Progression In Lung Cancer Patients Research Articles

Bioinformatic analysis of differentially expressed genes in lung cancer bone metastasis and their implications for disease progression in lung cancer patients.

Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer-related death worldwide. Moreover, it is highly susceptible to distant metastasis, which is the main cause of pain in advanced lung cancer, and frequently occurs in the bone. This study aimed to identify the differentially expressed genes (DEGs) related to metastatic bone disease in lung cancer using bioinformatics methods and to analyze the risk factors influencing the incidence of secondary bone metastasis in lung cancer. Gene expression profiles from the GSE175601 and GSE10799 datasets in the Gene Expression Omnibus (GEO) database were analyzed to screen for the DEGs associated with lung cancer bone metastasis. The STRING database was used to construct a protein-protein interaction (PPI) network, and the MCODE plugin was used to identify the key genes. The expression of these important genes in lung tumor tissues and their correlation with prognosis were validated in The Cancer Genome Atlas (TCGA) database. An examination of clinical data from patients diagnosed with stage IV lung adenocarcinoma treated at the Anhui No. 2 Provincial People's Hospital was conducted. Immunohistochemistry was used to examine the expression of key genes in lung cancer tumor tissues. A binary logistic regression analysis was conducted to examine the interactions in the expression of critical genes associated with bone metastasis in lung carcinoma patients. In total, 59 DEGs were identified in the GSE175601 and GSE10799 datasets through Venn diagram construction. The PPI network analysis revealed two significant modules and eight candidate genes (LAPTM5, LCP2, CD53, ARHGAP25, C1QA, DES, MYH11, and VIM). According to TCGA database analysis, in carcinogenic tissues of the lung, the expression of these eight critical genes is downregulated. Further, only the lung cancer patients who had high expressions of ARHGAP25 had an improved progress-free interval (PFI) (P<0.05), disease-specific survival (DSS), and overall survival (OS). Of the 49 with stage IV lung adenocarcinoma patients included in the study, 27 (55.10%) developed bone metastasis. The immunohistochemical (IHC) results indicated that the expression score of ARHGAP25 was significantly lower in the group with bone metastasis (3.93±2.95) than the group without bone metastasis (6.64±3.62) (P=0.006). The proportion of patients with low ARHGAP25 expression was significantly higher in the group with bone metastasis (70.37%, 19/27) than the group without bone metastasis (31.82%, 7/22) (P=0.007). The binary logistic regression analysis identified serum alkaline phosphatase (ALP) and ARHGAP25 expression levels as independent risk factors for the occurrence of secondary bone metastatic disease in lung carcinoma patients. The key gene ARHGAP25 identified through bioinformatics for lung cancer bone metastasis was significantly downregulated. Its low expression constitutes an independent risk factor for secondary bone metastatic disease in patients with lung carcinoma.

Exploring readiness for discharge, quality of discharge teaching, and fear of disease progression in lung cancer patients undergoing chemotherapy: A correlation analysis.

To explore the correlation between the current status of discharge preparation, quality of discharge teaching, and fear of disease progression among patients with lung cancer undergoing chemotherapy to provide a basis for improving patients' level of preparation. In this cross-sectional study, convenience sampling was used to select 452 patients with lung cancer who received chemotherapy and were admitted to the Department of Medical Oncology of the Cancer Hospital, between February 2023 and April 2023. A general information questionnaire, discharge preparation scale, quality of discharge teaching scale, and fear of disease progression scale were used to conduct surveys 2 h before the patients were discharged. The score for discharge preparation among lung cancer patients with chemotherapy was 99.11 ± 14.79 and the item score was 8.26 ± 1.23. The score for quality of discharge teaching was 193.23 ± 37.69, and that for fear of disease progression was 25.47 ± 8.92. Multiple linear regression analysis showed that sex, marital status, treatment period, quality of discharge teaching, and fear of disease progression influenced discharge readiness among patients with lung cancer receiving chemotherapy. Pearson's correlation analysis showed that the total quality of the discharge guidance score was positively correlated with the discharge readiness score (r = 0.288, p < 0.001). In contrast, the total fear of disease progression score was negatively correlated with the discharge preparation score (r = -0.252, p < 0.001). Discharge readiness among patients with lung cancer receiving chemotherapy was relatively at the good level, and there was a significant correlation between readiness for discharge, discharge teaching and fear of disease progression in these patients. Therefore, it is necessary to provide effective discharge guidance and implement targeted intervention measures to further improve patient preparation, reduce the fear of disease progression, and promote patient ability of coping with the disease and overall satisfaction.

