Search

The process of lung carcinogenesis is still not well understood and involves different levels of regulation of several genes. The search for molecular biomarkers, which can be applicable to clinical practice, has been the focus of various studies. XIAP-associated factor 1 (XAF1) was previously shown to be downregulated in many types of tumors, including squamous cell lung cancer. XAF1 is a pro-apoptotic protein and its restoration was found to sensitize cancer cells to apoptotic stimuli; however, the precise mechanism involved in the downregulation of XAF1 in tumors is unknown and promoter hypermethylation or heat-shock transcription factor 1 (HSF1) may be involved. Therefore, the aim of the present study was to evaluate the expression of XAF1 in tumors and adjacent non-tumor specimens from non-small cell lung cancer (NSCLC) patients, and its potential association with various factors including clinicopathological characteristics and other genes involved in NSCLC. Our results indicated that XAF1 expression was markedly altered in NSCLC tumor samples when compared to that found in normal lung tissues. Predominantly, XAF1 was downregulated in the tumors, except in never-smoker patients. In addition, XAF1 may also be important in the whole cell stress mechanism where the p53 status is crucial.

Summary Background Oral mucositis is a major event increasing treatment costs of head and neck squamous cell carcinoma (HNSCC) patients treated with chemoradiation (CRT). This study was designed to estimate the cost-effectiveness of low-level laser therapy (LLLT) to prevent oral mucositis in HNSCC patients receiving CRT. Methods From June 2007 to December 2010, 94 patients with HNSCC of nasopharynx, oropharynx, and hypopharynx entered a prospective, randomized, double blind, placebo-controlled, phase III trial. CRT consisted of conventional radiotherapy (RT: 70.2 Gy, 1.8 Gy/d, 5 times/wk) + concurrent cisplatin (100 mg/m2) every 3 weeks. An InGaAlP (660 nm–100 mW–4 J/cm2) laser diode was used for LLLT. Results From the perspective of Brazil’s public health care system (SUS), total costs were higher in Placebo Group (PG) than Laser Group (LG) for opioid use (LG = US$ 9.08, PG = US$ 44.28), gastrostomy feeding (LG = US$ 50.50, PG = US$ 129.86), and hospitalization (PG = US$ 77.03). In LG, the cost was higher for laser therapy only (US$ 1880.57). The total incremental cost associated with the use of LLLT was US$ 1689.00 per patient. The incremental cost-effectiveness ratio (ICER) was US$ 4961.37 per grade 3–4 OM case prevented compared to no treatment. Conclusions Our results indicate that morbidity was lower in the Laser Group and that LLLT was more cost-effective than placebo up to a threshold of at least US$ 5000 per mucositis case prevented. Clinical trial information: NCT01439724.

Objective Pemetrexed plus carboplatin offers survival advantage in first line treatment of advanced lung cancer patients with performance status of 2. We estimated the cost-effectiveness of this combined regimen compared to pemetrexed alone in a Brazilian population. Methods A cost-effectiveness analysis was conducted based on a randomized phase III trial in patients with advanced non-small cell lung cancer (NSCLC) and ECOG performance status of 2 (PS2), comparing doublet regimen pemetrexed plus carboplatin with pemetrexed alone. The perspective adopted was the public health care sector over a three-year period. Direct medical costs and survival time were calculated from patient-level data and utility values were extracted from the literature. Sensitivity analyses were performed to evaluate uncertainties in the results. Results and conclusion The combined regimen pemetrexed plus carboplatin yielded a gain of 0.16 life year (LY) and 0.12 quality-adjusted life year (QALY) compared to pemetrexed alone. The total cost was 17,674.31 USD for the combined regimen and 15,722.39 USD for pemetrexed alone. The incremental cost-effectiveness ratio (ICER) was $12,016.09 per LY gained and $15,732.05 per QALY gained. The factors with the greatest impact on the ICER are pemetrexed price and the time to progression utility value. The cost-effectiveness acceptability curve showed an upper 90% probability of pemetrexed plus carboplatin being cost-effective with a threshold between two and three GDP per capita. Our study suggests superiority of the combined pemetrexed plus carboplatin regimen in terms of efficacy as well as cost-effectiveness in advanced NSCLC patients with a poor performance status of 2.

Some proteins, canonically not associated with amyloid diseases, can aggregate into amyloid-like fibrils under special conditions. Our group hypothesized that stressful cancer microenvironment might induce the formation of insoluble deposits of p53 mutant protein. A cohort of 28 non-small cell lung cancer (NSCLC) patients was used to test the aforementioned hypothesis. Tumor specimens were assessed for TP53 mutations using DNA sequencing and for amyloid formation by Congo red staining. TP53 mutations were present in 57% of patients, whereas no amyloid deposits were detected in tissue sections under polarized light microscopy. Mutant p53 proteins are not associated with the appearance of amyloid-like fibrils in NSCLC samples, and DNA sequencing remains the standard method to detect such abnormality.

e21159Background: Around 50% of all acquired resistance to first or second-generation EGFR-TKIs during the treatment of NSCLC can be attributed to T790M mutation. Clinical trial data demonstrated s...

