Outcome Of Advanced Lung Cancer Research Articles

The Impact of Next-Generation Sequencing Workflows on Outcomes in Advanced Lung Cancer: A Retrospective Analysis at One Academic Health System

Purpose: Broad-based molecular testing with next-generation sequencing (NGS) is now the standard of care in advanced non-small cell lung cancer (NSCLC). Two approaches to molecular testing are (1) reflexive testing at pathologic NSCLC confirmation, often using an in-house molecular panel, and (2) send-out testing to private vendors, ordered by a clinician. This study explored the outcomes with reflex versus send-out testing. Methods: A retrospective chart review was conducted of patients diagnosed with de novo stage IV NSCLC in 2019 and 2020 at three hospitals in the same system, one academic hospital (Northwestern Memorial Hospital, or NMH) utilizing reflex, in-house NGS, and two community-based hospitals (Central DuPage Hospital, or CDH, and Delnor, or D) sending out tissue samples for testing. The outcomes assessed were the time from biopsy to results, biopsy to treatment, the incidence of first-line targetable mutations and the use of first-line targeted therapies, and overall survival. Results: In total, 191 patients met the inclusion criteria, 85 at NMH, 106 at CDH + D, and in total, 131 in 2019 and 60 in 2020. The time to results was significantly shorter with reflexive NGS when compared with send-out testing; the time to treatment was also shorter but not statistically significant. At CDH + D, the time to results was significantly shorter with a limited panel than with comprehensive testing, but the time to treatment was similar. NGS testing rates were 95% at NMH and 84.5% at CDH + D (p = 0.009), with 31.0% at NMH receiving 1L targeted therapies versus 20.8% at CDH + D (p = 0.08). In 2019, the median time from biopsy to treatment was 35 days at NMH and 38 days at CDH and Delnor; in 2020, time to treatment was 26 days and 37 days, respectively. Overall survival trended longer in 2020 relative to 2019 independent of site. Conclusion: Reflexive NGS testing is associated with a shorter time to actionable results and higher rates of first-line targetable mutations than send-out testing. In practices with send-out testing, limited panels had slightly faster turnaround times but no difference in time to treatment. If resources allow, reflexive NGS should be considered in healthcare systems for patients with NSCLC.

Enhancing Intrapleural Hyperthermic Chemotherapy for Lung Cancer: Insights from 3D and PDX Models

Background/Objectives: Malignant pleural effusion (MPE) in lung cancer indicates systemically disseminated advanced lung cancer and is associated with poor survival. Intrapleural hyperthermic chemotherapy (IPHC) is a promising treatment for MPE; however, its biological basis is not fully understood. IPHC can enhance anticancer drug efficacy, particularly in drug-resistant cancers. This study investigated the effects of hyperthermia on cisplatin cytotoxicity in lung cancer cell lines, patient-derived tumor cells, and a patient-derived xenograft (PDX) model. Methods: Lung cancer cell lines (A549 and H2170) and patient-derived tumor cells were cultured in 2D/3D systems and treated with cisplatin under varying temperatures (37 °C, 43 °C, and 45 °C) and exposure times (5, 15, and 30 min). Antiproliferative effects were evaluated using LDH and CCK-8 assays. Optimal conditions identified in cell culture experiments were validated using a PDX model; tumor growth inhibition, delay, and protein expression were analyzed post-treatment. Results: Hyperthermia significantly enhanced the antitumor efficacy of cisplatin at 43 °C and 45 °C, with comparable effects under 15 and 30 min exposure. In the PDX model, IPHC showed increased tumor inhibition and necrosis and delayed tumor regrowth, particularly at higher cisplatin doses. Protein expression analysis revealed that hyperthermia decreased EGFR expression and increased levels of apoptosis-related proteins, including cleaved PARP and caspase-3. Conclusions: IPHC with cisplatin demonstrated enhanced antitumor efficacy in vitro models, particularly in drug-resistant lung cancer, indicating its potential as a valuable adjunct to existing treatment regimens for lung cancer and for improving patient outcomes in advanced lung cancer with MPE or pleural metastasis.