Computed tomography-based radiomics quantification predicts epidermal growth factor receptor mutation status and efficacy of first-line targeted therapy in lung adenocarcinoma.

BackgroundBiomarkers that predict the efficacy of first-line tyrosine kinase inhibitors (TKIs) are pivotal in epidermal growth factor receptor (EGFR) mutant advanced lung adenocarcinoma. Imaging-based biomarkers have attracted much attention in anticancer therapy. This study aims to use the machine learning method to distinguish EGFR mutation status and further explores the predictive role of EGFR mutation-related radiomics features in response to first-line TKIs.MethodsWe retrospectively analyzed pretreatment CT images and clinical information from a cohort of lung adenocarcinomas. We entered the top-ranked features into a support vector machine (SVM) classifier to establish a radiomics signature that predicted EGFR mutation status. Furthermore, we identified the best response-related features based on EGFR mutant-related features in first-line TKI therapy patients. Then we test and validate the predictive effect of the best response-related features for progression-free survival (PFS).ResultsSix hundred ninety-two patients were enrolled in building radiomics signatures. The 13 top-ranked features were input into an SVM classifier to establish the radiomics signature of the training cohort (n = 514), and the predictive score of the radiomics signature was assessed on an independent validation group with 178 patients and obtained an area under the curve (AUC) of 74.13%, an F1 score of 68.29%, a specificity of 79.55%, an accuracy of 70.79%, and a sensitivity of 62.22%. More importantly, the skewness-Low (≤0.882) or 10th percentile-Low group (≤21.132) had a superior partial response (PR) rate than the skewness-High or 10th percentile-High group (p < 0.01). Higher skewness (hazard ratio (HR) = 1.722, p = 0.001) was also found to be significantly associated with worse PFS.ConclusionsThe radiomics signature can be used to predict EGFR mutation status. Skewness may contribute to the stratification of disease progression in lung cancer patients treated with first-line TKIs.

Cell-Free Tumor DNA (ctDNA) Utility in Detection of Original Sensitizing and Resistant EGFR Mutations in Non-Small Cell Lung Cancer (NSCLC).

Background: Recent studies have demonstrated the utility of cell-free tumor DNA (ctDNA) from plasma as an alternative source of genomic material for detection of sensitizing and resistance mutations in NSCLC. We hypothesized that the plasma level of ctDNA is an effective biomarker to provide a non-invasive and thus a less risky method to determine new resistance mutations and to monitor response to treatment and tumor progression in lung cancer patients. Methods: This prospective cohort study was approved and conducted at the Peter Brojde Lung Cancer Centre, Montreal. Blood was collected in STRECK tubes at four time points. DNA was extracted from plasma, and ctDNA was analyzed for the presence of mutations in the EGFR gene using the COBAS® EGFR v2 qPCR (Roche) test. Results: Overall, 75 pts were enrolled in the study. In total, 23 pts were TKI-naïve, and 52 were already receiving first-line TKI treatment. ctDNA detected the original mutations (OM) in 35/75 (48%) patients. Significantly higher detection rates were observed in TKI-naïve patients compared to the TKI-treated group, 70% versus 37%, respectively (p = 0.012). The detection of the original mutation at the study baseline was a negative predictor of progression-free survival (PFS) and overall survival (OS). The resistance mutation (T790M) was detected in 32/74 (43%) patients. In 27/32 (84%), the T790M was detected during treatment with TKI: in 25/27 patients, T790M was detected at the time of radiologic progression, in one patient, T790M was detected before radiologic progression, and in one patient, T790M was detected four weeks after starting systemic chemotherapy post progression on TKI. At the time of progression, the detection of T790M significantly correlates with the re-appearance of OM (p = 0.001). Conclusion: Plasma ctDNA is a noninvasive patient-friendly test that can be used to monitor response to treatment, early progression, and detection of acquired resistant mutations. Monitoring of clearance and re-emergence of driver mutations during TKI treatment effectively identifies progression of the disease. As larger NGS panels are available for ctDNA testing, these findings may also have implications for other biomarkers. The results from ongoing and prospective studies will further determine the utility of plasma testing to diagnose, monitor for disease progression, and guide treatment decisions in NSCLC.

P24.11 Cell-Free Tumor DNA (ctDNA) Utility in Detection and Monitoring EGFR Mutations in Non-Small Cell Lung Cancer (NSCLC)

Recent studies have demonstrated the utility of cell-free tumor DNA (ctDNA) from plasma as an alternative source of genomic material for detection of sensitizing and resistance mutations in NSCLC. We hypothesized that plasma level of ctDNA is an effective biomarker to provide non-invasive, and thus a less risky method to determine new resistance mutations and to monitor response to treatment and tumour progression in lung cancer patients.

