired diagnostic molecular pathology was available in 51 patients with adequate tissue from MLCs. MLC pairs stratified by mutation type are depicted in Table 1. In 49 patients, both MLCs were adenocarcinomas (20= extended panel: sizing assays/Sanger sequencing/Sequenom, 29=limited panel: EGFR/KRAS sizing assay/Sanger sequencing): 51% (n=25/49) had concordant molecular results, suggesting a common tumor clone, and 49% (n=24/49) had discordant results. In 1 patient, one MLC was an adenocarcinoma and the other was a squamous carcinoma, and had discordant molecular results by limited panel testing. In 1 patient, both MLCs were squamous carcinomas, and had concordant molecular results by limited panel testing. In patients where MLCs both had a KRAS mutation (n=11), 3 pairs had the same mutation (KRAS G12C, KRAS G12D, KRAS G12F), and 8 had different mutations. Table 1: Multiple Lung Cancer: Molecular DataFigure 1
Conclusion:
Martini-Melamed criteria and comprehensive pathologic assessment, are currently used to diagnose MLCs. Assuming separate MLC lesions harbor distinct molecularly defined clones, paired molecular testing using limited panels is not sufficient to diagnose MLCs. Concordant molecular profiles do not necessarily define whether a lesion is an MLC or a metastatic lesion. Paired prospective testing of suspected MLC lesions including broader molecular tests such as DNA, RNA, protein expression and immune correlates, may advance our understanding of the biology of these tumors.
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P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-075 - Phase 2 Trial of Bortezomib in KRAS G12D Mutant Lung Cancers (ID 2943)
09:30 - 09:30 | Author(s): K. Woo
- Abstract
Background:
KRAS mutations are the most common oncogenic drivers in lung cancers without any approved targeted therapy. Preclinical evidence suggests that KRAS mutations are highly dependent on the NF-kB pathway. Bortezomib, a small molecule proteasome inhibitor, has been shown to downregulate the NF-kB pathway and lead to objective responses in patients with KRAS G12D in early phase clinical trials. In this single-institution, open label, phase II study we assessed the efficacy and safety of subcutaneous bortezomib in KRAS mutant lung cancers.
Methods:
Patients with advanced KRAS G12D mutant lung cancers were eligible. Bortezomib was administered at 1.3mg/m2/dose subcutaneously on days 1, 4, 8, and 11 of a 21 day cycle until disease progression or unacceptable toxicity. The primary objective was radiographic response rate (RECIST version 1.1). The secondary endpoints were progression free survival (PFS) and overall survival (OS) determined from the time of first bortezomib treatment. Simon two-stage minimax design was used (H0=10%, H1=30%, power=90%).
Results:
Sixteen patients with KRAS G12D mutant lung adenocarcinomas were treated on study: 44% women, 38% never smokers, 31% former smokers ≤15 pack years, and 69% with invasive mucinous adenocarcinomas. Patients received treatment for a median of 2 months (range 1-12months). One patient had a partial response with a 66% reduction in disease burden (6% observed rate, 95% CI 0.2 to 30.2%). Of the 6 patients (40%) with stable disease, 2 remained on study for over 5 months. The median PFS was 1 month (95% CI 1-6). The median OS was 13 months (95% CI 6-NA). The median OS from date of diagnosis of metastatic disease was 39 months (95% CI 35-NA). The most common treatment-related toxicities of any grade were fatigue (50%), diarrhea (38%), nausea (31%), and papulopustular rash (31%). Treatment-related peripheral neuropathy occurred in 25% of patients (3 patients with grade 1, 1 patient with grade 2).
Conclusion:
In patients with G12D KRAS mutant lung cancers, bortezomib was well tolerated and associated with modest anti-tumor activity and durable disease control in a small subset of patients. Further investigation into predictive biomarkers for the efficacy of bortezomib should be pursued. Without a clear biomarker, no further study of bortezomib in KRAS- mutant lung cancers is warranted.
