Stereotactic Body Radiation Therapy Is Effective and Safe in Patients with Early-Stage Non-Small Cell Lung Cancer with Low Performance Status and Severe Comorbidity

Background: The purpose of this study was to assess stereotactic body radiation therapy (SBRT) results and toxicity for stage I non-small cell lung cancer patients with low performance status and severe comorbidity. Patients and Methods: From September 2008 to April 2010, 36 patients with 38 lesions were treated with hypofractionated SBRT. All except one were medically inoperable, had low performance status and/or severe cardiovascular and/or cardiopulmonary comorbidity. The patients were immobilized in an Elekta stereotactic body frame to improve setup accuracy, and four-dimensional CT scans were used for target delineation. Fractions of 15 Gy were prescribed to cover the planning target volume, giving a total dose of 45 Gy, with 1 fraction every second day. Cone beam CT was applied at each fraction to correct for setup errors. The patients were followed with toxicity evaluation and radiographic follow-up. Results: Median follow-up time was 13.8 months (0–21 months). The local tumor control after 12 months was 100%. Four patients developed regional relapse about 12 months after SBRT. The 1-year disease-free survival was 83%. The median tumor shrinkage at 1 year was 22 mm. Three patients experienced systemic relapse after 13 months. One patient developed grade 3 chest pain toxicity and 16 patients reported temporary grade 1 chest pain toxicity. Two patients reported temporary increased dyspnea. No patient experienced a reduction of the performance status after SBRT. Conclusion: SBRT is an effective and safe treatment modality for elderly patients with early-stage non-small cell lung cancer, having low performance status and severe comorbidity. It is possible to achieve high local control rates with good tolerance

Real-world treatment outcomes with brigatinib in patients with pretreated ALK+ metastatic non-small cell lung cancer

Brigatinib; NSCLC; Inhibidor de la tirosina quinasaBrigatinib; NSCLC; Inhibidor de la tirosina quinasaBrigatinib; NSCLC; Tyrosine kinase inhibitorBackground The next-generation ALK inhibitor brigatinib is approved for use in patients with ALK inhibitor-naïve ALK-positive advanced NSCLC and in patients previously treated with crizotinib. A phase II trial showed that brigatinib is active in patients with ALK-positive metastatic NSCLC (mNSCLC) who had progressed on prior crizotinib (response rate 56 %, median PFS 16.7 months, median OS 34.1 months). We report final data from the UVEA-Brig study of brigatinib in ALK inhibitor-pretreated ALK-positive mNSCLC in clinical practice. Methods UVEA-Brig was a retrospective chart review of patients treated with brigatinib in Italy, Norway, Spain and the UK in an expanded access program. Adults with ALK-positive mNSCLC, including those with brain lesions, resistant to or intolerant of ≥1 prior ALK inhibitor and ECOG performance status ≤3 were eligible. Patients received brigatinib 180 mg once daily with a 7-day lead-in at 90 mg. The objectives were to describe patient characteristics, clinical disease presentation, treatment regimens used and clinical outcomes. Results Data for 104 patients (male: 43 %; median age: 53 [29–80] years; ECOG performance status 0/1/2/3: 41/41/10/5 %; brain/CNS metastases: 63 %) were analyzed. Patients had received a median of 2 (1–6) lines of systemic therapy prior to brigatinib (37.5 % received ≥3) and a median of 1 (1–5) lines of prior ALK inhibitor-containing therapy (crizotinib 83.6 %; ceritinib 50.0 %; alectinib 6.7 %; lorlatinib 4.8 %). At the time of analysis, 77 patients had discontinued brigatinib. Overall, the response rate was 39.8 %, median PFS was 11.3 (95 % CI:8.6–12.9) months and median OS was 23.3 (95 % CI: 16.0–NR) months. Four patients discontinued brigatinib treatment due to adverse events. 53 patients received systemic therapy after brigatinib, 42 with an ALK inhibitor (lorlatinib, n = 34). Conclusions These real-world data indicate the activity and tolerability of brigatinib in patients with ALK-positive mNSCLC who were more heavily pretreated than patients included in clinical trials.This study was funded by Takeda Pharmaceuticals International AG, Zurich, Switzerland

