bluuebunny/crossref_metadata_2025 huggingface dataset:
Staging in multidisciplinary (MDC) v serial care (SC) lung cancer (LCa) patients (Pts).
Authors: Smeltzer Matthew , Faris Nicholas Ryan , Rugless Stewart Fedoria Elaine , Ray Meredith , Boateng Nana , Meadows Meghan Brooke , Foust Courtney , Jackson Bianca , Patel Anita , Fehnel Carrie , Houston-Harris Cheryl , Signore Raymond S , Robbins Edward T , Osarogiagbon Raymond U.
Published: September 2018

e20079

Background: Multi-modal staging is associated with improved survival for pts with LCa. We evaluated the thoroughness of clinical staging within and outside a co-located MDC. Methods: Prospective cohort study comparing newly-diagnosed LCa patients in MDC to serially referred (SC) pts within the same healthcare system. Pts were enrolled before treatment began. Stage-confirmation was defined as invasive biopsy of a stage-defining lesion. Bimodal staging involved use of either PET scan or invasive biopsy with CT scan, trimodal staging involved all 3. We used the chi-square test and multivariable logistic regression. Results: From 2014-16, 162 pts were enrolled into MDC, 318 into SC. MDC pts were older (median age 69 v 66), more likely to be black (37% v 29%), and less likely to be commercially insured (36% v 43%) than SC pts. MDC pts had node positive disease identified by PET/CT in 70% of cases, but only 42% in SC (p=0.003). MDC pts were more likely to be clinical M0 (70% vs. 55%). M1b pts were biopsied in 45% of MDC v 36% of SC cases. MDC pts were more likely to have bimodal (90% v 73%) and trimodal staging (51% v 29%) (both p<0.0001, Table 1). The stage-confirmation rate (OR: 1.93 [CI 1.32,2.84]); p=0.0007) and mediastinal stage confirmation rate (OR: 2.16[1.46,3.18]; p=0.0001) were both significantly higher in MDC (Table 1). Adjusting for age, gender, clinical N stage, and histology, these results remained significant (aOR=2.13, p=0.0003); (aOR=2.35, p<0.0001). A subgroup of SC patients (N=64) was discussed at a tumor board. This group had a stage confirmation rate (48%) and mediastinal stage confirmation rate (44%) intermediate between MDC and pure SC (p=0.007, p<0.0001). Conclusions: MDC effectively reached a higher percentage of underserved persons based on age, race, and insurance status, while providing significantly more thorough clinical staging. A tumor board alleviated, but did not eliminate, the gap. Clinical trial information: NCT02123797. [Table: see text]
Dual time PET-CT for mediastinal nodal staging in patients diagnosed with non-small cell lung cancer in an area with high prevalence of infectious granulomatous disease (LACOG-0114).
Authors: Hochhegger Bruno , Tsukazan Maria Teresa Ruiz , Bortolotto Vanessa Rezende , Vieira Arthur , Fritscher Carlos Cezar , Zanini Mara Lise , Berdichevski Eduardo Herz , Vilas Eduardo , da Silva Vinicius Duval , Pinto José Antônio Lopes de Figueiredo , Fritscher Leandro Genehr , Hartmann Louise , Alba Marcos , Schneider Airton , Debiasi Marcio , Zaffaroni Facundo , Martínez-Mesa Jeovany , Barrios Carlos H. , Werutsky Gustavo
Published: September 2018

e20083

Background: The role of dual-time-point PET/CT acquisition for mediastinal node staging in non-small cell lung cancer (NSCLC) is still controversial. Interpretation of PET/CT results is challenging in areas with high prevalence of infectious granulomatous diseases, whereas the use of dual-time PET/CT could reduce the false-positive results. This study aims to evaluate the performance of dual-time PET-CT for mediastinal node staging in patients with NSCLC in an area with high prevalence of infectious granulomatous diseases (i.e. 99 cases of tuberculosis per 100.000 habitants). Methods: Patients diagnosed with clinical stages I-III NSCLC performed dual-time-point PET/CT (images acquired in hour 1 and 2) followed by mediastinal lymph node biopsy. Different cut-offs for SUV were evaluated to test accuracy in each time-point. Results: One hundred patients were enrolled, of which 85 had mediastinal node biopsy after PET-CT. Median age was 65 years (range 47-80), 49 (58%) were male, 80 (94%) were current or former smokers, and 1 (1.2%) had history of tuberculosis. Dual-time-point acquisition results were similar to those in single-time-point (Table 1). The highest sensitivity (87%) and NPV (90%) was achieved when a cut-off SUV > 0 was used. Conclusions: Dual-time point PET/CT did not improve accuracy of PET/CT-based LN staging in NSCLC in an area with high prevalence of infectious granulomatous diseases. [Table: see text]
First experience with osimertinib in patients with T790M mutation previously treated with EGFR – TKIs in Croatia.
Authors: Jakopovic Marko , Bitar Lela , Cucevic Branka , Plestina Sanja , Mazuranic Ivica , Seiwerth Sven , Hecimovic Ana , Vukic Dugac Andrea , Jankovic Mateja , Redzepi Gzim , Samarzija Miroslav
Published: September 2018

