tbuckley/cabot-search huggingface dataset:
The landscape of clinically actionable ALK/MET/RET/ROS1 fusions to reveal a shared pattern of protein domains in fusion partners.
Authors: Lauren Ritterhouse, Dora Dias-Santagata, Valentina Nardi, A. John Iafrate, Long P. Le, Jochen K Lennerz
Journal: Journal of Clinical Oncology (2016)

11560 Background: Scalable next-generation sequencing methods for the detection of gene fusions have become available. Currently, the landscape of clinically reported ALK/RET/ROS1 fusion partners and MET exon14 skipping has not been determined. Methods: From 9/2013 until 2/2016, we genetically screened cancer samples from patients considered for targeted therapy in a CLIA-certified laboratory. Nucleic acids from FFPE-samples ( > 15% tumor purity) were subjected to anchored multiplex PCR for targeted next-generation sequencing, allowing the detection of gene rearrangements without prior knowledge of the fusion partner. Results: Review of 1798 clinical fusion assay reports identified a total of 90 patients with intergenic ALK/RET/ROS1 fusions or intragenic MET exon14 skipping (5%). MET exon14 skipping (n = 24) was more frequent than ROS1 fusions (n = 11; p= 0.023). Notably, RET fusions (n = 27) were as frequent as ALK-rearrangements (n = 28; p= 1.0) and RET showed the greatest variability in translocation partners. Review of the protein domains encoded by the 17 intergenic fusion partners (Table 1) demonstrated that 10 predicted fusion proteins contained so-called coiled-coil domains (58%). These structural motifs are known for their involvement in intracellular trafficking. The presence of coiled-coil domains (CC) in 58% of intergenic ALK/RET/ROS1 fusions cannot be merely explained by their frequency in the human proteome (~8%; n = 2400/29024 proteins; p< 0.0001). The striking prevalence of coiled-coil domains in the landscape of kinase fusions may carry pathobiologic, diagnostic, and therapeutic relevance. Conclusions: The landscape of ALK/RET/ROS1 rearrangement partners reveals domain similarities across otherwise mutually exclusive genetic subgroups. Gene Fusion partner CC Tissue(n) ATIC ALK H(1) CCDC30 ROS1 + T(1) CDDC6 RET + T(4) L(4) CD74 ROS1 L(4) EML4 ALK L(24) ERC1 RET + L(1) ETV6 RET SG(1) EZR ROS1 + L(1) HIP1 ALK + L(1) KIF5B RET + L(9) A(1) NCOA4 RET + T(3) C(1) RASAL2 RET T(1) RUFY2 RET + L(2) SDC4 ROS1 L(4) STRN ALK + T(1) TFG ROS1 + L(1) THSB1 ALK ST(1) MET MET L(24) Abbr.(n = ): Lung(75), Thyroid(10), Salivary gland(1), Adrenal(1), Colon(1), Heme(1), Soft tissue(1)
Difference in cardiovascular disease incidence by sociodemographic factors in adolescent and young adult (AYA) cancer survivors.
