bluuebunny/crossref_metadata_2025 huggingface dataset:
RET fusion in first/third-generation EGFR-TKIs resistance in advanced non-small cell lung cancer.
Authors: Yao Yu , Zhang Min , Liu Xiuju , Zhao Jun , Cheng Xiangyang , Zeng Aiping , Kong Jinliang , Zhang Hongliang , Chen Rongrong , Xia Xuefeng
Published: May 2019

e20634

Background: EGFR-TKIs is the standard first/second-line treatment for EGFR-mutant advanced non-small-cell lung cancer (NSCLC). The mechanisms of EGFR-TKIs resistance are still under exploration. Acquired fusion have been reported contribute to EGFR-TKIs resistance. Here we focus on RET fusion in first/third-generation EGFR-TKIs resistant NSCLC. Methods: We retrospectively reviewed 3600 cases of EGFR-TKIs resistant NSCLC samples from 2016 to 2018 in our institute. Tumor biopsy, ctDNA or pleural effusion samples were analyzed using hybridization capture-based NGS ER-seq method, which enables simultaneously assess single-nucleotide variants (SNV), insertions/deletions (indel), rearrangements and somatic copy-number(CNV) variation at least 59 genes (range 59-1021 genes). Results: Seven cases with RET fusion were identified (7/3600, 0.2%), with co-occurring EGFR mutations. All were adenocarcinoma, median diagnosis age was 55 years old (range 38-84), four male and three female. Most common RET fusion subtype was CCDC6-RET (5/7, 71%), the other was NCOA4-RET (2/7, 29%). The primary EGFR mutation include four EX19del and three L858R. Six patients received prior first and third-generation EGFR-TKIs treatment. The seventh patient had received only gefitinib treatment, EGFR L858R + T790M + NCOA4-RET were discovered in his plasma when disease progression. Interestingly, one patient had EGFR EX19del + T790M + C797S (cis) + CCDC6-RET in plasma after osimertinib resistance. One patient who had EGFR L858R and NCOA4-RET chose lenvatinib, a RET inhibitor, and had a progression free survival of seven months. Conclusions: Broad NGS panel test suggests that RET fusion could be a rare mechanism of EGFR-TKIs resistance, include first and third-generation. There is no currently target treatment strategy available for these patients, and further investigations, like change target therapy drug or combined target therapy are needed.
Apparent diffusion coefficient and genetic mutations as effective indexes for radiotherapy time of brain metastases from lung cancer retrospective analysis.
Authors: Ren Ruimei
Published: May 2019

e20641

Background: The potential value of apparent diffusion coefficient (ADC) before chemoradiotherapy and genetic mutation as monitors for radiotherapy time of lung adenocarcinoma patients with brain metastases were retrospective analysed. Methods: Fifty-seven patients of lung adenocarcinoma with brain metastases were enrolled into the clinical trial. Conventional magnetic resonance imaging (MRI) examination and diffusion weighted imaging (DWI) were performed one week before therapy and after two cycles of chemotherapy or after one month targeted therapy. Symptoms such as headache, nausea, vomiting would be alleviated with mannitol and dexamethasone. Chemotherapy,once every 3 weeks, using in these patients with wild gene included pemetrexed, DDP, bevacizumab (pemetrexed 500mg per square meter ; DDP 75mg per square meter and bevacizumab 15mg per kilogram). 27 Patients with genetic mutations includ ed 1 patient with ALK genetic mutations, 2 patients with T790 genetic mutations, the presence of EGFR mutations was determined by the presence of deletions with exons 19 in 9 patients and 20 in 10 patients and L858R point mutations in exon 21 in 5 patients. Patients with genetic mutations were given targeted drug therapy. After these above treatment, if brain metastasis symptoms persist, brain radiotherapy was performed ahead of schedule. Patients with no obvious symptoms or relieved symptoms after targeted therapy or chemotherapy, two-month review was performed with enhanced MRI, radiotherapy was not added until the lesion no longer continues to shrink. Results: In the cohort of patients with wild gene , when ADC values less than 1.01 in 15 patients, the maximum diameter of tumors were significantly decreased after two treatment cycles, While 14 patients with ADC values greater than 1.01, the maximum diameter of the tumors are no difference after two treatment cycles. After targeted therapy for one month, In patients with ALK and T790 genetic mutations, the maximum diameter of tumors were significantly decreased, while no difference in 18 patients and decreased in 6 patients with presence of EGFR. Conclusions: ADC values and genetic mutation may as effective indexes of radiotherapy time for lung adenocarcinoma patients with brain metastases.
Analysis of real-world data (RWD) on treatment (tx) sequencing in patients with advanced non-small cell lung cancer (aNSCLC).
Authors: Ma Meng , Zhou Xiang , Goldsweig Howard , Hahner Nicholas , Han Dianwei , Dietz Matthew , Jones Scott , Mullaney Tommy , Redfern Arielle , Jappe Whitney , Liu Zongzhi , Yadav Kamlesh , Zimmerman Michelle , Prentice Tony , Pan Qi , Hirsch Fred R. , Oh William K. , Schadt Eric E. , Li Dan , Chen Rong
Published: May 2019

