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O. Arrieta Rodriguez
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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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MINI02.03 - Overexpression of CD47, Decrease of Apoptosis and Phagocytosis of Neutrophils in Advanced Non-Small Cell Lung Cancer Patients (ID 2265)
10:45 - 12:15 | Author(s): O. Arrieta Rodriguez
- Abstract
- Presentation
Background:
Lung cancer is the leading cause of cancer death worldwide and most of the patients are diagnosed with advanced disease. Inflammatory components play a key role in tumor progression and survival. Neutrophils are increased in blood of patients with lung cancer and they are associated with poor clinical outcomes. CD47 is a protein which control cell communication, apoptosis, adhesion and proliferation and it has been found increased in cancer and related with phagocytosis evasion mechanism.The aim of this study was to evaluate CD47 expression levels on peripheral neutrophils, also assess the phenotype, apoptosis, activation state, reactive oxygen species production of neutrophils between patients with Non-Small Cell Lung Cancer (NSCLC) and healthy subjects.
Methods:
Fifty NSCLC patients (stage IIIB and IV) naive to treatment and 25 healthy subjects were analized for: CD47 peripheral blood expression, neutrophils phenotype and activation state, evaluation of apoptosis and phagocytosis by flow cytometry. Reactive oxygen species (ROS) production by circulating neutrophils upon stimulation with PMA was assessed by flow cytometry. For the phagocytosis assay, PMNC were labeled with CMFDA and were cultured in RPMI for 24 hrs. To obtain apoptotic target cells, 24h PMNC were labeled with Annexin-V. For the evaluation of phagocytosis, the neutrophils from NSCLC patients were co-cultured with THP-1 cells. The percentage of phagocytosis was assessed by flow cytometry.
Results:
Our results showed a lower percentage of total CD47 in peripheral blood cells in NSCLC patients compared to controls [P=0.042]. Mean Fluorescence Intensity (MFI) of CD47 was higher in patients [P<0.001]. The percentage of CD66b+ cells characterized as neutrophils was higher in patients as well as their MFI of CD47 [P< 0.001]. MFI of CD66b was higher in patients [P< 0.0178]. This would be related with a more activated state. We found that a higher disease stage (IIIB vs. IV) associated with a higher MFI of CD47 [P=0.020]. Plasma pro-inflammatory cytokines, was increased in patients compare to controls IL-6 (P<0.002), IL-8 (P<0.001), IL-12p70 (P<0.008), TNF (0.010) and IFN-g (P<0.001). MFI of CD47 >1635.5 was associated with a higher median Overall survival (P= 0.007). We found a decrease of AnnexinV+/7AAD+ in neutrophils of patients [P=0.0317]. Caspases 3 and 7 were found decreased in neutrophils of patients [P= 0.049]. Oxygen species (ROS) production of neutrophils upon PMA stimulation was increased in patients [P=0.029], suggesting it might play a role in immune effector function. Phagocytosis of apoptotic neutrophils by differentiated THP-1 cells was decrease in cancer patients cells (P=0.0445). Mean fluorescence Intensity of CD47 was increased after 24 hrs in patients [P=0.0408]. This result suggests that neutrophils from patients avoid being engulfed and this may be associated with overexpression of CD47.
Conclusion:
Taken together, these findings suggest that these are altered mechanisms by which neutrophils evade anti-tumor immune response and their increased expression of CD47 is a potential therapeutic target for NSCLC.
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MINI 10 - ALK and EGFR (ID 105)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:T. Yap, T. Li
- Coordinates: 9/07/2015, 16:45 - 18:15, Mile High Ballroom 1a-1f
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MINI10.15 - Discussant for MINI10.09, MINI10.10, MINI10.11, MINI10.12, MINI10.13, MINI10.14 (ID 3401)
16:45 - 18:15 | Author(s): O. Arrieta Rodriguez
- Abstract
- Presentation
Abstract not provided
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MINI 16 - EGFR Mutant Lung Cancer 2 (ID 130)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:G.J. Riely, M.C. Garassino
- Coordinates: 9/08/2015, 16:45 - 18:15, Four Seasons Ballroom F3+F4
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MINI16.11 - Plasma HGF Reduction Is Associated with Better Prognosis in EGFR-Positive Advanced Lung Adenocarcinoma Patients Treated with Afatinib (ID 1729)
16:45 - 18:15 | Author(s): O. Arrieta Rodriguez
- Abstract
- Presentation
Background:
Afatinib, an irreversible tyrosine kinase inhibitor (TKI), has shown clinical benefits and prolonged progression free survival in EGFR mutated patients. HGF, a ligand of c-MET, may be involved in resistance to EGFR-TKIs.
Methods:
A total of 66 patients with advanced lung adenocarcinoma (stage IIB and IV) and documented progression to first-line chemotherapy were enrolled to receive afatinib 40 mg/day. Mutational EGFR and HER-2 status were assessed by RT-PCR. HER2 amplification was evaluated by FISH. Plasma HGF levels were measured by ELISA before and 2 months after the start of treatment with afatinib. We assessed the change in plasma HGF levels and the association with objective response rate (ORR), progression free survival (PFS) and overall survival (OS). The protocol is registered in ClinicalTrials.gov (NCT01542437).
