bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of treatment patterns in patients with malignant mesothelioma in the United States: A retrospective database analysis.
Authors: Wu Bingcao , Pawaskar Manjiri , Tunceli Ozgur , Dalvi Tapashi , Ibrahim Ramy A. , Tavakkoli Fatemeh , Deeter Robert
Published: March 2020

e18543

Background: Mesothelioma is a rare malignancy primarily attributed to asbestos exposure and has limited life expectancy. This study examined patient characteristics, and treatment patterns in commercially insured mesothelioma patients in real world setting. Methods: Patients aged ≥18 yrs with mesothelioma diagnosis were identified using ICD-9 and CPT codes/clinical algorithm between 7/1/2006 and 4/30/2011 from HealthCore Integrated Research Database. Patients with other cancers and without continuous insurance enrollment for ≤ 6-mos before or 12-mos post-diagnosis were excluded. Treatments were grouped into surgery, systemic chemotherapy (Ctx), and best supportive care (BSC) and were assessed descriptively. Results: A total of 184 patients were identified (mean age 64 yrs with 41% patients between 45 and 64 yrs old and 48% ≥65 yrs old, 64% males) with diagnosis of mesothelioma. 61% patients had pleural, 25% had peritoneal and 14% had pericardial disease. Only 10% patients received surgery, 27% received Ctx, while 50% received BSC (including radiation). Among patients who received 1st line Ctx (mean duration 90 days), almost half of patients received pemetrexed based regimen {pemetrexed + cisplatin (18%) or carboplatin (10%) and pemetrexed alone (20%)} followed by carboplatin monotherapy (42%). Among 41% who received 2nd line Ctx regimens (mean duration 105 days), most commonly used (65%) were pemetrexed based regimens {pemetrexed alone (35%) and pemetrexed + cisplatin (15%) or carboplatin (15%)} followed by single agent gemcitabine (15%). No patients received vinorelbine (0%). In patients who received Ctx, 35% died before receiving 2nd line Ctx and an additional 15% of patients died before receiving 3rd line Ctx. Only 16% received 3rdline Ctx. Around 41% patients had at least one emergency room visit and 80% had at least one hospitalization. Conclusions: Mesothelioma is predominant in males and older adults in commercially insured patients in the United States. Systemic chemotherapy remains the main treatment strategy with pemetrexed based therapy being most commonly used regimen. This study highlights limited treatment options and high unmet need in this population.
Clinical significance of downstaging in patients treated with chemoradiotherapy for limited-disease small cell lung cancer.
Authors: Go Se-Il , Keam Bhumsuk , Kim Tae Min , Lee Se-Hoon , Kim Dong-Wan , Kim Hak Jae , Wu Hong-Gyun , Chung Doo Hyun , Heo Dae Seog
Published: March 2020

e18555

Background: Limited-disease small cell lung cancer (LD-SCLC) patients who do not achieve complete remission (CR) have a considerable relapse rate. The change of tumor burden after treatment can be related with prognosis, the change of TNM stage may influence the outcome of treatment. We investigated the impact of downstaging on overall survival (OS) in LD-SCLC patients treated with chemoradiotherapy (CRT). Methods: We retrospectively reviewed the 210 LD-SCLC patients, who were treated with CRT at Seoul National University Hospital from Apr 1999 to Nov 2012. The relationship between downstaging and OS was analyzed, and subgroup analysis on the responders was performed. Results: Patients showing CR, partial remission (PR), and stable disease (SD)/progressive disease (PD) were 37.1% (n=78), 46.2% (n=97), and 16.7% (n=35), respectively. The median OS for CR, PR, and SD/PD were 47.9 months (mo), 21.8 mo, and 11.2 mo, respectively (P <0.001). Patients showing downstaging and no change/upstaging were 61.5% (n=129) and 38.5% (n=81), respectively. The median OS for downstaging and no change/upstaging were 36.5 mo and 14.4 mo, respectively (P <0.001). Among the 97 patients achieving PR, OS were statistically differed by downstaging (26.0 mo in patients with downstaging and 17.7 mo in patients without downstaging [P =0.021]). In the multivariate analyses, female, downstaging, lower initial TNM stage, and prophylactic cranial irradiation were independent good prognostic factors for OS. Conclusions: Downstaging was independent prognostic factor in LD-SCLC. Especially, downstaging is useful for further stratification of patients achieving PR. Additional treatments after CRT may be needed for the patients who achieving PR without downstaging.
Is erlotinib for first-line use in EGFR+ non-small-cell lung cancer cost-effective?
Authors: Veenstra David L , Bajaj Preeti S. , Carlson Josh John , Goertz Hans-Peter
Published: March 2020

e19001

Background: A recent phase III clinical trial, EURTAC, demonstrated that first-line treatment with erlotinib significantly improved progression-free survival (PFS) compared with standard chemotherapy in advanced non-small cell lung cancer (NSCLC) patients whose tumors harbored epidermal growth factor receptor (EGFR) mutations (Rosell 2012). We sought to estimate the cost-utility of treatment with erlotinib in this patient population from the US payer perspective. Methods: We developed a Markov model with three health states: PFS, progression, and death. Patients received treatment until progression, unacceptable toxicity or death; patients randomized to chemotherapy received a maximum of 4 treatment cycles. Transition probabilities were extrapolated from the trial. Median PFS was 9.7 months in patients receiving erlotinib and 5.2 months in patients receiving chemotherapy (p<0.0001). Cost and utility data were obtained from the literature. Probabilistic sensitivity analysis (PSA) was performed to assess uncertainty. We evaluated two scenarios: 1) first-line erlotinib vs. first-line chemotherapy, and 2) first-line erlotinib and mixed second-line treatments vs. first-line chemotherapy and second-line erlotinib. Results: First-line treatment with erlotinib vs. chemotherapy resulted in an increase of 0.60 life-years or 0.44 quality-adjusted life-years (QALYs). Mean total costs were $59,300 in the erlotinib arm and $17,800 in the chemotherapy arm, yielding an incremental cost-effectiveness ratio (ICER) of $98,338 with a 53% probability of being cost-effective at a willingness to pay (WTP) of $100,000/QALY. In the second scenario, the ICER was $50,002/QALY, with a 66% probability of being cost-effective. The main cost drivers in the model were the time spent in the PFS health state and drug costs. Conclusions: Treatment with erlotinib in first-line EGFR-positive NSCLC results in increased costs but also substantial increases in QALYs, demonstrating that this personalized approached to treatment may be cost-effective.
Development of brain metastases in stage III/IV non-small cell lung cancer patients treated with or without erlotinib.
Authors: Liu Jing , Kong Li , Meng Xue , Yue Jinbo , Sun Xindong , Yu Jinming
Published: March 2020

