Clinical characteristics of NSCLC harboring ALK 2p23 translocation at Cleveland Clinic.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18085-e18085
Author(s):  
Yan Feng ◽  
Nathan A. Pennell ◽  
Julia Samsa ◽  
Christopher Lanigan ◽  
A. Valeria Arrossi ◽  
...  

e18085 Background: The ALK 2p23 translocation, ALK(+), is an important druggable target in 5-7% of non-small cell lung cancer (NSCLC). However, the break-part FISH assay is labor-intensive. Better understanding of the target population’s clinical features and alternative screening tests are desirable to enable cost-effective patient selection for molecular therapy. Methods: NSCLC patients (N=120) seen at the Cleveland Clinic (CC) who had clinical screening ALK 2p23 FISH (Abbott Molecular) were included in this retrospective analysis. Biopsy specimens were also tested using immunohistochemistry (IHC) for ALK overexpression via clone D5F3 (Cell Signaling Tech.) with OptiView ultrasensitive detection (Ventana Medical Sys.). Clinical data were extracted from electronic medical records. Comparison was performed using Fisher’s exact test, Wilcoxon rank sum test or log-rank test. Results: Of the 120 tumors tested, 34 (28.3%) were ALK(+) by FISH, predominantly adenocarcinomas (33/34). 97% of the samples were also tested by ALK-IHC, with a concordance rate of 99%. Comparing to ALK (-) group, ALK(+) patients were younger (median 53 vs 65, p<0.01) and mostly never/light smokers (91% vs 43%, p<0.01). ALK(+) tumors tended to have higher number of metastatic sites at diagnosis, especially for liver metastasis (26.5% vs 10.5%, p=0.04). Interestingly, venous thrombosis (DVT/PE) was also significantly more common in ALK(+) patients (35.3% vs 16.3%, p=0.03). 17 (50%) patients were treated with crizotinib in the ALK(+) group. Two cases with positive screening ALK-IHC helped to identify FISH(+) tumor areas. Of those tumors with EGFR status available (n=103), 6 were EGFR mutation-positive, all being ALK(-). No significant OS difference was seen in ALK(+)/EGFR(-) patients (n=28) compared to ALK(-)/EGFR(-) patients (n=69). Conclusions: ALK 2p23 (+) NSCLC at CC was more commonly seen in younger patients and never/light smokers. They tended to have greater number of metastases, especially in the liver, and significantly higher risk of venous thrombosis. ALK-ultrasensitive IHC using the D5F4 clone helped to identify FISH(+) tumor areas and may be considered a cost-effective screening test demonstrating high concordance with ALK FISH.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20526-e20526
Author(s):  
Nuria Pardo Aranda ◽  
Cristina Viaplana ◽  
Jordi Remon ◽  
Alex Martinez Marti ◽  
Susana Cedres Perez ◽  
...  

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


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21032-e21032
Author(s):  
Xuanzong Li ◽  
Linlin Wang