Results:
We identified 2 patients carrying a HER2 mutation and both presented stable disease (SD). HER2 amplification was not detected. HGF-positive plasma reduction status had a significant higher ORR (75.0% vs 44.1% p= 0.011), and was strongly associated with longer PFS (HR 0.40 [95% CI 0.18 - 0.87], p= 0.02) and OS (HR 0.31 [0.13 - 0.71] p=0.006). A stratified multivariate analysis in EGFR mutated patients showed that the HGF plasma levels reduction remains as a significant and independent factor associated with longer PFS (HR 0.34 [95% CI 0.13 - 0.89] p= 0.04) and OS (HR 0.34 [95% CI 0.13 - 0.88] p= 0.02).
Conclusion:
HGF plasma levels reduction is strongly related to better outcomes with afatinib therapy, irrespective of EGFR mutation status. The lack of reduction might allow the identification of a subgroup of patients who will not expected to respond and could benefit with the use of drugs targeting the HGF-c-Met axis. Further studies are warranted.
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MINI 29 - Meta Analyses and Trial Conduct (ID 156)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:D. Morgensztern, M. Redman
- Coordinates: 9/09/2015, 18:30 - 20:00, Mile High Ballroom 2a-3b
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MINI29.04 - The Use of Metformin and Proper Glycemic Control Are Associated with Improved Survival in Non-Small Cell Lung Cancer Patients (ID 1612)
18:30 - 20:00 | Author(s): O. Arrieta Rodriguez
- Abstract
- Presentation
Background:
Previous population-based studies have shown an association between metformin use and improved survival among diabetic patients with lung cancer. We sought to analyze the effect of diabetes and its treatment in terms of survival in Mexican patients with lung cancer treated at a single institution
Methods:
1106 patients were included. Outcomes were compared between patients with (n=186) and without diabetes (n=920). Characteristics associated with antidiabetic treatment and with proper glycemic control (defined as mean plasma glucose <130mg/dL) were examined. Overall survival (OS) among the different patient populations was analyzed using Kaplan-Meier curves and multivariate analysis was used to determine the influence of patient and tumor characteristics on survival
Results:
OS for the entire population was 18.3 months (95% CI 16.1-20.4). There was no difference in OS between diabetic and non-diabetic patients (18.5 vs 16.4 months, p = 0.62). Diabetic patients taking metformin had a superior OS than those taking other antidiabetic treatment (25.6 vs 13.2 months, p = 0.001), and those with proper glycemic control had a better OS than those without proper glycemic control (40.5 vs 13.2 months, p<0.001). Both the use of metformin (HR 0.57 p = 0.017) and proper glycemic control (HR 0.40, p =0.002) were significant protective factors in the diabetic patient population.
Conclusion:
Proper glycemic control and metformin use have a beneficial effect on the survival of patients with diabetes and lung cancer. Studies using metformin in lung cancer should include measures of proper glycemic control as fundamental variables.
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ORAL 29 - MASCC-IASLC Joint Session: Palliative and Supportive Care (ID 136)
- Event: WCLC 2015
- Type: Oral Session
- Track: Palliative and Supportive Care
- Presentations: 1
- Moderators:A. Molasiotis, P. Van Houtte
- Coordinates: 9/08/2015, 16:45 - 18:15, 708+710+712
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ORAL29.06 - Skeletal Muscle and Lean Body Mass Loss Are Associated with Poorer Prognosis in Patients with NSCLC Treated with Afatinib (ID 3053)
16:45 - 18:15 | Author(s): O. Arrieta Rodriguez
- Abstract
- Presentation
Background:
Irreversible tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR) such as afatinib have shown clinical benefits and prolonged survival in patients with NSCLC. Weight loss and sarcopenia are common in NSCLC patients and have been recognized as important prognostic factors of toxicity and survival. The aim of this study was to assess the impact of muscle and
Methods:
Patients diagnosed with NSCLC, who progressed to prior chemotherapy, received 40 mg of afatinib. Skeletal muscle (SM) was quantified by computed tomography scan analysis using pre-established Hounsfield (HU) unit threshold and lean body mass (LBM) was calculated with the following formula: LBM (kg)=(0.30 × (skeletal muscle area at L3 using CT (cm[2]))+6.06). These variables were estimated at baseline (T0) and after four months of treatment with afatinib (T1).
Results:
Eighty-four patients were assessed at baseline. 70.2% were female, mean age was 59.3±1.6 years, 94% had adenocarcinoma, 53.6% received afatinib as 2nd line of treatment, and 91.7% had a good performance status (ECOG 0-1). Patients included were both EGFR+ (23.8%) and EGFR- (76%). Body composition evaluation was obtained at T0 and T1 in 46 patients, median differences (∆) between T0 and T1 for SM, LBM and weight were -1.4(-56.8, +27.9 cm[2]), -0.42(-17,-8 kg) and -0.1(-12,+6), respectively, and were not statistically significant. Median OS and PFS were 23.8(17.9-29.7) months and 8.9(5.5-12.4) months, respectively (including EGFR+ and EGFR-). Weight loss was not statistically associated with poorer OS or PFS. However, SM and LBM loss greater that the median had a negative impact on PFS and OS. Figure 1(Figure1).