Authors: Theresa Keegan, Lawrence H. Kushi, Qian Li, Ann Brunson, Marcio H. Malogolowkin, Theodore Wun
Journal: Journal of Clinical Oncology (2017)

6565 Background: AYA cancer survivors are at increased risk of developing cardiovascular disease (CVD) compared to AYAs without a history of cancer. In AYA cancer survivors, few population-based studies have focused on CVD risk and none have considered whether the occurrence of CVD differs by sociodemographic factors. Methods: Analyses focused on 64,918 patients aged 15-39 y at diagnosis for one of 14 first primary cancers during 1996-2010 and surviving &gt; 2 years after diagnosis, with follow-up through 2013. Data were obtained from the California Cancer Registry and State hospital discharge data. CVD included coronary artery disease, heart failure, and stroke. We estimated the cumulative incidence of developing CVD, accounting for death as a competing risk, stratified by race/ethnicity, neighborhood socioeconomic status (SES) at diagnosis, health insurance status at diagnosis/initial treatment and cancer type. We examined the impact of CVD on mortality using multivariable Cox proportional hazards regression with CVD as a time-dependent covariate. Results: Overall, 2374 (3.7%) patients developed CVD, and 7690 (11.9%) died over the follow-up period. Survivors of acute myeloid leukemia (12.6%), acute lymphoid leukemia (11.1%), central nervous system cancer (9.0%) and non-Hodgkin lymphoma (6.0%) had the highest incidence of CVD at 10-years. Incidence was significantly higher among Blacks (6.7%) at 10-years than non-Hispanic Whites (3.0%), Hispanics (3.7%) and Asian/Pacific Islanders (3.7%) (p &lt; 0.001). AYA survivors with public or no insurance (vs private) had a higher 10-year incidence of CVD (5.8% vs 2.9%; p &lt; 0.001), as did survivors residing in low (vs high) SES neighborhoods (4.1% vs 2.7%; p &lt; 0.001). These sociodemographic differences in CVD incidence were apparent across most cancer sites. The risk of death was increased by five-fold or higher among AYAs who developed CVD. Conclusions: AYA cancer survivors who were uninsured or publicly insured, of Black race/ethnicity, or who resided in lower SES neighborhoods are at increased risk for developing CVD and experiencing higher mortality. The proactive management of CVD risk factors in these subgroups may improve patient outcomes.
Oncologists’ awareness, knowledge, and perceptions of value frameworks.
Authors: William Bruce Wong, Arliene Ravelo, Marco DiBonaventura, Bijal Shah-Manek
Journal: Journal of Clinical Oncology (2017)

e18317 Background: The increasing prevalence of cancer coupled with approvals of new drugs and technologies have brought increased scrutiny to cost/benefit of treatments in oncology. To address the rising concern about oncology drug costs, several stakeholders have developed frameworks to help assess the value of oncology regimens. The objective of this study was to assess oncologists’ perceptions, awareness and knowledge of all oncology value frameworks in the US. Methods: Data were collected from an electronic cross-sectional survey of 200 US-based oncologists recruited from an online panel. Oncologists were asked about their knowledge and perceptions of four value frameworks – the National Comprehensive Cancer Network’s (NCCN) Evidence Blocks, American Society of Clinical Oncology (ASCO) Value Framework, Institute for Clinical and Economic Review (ICER) Value Framework and Memorial Sloan Kettering (MSK) Drug Abacus framework. Findings were reported descriptively. Results: Oncologists were most familiar with the NCCN Evidence Blocks (90%) followed by the ASCO Value Framework (84%), ICER value framework (57%) and Drug Abacus (56%). Among those that were familiar with the value frameworks, almost equal proportions found the NCCN Evidence Blocks vs. ASCO Value Framework to be “useful/very useful” (75% vs. 74%) followed by ICER Value Framework (64%) and Drug Abacus (56%). More than three out of four oncologists surveyed (76%) had used value frameworks in the past, with NCCN Evidence Blocks being used most often (61.5%) followed by ASCO Value Framework (48.4%), ICER Value Framework (21%) and Drug Abacus (15%). NCCN Evidence Blocks was ranked highest for its ease of use, comprehensiveness, feasibility for use in the clinical setting, ability of patients to understand and most favorable overall, followed by ASCO Value Framework, ICER Value Framework and Drug Abacus. Conclusions: The majority of oncologists were familiar with value frameworks and had used them in the past. Of the four oncology Value Frameworks, NCCN Evidence Blocks were perceived most favorably by oncologists followed by ASCO Value Framework.