e20642

Background: While optimal sequencing of systemic therapy in aNSCLC is critical to achieve maximal clinical benefit, it is practically challenging to study tx sequencing through clinical trials. RWD allow retrospective, observational studies to examine tx patterns and associated clinical outcomes. Methods: 1,609 aNSCLC patients who received systemic therapies at Mount Sinai hospitals were analyzed for the number of line of therapy (LOT), therapeutic modalities (chemotherapy, targeted therapy and immunotherapy), and the sequence in which treatments were given when LOT > 1. Time to tx discontinuation (TTD) was used as a surrogate clinical endpoint for outcomes. Results: 578 of the 1,609 (36%) patients received more than one LOT. 356 (22%) received tyrosine kinase inhibitors (TKIs), and 297 (16%) received immune checkpoint inhibitors (CPIs). Kaplan-Meier analysis revealed that among 297 patients who received CPIs, median TTD was longer in the 1st line setting (295 days, 95% CI 169 to 523; n=132) than when LOT > 1 (169 days, 95% CI 113 to 269; n=165), although the difference was not statistically significant (P=0.092, log-rank test). No difference of TTD on TKIs was observed between LOT = 1 and LOT > 1 (P=0.51). With respect to tx sequencing, when patients (n=94) received TKIs as the 1st LOT, 60%, 35%, and 5% of them received another TKI, chemotherapy, or a CPI-containing regimen, respectively, as the 2nd LOT. Among patients (n=370) who progressed on 1st line platinum-based chemotherapy, 52%, 32%, and 16% received another chemo regimen, a CPI-containing regimen, or a targeted therapy, respectively, as the 2nd LOT; these percentages shifted significantly toward more CPIs (24%, 66%, 10% for chemo, CPI, targeted, respectively) when only 2016-2018 data were examined. In the 2nd line setting after platinum therapy, TTD was significantly longer in the CPI group (332 days, 95% CI 169-484) compared to the chemo group (88 days, 95% CI 65-100; P<0.0001), consistent with results from pivotal clinical trials. Conclusions: As the tx algorithm of aNSCLC has been evolving rapidly, we observed diverse tx patterns in RWD. Various tx sequences may impact patient outcomes, and therefore warrant further investigation.
Phase (Ph) I/II study of pembrolizumab (P) with gemcitabine (G) in patients (pts) with previously-treated advanced (Adv) non-small cell lung cancer (NSCLC).
Authors: Sanborn Rachel E. , Duffy Regan M. , Fisher Brenda K , Perlewitz Kelly Shea , Wallen Herschel D. , Li Rui , Redmond William L , Koguchi Yoshinobu , Fox Bernard A.
Published: May 2019

e20652

Background: P has demonstrated improved survival alone or with chemotherapy in untreated adv NSCLC. G may increase antigen cross-presentation and prime CD8 T cell response via tumor apoptosis. This study evaluated P + G in pts with previously-treated adv NSCLC naïve to anti-PD1. Methods: The study included ph 1 (previously reported), then single arm ph II, 1-3 prior therapies, regardless of PD-L1 status. Treatment: G, 1250 mg/m2, Days (D) 1 & 8 + P 200 mg D 1; 21-day cycles. G given max 6 cycles, P max 2 years. Tumor tissue was collected for PD-L1 (22C3). Immune response via whole blood immunophenotyping and ProtoArray was conducted. Results: 16 pts enrolled. Male/Female: 8/8; Age 53-75 (Median 64.5); ECOG 0/1: 2/14 pts, respectively. Median prior therapies: 1 (Range (R) 1-3). Median cycles: 4 (R 1-24). Primary reason for discontinuation: progression. Toxicity was primarily attributed to G, including Gr 3: neutropenia (5), leukopenia (3), anemia (2); lymphopenia, URI, hyponatremia (1 each). Gr 4: 1 hypoxia attributed to intrapulmonary hemorrhage from G. Other toxicities attributed to both G and P included dyspnea (2), pneumonitis (2) (Gr 3). Progression free survival (PFS): 3.2 months (m) (R 0.6-18.5 m). Overall survival (OS) is not yet mature (4 pts in follow up). 14/16 pts were evaluable for response. Stable disease (SD): 9 (56%); partial response (PR): 2 (13%); progression (PD): 3 (19%). 2 pts discontinued prior to first evaluation (1 pulmonary hemorrhage; 1 clinical progression). 1 pt had SD as best response for 18.5 m before PD. Disease control rate (DCR; CR + PR + SD): 56%. 12 pts were PD-L1 evaluable (central). 2 pts had PD-L1 testing through alternate source (22C3). Of the 14 pts with PD-L1 result: PD-L1 0%: 8 (50%); PD-L1 10-40%: 3; ≥50%: 3 (19% each) PFS of 0% PD-L1: 3.75 m (1 PR, 6 SD; DCR 88%). PFS ≥50% PD-L1: 3 m (1 SD, 0 PR). Exploratory immune profiling showed late peripheral immune activation in 3 of 6 pts with Cycle 6 samples (all SD; PFS 5.8 m). ProtoArray analysis is pending. Conclusions: P+G was a feasible combination, without unexpected toxicity. The majority of pts had 0% PD-L1 expression. PFS was not associated with PD-L1 level. PFS did not differ from G or P alone. OS pending. Clinical trial information: NCT02422381.
Real-world clinical experience of the Galician Lung Cancer Group: Afatinib in patients with EGFR positive mutation.
Authors: Agraso Busto Sara , Varela Vanesa , Fernández Núñez Natalia , Firvida Jose-luis , Santomé Lucía , Afonso Francisco Javier , Azpitarte Cristina , De Dios Alvarez Noemi , Garcia Jorge , Campos Balea Begoña , Areses Manrique Maria Carmen , Pereiro Corbacho Diego , Huidobro Gerardo , Lazaro Quintela Martin , Casal Rubio Joaquín
Published: May 2019