P4.11D.011 Evaluating the Impact of Performance Status on Outcomes in Advanced Lung Cancer: A Phase II Clinical Trial

P4.11D.011 Evaluating the Impact of Performance Status on Outcomes in Advanced Lung Cancer: A Phase II Clinical Trial

Immune signatures of patients with advanced non-small-cell lung cancer for efficacy prediction after immunotherapy.

Programmed cell death protein 1 ligand 1 (PD-L1) expression alone may not be the optimal predictor of immunotherapy (IO) efficacy in advanced non-small cell lung cancer (NSCLC). Evaluation of circulating immune signatures using mass cytometry is a promising technique for predicting IO response and prognosis. The utility of circulating immune signatures for efficacy prediction after IO in advanced NSCLC remains to be elucidated. To assess the feasibility of circulating immune cells and cytokines in predicting tumor response to IO in advanced NSCLC. A prospective observational study. To investigate dynamic changes in immune signatures, blood specimens were prospectively collected from patients with NSCLC at baseline and following chemotherapy (C/T) and/or IO. Mass cytometry and enzyme-linked immunosorbent assay were used to characterize immune signatures and cytokine patterns to identify correlations between immune profiles and treatment efficacy. The study enrolled 45 patients. The proportion of circulating natural killer (NK) cells and CD8+ T cells significantly increased after IO alone treatment. Cell levels of PD-1+CD8+ T cells, PD-1+CD4+ T cells, TIM-3+CD8+ T cells, LAG-3+ NK cells, and LAG-3+CD8+ T cells significantly decreased in patients with treatment response to IO alone. Tumor necrosis factor-alpha (TNF-α) levels significantly increased after IO alone treatment. Patients with high PD-1+CD8+ T cells before IO alone treatment had lower overall survival (OS) compared to those with low levels. Patients with high LAG-3+CD8+ T cells before chemotherapy plus immunotherapy treatment had lower OS compared to those with low levels. Responses to IO in NSCLC were correlated with declines in specific exhausted T cells, suggesting that IO may exert therapeutical efficacy by decreasing circulating exhausted T cells, which were associated with poorer survival, while also increasing TNF-α. These results highlight the prognostic value of monitoring changes in circulating exhausted T cells to predict IO response and survival outcomes in advanced lung cancer.

Gender Differences and Immunotherapy Outcome in Advanced Lung Cancer.

In developed countries, lung cancer is the leading cause of cancer-related death in both sexes. Although cigarette smoking represents the principal risk factor for lung cancer in females, the higher proportion of this neoplasm among non-smoking women as compared with non-smoking men implies distinctive biological aspects between the two sexes. Gender differences depend not only on genetic, environmental, and hormonal factors but also on the immune system, and all these aspects are closely interconnected. In the last few years, it has been confirmed that the immune system plays a fundamental role in cancer evolution and response to oncological treatments, specifically immunotherapy, with documented distinctions between men and women. Consequently, in order to correctly assess cancer responses and disease control, considering only age and reproductive status, the results of studies conducted in female patients would probably not categorically apply to male patients and vice versa. The aim of this article is to review recent data about gender disparities in both healthy subjects’ immune system and lung cancer patients; furthermore, studies concerning gender differences in response to lung cancer immunotherapy are examined.

PD-L1 Expression and Outcome in Patients with Metastatic Non-Small Cell Lung Cancer and EGFR Mutations Receiving EGFR-TKI as Frontline Treatment.

