bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular matching and treatment strategies for lung cancer at Dartmouth-Hitchcock Medical Center: A three year review of a molecular tumor board.
Authors: Bernhardt Erica , Chamberlin Mary D. , Gorlov Ivan P , Blumental de Abreu Francine B , Bloch Katarzyna J , Peterson Jason D , Tsongalis Gregory J. , Shirai Keisuke , Dragnev Konstantin H. , Miller Todd W. , Tafe Laura J. 
Published: September 2018

e20585 Background: Matching of actionable tumor mutations with targeted therapy has been shown to increase response rates and prolong survival in lung cancer patients. Drug development and trials targeting genetic alterations are expanding rapidly. We describe the role of a Molecular Tumor Board (MTB) in the design of molecularly informed treatment strategies in our lung cancer patient population. Methods: DNA from tumor specimens was sequenced to identify coding mutations using a 50-gene targeted next-generation sequencing panel (Ampliseq v2). Cases were evaluated by a multidisciplinary MTB that included medical oncologists, hematologists, molecular and anatomic pathologists, genetic counselors, and basic science researchers who suggested a course of treatment based on the patient’s molecular findings. Results: During a three-year period, 88 patients were presented to the MTB. Of these, 21 patients had lung cancer (23.9%). All patients lacked common (indicated for FDA approved drug) activating EGFR and ALK mutations. One patient was stage IIIb, all others were stage IV; 18 had previously received at least one prior line of therapy (range 0-5). Suggestions for treatment with a targeted therapy were made for 19 of 21 (90.5%) and four patients underwent treatment with a MTB-suggested targeted agent (21.1%); two as part of a clinical trial. One patient received targeted therapy for 27 months before his disease eventually progressed. Barriers to treatment with targeted therapy included: ineligibility for study (n = 2), lack of interest in study/distance to travel (n = 2), lack of disease progression (n = 2), death/hospice enrollment (n = 5), decision to treat with immunotherapy (n = 3), and unknown (n = 1). Conclusions: For the majority of lung cancer patients, the MTB was able to provide suggestions based on targetable genetic alterations. The largest barriers to treatment were death and hospice enrollment indicating that molecular testing and presentation to the MTB at earlier stages of disease may increase the number of patients who ultimately are eligible for treatment with a targeted agent.
A phase IV study using multi-omics to identify mechanisms of response and resistance to crizotinib in ALK+ advanced non-small cell lung cancer (NSCLC) patients with distinct progression free survival outcomes.
Authors: Couetoux du Tertre Mathilde , Tremblay Lise , Bouchard Nicole , Diaconescu Razvan , Blais Normand , Camlioglu Errol , Constantin Andre , Hoffert Cyrla , Gambaro Karen , Srivastava Archana , Greenwood Celia , Couture Christian , McNamara Suzan , Batist Gerald , Cohen Victor , Agulnik Jason Scott 
Published: September 2018

e20588 Background: Crizotinib is the current first-line standard of care for ALK+ NSCLC with response rates reaching 65% [1] . However, most patients progress within 1 or 2 years and mechanisms of resistance remain unknown for approximately 30% of patients [2] . [1] Shaw et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. NEJM 368: 2385-2394, 2013. [2] Doebele et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res 2012; 18:1472-1482 Methods: Eligible patients had locally advanced or metastatic ALK+ NSCLC. Patients were asked to undergo a repeat tumor biopsy at time of progression and serial bloods and archived primary tumor were collected. Responses were assessed by RECIST 1.1. ctDNA and protein expression on serial blood will be evaluated over the course of treatment. Tumors were profiled using exome sequencing and targeted genomic analysis to identify novel mutations associated with response. Results: 24 patients with stage IV adenocarcinoma received crizotinib as first-line (n = 22) and second-line (n = 2) treatment. Mean age was 60 y (range 41-80). 4% were smokers, 33.5% were former and 62.5% were never-smokers. At data cutoff (Jan 26, 2017), 16 patients have discontinued treatment (14 due to progression and 2 withdrew). The median PFS markedly differed in non-responders (patients with immediate progression) vs responders (patients with initial response or stable disease) (1.8 vs. 27 months). Profiling was performed to identify the genomic traits in tissue and blood that correlate to treatment response. Conclusions: We identified a previously unrecognized subset of patients treated with crizotinib with an exceptionally long PFS. We also observed a subset of patients intrinsically resistant to crizotinib despite harboring ALK+. There are no known predictive biomarkers which can identify patients that will have a long-lasting response or who may not derive benefit from crizotinib. The multi-omics profiling applied to these groups may provide novel insights into mechanisms of response and resistance to crizotinib. Clinical trial information: NCT02041468.
Patient-reported outcomes in patients with NSCLC who progress on 1st-/2nd-generation EGFR TKIs.
Authors: Skinner Karen E , Fernandes Ancilla , Walker Mark Stephen , Pavilack Melissa , Vanderwalde Ari M. 
Published: September 2018

