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Carlos Camps
Moderator of
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ES02 - Management of Oncogene Addicted Patients with Stage III NSCLC (ID 5)
- Event: WCLC 2019
- Type: Educational Session
- Track: Treatment of Locoregional Disease - NSCLC
- Presentations: 4
- Now Available
- Moderators:Carlos Camps, Helena A Yu
- Coordinates: 9/08/2019, 10:30 - 12:00, Vancouver (2003)
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ES02.01 - Biomarker Testing in LA Disease (Now Available) (ID 3155)
10:30 - 12:00 | Presenting Author(s): Helena A Yu
- Abstract
- Presentation
Abstract
Routine biomarker testing in metastatic lung cancer has led to enormous improvements in outcomes for our patients with metastatic lung cancers. Oncogene testing has allowed us to identify the 50% of patients with metastatic lung cancer that are eligible for targeted therapies1. Consistently, targeted therapy for EGFR, ALK, ROS1, RET, BRAF have demonstrated superior progression-free survival compared to standard cytotoxic chemotherapy2. Identification of these genomic biomarkers has provided additional treatment options for our patients that are more effective and less toxic than standard treatments. In addition, serial biomarker testing allows us to also identify mechanisms of resistance to targeted therapy which can then inform subsequent treatment decisions. PDL1 testing is also routinely performed in the metastatic setting and assists us in identifying patients that may benefit from immunotherapy alone instead of first-line combination immunotherapy and chemotherapy treatment3. PDL1 testing allows us to predict likelihood of response to immunotherapy and selects patients that we can de-escalate treatment; patients with high PDL1 expression derive benefit from treatment with immunotherapy alone. Routine utilization of biomarker testing in metastatic lung cancer is easily the most importance advancement in this field to date.
Current recommendations
Biomarker testing for patients with locally advanced lung cancers is currently not recommended in the NCCN guidelines or any expert guidelines. This is likely because the current management for locally advanced lung cancers do not incorporate the use of biomarkers. Patients currently receive adjuvant durvalumab after concurrent chemoradiation for stage 3 disease irrespective of PDL1 status. Currently, adjuvant targeted therapies after definitive resection or radiation are not recommended in the NCCN or other cancer care guidelines.
Oncogene testing
The risk of recurrence for early stage lung cancers remain high. After surgical resection, adjuvant chemotherapy for high risk stage 1B, stage 3 and stage 4 and post-operative radiation for patients with mediastinal lymph node involvement are both recommended are they improve survival. Despite this, there is a large subset of patients that will have recurrent disease. Because of their demonstrated superiority over chemotherapy in the metastatic setting, there is great interest in assessing whether adjuvant targeted therapies would improve outcomes in the locally advanced disease setting. EGFR mutant lung cancer is the largest oncogene subset in which the bulk of previous studies have been done. However, all studies to date have been subsets of larger unselected patients (RADIANT study) or single arm studies (SELECT study). These smaller studies have shown a disease-free survival benefit but have been underpowered to demonstrate a survival benefit. There are several well-designed large studies ongoing that will definitively demonstrate whether adjuvant EGFR inhibitors improve overall survival. The ALCHEMIST study is a phase 3 randomized cooperative group study assessing erlotinib versus observation for patients with stage IB-IIIA resected lung cancers; accrual is ongoing. The ADAURA study is a randomized phase 3 study where patients with stage IB-IIIA resected lung cancers are randomized to osimertinib versus placebo for 3 years with a primary objective of DFS and a secondary objective of overall survival. These studies will help answer the question as to whether adjuvant targeted therapy should be utilized.
PDL1 testing
In stage 3 lung cancers, more than 60 percent of patients will ultimately die of their lung cancer4. Adjuvant durvalumab has improved outcomes with a clear improvement in overall survival but many patients still recur and ultimately die of their disease. An unplanned subset analysis of the PACIFIC study suggests that patients with PDL1 0% expression may not derive benefit from durvalumab. Further assessment will be needed to ascertain whether PDL1 expression can be used to select patients who would derive benefit from adjuvant durvalumab. Due to their efficacy in the metastatic setting, there are a significant number of studies looking at immunotherapy as both neoadjuvant and adjuvant treatment for locally advanced disease. Just as we utilize PDL1 as a biomarker that helps select appropriate therapies in the metastatic setting, I see similar use of PDL1 in the future in the locally advanced setting.
Future directions
As personalized medicine infiltrates our care of patients with lung cancers, we will need biomarker results for patients with locally advanced lung cancer to better tailor and personalize their care. In particular, if the EGFR TKI studies demonstrate improved overall survival with adjuvant EGFR TKI, we will certainly need to incorporate biomarker testing as standard of care for locally advanced disease. In addition, because a significant portion of patients recur, already having molecular test results available which were done on their surgical sample, makes their care later more stream-lined. We also need to assess whether PDL1 is a useful biomarker to select patients for immunotherapy in the adjuvant setting. Results from ongoing clinical trials will provide definitive answers.
Works cited:1. Jordan, E.J., et al. Prospective Comprehensive Molecular Characterization of Lung Adenocarcinomas for Efficient Patient Matching to Approved and Emerging Therapies. Cancer discovery 7, 596-609 (2017).
2. Sequist, L.V., et al. Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations. Journal of clinical oncology : official journal of the American Society of Clinical Oncology (2013).
3. Reck, M., et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. The New England journal of medicine 375, 1823-1833 (2016).
4. Pisters, K.M., et al. Cancer Care Ontario and American Society of Clinical Oncology adjuvant chemotherapy and adjuvant radiation therapy for stages I-IIIA resectable non small-cell lung cancer guideline. Journal of clinical oncology 25, 5506-5518 (2007).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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ES02.02 - Management of EGFR LA Disease (Now Available) (ID 3156)
10:30 - 12:00 | Presenting Author(s): Keunchil Park
- Abstract
- Presentation
Abstract
Management of EGFR mutation(+) Locally Advanced Non-Small Cell Lung Cancer
Keunchil Park, MD, PhD
Division of Hematology-Oncology, Samsung Medical Center,
Sungkyunkwan University School of Medicine, Seoul, Korea
The standard of care for the locally advanced non-small cell lung cancer(LA-NSCLC) is concurrent chemoradiotherapy(CCRT). Recently, the addition of consolidation immune checkpoint inhibitor following CCRT demonstrated improved outcome and is now recommended as the new standard of care for this heterogeneous group of LA-NSCLC patients. In advanced/metastatic setting EGFR mutation (+), NSCLC cancer patients define a unique subset with a dramatic response to the EGFR TKIs. Currently, molecular profiling of tumor tissue for EGFR mutations (as part of multiplex testing) is a routine procedure at the time of initial diagnosis of patients with recurrent or metastatic NSCLC. For advanced or metastatic EGFR mutant NSCLC patients EGFR TKI therapy is the treatment of choice and the median overall survival is > 30 months.