Abstract B032: Inappropriate AR reactivation-induced redox stress as a novel therapeutic target in castration-resistant prostate cancer
Authors: Govindi J. Samaranayake, Clara I. Troccoli, Mai Q. Huynh, Rolando D.Z. Lyles, Deukwoo Kwon, Yuguang Ban, Steven Xi Chen, Merce Jorda, Kerry Burnstein, Priyamvada Rai
Journal: Cancer Research (2018)

Abstract Androgen deprivation therapy (ADT) initially suppresses prostate cancer (PC) progression. However, castration-resistant PC (CRPC) cells inevitably emerge, resulting in incurable disease. We recently demonstrated that AD produces a form of cellular senescence leading to outgrowth of CRPC subpopulations from the AD-sensitive parental cells. Gene expression profiling studies comparing the parental LNCaP line to the senescence-resistant, early CRPC variant, LNCaP SB5, revealed an enrichment of redox-protective proteins in the latter under AD conditions. This finding suggests that redox stress due to hyperactivated mitogenic/survival signaling or metabolic stresses may be an important and understudied Achilles heel in the progression to CRPC. Here we present the effects of inhibiting thioredoxin-1 (TRX1), a redox-protective protein that was identified as being elevated in our early CRPC LNCaP SB5 model as well as in human CRPC vs. AD-responsive PC datasets. Suppression of TRX1 expression via shRNA led to profound growth suppression of CRPC cells, relative to their AD-sensitive counterparts, and significantly reduced CRPC xenograft tumor growth. Furthermore, under AD, TRX1 suppression promoted p53-induced cell death, which was accompanied by increased reactive oxygen species (ROS). Curiously, TRX1 inhibition led to increased AR and Sp1 expression under AD, and the oxidative stress effects associated with TRX1 inhibition could be mitigated by depleting AR expression. These in vitro and in vivo results were recapitulated using PX-12 a phase I-approved pharmacologic TRX1 inhibitor. Thus our results point to TRX1 as a critical requirement for protecting against redox stress evoked by the inappropriate reactivation of AR in a low-androgen environment in CRPC. Our work provides a rationale for using TRX1 inhibitors in conjunction with ADT to limit CRPC. Citation Format: Govindi J. Samaranayake, Clara I. Troccoli, Mai Q. Huynh, Rolando D.Z. Lyles, Deukwoo Kwon, Yuguang Ban, Steven Xi Chen, Merce Jorda, Kerry Burnstein, Priyamvada Rai. Inappropriate AR reactivation-induced redox stress as a novel therapeutic target in castration-resistant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B032.
Can nutritional status predict survival in patients with advanced non-small cell lung cancer?
Authors: Sookyung Lee, Youngkwang Seo, Wankyu Eo, Sehyun Kim, Bumsang Shim
Journal: Journal of Clinical Oncology (2018)

e21096 Background: This study investigated the prognostic impact of nutritional status on survival in patients with advanced non-small cell lung cancer (NSCLC). Methods: This study retrospectively reviewed the medical records of patients with pathologically confirmed advanced NSCLC. The clinicopathological characteristics of age, sex, body mass index (BMI), histologic type of tumor, Eastern Cooperative Oncology Group Performance Status (ECOG-PS), biochemical factors of C-reactive protein (CRP) levels and white blood cell (WBC) counts, and prognostic nutritional index (PNI) at the initiation of Korean Medicine (KM) treatment were assessed. Overall survival (OS) was calculated using Kaplan–Meier analysis and compared using log-rank tests. Univariate and multivariate analyses of Cox proportional hazards regression were used to evaluate the prognostic impact for survival. Results: Of the 183 enrolled patients, 166 (90.7%) had stage IV NSCLC, 70 (38.3%) had ECOG-PS scores of 2, and 109 (60%) underwent prior systemic therapy. Univariate analysis revealed that older age (≥65 years; p =0.006), male sex (p= 0.029), decreased BMI ( < 21 kg/m2; p =0.011), poor ECOG-PS ( = 2; p <0.001), squamous cell carcinoma (p= 0.013), increased CRP levels ( > 1.0 mg/dL; p< 0.001), increased WBC counts ( > 11,000 cells/㎕; p< 0.001), and decreased PNI (≤45.6; p< 0.001) were associated with poor survival outcomes and increased mortality. After controlling for confounding factors, the multivariate proportional hazards model revealed that CRP levels, BMI, and PNI were independent prognostic factors for survival. Elevated PNI (hazards ratio (HR), 0.49; 95% confidence interval (CI), 0.33–0.71; p <0.001) and high BMI (HR, 0.64; 95% CI, 0.45–0.91; p =0.012) were associated with prolonged survival, whereas increased CRP levels (HR, 1.95; 95% CI, 1.34–2.84; p <0.001) were associated with poor survival. Conclusions: This study demonstrated that the indicators of nutritional status, PNI and BMI, were significant independent prognostic factors for survival, and were comparable to the that of the CRP levels.