Real-World Journey of Unresectable Stage III NSCLC Patients:Current Dilemmas for Disease Staging and Treatment

Daily-practice challenges in oncology have been intensified by the approval of immune checkpoint inhibitors (ICI). We aimed to outline current therapy policies and management of locally advanced unresectable stage III non-small-cell lung cancer (NSCLC) in different countries. One thoracic oncologist from each of the following countries—Belgium, Croatia, Greece, Israel, the Netherlands, Norway, Poland, Portugal, Romania, Slovenia, and Switzerland—participated in an electronic survey. Descriptive statistics were conducted with categorical variables reported as frequencies and continuous variables as median and interquartile range (IQR) (StataSE-v15). EBUS (endobronchial ultrasound bronchoscopy) was used either upfront or for N2 confirmation. Resectability is still a source of disagreement; thus, decisions vary within each multidisciplinary team. Overall, 66% of stage III patients [IQR 60–75] undergo chemoradiation therapy (CRT); concurrent CRT (cCRT) accounts for most cases (~70%). Performance status is universally used for cCRT eligibility. Induction chemotherapy is fairly weighted based on radiotherapy (RT) availability. Mean time to evaluation after RT completion is less than a month; ICI consolidation is started within six weeks. Durvamulab expenditures are reimbursed in all countries, yet some limiting criteria exist (PD-L1 ≥ 1%, cCRT). No clear guidance on therapies at Durvamulab progression exist; experts agree that it depends on progression timing. Given the high heterogeneity in real-world practices, standardized evidence-based decisions and healthcare provision in NSCLC are needed

GeneCount: genome-wide calculation of absolute tumor DNA copy numbers from array comparative genomic hybridization data

Absolute tumor DNA copy numbers can currently be achieved only on a single gene basis by using fluorescence in situ hybridization (FISH). We present GeneCount, a method for genome-wide calculation of absolute copy numbers from clinical array comparative genomic hybridization data. The tumor cell fraction is reliably estimated in the model. Data consistent with FISH results are achieved. We demonstrate significant improvements over existing methods for exploring gene dosages and intratumor copy number heterogeneity in cancers

The RGD Domain of Human Osteopontin Promotes Tumor Growth and Metastasis through Activation of Survival Pathways

BACKGROUND:Human osteopontin (OPN), a known tumor associated protein, exists in different isoforms, whose function is unclear. It also possesses a RGD domain, which has been implicated in diverse function. Here, we use genetic approaches to systematically investigate the function of the RGD domain in different OPN isoforms on tumor progression and metastasis for 2 different solid tumor models. METHODOLOGY/PRINCIPAL FINDINGS:Using isoform-specific qRT-PCR, we found that OPN-A and B were the main isoforms overexpressed in evaluated human tumors, which included 4 soft tissue sarcomas, 24 lung and 30 head and neck carcinomas. Overexpression of either OPN-A or B in two different cell types promoted local tumor growth and lung metastasis in SCID mouse xenografts. However, expression of either isoform with the RGD domain either mutated or deleted decreased tumor growth and metastasis, and resulted in increased apoptosis by TUNEL staining. In vitro, whereas mutation of the RGD domain did not affect cell-cell adhesion, soft agar growth or cell migration, it increased apoptosis under hypoxia and serum starvation. This effect could be mitigated when the RGD mutant cells were treated with condition media containing WT OPN. Mechanistically, the RGD region of OPN inhibited apoptosis by inducing NF-kappaB activation and FAK phosphorylation. Inhibition of NF-kappaB (by siRNA to the p65 subunit) or FAK activation (by a inhibitor) significantly increased apoptosis under hypoxia in WT OPN cells, but not in RGD mutant cells. CONCLUSION/SIGNIFICANCE:Unlike prior reports, our data suggest that the RGD domain of both OPN-A and B promote tumor growth and metastasis mainly by protecting cells against apoptosis under stressed conditions and not via migration or invasion. Future inhibitors directed against OPN should target multiple isoforms and should inhibit cell survival mechanisms that involve the RGD domain, FAK phosphorylation and NF-kappaB activation