e20590 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are recommended for patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC). Limited data are available regarding patient-reported outcomes (PROs) in patients who experience progression on 1st-/2nd-generation TKI treatment, which was the focus of this study. Methods: A retrospective chart review of patients with advanced NSCLC (stage IIIb/IV) from 10 US community oncology practices was conducted. Patients were included if they were diagnosed between 1/1/2008 and 1/1/2015, were treated with erlotinib or afatinib (TKIs) either first line (1L) or second line (2L), and had disease progression (per clinician’s assessment) prior to 10/31/2015. Eligible patients with ≥1 Patient Care Monitor record were included in this subset analysis. Linear mixed models were used to evaluate select PROs. Results: The study included 364 patients: 77.7% white, 17.3% African American; and mean (SD) age 66.3 (11.3) years. Of the 241 patients who received systemic anticancer therapies after progression, 33.2% continued on TKIs ± chemotherapy (66.8% chemotherapy alone). PROs were available for 71 of 364 patients. We found that progression was associated with worsening in acute distress, despair, and difficulty breathing ( P< .001, P< .001, P= .048, respectively). Disease progression was also associated with worsening of vomiting and nausea ( P< .001, P= .023, respectively). Patient-reported rash symptoms improved from the TKI treatment period to the post-progression period ( P= .044), which aligned with the incidence of rash in the patient records (61.0% during TKI, 32.9% after progression). Conclusions: As expected, disease progression was associated with worsening of patient psychological symptoms and difficulty in breathing. Interestingly, as disease progressed and patients transitioned from TKI therapies to chemotherapies, there was worsening of vomiting and nausea and a decrease in patient-reported rash symptoms. These findings underscore the need for therapeutic options that improve patient symptomatology after progression on 1st-/2nd-generation EGFR TKIs.
Real-world treatment sequencing in advanced non-small cell lung cancer (aNSCLC).
Authors: Radtchenko Janna , Feinberg Bruce A. 
Published: September 2018

e20593 Background: The rapidly expanding arsenal of systemic therapies for aNSCLC warrants a better understanding of treatment sequencing. This study evaluated the benefits of sequence choice through time to discontinuation (TTD). Methods: Using Inovalon’s MORE2 Registry®claims data for July 2013–2014, patients (pts) with aNSCLC identified by ICD-9 codes and treated with chemotherapy (chemo) or targeted therapy (TT; erlotinib, ceritinib, afatinib, or crizotinib) were selected. Pts >18 years of age and treated with first-line (1L) therapy within 6 months of diagnosis were eligible. Pts with small cell lung cancer or secondary malignancies, or pts enrolled in a trial, were ineligible. TTD (time from 1L start to 2L stop + 90 days, or switch to 3L were analyzed by sequence group: chemo-to-chemo (A), chemo-to-TT (B), TT-to-chemo (C), and TT-to-TT (D). All-cause TTD was assessed using Kaplan–Meier curves. Pt characteristics were assessed using descriptive statistics. Results: Of 5,319 pts, 567 (11%) received 1L TT and 4,752 (89%) received 1L chemo; 2,198 pts (41%) progressed to 2L. Significant differences were noted between groups (table). Group D had the most women and longest mean follow-up time and TTD. Group C had the lowest mean age and greatest proportion of 3L pts. Group B had the highest mutation testing rate and second longest mean TTD. Conclusions: The positive impact of precision medicine on TTD is striking. The fact that chemo following 1L TT resulted in the lowest TTD calls this strategy into question. Research is warranted to address the continued role of salvage chemo in TT eligible aNSCLC. [Table: see text]
Nutritional and functional status impairments to predict early death in elderly patients with advanced non-small-cell lung cancer (NSCLC).
Authors: Luciani Andrea , Careri Carmela , Bocci Barbara , Violati Martina , Guidi Alessandro , Blasi Miriam , Bordin Veronica , Caldiera Sarah , Zonato Sabrina , Ferrari Daris 
Published: September 2018