e20654

Background: Treatment with tyrosine kinasa inhibitors has been a revolution for the patients with non-small cell lung cancer and EGFR positive mutation, especially in patients with exon 19 deletions. Afatinib seems one of the best options of treatment. Methods: Retrospective study on patients from differents hospitals in Galicia (Spain) diagnosed of metastasic lung adenocarcinoma with EGFR positive mutation who have received first line treatment with afatinib between July 2015 and September 2018 were included. The main objective was to compare our clinical experience concerning response rate, progression free survival and toxicity with published data. Results: 45 caucasians patients were included in our analysis (33 women, 12 men). Median age was 71.2 years (range 39-91 years) and 29 patients had never smoked. Exon 19 deletion was the most common mutation (41 patients, 91.1%). The objective overall response was 68.9% (95% CI: 82.4-55.3), complete responses were observed in 6 patients (13.3%) and partial responses were found in 25 patients (55.6%). Stable disease was observed in 8 patients (17.8%) and disease progression in 1 patient (2.2%), 5 patients have not been re-evaluated (11.1%). Median progression free survival (PFS) was 27 months (95% CI: 14.8-39.1) and overall survival was not reached. Common adverse events grade 3/4 were mucositis and skin toxicity in 11 patients (24.4%) and diarrhea in 6 patients (13.3%), respectively. The dose was reduced in 28 patients (62.2%) and treatment was discontinued in 8 patients (17.8%) owing to adverse events. Conclusions: Median PFS in our patients is 15 months longer than the information retrieved from differents studies with similar response rates and toxicity. This might be due to a majority of population with exon 19 deletion which, according to published data, seems to benefit more from afatinib than from other EGFR mutations.
A retrospective study evaluating clinical predictors of duration of response to immune checkpoint inhibitors in patients with advanced non-small cell lung cancer.
Authors: Ibrahim Yahya , Sankar Keerthana , Mouzaihem Hassan , Kim Seongho , Haddad Amy , Mamdani Hirva
Published: May 2019

e20665

Background: Immune Checkpoint Inhibitors (ICI) with/without chemotherapy has become the standard of care for the treatment of advanced/metastatic non-small cell lung cancer (NSCLC). Similar to the response rate, durability of response to ICI is quite variable. While programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB) have been described to predict response to ICI, little is known about the clinical predictors of duration of response (DoR). Methods: A retrospective chart review of patients (pts) with advanced NSCLC treated with ICI based therapy at Karmanos Cancer Institute was conducted. Data were collected on demographics, clinical characteristics, and tumor characteristics. Univariable and multivariable cox regression analyses were performed for six pre-chosen covariates (histology, prior radiation therapy, brain metastasis, occurrence of immune-related adverse events (irAEs), statin use and smoking status) to see the associations with the DoR to ICI. Results: One hundred thirty-one pts were included in the analysis (68% adenocarcinoma, 60% received prior radiation, 20% had brain metastasis, 26% developed irAEs, 33% were on a statin, 69% former smokers, 12% current smokers and 19% never smokers). Overall median DoR was 149 days (range, 14-1934 days). On multivariable analysis, longer DoR to ICI was observed in pts with non-adenocarcinoma histology (HR: 0.65; p = 0.050; CI: 0.42-1.00, median DoR 242.5 days) and current smokers (HR: 0.53; p = 0.031; CI: 0.30-0.95, median DoR 206.5 days). Other variables, including the presence of brain metastasis, prior radiation therapy, occurrence of irAEs and statin use had no significant relationship with the DoR. Conclusions: Tumor histology and smoking status were statistically and clinically significant predictors of durability of response to ICI in advanced NSCLC, presumably secondary to higher tumor mutational burden. Presence of brain metastasis did not adversely impact DoR to ICI.
A novel biophysical based marker with multilevel, multiparameter expression for early stage cancer detection.
Authors: Wu Junjie , Jiang Gengxi , Ji Jiansong , Du Xuedong , Lin Yue , Tao Hongmei , Tang Xing , Yu Chris Chang
Published: May 2019

e20673

Background: Early stage cancer detection remains to be elusive despite of many years of efforts. In this work, a bio-physical based marker (named Cancer Differentiation Analysis (CDA)) with multi-level and multi-parameter expression features has been developed which has shown a number of clear advantages over the traditional approaches such as bio-chemistry based marker, circulating tumor cell (CTC) and circuiting DNA (ct-DNA). In stage I non-small cell lung cancer (NSCLC), sensitivity and specificity reached a record high of 85.2% and 93.0%, respectively. Methods: In this study, 832 NSCLC cancer samples with pathological information and 642 samples from healthy individuals were measured in a single blind test. Peripheral blood of each individual was drawn in EDTA tubes. One class of bio-physical property in blood samples was utilized for CDA tests. The CDA data were first processed using an algorithm built from data base and subsequently analyzed using SPSS. The results were shown in the table. Results: The results indicated that CDA technology has a very good sensitivity and specificity even at stage I (85% and 93%, respectively), which is much better than those previously reported results by other methods. Conclusions: Initial results showed that CDA technology could effectively screen NSCLC patients from healthy individuals. As a novel bio-physical based cancer detection approach with multi-level and multi-parameter expressions, CDA technology could be a potential candidate for early stage cancer screening. [Table: see text]
ALK resistance mutations and co-occurring genetic alterations to the ALK tyrosine kinase inhibitors in lung cancer.
Authors: Yang Jin-Ji , Zhang Chi , Zhao Jun , Dai Pingping , Lin Gen , Han Liankui , Chen Chen , Guan Yan-Fang , Yang Ling , Yi Xin , Xia Xuefeng
Published: May 2019