e19011

Background: Non-small cell lung cancer (NSCLC) has a risk of death from brain metastases (BM) that exceeds potential mortality from extracranial disease progression. Erlotinib has been proved to be effective for NSCLC patients. We hold a study to evaluate value of erlotinib in preventing BM in stage III/IV NSCLC patients. Methods: Pathologically confirmed NSCLC stage III/IV patients were included and divided into erlotinib group and control group according to whether erlotinib administration (at least one month) in 1- or 2-line therapy or not. Stage IV patients with BM were excluded. Patients with any EGFR-TKI treatment were excluded from control group. Times of erlotinib administration to BM and to death or last follow-up were recorded for erlotinib group. Times of corresponding 1- or 2-line chemotherapy to BM and to death or last follow-up were recorded for control group correspondingly. Time to BM, 1- and 2-year incidence of BM were end points. Results: 140 patients were included (68 in erlotinib group and 72 in control group) and all clinical characteristics between two groups were balanced. At a median follow-up of 20.0 months, the median time to BM for all patients was 28.0 months (95% CI, 23.795-32.205 months). 1- and 2-year incidence of BM were 17.8% (95% CI, 10.744-24.856%) and 38.8% (95% CI, 27.236-50.364%) respectively. The median time to BM were 42.0 months (95% CI, 15.567-68.433 months) and 19.0 months (95% CI, 11.305-26.695 months) (P=0.028) for erlotinib group and control group. Erilotinib group has a lower BM incidence than control group (1-year: 14.4%, 95% CI: 4.992%-23.808%, vs 21.1%, 95% CI: 10.712%-31.488%, P=0.384; 2-year: 26.2%, 95% CI: 18.712%-33.688%, vs 50.2%, 95% CI: 34.128%-66.272%, P=0.005). Multivariate analysis shows interval to BM were longer for erlotinib group (HR, 2.531; 95% CI, 1.272-5.051; P=0.008) and stage III disease (HR, 2.093; 95% CI, 1.035-4.231; P=0.040). Conclusions: Erlotinib administration improves time to BM and 2-year incidence of BM of stage III/IV NSCLC patients. Erlotinib administration and stage III disease predicts lower incidence of BM in all patients.
The association of toxicities and outcomes with circulating endothelial cells (CEC) in non-small cell lung cancer (NSCLC) patients (pts) treated with bevacizumab (Bev).
Authors: Hashemi Sadraei Nooshin , Du Lingling , Yadav Ruchi , Grane Ronald , Jacobs Barbara , Hamulak John , Ma Patrick C. , Pennell Nathan A. , Elson Paul , Borden Ernest C.
Published: March 2020

e19012

Background: Bev in combination with chemotherapy (CT) is a standard treatment for pts with stage IV NSCLC. However, there are no established biomarkers to improve benefit-to-risk profile of therapy. CEC are a marker of vascular turnover. We hypothesized CEC may be associated with treatment outcome/toxicity. Methods: Stage IV NSCLC pts were treated with Bev along with CT of choice per clinician. CEC were measured at baseline and after 2 cycles of Bev-containing therapy. CellSearch (Veridex, New Jersey) was used to capture and quantify CEC via immunomagnetic and immunofluorescence techniques. CEC were enumerated as nucleated, CD146+/CD105+/CD45- cells in 4 mL of blood. For comparison, baseline CEC were also collected in 3 other groups; healthy subjects, stage I-III NSCLC, and advanced solid tumor pts. Chi-square tests and non-parametric methods were used to assess associations between CEC and pt/disease characteristics, toxicity, and proportional hazards models were used for comparisons of progression free and overall survival (PFS and OS). Results: Evaluated were 62 individuals: 29 stage IV NSCLC, 10 stage I-III NSCLC, 13 advanced solid tumors (melanoma, sarcoma, renal and adrenal cancers), and 10 healthy subjects. The median of CEC/ml blood in healthy subjects was 6. Based on its distribution, CEC >13/ml was deemed elevated. Elevated CEC was seen in 48% of stage IV NSCLC (median 12/ml), in comparison to 20% of stage I-III NSCLC (8/ml) and 23% of advanced solid tumors (6/ml) Baseline CEC in stage IV NSCLC was independent of patient/ disease characteristics including site of disease and tumor size. CEC increased during treatment in most patients (61%). CEC doubling between baseline and cycle2 was associated with more cytopenia and hemorrhage. (75% vs 20%, p=0.05 and p=0.03 for absolute and relative CEC changes). Baseline CEC and changes during treatment did not correlate with response (p≥ 0.32) and pts with elevated baseline CEC had a trend towards worse PFS (p=0.09) and OS (p=0.10). Conclusions: CEC are commonly elevated in advanced NSCLC. CEC increases may be predictive of adverse events from Bev-CT and when elevated at baseline may suggest worse PFS.
Impact of dendritic cells combining with cytokine-induced killer cells synergized chemotherapy in patients of advanced non-small cell lung cancer.
Authors: Zhong Runbo , Zhong Hua , Han Baohui
Published: March 2020