Conclusion:
SM and LBM changes throughout treatment with EGFR TKIs should be evaluated. Nutritional interventions should be focused on the maintenance of SM and LBM. Further clinical trials should focus on interventions improving these body composition variables since they are associated with better OS and PFS in patients with NSCLC treated with afatinib.
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ORAL 30 - Community Practice (ID 141)
- Event: WCLC 2015
- Type: Oral Session
- Track: Community Practice
- Presentations: 1
- Moderators:P.S.S. Kho, R. Jotte
- Coordinates: 9/08/2015, 16:45 - 18:15, Mile High Ballroom 2c-3c
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ORAL30.07 - Different Mutation Profiles and Clinical Characteristics Among Hispanic Patients with NSCLC Could Explain The 'Hispanic Paradox' (ID 748)
16:45 - 18:15 | Author(s): O. Arrieta Rodriguez
- Abstract
- Presentation
Background:
Sixteen percent of the U.S. population is Hispanic, predominantly of Mexican ancestry. Recently, two independent American reports demonstrated a higher overall survival (OS) in Hispanic populations compared with non-Hispanic-white populations (NHW) in patients with non-small-cell lung cancer (NSCLC) diagnosis. The latter even when most of the Hispanics are diagnosed at advanced stages of disease and are low-income patients. The aim of our study was to analyze the clinical, pathological, and molecular characteristics as well as the outcomes in a cohort of NSCLC Hispanic patients from the National Cancer Institute of Mexico that could explain this "Hispanic Paradox".
Methods:
A cohort of 1260 consecutive NSCLC patients treated at the National Cancer Institute of Mexico from 2007-2014 was analyzed. Their clinical- pathological characteristics, the mutation-status of EGFR and KRAS and the prognosis were evaluated.
Results:
Patients presented with stages of disease: II (0.6%), IIIa (4.8%), IIIb (18.4%) and IV (76.3%). NSCLC was associated with smoking in 56.5% of the patients (76.7% of male vs. 33.0% of female patients). Wood smoke exposure (WSE) was associated with 37.2% of the cases (27.3% in men vs. 48.8% in women). The frequency of EGFR mutations was 28.1% (18.5% in males vs. 36.9% in females, p<0.001) and the frequency for KRAS mutations was 10.2% (10.3% men vs. 10.1% in women p= 0.939). The median OS for all patients was 23.0 months [CI95% 19.4-26.2], whereas for patients at stage IV, it was 20.1 months [CI 95% 16.5-23.7]. The independent factors associated with the OS were as follows, the ECOG Performance Status, stage of disease, EGFR and KRAS mutation status.
Conclusion:
The high frequency of EGFR mutations and low frequency of KRAS mutations in Hispanic populations and different prevalence in lung cancer-related-developing risk factors compared with Caucasian populations, such as the lower frequency of smoking exposure and higher WSE, particularly in women, might explain the prognosis differences between foreign-born-Hispanics, US-born-Hispanics and NHWs.
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ORAL 41 - Immune Biology, Microenvironment and Novel Targets (ID 159)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:S.K. Padda, R. Nemenoff
- Coordinates: 9/09/2015, 18:30 - 20:00, Four Seasons Ballroom F1+F2
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ORAL41.03 - Myeloid Derived Supressor Cells and Their Clinical Relevance in Non-Small Cell Lung Cancer (ID 2946)
18:30 - 20:00 | Author(s): O. Arrieta Rodriguez
- Abstract
- Presentation
Background:
Lung cancer is the leading cause of cancer death worldwide and most of the patients are diagnosed with advanced disease. Myeloid-derived suppressor cells (MDSCs) are major contributors to tumor immune tolerance and targeting them can improve antitumor activity.
Methods:
We investigated the CD33[+]CD11b[+]CD66b[+]CD15[+]VEGFR-1[hi] MDSCs frequency in 120 non-small cell lung cancer (NSCLC) treatment-naive patients, with stage IIIB and IV of disease. We analyzed 1-year survival and its prognostic significance in relation to outcome analysis as well as its potential immunosuppression over cytotoxic CD8[+] T lymphocytes. The immunophenotyping of cell population was performed with multiparametric technique by flow cytometry.
Results:
We found a significant increase compared with controls in: Percentage of CD33[+]CD14[-]CD11b[+]CD66b[+]CD15[+ ](10.4 ± 5.01% vs. 3.1 ± 1.7% P<0.0001); Mean Fluorescence intensity (MFI) of VEGFR on MDSCs (P<0.001); plasma levels of arginase-1 (P<0.01); arginase-1 enzymatic activity (P<0.05); plasma levels of TGF-β (P<0.0001), IL-10 (P=0.0027) and IL-6 (P<0.0001). On the other hand, we found a significant decrease compared with controls in: Plasma levels of IFN-γ (P<0.0001); CD8[+] T cells (P<0.001); CD8[+]T cells IFN-γ production co-cultured with MDSCs (N=10; P<0.001) and MFI of CD3ζ chain (N=10; P<0.05). The percentage of MDSCs was negatively related to the percentage of CD8[+] T cells in the peripheral blood (N=155, R=-0.3045, P=0.0167). Finally, we found an inverse correlation between circulating MDSCs percentages and overall survival (P=0.09).