BackgroundEpidermal growth factor receptor (EGFR) mutations are most common in Eastern Asia, and frequencies of 30–50% have been reported. EGFR-tyrosine kinase inhibitors (TKIs) are recommended as first-line therapeutic options for non-small cell lung cancer (NSCLC) with sensitizing EGFR mutations. Several immune checkpoint inhibitors have been successful in improving the outcomes of advanced lung cancer. The expression of programmed cell death-ligand 1 (PD-L1) on tumor cells plays an important role in predicting the efficacy of programmed cell death protein 1/PD-L1 inhibitors. The role of PD-L1 expression in tumors with EGFR mutation and its influence on clinical outcomes remain controversial.MethodsPatients with newly diagnosed metastatic NSCLC with sensitizing EGFR mutations who received the standard treatment, ie, EGFR-TKIs for mutant adenocarcinoma as the first-line treatment, were enrolled in this retrospective study. EGFR mutations and PD-L1 expression levels were detected by Cobas RT-PCR and Dako 22C3 immunohistochemistry staining, respectively.ResultsFrom January 2011 to February 2019, 114 patients were enrolled. The average age was 62 years (range 34–92), and 45 (39.5%) patients were male. Among these patients, EGFR mutation analysis revealed exon 19 in-frame deletion in 55 (48.2%) patients, exon 21 L858R in 53 (46.5%) patients, and uncommon mutations in 6 (5.3%) patients. Among these patients with EGFR mutations, PD-L1 expression levels by tumor proportion score (TPS) were <1% in 54 (46.9%) patients, 1–49% in 50 (44.2%) patients, and ≥50% in 10 (8.8%) patients. All patients received EGFR-TKIs as first-line treatment, and in the Kaplan-Meier analysis, progression-free survival was not significantly different among groups with different PD-L1 expression status.ConclusionFor patients with metastatic NSCLC and EGFR mutations, PD-L1 expression is not uncommon, but no significant influence on clinical outcomes was observed in patients receiving standard initial treatment.

Outcome of advanced lung cancer with central airway obstruction versus without central airway obstruction.

Patients with central airway obstruction (CAO) from advanced lung cancer present with significant morbidity and are assumed to have lower survival. Hence, they are offered only palliative support. We asked if patients who have advanced lung cancer with CAO (recanalised and treated) will behave similarly to those with advanced lung cancer without CAO.This study was a retrospective review of the medical records of the patients managed for advanced lung cancer during 2010 and 2015 at our institution.85 patients were studied. Median survival and 1-, 2- and 5-year survival were 5.8 months, 30.3%, 11.7% and 2.3% versus 9.3 months, 35.7%, 9.6% and 4.7%, respectively, in the CAO and no CAO groups (p=0.30). More patients presented with respiratory failure (15 (35%) versus none; p=0.0001) and required assisted mechanical ventilation (10 (23.3%) versus none; p=0.001) in the CAO group compared with the no CAO group. Fewer patients received chemotherapy in the CAO group (11 (25.5%)) compared with the no CAO group (23 (54.7%); p=0.008).There was no difference in survival among patients with advanced lung cancer whether they presented with CAO or without CAO. Survival was similar to those without CAO in patients with recanalised CAO despite greater morbidity and lesser use of chemotherapy, strongly advocating bronchoscopic recanalisation of CAO. These findings dispel the nihilism associated with such cases.

Baseline peripheral blood biomarkers associated with clinical outcome of advanced lung cancer in patients treated with anti-PD-1 antibody.