Toxicity, tolerance and outcomes of carboplatin based CTRT ( concurrent chemoradiation) in head and neck cancers in patients who were not fit for cisplatin based CTRT.
Authors: Vibhor Sharma, Vijay Maruti Patil, Vanita Noronha, Amit Joshi, Sachin Dhumal, Kumar Prabhash
Journal: Journal of Clinical Oncology (2016)

e17539 Background: Cisplatin based chemoradiation (CTRT) is the standard of care in locally advanced head and neck cancers. Limited treatment options are available in patients who are not fit for cisplatin based CTRT. This audit was carried out to study the toxicity, tolerance and outcomes of carboplatin based CTRT in patients who were not eligible for cisplatin based CTRT. Methods: A total of 63 locally advanced head and neck cancer patients treated between January 2011 - October 2015 , were administered carboplatin based CTRT. The dose of carboplatin was AUC-2 weekly for a maximum of 7 cycles. SPSS version 16 was used for analysis. Descriptive statistics is performed. Toxicity is coded in accordance with CTCAE version 4.03. Progression free survival (PFS) and overall survival (OS) were estimated by Kaplan Meier survival analysis.Cox proportional hazard model was used for identifying factors affecting PFS and OS. Results: The reason for medical unfitness for cisplatin were low serum creatinine clearance in 41 patients (63.5%), sensorineural hearing loss in 18 patients (27.0%), uncontrolled medical comorbidity in 03 patients (4.8%)and old age in 1 patient (1.6%). 53 patients (84.1%) completed radiation and the median number of carboplatin cycles were 6 (IQR 5-7). Grade 3-4 toxicity was seen in 32 patients (50.8%). The rate of grade 3-4 mucositis and weight loss was 22.2% (14 patients) and 17.5% (11 patients) respectively. The median OS and PFS were 27.1 months (95%CI 19.6-34.6 months) and 14.4 months (95%CI 07.1-21.7 months) respectively. The factor influencing PFS was age (HR 1.07, 95% CI 1.001-1.137, p-0.046) while the same factor influenced OS also( HR 1.15, 95% CI 1.044-1.268, p-0.005). Conclusions: Carboplatin based CTRT is well tolerated in patients unfit for Cisplatin and seems to have superior outcomes than those reported in radical radiotherapy studies.
Treatment of BRAF-mutated metastatic melanoma patients with targeted therapy combinations or immunotherapy in real world setting.
Authors: Janja Ocvirk, Marija Ignjatovic, Martina Rebersek, Marko Boc
Journal: Journal of Clinical Oncology (2018)

e21630 Background: Evaluation of efficacy and safety of pembrolizumab (P), vemurafenib plus cobimetinib (V+C) and dabrafenib plus trametinib (D+T) was done in a retrospective analysis of patients (pts) with BRAF-mutated metastatic melanoma (BRAF+ mM) in routine clinical practice. Methods: Baseline characteristics, efficacy data and treatment-related adverse events were collected from 83 BRAF+ mM pts who were treated in 1st line setting: 41 pts with V+C, 25 pts with D+T and 17 pts with P. Results: In 24-month period, 167 pts were diagnosed with unresectable or mM and tumor tissue was positive for BRAF V600E/K/R mutation (88% BRAF V600E, 11% BRAF V600K and 1% BRAF V600R) in 87 pts (52%). Baseline characteristics were slightly different among treatment groups: median LDH level was lower in D+T group and disease stages with more favorable prognosis were more frequent in P group. In V+C, D+T and P treated pts groups median age was 54.8, 