e20518

Background: EGFR T790M mutation is responsible for around 60% cases of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in patients who have lung cancer with an activating EGFR mutation. Methods: We administered osimertinib 80 mg once daily in 8 patients with advanced lung cancer who had radiologically documented disease progression after previous treatment with first and second-line EGFR tyrosine kinase inhibitors. Results: We treated 8 patients with osimertinib with stage IV lung adenocarcinoma. Four patients were males and four were females, median age 62 (raging from 54 to 82). Four patients were never smoker, and four were ex-smokers. All patients had initially deletion 19 in EGFR gene and then developed T790M mutation. In all patients T790M was proven from tumor tissue. Majority of patients were ECOG 1. All patients were previously treated with first or second line EGFR TKIs (erlotinib, gefitinib or afatinib) and had radiologically documented disease progression. Three patients were treated with osimertinib in third line setting, 2 in fourth, one in fifth, one in sixth and one even in tenth line setting. Median time to response was 4 weeks (raging from 3 to 7). All 8 patients had partial response (PR) with still no recorded disease progression. Duration of response is from 7 to 46 weeks and still ongoing. No significant side effects were observed. Conclusions: Osimertinib is highly active in patients with lung adenocarcinoma which harbor EGFR T790M mutation who had had disease progression during prior therapy with EGFR tyrosine kinase inhibitors. There were no serious side effects of treatment.
Programmed cell death receptor ligand 1 (PD-L1) expression: Epidermal growth factor receptor (EGFR) and Kirsten RAS (KRAS) mutations in second-line therapy (2L) non-small cell lung cancer (NSCLC) patients—A Danish cohort study.
Authors: Cronin-Fenton Deirdre , Dalvi Tapashi , Hedgeman Elizabeth , Nørgaard Mette , Pedersen Lars , Hansen Hanh , Fryzek Jon , Lawrence David , Walker Jill , Mellemgaard Anders , Rasmussen Torben Riis , Shire Norah , Rigas James R. , Potter Danielle , Hamilton-Dutoit Stephen , Sørensen Henrik Toft
Published: September 2018

e20523

Background: In NSCLC patients who received 2L therapy, we examined the association of PD-L1 expression, mutations in KRAS and EGFR and survival. Methods: 2L NSCLC patients diagnosed during 2001-2012 and with sufficient archival tumour tissue were selected from the Danish Lung Cancer Group Registry. We retrieved patient data from population-based medical registries, and paraffin-embedded tumor tissue from pathology archives. We assessed PD-L1 expression using the Ventana IHC (SP263) validated assay (using 25% cutoff for positivity), and genotyped KRAS and EGFR via PCR-based kits. Follow-up was from the start of 2L therapy to death, emigration, or 31/12/2014. We used Cox regression to compute hazard ratios (HR) and associated 95% confidence intervals (95%CI) for PD-L1, EGFR and KRAS. Results: Among 368 patients, 204 (55%) were men, 250 (68%) were aged >60 years at diagnosis, and 95% were ever-smokers. 233 (63%) had adenocarcinoma, 90 (24%) had PD-L1 positive tumors, 28 (8%) had EGFR mutations, and 113 (31%) had KRAS mutations. In the PD-L1 positive tumors, 7% had EGFR and 37% KRAS mutations, respectively. In the PD-L1 negative tumors, 9% had EGFR and 32% KRAS mutations, respectively. Patients with KRAS mutations had shorter survival compared with wild-type patients. Survival was longer for patients with EGFR mutations compared with wildtype patients. PD-L1 expression did not correlate with survival (Table). Conclusions: Our findings suggest that EGFR and KRAS mutations, but not PD-L1 expression, correlate with survival in 2L NSCLC patients. [Table: see text]
Outcome of KRAS mutated (m) non-small cell lung cancer (NSCLC) patients (pts) treated with immune checkpoint inhibitors (immuneCI).
Authors: Pardo Aranda Nuria , Viaplana Cristina , Remon Jordi , Martinez Marti Alex , Cedres Perez Susana , Navarro Alejandro , Martinez de Castro Ana Maria , Villacampa Guillermo , Carbonell LLuisa , Hernando Alberto , Vivancos Ana , Dienstmann Rodrigo , Felip Enriqueta
Published: September 2018

e20526

Background: The most frequent genetic alteration in advanced NSCLC is KRASm in ~25% of tumors. This event associates with smoking pattern and high mutational burden, which correlate with the efficacy of CI in NSCLC. There is in silico evidence that coexisting KRASm and TP53m positively impact immuneCI benefit , but this association needs clinical validation. Methods: We retrospectively assess the efficacy of PD-1/PDL-1 CI (atezolizumab, pembrolizumab, nivolumab or durvalumab) in a cohort of NSCLC patients whose tumors were KRASm (with or without coexisting TP53m) as assessed by a next-generation sequencing test. Endpoints were clinical benefit rate (CBR), defined as partial response or stable disease > 4 months (m), and time to progression (TTP) on immuneCI. Fisher-exact test and log-rank test P values are described. Results: 25 pacients were identified, 68% female, median age 54 y (33-75), 95% former/current smoker; 95% adenocarcinoma; 59% with 2 or more metastatic sites; 36% immuneCI as third-line or beyond (median time from first-line to immuneCI of 7.5 m). 20 tumors had KRASm in codon 12, 3 codon 13 and 2 in codon 61. Overall, CBR was 36% (CI95% 19%-57%) and median TTP was 3.7 m (CI95% 2.2-NA). Coexisting KRASm/ TP53m (n = 11) did not associate with higher CB (27% vs 50%, p = 0.56). A trend for lower TTP in the KRASm/ TP53m vs TP53 wild-type was observed (2.1 vs 5.6 m, HR 0.3; p = 0.11). Conclusions: NSCLC patients whose tumors are KRASm can have substantial benefit with immuneCI. In our series, the population with KRASm/ TP53m tumors did not derive higher clinical benefit from this therapeutic intervention
Apatinib plus icotinib in treating advanced non-small-cell lung cancer after icotinib treatment failure.
Authors: Xu Jianping , Liu Xiaoyan , Yang Sheng , Zhang Xiangru , Shi Yuankai
Published: September 2018