9068 Background: Success of a target therapy is directly correlated with the accuracy of its companion diagnostic test. Without a corresponding biomarker, target therapy may yield shorter survival, waste time, increase burdens and costs. As important as conducting cost-effectiveness studies for therapies, it is also valuable to compare different molecular tests. In lung cancer, the mutational status of EGFR and translocation of ALK and ROS-1 are commonly tested to offer the best intervention. Our objective is to evaluate the cost-effectiveness of a unique exam using NGS versus other routinely used tests such as the ones which involve RT-PCR and FISH. Methods: Target population is NSCLC, adenocarcinoma, and candidates to first-line therapy. Strategy 1: test EGFR mutation if EGFR test is negative, individual follow to FISH for ALK; if FISH is negative, follow to FISH for ROS-1. Strategy 2: differs from 1 since FISH for ALK and ROS are requested together. Strategy 3: all individuals are submitted to NGS (multicomplex platform which include EGFR, ALK, ROS-1 and other genes). Tests could also be classified as unknown due to the quality of tumor sample. Prevalence of biomarker, test accuracy and proportion of unknown results were used to calculate each decision tree branch. Sensitivity and specificity was obtained from literature review using Sanger as reference standard for RT-PCR tests and NGS. The study was analyzed from a healthcare-payer perspective based on Brazilian private sector. Costs were based on data from diagnostic companies, ANS and AMB-CBHPM 2016. Results: The use of NGS added 24% extra cases correct identified as well as extra costs (US$ 800.76; PPP 2015) attributed to the molecular testing. The ICER comparing NGS with sequential tests was US$ 3,381.82/correct case detected. Comparing strategy 2:1, the ICER was US$937.86/correct case detected. Conclusions: this study is part of an effort to integrate companion diagnostics discussions on precision medicine and covered drugs in the Brazilian health system. These findings can also subsidy cost-effectiveness studies that incorporates subsequent treatments and survival.

Non-small cell lung Cancer (NSCLC) is extremely resistant to chemotherapeutic agents, such as cisplatin. High expression of the inflammatory enzyme Cyclooxygenase-2 (COX-2) has been shown to inhibit chemotherapy-induced apoptosis, but little is known about COX-2 regulation upon drug treatment. Recent data indicate the tumor suppressor protein p53 as an important regulator of COX-2. Therefore, TP53 status could change tumor sensitivity to chemotherapy through induction of the anti-apoptotic protein COX-2. The main objective of this work was to analyze the effect of chemotherapy on the expression of COX-2, according to TP53 status. We report herein that lung cancer cell lines expressing wild-type p53, when exposed to cisplatin treatment, induced COX-2 (mRNA and protein), with concurrent synthesis of prostaglandins (PGE 2 ). In contrast, COX-2 expression was not changed after cisplatin treatment of cells containing an inactive form of p53. Further, after silencing of wild-type p53 expressed in A549 cells by RNA interference, cisplatin was no longer able to induce COX-2 expression. Therefore, we suggest that induction of COX-2 by cisplatin in NSCLC cell lines is dependent on p53. For paclitaxel treatment, an increase in COX-2 mRNA expression was observed in H460 and A549 (wild-type p53 cell lines). Moreover, paclitaxel treatment increased COX-2 expression in ACC-LC-319 cell lines (p53 null), showing a p53-independent effect. These data may have therapeutic implications in the selection of patients and strategy for future COX-2 inhibition trials.

6071 Background: Oralmucositis (OM) is a main factor for increasing treatment costs in head and neck squamous cell carcinoma (HNSCC) patients (pts) treated with chemoradiation (CRT). This study was designed to estimate the cost-effectiveness of LLLT to prevent oral mucositis in HNSCC patients submitted to CRT. Methods: From June 2007 to Dec 2010, 94 patients with HNSCC of nasopharynx, oropharynx and hypopharynx entered a prospective, randomized, double blind, placebo-controlled, phase III trial (47 LLLT (LG) and 47 placebo (PG)). CRT consisted of conventional RT 70.2 Gy (1.8Gy/d, 5 times/wk) + concurrent cisplatin 100 mg/m2 every 3 wks. The LLLT used daily was a diode InGaAlP (660nm-100mW-4J/cm²). OM evaluation was done by WHO and OMAS scale. The resources used by patients in both groups were documented during the trial. Unit costs for procedures were obtained from a public reference list (SIGTAP / SUS) as of Jan 2012 and unit costs for drugs were based on ex-factory prices. The cost per laser session was US$ 34.00 (exchange rate from Brazilian currency to US dollar = 1.95) for the baseline analysis. Costs of RT, chemotherapy, fluconazole and chlorhexidine 0.12% were equivalent in both groups and therefore not included in the analysis. Hospitalization rates associated with the treatment of oropharyngeal or oral mucositis were not documented in the study and were estimated according to previously published data. Results: Under the perspective of the Brazilian public healthcare system (SUS), total costs were higher in PG than LG on opioide use (LG= US$ 29.45; PG= US$143.72, gastrostomy (LG= US$ 41.69; PG= US$107.22 ) and hospitalization (PG= US$ 63.59). In LG costs were higher with laser therapy (US$ 1,549.50). The total incremental cost associated with the use of LLLT was US$ 1,306.61 per patient. The incremental cost-effectiveness ratio (ICER) was US$ 3,838.16 per case of grade 3 and 4 mucositis avoided when compared with no treatment. Conclusions: Our results indicate that laser group had a smaller morbidity during treatment and LLLT is cost-effective when compared to pacebo under a threshold of at least US$ 4,000 per avoided mucositis case. Clinical trial information: NCT01439724.