e21032 Background: Previous studies suggested that MET exon 14 ( METex14) mutation regarding as a distinct subset was sensitive to MET-inhibitors, but poorly response to immunotherapy. Conversly, MET non-exon-14 (non-ex14) mutations including those undetermined functions and affecting the kinase or extracellular domains were found to be associated with the resistance to MET-inhibitors. However, therapeutic strategies for MET-non-ex14 mutant cancer are still largely unknown, and the relationship between MET-non-ex14 mutations and the efficacy of immune checkpoint inhibitors (ICIs) has never been reported. Using two public ICIs-treated cohorts, we aimed to assess the role of MET mutations including both METex14 and MET-non-ex14 mutations in NSCLC patients undergoing ICIs therapy. Methods: A total of 385 ICIs-treated NSCLC patients were enrolled to our study. MET mutations were defined as any nonsynonymous mutations, and we divided them into METex14 and MET-non-ex14 mutation subsets according to the mutated-position on MET. Kruskal-Wallis test was used to analyze the difference of tumor mutational burden (TMB) score, and the Fisher’s exact test was applied to compare the rates of durable clinical benefit (DCB). Log-rank test was used to analyze the differences between Kaplan-Meier survival curves. Results: In the entire cohort, we found that 17 patients (17/385, 4.4%) had MET mutations, most of which were pure METex14 mutations (10/17, 58.8%). The median TMB of patients in the entire NSCLC cohort was 6.89 mut/Mb. MET-non-ex14 mutant patients (7/385, 1.8%) possessed a significantly higher TMB than METex14-mutant (10/385, 2.6%) and MET wild-type (368/385, 95.6%) sub-cohorts, respectively (median TMB, 17.92 mut/Mb versus 4.17 mut/Mb, p = 0.008; 17.92 mut/Mb versus 6.96 mut/Mb, p = 0.01, respectively). DCB was more common in patients harbored MET-non-ex14 mutations than patients with METex14 mutations and MET wild-type (66.7% versus 14.3%, p = 0.103; 66.7% versus 29.9%, p = 0.075, respectively). We found that patients with MET-non-ex14 mutations had a numerically longer progression free survival (PFS) than those with METex14 mutations and MET wild-type (p = 0.169). Moreover, the PFS was significantly longer in MET-non-ex14-mutant subgroup than patients with METex14 mutations (median PFS, 9.1 versus 2.1 months, p = 0.025). Correspondingly, the overall survival (OS) was significantly longer in MET-non-ex14-mutant subgroup than their wild-type counterparts (median OS, not reached versus 11 months, p = 0.039). Additionally, patients with MET-non-ex14 mutations exhibited relatively better OS versus METex14-mutant patients (median OS, not reached versus 18 months, p = 0.175). Conclusions: MET-non-ex14 mutations were associated with higher TMB, improved DCB rate, and could act as a favorable prognostic biomarker in ICIs-treated NSCLC patients.


2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7103-7103 ◽  
Author(s):  
P. Comella ◽  
S. Palmeri ◽  
G. De Cataldis ◽  
G. Filippelli ◽  
R. Cioffi ◽  
...  

7103 Background: We previously reported that triplets with P-gemcitabine (G) plus vinorelbine (V) (PGV) or paclitaxel (T) (PGT) prolonged the survival (S) of advanced NSCLC patients (pts) in comparison with P-based doublets (PG or PV). Aims of the present study were: (1) to compare (log-rank test) the S of P-based triplets vs P-free doublets, and (2) to compare (Fisher test) safety and response rate (RR) of T- and V-regimens. Methods: A 2x2 factorial design was adopted. Pts aged ≤ 70 years, with PS (ECOG) < 2, inoperable stage IIIA, IIIB, or IV NSCLC were randomly treated with: GV = G 1,000 mg/m2 + V 25 mg/m2 on day (D) 1 and 8; GT = G 1,000 mg/m2 + T 125 mg/m2 on D 1 and 8; PGV = P 50 mg/m2 on D 1 and 8 + GV; PGT = P 50 mg/m2 on D 1 and 8 + GT. In all arms, cycles were repeated Q 3 weeks. Only responder pts after 3 cycles received further chemotherapy (CT). Thoracic RT was delivered after CT to pts with intra-thoracic disease. 330 events were required to have a 90% power to demonstrate (two-sided P < 0.05) a 30% reduction of hazard of death. Results: From April 2001 to December 2005, 431 pts were recruited in the 4 arms. Characteristics in % were well balanced in P-based triplets and P-free doublets: males, 84/91; PS 0, 25/23; squamous cell carcinoma, 38/42; weight loss, 22/29; stage IV, 66/65; CNS metastases, 5/8; ≥ 2 metastatic sites, 29/30. So far, 411 pts were assessed for response: RR of triplets vs doublets was 88/204 (43%) vs 68/207 (33%) (P = 0.020), and of T-based vs V-based regimens was 40% vs 36% (P = 0.218). To date, 313 deaths were registered: median and 1-year S were 10.6 mo. and 41% for pts treated with triplets, and 10.4 mo. and 39% for pts treated with doublets (P = 0.786). Over initial 3 courses, occurrence of grade ≥ 3 toxicity (T vs V, % pts) was: neutropenia, 18% vs 30% (P < 0.004); febrile neutropenia, 4% vs 7%; platelets, 7% vs 12% (P = 0.056); anemia, 5% vs 7%; vomiting, 1% vs 2%; diarrhea, 6% vs 3%; stomatitis, 3% vs 0.5%. Grade ≥ 2 neurotoxicity occurred in 1% of both groups. Conclusions: Activity was significantly higher with P-based triplets, but they did not affect the OS. T-based regimens were equally active and less toxic than V-based regimens. Therefore, the GT regimen may represent a new standard of care for advanced NSCLC pts. No significant financial relationships to disclose.