54.3 and 56.3, respectively; % of males 71%, 76% and 71%; elevated LDH level in 59%, 52% and 59% of pts, stages M1c(0)-M1d(1) 78%, 80% and 53% of pts. In pts with assessable disease (88% in V+C, 68% in D+T and 82% in P group) the overall response rate (ORR) was 64% in V+C, 76% in D+T and 64% in P group. Disease control rate (DCR) was 89% in V+C, 82% in D+T and 71% in P group. Median progression-free survival (PFS) was 7.9 months (95% CI, 5.5-10.2) in V+C group, 5.9 months (95% CI, 3.6-8.1) in D+T group and 8.2 months (95% CI, 4.6-11.8) in P group. Median overall survival (OS) was 10.1 months (95% CI, 7.4-12.8) in V+C, 6.1 months (95% CI, 3.8-8.3) in D+T and 9.2 months (95% CI, 5.6-12.7) in P group. At the time of analysis 39% of pts are alive in V+C group, 76% in D+T and 77% in P group and still on treatment 21%, 72% and 53% of pts, respectively. The best outcomes had subgroup of pts with normal LDH level: DCR was 100% in V+C, 100% in D+T and 70% in P group, with 57%, 100% and 70% pts alive, respectively. Adverse events (AEs) of any grade were reported in 68% of pts in V+C, 64% in D+T and 35% in P group. AEs grade 3 or 4 were reported in 29% of pts in V+C, 0% in D+T and 12% in P group. Conclusions: Targeted therapy combinations and immunotherapy have shown meaningful efficacy with manageable safety profiles in real world setting.
The correlation between Crizotinib efficacy and molecular heterogeneity by next-generation sequencing in non-small cell lung cancer.
Authors: Tangfeng Lv, Yong Song, Qian Zou, Zhengbo Song, Hongbing Liu
Journal: Journal of Clinical Oncology (2018)

e21167 Background: Non-small cell lung cancer (NSCLC) patients harboring EML4-ALK fusion exhibited various duration of response to crizotinib. Molecular heterogeneity was also one of the factors that were resistant to crizotinib. This study investigated the relevance of molecular heterogeneity by next generation sequencing, with clinical efficacy of crizotinib. Methods: A total of 52 ALK-positive advanced NSCLC patients were enrolled. The genetic variation had been revealed by NGS. We identified different ALK fusion types, AF and additional coexisting mutations (ACMs), evaluated the correlation between above three factors and clinical response to crizotinib. Results: Among the group which was detected with ALK+ fusion by IHC, patients detected as ALK- fusion by NGS method associated with a shorter PFS, compared with ALK (+) patients by NGS. Moreover, for different ALK fusion types, the median PFS of variant 1/2/3, and other uncommon variants were 305 days, 557 days, 242 days and 370 days, respectively. Although no statistically significant difference, patients harboring ALK variant 2 seemed to display a longer PFS trend than other types of variants in this study. Significant difference was not exist in the relationship of ALK fusion AF and PFS (p= 0.639). We analyzed the relationship between ACMs/TP53/FAT3 and PFS, found that no statistically significant (p= 0.550/0.712/0.631). Conclusions: This study provides us with a new research direction in patients with ALK-positive NSCLC, and then we can continue to carry out the study of the correlation between the different contents of heterogeneity of gene mutation and TKI effect through the next-generation sequencing method.
First-in-human study of DS-6051b in patients (pts) with advanced solid tumors (AST) conducted in the US.