Circulating biomarkers for monitoring therapy response and detection of disease progression in lung cancer patients

Liquid biopsies have become of interest as minimally invasive ways to monitor treatment response in lung cancer patients. Circulating tumor DNA (ctDNA) and protein biomarkers are evaluated for their added value in monitoring therapy response and early detection of disease progression.Plasma and serum samples of non-small cell or small cell lung cancer patients were analyzed for driver mutations in ctDNA (EGFR, KRAS or BRAF) using droplet digital PCR and protein biomarkers (CA125, CEA, CA15.3, Cyfra 21-1, HE4, NSE, proGRP and SCCA) using electrochemiluminescence immunoassays. Biomarker concentration changes were compared with the outcome of CT-scans during therapy.The median difference of the concentration of ctDNA, CA125 and Cyfra21-1 was significantly lower in patients with partial response (PR) compared to patients with progressive disease (PD) on the first evaluation CT-scan (P<0.001, P=0.042 and P=0.020, respectively). A substantial agreement between ctDNA or CA125 response and radiographic response was observed (k=0.692 and k=0.792, respectively). The median difference of the concentration of ctDNA and Cyfra21-1 was also significantly lower in PR patients compared to PD patients at the last CT-scan during therapy (P<0.001 and P=0.026, respectively). An almost perfect agreement between ctDNA and radiographic response (k=0.827) and a moderate agreement between Cyfra21-1 response and radiographic response was observed (k=0.553).Serial testing of the concentration of ctDNA, Cyfra21-1, and possibly CA125 could be a useful added tool for monitoring therapy response and early detection of disease progression in lung cancer patients.

Heart dose and coronary artery calcification in patients receiving thoracic irradiation for lung cancer.

BackgroundThoracic irradiation (TIR) is associated with an increased risk of coronary artery disease (CAD) and coronary-related death. Lung cancer patients receive considerable doses of TIR, making them a high-risk population that may benefit from post-therapy surveillance. Coronary artery calcium (CAC) is a known biomarker of CAD development and may serve as a useful indicator of disease progression in this population. We hypothesized greater CAC progression in lung cancer patients subjected to higher whole heart radiation doses.MethodsCAC progression (pre- and >2 years post-TIR) from chest CT scans of lung cancer patients were evaluated. A 2:1 matched control population was established controlling for age, gender, race, and CT scan interval. Vessel-specific CAC presence, progression, and extension in pre- and post-interval CT studies was evaluated by two blinded reviewers using the ordinal method. Dosimetric treatment files were restored and contours of the whole heart and proximal left anterior descending artery (LAD) were created within existing plans to compute radiation doses (Pinnacle Treatment Planning Software). Binary logistic regression analysis identified factors predictive for CAC development. Multiple logistic regression analysis with hierarchal method was used to assess covariates.ResultsThirty-five patients and 65 controls (50% female) were evaluated; mean age 57 years, mean follow-up post-radiation 4.9±2.2 years. Average mean and maximum left anterior descending coronary artery (LAD) radiation doses were 19.9 Gy (95% CI, 14.1–25.7) and 30.7 Gy (95% CI, 23.8–37.5), respectively; 91.6% inter-observer variability. There was greater incidence of coronary calcification in irradiated patients (48.6% vs. 24.6%; P=0.01). In interval CT scans, a greater proportion of radiated patients demonstrated new coronary calcification (P=0.007) and extension within the LAD (P=0.003). Radiation exposure was the only independent predictor of new calcification (OR 3.1; 95% CI: 1.09–9.2).ConclusionsWe identified both an increase in the development and progression of CAC in lung cancer patients receiving TIR. Future studies utilizing alternative cancer populations and larger sample sizes are necessary to further correlate radiographic and dosimetric observations to cardiovascular events.

Training and validation study for sequential monitoring of CAMLs in circulation to predict ongoing progression in lung cancer patients undergoing definitive radiotherapy.