e19018

Background: Advanced non-small cell lung cancer (NSCLC) remains an incurable disease by following conventional chemotherapy and is the major cause of cancer–related mortality worldwide. Dendritic cells (DC) play a central role in the induction of an effective antitumor immune response. Cytokine-induced killer (CIK) cells, the subset of T lymphocytes, have a profound capacity to cytolytically eliminate cancer cells. This study was designed to evaluate how the times of receiving DC/CIKs vaccination following regular chemotherapy impact the overall survival time in patients of advanced lung cancer. Methods: 43 patients suffering from IIIB-IV NSCLC were enrolled in the study between August 2004 and December 2008, and all received four courses of vinolbine-platinum (NP) chemotherapy followed by vaccinated with carcinoembryonic antigen (CEA) peptide-pulsed autologus dendritic cells and CIK cells. Vaccination was repeated at 30-day intervals until the patient refused to accept. The adverse effect and overall survival (OS) were evaluated. Results: Median survival time (MST) of all patients was 19.50 months. The 1-, 2- and 3-year overall survival rate was 66.50%, 41.04%, 28.14% respectively. The 1-, 2- and 3-year overall survival rate of patients who received no less than two times of vaccination therapy was 83.92%, 74.59%, 49.73% and who received only one time was 59.44%, 23.71%, 17.78% respectively. A statistically significant difference between the two groups was identified (p=0.0052). The adverse effect as a result of chemoimmunotherapy was tolerable. Conclusions: Advanced NSCLC patients can benefit from the combination of DC-CIK vaccination followed conventional chemotherapy,and the more vaccination therapy received the longer overall survival time observed.
The occurrence of grade 4 adverse events and survival outcomes in patients with nonsquamous non-small cell lung cancer receiving bevacizumab with chemotherapy in the phase III PointBreak and AVAiL studies.
Authors: Villaruz Liza Cosca , Socinski Mark A. , Patel Jyoti D. , Leon Larry , Hazard Sebastien , Reck Martin
Published: March 2020

e19022

Background: Progression-free survival (PFS) is a key trial end point for clinical practice, as it relates to a change of treatment line. Grade 4 progression-free survival (G4PFS; defined as time from treatment start to the earlier of progressive disease [PD], onset of a G4 adverse event [AE], or death from any cause) is a composite end point incorporating a measure of tolerability to PFS. This post hoc analysis evaluates G4PFS and the effect of G4 AEs on PFS and overall survival (OS) in patients (pts) enrolled in PointBreak (PB) and AVAiL. Methods: Pts in PB were randomized to bevacizumab (BEV) 15 mg/kg q3w with carboplatin and paclitaxel (CP) or pemetrexed (CPem) for ≤4 cycles. Eligible pts received either BEV or BEV + Pem q3w until PD or unacceptable toxicity. Pts in AVAiL received cisplatin and gemcitabine for ≤6 cycles and either placebo or BEV (7.5 or 15 mg/kg) q3w until PD. AEs were graded via NCI-CTCAE v3.0. Kaplan-Meier and Cox model methods were used to estimate medians and hazard ratios (HRs) for PFS, G4PFS, and OS. PFS and OS were also compared in each arm for pts with occurrence of a G4 AE before week 12 of treatment vs those without. Results: Of those receiving BEV, ~30% of AVAiL pts and 38% of PB pts had a G4 AE. Uncomplicated neutropenia was the most common G4 AE in the CP + BEV arm of PB (26%) and in the BEV arms of AVAiL (11%). PFS, G4PFS, and outcomes by G4 AE occurrence are shown (Table). Conclusions: In both the PB and AVAiL trials, median G4PFS was numerically shorter than median PFS. G4 AE occurrence, however, did not affect subsequent PFS or OS in either trial. Clinical trial information: NCT00762034 and NCT00806923. [Table: see text]
Predictors of outcome for pemetrexed (Pem) in metastatic NSCLC (mNSCLC).
Authors: Jones Cortney Vanderbilt , Du Lingling , Elson Paul , Mekhail Tarek , Pennell Nathan A. , Hashemi Sadraei Nooshin
Published: March 2020

e19025

Background: Pemetrexed (Pem) is the first agent showing different efficacy based on histology in the treatment (tx) of NSCLC. Our goal was to identify outcome predictors in patients (pts) with metastatic NSCLC (mNSCLC) treated with pem. Methods: Retrospective data of pts with mNSCLC who received pem were analyzed. Variables included demographics, ECOG performance status (PS), disease sites, pre/post-pem tx, and toxicities. Clinical benefit defined as complete response (CR), partial response (PR), and stable disease (SD) >6 months, progression-free survival (PFS), and overall survival (OS) were analyzed using logistic regression and Cox proportional hazards model. Results: 240 pts were included. 55% male, 84% smokers. 68% adenocarcinomas, 10% squamous/adenosquamous carcinomas. Median age 64 years (range 34-84). Pem was given for a median of 4 cycles (range 1-73), as 1st line in 20% and 2nd line in 50%, given as a single agent in 69%. The most common toxicities were constitutional (50%) and GI related (29%). 31% of pts achieved CR (n=4) or PR, 33% progressed, 36% had SD. Front-line pem use (p=.0003), adenocarcinoma histology (p=.05), and non-pulmonic metastatic sites ≤2 (p=.01) were independent predictors of clinical benefit, with response rate of 71% for pts with all three features, compared to only 7% for pts with none of these features. Multivariable analysis of survival data revealed ECOG PS >1, non-pulmonic metastatic sites>2, and squamous/poorly differentiated histology predicted poor PFS and OS. In addition, interval from diagnosis to start of pem <12 months and male gender predicted poor PFS, while former/current smoker predicted poor OS. Pts with favorable features had a median PFS of 7.7 months, compared to 2.1 months with unfavorable features (p<.0001). A median OS of 16 months was achieved in pts with favorable features, compared to 5.9 months with unfavorable features (p<.0001). Conclusions: Front-line pem use, adenocarcinoma histology, and ≤2 non-pulmonic metastatic sites predict better response to pem. Poor PS, >2 non-pulmonic metastatic sites, squamous/poorly differentiated histology predict poor PFS and OS. An analysis of biomarkers is ongoing.
The predictive role of consecutive measurements of serum CEA for treatment efficacy in advanced non-small cell lung cancer patients harboring epidermal growth factor receptor mutations treated with gefitinib or erlotinib.
Authors: Chung Chi-Li , Chiang Ling-Ling , Yu Ming-Chih , Lin Sey-En , Hsiao Shih-Hsin
Published: March 2020