Despite the great success of EGFR TKI in metastatic NSCLC, the role of EGFR TKIs in LA-NSCLC is less well defined and controversial. Early clinical trials in unselected NSCLC patients failed to demonstrate the benefits of EGFR-TKIs as an adjuvant treatment. The first prospective randomized phase III trial to investigate the role of EGFR TKI in earlier stage NSCLC includes the SWOG 0023 study (J Clin Oncol 2008;26:2450-6) which failed to support the role of maintenance gefitinib (versus placebo) following definitive chemoradiation in unresectable stage III NSCLC. The CALGB 30106 phase II study also failed to show the benefits of adding gefitinib to sequential or concurrent chemoradiotherapy in unresectable stage III NSCLC (J Thorac Oncol 2010;5:1382-90). And the randomized prospective placebo-controlled adjuvant gefitinib trial in unselected patients with stage IB–IIIA resected disease (BR.19) was prematurely closed (J Clin Oncol 2013;31:3320-6). Another randomized double-blind trial in adjuvant NSCLC with tarceva (RADIANT) in patients with completely resected state IB to IIIA NSCLC whose tumors expressed EGFR protein by immunohistochemistry or EGFR amplification by fluorescence in situ hybridization did not show prolonged DFS (J Clin Oncol 2015;33:4007-14).
The prognostic or predictive value of EGFR mutation in early stage NSCLC patients is not well defined. In a retrospective single institutional analysis (J Thorac Oncol. 2012;7: 1815–1822), patients with resected stage I–III lung cancers and EGFR mutation have a lower risk of death compared to patients without EGFR mutation. There was a trend toward improvement in DFS among individuals with resected stages I to III lung adenocarcinomas harboring mutations in EGFR exon 19 or 21 who received adjuvant EGFR TKI therapy (J Thorac Oncol 2011;6:569–575).
There have been recently reported several prospective trials of adjuvant EGFR TKI in early stage NSCLC patients enriched with EGFR mutation.
CTONG1104 study (ADJUVANT), a randomized, open-label, phase III trial of adjuvant gefitinib for 24 months versus intravenous vinorelbine plus cisplatin for 4 cycles in patients with completely resected (R0), stage II–IIIA (N1–N2), EGFR-mutant (exon 19 deletion or exon 21 Leu858Arg) NSCLC, demonstrated that adjuvant gefitinib compared to cisplatin-based chemotherapy significantly increases disease-free survival, diminishes toxic effects, and improves HRQoL in patients with completely resected stage II–IIIA EGFR-mutant NSCLC (Lancet Oncol 2018; 19: 139–48).
In the phase II SELECT trial, adjuvant erlotinib for 2 years in patients with resected stage IA to IIIA EGFR-mutant NSCLC after standard adjuvant chemotherapy with or without radiotherapy (J Clin Oncol 2019;37:97-104) showed an improved 2-year DFS. Patients rechallenged with erlotinib after recurrence experienced durable benefits.
There are also some neoadjuvant trials of EGFR TKI for locally advanced NSCLC.
RTOG 1306, a randomized phase II study of individualized combined modality therapy for stage III NSCLC (12-weeks of either erlotinib hydrochloride or crizotinib followed by chemoradiation therapy in stage III NSCLC with EGFR TK mutations or EML4- ALK fusion). The primary objective was to assess whether patients with unresectable LA-NSCLC treated with EGFR or ALK TK targeted agents based on molecular characteristics have a longer progression-free survival than those treated with standard care therapy alone. The study was, however, unfortunately prematurely terminated due to poor accrual (NCT01822496).
CTONG 1103 is an open-label, randomized trial that compared the efficacy and safety of erlotinib versus gemcitabine plus cisplatin neoadjuvant therapy in patients with exon 19 or 21 EGFR mutations and untreated resectable stage IIIA-N2 NSCLC. The study did not meet the primary end point of ORR with 42 days of neoadjuvant erlotinib, but the secondary end point PFS was significantly improved (J Clin Oncol 37. © 2019; published at jco.org on June 13, 2019: DOI https://doi.org/10.1200/JCO.19.00075)
There are also several ongoing clinical trials of EGFR TKIs in resected stage IB - IIIA NSCLC with activating EGFR mutations.
The Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST) is a prospective randomized double-blind placebo-controlled trial to investigate the benefits of the addition of molecularly targeted agents after standard postoperative chemotherapy in patients with resected NSCLC (Clin Cancer Res:2015; 21(24); 5439–44). It is worth noting that the primary objective for the ALCHEMIST adjuvant trials is overall survival (OS).
ADAURA, a randomized phase III trial (osimertinib vs. placebo in patients with stage IB-IIIA NSCLC, following complete tumor resection with or without adjuvant chemotherapy; NCT02511106) has been designed to assess the efficacy and safety of adjuvant osimertinib versus placebo in patients with resected stage IB-IIIA EGFR mutation-positive (Ex19Del or L858R) NSCLC. The primary efficacy objective is DFS.
In brief, many neoadjuvant/adjuvant EGFR TKI trials in earlier stage of NSCLC have demonstrated its safety and feasibility with an improved DFS esp. in EGFR mutation(+) LA-NSCLC. However, the real question should be “Can we improve the ‘overall survival’ and thus ultimately the ‘cure rate’ of locally advanced NSCLC with EGFR mutation?” In order to address this issue, there remain several critical questions to be answered, e.g., who is most likely to benefit from adjuvant EGFR TKI, what is the optimal duration of adjuvant TKI, what is the best regimen, etc. Whether the earlier introduction of EGFR targeted therapy in less advanced NSCLC would lead to improved ‘Cure Rate’ remains to be seen in future prospective trials in a larger number of EGFR mutation(+) patients.