2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7624-7624
Author(s):  
P. A. Zucali ◽  
M. Gallegos Ruiz ◽  
E. Giovannetti ◽  
A. Destro ◽  
K. Floor ◽  
...  

7624 Background: Epidermal growth factor receptor tyrosine-kinase inhibitors (EGFR-TKIs) show anti-tumor activity in only 10% of Caucasian non-small cell lung cancer (NSCLC) patients. Aim of this study was to evaluate several biological parameters potentially related to EGFR, including c-Met activation, as potential markers of intrinsic resistance to EGFR-TKIs in NSCLC. Methods: P-Akt, p-Erk, c-Src, E-Cadherin, c-Met[pY1003] and c-Met[pY1230/1234/1235] status was immunohistochemically determined on a tissue micro-array of tumor samples from 51 NSCLC patients treated with gefitinib. EGFR, k-ras, and c-Met mutation analysis was also carried out. A panel of NSCLC cell lines expressing c-Met[pY1003] were treated with gefitinib (0.01–100μ M) alone or in combination with hepatocyte growth factor (40 ng/ml) and the c-Met-agonistic antibody DN-30 (80 μg/ml) for 72 hours in 0.5% FCS medium. Drug interaction between gefitinib and DN-30 was assessed, at a non-constant concentration ratio, using the combination index (CI) method. Results: There was no association between p-Erk, c-Src, E-Cadherin, c-Met[pY1230/1234/1235], and k-ras status and response or survival. EGFR exon 19 deletion and p-Akt nuclear staining were significantly associated with response (P<0.0001; Fisher's exact test) and longer time to progression (TTP) (P=0.007; log-rank test), respectively. High c-Met[pY1003] membrane staining was significantly associated with progressive disease (P=0.019; Fisher's exact test) and shorter TTP (P=0.0416; log-rank test), but not with survival. Multivariate analysis confirmed a significant relationship between c-Met[pY1003] and increased risk of disease progression (HR=2.464, 95% CI 1.293–4.696, P=0.006). No c-Met mutations were found. In vitro, the combination with DN- 30 synergistically (CI<1) enhanced gefitinib-induced growth inhibition in all c-Met[pY1003]-expressing NSCLC cells studied (H460, SW1573, A549 and H292). Conclusions: Activation of c-MET may be a biological marker of intrinsic resistance to gefitinib in NSCLC patients, and combined inhibition of c-Met and EGFR may be a suitable therapeutic approach in patients with activated c-Met[pY1003] tumors. No significant financial relationships to disclose.


2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Charles E. Rengifo ◽  
Rancés Blanco ◽  
Mercedes Cedeño ◽  
Milagros Frómeta ◽  
Enrique Rengifo

The tissue expression of low (LMW) and high (HMW) molecular weight cytokeratins and Ber-EP4 antigen in both small (SCLC) and non-small (NSCLC) cell lung carcinomas, as well as its correlation with a variety of clinic-pathological features, was evaluated. In general, 43/52 (82.7%) of NSCLC sections showed the expression of at least one type of cytokeratin while only 7/16 (43.7%) of SCLC were stained with both LMW cytokeratin and pan-cytokeratins antibodies. Remarkably, 18/52 (34.6%) of NSCLC were positive to both types of cytokeratins. However, none of SCLC showed this pattern of expression. In NSCLC patients, the increasing levels of HMW cytokeratins expression, as shown by 34βE12 antibody, correlated with the occurrence of disease recurrence (P=0.0057; Fisher’s exact test). Consequently, the expression of HMW cytokeratins was found to be associated with a poor 4-year overall survival of NSCLC patients (P=0.0315; Log rank test), not taking into account the histopathological classification of tumors. Similar results were obtained when 8-year overall survival was assessed (P=0.0103; Log rank test). Our results could suggest the assessment of HMW cytokeratins in a larger series of NSCLC samples in order to confirm the potential prognostic value of them.