Conclusion:
Our study provides evidence of an increased pool of CD33+CD11b+CD66b+CD15+VEGFR-1hi MDSCs in the peripheral blood of NSCLC patients. The suppressive effect, of MDSCs on CD8+ T lymphocytes, suggests an important role in mediating immunosuppression in NSCLC that should enable the development of a novel biomarker and thus might represent a potential target for therapeutic intervention.
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P1.11 - Poster Session/ Palliative and Supportive Care (ID 229)
- Event: WCLC 2015
- Type: Poster
- Track: Palliative and Supportive Care
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.11-006 - Association between Nutritional Status Variables and Fatigue Diagnosis in Patients with Non Small Cells Lung Cancer (ID 3013)
09:30 - 17:00 | Author(s): O. Arrieta Rodriguez
- Abstract
Background:
Cancer-related fatigue (CRF) is a common and persistent symptom experienced by patients with Non Small Cells Lung Cancer (NSCLC). It is produced by multifactorial factors including those associated to the disease itself, comorbidities, life style and/or treatment. Malnutrition is found in up to 80% of patients with advanced cancer and could be associated with the presence of CRF. Both, malnutrition and fatigue have a negative impact on many aspects of patients’ Health-related quality of life, treatment compliance and prognosis. The aim of this study was to associate nutritional status variables with the occurrence of CRF in patients with advanced NSCLC.
Methods:
Patients with advance stage NSCLC under different lines of treatment were prospectively evaluated. Fatigue was assessed by the FA-13 (EORTC) test; malnutrition and anorexia were diagnosed using Subjective Global Assessment (SGA) and (S/AC-12) FAACT, respectively. Weight loss in the last six months was calculated, albumin and hemoglobin levels were used as biochemical parameters of nutrition.
Results:
129 patients were included, 75 were female (58%), the mean age was 61.9±13.8 years, Adenocarcinoma histology was present in 92 patients (71.4%) and the rest were classified as other histology, 90 patients (69.8%) were in ≤2[nd ]line of treatment, 106 patients (83.5%) had a functional status between 0-1 and the rest between 2-3, according to SGA 79 patients (64.8%) had any grade of malnutrition, 94 patients (75.8%) had a weight loss ≥10kg in six months, 25 patients (19.4%) were diagnosed with anorexia, albumin mean was 3.8mg/dl and 55 patients (32%) had less than that, as well as Hemoglobin level mean was 12.7 mg/dl and 61 patients (35.5%) had a valor less than it. Nutritional variables associated with CRF are shown in Table 2. Nutritional variables as Malnutrition, weight loss ≥10% and albumin were related with higher presence of physical, emotional, cognitive and daily-life fatigue. Clinical variables as histology, line of treatment and functional status were analyzed and just poor functional status was associated with higher presence of physical, emotional, cognitive and daily-life fatigue (p≤0.01). Table 2.- Nutritional status variables related fatigue
FS: fatigue scoren=129 Physic-FS p Emotional-FS p Cognitive-FS p Daily-life-FS p Social-FS p Nutritional-Status Malnourished Wellnourished 42 25 <0.01 42 25 <0.01 42 25 0.001 33 33 0.001 0 0.224 Weight-loss (≥10% 6 months) ≥10 <10 50 33 0.003 50 33 0.001 42 25 0.002 67 33 0.006 0 0.273 Anorexia Yes No 67 33 <0.01 58 33 <0.01 58 25 <0.01 67 33 <0.01 33 0 0.02 Albumin-(gr/dL) <3.8 ≥3.8 42 33 0.004 42 25 0.003 42 25 0.004 33 33 0.002 0 0.212 Hemoglobin-(gr/dL) <12.7 ≥12.7 42 33 0.077 42 25 0.04 42 25 0.012 33 33 0.227 0 0.023
Conclusion:
Malnutrition, weight loss, anorexia, hypoalbuminemia and low hemoglobin are associated with CRF. Hence, timely nutritional evaluation should be considered in NSCLC patients. Early nutritional treatment could help to reduce treatment and disease related fatigue. Nutritional and psychological support might confer beneficial effects.
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P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.01-060 - Biweekly Irinotecan/Bevacizumab in Heavily Treated Advanced NSCLC and Survival According to TIMP1 and EGFR Expression (ID 2521)
09:30 - 17:00 | Author(s): O. Arrieta Rodriguez
- Abstract
Background:
Irinotecan and bevacizumab are effective against non-small cell lung cancer (NSCLC) and synergism with non-cross-resistance has been demonstrated in preclinical studies. Tissue inhibitor of metalloproteinases 1 (TIMP1) and EGFR regulates extracellular matrix catabolism and promotion of cell growth and anti-apoptotic activity in NSCLC.
Methods:
Forty nine patients with heavily treated metastatic NSCLC were enrolled from March 2011 to November 2014. Thirty-three (67%) had never been exposed to bevacizumab and 16 had received antiangiogenic therapy as part of their first-line (all had achieved a previous response for more than 6 months). Treatment consisted of a 90-min intravenous infusion of 125 mg/m[2] irinotecan on day 1 and 8 plus 7.5 mg/kg bevacizumab on day 1 (treatment was repeated every 3 weeks). In all patients the mutational status of KRAS and EGFR, as well as TIMP1 and EGFR expression was evaluated.