e20528

Background: Icotinib, a small-molecule EGFR TKI, has been approved as the first-line therapy for treating advanced non-small-cell lung cancer (NSCLC) in China. However, treatment failures frequently occurred in NSCLC patients with EGFR-sensitizing mutations. A phase II clinical trial has reported the beneficial survival of apatinib, a new small-molecular VEGFR TKI, in treating NSCLC (Zhang et al. 2012 ASCO, 7548). This retrospective study tried to investigate the efficacy and safety of apatinib plus icotinib as second- or third-line treatment in patients with advanced NSCLC. Methods: This study comprised 27 patients diagnosed with advanced NSCLC and treated with icotinib and apatinib as the second- or third-line therapy. Patients received oral icotinib (125 mg, tid), alone initially. When disease progressed, they received icotinib plus apatinib (500 mg, qd, orally). Treatment was continued until disease progression or unacceptable toxic effects. Efficacy was evaluated based on RECIST version 1.0 and toxic effects were assessed using the NCI-CTC version 2.0. Results: Followed up to December, 2016, the median time of apatinib treatment was 7.47 months, and 8 of 27 patients were dead. The median overall survival had not reached and the median progression-free survival (PFS) was 5.33 months (95% CI 3.63-7.03 months). Moreover, the objective response rate (ORR) was 11.1% and the disease control rate (DCR) was 81.5%. Fourteen patients received icotinib and apatinib as the second-line treatment, and the RR and DCR were 7.1% and 78.6%. The remaining 13 patients received drugs as the third-line treatment, with an ORR and a DCR of 15.4% and 84.6%. Additionally, 11 patients experienced icotinib monotherapy failure within 6 months with median PFS of 7.37 months (95% CI 4.17-8.57 months) and 16 patients experienced icotinib monotherapy failure after 6 months with median PFS of 2.60 months (95% CI 0.00-8.54 months). The common drug-related toxic effects included hypertension (44.4%), fatigue (37.0%) and hand-foot syndromes (18.5%). Conclusions: Apatinib plus icotinib is efficacious in treating patients with advanced NSCLC after icotinib treatment failure, with acceptable toxic effects.
Radiographic features of metastatic brain tumors from non-small cell lung cancer with ALK rearrangement.
Authors: Chu Li , Li Ruimin , Yang Xi , Xia Fan , Zhu Zhengfei
Published: September 2018

e20533

Background: Approximately 5% of Non-Small Cell Lung Cancer (NSCLCs) have ALK rearrangement, in which brain metastases are common. The radiographic features of metastatic brain tumors have not been previously studied. Finding the features of brain metastasis could help establishing the treatment pattern for the ALK-rearranged NSCLC patients. Methods: All NSCLC patients with ALK rearrangement (132 patients) were detected from March 2008 through December 2016. The metastatic brain tumors (34 patients) detected from July 2014 through December 2016 were divided into metachronous brain metastasis (MBM) and synchronous brain metastasis (SBM) groups according to the diagnosis time. All patients were followed up using brain magnetic resonance imaging (MRI). The number of brain tumors, size of the largest brain tumors, and size of peritumoral brain edema were compared between the two groups. Results: Thirty-four patients were observed.The number of brain tumors in ALK-rearranged NSCLC patients is 4.6 with 41.07mm Peritumoral Brain Edema Size (PBES). Only one patient has the military brain metastases. All patients were divided into two groups: metachronous (15 patients) and synchronous (19 patients). The two groups had rare active and former smoker. The SBM group had more female patients. The SBM group had larger number of brain tumors (6.1 VS 2.8), but there was no significant difference ( P= 0.0672). The MBM group had smaller brain tumors (14.2mm vs 20.9mm, P= 0.0798) with smaller PBES (25.7mm vs 53.2mm, P= 0.0018) and Peritumoral Brain Edema Index (PBEI) (0.9 vs 1.9, P= 0.0201) than the SBM group. Conclusions: Only one patient in SBM group has the military brain metastases. The SBM group has larger brain tumors with larger peritumoral brain edema and PBEI. The MBM patients have smaller ones. Our studies show that ALK-rearranged NSCLC patients have a small number brain tumors and relatively large PBES.
Combination of anti-PD-1/PD-L1 antibodies with chemotherapy or CTL4 antibodies for first-line treatment of advanced lung cancer.
Authors: Fan Yun , Xu Xiaoling
Published: September 2018

e20538

Background: Checkpoint inhibitors showed satisfactory efficacy in treating lung cancer. We conducted this meta-analysis to explore the therapeutic efficacy and safety of anti-PD-1/PD-L1 antibodies combine with chemotherapy or CTL4 antibodies as first-line treatment on advanced lung cancer. Methods: A quantitative meta-analysis was performed through a systematic search in PubMed, Web of Science, the conference abstracts and so on. The pooled ORR, 6-month progression-free survival rate (PFSR6m), and 1-year overall survival rate (OSR1y) were calculated and compared. 9 trials were included in this meta-analysis. Results: Our analyses demonstrated the pooled ORR and DCR of anti-PD-1/PD-L1 antibodies combine with chemotherapy for non-small-cell lung cancer were 48.0% (40.2–56.0 %) and 84.8 % (78.1– 89.7%), respectively. The pooled OR and DCR of anti-PD-1/PD-L1 antibodies combine with chemotherapy for small-cell lung cancer were 42.9% (18.5–71.2 %) and 73.6 % (32.8–94.1%), respectively. The pooled PFSR6m of anti-PD-1/PD-L1 antibodies combine with chemotherapy for NSCLC and SCLC were 62.9% (46.3–79.6%) and 27.6 % (18.9–36.2 %), respectively. The OSR1y of anti-PD-1/PD-L1 antibodies combine with chemotherapy for NSCLC and SCLC were 70.1 % (57.4%-82.8 %) and 32.0 % (25.2–38.9 %). In addition, the pooled ORR and DCR for anti-PD-1/PD-L1 antibodies plus CTL4 antibodies treatment group was 29.6% (11.4%-657.8%) and 48.7% (16.8%-81.7%), respectively. Conclusions: Anti-PD-1/PD-L1 antibody plus chemotherapy can serve as a promising treatment option for lung cancer. While patients treated anti-PD-1/PD-L1 antibodies plus CTL4 antibodies may benefit less compare with anti-PD-1/PD-L1 antibodies combine with chemotherapy. Encouraging activity with tolerable adverse effect was observed.
Long-term clinical outcomes of ALK inhibitors in patients with ALK-positive advanced non-small cell lung cancer.
Authors: Murakami Haruyasu , Ono Akira , Nakashima Kazuhisa , Omori Shota , Wakuda Kazushige , Kenmotsu Hirotsugu , Naito Tateaki , Takahashi Toshiaki
Published: September 2018