e19029

Background: Patients with non-small cell lung cancers (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations dramatically respond to EGFR tyrosine kinase inhibitors (TKIs) with approximately 70% response rate. Carcinoembryonic antigen (CEA) has been suggested to be associated with tumor recurrence, treatment efficacy and prognosis in some specific tumors. However, the role of CEA in NSCLC with EGFR mutations remains unclear. Therefore, we sought to elucidate whether the determination of serum CEA levels can predict the efficacy of EGFR TKIs in NSCLC harboring EGFR mutations. Methods: Medical records of 326 consecutive patients with advanced NSCLC between January 2007 and November 2012 were reviewed and a total of 104 patients with NSCLC harboring EGFR mutations treated with gefitinib or erlotinib ³2 weeks and with available data of serum CEA were identified for analysis. Results: Female, never smokers, adenocarcinoma histology and cases with pretreatment serum CEA ³ 5 ng/ml presented 63%, 76%, 96% and 68% of 104 eligible cases with mean age of 65.4 ± 13.7 years, respectively. The response rate of EGFR TKIs in patients with pretreatment CEA ³ 5 ng/ml was not significantly different (70% vs 91%, P = 0.339), and it was higher in those with reduction of CEA level after treatment than those without (94% vs 35%, RR=2.7, P <0.001). The average change of pre- and post-treatment CEA in respondents and non-respondents was negative 112 ± 181 ng/ml and positive 368 ± 514 ng/ml, P <0.001, respectively. In details, the pre- and post- treatment CEA levels in respondents were 246 and 71 ng/ml, P < 0.001, respectively, and those in non-respondents were 157 and 268 ng/ml, P= 0.019, respectively. Furthermore, the post-treatment CEA level increased by 14% in non-respondents and decreased by 52% in respondents. Conclusions: Reduction or elevation of post-treatment serum CEA can predict the treatment efficacy in NSCLC patients with EGFR mutations treated with gefitinib or erlotinib. Further studies aiming to investigate the value of serum CEA levels in tumor progression and survival are warranted.
Benchmarking population-based EGFR mutation testing in nonsquamous non-small cell lung cancer.
Authors: Shiau Carolyn Jane , Babwah Jesse Paul , Santos Gilda Da Cunha , Sykes Jenna R , Boerner Scott L. , Geddie William R. , Wei Cuihong , Kamel-Reid Suzanne , Hwang David M , Tsao Ming Sound
Published: March 2020

e19032

Background: Epidermal growth factor receptor (EGFR) mutation testing has become critical in the treatment of advanced non-small cell lung cancer (NSCLC) patients. This study involves a large cohort and epidemiologically unselected series of EGFR mutation testing for non-squamous NSCLC patients in a North American population, to determine mutation rates and define factors that influence success in routine clinical EGFR testing. Methods: Data from consecutive cases of Canadian province-wide testing during a 24-month period at a centralized diagnostic laboratory were reviewed. Samples were tested for exon 19 deletion and exon 21 L858R mutations using a validated PCR method with 1-5% detection sensitivity. Results: From 2,651 samples submitted, 2,404 samples were tested with 2,293 samples eligible for analysis. These included 1,780 histology and 513 cytology specimens. The overall test failure rate was 5.4%. Among successfully tested samples, the overall mutation rate was 20.6%. There were no significant differences in the failure rate, mutation rate, or mutation type found between histology and cytology samples. While tumor cellularity was significantly associated with test success or mutation rates in histology and cytology specimens respectively, mutations could be detected in all specimen types. Optimal histology samples contained ≥2 mm2of tumor tissue and ≥30% tumor cellularity. Optimal cytology cell-block samples have at least a few groups of nucleated cells dispersed throughout the block, regardless of tumor cellularity. Samples from metastatic deposits in bone, distant lymph nodes, and pleura showed higher mutation rates than primary lesions. Conclusions: Our current method for EGFR mutation testing is able to detect mutations in small tumor volume biopsies, typical of tissue obtained for initial diagnosis. EGFR mutation testing should be attempted in any type of specimen, histology or cytology. Cases that are suboptimal with a negative EGFR mutation result should be considered for repeat testing with an alternate tumor sample.
Epidermal growth factor receptor mutation (EGFRMUT) in non-small cell lung cancer (NSCLC) in the Middle East.
Authors: Jazieh Abdul Rahman , Jaafar Hassan Nadim , Mustafa Rasha , Rasul Kakil , Zekri Jamal , Gaafar Rabab Mohamed , Al Husaini Hamed Homoud , Azim Hamdy A. , Bamefleh Hanaa , Gasmelseed Ahmed
Published: March 2020