Results:
The median age was 60 years (range, 44-78 years), 57% was male and 75% had ECOG 0-1. The median follow-up was 13.2 months and twenty-three patients had received >3 prior lines. The ORR was 32% (95%CI 22% to 39%) and thirteen patients (26%) achieve stable disease. Median progression-free survival (PFS) rate was 4.4 months (95%CI 2.8-8.3) and median overall survival (OS) rate was 18.0 months (95%CI 16.2-30.7). Nine patients harbouring EGFR mutations had a long-lasting, partial response (>5 months after at least 4 prior lines). Major toxicity was myelosuppression (grade 3 neutropenia occurred in 32% of patients and thrombocytopenia in 8.3%). Three patients experienced febrile neutropenia, one patient suffered grade 4 diarrhoea, and non-haematological toxicity was usually mild. Shorter OS was found in patients with a higher expression of TIMP1 mRNA (P=0.0001) but not according to the expression of EGFR (P=0.14).
Conclusion:
Irinotecan plus bevacizumab resulted in favourable activity and manageable toxicity profiles as third or fourth line for patients with advanced NSCLC. Our results suggested that such regimen can represent a reasonable chemotherapeutic option, especially for subjects having EGFR mutations and low expression of TIMP1.
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 3
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-028 - BIM Deletion Polymorphisms in Hispanic Patients with Non-Small Cell Lung Cancer Who Carriers EGFR Mutations (CLICaP) (ID 2597)
09:30 - 17:00 | Author(s): O. Arrieta Rodriguez
- Abstract
Background:
Germline alterations in the proapoptotic protein Bcl-2-like 11 (BIM) can have a crucial role in diverse tumors. To determine the clinical utility of detecting BIM deletion polymorphisms (par4226 bp/ par363 bp) in EGFR positive non-small-cell lung cancer (NSCLC), we examined outcomes of patients (pts) with and without BIM alterations
Methods:
We studied 89 NSCLC pts with EGFR mutation who were treated with erlotinib between January 2009 and November 2014. BIM deletion was analyzed by PCR in formalin-fixed paraffin-embedded (FFPE) tissues of tumor biopsies. We retrospectively analyzed clinical characteristics, response rate, toxicity, and outcomes among patients with and without BIM deletion (del)
Results:
BIM deletion was present in 14 pts (15.7%). There were no significant differences between pts with and without BIM del in clinical characteristics or type of EGFR mutation; however, pts with BIM del had a worse overall response rate to erlotinib (42.9% vs. 73.3% for pts without BIM del; p=0.024) as well as a significantly shorter progression-free survival (PFS) (10.8 del+ vs. 21.7 months for pts without BIM del; p=0.029) and overall survival (OS) (15.5 del+ vs. 34.0 months for pts without BIM del; p=0.035). Multivariate Cox regression analysis showed that BIM deletion was an independent indicator of shorter PFS (HR 3.0; 95%CI 1.2-7.6; p=0.01) and OS (HR 3.4; 95%CI 1.4-8.3; p=0.006)
Conclusion:
The incidence of BIM del found in pts from Colombia is similar to that previously described in Asia; this alteration is associated with a poor clinical response to erlotinib and represents an independent prognostic factor for pts who had NSCLC with EGFR mutations
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P2.04-077 - PDL1 Expression in Metastatic Non-Small Cell Lung Cancer Patients from Colombia (CLICaP) (ID 2839)
09:30 - 17:00 | Author(s): O. Arrieta Rodriguez
- Abstract
Background:
Programmed cell death-1-ligand 1 (PD-L1) is involved in the ability of tumor cells to escape the host’s immune system. PD-L1 is selectively expressed in a number of tumors. The blockade of interactions between PD-1 and PD-L1 enhances the immune function in vitro and mediates antitumor activity in preclinical models. Recent studies have suggested that antibody-mediated blockade of PD-L1 induced durable tumor regression and prolonged stabilization of the disease in certain cancers including NSCLC. A recent study demonstrated that immunohistochemical (IHC) analysis detected no objective response in PD-L1-negative patients. However, 36% of the patients with PD-L1-positive tumors had a positive response.
Methods:
PD-L1 was assessed by IHC (Dako MAb) in 115 NSCLC patients, considering as positive a staining intensity ≥ 2 in more than 5% of cells. The driver mutation epidermal growth factor receptor (EGFR) was examined by direct sequencing and allele specific PCR. ALK FISH was performed using the Vysis ALK Break-Apart Probe. The correlations of PD-L1 expression with major clinicopathologic parameters and outcomes were analyzed.
Results:
Mean age was 64.3 years (SD+/-10.7), 66% were females, 83% had adenocarcinoma and 58% were former/current smokers. Fourteen patients (18%) had mutations in the EGFR and 19 (25%) were PD-L1+. PD-L1 was positive in fifty-nine patients (51%) and this condition was more frequent in the light or never smokers (p=0.05). In the same way PD-L1 positivity was significantly associated with presence of EGFR mutations (p=0.03), in tumors with a higher grade of differentiation (p=0.023) and in presence of vascular invasion (p=0.038). Patients with positive PD-L1 expresion had a longer progression free survival (PFS) (6.4 months vs. 3.0 months, p= 0.001) and overall survival (OS) (28.2 vs. 12.4 months; p=0.001).