e20599 Background: The anti-PD-1 antibodies nivolumab and pembrolizumab have demonstrated improved overall survival (OS) and progression free survival (PFS) in a subset of patients with metastatic or locally advanced lung cancer (LC). To date, no blood biomarkers have been identified to predict clinical outcome to anti-PD-1 agents. Methods: A retrospective analysis of 52 patients with advanced LC and treated with anti-PD-1 antibodies in a single institution was performed. White blood cell count (WBC), absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute neutrophil to absolute lymphocyte count ratio (ANC/ALC), absolute eosinophil count (AEC), and platelet counts at baseline before start of anti-PD-1 antibody were assessed. Kaplan–Meier and Cox regression analysis were done. Results: 48 patients were treated with nivolumab (92.3%) and 4 patients with pembrolizumab (7.7%). Median follow up was 13.6 months and median OS was 26 months. Higher baseline ANC and ANC/ALC ratio significantly correlated with worse clinical outcomes. Patients with baseline ANC &gt; 6060/mm3 had a significantly increased risk of death [hazard ratio (HR) = 2.46; 95% CI 1.12–5.42, P = 0.025] and of progression on anti-PD-1 antibody [HR = 2.41; 95% CI 1.25–4.64, P = 0.009] compared with patients with ANC ≤6060/mm3. Similarly, patients with baseline ANC/ALC ratio ≥ 4.59 had a significantly increased risk of death [HR = 2.41; 95% CI 1.11–5.24, P = 0.027] and of progression on anti-PD-1 antibody [HR = 2.08; 95% CI 1.10–3.95, P = 0.027] compared with patients with ANC/ALC &lt; 4.59. One year survival rate in patients who had ANC &lt; 3390/mm3, ANC 3390-6060/mm3 and ANC &gt; 6060/mm3 were 86.5%, 76.9% and 48.1% respectively. Conclusions: Increased baseline ANC and ANC/ALC were associated with poor PFS and OS in LC patients treated with anti-PD-1 antibodies. Although these findings need to be validated in a large sample size, our data suggested that baseline ANC and ANC/ALC ratio might help the risk stratification and assist treatment strategies. The potential predictive value of peripheral blood biomarkers for clinical outcomes to anti-PD-1 antibody should be further investigated in a prospective study.

Pembrolizumab Combination Improved Outcomes in Advanced Lung Cancer

Pembrolizumab Combination Improved Outcomes in Advanced Lung Cancer

Clinicopathological features and outcomes in advanced nonsmall cell lung cancer with tailored therapy.

Context:Lung cancer is an important cause of cancer-related deaths worldwide. There is an increasing incidence of lung cancer in never smokers and a shift of histology from squamous cell to adenocarcinoma globally in the recent past. Data on treatment outcomes with newer platinum doublets is scant from India.Aims:To study the clinicopathological features, response rates (RRs), progression-free survival (PFS), overall survival (OS), and the 1, 2, and 3 years survival, in patients with advanced nonsmall cell lung cancer (NSCLC).Materials and Methods:Data of all patients who received chemotherapy for Stage IIIB and IV NSCLC between January 2010 and June 2014 were retrospectively analyzed.Statistical Analysis Used:Univariate analysis for OS was done by plotting Kaplan–Meier curves and the log-rank test was used to calculate P values. Logistic regression analysis for OS was carried out using MedCalc statistical software.Results:A total of 353 patients received chemotherapy. Of these, 256 were evaluable for outcome parameters. The median age at presentation was 58 years with a male:female ratio of 2.53:1. The smoker:nonsmoker ratio was 1:1. Adenocarcinomatous histology was the most common both in smokers and nonsmokers reported in 70.8% patients. Epidermal growth factor receptor (EGFR) mutation and echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase translocation were seen in 35% and 3% of patients, respectively. The RR, median PFS, OS, 1, 2, and 3 years survival were 80%, 8 months, 12.1 months, 51.5%, 12.7%, and 4.2%, respectively. There was no significant survival difference among the treatment regimen used but the response to I line chemotherapy impacted survival. Female gender, performance status, and nonsquamous histology were significant predictors of OS (P = 0.0443, P = 0.0003, P = 0.048, respectively).Conclusions:There was an increase in the incidence of nonsmokers. Adenocarcinoma was the most common histology in both smokers and nonsmokers. Treatment outcomes in advanced lung cancer were better compared to the past with the advent of newer platinum doublets and EGFR tyrosine kinase inhibitors. The response to first-line chemotherapy significantly impacts outcomes in advanced NSCLC.

A practical measurement of thoracic sarcopenia: correlation with clinical parameters and outcomes in advanced lung cancer.

Thoracic sarcopenia can feasibly be measured from routine CT scans but does not correlate to patient-centred outcomes http://ow.ly/102UkQ

Real-time monitoring efficiency and toxicity of chemotherapy in patients with advanced lung cancer.