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ES02.03 - Management of Other Non EGFR Oncogene Addicted Tumors (Now Available) (ID 3157)
10:30 - 12:00 | Presenting Author(s): Charu Aggarwal
- Abstract
- Presentation
Abstract
Stage III non-small cell lung cancer accounts for heterogeneous group of diseases, due to differences in tumor size, location number of nodes involved, and lymph node station involved. Stage III non-small cell lung cancer comprises 2 distinct stages, stage IIIA and IIIB disease that have different prognosis, and are usually treated differently. Approximately 15% of all patients with newly diagnosed non-small cell lung cancer present with stage III disease. Options for stage III non-small cell lung cancer include surgery, with lobectomy or pneumonectomy depending on the tumor stage, and lymph node involvement. Chemotherapy may be administered in the neoadjuvant, concurrent or adjuvant setting. Radiation therapy can be given in a concurrent, sequential approach, or may be administered in the postoperative fashion. Combination approaches are often used, and due to the significant need of multi-modality therapy, treatment decisions are usually made in a multidisciplinary setting. The optimal therapeutic approach for patients with stage IIIA non-small cell lung cancer remains controversial. For subset of patients with T3 to T4 N0-1 disease, and superior sulcus location, surgery remains a viable and preferred option. However, the optimal treatment for patients with stage III A, with bulky lymph node involvement, or multi station lymph node involvement including N2 disease, remains an area of ongoing controversy. Tri-modality approaches using preoperative chemotherapy, or upfront chemoradiation therapy followed by surgery have been evaluated (1). For patients with surgically unresectable, or medically inoperable disease, concurrent chemoradiation therapy has been established as the standard of care for patients spanning the spectrum of stage IIIA and IIIB disease.
Recently, the PACIFIC trial demonstrated an improvement in progression free survival and overall survival with the administration of durvalumab as consolidation therapy (regardless of PDL-1 status) for patients who had not progressed after 2 or more cycles of definitive concurrent platinum-based chemoradiation therapy (2, 3). This approach represents a new paradigm in the management of unresectable NSCLC, and has now been adopted as standard of care.
Management of Stage III patients with non EGFR oncogene addicted tumors is an area of active research. ALK or ROS directed oral tyrosine kinase inhibitors (TKIs) are not typically administered in the adjuvant setting outside of a clinical trial. There are several trials evaluating the use of targeted therapies. ALINA, is one such trial, that is a phase III study of alectinib versus chemotherapy as adjuvant therapy in patients with stage IB–IIIA anaplastic lymphoma kinase-positive ALK positive NSCLC (4). Another study is comparing adjuvant alectinib versus adjuvant platinum-based chemotherapy in patients with ALK positive NSCLC, here the alectinib is administered for 2 years (NCT 03456076). The Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing (ALCHEMIST) trial is actively enrolling patients with operable NSCLC and will perform genetic screening of their tumors. Patients with EGFR mutation or ALK gene rearrangement in their tumor will be randomized to placebo versus erlotinib or crizotinib, respectively (NCT02194738). We await the results of these trials prior to routine incorporation of molecularly directed therapy in the management of locally advanced disease.
References:
1. Albain KS, Swann RS, Rusch VW, Turrisi AT, 3rd, Shepherd FA, Smith C, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet. 2009;374(9687):379-86. Epub 2009/07/28. doi: 10.1016/S0140-6736(09)60737-6. PubMed PMID: 19632716; PubMed Central PMCID: PMC4407808.
2. Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. The New England journal of medicine. 2017;377(20):1919-29.
3. Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. 2018; 379:2342-2350
4. Solomon BJ, Ahn JS, Barlesi F et al. ALINA: A phase III study of alectinib versus chemotherapy as adjuvant therapy in patients with stage IB–IIIA anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC). J Clin Oncol 37, 2019 (suppl; abstr TPS8569)
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ES02.04 - Concurrent, Sequential and Combination Immunotherapy Regimens in LA-NSCLC (Now Available) (ID 3158)
10:30 - 12:00 | Presenting Author(s): Mariano Provencio
- Abstract
- Presentation
Abstract
Immunotherapy in Oncogenic-Addicted Stage III Patients
At diagnosis of non small cell lung cáncer (NSCLC), at least 40% of patients are diagnosed at an advanced stage and a third locally advanced disease (stage III). The results of stage IIIA with induction treatment of clinical practice outside the clinical trial show a median survival of 22 months and a 3-year survival rate of 34%. Concurrent definitive chemoradiation has been established as the standard of care for unresectable stage IIIB (N3 disease) NSCLC, with a median overall survival (OS) of approximately 17 months. Strategies that have been investigated include induction chemotherapy, immunotherapy (IO), concomitant chemoradiotherapy, intensified radiotherapy and adjuvant treatment.
The role of IO in NSCLC with oncogenic-addicted tumors is so far unclear. In EGFR-mutation positive patients there seems to be a worse effect of IO compared to those patients without actionable mutations,; nevertheless, no safe conclusions can be drawn due to the lack of randomized trials addressing this clinical issue. The available information from second lines with IO in patients with actionable mutations, is currently found in 2 meta-analyses[1].
These meta-analyses show OS benefit between EGFR wild-type vs mutated patients with a Hazard Ratio (HR) of 0.67, p< 0.001, consistent in all the trials. There was no OS advantage for those with EGFR mutant tumors, with a HR of 1.11, p=0.54.
Of note, data from other studies were not included in these meta-analyses. Study CA209-012 showed patients with EGFR mutation, overall response rate (ORR) 14% mutated vs 30% in wild type and PFS at 24 weeks: 14% vs 51% respectively[2].
In KEYNOTE-001, best ORR based on mutation status was 15.8% in patients with EFGR mutation vs 37.1% without mutation, and 60% were unknown. Overall PD-L1 subgroups, EGFR mutated patients had lower ORR than patients with EGFR-wild type tumors. ORR was 20 % in TPS > 50% and 0% in patients with TPS<1% vs 12.7% in EGFR wild type[3]. An update of this study, and median OS in patients with EGFR mutation was 6 months (mo) (95%CI, 4.4-8.8) and 12 mo (95%CI, 9.2-14.3) in patients wild-type[4].
