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A. Mansfield
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MINI 02 - Immunotherapy (ID 92)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:P. Forde, S.J. Antonia
- Coordinates: 9/07/2015, 10:45 - 12:15, Four Seasons Ballroom F3+F4
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MINI02.08 - Bidirectional Cross-Talk between CD14+ Monocytes and Human Lung Cancer Cell Lines Results in Different Phenotypic and Functional Outcomes (ID 2497)
11:25 - 11:30 | Author(s): A. Mansfield
- Abstract
- Presentation
Background:
Myeloid cell infiltration of the tumor microenvironment is associated with decreased overall survival in multiple tumor types, including lung cancer. This myeloid cell infiltration represents a tissue component of the heterogeneous group of cells termed myeloid derived suppressor cells (MDSC), which can inhibit the endogenous anti-tumor response, direct angiogenesis, and promote tumor progression. In several studies of patients with non-small cell lung cancer (NSCLC), there is wide variation in the presence of myeloid cells in the tumor with increasing levels peripheral blood MDSC associated with poor survival. We have previously shown that CD14+ monocytes can be converted by the tumor microenvironment to an immune suppressive phenotype in non-Hodgkin lymphoma and glioblastoma. In this work, we expand on our earlier observations to include recruitment of CD14+ cells by lung cancer cell lines and their conversion to an immune suppressive phenotype. While most models of myeloid cells in the microenvironment describe the effects of these cells on non-malignant systems, we show that myeloid cells may have profound direct effects on the tumor.
Methods:
Human lung cancer cell lines were cultured and supernatants collected for ELISA. CD14+ cells were isolated from the peripheral blood of healthy volunteers using anti-CD14 immunomagnetic beads. Lung cancer cell lines and CD14+ cells were cocultured under a variety of low serum conditions with or without cisplatin. Changes in CD14+ cell HLA-DR expression and tumor cell survival were measured by flow cytometry. CD14+ cell migration through a permeable transwell membrane was measured in real time with live cell imaging.
Results:
Under normal culture conditions, 7 of 8 human lung cancer cell lines secreted detectable levels of CCL2, a major chemoattractant for monocytes, ranging from 30 to 10,000 pg/ml of CCL2 found in culture supernatants. CD14+ cells more robustly migrated towards cell lines with higher production of CCL2. The coculture system showed a differential impact on monocytes by the tested lung cancer cell lines which either reliably upregulated or downregulated CD14+ cell expression of HLA-DR. In 3 of 8 lung cancer cell lines, CD14+ cell HLA-DR was downregulated in a manner expected to promote local immune suppression. Under serum starvation conditions, one lung cancer cell line showed improved survival when cocultured with CD14+ cells. Similarly, coculture with CD14+ cells enhanced tumor survival of two cell lines after exposure to cisplatin.
Conclusion:
The studied lung cancer cell lines differ in the degree of CD14+ cell recruitment, CD14+ cell HLA-DR expression after coculture, and level of conferred survival benefit under stressful conditions. Taken together these results suggest that the variable myeloid involvement in lung cancer patients can be modeled using lung cancer lines. In addition, we have identified that for some tumors, monocytes confer a significant survival advantage that is not associated with immune or angiogenic responses. Future work is needed to explore the impact of CD14+ cells on lung tumor invasiveness, angiogenesis, and the mechanisms underlying these pro-tumor effects.
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MINI 13 - Genetic Alterations and Testing (ID 120)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:Y. Koh, R.K. Thomas
- Coordinates: 9/08/2015, 10:45 - 12:15, 205+207
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MINI13.14 - S768I Mutation in the EGFR Gene in Patients with Lung Cancer (ID 325)
12:00 - 12:05 | Author(s): A. Mansfield
- Abstract
- Presentation
Background:
Epidermal growth factor receptor (EGFR) mutations are relatively common oncogenic drivers in non-small cell lung cancer (NSCLC). Interestingly a number of patients have more than one mutation in EGFR. In order to understand whether these patients respond to EGFR inhibition, we reviewed our experience treating these patients. Herein we describe the Mayo Clinic experience with the S768I mutation of exon 20 of the EGFR gene.
Methods:
Relevant clinical and laboratory data were abstracted for selected cases, including evaluation of response after treatment with TKIs using the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Inclusion criteria were cases including EGFR S768I mutation performed at Mayo Clinic or elsewhere until December 2014. EGFR testing was performed following microscopic examination by a pathologist to identify and select areas of tumor for macrodissection and confirm sufficient tumor percent. The EGFR test is a PCR based assay employing allele specific amplification and is used to test for mutations within exons 18-21 of the EGFR gene, most recently using the FDA approved platform. When testing was performed elsewhere, bidirectional sequencing was used.