e20675

Background: Acquired ALK mutations pose a challenge in multiple ALK tyrosine kinase inhibitors (TKIs) for lung cancer. In our study, we examined the profiles of ALK resistance mutations and co-occurring genetic alterations after targeted therapy. Methods: Using targeted gene capture and next-generation sequencing technologies, we analyzed the somatic mutations from174 patients (pts) with post-TKI samples. Among them, 123 pts received first-generation TKI crizotinib only, 51 pts (34 with second-generation TKI, 17 with third-generation TKI) treated with multiple ALK-TKIs. Results: After the treatment of ALK-TKIs, 29% (50/174) patients developed ALK resistance point mutations, including G1202R (22 pts), G1269A (13 pts), L1196M (8 pts), D1203N (5 pts), F1174L (4 pts), I1171T (4 pts), E1210K (4 pts), G1128A (3 pts), F1174C (3 pts), C1156Y (1 pts), G1123S (1 pts), I1171S (1 pts), L1152R (1 pts), and 10 of them had multi-clone. Specifically, G1269A was found a higher proportion in crizotinib group contrast to multi-TKIs cohort (10/24 vs 3/26, p = 0.024). The recalcitrant G1202R was another common resistance mutation, but there was no significant difference between the two groups (p = 0.052). Other concurrent genetic alterations related to clinical response were usually observed in TP53 mutations (46%), furthermore it seemed to be more frequently detected in post-crizotinb compared with multi-TKIs (P = 0.023). Activated bypass signaling may promote tumor progression. In non-ALK resistance point mutations samples (n = 124), co-occurring genomic alterations in EGFR (32/124, p = 0.004) were significantly more enriched in crizotinib group (n = 99). The driver gene mutation may limit crizotinib response. However, EP300 (24%), CDKN2A (12%), TRIM58 (12%), STK11 (12%) or KRAS (8%) mutations were common in the multiple ALK-TKIs group (n = 25). Conclusions: In lung cancer patients, ALK resistance point mutations G1269A was significantly enriched in post-crizotinib, while patients with multiple ALK-TKIs may frequently found G1202R or L1196M. The co-occurring genetic alterations in TP53 or EGFR after the TKIs therapeutic may offer directions for further research and therapy in lung cancer.
Nomogram based on multivariable regression model estimates the overall survival of patients with nivolumab who were previously treated for advanced non-small cell lung cancer.
Authors: Tamiya Motohiro , Tamiya Akihiro , Go Hirofumi , Inoue Takako , Kimura Madoka , Kunimasa Kei , Nakahama Kenji , Taniguchi Yoshihiko , Shiroyama Takayuki , Isa Shun-Ichi , Nishino Kazumi , Kumagai Toru , Suzuki Hidekazu , Hirashima Tomonori , Atagi Shinji , Shintani Ayumi , Imamura Fumio
Published: May 2019

e20683

Background: Nivolumab (Nivo) has demonstrated with its efficacy against metastatic non-small cell lung cancer (NSCLC). However, it has been also reported that Nivo does not show beneficial effects in approximately 80% of patients. The predictive ability of biomarkers still is yet unclear; thus identifying biomarkers which better predict overall survival (OS) of such patients treated with Nivo is crucial. In this study, we conducted multivariable cox regression analysis including biomarkers and clinical factors measured at the time of initiating treatment with Nivo to assess predictive ability of OS of patients. Results of the multivariable analysis were elucidated with a nomogram which estimates the OS of Nivo in previously treated patients with advanced NSCLC. Methods: In this study, data for 201 patients treated with nivolumab during 17 December 2015 to 31 July 2016 at three respiratory medical centers in Japan were retrospectively reviewed. We collected clinical data at the time of nivolumab treatment commencement, and we evaluated two programmed cell death ligand 1 (PD-L1) immunohistochemistry (IHC) assay systems (22C3 and 28-8). Results: The median age at the time of administration nivolumab was 68 years, 135 patients were male, 157 patients had a smoking history, and 152 patients had a performance status (PS) score of 0–1. 39 patients had EGFR (37) or ALK (2) mutation positive. For 22C3 and 28-8, 36.3% and 36.8% of patients were negative, 17.4% and 14.4% had PD-L1 status of 1-49%, and 11.9% and 14.9% had PD-L1 status of ≥50%, 34.3% and 33.8% had PD-L1 status of missing, respectively. Kendall’s rank correlation coefficient between 22C3 and 28-8 was 0.8414. The median OS of all patients was 333 (95% confidence interval (CI): 116-520) days. In the multivariate analysis, PS score ≥2 (hazard ratio (HR): 2.23; 95%CI: 1.36-3.66 p < 0.001), high LDH level at baseline (HR: 1.13 95%CI: 1.03-1.24; p = 0.008, and progression disease (PD) of pre-treatment response (HR: 3.64 95%CI: 2.29-5.79 p < 0.001) were significantly associated with poor OS. There was not significant distance between PD-L1 status and OS of Nivo. Based on these analyses, we created the nomogram to estimate the OS of Nivo in previously treated patients with advanced NSCLC. Conclusions: PS score ≥2, high LDH levels at baseline, and PD of pre-treatment response were predictive of poor OS of Nivo, moreover the nomogram might be useful to estimate the OS of Nivo in previously treated patients with advanced NSCLC.
Cost-effectiveness of PD-L1 testing and tumor mutational burden testing of immune checkpoint inhibitors for non-small cell lung cancer.
Authors: Li Wenqian , Li Lingyu , Chen Naifei , Cui Jiuwei
Published: May 2019