2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20553-e20553 ◽  
Author(s):  
Iosune Baraibar ◽  
Ricardo Oroz ◽  
Marta Roman ◽  
Patricia Martin ◽  
Mariano Ponz-Sarvisé ◽  
...  

e20553 Background: NSCLC therapeutic paradigm has changed with immune checkpoint blockers. Biomarkers predicting clinical benefit are still lacking. As previously shown in melanoma, changes in absolute lymphocytes and neutrophils count (ALC and ANC) during IT (PD-1/PD-L1 inhibitors) may be related to response in NSCLC (Nakamuta et al, Oncotarget 2016). TTF1 expression has been associated with PD-L1 expression (Vieira et al, Lung Cancer 2016). We aimed to investigate TTF1 expression and changes in ALC and ANC after 2 cycles and their potential association with clinical outcomes to IT. Methods: We retrospectively analyzed 26 consecutive patients with stage IV NSCLC treated with IT at Clínica Universidad de Navarra (Spain) during 2016. Radiological response was evaluated according to RECIST v1.1. The potential correlation between ALC and ANC changes during the first two cycles and response to treatment [disease control rate (DCR) vs progression] was evaluated using Student’s T-test. Fisher’s exact test was used to study the association between changes in ALC ( < 1,000 vs > 1,000) and ANC ( < 4,000 vs > 4,000) after 2 cycles and response to IT. TTF-1 expression was correlated with treatment response. Overall survival (OS) was assessed with Kaplan-Meier analysis and Log-rank test according to ALC and ANC. Results: An ALC increase after 2 cycles was significantly associated with DCR compared to progression (192 vs -155; p = 0.043). ALC > 1,000 after 2 cycles was more frequent among patients experiencing DCR compared to progression (87% vs 50%; p = 0.07). ALC > 1,000 after 2 cycles was more frequently observed among patients with TTF1+ tumors (93% vs 55%; p = 0.03). Patients with ANC < 4,000 showed a longer median OS (NR vs 19.25 months; p = 0.03). TTF1 expression in adenocarcinoma (n = 18) was associated with response to IT (83% vs 16%, p = 0.01). Conclusions: Despite this retrospective small series’ limitations, our results show that ALC and ANC changes during IT and TTF1 expression may act as early predictors of clinical benefit in stage IV NSCLC patients treated with PD1/PD-L1 blockers. Our results warrant further investigation in larger prospective series.


1996 ◽  
Vol 3 (1) ◽  
pp. 47-53 ◽  
Author(s):  
Afaf Girgis ◽  
Philip Clarke ◽  
Robert C Burton ◽  
Rob W Sanson—Fisher

Background and design— Australia has the highest rates of skin cancer in the world, and the incidence is estimated to be doubling every 10 years. Despite advances in the early detection and treatment of melanoma about 800 people still die nationally of the disease each year. A possible strategy for further reducing the mortality from melanoma is an organised programme of population screening for unsuspected lesions in asymptomatic people. Arguments against introducing melanoma screening have been based on cost and the lack of reliable data on the efficacy of any screening tests. To date, however, there has been no systematic economic assessment of the cost effectiveness of melanoma screening. The purpose of this research was to determine whether screening may be potentially cost effective and, therefore, warrants further investigation. A computer was used to simulate the effects of a hypothetical melanoma screening programme that was in operation for 20 years, using cohorts of Australians aged 50 at the start of the programme. Based on this simulation, cost—effectiveness estimates of melanoma screening were calculated. Results— Under the standard assumptions used in the model, and setting the sensitivity of the screening test (visual inspection of the skin) at 60%, cost effectiveness ranged from Aust$6853 per life year saved for men if screening was undertaken five yearly to $12137 if screening was two yearly. For women, it ranged from $11 102 for five yearly screening to $20 877 for two yearly screening. Conclusion— The analysis suggests that a melanoma screening programme could be cost effective, particularly if five yearly screening is implemented by family practitioners for men over the age of 50.