In the Immunotarget Cohort study, patients with EGFR-mutation had response rates of 12% and PFS of 2.1 mo and with a positive correlation in patients with high expression of PDL1 and response.
The BIRCH[5] study, also not included in the meta-analyses, provides us with similar information, with higher response rates in patients with higher expression of PDL1 (31% vs 23%), even achieving similar PFS to wild type patients (7.6 vs 7.7 mo) or OS with 28.5 mo (20.1, NE) in mutant vs 20.1 mo (15.5, 31.1) in wild-type. The phase II ATLANTIC trial testing durvalumab as third-line treatment included the largest cohort of EGFR mutant patients treated with IO after progression of TKI and chemotherapy. According to PD-L1 expression (< 25% or ≥ 25%), durvalumab achieved a response rate (RR) of 3.6% and 14.1%, a similar median PFS 1.9 months and a median OS of 9.9 months and 13.3 months, respectively[6].
Despite improvements in the treatment of stage IV NSCLC with the introduction and dissemination of checkpoint inhibitors, very little progress has been made in the treatment of stage III. The PACIFIC trial was the first study to show a clear benefit for the approach. Patients were enrolled regardless of PD-L1 expression, and those with EGFR mutations were also eligible. The subgroup of patients with EGFR mutations did not clearly benefit from durvalumab maintenance. These patients were equally represented in the durvalumab (6%) and placebo (5.9%) arms. The HR was 0.76 in this setting, and whether because of a small sample size or true lack of efficacy, the findings were not significant (95% CI, 0.35–1.64).
In NADIM Study, a Phase II, with neoadjuvant chemotherapy and immunotherapy in stage III, unprecedented pCR rates observed (around 70%) and with down-staging around 90%. We did not include patients with actionable mutations, and we do not have information about other trials using chemo and IO. In KN 189 using combination of chemo and IO in stage IV, no sensitizing EGFR or ALK alteration were included. In the ImPOWER 150 study[7] comparing the use of bevacizumab plus atezolizumab plus carboplatin, plus paclitaxel versus carboplatin plus paclitaxel plus bevacizumab in first-line stage IV, provides interesting results in PFS, with a HR of 0.41 (95% CI: 0.22-0.78), in patients with common mutations (already treated with TKIs) in the arm with atezolizumab plus chemo better than the control arm.
In the light of these results, we may conclude that other biomarkers such as a tumor mutational burden (TMB) could be used in the future, but low TMB is especially significant among the oncogenic alterations strongly related with never-smokers, such as EGFR mutation and ALK rearrangements. Therefore, these data suggest a role for actionable mutations testing in the stage III setting and for additional trials specifically targeting EGFR-mutant patients and stage III disease.
[1] Lee CK, Man J, Lord S et al. Clinical and molecular characteristics associated with survival among patients treated with checkpoint inhibitors for advanced non-small cell lung carcinoma.A systematic review and meta-analysis. JAMA Oncol 2017
[2] Gettinger S, Chow LQ, Borghaei H et al. Nivolumab monotherapy for first-line treatment of advanced non-samll cell lung cancer. JCO, DOI: 10.1200/JCO.2016.66.9929.
[3] Hellman M et al. Efficacy of pembrolizumab in key subgroups of patients with advanced NSCLC. 16th World Conference on Lung Cancer, 2015.
[4] Leighl NB, Hellamn MD, Hui R, et al. KEYNOTE-001: 3-year overall survival for patients with advanced NSCLC treated with pembrolizumab. ASCO 2017.
[5] Carcereny E, Felip E, Reck M, et al. Updated efficacy results from the BIRCH study: First-line atezolizumab therapy in PD-L1 –selected patients with advanced NSCLC. World Conference on Lung Cancer 2017.
[6] Garassino MC, Cho B-C, Kim J-H, Mazières J, Vansteenkiste J, Lena H, et al. Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study. Lancet Oncol 2018;19:521–36.
[7] Socinski M, Jotte RM, Capuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. NEJM DOI: 10.1056/NEJMoa176948.
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MA04 - Models and Biomarkers (ID 122)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Biology
- Presentations: 2
- Now Available
- Moderators:Montse Sanchez-Cespedes, Kwok-kin Wong
- Coordinates: 9/08/2019, 13:30 - 15:00, Interlaken (1988)
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MA04.03 - Lung Tumorspheres Characterization Reveals Cancer Stem-Like Cells Potential Targets and Prognostic Markers in Non-Small Cell Lung Cancer (Now Available) (ID 2269)
13:30 - 15:00 | Author(s): Carlos Camps
- Abstract
- Presentation
Background
Non-small cell lung cancer (NSCLC) is the leading cause of death cancer-related worldwide due to late diagnosis and high resistance against treatments. This resistance has been associated to cancer stem-like cells (CSCs), a highly tumorigenic subpopulation for which the identification of targets and biomarkers is still under development.
Method
Tissue samples from 8 NSCLC patients were successfully established and cultured using a sphere-forming assay for CSCs enrichment. Adherent counterparts were used as differentiated control cells. Proliferation, chemorresistance, invasion and differentiation capacities were tested in vitro, whereas tumor initiation capacity was determined in vivo. The expression of 44 CSCs-related genes was assessed by qPCR and protein expression of the best contributors to distinguish adherent cells from tumorspheres was determined by immunoblot and immunofluorescence. The prognostic role of these genes was evaluated in a cohort of 661 resected NSCLC patients from TCGA and validated in an independent cohort of 114 resected lung adenocarcinoma patients.
Result
Patient-derived tumorspheres showed unlimited exponential growth, high resistance against chemotherapy, great invasion and differentiation capacities in vitro in addition to a higher tumorigenic potential than adherent cells in vivo. The expression of 17 genes was significantly overexpressed in lung tumorspheres, being NANOG, NOTCH3, CD44, CDKN1A, SNAI1, and ITGA6 the best contributors. Proteins encoded by these genes were consistently increased in tumorspheres from adenocarcinoma patients and showed differential localization and expression patterns. The expression of CDKN1A, SNAI1 and ITGA6 was associated to prognosis based on Cox regression analysis (Z-score > 1.5), so their absolute regression coefficients from a multivariate model were used to calculate a gene expression score. Kaplan-Meier survival analysis showed that patients with high score have shorter OS in the entire cohort [37.7 vs. 60.4 mo., p = 0.001] and the adenocarcinoma subcohort [36.6 vs. 53.5 mo., p = 0.003], but not in squamous cell carcinoma one. Multivariate analysis indicated that this gene expression score was an independent biomarker of prognosis for OS in both, the entire cohort [HR: 1.498; 95% CI, 1.167-1.922; p = 0.001] and the adenocarcinoma subcohort [HR: 1.869; 95% CI, 1.275-2.738; p = 0.001]. The prognostic value of this score was confirmed in an independent cohort of 114 lung adenocarcinoma patients (42.90 vs. NR mo, p = 0.020).