e20689

Background: Immunotherapy that targeted programmed death ligand 1 (PD-L1)–programmed death 1 (PD-1) pathway showed great benefit on survival compared with other therapies, especially with certain assessments before. However, the high costs limit its use. This cost-effectiveness analysis aimed to measure the significance of various assessments in immunotherapy. Methods: A decision-tree model was established based on the data of OAK study, we compared the economic benefit between immunotherapy and chemotherapy in no test group, PD-L1 test group and tumor mutational burden(TMB) test group respectively with a willingness-to-pay threshold of 3× the per capita gross domestic product ($29307/quality-adjusted life year [QALY]). Besides, we also balanced the benefit of immunotherapy among different groups. Furthermore, we also considered different costs of TMB tests due to the various methods of detection. Sensitivity analyses were conducted to evaluate the stability. Results: Immunotherapy was cost-effective compared with chemotherapy in all groups. Immunotherapy with PD-L1 test achieved economic benefit when comparing with both TMB test group and no test group. However, TMB test group was not cost-effective compared with no test group. The results from average CE and net benefit were consistent. Tissue-based TMB test was the most cost-effective TMB detection methods. One-way sensitivity analyses reflected the impact of utilities. Conclusions: Immunotherapy was cost-effective compared with chemotherapy. PD-L1 test was the most cost-effective immunotherapy test. [Table: see text]
The use of liquid and tissue biopsy genomic testing in lung cancer: A single-institution experience.
Authors: Marina Natalia , Do Tien Phuc , Namireddy Praveen , Sharma Nitika , Cherry Cynthia R. , Parent Teresa , Bowling Mark , Walker Paul R.
Published: May 2019

e20692

Background: Liquid biopsy is an evolving minimally invasive technique to detect cell-free DNA (cfDNA) and cfRNA mutations by next generation sequencing (NGS) in plasma. In our Thoracic Oncology Program, we compared plasma liquid biopsy and tissue-based NGS assay results. Methods: Circulogene Theranostics Personalized Gene Profile (CGP), a 50-gene plasma NGS panel with proprietary direct-on-specimen enrichment technology, and tissue Caris Molecular Intelligence (CMI) NGS cfDNA and cfRNA including microsatellite instability (MSI)/microsatellite stability (MSS) and total mutational burden (TMB) results were retrospectively compiled and compared upon diagnosis. Results: 106 non-surgical lung cancer patients (median age 65 years, range 27-88; 66 men, 40 women) underwent CGP testing. 49 patients had sufficient tissue for comparative CMI. MSI detected in 20.4% (10/49) by CGP; no tissue MSI was found by CMI (0/44). 3 out of 4 (75%) MSI detected by CGP had high TMB ≥ 10 mut/Mb by CMI. 75% MSS patients by CGP had low TMB (12/16). Comparative plasma versus tissue mutations findings: TP53 mutations 60.3% (64/106) CGP and 69.3% (34/49) CMI. CGP TP53 mutated patients, high TMB 70.5 % (20/34) by CMI; EGFR mutations 13.2% (14/106) CGP and 14.2% (7/49) CMI; KRAS mutations 2.8 % (3/106) by CGP versus 28.5% (19/49); one ROS1 by CGP missed by CMI and one ALK by CGP insufficient tissue CMI. A higher frequency of BRAF 16.9% (18/106), PIK3CA 28.3% (30/106), PTEN 22.6% (24/106), and MET 7.5% (8/106) alterations was identified by plasma/CGP than comparative tissue/CMI 6.1% (3/49), 2% (1/49), 6.1% (3/49), and 0% (0/49) respectively. Conclusions: Our findings indicate that Circulogene liquid biopsy NGS detected common mutations, including actionable variants in lung cancer, providing expanded and complementary tumor molecular biology and therapeutic information to tissue NGS.
Clinical benefit of EGFR-TKIs plus radiotherapy for treating EGFR-mutated metastatic non-small cell lung cancer.
Authors: Wang Ran Lin , Li Tao , Lv Jiahua , Sun Chang , Shi Qiuling
Published: May 2019

e20694

Background: Despite the high response rate and prolonged OS of patients with EGFR mutations treated with gefitinib or erlotinib, there are still major clinical obstacles. The local control rate is still low, only 19.4%–58%, with first-line treatment using EGFR-targeted therapy. The aim of this study is to provide scientific evidence to support the clinical benefits of EGFR-TKI combined with radiotherapy compared to EGFR-TKI alone. Methods: From February 2015 to May 2017, a total of 103 patients with stage IV EGFR-mutated NSCLC treated at Sichuan Cancer Hospital & Institute were analysed retrospectively. 50 patients were treated with EGFR-TKIs (gefitinib or erlotinib) plus radiotherapy (Group TKI-RT) and 53 patients received EGFR-TKIs alone (Group TKI). Tumour response, survival and toxicities were compared between the two groups. Results: Median follow up time was 11.7 months (range: 2.8–36.3 months). The overall response rate (ORR) and disease control rate (DCR) in Group TKI-RT vs. Group TKI were 62% vs. 37.7% (P = 0.014) and 88% vs. 75.5% (P = 0.101), respectively. The median progression-free survival (PFS) and median overall survival (OS) in Group TKI-RT were superior to those of Group TKI (18.87 months vs. 12.80 months, P = 0.035 and 23.10 months vs. 18.30 months, P = 0.011). OS rates in Group TKI-RT and Group TKI were 56.0% vs. 35.8% at 1-year (P = 0.04) and 16.0% vs. 3.8% at 2-year (P = 0.036). Multivariate Cox model found that TKI-RT related to significantly better OS (hazard ratio = 0.209; 95% CI, 0.066 to 0.661; P = 0.008) than TKI alone. Adverse events did not differ significantly between the two groups. Conclusions: Compared with EGFR-TKIs alone, EGFR-TKIs combined with radiotherapy was well tolerated and showed benefit in tumour response and survival for EGFR mutation-positive metastatic NSCLC patients.
Improvement of lung cancer risk prediction adding SNPs to the HUNT Lung Cancer Model: A HUNT Study.
Authors: Røe Oluf D. , Nguyen Olav Toai Duc , Lakiotaki Klio , Tsamardinos Ioannis , Lagani Vincenzo , Markaki Maria
Published: May 2019