BackgroundThe Response Evaluation Criteria in Solid Tumors (RECIST) guideline and Common Terminology Criteria for Adverse Events (CTCAE) criteria are used to assess chemotherapy efficiency and toxicity in patients with advanced lung cancer. However, no real-time, synchronous indicators that can evaluate chemotherapy outcomes are available. We wanted to evaluate tumor response and toxicity in advanced lung cancer chemotherapy by using a novel synchronous strategy.ResultsWe enrolled 316 patients with advanced lung cancer who were treated with cisplatin-based therapy and followed up them for 3 years. Plasma was obtained before and after every chemotherapy cycle. We quantitative assayed total plasma DNA and methylation of the APC/RASSF1A genes. Four parameters were assessed: methylation level before chemotherapy (meth0 h), methylation level 24 h after chemotherapy (meth24 h), total plasma DNA concentration before chemotherapy (DNA0 h), and total plasma DNA concentration 24 h after chemotherapy (DNA24 h). When meth24 h > meth0 h of at least one gene was used to predict tumor response, the correct prediction rate was 82.4 %. Additionally, patients for whom DNA24 h/DNA0 h ≤ 2 had mild toxicities. Therefore, meth24 h > meth0 h and DNA24 h/DNA0 h ≤ 2 were defined as criteria for better tumor response and fewer adverse events with a high correct prediction rate (84.7 %).ConclusionsQuantitative analysis of total plasma DNA and plasma APC/RASSF1A methylation provide a real-time synchronous rapid monitoring indicator for therapeutic outcomes of advanced lung cancer, which could be a reference or supplementary guidelines in evaluating chemotherapy effects.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-015-0150-9) contains supplementary material, which is available to authorized users.

Effect of prior cancer on outcomes in advanced lung cancer: implications for clinical trial eligibility and accrual.

Prior cancer is a common exclusion criterion in lung cancer trials. This practice reflects concerns that prior cancer may affect trial conduct or outcomes. However, the impact of prior cancer on survival in lung cancer is not known. We identified patients older than age 65 years with stage IV lung cancer diagnosed between 1992 and 2009 in the Surveillance, Epidemiology, and End Results-Medicare linked registry. Prior cancer was characterized by type, stage, and timing. All-cause and lung cancer-specific survival were compared between patients with and without prior cancer using propensity score-adjusted Cox regression. Overall, 102 929 patients with stage IV lung cancer were identified, of whom 14.7% had a history of prior cancer. More than two-thirds (76.0%) of prior cancers were localized or regional stage; most were diagnosed five or fewer years prior to the lung cancer diagnosis. In propensity score-adjusted analysis, patients with prior cancer had better all-cause (hazard ratio [HR] = 0.93, 95% confidence interval [CI] = 0.91 to 0.94) and lung cancer-specific (HR = 0.81, 95% CI = 0.79 to 0.82) survival. In a simulated clinical trial-eligible population (age <75 years, no comorbidity, treated with chemotherapy), similar trends were noted. In subset analyses according to stage, type, and timing of prior cancer, no group of patients with prior cancer had inferior survival compared with patients without prior cancer. Among patients with stage IV lung cancer, prior cancer does not convey an adverse effect on clinical outcomes, regardless of prior cancer stage, type, or timing. Broader inclusion in clinical trials of advanced lung cancer patients with a history of prior cancer should be considered.

Targeted Therapy For Lung Cancer: Reviewing the Cost and Its Effect on Treatment Decisions

SUMMARY Novel targeted therapies that improve outcome in advanced lung cancer should be adopted. However, given the high costs of targeted therapies and companion molecular testing, the affordability and cost–effectiveness of novel agents are of growing relevance in policy decisions. Incremental cost–effectiveness ratios in excess of US$200,000 per quality-adjusted life year have been described in published literature evaluating currently approved agents. Differing willingness to pay thresholds in different countries determine which therapies will be funded in a given healthcare system. Cost-containment strategies to address costs of molecular testing and drug acquisition need to be implemented. Drug manufacturers, healthcare payers and oncologists have a shared responsibility to ensure that novel therapies are affordable and accessible to patients in need.