e19035

Background: EGFR mutation is an important therapeutic marker for the management of NSCLC with known ethnic variations. Our study aims at determining the prevalence of the mutation in the Middle East and its correlation with demographic and clinical features. Methods: A multisite retrospective study was conducted including institutions from Saudi Arabia, UAE, Qatar and Egypt. All consecutive patients (pts) with NSCLC tested for EGFRMUT were eligible. Data were obtained on demographic and disease characteristics, and EGFR test results. Institutional Review Board approval was obtained from all participating sites. Results: Data on 201 patients were obtained. Median age was 61 years (51 - 69), 140 (69.65%) were males and 174 pts were Arab (86.57%) Tumor histology subtypes were adenocarcinoma in 175 patients (87.07%), squamous cell carcinoma in 15 pts (7.46%) and others in 11 pts (5.48%). EGFRMUT was detected in 66 pts, with (36.50%) prevalence in adenocarcinoma. No squamous cell carcinoma harbored EGFRMUT. The most frequent abnormality detected was in exon 19 in 39 pts (57.36%), abnormalities in exon 21 in 22 pts (32.35%) and in exon 18 in 7 pts (10.29%). Two pts had dual mutations on exons 19 and 21. Univariate and multivariate analyses revealed significant predictors for having EGFRMUT to be: female gender (42.42 % vs. 27.7% in males, p= 0.0096), non-smoking status (81.82% vs. 16.21% in smokers, p=0.0001) and adenocarcinoma subtypes (36.25 % vs. 15.38% in others, p=0.035). There was no difference between Arabs and non-Arabs. Conclusions: This is the first study from our region to report the prevalence of EGFRMUT in ME population which seems to be similar to Far East population with similar clinical predictors. Studies about the impact of targeted therapy in our patient’s population are underway.
Evaluation of the prognostic/predictive role of tumor EGFR and KRAS mutations in Greek metastatic non-small cell lung cancer patients treated with first-line chemotherapy.
Authors: Linardou Helena , Kosmidis Paris A. , Kotoula Vassiliki , Karavasilis Vasilios , Eleftheraki Anastasia G , Lazaridis Georgios , Daskalaki Emily , Lakis Sotiris , Charalambous Elpida , Samantas Epaminontas , Pectasides Dimitrios G. , Bafaloukos Dimitris , Fountzilas George
Published: March 2020

e19048

Background: KRAS mutations are reported in 20-25% of non-small cell lung cancer (NSCLC). Little is known about the prognostic/predictive role of KRAS in advanced NSCLC, with conflicting results among small studies. Recent evidence showed that KRAS mutations could predict for worse outcome in patients treated with platinum-based adjuvant chemotherapy. Methods: KRAS and EGFR genotypes were evaluated in 414 NSCLC patients with available clinical data, diagnosed from March 2000 to December 2012 (tissue blocks from the HeCOG tumor repository). KRAS and EGFR mutations were associated with clinicopathological parameters (mutated vs. wild-type). Outcome comparisons were performed in 214 metastatic patients with treatment data available, following 1st-line chemotherapy without tyrosine kinase inhibitors. Results: The majority of the patients were male (80%), current smokers (53%), with adenocarcinoma (AC) histology (65%). EGFR mutations were found in 10% and KRAS mutations in 17% of all histological types, while in AC they were 14% and 21%, respectively. Most EGFR mutations were classical (79%), while most common KRAS mutations were p.G12C (39%), p.G12D (30%) and p.G12V (15%). Two tumors had concurrent EGFR and KRAS mutations. EGFR mutations were significantly associated with female gender, AC histology and non-smoking status, as previously described. KRAS mutations were associated with AC histology and younger age (<60). At a median follow-up of 31 months, EGFR status did not show any significant associations with OS or PFS, while KRAS mutations were prognostic for worse OS compared to KRAS and EGFR wild-type tumors (HR=1.67, CI=1.08-2.59, p=0.021). This effect was also significant (p=0.022) in the presence of treatment type, with platinum-based therapy being a positive prognostic factor for OS (HR=0.62, CI=0.4-0.92, p=0.019). The association of KRAS mutations with PFS was not significant. Conclusions: EGFR and KRAS genotype incidences are presented for the first time for Greek metastatic NSCLC patients. In this setting, the presence of KRAS mutations significantly increases and platinum 1st-line treatment decreases the risk of death.
Model-based estimates of tumor growth inhibition (TGI) metrics to predict for overall survival (OS) in first-line non-small cell lung cancer (NSCLC).
Authors: Claret Laurent , Mancini Pierre , Sebastien Bernard , Veyrat-Follet Christine , Bruno Rene
Published: March 2020

e19049

Background: A survival model using change in tumor size at week 8 from baseline (CTS) (Clin Pharmacol Ther 86:167-174, 2009) was used to predict OS of the motesanib phase III study in NSCLC (Clin Pharmacol Ther 92:631-634, 2012). However CTS may not fully capture treatment effect on OS. We investigated other TGI metrics to predict OS using historical phase III data. Methods: Various TGI metrics, CTS, time to growth (TTG), and tumor growth rate (G), were estimated using two longitudinal tumor size models (Clin Cancer Res 17:907-917, 2011, PAGE 21 [www.page-meeting.org/?abstract=2328], 2012, JCO in press, 2013) developed from phase III data (1218 1st-line patients with NSCLC treated with doxetaxel (D) plus cisplatin (Cs) or carboplatin (Cb) or vinorelbine (V) plus Cs) (J Clin Oncol, 21:2016-3024, 2003). TGI metrics and baseline prognostic factors were assessed in univariate Cox and multivariate parametric survival models. Alternative models were qualified by simulating OS distributions in 1000 replicates of the phase III study and checking that observed OS distribution belongs to the 95% prediction intervals. Results: In a univariate analysis all TS metrics were strong predictors of OS (p<0.0001). TTG and G were similar and much better than CTS (likelihood ratio test). OS was best described by a log-normal distribution and the influence of the covariates was assessed based on linear regression of the logarithm of OS (days). Parameter estimates of the best multivariate model are shown in the Table. The model was qualified in predicting OS distributions in the 3 arms (D+Cs, D+Cb, V+Cs). Conclusions: With further external validation, this model could be used to analyze longitudinal NSCLC tumor size data and their relationship to OS, in phase II studies of new agents and support end-of-phase-II decisions. [Table: see text]
The association between COX-2 polymorphisms and hematologic toxicity in patients with advanced non-small-cell lung cancer treated with platinum-based chemotherapy.
Authors: Fei Zhou
Published: March 2020