e20696

Background: A novel validated model for risk prediction of lung cancer, the HUNT Lung Cancer Model predicts 6- and 16-year risk of lung cancer with a C-index = 0.879 and 6-year AUC = 0.87. The model is valid for smokers and ex-smokers of any intensity and quit time and includes seven variables; age, BMI, pack-years, smoking intensity (cigarettes per day), quit time, daily cough in periods of the year and hours of daily indoors smoke exposure. Genome-wide association studies (GWAS) have consistently identified specific lung cancer susceptibility regions. We aimed to improve performance of the HUNT model by integrating the most significant Single Nucleotide Polymorphisms (SNPs). Methods: Lung cancer cases (n = 484) and controls without other cancer (n = 50337) were genotyped for 22 SNPs located in GWAS-identified lung cancer susceptibility regions. Variable selection and model development used backwards feature selection with Akaike Information Criterion in multivariable Cox regression models. Internal validation used bootstrap to assess the change in area under the receiver operator characteristic curve (AUC) in order to compare nested models with and without genetic variables in the ever-smokers´ population (n = 456 cases, n = 28633 controls). We also used likelihood based methods for significance testing. Results: Variable selection and model development in the general population yielded six SNPs, rs1051730, rs11571833, rs13314271, rs2131877, rs2736100 and rs4488809. The added genetic information from these SNPs to the HUNT model, resulted in an improvement according to F test of the nested models (ANOVA p-value 0.000002425). The AUC of the augmented model was 0.881 (95% CI [0.869 0.892]) vs 0.869 without SNPs. Conclusions: In a highly predictive clinical risk prediction model, the integration of SNPs could further improve model performance according to likelihood based methods. Further refinement and validation of this integrated model is needed for clinical use.
A joint model of tumor size dynamics and survival with new lesions in EGFR mutation-positive non-small cell lung cancer patients with treatment of gefitinib or carboplatin and paclitaxel.
Authors: Dunyak James , Yan Hong , Al-Huniti Nidal
Published: May 2019

e20697

Background: Tumor dynamics have been serving as significant predictors in diagnosis, staging, prognosis and treatment of patients with non-small cell lung cancer (NSCLC). The purpose of this study is to propose a joint model that links the longitudinal tumor burden to progression free survival (PFS) with the appearance of new lesion in a population of NSCLC patients with gefitinib treatment or Carboplatin/Paclitaxel. Methods: The model was extended to the estimation of new lesion based on a previously developed tumor size and survival joint model. The derivative of the tumor loads and the probability of new lesions served as biomarkers in the survival submodel. Parameters were estimated from the posterior distribution in a Bayesian framework and numerical study was realized with R and STAN. A total of 434 NSCLC patients with EGFR mutation positive treated with gefitinib or chemotherapy (carboplatin+paclitaxel) from IPASS (‘NCT00322452’) were used to construct the model. Predictions were performed on the IFUM study (‘NCT01203917’) with 102 EGFR mutation positive NSCLC patients. Results: The model performed well in PFS prediction in both within-sample and out-of-sample estimations. Further improvement of model specifications is necessary since the tumor load developing rate and appearance of new-lesion negatively impacted survival predictions. About 90% accuracy was realized by the joint model when recapitulating the outcomes from the response evaluation criteria in solid tumors (RECIST). The appearance of new lesion contributed less than tumor size in accommodating drug effect when comparing progression-specific hazards. Conclusions: This Bayesian joint model well recapitulated the outcomes from the RECIST with sequentially updated tumor size that linked to survival predictions. New insights of relative predictive values were provided by the joint model regarding the components of RESICT.
Advance care planning and terminal intensive care unit admissions for cancer patients: We can do better.
Authors: Heng Joseph , Sedhom Ramy , Smith Thomas J.
Published: May 2019

e23000

Background: Terminal oncology intensive care unit (ICU) admissions are associated with high healthcare costs and decreased quality of life. Chemotherapy can be given in non-curative settings to optimize symptom control, but use of it at the end of life does not improve longevity. In addition, goals of care are too often not addressed for patients at high risk of death. Methods: We carried out a retrospective review identifying patients of a large academic cancer center who were admitted to and expired in an ICU between January 1, 2017 to December 31, 2018. Results: 120 patients met inclusion criteria. Median age was 58 years. Only 15.0% (n = 18) of all patients had advance directives. The majority of patients (94.1%, n = 113) were FULL CODE on admission. Median duration of admission was 10 days. Median time to death from ICU admission was 7.5 days. 65.0% (n = 78) of all patients were intubated, while 15.0% (n = 15) received CPR. 58.3% (n = 70) of the study population had solid malignancies; of note, 97.1% (n = 68) of these patients were metastatic at presentation and had a median ECOG performance status of 2. Patients with metastatic solid tumors typically have a more indolent course of progression compared to patients with hematologic malignancies. However, only 23.5% (n = 16) had discussed goals of care or code status with their outpatient oncologists, despite many seeing them within the last month prior to admission (83.8%, n = 57). Similarly, only 4.0% (n = 2) of patients with hematologic malignancies had advance care planning discussions with their oncologists prior to their terminal ICU admission. 27.5% (n = 33) of all patients had an inpatient palliative care consult. The inpatient pulmonary/critical care team had a high rate of inpatient code status transitions, with 85.6% (n = 97) of FULL CODE admissions transitioning to DNR/DNI. Conclusions: These findings reflect contemporary practice at a major academic cancer center. Despite most patients having regular contact with their outpatient oncologists, the intensity of health care utilization noted highlights a need to optimize recognition of patients at high risk of death and to engage patients in advance care planning discussions to avoid terminal ICU admissions.
Place of death and chemotherapy use at the end of life in colorectal cancer.
Authors: Schütte Katharina , Kroggel Tobias , Rentsch Anke , Schuler Ulrich S. , Heuchel Conrad , Folprecht Gunnar
Published: May 2019