e20600 Background: Early death for some patients can be explained by direct effect of tumor or can be secondary to cancer treatment.As for many patients it is not fully predictable, the factors influencing and determining early death in older individuals receiving chemotherapy for advanced NSCLC were analyzed. Methods: Advanced NSCLC patients, > 70 years, ECOG performance status 0-1, treatment naïve, stage IIIB and IV, EGFR and ALK negative, were eligible. Geriatric assessment was performed at baseline and included: Performance status, ADLs, IADLs, CIRSG score and index, Mini Nutritional Assessment (MNA), Mini Mental State Evaluation (MMSE), educational and social status assessment, Geriatric Depression Scale (GDS).All patients, according to their classification in frail, vulnerable or fit, received best supportive care, monotherapy or doublet chemotherapy.For all patients data on number of cycles, response, discontinuation of treatment, dose reductions, grade 3/4 hematological and non-hematological toxicity were recorded. Patients who died within 90 days of diagnosis were considered.A descriptive statistic was calculated and a logistic regression analysis with the assessment of factors and covariates influencing early death events was performed. Results: From June 2010 to March 2016, 204 patients were assigned to platinum-based doublet (n = 73) or single-agent chemotherapy (n = 131).Median age was 75, 72% were males, 52% had non-squamous histology. Median number of cycles was 4, and was 3 for comorbidities. IADLs were impaired in 42%, ADLs in 6%,MNA in 15% and MMSE 10% of patients.Sixty-eight percent of patients were dead at the time of the analysis; 24% (49/204) had partial response, 25% (51/204) had stable disease and 51% (104/204) had progressive disease.At multivariate logistic model IADLs (p 0.001, OR 1.4 95%CI 0.4-1.6),MNA (p 0.001, OR 1.35 CI 0.1-1.35) and polypharmacy (p 0.008, OR 1.2 CI 1-1.4) were significantly associated with the occurrence of early death. Conclusions: The identification and management of patients with nutritional and functional impairments could help oncologists to reduce the risk of early death during chemotherapy for advanced NSCLC.
Presence of genetic aberrations in patients with brain metastases from non-small cell lung cancer (NSCLC) and clinical outcomes.
Authors: Press Robert H. , Zhang Xinyan , Cassidy Richard John , Ferris Matthew Jeffrey , Zhong Jim , Steuer Conor Ernst , Pillai Rathi Narayana , Owonikoko Taofeek Kunle , Ramalingam Suresh S. , Patel Pretesh R , Curran Walter John , Shu Hui-Kuo George , Sica Gabriel , Higgins Kristin Ann 
Published: September 2018

e20604 Background: Historically, survival in patients (pts) with NSCLC brain metastases (BM) is poor, however, improved systemic therapies are now available including targeted therapies and immunotherapy. We sought to evaluate the prevalence of genetic alterations in pts with BM from non-squamous (NS) lung cancer, and to determine clinical outcomes in the modern era. Methods: With IRB approval, pts with BM from NS-NSCLC from 1/2010-1/2016 with genetic testing were captured and retrospectively reviewed. Snapshot genotyping was performed prior to 1/2014, after which Next Generation Sequencing was utilized, along with FISH lung cancer panel. Genes examined included: EGFR, ALK, RET, ROS1, TP53, KRAS, NRAS, MET, PTEN, BRAF, FBXW7, MAP2K1, APC, PIK3CA, CTNNB1, and SMAD4. Univariable and multivariable analysis (MVA) were utilized to assess factors associated with overall survival (OS). Results: 92 pts were included. Median number of BM was 4 (range 1-45). Median age was 64 (32-90 years). 59.8% were male. 38% received targeted therapy, 11% received immunotherapy, and 70% received conventional chemotherapy. 52.2% and 47.8% received whole brain radiotherapy and stereotactic radiosurgery, respectively. Median OS from first brain radiotherapy (RT) was 10.7 months (0.1-56.4). EGFR mutation, ALK fusion, ROS1 rearrangement, and RET rearrangement occurred in 27.5%, 5.2%, 1.7%, and 0% of pts. EGFR L858 and EGFR T790 mutations occurred in 19.2% and 2.7% of all pts. TP53, KRAS, and NRAS mutations occurred in 63.9%, 28.8% and 7% of pts. All other mutations had an incidence of less than 3%. On MVA, targeted therapy (HR 0.43 95% CI 0.22-0.86), immunotherapy (HR 0.04 95% CI 0.01-0.3), surgical resection (HR 0.38 95% CI 0.18-0.81), and ECOG performance status (0.23 95% CI 0.1-0.54) were associated with improved OS. No specific genetic aberration, RT modality, or number of BM was associated with OS. Conclusions: In pts with BM from NS-NSCLC, the most common molecular aberrations include TP53, EGFR, and KRAS mutations. Treatment with brain RT and modern systemic therapies yields a median survival greater than ten months. The use of targeted therapy or immunotherapy was associated with increased OS.
Patterns of disease progression in advanced non-small cell lung cancer patients treated with PD-1 inhibitors.
Authors: Qin Angel , Kalemkerian Gregory Peter , Schneider Bryan J. , Hassan Khaled Aref , Cease Kemp Bailey , Zhao Lili , Warren Edus H. , Ramnath Nithya 
Published: September 2018