e19059

Background: Overexpression of COX-2 is thought to contribute to tumor promotion and carcinogenesis through stimulating cell proliferation, inhibiting apoptosis, and enhancing the invasiveness of cancer cells. Apoptosis-related molecules are potential predictive markers of survival and toxicity outcomes for platinum treatment. This study aimed to investigate the association between COX-2 polymorphisms and the occurrence of grade 3 or 4 toxicity in advanced non–small cell lung cancer patients treated with platinum-based chemotherapy. Methods: Two hundred and twelve patients with inoperable stage IIIB-IV receiving first-line chemotherapy between 2007 and 2009 were recruited in this study. Four functional COX-2 polymorphisms were genotyped by PCR-based restriction fragment length polymorphism (RFLP) methods. Results: The incidence of grade 3 or 4 hematologic toxicity was significantly higher in G allele carriers of the COX-2 −1195G/A (rs689466) polymorphism compared to wild-type homozygotes AA (P value = 0.013; odds ratio, 2.30; 95% confidence internal, 1.20-4.42) and still significant after a Bonferroni correction. More statistically significant difference was found in grade 3 or 4 leukocytopenia (P value = 0.010; OR=2.28; 95%CI=1.28-6.05). No other significant association between genotype and toxicity was observed in the study. The haplotype analysis showed the haplotype AGG was associated with a reduced risk of grade 3 or 4 hematologic toxicity (P value= 0.015; OR= 0.61; 95%CI =0.41-0.91) while the haplotype GGG was associated with an increased risk of grade 3 or 4 hematologic toxicity (P value=0.008; OR=1.71; 95%CI=1.15-2.54), global X2= 6.9825, df =2, P = 0.030. Conclusions: This investigation, for the first time, suggests that polymorphism in COX-2 −1195G/A may be a useful bio-marker to predict severe hematologic toxicity in NSCLC patients after platinum-based chemotherapy.
The prognostic value of gene expressions of ERCC1 and RRM1 in non-small cell lung cancer.
Authors: Hasturk Serap , Olgunus Ozlem , Tuli Abdullah , Dundar Ebru , Unlu Emine Ozgur
Published: March 2020

e19071

Background: Non small cell lung cancer is the most common cause of death due to cancer in the world. The role of ERCC1 and RRM1 genes has been researched in prediction of lung cancer prognosis and response of patients to chemotheraphy. We aimed to evaluate the effects of ERCC1 and RRM1 gene expressions profiles on the prediction of the prognosis and the treatment on bronchoscopy specimens of advanced stage NSCLC patients. Methods: The levels of ERCC1 and RRM1 gene expressions were studied for 76 patients which were diagnosed by bronchoscopic biopsy parafin embedded tissue samples. The RRM1 and ERCC1 gene expression profiles were examined by RT-PCR method. Forty were diagnosed with squamous cell cancer, 24 with adenocarcinoma, 12 with NOS NSCLC. Thirty patients were chemotherapy native, 33 were received gemcitabine-cisplatin and 13 were received docetaxel- cisplatin doublets chemotherapy. Results: The mean age of the patients in the study was 59.8±9.3 (years ± SD). The levels of gene expressions of ERCC1 and RRM1 were found to be 2-9 (median 4.9), and 1.3-17.7 (median 6.8). No significant difference was detected between ERCC1 and RRM1 levels and age, gender, histologic type, ECOG, weight loss when the median gene expression levels were used as cut off value. Also, no significant difference was observed for survival analysis among the patients that have low ERCC1 mRNA level (p=0.41). The level of gene expression of ERCC1 was lower in patients with advanced stage (p=0.06). In addition, no significant difference was detected for the survival analysis within the patients that have the low and high RRM1 mRNA levels (p=0.43). When the survival analyses were evaluated between the patients who had chemotherapy and the ones who did not; no significant difference was detected according to ERCC1 and RRM1 levels. Conclusions: We conclude that the analysis of ERCC1 and RRM1 gene expression profiles based on bronchoscopy obtained samples appeares feasible, but the methodology and cut off points that was used to classify expression level as ‘high’ or ‘low’ would require further optimization. These two gene signature proposed for advanced stage NSCLC may not be useful, particularly not ready for clinical application.
Association of brain metastasis in non-small cell lung cancer.
Authors: Zhao Yu , Guo Huiqin , Lu Jiangyang , Christiani David C. , Lin Xihong , Wang Zhaoxi
Published: March 2020

e19081

Background: Brain metastases are the main cause of non-small cell lung cancer (NSCLC) relapse and death. However, it is difficult to predict which NSCLC patient will develop brain metastasis. We have observed and summarized the relationship between the clinical and molecular biological features including EGFR mutation status and brain metastases in a prospectively enrolled case series, and developed a multivariable model in this study. Methods: The study enrolled 184 Chinese NSCLC patients with at least 18 months follow-up period. Clinical information including age, smoking history, lymph node status, pathological stage, primary location and histological type of the tumor and EGFR (including exon 19 and 21) and KRAS mutation status were collected and analyzed. Univariate and multivariate Cox regression analysis was run to investigate risk factors of brain metastasis from these features. A risk model based on these risk factors was constructive. Results: 13.0% (24/184) patients were diagnosed as brain metastasis. EGFR mutation (P=0.026), younger age (P=0.034) and lymph node metastasis (P=0.038) were associated with brain metastasis. A Cox model based on these 3 factors was founded and the risk of brain metastasis was 1.9% (1/53), 8.3% (5/60) and 25.4 % (18/71) in low, intermediate and high risk group, respectively (P<0.001). Conclusions: EGFR mutation, younger age and lymph node metastasis are associated with brain metastasis in NSCLC patients. If confirmed in clinical trials, high risk patients may be considered for prophylactic cranial irradiation therapy in future clinical trials
Treatment strategies after failure to reversible tyrosine kinase inhibitors (rTKI) in EGFR mutant (mut) non-small cell lung cancer (NSCLC) patients (p): A retrospective analysis of 41 Spanish p.
Authors: Remon Jordi , Moran Teresa , Alcaraz Diego , Capdevila Laia , Porta Rut , Reguart Noemi , Lianes Pilar , Carcereny Costa Enric , Bosch-Barrera Joaquim , Rosell Rafael
Published: March 2020