The prognostic effect of KRAS mutations in non-small cell lung carcinoma revisited: A norwegian multicentre study

Background: due to emerging therapeutics targeting KRAS G12C and previous reports with conflicting results regarding the prognostic impact of KRAS and KRAS G12C in non-small cell lung cancer (NSCLC), we aimed to investigate the frequency of KRAS mutations and their associations with clinical characteristics and outcome. Since mutation subtypes have different preferences for downstream pathways, we also aimed to investigate whether there were differences in outcome according to mutation preference for the Raf, PI3K/Akt, or RalGDS/Ral pathways. Methods: retrospectively, clinicopathological data from 1233 stage I–IV non-squamous NSCLC patients with known KRAS status were reviewed. KRAS’ associations with clinical characteristics were analysed. Progression free survival (PFS) and overall survival (OS) were assessed for the following groups: KRAS wild type (wt) versus mutated, KRAS wt versus KRAS G12C versus KRAS non-G12C, among KRAS mutation subtypes and among mutation subtypes grouped according to preference for downstream pathways. Results: a total of 1117 patients were included; 38% had KRAS mutated tumours, 17% had G12C. Among KRAS mutated, G12C was the most frequent mutation in former/current smokers (45%) and G12D in never smokers (46%). There were no significant differences in survival according to KRAS status, G12C status, among KRAS mutation subtypes or mutation preference for downstream pathways. Conclusion: KRAS status or KRAS mutation subtype did not have any significant influence on PFS or OS

Time intervals and routes to diagnosis for lung cancer in 10 jurisdictions: cross-sectional study findings from the International Cancer Benchmarking Partnership (ICBP)

OBJECTIVE: Differences in time intervals to diagnosis and treatment between jurisdictions may contribute to previously reported differences in stage at diagnosis and survival. The International Cancer Benchmarking Partnership Module 4 reports the first international comparison of routes to diagnosis and time intervals from symptom onset until treatment start for patients with lung cancer. DESIGN: Newly diagnosed patients with lung cancer, their primary care physicians (PCPs) and cancer treatment specialists (CTSs) were surveyed in Victoria (Australia), Manitoba and Ontario (Canada), Northern Ireland, England, Scotland and Wales (UK), Denmark, Norway and Sweden. Using Wales as the reference jurisdiction, the 50th, 75th and 90th percentiles for intervals were compared using quantile regression adjusted for age, gender and comorbidity. PARTICIPANTS: Consecutive newly diagnosed patients with lung cancer, aged ≥40 years, diagnosed between October 2012 and March 2015 were identified through cancer registries. Of 10 203 eligible symptomatic patients contacted, 2631 (27.5%) responded and 2143 (21.0%) were included in the analysis. Data were also available from 1211 (56.6%) of their PCPs and 643 (37.0%) of their CTS. PRIMARY AND SECONDARY OUTCOME MEASURES: Interval lengths (days; primary), routes to diagnosis and symptoms (secondary). RESULTS: With the exception of Denmark (-49 days), in all other jurisdictions, the median adjusted total interval from symptom onset to treatment, for respondents diagnosed in 2012-2015, was similar to that of Wales (116 days). Denmark had shorter median adjusted primary care interval (-11 days) than Wales (20 days); Sweden had shorter (-20) and Manitoba longer (+40) median adjusted diagnostic intervals compared with Wales (45 days). Denmark (-13), Manitoba (-11), England (-9) and Northern Ireland (-4) had shorter median adjusted treatment intervals than Wales (43 days). The differences were greater for the 10% of patients who waited the longest. Based on overall trends, jurisdictions could be grouped into those with trends of reduced, longer and similar intervals to Wales. The proportion of patients diagnosed following presentation to the PCP ranged from 35% to 75%. CONCLUSION: There are differences between jurisdictions in interval to treatment, which are magnified in patients with lung cancer who wait the longest. The data could help jurisdictions develop more focused lung cancer policy and targeted clinical initiatives. Future analysis will explore if these differences in intervals impact on stage or survival