e20607 Background: The PD-1 inhibitors nivolumab and pembrolizumab are approved for the treatment of advanced non-small cell lung cancer (NSCLC), but little is known about patterns of disease progression when these agents fail. Understanding patterns of failure is key to developing strategies to improve duration of response to these agents. Methods: We gathered clinical and radiographic data on patients treated at the University of Michigan and the Ann Arbor VA for advanced NSCLC with standard-dose nivolumab (n = 68) or pembrolizumab (n = 23) after progression on platinum-based chemotherapy. Sites of disease progression were described as local (within the same lobe as primary disease), nodal (thoracic), or distant. Results: 91 patients were evaluable, of whom 56 (61.5%) had progression of disease after an average duration of therapy of 3.2 months (95%CI, 2.6-3.8). 10 (17.9%) patients had progression at local sites alone, 3 (5.4%) at nodal sites alone, 12 (21.4%) at distant sites alone, and 31 (55.4%) at a combination of sites. Overall, 41 (73.2%) had progression at distant sites. There was no statistically significant difference in clinical factors ( i.e. age, histology, comorbidity index) between progressors vs. non-progressors or distant-progressors vs. non-distant progressors. Of 37 patients who had prior radiation, 17 (45.9%) had progression at an irradiated site, with patients who had local and/or nodal progression more likely to have received radiation at site of progression (p = 0.01). The most common distant sites of progression were liver (13), bone (10), and brain (9). Conclusions: The most common site of disease progression was distant, with the liver being the most commonly involved site. This may be due to the immunotolerogenic environment of the liver, which is characterized by high IL-10 concentration and propagation of suppressive regulatory T cells, which can dampen activation of cytotoxic T cells. Prior irradiation did not seem to prevent disease progression. Our preliminary analysis suggests that the efficacy of checkpoint inhibitors is hindered in immune-privileged sites. Strategies to overcome immune tolerance should be investigated to improve duration of response to these agents.
Objective response rate and progression-free survival as surrogate endpoints for overall survival and the impact of crossover and unbalanced post-progression treatments: A systematic review and meta-analysis in second- and further-line therapy of advanced non-small cell lung cancer.
Authors: Pfeiffer Boris , Hashim Mahmoud , Bartsch Robert , Postma Maarten , Heeg Bart 
Published: September 2018

e20609 Background: Correlations between overall survival (OS) and objective response rate (ORR) or progression-free survival (PFS) are poor. We aimed to evaluate the impact of crossover and unbalanced subsequent treatments on ORR and PFS as surrogate endpoints for OS in patients with advanced NSCLC receiving second- and further-line therapy. Methods: A systematic literature review of randomized clinical trials of systemic treatment for patients with stage IIIB/IV NSCLC receiving second- and further-line therapy was performed. Weighted (by trial size) linear regression models were fitted with the absolute difference in ORR or median PFS as an independent variable and the absolute difference in median OS as a dependent variable. The analysis was repeated in predefined subsets based on crossover and balance of post-progression therapies. Surrogate threshold effect (STE) was estimated using prediction intervals. Results: 146 trials (43,061 patients) fulfilled the eligibility criteria. In all treatment arms, the mean ORR, median PFS, and median OS were 12.2% (standard deviation [SD] 11.2%), 3.2 months (SD 1.3), and 9.6 months (SD 4.1), respectively. ORR and PFS had very weak (R = 0.181; 95% CI: 0.016-0.337) and weak (R = 0.254; 95% CI: 0.074-0.418) relationships, respectively, with OS. However, within trials that did not allow crossover and reported balanced post-progression treatments, ORR and PFS had moderate (R = 0.528; 95% CI: 0.081-0.798) and strong (R = 0.778; 95% CI: 0.475-0.916) relationships, respectively, with OS. STE estimation indicated that trials that show statistically significant treatment effect size of ≥41.0% ORR or ≥4.15 median PFS months can be expected to show significant OS benefit with sufficient certainty. Conclusions: Surrogacy of ORR and PFS for OS might be better estimated in trials that do not allow crossover and report balanced post-progression treatments. Presented STE calculation can be used to estimate the expected effect on OS when either ORR or PFS are used as primary endpoints.
Coexistence of rearranged during transfection (RET) variants and activating EGFR mutations with their molecular implications in lung adenocarcinomas.
Authors: Kim Jeong-Oh , Shin Jung-Young , Kim Min Young , Son Kyoung Hwa , Jung Chan-Kwon , Kim Tae-Jung , Kim Su Young , Sung Sook-Whan , Park Jae Kil , Ro Sang Mi , Bae Sang-Ju , Min Hyun-Jung , Kang Jin Hyoung 
Published: September 2018