Conclusion:
Although the study sample is small, PD-L1 positivity correlates with PFS and OS. This results supports that PD-L1 might be a critical factor in the use of NSCLC immunotherapy.
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P2.04-078 - Functional Characterization of NK Cells in Non-Small Cell Lung Cancer (ID 2975)
09:30 - 17:00 | Author(s): O. Arrieta Rodriguez
- Abstract
Background:
Lung cancer is the leading cause of cancer death worldwide and most of the patients are diagnosed with advanced disease. Lung cancer is the leading cause of cancer death worldwide. Natural killer (NK) cells are important effector cells in control of infected, malignant, and tumor cells. The aim of this study was to investigate the activation state and cytotoxic potential of NK peripheral cells in patients with Non-Small Cell Lung Cancer (NSCLC).
Methods:
We investigated the relationship between NK cells apoptosis and Fas expression. NK cell apoptosis, Fas and Fas-L, NKG2D, CD69, KIR, CD244, CD122 and CD161 receptors were evaluated with multiparametric flow cytometry. We further evaluated the cytotoxic activity of NK cells and IFN-gamma expression. For this purpose, we simultaneously analyzed the loss of intracellular perforin and the surface expression of CD107a/b as well as the intracellular IFN-gamma expression with multiparametric flow cytometry.
Results:
Our results showed that Fas-positive NK cells in lung cancer patients were higher than healthy controls (P<0.001). These results also showed that up-regulation of Fas expression is related to increased apoptosis of circulating NK cells. Regarding the cytotoxic capacity, our results showed that upon PMA stimulation, the expression of surface CD107a/b and loss of intracellular perforin of NK cells from patients with NSCLC were not correlated indicating an impaired functional cytotoxic activity. Interestingly, we also found that, IFN-gamma (P<0.005) and NKG2D expression were also impaired significantly (P<0.001).
Conclusion:
The results from this study suggest a possible NK cells anergy state. Our description will help to provide a mechanistic insight into tumor immune escape via negative regulation of NK cell innate function; however, the underlying mechanisms remained to be addressed.
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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: 2
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-047 - Weekly Paclitaxel plus Bevacizumab in Heavily Pre-Treated Non-Small-Cell Lung Cancer (NSCLC) Patients (ID 3062)
09:30 - 17:00 | Author(s): O. Arrieta Rodriguez
- Abstract
Background:
Combination of weekly paclitaxel and bevacizumab showed synergistic effect, anti-tumor efficacy and a good toxicity profile in patients with non small cell lung cancer (NSCLC). We retrospectively reviewed safety and efficacy of this regimen in metastatic non-squamous NSCLC as fourth-line therapy or beyond.
Methods:
Thirty nine patients were included between November 2011 and December 2014; those were bevacizumab eligible and received weekly paclitaxel (80 mg/m[2], days 1, 8 and 15 every 21 days) plus bevacizumab (7.5 mg/kg at day 1) after three prior lines of chemotherapy. Efficacy was evaluated by CT-scan every 10 to 12 weeks and treatment was continued until progression or unacceptable toxicity. Main outcomes were overall response rate (ORR), progression free survival (PFS) and overall survival (OS).
Results:
Median age 61 (44-78), female 51.3%, never smokers 53.8%, ECOG >2 25.6% and more than four previous lines 53.8%. All patients were treated with a first-line platinum-based doublet with (38.5%) or without bevacizumab (61.5%) and all of them received docetaxel as second-line (ORR 33.4/SLP 4.6 months, CI95% 2-6.7). With weekly paclitaxel/bevacizumab the ORR was 36% and 28.2% achieved stable disease for at least 3 months. Median PFS was 5.8 months (CI95% 4.6-7.1) and OS was 18.0 months (CI95% 15.2-34.2). Grade 3-4 adverse events included neutropenia (10%), onycholysis (7.6%) and infection (5%). One patient died from a massive hemoptysis and prolonged responses were observed in two patients who had received bevacizumab as part of first-line chemotherapy and in another one who harbored an ALK rearrangement.
Conclusion:
In this retrospective series, our results suggest that weekly paclitaxel/bevacizumab had a good safety and efficacy profile in heavily pre-treated metastatic NSCLC.
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P3.01-067 - Pemetrexed (P)/Carboplatin/Bevacizumab (B) Followed by Maintenance P/B in Hispanic Patients with Non-Squamous NSCLC (ID 2507)
09:30 - 17:00 | Author(s): O. Arrieta Rodriguez
- Abstract
Background:
The present study evaluated the efficacy and safety of pemetrexed, carboplatin and bevacizumab, followed by maintenance pemetrexed and bevacizumab, in chemotherapy-naïve patients with stage IV non-squamous non-small cell lung cancer (NSCLC).