Conclusion
Proteins encoded by NANOG, NOTCH3, CD44, CDKN1A, SNAI1, and ITGA6 are potential targets against lung CSCs. Elevated gene expression levels of CDKN1A, SNAI1 and ITGA6 are associated with worse prognosis.
Funded by CB16/12/00350 from CIBEROnc, PI12-02838, and PI15-00753 from ISCIII and Fundacion Arnal Planelles.
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MA04.09 - Study of Exosomes in NSCLC for Biomarkers Searching (Now Available) (ID 2417)
13:30 - 15:00 | Author(s): Carlos Camps
- Abstract
- Presentation
Background
Exosomes are small membranous vesicles secreted by a most type of cells (especially in tumoral processes), around 40-130 nm of size, that carry relevant information to distant tissues and being able to modulate its physiology. Exosomes have been detected in different clinical samples and may play a key role in NSCLC, participating in several processes such as horizontal transfer of RNA from tumor to microenvironmental cells, angiogenesis, pre-metastatic niche formation, immunosuppression; and could also be key elements in stem cell differentiation (from different origins).
The principal objective of this study was to analyze the exosomes cargo from NSCLC cell lines and primary cultures with diverse characteristics under different growth conditions: suspension cultures with cancer stem cells (CSCs) features and monolayer cultures.
Method
Primary cultures from resected NSCLC patients and NSCLC cell lines were successfully established. Differentiated tumor cells were cultured under adherent conditions (2D) whereas CSCs were established in suspension cultures (3D tumorspheres). Exosomes isolation was performed by ultracentrifugation. Exosomes characterization was carried out through nanovesicles tracking analysis (NTA) and electron microscopy; and the determination of surface markers through immunoblot and flow cytometry. Exosomal DNA was extracted in order to determine the mutational status of the EGFR and RAS genes by BEAMing Digital PCR (Sysmex). Transcriptomic analysis has been carried out from exosomal RNA through whole genome gene expression microarrays, (Affymetrix). The data was normalized by Robust Multi-Array Average (RMA) and analyzed using Transcriptome Analysis Console (TAC), MultiExperiment Viewer (MeV) software and Partek Genomics Suite. Statistical significance was established at (p ≤ 0.01).
Result
In reference to the characterization, NTA and electron microscopy showed that exosomes were obtained free of cellular debris and their size ranges from 108-125 nm, according to the size of tumor-derived microvesicles. Exosomal surface markers analyzed by immunoblot and flow cytometry were detected in samples, confirming proper isolation. Mutational analysis of EGFR and RAS genes performed on exosomal DNA shown the same pattern displayed by the origin cells. Transcriptomic analysis of the exosomal content showed that the expression of mRNAs, miRNAs and precursors were significantly different between 3D and 2D-derived exosomes. Finally, a pathway enrichment analysis was carried out to know in which biological processes (cancer-related) are involved.
Significant differential expressions were also found between mRNAs, miRNAs and pre-miRs present in exosomes from adenocarcinoma (ADC) vs. squamous cell carcinoma (SCC). Interestingly, 7 miRNAs differentially expressed in exosomes (miR-200c; miR-29a; miR-339; miR-224; miR-31; miR-21; miR-33a) had already been identified as overexpressed in tumor tissue from NSCLC patients by our group. Moreover, miR-339 y miR-21 were related to prognosis (p < 0.05) in ADC group.
Conclusion
Differences in exosomal mRNA, miRNAs and pre-miRs expression have been observed between: i) lung-tumorspheres vs. more differentiated tumor cells and ii) ADC vs. SCC cultures. In addition, the same mutational pattern was detected in exosomes as compared with their parental cultures. Therefore, exosomes can be a useful source for biomarkers analysis in NSCLC.
Supported by grant GV/2018/026, PI18/00266, & Asociación Española Contra el Cáncer (AECC Valencia).
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P1.03 - Biology (ID 161)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.03-15 - Non-Invasive Detection of Secondary Resistance Mutations in ALK-Positive NSCLC Patients by Next-Generation Sequencing (ID 1658)
09:45 - 18:00 | Author(s): Carlos Camps
- Abstract
Background
ALK inhibitors have led to important improvements in ALK-positive non-small cell lung cancer (NSCLC) patient’s survival and quality of life. However, despite the good responses, resistance mutations inevitably emerge. Several resistance mutations in ALK domain have been describe. Remarkably different mutations can confer different sensitivities to different ALK inhibitors. However, 2nd and 3rd line treatment is often prescribe empirically without knowing the molecular mechanism underlying treatment failure.
Method
21 samples from ALK-positive NSCLC patients were collected at disease progression. Circulating Nucleic Acids were isolated from platelets, exosomes and plasma. Libraries were prepared using 20ng of template and Oncomine™ Pan-Cancer Cell-Free Assay. Samples were sequenced on an Ion GeneStudio S5 Plus System. Sequencing data was first analyzed using Torrent Suite software. Subsequently variant calling, annotation and filtering was performed on the Ion Reporter (v5.10) platform using the Oncomine TagSeq Pan-Cancer Liquid Biopsy w2.1 workflow.
Result
In 14 (67%) patients a somatic mutation was identified in the plasma sample collected at disease progression. The average number of mutations detected per sample was 2.6. Noteworthy, 14 mutations were found in oncogenes that have been previously associated with ALK inhibitors resistance (5 mutations in ALK locus, 4 mutations in PIK3CA, 1 mutation in EGFR, 1 mutation in KIT, 1 mutation in KRAS, 1 mutation in MTOR and 1 mutation in MYC). The rest of mutations (N=21) were found in TP53 gene. Secondary resistance mutation in ALK locus occurred in 24% of the cases. Specifically, p.G1269A (N=2), p.G1202E (N=1), p.R1275Q (N=1) mutations were found in ALK-positive NSCLC who had progressed on crizotinib and p.G1202R mutation was found in 1 ALK-positive NSCLC who had progressed on ceritinib.