Authors: Kyriakos P. Papadopoulos, Leena Gandhi, Pasi A. Janne, Sai-Hong Ignatius Ou, Alice Shaw, Terri Robin Goldberg, Jonathan Greenberg, Xuemin Gu, Masaya Tachibana, Giorgio Senaldi, Ryota Shiga, Hamim Zahir, Kenji Nakamaru, Erkut Borazanci
Journal: Journal of Clinical Oncology (2018)

2514 Background: DS-6051b is an oral, small molecule receptor tyrosine kinase inhibitor with high affinity for ROS1 and NTRK kinases. Preclinical studies demonstrated activity against tumors harboring ROS1 or NTRK fusion genes. We report results from the dose escalation (ESC) and food effects (FE) portion of a phase 1/1b study of DS-6051b with follow-up through October 2017. Methods: Pts aged ≥18 y with ASTs harboring ROS1 and NTRK mutations/fusion genes or with neuroendocrine tumors (NET) or with tumor-induced pain (TIP), regardless of ROS1/NTRK status, were eligible. Pts with ROS1 non-small cell lung cancer (NSCLC) progressing on crizotinib (CRZ) or > 1 ROS1 inhibitor were included. Primary objectives: determine the maximum tolerated dose (MTD), assess safety/tolerability (ESC) and determine FE on the pharmacokinetics (PK) of a single 400-mg daily (QD) DS-6051b dose with/without food. PK and antitumor activity were also assessed. A design of accelerated titration followed by modified continuous reassessment method and escalation with overdose control was used (50–1200 mg QD or 400 mg twice daily). Tumor assessments were every 3 cycles by RECIST 1.1. Results: In ESC, 35 pts (n = 14 NET; n = 9 TIP; n = 2 NET/TIP; n = 10 AST with ROS1/NTRK [n = 1 NTRK fusion; n = 9 ROS1 fusion including 7 NSCLC with prior CRZ]) enrolled, with 31 tumor evaluable. Dose-limiting toxicities (grade [G] 3 increased transaminases) occurred in 2 pts (1200 mg QD dose); 800 mg QD was the MTD. TEAEs G ≥3 occurred in 69% (overall) and 31% (drug-related) and all serious TEAEs in 20% (overall) and 9% (drug-related) of pts. Most common TEAEs were gastrointestinal disorders (89%); the majority (71%) G1/2. Peak concentration (Cmax) and AUC increases were generally dose-proportional. Of 6 tumor evaluable NSCLC ROS1 pts with prior CRZ, 2 had partial response (PR) and 2 had stable disease (SD). Two other pts (n = 1 NTRK fusion thyroid cancer; n = 1 NET) had PR. Prolonged SD (6.9–27.2 months) was observed in 4 (40%) of 10 tumor-evaluable NET pts. In FE (n = 11), food intake had a modest PK effect: Cmax and AUC increased by 30-45%. Conclusions: DS-6051b was well tolerated up to 800 mg QD. The observed efficacy signal in targeted populations warrants further evaluation. Clinical trial information: NCT02279433.
Contribution of microarrays of gene expression (MAGE) to the definition of PET/CT as a qualified biomarker of early response in metastatic patients.
Authors: Manuel Sureda, Aurora Crespo-Jara, Ramon Gonzalez Manzano, Maria del Carmen Redal, Francisco Javier Garcia-Cases, Elena Mª Martinez Navarro, Antonio Brugarolas
Journal: Journal of Clinical Oncology (2017)

11573 Background: Proliferating cancer cells consume elevated quantity of glucose, converted into lactate regardless the presence of oxygen (Warburg effect). This effect has been useful for imaging metabolically active tumors with FDG-PET, although its use in early response is controversial. Molecular mechanisms of FDG uptake are not fully understood. We have used MAGE to determine the most relevant genes involved in FDG uptake. Methods: Fresh-frozen tumor biopsies and quantitative basal FDG-PET/CT were obtained from metastatic lesions in cancer patients. Total tumor RNA was hybridized to a whole human genome oligonucleotide microarray. Gene expression signature-based prediction, using the most relevant genes involved in FDG uptake measured by SUV, was finally determined by Partial Least Squares (PLS). The interpretation of biological phenomena (IBP) derived from the selected genes was made by means of different public statistical bioinformatics resources. Results: 71 patients with different histological diagnosis were included in the training cohort and 13 in the validation one. 909 probes correlated significantly with SUV: 333 positively and 576 negatively. A predictive signature based on these 909 probes was built using PLS-3, with an RMSE in the validation set of 0.645 (within the 95% CI of RMSE determined in the training set). In IBP, other biological processes were more relevant than glycolysis in FDG uptake: RNA processing, ribosome biogenesis, protein processing, cell adhesion, cytoskeleton organization, angiogenesis and autophagy. Conclusions: This PLS-3-built signature is the first reported one that can accurately predict SUV. FDG uptake is a complex phenomenon that involves multiple biological processes, confirming the value of PET/CT in early response.