3053 Background: Cancer Associated Macrophage-Like cells (CAMLs) are a recently described circulating stromal cell common in the peripheral blood of cancer patients that are prognostic for progressive disease. Further, it has been shown that changes in CAML size (i.e. enlargement above 50µm) can predict progression free survival (PFS) in thoracic cancers (e.g. lung). We enrolled 104 unresectable non-small cell lung cancer (NSCLC) patients, with an initial training set review of 54 patients, to determine if change in CAML size after radiation therapy was predictive PFS. Methods: A 2 year single blind prospective study was undertaken to test the relationship of ≥50µm CAMLs to PFS based on imaging in lung patients before and after induction of chemo radiation, or radiation therapy. To achieve a 2-tailed 90% power (α = 0.05) we recruited a training set of 54 patients and validation set of 50 patients all with pathologically confirmed unresectable NSCLC: Stage I (n = 14), Stage II (n = 16), Stage III (n = 61) &amp; Stage IV (n = 13). Baseline (BL) blood samples were taken prior to start of therapy &amp; a 2nd blood sample (T1) was taken after completion of radiotherapy (~30 days). Blood was filtered by CellSieve filtration and CAMLs quantified. Analysis by CAML size of &lt; 49 µm or ≥50 µm was used to evaluate PFS hazard ratios (HRs) by censored univariate &amp; multivariate analysis. Results: CAMLs were found in 95% of samples averaging 2.7 CAMLs/7.5mL sample at BL, with CAMLs ≥50 µm having reduced PFS (HR = 2.2, 95%CI1.3-3.8, p = 0.003). At T1, 18 patients had increased CAML size ≥50 µm with PFS (HR = 4.6, 95%CI2.5-8.3, p &lt; 0.001). In total, ≥50 µm CAMLs at BL was 76% accurate at predicting progression within 24 months while ≥50 µm CAMLs at T1 was 83% accurate at predicting progression. Conclusions: In unresectable NSCLC patients, enlargement of CAMLs during treatment is an indicator active progression. We identify that a single ≥50 µm CAML after induction of radiotherapy, in our training set and confirmed in our validation set, is an indicator of poor prognosis. We suggest that changes in CAML size during therapy may indicate the efficacy of therapy and could potentially help shape subsequent therapeutic decisions.

P3.04-09 Analysis of Repertoire Features of T Cell Receptor in Treat-Naïve EGFR Wild-Type Lung Cancer Patients by High-Throughput Sequencing

T cells can recognize peptides encoded by mutated genes. Assessment of the repertoire features of TCR is vital for us to deeper understand of immune behavior and immune response. However, detailed characterization of the peripheral blood T cell receptor (TCR) repertoire and its interaction with treat-naïve EGFR wild-type lung cancer patients have not been systemically studied. We used ultra-deep sequencing of rearranged genes in TCR β-chain (TCRβ) to profile the basic characteristics of T cells in peripheral blood samples of 27 treat-naïve EGFR wild-type lung cancer patients received chemotherapy as well as age- and gender-matched healthy donors without any history of cancer. Data showed that healthy donors had more TCR clonotypes and higher diversity while patients represented with restricted TCR repertoire. Interestingly, TCR repertoire was associated with TP53 mutation status, tumor volume, rapid progression and squamous cell carcinoma antigen (SCC) level in patients, but not with metastasis. Patients with TP53 mutation had fewer clonotypes (p=0.011), lower diversity (p=0.006) and higher clonality (p=0.054), while those with larger tumor volume and rapid progression following chemotherapy had fewer clonotypes (p=0.046 and p=0.011, respectively) in peripheral blood. peripheral blood TCR repertoire was not significant correlated with brain metastasis or bone metastasis. In addition, clonality was positive correlation with SCC Concentration (p=0.024,R=0.48,n=22). Our study promote a better knowledge about the T cells among treat-naïve EGFR wild-type lung cancer patients and provides new insight into the TCR repertoire associated with clinical presentation in lung cancer patients. And the TCR repertoire in peripheral blood samples before treatment may be used as a predictor of rapid progression in lung cancer patients treated with chemotherapy.

Abstract 1454: Glutamate dehydrogenase 1 mediates metabolic reprogramming and promotes tumor metastasis through CamKK2-AMPK signaling in LKB1-deficient lung cancer