Conclusion
Secondary ALK-TKI resistance mutations could be detected using liquid biopsies in a high proportion of patients. Non-invasive molecular profiling of samples collected at disease progression is feasible being useful for further treatment selection in ALK-positive NSCLC patients.
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P1.09 - Pathology (ID 173)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Pathology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.09-13 - Prognostic Value of TMPRSS4 Expression and Its Role as Diagnostic Biomarker by Liquid Biopsy in Early Stage NSCLC (ID 2499)
09:45 - 18:00 | Author(s): Carlos Camps
- Abstract
Background
Relapse rates in surgically-resected non-small cell lung cancer (NSCLC) patients are between 30-45% within 5 years of diagnosis, which reflects the clinical need to identify those patients at high risk of recurrence and death. TMPRSS4 is a serine protease that plays a role in lung cancer growth, development of metastasis and resistance to chemotherapy in NSCLC models. TMPRSS4 is overexpressed through promoter hypomethylation in NSCLC tumors.
Method
Two cohorts of NSCLC patients (MD Anderson (MDA), n=489; and Clinica Universidad de Navarra (CUN), n=95) were used to investigate the prognostic value of TMPRSS4. The WHO 2004 classification and 8th TNM edition was used for tumor stratification. We have also developed a method to quantify he degree of TMPRSS4 and SHOX2 methylation status in liquid biopsy (plasma and bronchoalveolar lavages (BALS)) by digital droplet PCR (ddPCR), in tumor-free individuals and patients with NSCLC.
Result
High levels of TMPRSS4 were significantly associated with reduced relapse-free survival (RFS, p<0.001) and overall survival (OS, p<0.001) in the MDA cohort, and with OS in the CUN cohort (p<0.049). In univariate Cox regression analysis using the MDA cohort, high TMPRSS4 levels were RFS (HR=2.09; 95% IC [1.53-2.87], p<0.001) and OS (HR=1.82; 95% IC [1.38-2.41], p<0.001). In multivariate analyses, TMPRSS4 was found as an independent prognostic factor for both RFS (HR=1.82, IC [1.28-2.60], p<0.001) and OS (HR=1.44, IC [1.07-1.94], p<0.014).
Conclusion
In our MDA cohort, stage IA and stage IB showed no statistical differences for RFS (p=0.27) or OS (p<0.001). However, when considering the protein expression of TMPRSS4 we were able to substratify stage IA patients in low and high risk patients, since those with high TMPRSS4 levels showed a significantly reduced RFS (p=0.002) and OS (p<0.001). Similar tendency was observed for stage IB, although statistical differences were not found.
After successful establishment of the ddPCR conditions for TMPRSS4 and SHOX2 methylation status, we analyzed plasmas and BALS in case-control studies. In BALS (79 NSCLC patients and 26 controls), significant hypomethylation (p<0.01) was found for TMPRSS4 in the case of patients with early stage NSCLC in comparison with controls, with an AUROC of 0.72 (95% IC, 0.57-0.87) (p=0.008). SHOX2 was significantly hypermethylated in BALS from early stage NSCLC compared to controls (p<0.01), with an AUROC of 0.71 (95% IC, 0.56- 0.86) (p=0.01). In the case of plasmas (89 NSCLC patients and 25 controls): in early stages, a significant hypomethylation was found for TMPRSS4 (p<0.05), with an AUROC of 0.73 (95% IC, 0.54-0.90) (p=0.015). For SHOX2, only late stages NSCLC showed significant hypermethylation with respect to controls (p<0.05), with an AUROC of 0.68 (95% IC, 0.54-0.80) (p=0.025).
High TMPRSS4 levels are associated with worse prognosis in NSCLC patients. TMPRSS4 expression significantly discriminates patients with higher risk of disease progression and poor survival outcome in early stage NSCLC. Methylation status of TMPRSS4 can be used in both plasma and BALS to identify patients with NSCLC.
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P2.03 - Biology (ID 162)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 4
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.03-08 - Analysis of Immunosuppressive Factors Produced by CSCs Revealed Galectin-3 as Immune Modulator with Prognostic Value in NSCLC Adenocarcinoma (ID 1855)
10:15 - 18:15 | Author(s): Carlos Camps
- Abstract
Background
The study of the tumor microenvironment is leading to a better understanding of the tumor escape from immunosurveillance and immunotherapy response. Cancer stem cells (CSCs) are targets poorly recognized by the immune surveillance system given that they favor an immunosuppressive microenvironment. The aim of this work is to study the interactions between CSCs and the immune microenvironment in NSCLC.
Method
Tumor cells from 8 resected NSCLC patients and 12 cell lines were cultured using a sphere forming assay for CSCs enrichment. Adherent cultures were established as differentiated controls. The gene expression of IL-4, IL-10, IL6, IL8 LGALS-3 was analyzed by RTqPCR. Gene expression results were validated at a protein level by a sensitivity bead-based multiplex immunoassay using the Millipore kit for Luminex 100/200. The prognostic value of these factors in silico was determined in a cohort of 661 patients from The Cancer Genome Atlas (TCGA) cohort. Prognostic value was assessed by Cox regression and Kaplan‐Meier curves ﴾long rank‐test﴿, considering significant when p<0.05.
Result
Patients’ median age was 67 years [57-74], 62% were male, and 62.5% were adenocarcinomas (ADC). Gene expression analysis revealed that lungspheres had significantly higher expression of LGALS3 compared to differentiated adherent cells. On the contrary, adherent cells had significantly higher expression of IL6. In concordance with gene expression levels, we observed significant differences in the secretion of these two soluble factors (IL-6 and Galectin-3) between adherent cells and tumorspheres. Neither expression nor secretion levels of IL-10 and IL-4 were detectable. We had not observed significant results for IL-8. Survival analysis showed that ADC patients with higher LGALS3 expression had significantly decreased overall survival (OS, 40.49 vs. 87.90 months, p= 0.005) and relapse-free survival (25.28 vs. 41.25 months, p=0.003) than the group with LGALS3 expression below the median. The multivariate analysis showed that LGALS3 expression can be established as an independent prognostic biomarker for OS [HR=1.75; 95% CI, 1.19-2.59; p=0.004] and for PFS in lung adenocarcinoma [HR=1.68; 95% CI, 1.22-2.32; p= 0.001].