Effect of Prior Cancer on Outcomes in Advanced Lung Cancer: Implications for Clinical Trial Eligibility and Accrual: Outcomes/Health Services Research

We have previously shown that prior cancer is excluded in over 80% of lung cancer clinical trials. Depending on clinical trial eligibility criteria, this practice results in exclusion of up to 18% of potential patients for some lung cancer trials. To inform future decisions about this widespread clinical trial policy, we determined the characteristics and prognostic impact of prior cancer diagnoses among patients with stage 4 lung cancer.

Costs and outcomes in stage IV non-small cell lung cancer at an urban safety net hospital.

14 Background: Stage IV NSCLC is an incurable illness with significant morbidity. Chemotherapy prolongs average survival from 6 to 10 months and targeted therapies further reduce morbidity and prolong survival. These advances pose financial challenges for safety net hospitals, which may also disproportionately feel the impact of racial disparity. Outcomes in advanced lung cancer may thus differ in the underserved population and resources may not be allocated optimally. Methods: A retrospective review was conducted on all patients diagnosed with Stage IV NSCLC between 2005 and 2011 at Boston Medical Center, an urban safety net hospital. Data were collected on survival from time of diagnosis, type and duration of treatment, utilization of healthcare resources, as well as detailed personal characteristics. We calculated costs of treatment for all patients. We assessed the effect of treatment and patient characteristics on survival. Results: Of 198 patients analyzed, 57% were white, 32% were black, 6% were Hispanic. 11% were homeless. 57% did not receive antineoplastic therapy, 24% received cytotoxic chemotherapy, 18% received combined cytotoxic and targeted therapy. Median survival was 5.0 months without therapy, 7.0 months with cytotoxic chemotherapy and 9.2 months with combined therapy. Any therapy was associated with 56% longer survival. Hazard of death in white patients was 0.68 relative to non-white patients. Median total and monthly costs for patients on no therapy were $70,000 and $14,000, on cytotoxic chemotherapy were $112,000 and $19,000 and on combined therapy were $247,000 and $26,000. Cost per month of survival was $12,000 less for white patients and $15,000 more for homeless patients. Conclusions: The majority of patients did not receive antineoplastic therapy, despite robust survival gains associated with its use. Untreated patients nevertheless incurred a high cost of care. White patients showed better survival at a lower cost. Further topics for study and intervention in this population include barriers to therapy, early involvement of palliative and home-based care in patients not suitable for treatment, strategies for cancer care in the homeless, as well as closer inquiry into drivers of racial disparity.

CD14+S100A9+ Myeloid-derived Suppressor Cells Portend Decreased Survival in Patients with Advanced Lung Cancer