e23006

Background: Over the last decades, new drugs and multidisciplinary treatment increased the therapeutic options for palliative treatment of colorectal cancer (CRC). It is unclear, whether these options led to a more aggressive therapy at the end of life. Methods: For this retrospective cohort trial, we identified all stage IV CRC patients who received their complete therapy at an university hospital in Germany and investigated the use of palliative chemotherapy at the end of life (EOL) and the place of death (POD). Results: Between 01/2002 and 12/2012, 245 patients were treated with palliative chemotherapy for stage IV CRC and were evaluable for duration of palliative chemotherapy and place of death. 21% of the patients received chemotherapy within the last 30 days and 9% within 14 days before death. Overall survival of patients with chemotherapy use within the last 30 days of life was significantly shorter compared to patients without chemotherapy in the last month of life (12 vs. 20 months, p = 0.02), duration of palliative chemotherapy was non-significantly shorter (11 vs. 15 months, p = 0.29). Chemotherapy use was significantly more frequent used within 30 days before death from 2009-2012 (24%) compared to 2002-2005 (17%), p = 0.001. 58% of patients died in their residence (at home or in a nursing home), 27% on a general hospital ward (GHW)/ intensive care unit (ICU) and 15% on a palliative care unit (PCU) or hospice. Patients ≥70 years died significantly more often in their residence (70% vs. 53%; p = 0.013). From 2002-2005 to 2010-2012, less patients died in a GHW or ICU of acute care hospitals (39% vs. 16%; p = 0.007). Patients with a distance of ≤45 minutes to our institution more often died at home and in a PCU, Patients with a short therapy-free interval before death more often died in a hospital, (with chemotherapy in the last 30 days: 38%, with chemotherapy in the last 14 days: 45%). Conclusions: Although chemotherapy use at the EOL increased over the decade, more patients were able to die at home. Older patients and patients living in an urban centre more often died at home indicating that conditions for home care have improved independent of the duration of chemotherapy. However, patients with chemotherapy use at the EOL more often die in hospital.
A community oncology end-of-life care program: Results for hospice length of stay analysis.
Authors: Akhtar Adil Jamal , Margolis Jeffrey H. , Scott-Barney Tammy , Zekman Richard Philip , Muskovitz Andrew A. , Qamruzzaman Yusuf , Ballouz Samer , Ibrahim Mohammed , Maxwell Karma , Stortz Lexi , Fabbiano Maria , Sheth Karna
Published: May 2019

e23008

Background: Michigan Health Professionals (MHP) is a large multispecialty physician group. MHP Oncology Division participates in quality improvement projects. Palliative and End of Life (EOL) care has been identified as one of the quality improvement areas. A comprehensive community oncology program for early and timely involvement of palliative and EOL care was launched in October 2017. Methods: MHP Palliative and End of life care committee was created of mostly oncologists who are board certified in Palliative care and Hospice. The program, which included pre-program training, user-friendly referral process, and live physician engagement for early involvement of palliative care (PC) and EOL care was developed and implemented. A partnership was created with Premier Hospice to integrate EOL care services with the oncology offices and to collect data. Historical data for average hospice length of stay (LOS) in hospice service for MHP oncology patients was analyzed by Integra Connect. Results: From 1/1/2018 to 12/31/2018 a total of 133 patients (MHP-T) were referred and admitted to Hospice service. Sixty-one patients were on PC service (PC group) and 72 patients (NonPC group) were referred directly to hospice. Total of 527 patients from 2012 to 2017 were analyzed for historical comparison group (HC) and 124 patients were analyzed for MHP-T group. Average LOS was 16.8 days in the HC group. Average LOS for the MHP-T, PC group and NonPC group improved to 34, 35 and 33 days respectively. HC group had 82.2% of patients with average LOS < 30 days. After program implementation average LOS < 30 days improved to 63.7% MHP-T group, 60.0% PC group and 66.7% NonPC group. In HC group, 92 out of 527 patients had average LOS of 2 days or less. Only 2 patients out of 124 patients had average LOS of 2 days or less since the launch of MHP community oncology program. Conclusions: Early and timely patient referral to the EOL care services resulted in average hospice LOS which is more than double as compared to historical comparison group. Fewer number of patients had average LOS of < 30 days and LOS of 2 days or less as compared to the historical comparison group. There was a trend towards higher LOS observed for patients who were under palliative care (PC) before hospice admission.
Competing causes of death in patients with neuroendocrine tumor.
Authors: Low Soon Khai , Hoang Trong Bao Long , Bahaie Nourelhoda Sami , Giannis Dimitrios , Tawfik Gehad Mohamed , Lee Shin Yin , Huy Nguyen Tien
Published: May 2019