e20542

Background: Anaplastic lymphoma kinase (ALK) inhibitors show high clinical efficacy in patients with ALK-positive advanced non-small cell lung cancer (NSCLC). However, the long-term clinical outcomes remain unknown. Methods: We retrospectively reviewed medical records of patients with ALK inhibitor-naïve ALK-positive advanced NSCLC who initiated alectinib or crizotinib therapy at the Shizuoka Cancer Center between June 2010 and December 2011. Results: This retrospective study included 14 patients (male/female, 5/9; PS 0/1, 6/8; adenocarcinoma/adenosquamous carcinoma, 13/1; smoker/never smoker, 8/6; brain metastasis presence/absence, 5/9; number of prior chemotherapy regimens 0/1/≥2, 1/7/6; alectinib/crizotinib, 4/10) with a median age of 55 years (range, 28-71). At the data cut-off (January 16, 2017), three patients were still receiving first ALK inhibitors (alectinib in two patients and crizotinib in one). One patient requested the discontinuation of alectinib therapy after five years. One patient discontinued crizotinib therapy due to unacceptable toxicity. Nine patients discontinued first ALK inhibitors due to disease progression. The overall response rate was 78.6% with complete response in two patients (14.3%), partial response in nine (64.3%), stable disease in one (7.1%), and progressive disease in two (14.3%). The median progression-free survival (PFS) for all 14 patients was 15.3 months, and the five-year PFS rate was 35.7%. The five-year PFS rates in patients treated with alectinib and crizotinib were 75.0% and 20.0%, respectively. The median overall survival (OS) for all 14 patients was 36.8 months, and the five-year OS rate was 42.9%. The five-year OS rates in patients treated with alectinib and crizotinib were 75.0% and 30.0%, respectively. Conclusions: ALK inhibitors showed favorable long-term clinical outcomes in patients with ALK inhibitor-naïve ALK-positive advanced NSCLC, especially in patients treated with alectinib.
Real-life use of nivolumab in non-small cell lung cancer: A multicentric cohort to determine its clinical efficacy and predictive factors of early progression.
Authors: Corny Jennifer , Costantini Adrien , Renet Sophie , Fallet Vincent , Jouveshomme Stephane , Giroux Leprieur Etienne , Duchemann Boris , Selvarathnam Shobanya , Beaussier Hélène , Brosseau Solenn , Hajouiji Linda , Taillade Laurent , Doucet Ludovic , Zalcman Gerard , Friard Sylvie , Tredaniel Jean , Wislez Marie , Jardin Meryam , Cadranel Jacques
Published: September 2018

e20543

Background: Nivolumab (NIV) is now widely used in ≥ 2ndline of advanced non-small cell lung cancer (NSCLC). The aims of this real-life study were (1) to evaluate its efficacy, (2) to identify predictive factors of worsening under NIV. Methods: This retrospective multicentric study (8 Thoracic Oncology regional centers) included all patients treated by NIV in 2015 (follow-up until 2016, June 30th). Demographics and tumor characteristics were extracted. Objective tumor response was assessed by computerized tomography (RECIST v1.1). Median NIV treatment duration and overall survival (OS) were calculated. Clinical and biological factors evaluated as predictive markers of earlyprogression (discontinuation before 1stevaluation) were: NSCLC histology, PS, smoking-history, number of previous chemotherapy received and initial albumine (alb), C-reactive protein (CRP) and lactate dehydrogenase (LDH) serum levels. For these factors, patients quickly worsened and responders were compared (Student’s t-test, Chi-2 test). Results: Our cohort included 297 patients (non-squamous NSCLC n = 181 [61%]; PS > 1 n = 66 [22%]). At first evaluation, partial response was observed in 16% (n = 47), stable disease in 18% (n = 54) and progression in 49% (n = 144). A total of 45 patients (15%) were early progressors and no evaluation could be performed. Median NIV duration of treatment was 2.8 months [0-15], OS 6.9 months [0-16] (n = 146 still alive on June 30th, 2016). Early progressor patients were PS > 1 in 42% versus (vs) 21% for responders (mean PS 1.7 vs 1.0 for responders (p < 0.001)) and an alb level of 29.9 g/L vs 33.6 (p = 0.03). Mean CRP (p = 0.06) and LDH (p = 0.08) serum levels, NSCLC histology (p = 0.64), smoking-history (p = 0.08), number of previous chemotherapy (p = 0.90) were non-significant. Conclusions: This study confirms that NIV may be effective in NSCLC, with a 16% objective response rate. However early progression observed in 15% of patients was associated with a lower initial alb level and a higher PS. Missing data for LDH and CRP levels may have influenced their non-significance. Further studies must be realized to determine the interest of these factors as predictive markers.
Impact of early progression on prognosis for non-small cell lung cancer patients with EGFR mutation.
Authors: Yoshitsugu Kanako , Kenmotsu Hirotsugu , Omae Katsuhiro , Omori Shota , Nakashima Kazuhisa , Wakuda Kazushige , Ono Akira , Naito Tateaki , Murakami Haruyasu , Takahashi Toshiaki
Published: September 2018