Abstract Although elevated glutaminolysis has been demonstrated in cancer cells, the precise mechanism by which glutaminolysis is exploited to promote tumor metastasis has not been elucidated. Lung cancer frequently metastasizes and is the leading cause of cancer-related death worldwide. Loss of LKB1 is associated with increased metastasis and poor prognosis in lung cancer, but the development of targeted agents in LKB1-deficient lung cancer is still in its infancy. Our recent study reveal that glutamate dehydrogenase 1, upregulated upon detachment via the transcription factor pleomorphic adenoma gene 1 (PLAG1), provides anti-anoikis and pro-metastatic signals in LKB1-deficient lung cancer. Mechanistically, the GDH1 product alpha-KG activates CamKK2 by enhancing its substrate AMPK binding and triggers CamKK2-mediated AMPK signaling, which contributes to energy production that confers anoikis resistance. The effect of GDH1 on AMPK is evident in LKB1-deficient lung cancer, where AMPK activation predominantly depends on CamKK2. Targeting GDH1 with the small molecule GDH1 inhibitor R162 led to attenuated anoikis resistance and tumor metastasis in an LKB1-deficient lung patient-derived xenograft model. Correlation studies between GDH1 signaling and metastatic cancer progression in lung cancer patients further validated the clinical relevance of our finding. Our study provides insight into the molecular mechanism by which GDH1-mediated metabolic reprogramming of glutaminolysis mediates lung cancer metastasis. This knowledge could be leveraged for the development of effective therapeutic strategies for patients with LKB1-deficient lung cancer. Citation Format: Sumin Kang, Lingtao Jin, Chaoyun Pan, Jaemoo Chun. Glutamate dehydrogenase 1 mediates metabolic reprogramming and promotes tumor metastasis through CamKK2-AMPK signaling in LKB1-deficient lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1454.

Sequential monitoring of CAMLs in circulation as predictive of progression in lung cancer patients undergoing definitive radiotherapy.

e21062Background: Cancer Associated Macrophage-Like cells (CAMLs) are a recently described circulating stromal cell common in the peripheral blood of patients with solid tumors. Further, CAMLs ≥50µ...

High co-expression of IL-34 and M-CSF correlates with tumor progression and poor survival in lung cancers

Despite recent advances in diagnosis and treatment of lung cancers, the 5-year survival rate remains unsatisfactory, which necessitates the identification of novel factors that associates with disease progression and malignant degree for improving diagnostic and therapeutic strategies. Recent progress in cancer immunology research has unveiled critical roles for colony stimulating factor 1 receptor (CSF1R) in multiple aspects of the tumor microenvironment. CSF1R is expressed on tumor-associated macrophages (TAMs), and mediates important pro-tumorigenic functions. CSF1R also provides critical autocrine signals that promote cancer cell survival and proliferation. Activation of CSF1R can be achieved by two independent ligands; macrophage colony-stimulating factor (M-CSF) and interleukin 34 (IL-34). Accordingly, the expression of these ligands in cancer is expected to result in poor prognosis. In this study, we show that IL-34 and M-CSF expression correlates with poor survival in a cohort of lung cancer patients. Importantly, high co-expression of IL-34 and M-CSF associates with the poorest survival compared to cancers that show weak or absent expression of the two ligands. Furthermore, high expression of IL-34 and M-CSF associates with advanced stages of lung cancers. Together, these results indicate a correlation between IL-34/M-CSF expression with poor survival and disease progression in lung cancer patients.

MINI01.19: Cost Analysis of Pemetrexed-Platinum with Maintenance vs. Paclitaxel-Carboplatin-Bevacizumab with Maintenance in Patients with Lung Cancer

Given minimal differences in efficacy between pemetrexed and bevacizumab in first-line treatment to progression, based on the PRONOUNCE and POINTBREAK Phase III studies, evidence-based decision making regarding optimum treatment strategy may be driven by potential differences in healthcare resource utilization (HCRU) and costs. Real-world data from commercial and Medicare supplemental insurance claims in the U.S. were used to compare HCRU and costs associated with continuation maintenance with bevacizumab and pemetrexed. Insurance claims data from Truven Health Analytics Marketscan Databases were used to identify lung cancer patients who initiated treatment with pemetrexed-platinum or paclitaxel-carboplatin-bevacizumab between March 2009 and June 2013 and continued monotherapy following ≥4 administrations of first-line treatment. Patients were followed up to 12 months from treatment initiation to identify subsequent claims for healthcare services. HCRU and costs were evaluated from initiation of first-line treatment to end of 12-month follow-up (or death or disenrollment) and from initiation of first-line treatment through end of maintenance. Propensity score bin bootstrapping methods were used to adjust for demographic and clinical differences between treatment cohorts. The pemetrexed-platinum maintenance cohort included 509 patients (104 cisplatin, 405 carboplatin), and the paclitaxel-carboplatin-bevacizumab maintenance cohort included 177 patients. Pemetrexed-platinum patients were older (62.7 vs. 60.5, p<0.009), more likely to live in the Northeast (21.6% vs 9.04%, p<0.003), and had higher comorbidity burden (mean Charlson Comorbidity Index 2 vs. 1.7, p<0.014). Pemetrexed-platinum patients were more likely to have pulmonary heart disease (11.0% vs. 4.52%, p=0.038), chronic pulmonary disease (47.0% vs. 35.0%, p=0.023), and brain metastasis (23.0% vs. 13.6%, p=0.028). In the 6 months prior to treatment initiation, pemetrexed-platinum patients were more likely to have had an emergency room visit (34.4% vs. 21.5% and inpatient stay (48.7% vs. 33.9%), and had higher total costs ($38,796 vs. $31,161, p=0.014). During the period from treatment initiation to end of maintenance, mean total costs per patient per month were $2,600 (95% CI [$2560, 2640]) lower for pemetrexed-platinum patients compared to paclitaxel-carboplatin-bevacizumab patients, primarily due to lower outpatient costs. In the 12-month period following initiation of first-line treatment, mean total costs per patient per month were $1,653 (95% CI, [$1617, $1688]) lower for pemetrexed-platinum patients, again due to lower outpatient costs. Mean total costs per patient per month were significantly lower for pemetrexed-platinum patients compared to paclitaxel-carboplatin-bevacizumab patients in the setting of first-line treatment to progression in lung cancer patients with commercial or Medicare supplemental health insurance.