Mutasjonstesting ved ikke-småcellet lungekreft

Bakgrunn. Epidermal vekstfaktorreseptor (EGFR) tyrosinkinasehemmere (EGFR-TKI) er en relativt ny klasse legemidler til behandling av ikke-småcellet lungekreft. Den nasjonale faggruppen for lungekreft, Norsk Lunge Cancer Gruppe, anbefaler at pasienter med ikke-småcellet lungekreft testes for mutasjoner i EGFRgenet. Vi rapporterer her erfaringene som er gjort etter at slik testing ble innført i Norge i 2010. Materiale og metode. Opplysninger om hvor mange som er testet, kjønnsfordeling, histopatologiske data og analyseresultater er samlet inn fra de molekylærpatologiske laboratorier ved universitetssykehusene i Tromsø, Trondheim, Bergen og Oslo for perioden mai 2010 til mai 2011. Resultater. 1 058 pasienter med lungekreft ble testet for mutasjoner i EGFRgenet i denne perioden, hvilket svarer til ca. halvdelen av alle som fikk diagnosen ikke-småcellet lungekreft. Mutasjon ble påvist hos 123 pasienter (11,6 %). Det var en høyere andel mutasjonspositive kvinner enn menn (17,6 % mot 6,3 %, p < 0,001), og lavere andel ved plateepitelkarsinom enn ved andre histopatologiske undertyper (3,0 % mot 12,9 %, p = 0,001). Av 80 cytologiske prøver var ni (11,3 %) positive. Fortolkning. På bakgrunn av den relativt høye mutasjonsfrekvensen og et ikke ubetydelig antall positive i plateepitelkarsinomgruppen, anbefaler vi videreføring av mutasjonstesting av alle pasienter med ikke-småcellet lungekreft

Immune Cell Composition in Human Non-small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in the world. Immunological analysis of the tumor microenvironment (immunoscore) shows great promise for improved prognosis and prediction of response to immunotherapy. However, the exact immune cell composition in NSCLC remains unclear. Here, we used flow cytometry to characterize the immune infiltrate in NSCLC tumors, non-cancerous lung tissue, regional lymph node, and blood. The cellular identity of &gt;95% of all CD45+ immune cells was determined. Thirteen distinct immune cell types were identified in NSCLC tumors. T cells dominated the lung cancer landscape (on average 47% of all CD45+ immune cells). CD4+ T cells were the most abundant T cell population (26%), closely followed by CD8+ T cells (22%). Double negative CD4−CD8− T cells represented a small fraction (1.4%). CD19+ B cells were the second most common immune cell type in NSCLC tumors (16%), and four different B cell sub-populations were identified. Macrophages and natural killer (NK) cells composed 4.7 and 4.5% of the immune cell infiltrate, respectively. Three types of dendritic cells (DCs) were identified (plasmacytoid DCs, CD1c+ DCs, and CD141+ DCs) which together represented 2.1% of all immune cells. Among granulocytes, neutrophils were frequent (8.6%) with a high patient-to-patient variability, while mast cells (1.4%), basophils (0.4%), and eosinophils (0.3%) were less common. Across the cohort of patients, only B cells showed a significantly higher representation in NSCLC tumors compared to the distal lung. In contrast, the percentages of macrophages and NK cells were lower in tumors than in non-cancerous lung tissue. Furthermore, the fraction of macrophages with high HLA-DR expression levels was higher in NSCLC tumors relative to distal lung tissue. To make the method readily accessible, antibody panels and flow cytometry gating strategy used to identify the various immune cells are described in detail. This work should represent a useful resource for the immunomonitoring of patients with NSCLC