e19089

Background: Different therapeutic approaches have been used in the clinical setting in NSCLC p harbouring EGFR mutations progressing to rTKI, although the standard of care in this situation is still not well established. Methods: A multi-institutional database from four different centers in Spain was review to identify EGFR mut p with acquired resistance to rTKI in order to evaluate the therapeutic strategies after rTKI failure and the effect on the post-progression survival (PPS) of these treatments. Results: 41 p with acquired resistance to rTKI were identified: 63% female; median (m) age 62 ±11 yrs; 95% Caucasian; del19 76%, never or light former smokers 100%; 90.2% adenocarcinomas; 51 % received TKI as first line therapy; 85% were initial stage IV .mPFS for the rTKI was 8.4 months (mo) and mOS was 29.7 mo for the entire population. P were treated with a median of 2 therapeutic strategies after the rTKI failure. 6 therapeutic strategies have been identified. As immediate approach, 16 p were switched to chemotherapy (CT) with a mPPS of 3 mo. 9 p were switched to an irreversible TKI obtaining a mPPS of 3.9 mo. rTKI plus other drug was maintained in 11 p: rTKI plus CT in 9 p with a mPPS of 4 mo and rTKI plus other drug different to CT in 2 with a mPPS of 2 mo. Despite the progression, rTKI was maintained in 2 p considered slow progressors and local therapy, in addition to the rTKI, was administered in 3 p with oligoM1progressive disease obtaining a mPPS of 1.4 and 36 mo, respectively. 8 p were treated sequentially with ≥5 strategies. These p attained a mOS of 27.7 mo. Conclusions: The combination of different strategies when treating EGFR mut p after rTKI failure may impact the survival especially when p are candidates to receive some of this treatments sequentially. These strategies may reflect different subsets of EGFR mut disease.
Efficacy study of metronomic chemotherapy in metastatic NSCLC.
Authors: Srinivas B. J. , Radheshyam Nayak , Gunasagar C. , Govind Eriat , Vidya Veldore H. , Raghavendra Rao M. , Kamat Mangesh , Siddartha Roy
Published: March 2020

e19092

Background: Metastatic lung cancer patients are at best treated palliatively. We evaluated the effects of metronomic chemotherapy on survival outcomes in this population. Methods: Thirty four subjects with treatment refractory (n=26) and treatment naive (n=7) metastatic lung cancer were included in a open label single arm efficacy study of metronomic chemotherapy. Patients were given a chemotherapy regimen of Tab. Cyclophsophamide 50 mg once daily and cap. etoposide 50 mg once daily, 3 weeks on and one week off in 28 day cycle over a minimum period of 3 months or until the progression of their disease whichever was earlier. Patients were assessed for treatment response using RECIST criteria (version 1.1) and duration of progression free survival and overall survival. Data were analysed using Kaplan Meier survival analysis. Results: The mean age of the study population was 63.4 ±11.2 years. The mean duration of metronomic chemotherapy was 94.9 ±60.4 days. Overall 64.7% had progressive disease and 26.5% had stable disease. There was a significant improvement in overall survival in those with ECOG performance status of 1 compared to ECOG status of 2 (median survival =240 vs.52 days, Log Rank Mantel Cox =11.32, p=0.001) and pathology grade 2 compared to grade 3 (median survival =200 vs. 37 days, Breslows Wilcoxon =5.76, p=0.02) and stable disease on RECIST compared to progressive disease following metronomic chemotherapy (Median survival =360 vs. 50 days, Log Rank Mantel Cox =8.68, p=0.003). There was also a significant improvement in progression free survival in those with ECOG performance status of 1 compared to ECOG status of 2 (median survival =98 vs. 52 days, Log Rank Mantel Cox =6.62, p=0.001) and in grade 2 compared to grade 3 disease (mean survival =97 vs.32 days, Log Rank Mantel Cox =4.73, p=0.03). Tumor load and multiple organ sites of disease did not seem to influence survival. Conclusions: The results suggest stable response in about one third of study population, favorable progression free and overall survival rates following metronomic chemotherapy. Performance status is important predictors in this category of population.
EML4-ALK mutation in Austrian patients with NSCLC: A multicenter study.
Authors: Hochmair Maximilian J. , Setinek Ulrike , Efstathiades Thomas , Kirchbacher Klaus , Mohn-Staudner Andrea , Arns Britt-Madeleine , Gulesserian Melina , Dworan Nina , Breyer Marie , Patocka Kurt , Burghuber Otto
Published: March 2020