e20610 Background: RET rearrangements have been identified in 1-2% of lung adenocarcinomas. The most common fusion is the KIF5B-RET, the function and roles of the RET fusion oncogene, and its downstream signaling molecules remain unclear. Methods: We constructed a tissue microarray (TMA) comprising 581 resected tumor tissues from lung adenocarcinoma patients and investigated them using FISH with RET break-apart and KIF5B-RET SY translocation probes. NanoString’s nCounter technology was used to assay RETtranscripts. We evaluated the protein expressions of RET and RET-related signaling molecules, including p-AKT and p-ERK, using TMA-based IHC staining. Results: Using FISH, we identified 51 cases (8.8%) of RET variants and 10 cases (1.7%) of KIF5B-RET fusion genes among the 581 cases. RET protein expression was lower in the group harboring KIF5B-RET fusion gene than that in the group harboring a wild type RET gene. We found the activating EGFR mutations in 11 (21.6%) cases of 51 RET variants. For the group with KIF5B-RET fusion gene, the expression of p-ERK was significantly lower in EGFR mutation subgroup with presence of RET protein compared to EGFR mutation subgroup with absence of RET protein. For the group with RET rearrangement, there were significant differences in the expression level of p-AKT (P = 0.028) and, p-ERK protein expression was remarkably increased, especially in cases with no RET protein expression. Conclusions: Taken together, the expression of p-ERK protein was meaningfully increased in the RET variants group regardless of RET protein expression. This result suggests that RET inhibitors combined with ERK inhibitors may be an effective treatment strategy for lung adenocarcinoma patients harboring the RET variants.
A phase 1B study of SNX-5422 plus carboplatin (C) and paclitaxel (P) in patients with advanced non-small-cell lung cancer (NSCLC).
Authors: Gutierrez Martin , Giaccone Giuseppe , Liu Stephen V. , Hao Zhonglin , Hilton Christie , Hinson James M , Orlemans Everardus Otto , Drilon Alexander E. 
Published: September 2018

e20622 Background: SNX-5422 is an orally bioavailable pro-drug of SNX-2112, a highly potent and selective heat shock protein (Hsp) 90 inhibitor with synergy with platinum and paclitaxel. In this study, SNX-5422 + C/P followed by SNX-5422 maintenance therapy was examined in patients (pts) with NSCLC. Preliminary study results from the first 12 pts established the maximum tolerated dose (MTD) for SNX-5422 as 100 mg/m2 for the combination, with one G3 dose limiting toxicity (DLT) of diarrhea. The updated efficacy and safety results following enrollment completion (N = 20) are presented. Methods: Eligible pts had NSCLC (EGFR wild-type or non-sensitizing mutation) and ≤1 prior line of chemotherapy. Pts received C (AUC 5) and P (175 mg/m2) every 3 weeks for up to 6 cycles and SNX-5422 every other day (starting at 50 mg/m2) for 21 of 28 days, with a standard 3+3 dose escalation design during the combination, followed by SNX-5422 (100 mg/m2 every other day) monotherapy for maintenance until disease progression. Results: Twenty pts with NSCLC (pathology assessment: 18 adenocarcinoma, 2 squamous cell carcinoma) were enrolled (mean age, 59 yrs), with 19 evaluable for efficacy. Best response was partial response in 37% (7/19) of pts, stable disease in 58% (11/19) of pts, and progressive disease in 5% (1/19) of pts. Twelve of the 19 pts (63%) continued maintenance SNX-5422 monotherapy, and 7 of the 12 (58%) received therapy for ≥8 cycles. Four pts had G3 DLTs with combined therapy (considered possibly related to ≥1 agent): diarrhea (1 pt discontinued), increased alanine aminotransferase/aspartate aminotransferase (ALT/AST) (1), nausea, vomiting, and diarrhea (1), and peripheral sensory neuropathy (1). The most common adverse events considered possibly related to the combination were diarrhea (n = 14), nausea (n = 10), fatigue (n = 8), alopecia (n = 5), and vomiting (n = 5), and the majority of these events were G1/2. Conclusions: SNX-5422 added to C/P was well-tolerated at doses up to 100 mg/m2, and preliminary efficacy of this combination in NSCLC warrants further study. Clinical trial information: NCT01892046.