Results:
1,527 cases of NSCLC that underwent EGFR testing were reviewed and the S678I mutation was present in 9 patients (0.59%), 4 of which were female. Median age at diagnosis was 61 years (range 49-68 years), 5 patients were never smokers and no subjects were current smokers at the time of diagnosis. The stage at diagnosis was I in 2, III in 3 and IV in 4 patients, respectively. All specimens were adenocarcinomas with 5 of them being grade 3. Only 3 cases had an isolated S768I mutation, 4 cases had a concurrent G719S mutation and 2 cases had a concurrent L858R mutation. The tumor responses of patients with stage IV disease are shown in the table. One patient with a concurrent S768I and L858R mutation with stage IIIa disease received curative intent lobectomy after neoadjuvant treatment with erlotinib. Erlotinib was discontinued in one case due to fatigue. Table: Response of S768I mutations to erlotinib by RECIST 1.1Mutation(s) Best response on erlotinib PFS (months) Overall survival (months) S768I alone Progressive disease 3 5 S768I + G719 Partial response 6 23 S768I + G719S Stable disease 12 33 S768I + L858R Stable disease 30 51+
Conclusion:
S768I mutations in exon 20 of the EGFR are rare and are commonly seen in conjunction with common EGFR mutations. Due to its rarity and the variability of responses of treated cases, its exact prognostic and predictive role is not fully understood. Better understanding of its function and sensitivity to newer TKIs will allow for better management of patients with this mutation.
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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P2.03 - Poster Session/ Treatment of Locoregional Disease – NSCLC (ID 213)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.03-025 - Predictors of Relapse and Evaluation of Post-Operative Radiotherapy in Patients with Resected Stage III (N2) Non-Small Cell Lung Cancer (ID 1291)
09:30 - 09:30 | Author(s): A. Mansfield
- Abstract
Background:
For patients with stage III (N2) NSCLC treated with surgical resection, chemotherapy improves survival, whereas the role of PORT is controversial. The purpose of this study was to evaluate risk factors for recurrence and the role of PORT in a modern series of patients with surgically resected stage III (N2) NSCLC.
Methods:
A retrospective review was performed of patients with Stage III (N2) NSCLC who underwent curative intent surgical resection at our institution between February 1999 and January 2012. Patients who received neoadjuvant RT were excluded. Chi-Square or Fisher’s exact tests assessed associations between patient/disease characteristics and receipt of PORT. Local control was defined as lack of disease recurrence within the radiation field for PORT patients, or in the mediastinum or resection area for chemotherapy patients. Overall survival (OS), local control (LC), and metastasis-free survival (MFS) were estimated from the date of surgery using the Kaplan Meier method, with between-group comparisons (PORT vs. no PORT) made with the Log-rank test. Univariate Cox proportional hazards models were used to assess association of patient/disease characteristics and outcomes.
Results:
A total of 76 patients were included. Median age was 62.5 years. Histology was adenocarcinoma in 66%. Clinical N stage was N0 (51%), N1 (4%), or N2 (45%). Baseline positron emission tomography staging was performed in 91%. Pre-operative chemotherapy was administered to 21%. Surgery was pneumonectomy in 16%. Median (range) number of positive pN2 nodes was 1 (0-15). Seven patients with biopsy-proven cN2 had negative pN2 nodes after induction chemotherapy. Extranodal extension occurred in 9%. Surgical margins were positive in 4%. Chemotherapy (preoperative and/or postoperative) was administered to 83%. PORT was administered to 41 patients (54%) with a median (range) dose of 50 (41.4 – 60) Gy. Factors associated with increased likelihood of receiving PORT were increasing age (p=0.006) and no receipt of chemotherapy (p=0.0001). Median follow-up time for living patients was 4.5 (range 0.2 – 15.4) years. For all patients, OS at 5 years was 65%. OS at 5 years for patients receiving PORT vs. no PORT was 71% vs. 58% (p=0.19). For all patients, LC at 5 years was 84%. LC at 5 years for patients receiving PORT vs. no PORT was 89% vs. 77% (p=0.16). Factors associated with decreased LC were male gender (p=0.004), pT3/4 (vs. pT1/2, p=0.008). For all patients, MFS at 5 years was 61%. MFS at 5 years for patients receiving PORT vs. no PORT was 62% vs. 61% (p=0.89).
Conclusion:
In this modern series of patients with surgically resected stage III (N2) NSCLC, patients who received PORT (vs. no PORT) had numerically higher rates of OS and LC, although these differences were not statistically significant, potentially related to limited statistical power.