Numerical indices based on circulating tumor DNA for the evaluation of therapeutic response and disease progression in lung cancer patients.

Monitoring of disease/therapeutic conditions is an important application of circulating tumor DNA (ctDNA). We devised numerical indices, based on ctDNA dynamics, for therapeutic response and disease progression. 52 lung cancer patients subjected to the EGFR-TKI treatment were prospectively collected, and ctDNA levels represented by the activating and T790M mutations were measured using deep sequencing. Typically, ctDNA levels decreased sharply upon initiation of EGFR-TKI, however this did not occur in progressive disease (PD) cases. All 3 PD cases at initiation of EGFR-TKI were separated from other 27 cases in a two-dimensional space generated by the ratio of the ctDNA levels before and after therapy initiation (mutation allele ratio in therapy, MART) and the average ctDNA level. For responses to various agents after disease progression, PD/stable disease cases were separated from partial response cases using MART (accuracy, 94.7%; 95% CI, 73.5–100). For disease progression, the initiation of ctDNA elevation (initial positive point) was compared with the onset of objective disease progression. In 11 out of 28 eligible patients, both occurred within ±100 day range, suggesting a detection of the same change in disease condition. Our numerical indices have potential applicability in clinical practice, pending confirmation with designed prospective studies.

DNA Methylation of the Homeobox Genes PITX2 and SHOX2 Predicts Outcome in Non–small-cell Lung Cancer Patients

Biomarkers that facilitate prediction of disease progression in lung cancer patients might be clinically valuable in optimizing individualized therapy. In this study, the ability of the DNA methylation biomarkers PITX2 and SHOX2 to predict disease outcome in lung cancer patients has been evaluated. Quantitative, methylation-specific (HeavyMethyl), real-time polymerase chain reaction assays were used to measure DNA methylation of PITX2 and SHOX2 in bisulfite-converted DNA from formalin-fixed, paraffin-embedded tissues from 474 non-small-cell lung cancer patients. In univariate Cox Proportional Hazard analysis, high methylation of SHOX2 and PITX2 was a significant predictor of progression-free survival [SHOX2: n=465, hazard ratio (HR)=1.395 (1.130 to 1.721), P=0.002; PITX2: n=445, HR=1.312 (1.059 to 1.625), P=0.013]. Patients with low methylation of either PITX2 and/or SHOX2 (n=319) showed a significantly higher risk of disease progression as compared with patients with higher methylation of both genes [n=126; HR=1.555 (1.210 to 1.999), P=0.001]. This was particularly true for the subgroup of patients receiving no adjuvant radiotherapy or chemotherapy [n=258, HR=1.838 (1.252 to 2.698), P=0.002]. In multivariate analysis, both biomarkers added significant independent prognostic information to pT, pN, pM, and grade. Another interesting finding of this study was that SHOX2 and PITX2 DNA methylation was shown to be inversely correlated with TTF1 (also known as NKX2-1) expression (PITX2: P=0.018, SHOX2: P<0.001). TFF1 expression was previously found to be associated with improved survival in the same patient cohort. DNA methylation of PITX2 and SHOX2 is an independent prognostic biomarker for disease progression in non-small-cell lung cancer patients.