e20570

Background: For epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) patients, EGFR-tyrosine kinase inhibitors (TKIs) improve progression free survival compared with cytotoxic chemotherapy. However, some patients show early progression (EP) in first-line EGFR-TKI treatment, and their prognosis is still unclear. This study aimed to examine the implications of EP for prognosis of EGFR mutant NSCLC patients. Methods: Advanced EGFR mutant NSCLC patients treated with gefitinib (GEF) as first-line between 2005 and 2015 at Shizuoka Cancer Center were retrospectively reviewed. EP on GEF was defined as disease progression before 180 days according to the Jackman criteria. Results: Forty-five of 198 patients treated with GEF as first-line, showed EP. Patient characteristics was as follows (with EP/ without EP) : median age (range), 69 (32-88)/ 70 (35-92) years; male, 40/ 28%; ECOG performance status (PS) 0-1, 64/ 79%; deletion in exon 19 (del 19), 36/ 53%; L858R in exon 21, 53/ 43%; never smoker, 44/ 65%; liver metastasis, 27/ 12%; brain metastasis, 44/ 37%. The median overall survival was 395 days (95% CI: 267-547 days) for patients with EP and 979 days (95% CI: 808-1124 days) for those without EP. Post progression survival after treatment with GEF was significantly shorter in patients with EP (median: 254 days vs. 420 days, HR: 0.55 (95% CI: 0.39-0.79), P < 0.05). Among patients with EP, 56% received subsequent chemotherapy (patients without EP: 71%). In univariate analysis, EP was significantly associated with four factors; liver metastasis, smoking history, PS 2-4, absence of del 19. In multivariate analysis, smoking history (OR: 0.38, 95% CI: 0.18-0.80), PS 2-4 (OR: 0.43, 95% CI: 0.19-0.98), and del 19 (OR: 2.15, 95% CI: 1.04-4.45) were significantly correlated (P < 0.05) with EP. Conclusions: Patients with EP during first-line GEF therapy for advanced EGFR mutant NSCLC showed poor prognosis. Since smokers, patients with PS 2-4, or absence of del 19 tend to show EP, improving first-line treatment is necessary to improve their prognosis.
Clinical profile, pathological characteristics, mutational profile and disease outcome of non-small cell lung cancer patients treated at the Benavides Cancer Institute-University of Santo Tomas Hospital : A five-year study.
Authors: Bautista Maria Diana Aileen Chua , Caguioa Priscilla B.
Published: September 2018

e20580

Background: Lung cancer is the most commonly diagnosed cancer worldwide and its incidence continues to grow. Lung cancer mortality and survival rates vary markedly by race and ethnicity resulting into a public health burden that differs by population subgroups. This study determined the association of the clinical profile, pathological characteristics and mutational profile with the disease outcome of Non Small Cell Lung Cancer patients at the Benavides Cancer Institute – University of Santo Tomas Hospital from January 1, 2007 to December 31, 2011. Methods: This is a retrospective descriptive study. Medical records of all of patients diagnosed with non-small cell lung cancer were included. Results: A total of 80 patients with non small cell lung cancer were treated, 78.75% (63) were adenocarcinoma and 13.75% (11) were squamous cell carcinoma. Overall 5-year survival rate was at 5%. The 1 year, 2-year, 3-year survival rates were 38.75%, 21.25% and 12.5% respectively with the mean survival time of 1.6 years. The mean survival time of patients who received adjuvant treatment was 26 months, while for metastatic patients was 18 months. Only the stage at time of diagnosis was correlated with overall survival. Age, gender, family history, smoking history, number of pack years smoking history, histologic subtype, response after first line of treatment and sites of metastases were not associated with overall survival. EGFR mutational analysis was not performed in this study since it was not the standard of care and had limited availability in low to middle income countries at the time of the study period. Conclusions: Similar to global incidence, adenocarcinoma remains the most common type of lung cancer in our center. Stage at diagnosis predicts overall survival among lung cancer patients. There is a need for molecular immunotyping to further characterize patients and response to treatment.
Association of KRAS mutations detected via liquid biopsy in metastatic non-small cell lung cancer patients with high levels of FDG-PET SUV.
Authors: Kim Seo-Hyun , Karo Ammar , Buckingham Lela , Basu Sanjib , Borgia Jeffrey Allen , Bonomi Philip , Batus Marta , Fidler Mary J.
Published: September 2018

e20594

Background: We had previously evaluated the relationship between FDG-PET SUV with TP53 and KRAS mutations in formalin fixed paraffin embedded tissue (FFPE) in non-small cell lung cancers (NSCLC) in which genomic profiling had been performed. Considering FDG-PET SUV as a surrogate of glycolysis, we found TP53 and KRAS mutations were associated with increased glycolytic activity. The aim for this study was to evaluate KRAS and TP53 in circulating tumor DNA (ctDNA) in relation to FDG-PET SUV in a different cohort of NSCLCs in which genomic profiling was performed on peripheral blood. Methods: All stage IV NSCLC patients with genomic analysis from ctDNA and baseline FDG-PET scans between December 2014 and November 2016 were included. Associations between KRAS and TP53 mutations and maximal standard uptake value (SUVmax) were assessed using the Mann-Whitney and Kruskal-Wallis test. A subset analysis studying all KRAS positive patients from FFPE and ctDNA was performed based on the specific KRAS mutation. Results:122 patients had FDG-PET scans and genomic analyses of their circulating tumor cells. 62 (51%) patients had a TP53 mutation, 20 (17%) patients had a KRAS mutation, and 13 (11%) patients had both TP53 and KRAS mutations. Patients with a KRAS mutation had a higher SUVmax with a mean of 12.32 (p = 0.019). The presence of TP53 alone or concurrent TP53/KRAS was not significantly related to SUVmax. Analyzing 48 patients with KRAS mutation from FFPE and ctDNA assay, 16 patients had mutations of G12C and 9 patients had G12V. The presence of the G12C mutation was particularly highly correlated with higher SUVmax with a mean of 17.68 (p = 0.0006). Conclusions: In analyzing ctDNA, a larger cohort, mutations in KRAS had the strongest correlation with increased SUVmax. Targeting glycolysis and cellular metabolism could be a potential therapeutic strategy for patients with KRAS mutations. Although individual numbers are small, KRAS subtype analysis showed the presence of the G12C mutation might have the strongest relationship with SUV max and increased glycolysis.
Expanded molecular routine testing for targetable mutations in non-small cell lung cancer to reveal frequent co-occuring mutations.
Authors: Kostenko Anna , Fassunke Jana , Steinhauser Susanne , Scheffler Matthias , Merkelbach-Bruse Sabine , Michels Sebastian Yves Friedrich , Fischer Rieke Nila , Nogova Lucia , Hellmich Martin , Zander Thomas , Buettner Reinhard , Wolf Juergen ,   For the Network Genomic Medicine
Published: September 2018