Conclusion
Our results suggest that Galectin-3 highly secreted by lung CSCs can be involved in the modulation of the immune microenvironment. Moreover, Galectin-3 is an independent prognostic biomarker for overall survival and relapse-free survival in lung adenocarcinomas.
Supported by grants CB16/12/00350, PI18/00266 and PI15-00753 from ISCIII and ACIF/2018/275 from GVA and FSE
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P2.03-16 - Agreement Between Different Methodologies for Non-Invasive p.T790M and EGFR Sensitizing Mutation Testing (ID 1965)
10:15 - 18:15 | Author(s): Carlos Camps
- Abstract
Background
Tyrosine kinase inhibitors (TKIs) are the current standard of care for patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC). However, most patients progressed within 1 to 2 years. The EGFR p.T790M mutation is the most common resistance mechanism to first and second generation EGFR TKIs. The identification of p.T790M mutation is of considerable clinical relevance as osimertinib has demonstrated clinical efficacy in this setting. Guidelines recommend testing for the p.T790M mutation in blood at relapse to TKIs, and re-biopsy only in case of a negative result. Several blood based methodologies for detection of EGFR mutations have been developed in the recent years. However, the number of comparison studies between platforms is very limited.
Method
This is a multicenter, cross-sectional study (ClinicalTrials.gov Identifier: NCT03363139) performed by the Spanish Lung Cancer Group. Samples from 75 consecutive EGFR mutant NSCLC patients were collected at disease progression to first line TKI treatment. The presence of EGFR mutations in the cfDNA was evaluated in 39 samples by 7 methodologies, namely: Cobas® EGFR Mutation Test v2 (Roche Diagnostics), Therascreen EGFR Plasma RGQ PCR Kit (Qiagen), QuantStudio® 3D Digital PCR System (Thermofisher), a 5′-nuclease real-time PCR (TaqMan®) assay in presence of PNA, OncoBEAM EGFR (Sysmex Inostics), NGS with two different gene panels: Oncomine® (Thermofisher) and Lung Cancer Panel (Qiagen). The agreement between methodologies was assessed using the kappa coefficient (K) and its corresponding 95% confidence intervals (95% CI). For quantitative variables the concordance correlation coefficient (ccc) was used.
Result
Complete results are available for 39 patients. Overall, the agreement between all methodologies for the detection of p.T790M mutation as well as the original EGFR sensitizing mutation was good (K=0.669; 95CI: 0.504-0.835 and K=0.750 95CI: 0.599-0.899 respectively). Remarkably, the agreement between FDA-approved methodologies for p.T790M detection was almost perfect (K=0.926; 95CI: 0.712-1) and good for the EGFR sensitizing mutations (K=0.657; 95CI: 0.417-0.902). Similarly, the agreement between NGS-based methodologies for the detection of p.T790M and the EGFR activating mutations was very high (K=0.843; 95CI: 0.567-1 and K=0.872 95CI: 0.595-1 respectively). Moreover, concordance between both technologies for p.T790M and EGFR sensitizing mutation mutant allele frequency was excellent (ccc=0.956; 95CI: 0.906-1 and ccc=0.980 95CI: 0.950-1 respectively). The proportion of samples that were positive for p.T790M detection varied from 28% (PCR based technologies) to 37% depending on the methodology.
Conclusion
NGS and PCR-based methodologies show a good to excellent agreement for the detection of EGFR mutations, including the p.T790M. Our results support the use of liquid biopsies for non-invasive testing of clinically relevant mutations (Data from the whole cohort will be presented at the meeting).
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P2.03-33 - ctDNA Levels Significantly Predicts Survival in NSCLC Patients with an EGFR Activating Mutation (ID 2016)
10:15 - 18:15 | Author(s): Carlos Camps
- Abstract
Background
Circulating tumor DNA (ctDNA) have been shown to be useful for non-invasive biomarker testing in non-small cell lung cancer (NSCLC). In addition, there is growing evidence supporting that ctDNA levels can be useful for tumor response to treatment monitoring. Nevertheless, data from large prospective clinical longitudinal studies still limited.
Method
300 plasma samples from 100 advanced NSCLC patients, with tumors harboring an EGFR activating mutation and treated with a first line tyrosine Kinase inhibitor were analyzed. Samples were collected before the start of treatment, at first follow up evaluation, at 7 month and at disease progression. ctDNA was analyzed by dPCR.
Result
Median follow up was 11.3 months. There were not significant differences in progression free survival (PFS) or overall survival (OS) according to treatment (erlotinib, afatinib or gefitinib). Patients harboring a deletion in exon 19 or a mutation in exon 21 exhibited better survival than those with an insertion in exon 20 (P<0.001). dPCR detected EGFR sensitizing mutation in 77% of the pre-treatment samples. ctDNA levels before the start of the treatment did not significantly predict survival, although a tendency was observed, with patients with high levels of ctDNA showing poorer outcome. On the contrary, patients in which the EGFR sensitizing mutation was undetectable at first follow up had a markedly better PFS and OS (HR=2.7; 95IC= 1.4-5.5 and HR= 5.5 95IC: 1.8-17 respectively). In the same way, patients in which the EGFR sensitizing mutation remained negative at 7months had a significantly increased PFS (HR: 2.8; 95IC: 1.2-6.6). None of the patients with undetectable levels at 7 months has deceased.
Conclusion
ctDNA levels is of prognostic significance in EGFR positive NSCLC patients with advance disease and can be useful to monitor treatment outcome
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P2.03-38 - Identification of a Novel Synthetic Lethal Vulnerability in Non-Small Cell Lung Cancer by Co-Targeting TMPRSS4 and DDR1 (ID 2191)
10:15 - 18:15 | Author(s): Carlos Camps
- Abstract
Background
Synthetic lethality has been defined as the inability of cells to proliferate when co-targeting two genes, with a synergistically superior inhibition than that found for each individual gene. Consistent co-expression of two genes involved in a similar function is a predictor of synthetic lethality, a strategy that is being applied to find out novel cancer vulnerabilities.