Abstract B4: A “DNA replication stress” gene signature associated with a poor prognosis in early non-small cell lung cancer

Abstract The conventional clinical staging classification is not sufficient to predict the survival of patients who suffer from early lung cancer. Additional prognostic factors are then needed to better forecast their outcome. Since perturbation of the genome replication i.e. the so-called “replicative stress” is admitted to contribute to neoplasia from its early stages, we hypothesized that genes involved in such process may therefore represent a still under-explored source of such biomarkers. We specifically assessed in primary tumors and adjacent normal tissues from a series of 93 patients suffering from early- or mid-stage non-small cell lung adenocarcinoma the expression (RT-qPCR) of 77 “DNA replication” genes involved in either initiation/licensing at the 50,000 replication origins dispersed along the genome, elongation of DNA chains onto damaged or undamaged DNA, maintenance of stalled DNA replication forks or intra-S phase DNA damage processing and signaling. A 4-gene signature separated patients to high-risk and low-risk subgroups with significantly different survival. This prognostic effect was independent on age, sex, treatment, stage classification and expression of proliferation markers. We propose that a “cancer replisome” signature could be a predictor of the cancer survival and might also help understanding the molecular mechanisms underlying tumor progression in lung cancer patients.

Benefits and risks of using erythropoiesis-stimulating agents (ESAs) in lung cancer patients: Study-level and patient-level meta-analyses

In anemic patients receiving myelosuppressive chemotherapy, erythropoiesis-stimulating agents (ESAs) raise hemoglobin levels and reduce transfusion requirements, but ESA-related safety concerns exist. To evaluate ESA benefits and risks in lung cancer, we conducted meta-analyses of data from controlled ESA trials conducted in lung cancer patients. Study-level analyses included controlled ESA trials reporting lung cancer mortality, identified from the 2006 Cochrane ESA report and from a systematic search for studies published through December 2010. Patient-level analyses included data from lung cancer patients receiving chemotherapy in Amgen studies evaluating darbepoetin alfa (DA) vs placebo. Study-level and patient-level analyses examined deaths, progression, and transfusion incidence. Patient-level analyses also examined adverse events (AEs) and fatigue.In a study-level meta-analysis of nine ESA studies of 2342 patients receiving chemotherapy, the ESA odds ratio (OR) was 0.87 (95% confidence interval [CI] 0.69–1.09) for mortality; the overall random-effects risk difference (95% CI) for mortality was −0.02 (−0.06, 0.02). The ESA OR (95% CI) for disease progression in five chemotherapy studies reporting progression was 0.84 (0.65–1.09). The ESA odds ratio (95% CI) was 0.34 (0.28–0.41) for transfusion incidence.In a patient-level meta-analysis of four studies evaluating 1009 patients through follow-up, the median survival time was 41 weeks with DA and 38 weeks with placebo. During the combined study and follow-up periods, 80% of placebo-group patients and 74% of DA patients died (mortality hazard ratio [HR] 0.90 [95% CI, 0.78–1.03] for DA); results were similar for small cell lung cancer and non-small cell lung cancer. Overall, 87% of placebo patients and 84% of DA patients progressed or died. Fewer DA patients had transfusions (week 5 through end-of-study, DA 19%, placebo 43%). AEs included thrombotic/embolic events (DA 10.5%, placebo 7.2%), cerebrovascular disorders (DA 3.7%, placebo 4.2%), pulmonary edema (DA 0.4%, placebo 1.0%) and pulmonary embolism (DA 1.8%, placebo 0.6%).These meta-analyses suggest that ESAs reduce transfusions without increasing mortality or disease progression in lung cancer patients undergoing chemotherapy.

PI3K/PTEN/AKT/mTOR pathway genetic variation predicts toxicity and distant progression in lung cancer patients receiving platinum-based chemotherapy

Non-small cell lung cancer (NSCLC) is still the leading cause of cancer-related deaths. The effect of the PI3K/PTEN/AKT/mTOR signaling pathway on cancer treatment, including NSCLC, has been well documented. In this study, we analyzed associations between genetic variations within this pathway and clinical outcomes following platinum-based chemotherapy in 168 patients with stage IIIB (wet) or stage IV NSCLC. Sixteen tagging SNPs in five core genes ( PIK3CA, PTEN, AKT1, AKT2, and FRAP1) of this pathway and identified SNPs associated with development of toxicity and disease progression. We observed significantly increased toxicity for patients with PIK3CA:rs2699887 (OR: 3.86, 95% CI: 1.08–13.82). In contrast, a SNP in PTEN was associated with significantly reduced risk for chemotherapeutic toxicity (OR: 0.44, 95% CI: 0.20–0.95). We identified three SNPs in AKT1 resulting in significantly decreased risks of distant progression in patients carrying at least one variant allele with HRs of 0.66 (95% CI: 0.45–0.97), 0.52 (95% CI: 0.35–0.77), and 0.62 (95% CI: 0.42–0.91) for rs3803304, rs2498804, and rs1130214, respectively. Furthermore, these same variants conferred nearly 2-fold increased progression-free survival times. The current study provides evidence that genetic variations within the PI3K/PTEN/AKT/mTOR signaling pathway are associated with variation in clinical outcomes of NSCLC patients. With further validation, our findings may provide additional biomarkers for customized treatment of platinum-based chemotherapy for NSCLC.