e20596

Background: Using next-gen sequencing of predefined gene panels in routine clinical diagnostics of lung cancer allows, in contrast to single-gene assays, assessment of co-occuring mutations, which might underly heterogeneity of response to targeted drugs and survival. The Network Genomic Medicine (NGM) performs high sensitive next generation sequencing (NGS) based routine molecular diagnostics on a central platform for about 5000 inoperable lung cancer patients (pts) annually in Germany. Methods: NGS panel used in NGM consists of 17 genes to cover potentially targetable aberrations. Mutation analyses were run on an Illumina (MySeq) platform, while FISH analyses were performed separately. In 2016, we have started the evaluation of all NGM pts with available clinical data who had received NGS-based molecular diagnostics. In particular, we have focused on non-squamous (non-sq) and squamous (sq) NSCLC pts with co-occurring mutations: their frequency, significance and impact on overall survival. Results: From 2014 molecular genotyping was performed for 7,893 NGM pts (n = 7,246 NSCLC (5,667 non-sq and 1,487 sq pts) and n = 489 SCLC) with eligible clinical data. Genetic alterations in transformation-associated pathways were found in 79 % of all NSCLC pts. Furthermore, co-occurring mutations were detected in 39 % of these pts: 40 % in non-sq and 37 % in sq NSCLC. 11 % of pts had more than 2 co-occurring mutations. 1 % of all pts had 5 co-occurring mutations. The most frequent paired mutations were KRAS, EGFR and MET each with TP53 in non-sq and FRGF1 and TP53 in sq NSCLC. The incidences and significance of 3, 4 and 5 co-mutations as well as the impact of these co-occurring mutations on overall survival will be presented. Conclusions: Frequent occurrence of co-occuring mutations in transformation – associated pathways underlines the genetic heterogeneity also of lung cancer with classical driver mutation and the impact of co-occurring mutations on survival. This work confirms the use of molecular multiplex testing in routine molecular diagnostics of NSCLC. Assessment of co-occuring mutations will help to further specify genetically defined subgroups of lung cancer with therapeutic relevance.
The utilization of pre-treatment neutrophil to lymphocyte ratio as a predictive marker for response to nivolumab therapy in non small cell lung cancer.
Authors: Preeshagul Isabel Ruth , Sullivan Kevin M. , Paul Doru , Seetharamu Nagashree
Published: September 2018

e20634

Background:The tumor immune environment is integral in lung cancer progression. Cancer cells attract neutrophils through chemokine signaling pathyways into the tumor stroma. Neutrophils promote angiogenesis, metastasis and inhibit apoptosis whereas lymphocytes assist with tumor defense. Increased peritumoral neutrophil-to-lymphocyte ratio (NLR) has been shown to mediate T cell anergy and tumor immune evasion. In solid tumor pre-clinical models, elevated blood NLR correlates with increased tumor neutrophil infiltration and decreased CD3(+) T-cell infiltration. Immunotherapy is a promising anticancer strategy in Non-Small Cell Lung Cancer (NSCLC). We hypothesized that peripheral blood NLR could serve as a predictive marker for clinical benefit (CB) from this intervention. Methods:A single institution retrospective analysis of 81 patients with NSCLC treated with Nivolumab from July 2015 to November 2016. Each patient’s NLR was calculated prior to starting Nivolumab. A cut-off of 5 categorized NLR as high or low based on prior studies. The presence or absence of CB (objective response or stable disease per RECIST 1.1) after at least 3 months of therapy was determined. Descriptive statistics were utilized to summarize the data. Fischer exact test was used to compare proportions and student t test to compare means. Results:79 patients were included. 54 (68%) had low NLR and 25 (31.6%) had high NLR. 44 patients (81.48%) in the low NLR group and 7 (28%) in the high NLR group experienced CB (28%) at 3 months. This difference was statistically significant (P = 0.0001). The mean time to progression(TTP) for the low NLR population was 5.53 months, as compared to 2.39 months in the high NLR group( p = 0.0001) (95% confidence interval 1.59 to 4.55).The mean TTP in the CB cohort was 6.42 months in the low NLR group and 4.43 months in the high NLR group (p = 0.0052 ) (95% CI 0.61 to 3.39). Conclusions:The immune response to cancer is lymphocyte dependent. In our study, the majority of patients with low NLR experienced CB from Nivolumab whereas most of the patients with elevated NLR did not. NLR as a predictive biomarker should be further investigated in large prospective studies.
Costs and values of the immune check point inhibitors antibodies in non-small cell lung cancer.
Authors: Guirgis Helmy M. , Langer Corey J.
Published: September 2018