It has been clearly shown from multiple preclinical studies that myeloid-derived suppressor cells (MDSC) serve as a target for inhibiting tumor growth (1–3). Although studies in humans have shown the presence of MDSC in different pathological conditions, understanding their clinical significance in cancer requires the full characterization of these cells. The characteristics of MDSC have been described for several human malignancies, including melanoma, colon cancer, and renal cell carcinoma, but the identification of a unique set of markers for human MDSC has been challenging because MDSC gene expression varies in different tumor types. Feng and colleagues in this issue of the Journal (pp. ) describe the characteristics of the CD11b+CD14+S100A9+ monocytic MDSC and their clinical relevance in patients with advanced non–small cell lung cancer (NSCLC) (4). The identification of markers for the characterization of MDSC in lung cancer is useful because only limited data are available on specific markers. The authors evaluated the characteristics of MDSC in the peripheral blood of patients with NSCLC [adenocarcinoma, 40; squamous cell carcinoma, 6; and nonclassified NSCLC, 6] in comparison to 17 healthy control subjects. In addition, 40 patients who received cisplatin-based chemotherapy in a randomized prospective trial were evaluated for the predictive role of MDSC. The authors demonstrated that there was a higher proportion of CD11b+CD14+ than CD11b+CD14− MDSC in the peripheral blood mononuclear cells of patients with NSCLC, and the frequencies of both subsets were higher in patients with NSCLC in comparison to healthy control subjects. Both subsets of MDSC had similar suppressive activity on CD8 T-cell proliferation and IFN-γ production. In contrast, CD11b+CD14+ cells from healthy donors showed no suppressive ability on CD8+ T-cell proliferation or IFN-γ production. Through inhibitor and antibody-mediated blocking experiments, the authors showed that the CD11b+CD14+ MDSC–mediated suppression of CD8 T cells in vitro was via arginase, inducible nitric oxide synthase, the IL-13/IL-4Rα axis, and IL-10. The levels of S100A9+ expression by CD11b+CD14+ correlated with their suppressive ability. Furthermore, high levels of CD11b+CD14+S100A9+ MDSC were associated with poor response to cisplatin-based chemotherapy and predicted shorter progression-free survival. Although the CD11b+CD14− subpopulation of MDSC had an inhibitory ability that was comparable to the CD11b+CD14+ cells, there was no association of these cells with performance status or treatment response of patients with NSCLC to chemotherapy. The findings of this study are significant as they show that S100A9 can serve as an important marker for the further characterization of the CD11b+CD14+ MDSC in patients with advanced NSCLC. The results of this study corroborate the findings from a previous study that demonstrated an increase in the population of CD14+ S100A9+ MDSC in the peripheral blood from patients with colon cancer in comparison with healthy control subjects (5). Since solid tumors contain a significant population of tumor-infiltrating myeloid cells that promote tumor growth, the lack of evaluation of the characteristics of MDSC from the NSCLC samples is a limitation of this study. It is not known if the CD11b+CD14+S100A9+ MDSC are present in the lung tumor microenvironment of the patients with advanced NSCLC. Nevertheless, the results of this study demonstrate that levels of CD11b+CD14+S100A9+ MDSC in peripheral blood can serve as a predictor of response to chemotherapy in patients with advanced lung cancer. Further investigations are required to determine whether modulating the levels and activities of CD11b+CD14+S100A9+ MDSC would improve patient outcome in advanced lung cancer. MDSC play a central role in immune suppressive pathways and tumor progression, and modulating the activities of this population could prove beneficial as an innovative therapeutic strategy against lung cancer.

Germline genetic variations in drug action pathways predict clinical outcomes in advanced lung cancer treated with platinum-based chemotherapy

Genetic polymorphisms contribute to interindividual variation in drug response. However, a single polymorphism is likely to exhibit a modest effect. Therefore, we applied a pathway-based approach to evaluate the cumulative effect of multiple polymorphisms on clinical outcome of patients with non-small cell lung cancer. We genotyped 25 functional polymorphisms in 16 key genes involved in cisplatin metabolism and action and evaluated their associations with overall survival in 229 non-small cell lung cancer patients receiving first-line cisplatin-based chemotherapy. Several biologically plausible main effects were identified in individual analysis. More importantly, when six polymorphisms in nucleotide excision repair genes were analyzed jointly, a significant trend of reduced risk of death with decreasing number of putative unfavorable genotypes was observed (P for trend < 0.001 and log rank P < 0.001). Survival tree analysis revealed potential higher-order gene-gene interactions and categorized subgroups with dramatically different survival experiences, based on distinct genotype profiles. The median survival time was 78.5 months for terminal node 1 in the low-risk group, 15.1 months for terminal node 10 in the medium-risk group, and 6.7 months for terminal node 9 in the high-risk group (log rank P < 0.001). We also constructed a prediction hazard model. The area under the curve increased from 0.71 (using clinical variables only) to 0.84 (using clinical, epidemiological, and genetic variations from survival tree analysis). Our results highlight the clinical potential of taking a pathway-based approach and using survival tree analytic approach to identify subgroups of patients with distinctly differing outcomes.

C6-02: Prospective study assessing MDm2 309 and p53 Arg72Pro single nucleotide polymorphism (SNPs) and clinical outcome in advanced lung cancer

C6-02: Prospective study assessing MDm2 309 and p53 Arg72Pro single nucleotide polymorphism (SNPs) and clinical outcome in advanced lung cancer