e23009

Background: Increasing survival of patients with neuroendocrine tumors (NETs) may be associated with higher risk of mortality due to causes other than the primary NET, namely the competing causes of death (CCD). Therefore, our study focused on comprehensively investigating the magnitude of the CCD on the overall NET mortality and the associated demographic, clinicopathologic and treatment factors using data from the Surveillance, Epidemiology, and End Results (SEER) database. Methods: Patients with histologically confirmed primary NET diagnosed from 1973 through 2015 were identified using the SEER-9 registries for subsequent data collection and analysis. CCD were stratified and analyzed using standardized mortality ratios (SMRs) as measures of the relative risks of mortality for NET patients in comparison to the general population in the US adjusted by age, sex and race over the same time period. Competing risk regression analysis was performed using Fine and Gray multivariate regression model. Results: A total of 29,981 NET patients were included, 5481 (42.5%) of which deceased due to CCD. Overall SMR attributed to CCD was 2.50 [95% Confidence interval (CI): 2.43–2.56]. The SMR of non-cancer CCD was 2.65 (95% CI:2.58–2.73) and that of SPN was 1.91 (95% CI:1.79–2.04). Heart diseases and other cardiovascular diseases accounted for approximately half of all non-cancer CCD. SPN mortality accounted for 16.1% of CCD, with lung and bronchus cancer being the most prevalent. Stratification by the year of diagnosis revealed a drastic rise in CCD was observed in the last decade between 2005 and 2015, during which the SMR peaked. Advanced age, black race, small intestinal and gastric NETs, and cancer-directed surgery were significantly associated with an increased risk of CCD (p<0.001). Interestingly, female sex, pancreatic NETs, recto-anal NETs, NETs of unknown primary site, race other than white and black, distant and regional spread, chemotherapy and radiotherapy were significantly associated with a decrease in the incidence of CCD. Conclusions: CCD play an increasingly significant role in NET mortality in recent years, especially for those with higher risk of CCD. Further prospective studies are needed to evaluate the association of NETs with these CCD.
A prospective study of the impact of chemotherapy-related toxicities on the quality of life in elderly patients with cancer.
Authors: Kotne Sanketh , Ponnada Bharadwaj , Philip Arun , Keechilat Pavithran
Published: May 2019

e23013

Background: Treatment of cancer in elderly is challenging. Majority of the elderly cancer patients are offered chemotherapy based on their performance scale and geriatric assessment tools are not routinely employed in clinical practice as they are time consuming and cumbersome. Aim: The primary objective was to estimate the incidence of chemotherapy related adverse events in newly diagnosed elderly cancer patients above 65 years of age treated at a tertiary cancer institute in southern India. The secondary objective was to predict and assess the factors associated with chemotherapy related toxicities in the elderly patients using the Cancer and Aging Research Group's (CARG) scoring tool and to study the quality of life and to assess the nutritional status and the mental status in elderly cancer patients above 65 years of age. Methods: A prospective cross-sectional study was done among 179 patients with age ≥ 65 years, a solid organ cancer (any type or stage) from February 2017 to August 2018. Prechemotherapy comprehensive geriatric assessment (CGA) with Older People’s Quality of Life Questionnaire (OPQOL-35), Mini Nutritional assessment (MNA) and Folstein’s Mini Mental status examination (MMSE) was done at baseline, 2 months and 6 months. CARG tool was used to predict the risk of chemotherapy toxicity with the standard and modified dose. Results: The mean age was 68.53 years. Majority of the patients had breast cancer 29.60%. The proportion of lung cancer, prostate cancer, stomach cancer, colorectal and ovarian cancers were 21.80%,10.60%, 9.50%, 14.5% and 7.30% respectively. Other cancers were seen in 5 patients (2.79%). 40 (22.30%) patients had received anthracycline based chemotherapy. 143 (79.90%) had received standard dosing chemotherapy.118 (65.90%) & 125 (69.80%) out of 179 patients had developed hematological toxicities and non- hematological toxicities respectively. According to the ROC curve for the CARG tool risk of toxicity with standard & modified dosing and hematological & non- hematological toxicities, the accuracy of the test is 60.89% indicating its poor predictive validity. There is a decline in the CGA at 2 months follow-up, but there was an improvement after assessment at 6 months. Conclusions: Comprehensive geriatric assessment at base line is required to adequately analyse patient’s risk of chemotherapy related toxicities. In our study, the patients have tolerated the chemotherapy well in spite of receiving standard dosing.
Neutrophil to lymphocyte ratio ≥4 correlates with 6-month postoperative mortality in cancer patients age >75.
Authors: Ali Imran Yousuf , Sarraf Saman , Downey Robert J. , Kim Soo Jung , Alexander Koshy , Korc-Grodzicki Beatriz , Shahrokni Armin
Published: May 2019

e23014

Background: We assessed the correlation between elevated neutrophil to lymphocyte ratio (NLR), a pro-inflammatory biomarker, with patient frailty and post-operative 6-month mortality. Methods: Patients aged ≥75 evaluated preoperatively by the Memorial Hospital Geriatrics Service completed a geriatric assessment (GA). NLR was determined from preoperative blood work. Patients were included if they underwent elective surgery between 2015-2018 with hospital length of stay (LOS) ≥ 1 day and had ≥ 6 month follow up. Univariate analysis was used to determine correlation between GA domains and NLR. Multivariable regression (MVR) analysis was used to assess the relationship of frailty and NLR with postoperative 6-month mortality. Results: 1028 patients (median age 80) were included. 323 patients (31.4%) had NLR ≥ 4. By univariate analysis, patients with NLR ≥4 were often male ( 57% vs. 45%), had Karnofsky Performance Status (KPS) < 90 (44% vs. 37%), were dependent for instrumental activities of daily living (iADL) (53% vs. 44%), had social activity limitation (57% vs. 49%) (all p < 0.05) and Timed Up and Go test (TUG) > 10 seconds (40% vs. 33%, p = 0.06). Other conditions, particularly cognitive function, weight loss, polypharmacy did not differ between groups, nor did operative time and blood loss. Patients with NLR ≥4 experienced more major adverse surgical events (8% vs. 5% , p = 0.03) and had longer LOS (9 vs. 6.3, p < 0.001). After six months, 12% and 5% of the NLR≥4 and NLR < 4 groups respectively had died. By MVR analysis, patients with NLR≥4 were at higher risk for 6-month mortality (OR = 1.91, p = 0.01) after adjustment for gender, KPS, iADL, TUG, social activity, major adverse surgical events, LOS, and metastatic disease status. Conclusions: NLR ≥4 was associated with components of the GA but correlated with risk for major adverse surgical events and 6-month postoperative mortality. Ongoing work directed at clarifying the relationship between NLR and risk of specific complications to help plan interventions is needed.