e20644

Background: Costs (C) and values (V) of the check point inhibitors antibodies have not been compared. Our objectives were to weigh and compare C and V of Nivolumab (Nivo), Atezolizumab (Atezo) and Pembrolizumab (Pembro) vs. Docetaxel (Doc) in 2nd-line non-small-cell lung cancer (NSCLC). Methods: Median overall survival gain over control (OS), hazard ratios (HR), doses and prices posted by parent companies were quoted. Probability of survival (PoS) was calculated as (1.0- HR). Values were computed at 4-week (w) as 4wC/PoS and one-year as C/life-year gain (LYG). Results: Doc OS was 72 days, HR not reported, generic 4wC < $500 and C/LYG 26,896. In comparison, in non-enriched non-squamous (sq-) Nivo C/LYG was 558,313, Atezo 618,244, Pembro 659,059. Nivo OS was 84, HR 0.73, 4wC $10,021 and 4wV 37,115 improving in > 10% PD-L1 positive to OS 264, HR 0.27 and 4wV 13,727. Atezo OS was 87, HR 0.73, 4wC $11,493 and 4wV 42,567 improving in medium- high PD-L1 to 150, 0.46 and 4wV 21,283 respectively. Pembro demonstrated OS 57, HR 0.71, 4wC $8,027 and 4wV 27,679 improving in > 50% PD-L1 to 201, 0.54 and 4wV 17,450. Conclusions: Doc, without accounting for adverse events and quality of life, remains a valuable drug in 2nd-line NSCLC. In PD-L1- enriched non-sq, Nivo, Atezo and Pembro consistently demonstrated marked V improvement to justify their C. The limited available data and the inherent problems of drug comparison preclude favoring one ICPIA over another. References: Doc: Shepherd FA et al. JCO 18:2095, 2000; Nivo: Checkmate 057, Brahmer JN et al. NEJM 373: 123, 2015; Atezo: POPLAR; Pembro: KEYNOTE-010.
MET exon 14 mutations in advanced lung adenocarcinoma: Frequency and coexisting alterations.
Authors: Bruno Rossella , Lupi Cristiana , Landi Lorenza , Alì Greta , Sensi Elisa , Proietti Agnese , Giannini Riccardo , Condello Vincenzo , Denaro Maria , Giordano Mirella , Macerola Elisabetta , Poma Anello Marcello , Nuti Simona , Niccoli Cristina , Pelliccioni Serena , Tiseo Marcello , Cappuzzo Federico , Fontanini Gabriella
Published: September 2018

e20656

Background: In lung cancer the evaluation of MET, a tyrosine kinase receptor involved in tumor growth and invasiveness, for copy number amplification and point mutations is relevant for prognosis and therapy. In lung adenocarcinoma (ADC) MET amplification is observed in 1-2% and MET mutations in 3-4% of cases. Mutations mainly occur in exon 14 (ex14), which encodes for the juxtamembrane negative regulatory domain, including splice site alterations and missense mutations within the exon.Commonly, MET ex14 alterations, in particular splice site ones, are mutually exclusive with other driver mutations, but co-occurrence with MET and MDM2 amplification and KRAS mutations was described. We evaluated METex14 mutation frequency and coexistence with additional driver alterations in a prospective cohort of Italian ADC patients. Methods: 315 ADC patients were tested (January-December 2016) for MET ex14 alterations by Sanger Sequencing on formalin-fixed paraffin-embedded tissues and cytological smears (tumor cells > 40%). MET positive cases were screened also for other oncogenes, among which KRAS, BRAF and PIK3CA, using a MALDI-TOF platform, and for ROS1 translocations and MET amplification by FISH. Results: 16 patients (5%) were MET positive: 7 splice site mutations (43%) and 9 (57%) other alterations within ex14. Among splice site mutations 1 co-occurred with ROS1 translocation and 1 with MET amplification. Among other mutations we found 5 T1010I missense mutations: 3 co-occurring with G12D/G13C/Q61H KRAS, 1 with G469A BRAF and 1 with a MET intron 13 point mutation; 2 R988C mutations: 1 with G13C KRAS and 1 with G13C KRAS plus ROS1 translocation; 1 P1026S mutation and 1 frameshift deletion (p.A991del;R992fs*999), both with G12C KRAS. Conclusions: Splice site mutations cause MET activation by exon skipping and increase sensitivity to tyrosine-kinase inhibitors, whereas how other ex14 mutations affect MET function is not fully understood. In our cohort we found a high rate of METex14 mutations together with alterations in other oncogenes, mostly KRAS. The interaction of MET with cancer signaling pathways deserve further investigation in order to better define the role of ex14 mutations in the context of target therapy.
Advancing evidence-based decisions in the management of EGFR-mutated metastatic NSCLC.
Authors: Herrmann Tara , Warters Martin , Blevins Douglas , Fidias Panos
Published: September 2018