Motexafin gadolinium: gadolinium (III) texaphyrin, gadolinium texaphyrin, Gd-Tex, GdT2B2, PCI 0120.

Motexafin gadolinium [gadolinium (III) texaphyrin, gadolinium texaphyrin, Gd-Tex, GdT2B2, PCI 0120] is a radiosensitising agent developed for use in cancer therapy. It is cytotoxic in haematological malignancies by selectively localising in cancer cells that have high rates of metabolism. Motexafin gadolinium inhibits cellular respiration resulting in the production of reactive oxygen species and inducing apoptosis. It is being developed by Pharmacyclics in the US. Bulk motexafin gadolinium is supplied to Pharmacyclics by the US company, Celanese, through a manufacturing and supply agreement between the two companies. In June 2003, at the 39th Annual Meeting of the American Society of Clinical Oncology (ASCO-2003), the importance of having an agent for the treatment of brain metastases from lung cancer was highlighted. Results of a phase III study were presented that showed that motexafin gadolinium treatment was associated with a delay in time to neurological and neurocognitive progression in lung cancer patients. This was an important finding, as 46.6% of lung cancer patients already have brain metastases at the time of initial diagnosis, compared with only 2.7% of breast cancer patients. Brain metastases are also often the only site of metastatic disease in patients with lung cancer. In December 2002, Pharmacyclics began a phase III trial of motexafin gadolinium in patients with brain metastases (brain cancer in phase table) from lung cancer in the US, Europe, Canada and Australia. The trial is known as the Study of neurologic progression with Motexafin gadolinium And Radiation Therapy (SMART) and will compare whole-brain irradiation with whole-brain irradiation plus motexafin gadolinium in 550 patients. The primary efficacy endpoint is time to neurological progression and the secondary endpoints are survival and neurocognitive function. In January 2003, the US FDA completed its Special Protocol Assessment (SPA) of the SMART trial with a positive result and by June 2003, enrollment had begun. In addition, phase I trials are underway in children with intrinsic pontine glioma and adults with head and neck, lung and pancreatic cancers. A phase II trial is also being conducted in the US in patients with glioblastoma multiforme. Enrollment in this trial has been completed and preliminary results have been reported. Pharmacyclics has completed enrollment and follow-up of adults in its pivotal phase III trial of motexafin gadolinium as a radiation sensitiser for the treatment of brain metastases. The trial was conducted at 35 centres in Europe, Canada and the US. Full results from this initial phase III trial were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in Orlando, Florida, USA, held in May 2002. Pharmacyclics also announced in October 2002, at the 44th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO), that motexafin gadolinium significantly prolonged time to neurological progression when added to whole brain radiation therapy and reduced the number of deaths in patients with brain tumour. Pharmacyclics announced in September 2000 that it has initiated two NCI-sponsored phase I trials conducted under a Cooperative Research and Development Agreement (CRADA) between Pharmacyclics and the NCI. The first trial, conducted in patients with stage IIIA non-small cell lung cancer, was designed to determine the safety of two different dosing regimens of motexafin gadolinium during preoperative radiotherapy after induction chemotherapy. The second study was designed to examine the use of motexafin gadolinium in combination with stereotactic Gamma Knife radiosurgery in patients with primary glioblastoma mutiforme. Two phase I clinical trials have also been conducted for the treatment of newly diagnosed glioblastoma multiforme at the UCLA Jonsson Comprehensive Cancer Center, USA. These phase I studies were sponsored by the NCI and were conducted under a CRADA with the NCI. Pharmacyclics has also completed multicentre US phase II clinical trials of motexafin gadolinium fin gadolinium in patients with metastatic tumours of the brain who require whole brain radiotherapy. Motexafin gadolinium is in a phase II trial in patients with lymphomas and multiple myeloma in the US.

Motexafin gadolinium prolongs time to neurologic progression in lung cancer patients with brain metastases: results of a randomized phase III trial

Motexafin gadolinium prolongs time to neurologic progression in lung cancer patients with brain metastases: results of a randomized phase III trial