Methods:
The patients were administered pemetrexed (500 mg/m[2]), carboplatin (AUC 5.0 mg/ml/min) and bevacizumab (7.5 mg/kg) intravenously every three weeks for up to four cycles. Patients who did not experience tumor progression remained on maintenance pemetrexed and bevacizumab until disease progression or unacceptable toxicity. Primary endpoints were overall response rate (ORR), progression free survival (PFS) and overall survival (OS).
Results:
Hundred forty-four Colombian patients were included and received treatment. The median age was 64 years (range, 32-86 years), 61% was female and 55% had some history of tobacco exposure. The median follow-up was 13.8 months, and the median number of manteinance cycles was 8 (range, 1- 32). Among patients assessable for response, the ORR was 66% (95%CI, 47% to 79%). Median progression-free and overall survival rates were 7.9 months (95%CI 5.9-10.0 months) and 21.4 months (95%CI 18.3 to 24.4 months), respectively. Grade 3/4 hematologic toxicity was anemia (14%), neutropenia (8%), and thrombocytopenia (16%). Grade 3/4 nonhematologic toxicities were proteinuria (2%), venous thrombosis (4%), fatigue (11%), infection (6%), nephrotoxicity (2%), and sensory neuropathy (4%). There was no grade 3 or greater hemorrhagic events or hypertension cases.
Conclusion:
Overall, pemetrexed and carboplatin plus bevacizumab, followed by maintenance pemetrexed and bevacizumab, was effective and tolerable in hispanic patients with non-squamous NSCLC. This regimen was associated with acceptable toxicity and prolonged OS.
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 2
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-020 - ALK Rearrangements Epidemiology in Latin America (CLICaP) (ID 2957)
09:30 - 17:00 | Author(s): O. Arrieta Rodriguez
- Abstract
Background:
Latin American countries are heterogeneous in terms of lung cancer incidence, ethnicity, and exposure to potential carcinogens. The discovery of the echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) translocation as an oncogenic driver has led to the development of novel therapies with activity in vitro and in the clinic. In this study we evaluated the frequency and clinical characteristics of ALK rearrangements in six Latin-American countries.
Methods:
A total of 2799 biopsies of advanced NSCLC patients from 6 countries of Latin America (Argentina, Colombia, Costa Rica, Panama, Ecuador, and Mexico) were evaluated by the method fluorescence in situ hybridization (FISH) for detection of ALK-rearrangements. Demographic and clinicopathologic characteristics were analyzed.
Results:
The FISH analyses showed positive ALK fusion gene status in 6.55% (181/2761) of the total sample from all participating countries. ALK+ for each country was a follows: Argentina 6.08% (105/1726), Colombia 4.83% (10/207), Costa Rica 4.83% (2/49), Mexico 8.57% (64/746), and Panama 0% (0/33). Ecuador only used immunohistochemistry for ALK detection rearrangement; therefore, these samples were excluded from FISH technique analysis.
Conclusion:
The frequency of ALK rearrangement in Latin America is higher than previously reported for the Caucasian and Japanese populations. In addition, there is significant continental variability. Until now, FISH for ALK testing is not widely available in Latin America due to its high cost, time-consumption and result interpretation. There is an increased need to develop a common platform for genomic evaluation in developing countries.
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P3.04-090 - Association of Nuclear Expression of RAR Beta and YY1 with Prognosis in Advance Non-Small Cell Lung Cancer (ID 1697)
09:30 - 17:00 | Author(s): O. Arrieta Rodriguez
- Abstract
Background:
Lung cancer is the most common cause of cancer-related death worldwide and it is responsible for approximately 1.4 million deceases per year. In Mexico, the NSCLC cause more than 6,697 deaths annually. Approximately, 85% of all lung cancer corresponds to NSCLC and unfortunately at diagnosis 60% patients have advanced unresectable disease with a very poor prognosis. The standard of care treatment for advanced disease is platinum-based doublet chemotherapy, this present an objective response rates of 19% to 37% with a 7 to 10 months of median survival. The identification of molecular alteration in NSCLC has transformed the clinical management of this disease, increasing the survival and improves the response in patients. The genetic alterations affect a common group of oncogenic signaling pathways such as retinoid receptors (RR) and yin and yang 1 (YY1) resulting in lung cancer development and progression. The nuclear RR may play a critical role in the process of lung carcinogenesis. In NSCLC, reduction in the levels of mRNA RARβ and RARα have associated with lack of response to treatment and progression. As the same manner, YY1 is a key regulator of multiple signaling pathways involved in differentiation, replication, cellular proliferation and oncogenic transformation. The role of YY1 in development of cancer depend upon the context in which it binds. It could activate a variety of oncoproteins attenuates the stability of the tumor suppressor such as p53 or mediates the activation of genes with tumor-suppressive functions. The aim of this study was to analyze the expression of RARα, RARβ and YY1 and its relationship with overall survival in patients with advanced NSCLC.
Methods:
This was an observational study, where patients with advanced NSCLC at the National Cancer Institute of Mexico City from July 2005 to December 2011 were enrolled. The expression of RARα, RARβ and YY1, was determinate with immunohistochemistry by mean digital pathology and analyzed by Image-Pro Plus.