e20663

Background: In patients diagnosed with metastatic NSCLC it is now essential to identify targetable mutations and markers of treatment resistance in order to determine the appropriate therapy. A study was conducted to determine if simulation-based educational interventions to address clinical practice gaps could improve decisions of oncologists in the management of EGFR-mutated metastatic NSCLC. Methods: A cohort of US-oncologists who participated in a virtual patient simulation (VPS)-based education was evaluated. The VPS consisted of 2 cases that allowed oncologists to assess the patient and choose from a database of diagnostic possibilities matching the scope and depth of practice. Clinical decisions were analyzed using a decision engine, and instantaneous clinical guidance (CG) employing current evidence-based and expert faculty recommendations was provided after each decision. Oncologists were allowed a second chance at each decision point and decisions before and after CG were compared using a 2-tailed paired T-test to determine differences from pre- to post CG. P values are shown as a measure of significance; with P < .05 statistically significant. Results: 197 oncologists made clinical decisions within the simulation. As a result of CG, significant improvements were observed in: Ordering EGFR mutational testing (16%, P= 0.008) and making an accurate diagnosis (36%) Selecting an EGFR TKI in the first-line setting (24%, P< 0.001) Ordering a PET scan to assess disease progression (10%) and in diagnosing patients with EGFR T790M disease that is resistant (29% , P< 0.001) Evidence-based treatment selection for individuals whose disease progressed on first-line therapy (19%, P= .003) Number of oncologists who ordered adverse event education and counseling (23%, P< .001) Conclusions: This study showed improvements in evidence-based practices of oncologists in the diagnosis and management of EGFR-mutated NSCLC; demonstrating that VPS-based instruction that immerses and engages oncologists for an authentic, practical and16. consequence-free learning experience can result in an increase in appropriate clinical decisions. Therefore, VPS may have a role in improving the quality of patient care.
LungMATCH: Rates of molecular testing in the lung cancer community.
Authors: King Jennifer C. , Ciupek Andrew , Perloff Tara , Blanchard Ashley , Mason Kimberly , Blais Edik , Bender R Joseph , Halverson David , Madhavan Subha , Petricoin Emanuel
Published: September 2018

e20671

Background: For metastatic non-small cell lung cancer (NSCLC), guidelines include molecular testing for actionable biomarkers and recommend broad profile testing. Yet previous studies indicate that not all patients with NSCLC receive testing, even for actionable mutations in EGFR, ALK, and ROS. We hypothesized low testing rates for patients calling a community HelpLine and that we could increase rates with one-on-one caller education and free precision medicine services. Methods: Caller statistics were collected on the toll-free Lung Cancer Alliance (LCA) HelpLine from Sept 1, 2016 – Jan 31, 2017. Recruitment to the LungMATCH molecular testing program began Nov 10, 2017. Patients are recruited through conversations on the LCA HelpLine, then consented into Perthera Cancer Analysis (PCA) through an IRB-approved registry protocol. PCA includes tissue acquisition, multi-omic molecular profiling, and medical review of testing results and clinical and treatment history. PCA reports are returned to both treating physicians and patients. Data is being collected longitudinally on treatment decisions, patient outcomes including progression-free and overall survival, and patient experience. Results: Data from the LCA Helpline identified a gap in molecular testing. 50% (57/115) of patients asked if they received any kind of molecular testing replied "No". Of 32 patients who were tested and knew the results, patients indicated potentially actionable changes in EGFR(15), ALK(8), PD-L1(3), RET, MET, BRAF, and HER2, along with KRAS (4). Since LungMATCH launch, 23 interested patients were referred for PCA. Six patients consented and are undergoing PCA with seven more in the consent process. Reasons for non-consent include: doctor refusal, initiation of testing at the treating institution, concern about financial implications, and one death. Updated results will be presented. Conclusions: Our data indicate that patients with lung cancer are not receiving molecular testing in accordance to guidelines. To address this, we created a program through nonprofit-corporate partnership that navigates patients and their physicians through comprehensive precision therapy. This type of program is feasible and there is patient interest.
Phase II trial of AZD1775 in combination with carboplatin and paclitaxel in stage IV squamous cell lung cancer (sqNSCLC): Preliminary results.
Authors: Gray Jhanelle Elaine , Tanvetyanon Tawee , Creelan Ben C. , Antonia Scott Joseph , Haura Eric B. , Williams Charles C. , Yaseen Raheel , Schell Michael J. , Godin Robert , Rix Uwe , Monteiro Alvaro
Published: September 2018

e20672

Background: WEE1, a dual serine/threonine and tyrosine kinase involved in regulation of the G2/M cell cycle checkpoint, is an essential component for proper DNA damage response. In combination with platinum agents, the inhibition of WEE1 is expected to lead to unstable DNA replication structures, inability to repair DNA damage, loss of G2/M arrest and ultimately mitotic catastrophe. In NSCLC cell lines, we previously demonstrated that cisplatin exhibited enhanced effects in combination with AZD1775 (a WEE1 inhibitor). This trial tests AZD1775 combined with a platinum doublet in patients with sqNSCLC. Methods: In this single-arm phase II trial, patients with stage IV sqNSCLC receive intravenous (IV) carboplatin AUC 5, IV paclitaxel 175 mg/m2, and oral AZD1775 225 mg twice/day for 2.5 days every 21 days for 4-6 cycles followed by maintenance AZD1775 at the same doses. Antiemetics prior to each dose of AZD1775 are mandatory. The primary endpoint is response rate per RECIST v1.1, with overall and progression-free survival as secondary endpoints. Archival tissue specimens are collected for correlative analyses of p53, PAXIP1, and WEE1. Results: Interim analysis of the 15 patients [3/15 (20%) female] enrolled through 11/2016 show 14/15 (93%) were ECOG 1, and 1/9/5 (7%/60%/33%) were never/former/current smokers. The most frequent adverse events of any grade were diarrhea (53%), nausea (40%), and vomiting (33%). The 2 most common grade 3-4 adverse events were neutropenia (13%) and fatigue (20%). No patients required treatment discontinuation due to toxicity. Of the 10 patients evaluable for response, 3 (30%) had confirmed partial responses (PR), 1 (10%) had unconfirmed PR, 5 (50%) had stable disease (SD), and 1 (10%) had progressive disease for a disease control rate of 90%. In those with SD, tumors regressed by -15%, -22%, -23%, -26% and -28% at first scan. Conclusions: AZD1775 combined with carboplatin and paclitaxel is tolerable and demonstrates promising activity in advanced sqNSCLC patients. Nausea and vomiting are manageable with antiemetics. The study continues to enroll. Correlative biomarker analyses of the tissue are planned. More mature data will be presented. Clinical trial information: NCT02513563.