Sensors ◽  
2021 ◽  
Vol 21 (3) ◽  
pp. 736
Author(s):  
Kamila Malecka ◽  
Edyta Mikuła ◽  
Elena E. Ferapontova

Improved outcomes for many types of cancer achieved during recent years is due, among other factors, to the earlier detection of tumours and the greater availability of screening tests. With this, non-invasive, fast and accurate diagnostic devices for cancer diagnosis strongly improve the quality of healthcare by delivering screening results in the most cost-effective and safe way. Biosensors for cancer diagnostics exploiting aptamers offer several important advantages over traditional antibodies-based assays, such as the in-vitro aptamer production, their inexpensive and easy chemical synthesis and modification, and excellent thermal stability. On the other hand, electrochemical biosensing approaches allow sensitive, accurate and inexpensive way of sensing, due to the rapid detection with lower costs, smaller equipment size and lower power requirements. This review presents an up-to-date assessment of the recent design strategies and analytical performance of the electrochemical aptamer-based biosensors for cancer diagnosis and their future perspectives in cancer diagnostics.


2016 ◽  
Vol 43 (4) ◽  
pp. 799-803 ◽  
Author(s):  
Lauren Fitzpatrick ◽  
K. Alaine Broadaway ◽  
Lori Ponder ◽  
Sheila T. Angeles-Han ◽  
Kirsten Jenkins ◽  
...  

Objective.Juvenile idiopathic arthritis (JIA) affects children of all races. Prior studies suggest that phenotypic features of JIA in African American (AA) children differ from those of non-Hispanic white (NHW) children. We evaluated the phenotypic differences at presentation between AA and NHW children enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry, and replicated the findings in a JIA cohort from a large center in the southeastern United States.Methods.Children with JIA enrolled in the multicenter CARRA Registry and from Emory University formed the study and replication cohorts. Phenotypic data on non-Hispanic AA children were compared with NHW children with JIA using the chi-square test, Fisher’s exact test, and the Wilcoxon signed-rank test.Results.In all, 4177 NHW and 292 AA JIA cases from the CARRA Registry and 212 NHW and 71 AA cases from Emory were analyzed. AA subjects more often had rheumatoid factor (RF)-positive polyarthritis in both the CARRA (13.4% vs 4.7%, p = 5.3 × 10−7) and the Emory (26.8% vs 6.1%, p = 1.1 × 10−5) cohorts. AA children had positive tests for RF and cyclic citrullinated peptide antibodies (CCP) more frequently, but oligoarticular or early onset antinuclear antibody (ANA)-positive JIA less frequently in both cohorts. AA children were older at onset in both cohorts and this difference persisted after excluding RF-positive polyarthritis in the CARRA Registry (median age 8.5 vs 5.0 yrs, p = 1.4 × 10−8).Conclusion.Compared with NHW children, AA children with JIA are more likely to have RF/CCP-positive polyarthritis, are older at disease onset, and less likely to have oligoarticular or ANA-positive, early-onset JIA, suggesting that the JIA phenotype is different in AA children.


Author(s):  
Christina Greenaway ◽  
Iuliia Makarenko ◽  
Claire Abou Chakra ◽  
Balqis Alabdulkarim ◽  
Robin Christensen ◽  
...  

Chronic hepatitis C (HCV) is a public health priority in the European Union/European Economic Area (EU/EEA) and is a leading cause of chronic liver disease and liver cancer. Migrants account for a disproportionate number of HCV cases in the EU/EEA (mean 14% of cases and >50% of cases in some countries). We conducted two systematic reviews (SR) to estimate the effectiveness and cost-effectiveness of HCV screening for migrants living in the EU/EEA. We found that screening tests for HCV are highly sensitive and specific. Clinical trials report direct acting antiviral (DAA) therapies are well-tolerated in a wide range of populations and cure almost all cases (>95%) and lead to an 85% lower risk of developing hepatocellular carcinoma and an 80% lower risk of all-cause mortality. At 2015 costs, DAA based regimens were only moderately cost-effective and as a result less than 30% of people with HCV had been screened and less 5% of all HCV cases had been treated in the EU/EEA in 2015. Migrants face additional barriers in linkage to care and treatment due to several patient, practitioner, and health system barriers. Although decreasing HCV costs have made treatment more accessible in the EU/EEA, HCV elimination will only be possible in the region if health systems include and treat migrants for HCV.


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