Method
Large-scale bioinformatics analyses across 5 public databases were used to identify genes consistently co-expressed with TMPRSS4, a novel therapeutic target that we have previously identified in NSCLC. Pyrosequencing was used to evaluate methylation levels in patients and cell lines. Functional in vitro experiments and animal models were used to assess synthetic lethality of TMPRSS4 and DDR1 in NSCLC.
Result
Consistent co-expression between TMPRSS4 and DDR1 was found in all NSCLC databases evaluated. Similar to TMPRSS4, DDR1 promoter was hypomethylated in NSCLC in 3 independent cohorts and hypomethylation was an independent prognostic factor of disease-free survival. Treatment with 5-azacitidine increased DDR1 levels in cell lines, suggesting an epigenetic regulation. Cells lacking TMPRSS4 were highly sensitive to the cytotoxic effect of the DDR1 inhibitor dasatinib. TMPRSS4/DDR1 double knock-down cells, but not single knock-out cells suffered a G0/G1 cell cycle arrest with loss of E2F1 and cyclins A and B, increased p21 levels and apoptosis. Moreover, double knock-down cells were highly sensitized to cisplatin, which caused massive apoptosis (~40%). In vivo studies demonstrated tumor regression in mice injected with double knock-down-injected cells and lack of 18FDG-uptake by microPET analysis.
Conclusion
We have identified a novel vulnerability in NSCLC resulting from a synthetic lethal interaction between DDR1 and TMPRSS4. This may help designing therapeutic strategies to impair NSCLC growth by co-targeting both genes.
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P2.05 - Interventional Diagnostic/Pulmonology (ID 168)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Interventional Diagnostics/Pulmonology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.05-12 - Analysis of Biomarkers in Lung Cancer in Spain (ID 854)
10:15 - 18:15 | Author(s): Carlos Camps
- Abstract
Background
The analysis of biomarkers in lung cancer (LC) is currently one of the most important care needs, given the importance of their presence in the selection of specific treatments. Our objective was to know the implementation degree of these tests in a large cohort of patients in Spain using the Thoracic Tumor Registry (TTR) of the Grupo Español de Cáncer de Pulmón (Spanish Lung Cancer Group).
Method
The TTR is an observational cohort multicenter study of the LC in Spain. Information on patients (p) enrolled from August 2016 to December 2018. The study is conducted according to the Declaration of Helsinki and approved by the institutional review board of each participating institute. The registry was approved by the Spanish Drug Agency as a non-post-authorization, non-interventional study.
Result
A total of 7,872 patients from 58 Spanish sites were enrolled. Analysis of molecular markers considering all the LC stages: A molecular test, the most frequent being the EGFR test, was performed in 4,456 patients (67.5%). The proportion of biomarker evaluation has varied over time, ranging from 57.9% prior to 2012 up to 73.7% in 2017.
Molecular markers in patients with stage IV. Three thousand four hundred forty-six (3,446) patients (52.2%) had a stage IV on diagnosis. The molecular assessment of some biomarkers reached 81.4% of all the patients, there being differences between Regional Communities in regard to the molecular tests made.
There was performed some biomarker test in 92% of the 2570 patients with stage IV and adenocarcinoma histology. The analysis of ALK was tested in 79% of the patients, this being in 40% only 2 years ago. ROS was studied in 20% of the cases and EGFR in 92%.
Conclusion
Although no national plan exists for molecular biomarker analysis in LC in Spain, the implementation of the biomarkers analysis in all the hospitals that contribute to the TTR is high, as close to the maximum as possible. The increase in the ALK analysis in the last period is relevant. As regional differences exist, it would be of interest to go in depth to study its cause
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P2.10 - Prevention and Tobacco Control (ID 176)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Prevention and Tobacco Control
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.10-02 - Smoking Habit in Lung Cancer in Spain (ID 732)
10:15 - 18:15 | Author(s): Carlos Camps
- Abstract
Background
Tobacco is the leading cause of lung cancer. The fight against the smoking habit is essential and should be continuous, to detect the national situation that makes it possible to design health care policies against this consumption. To do so, the Grupo Español de Cáncer de Pulmón (Spanish Lung Cancer Group) made this analysis within the context of the Thoracic Tumor Registry (TTR).
Method
The TTR is an observational cohort multicenter study in Spain. The study is conducted according to the Declaration of Helsinki and approved by the institutional review board of each participating site. The registry was approved by the Spanish Drug Agency, as a non-post-authorization, non-interventional study.
Result
We collected data from 6,600 patients diagnosed of lung cancer from 58 different Spanish hospital sites.
A total of 3,039 patients were former smokers (46%), 2,611 were active smokers (39%) and only 866 (12%) patients stated to be non-smokers; the status in 2% is unknown. If we make a comparison by gender regarding the presence of this habit, large differences (p-valor < 0.001) are observed, with a greater number of non-smokers in women (37 % vs. 4.5% in males), while the percentage of former smokers is much higher in the males (53.4% vs. 27.9% in women) and a minor difference in active smokers (42.1% vs. 34.4% in women).
Significant differences were observed in the study on the distribution of the smoking habit by gender and year of diagnosis. An increase is also observed in the last two years regarding the percentage of patients who were active smoked, both for the total population as well as for each one of the two genders separately. The increase is greater among the women and, also, the number of women who are active smokers is greater in recent years.
Mean age of onset of the smoking habit is 18.2 years. Significant differences are observed between both genders (p-valor < 0.001), with a mean age of initiation of 17.9 years in the men (95%CI 17.6-18.2 years) and 19.2 years in the women (95%CI 18.5-19.8 years). Significant differences between Regional Communities were also found in the mean age at onset of the habit, with much lower levels in the Valencian Community (16.6 years) or Navarra (16.9 years) regarding other communities, such as the Region of Murcia (22.9 years) or the Balearic Islands (21.6 years)
Conclusion
Lung cancer in Spain is associated to tobacco consumption in 85% of the cases diagnosed. Consumption has shown an increase in both genders in recent years and is especially rapid and worrisome in women. Anti-smoking campaigns should be reactivated and the causes of the regional differences analyzed in depth