Results:
Eighty-five patients were included for the analysis. The mean and standard deviation of the nuclei expression of RARα, RARβ and YY1 were (106.7±97), (14±13) and (13±12). Patients with a high RARβ total expression have a better ECOG 0-1 vs 2-3 performance status (92.9 vs 74.4%). Non-smokers had a high nuclei expression of YY1 (61.9 vs <40.5%) and better median OS 15.6 (4.5-26.7 months). Nuclei expression of RAR-β was associated with the nuclei expression of YY-1 (R2 = 0.28; p-Value <0.0001). Also, the higher nuclei expression of RARβ was associated with a higher OS (27.5 vs 8.7 months) in both, the univariate analysis and multivariate analysis (p=0.016; p=0.037).
Conclusion:
The nuclei expression of both RARβ and YY1, could be used as biomarkers to NSCLC prognosis, specifically YY1 predicted a better response in patient that had never smoke.
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P3.06 - Poster Session/ Screening and Early Detection (ID 220)
- Event: WCLC 2015
- Type: Poster
- Track: Screening and Early Detection
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.06-026 - Gene Expression Signature to Predict Early Development of Brain Metastasis in Lung Adenocarcinoma (ID 1273)
09:30 - 17:00 | Author(s): O. Arrieta Rodriguez
- Abstract
Background:
Advances in systemic treatment have substantially improved the overall survival of advanced lung adenocarcinoma patients, and risk of brain metastases(BM) is higher. The survival of patients with symptomatic BM is poor. The identification of NSCLC patients with a high risk of developing BM would enable pre-emptive intervention to improve the outcome.
Methods:
A total of 53 biopsies of primary lung tumor adenocarcinoma stage IV treatment-naïve were analyzed for gene expression profiling using Affymetrix HuGene 1.0 ST and were processed in R using Bioconductor libraries. All patients were evaluated with brain MRI at diagnosis with a 3-month follow-up for BM development. Patients were classified into two groups: early-BM( < 6 months) and late-BM( > 6 months). A second independent cohort of 55 patients was analyzed to validate the gene expression signature (ClinicalTrials.gov: NCT00862173).
Results:
Samples were classified as early-BM(17) and late-BM(6), the remainder 30 never developed BM. Significant changes in gene expression of about100 genes were found. Eleven highly significant genes (B-stat > 12) were associated with process of cell-migrationCNN3(down-reg.) and adhesionCDH10(up-reg); anti-apoptosisBAG1(up-reg); immunological evasionSSX2(up-reg) and RAET1E(up-reg); signaling pathways related to RAS gene RAB9A(up-reg) and RAPGEF5(down-reg); mRNA-tRNA translocationDUS2L(up-reg); methylation controlNOC2L(up-reg); and members of the EGFR family EPGN(up-reg) and IGFR, IGF2BP1(up-reg).
Conclusion:
We describe an 11-gene signature that may predict the risk of BM which has the potential to classify patients and evaluate screening strategies that would facilitate pre-emptive interventional trials such as prophylactic cranial irradiation.
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P3.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 226)
- Event: WCLC 2015
- Type: Poster
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.08-009 - Diagnostic Efficacy of Electron Microscopy to Distinguish between Pleural Mesothelioma and Lung Adenocarcinoma in Pleural Effusion Cytology (ID 2310)
09:30 - 17:00 | Author(s): O. Arrieta Rodriguez
- Abstract
Background:
Mesothelioma is a mesodermic tumor localized in the pleura in 70-90% of the presentations. In most cases the diagnosis is made by computed tomography-guided biopsy or thoracoscopy. Characteristically mesothelioma includes papillary structures which make it difficult to distinguish from adenocarcinoma on hematoxylin and eosin stain, making this entity its main differential diagnosis. Immunohistochemical studies in biopsy specimens aids in the obtaining of a precise diagnosis. Notwithstanding it is often difficult to distinguish between both entities, in which case, electron microscopy is the gold standard as it allows to observe the abundant long thin microvilli (characteristic of the mesothelium) in tumor cells. Sometimes patients have only pleural effusion cytology which makes the diagnosis more challenging.
Methods:
Twenty-five pleural effusion cytology samples were studied to evaluate electron microscopy and its efficacy for diagnosis, as well as by immunohistochemistry for the diagnosis of either lung adenocarcinoma or mesothelioma.
Results:
Five pleural effusion samples with the histological diagnosis of mesothelioma and twenty with the histological diagnosis of adenocarcinoma, all with confirmed biopsies by immunohistochemistry. Of the five pleural effusion samples with histological diagnosis of mesothelioma, cytology in electron microscopy showed morphological characteristics of mesothelioma (long thin microvilli, dense junctions, desmosomes and tonofilaments ) in two samples (40%), and three were acellular (60%). Of the twenty pleural effusion samples with histologically confirmed diagnosis of adenocarcinoma (short microvilli, secretory vacuoles and intracytoplasmic lumens), eight were confirmed by electron microscopy (40%), eleven were acellular (55%), and one showed reactive mesothelium (5%).
Conclusion:
Pleural effusion cytology by electron microscopy showed that cells maintained their morphological features, either of mesothelioma or of lung adenocarcinoma, and can help in the diagnosis; however this is limited to the presence of cells in the pleural effusion