e19093

Background: EML4 (echinoderm microtubule-associated protein-like 4) - ALK (anaplastic lymphoma kinase) fusion-type tyrosine kinase, an oncoprotein found in a subgroup of non-small-cell lung cancer (NSCLC) predicts the response to ALK inhibitors. In general, AML4-ALK mutation is found in 2 to 7% of Caucasian patients with NSCLC and occurs more often in never and former smokers, adenocarcinomas, and younger, male patients. However, the frequency of EML4-ALK mutation in Austrian patients with NSCLC is unknown. The aim of the study was to evaluate the prevalence of EML4-ALK mutation in Austrian patients with NSCLC. Methods: From September 2011 to October 2012 tumour tissue from bronchoscopy, CT- and ultrasound guided biopsies and surgical specimen with histological type of adenocarcinoma and NSCLC NOS (Not Otherwise Specified) excluding squamous cell carcinoma, large cell carcinoma and neuroendocrine carcinoma were analysed for EML4-ALK mutations from 4 hospitals in Austria with high expertise in the management of lung cancer. Mutation detection was performed with a two-step procedure. First an immunhistochemical staining was done (ALK confirm/Ventana) and further on positive cases were tested by ALK FISH (dual colour breakapart FISH/Abbott Vysis). Results: In total 639 patients were analysed. EML4-ALK positive immunohistochemical staining was found in 35 patients (5,48%). 14 of these patients (2,19%) showed positive ALK FISH analysis. Conclusions: Frequency of EML-ALK mutations in Austrian patients with NSCLC was similar to other Caucasian peers.
Antimetastatic activity of ganetespib: Preclinical studies and assessment of progressions due to new lesions in the GALAXY-1 NSCLC trial.
Authors: Proia David A , Nagai Masazumi , Jimenez John-Paul , Zhang Chaohua , Sang Jim , Guo Wei , Beebe Kristin , Lee Min-Jung , Sequeira Manuel , Smith Donald , Acquaviva Jaime , He Suqin , Trepel Jane B. , Neckers Len , Bahcall Safi R. , Vukovic Vojislav M.
Published: March 2020

e19097

Background: Heat shock protein 90 (Hsp90) maintains the stability and activity of numerous signaling proteins involved in metastasis including FAK (tumor cell adhesion), MET and MMP9 (cell motility), VEGFR and PDGFR (angiogenesis), and HIF-1α (metabolism, proliferation, motility, angiogenesis). In the GALAXY–1 trial in advanced non-small cell lung cancer (NSCLC) patients, docetaxel (D) plus ganetespib (G), an Hsp90 inhibitor, showed encouraging improvement in overall survival compared to D alone. We evaluated the antimetastatic activity of ganetespib in preclinical models, and compared radiological disease progression due to new lesion formation in the two arms of the GALAXY–1 trial. Methods: Effects of ganetespib were investigated on the: (1) migration of cancer cells under normoxic and hypoxic conditions via scratch assay, (2) expression of metastatic signaling factors using immunoblotting and reverse phase array, (3) architecture of NSCLC tumor xenografts including micro-vasculature, hypoxia, and apoptosis by immunostaining, and (4) metastasis to the lung in both tail vein and orthotopic breast cancer in vivo mouse models. In the GALAXY–1 trial, development of new metastatic lesions was evaluated using serial computed tomography scans. Results: In vitro, ganetespib blocked the migration of cancer cells and reduced the expression of key drivers of metastasis including P-AKT, FAK, HER2, IGF-1R, MET, HIF-1α, and VEGF. In vivo, ganetespib significantly reduced tumor angiogenesis and proliferation. In patients, in the population in the GALAXY–1 trial that exhibited the strongest survival improvement (diagnosis of advanced disease >6 months, N=175), radiologic progressions due to new lesion formation were 19 (50%) vs. 5 (17%), for D vs. D+G, respectively, at time of abstract submission. Updated results will be presented. Conclusions: Ganetespib inhibits multiple processes involved in tumor metastasis. Preliminary data from the GALAXY–1 study support reduced frequency of progression due to new metastatic lesion formation in advanced NSCLC patients treated with ganetespib.
Retrospective analysis of the clinicopathologic profile of ALK-positive patients in the south of Spain.
Authors: Gonzalez de la Peña Miriam , Biscuola Michele , Sanchez Gastaldo Amparo , Alonso Miriam , Gomez Izquierdo Lourdes , Corral Jesus
Published: March 2020

e19105

Background: The anaplastic lymphoma kinase (ALK) fusion gene is a key oncogenic driver in a subset of patients with advanced non small cell lung cancer (NSCLC). ALK rearragement is detected in 2-7% of NSCLC patients. Fluorescence in situ hybridization (FISH) is the recommended method of detection. The clinical features of lung cancer that harbors ALK include light- or never-smokers, younger age, adenocarcinomas with acinar pattern or signet ring adenocarcinoma, and a lack of EGFR or KRASmutations. Crizotinib has shown an important benefit in terms of overall response rate (ORR) and progression free survival (PFS) in the 2nd/3rd line setting. Treatment related adverse events include gastrointestinal and visual disorders. Methods: Retrospective analysis of the clinico-pathological profile of ALK NSCLC patients between May 2011 and December 2012 in our region. Results: 10 cases (6,7%) were identified from 150 screened patients with adenocarcinoma histology and EGFR wild-type status. 7 (70%) patients were women. Median age at diagnosis was 62 years old (36-77). 9 (90%) patients were light-or-never smokers. All tumors were adenocarcinomas with EGFR wild-type status: Acinar growth pattern was detected in 4 cases (40%); 4 (40%) patients showed mucous cells and previous described signet-ring cells were detected in the last 2 (20%) cases. Only 5 (50%) patients received crizotinib therapy: 2 patients were treated during 1st line with partial response, 1 patient on 2nd line with stable disease and 2 patients received treatment in 3rdline with partial response. Only one patient required a dose reduction due to a grade 3 nausea and mucositis. Conclusions: Most of the patients with ALK rearragements in our serie have clinical and pathological characteristics to previously described. More women and older population were showed. In stead of the small sample size, pathological pattern based on acinar growth and mucous or signet-ring cells in adenocarcinomas with no EGFR mutation should guide the ALK screening. ORR and toxicity profile confirmed Crizotinib benefit as soon as ALK status was detected.