tbuckley/cabot-search huggingface dataset:
Promoting breast cancer screening after multiplex genetic panel testing (MGPT) and genetic counseling.
Authors: Gregory Idos, Allison W. Kurian, Charite Ricker, Duveen Sturgeon, Julie Culver, Kerry Kingham, Rachel Koff, Nicolette M. Chun, Courtney Rowe-Teeter, John Kidd, Brent Evans, Krystal Brown, Meredith Mills, Cindy Ma, Christine Hong, Kevin J McDonnell, Uri Ladabaum, James M. Ford, Stephen B. Gruber
Journal: Journal of Clinical Oncology (2018)

1581 Background: Cancer screening guidelines recommend that germline carriers with a pathogenic variant (PV) in a breast cancer susceptibility gene undergo more intensive breast screening including breast magnetic resonance imaging (MRI). We assessed the impact of genetic counseling and MGPT on adherence to recommended screening. Methods: In a prospective cohort study of 2000 patients undergoing MGPT, patients completed self-adminstered questionnaires to document breast cancer screening within one year of testing. Patients were surveyed at 3, 6, and 12 months after genetic results disclosure. Multivariable logistic regression was used to analyze an association between MGPT result and breast MRI after adjusting for study center, personal history of breast cancer and personal history of breast surgery. Results: 2000 patients completed MGPT and 1532 (77%) completed at least one follow-up survey. 242 (12%) tested positive for at least 1 PV in any one of 25 (or 28) genes. MGPT identified a PV in the following increased risk breast cancer genes: BRCA1 (n = 41), BRCA2 (n = 36), CHEK2 (n = 17), ATM (n = 16), NBN (n = 2), PALB2 (n = 9), TP53 (n = 6), and CDH1 (n = 1). Within 1 year, patients with a PV (OR = 2.1 95% CI [1.45-3.15], p < 0.001) were more likely to undergo MRI versus those testing negative. Patients with a PV in BRCA1/2 (OR = 3.5 95% CI [1.96-6.33], p < 0.001) or a moderate risk breast cancer gene (CHEK2, ATM, NBN) (OR = 3.3 95% CI [1.30-8.15], p = 0.012) were three times more likely to have MRI versus those testing negative. Patients with a PV in other high risk breast cancer genes (PALB2, TP53, or CDH1) were three times more likely to undergo MRI (OR = 3.5 95%CI [0.76-15.97], p = 0.107) versus those testing negative, but the results did not reach statistical significance. There was no difference in Breast MRI (OR = 1.0 95%CI [0.78-1.37], P = 0.814) use among those with a variant of uncertain significance (VUS) versus those with negative results. Conclusions: MGPT and genetic counseling prompted patients with a BRCA1/2 PV to appropriate adoption and adherence to breast cancer screening. There was no difference in screening between those with VUS or negative results. Clinical trial information: NCT 02324062.
Identification of Chemotherapy-Induced Leukemic-Regenerating Cells Reveals a Transient Vulnerability of Human AML Recurrence
Authors: Allison L. Boyd, Lili Aslostovar, Jennifer Reid, Wendy Ye, Borko Tanasijevic, Deanna P. Porras, Zoya Shapovalova, Mohammed Almakadi, Ronan Foley, Brian Leber, Anargyros Xenocostas, Mickie Bhatia
Journal: Cancer Cell (2018)
A CODAR-PCR assay using nucleic acids extracted from whole blood samples to provide superior sensitivity in EGFR T790M mutation detection and accurate prediction of osimertinib response in advanced NSCLC patients.
Authors: Qiong Zhao, Mingjiao Sun, Yongquan Dong, Yun Zhen, Huanhuan Yang, Xiaobin Yang, Liang Wang, Qi Lv, Xingmin Li
Journal: Journal of Clinical Oncology (2018)

e24221 Background: Plasma-derived circulating tumor DNA (ctDNA) has been the predominant source of nucleic acids for tumor mutation detection in today’s liquid biopsy technologies. However tumor-derived genetic materials also exist in other forms in blood.We developed and evaluated a highly sensitive liquid biopsy technology that features a modified ARMS-PCR using as template both DNA and RNA extracted from whole blood. Methods: We recruited 43 NSCLC patients previously treated but became resistant to first- or second-generation EGFR TKIs. Both whole blood and plasma samples were collected, and matching tissue biopsy samples in 8 patients. The results of the EGFR T790M mutation detection by the CODAR-PCR assay using both DNA and mRNA extracted from the whole blood samples were compared to those using ctDNA. For the discordant cases, droplet digital PCR (ddPCR) was performed on plasma ctDNA.13 patients harboring the T790M mutation as determined by the CODAR-PCR assay using the whole blood samples were prospectively treated with Osimertinib. Results: We identified more T790M mutation positive samples (22/43) with CODAR-PCR using DNA and RNA extracted from whole blood than using ctDNA isolated from plasma(19/43).The whole-blood-based CODAR-PCR and the plasma ctDNA-based assay have a positive percent agreement (PPA) of 94.7% and negative percent agreement (NPA)of 83.3% (kappa≈0.7681). The whole-blood-based CODAR PCR also has a higher sensitivity [83.3%(5/6)] than plasma ctDNA-based CODAR PCR [66.7%(4/6)]. In the five cases for which the plasma ctDNA-based and the whole blood-based assay results were discordant, ddPCR results were more concordant with the less sensitive plasma ctDNA-based assay results. Conclusions: We have developed a highly sensitive CODAR-PCR assay detecting EGFR T790M mutation with a limit of mutation detection at 0.01% in a background of wild-type DNA. Moreover, we demonstrated that using nucleic acids extracted from whole blood samples gives rise to a higher sensitivity in mutation detection and a greater predictive power for Osimertinib response than using ctDNA from plasma.
High pretreatment neutrophil-to-lymphocyte ratio (NLR) and its reactive increase as better predictors of poor clinical outcomes compared to tumor mutation burden (TMB) in solid tumor patients treated with immune checkpoint inhibitors (ICI).
Authors: Vaia Florou, Wungki Park, Alfredo Enrique Torres, Sandra Algaze, Diana Saravia, Breelyn A. Wilky, Jaime R. Merchan, Peter Joel Hosein, Albert Craig Lockhart, Gilberto Lopes
Journal: Journal of Clinical Oncology (2018)

e24109 Background: High NLR predicts resistance to ICIs in solid tumors. Neutrophil recruitment to tumor-draining lymph nodes post immunotherapy can exhaust cytotoxic T cells, thus promoting immunotherapy resistance. We combined NLR and DNLR [Delta NLR = NLR after first cycle - pretreatment NLR] to reflect reactive neutrophil recruitment in the peripheral blood. Methods: We identified 93 patients (pts) with solid tumors who received ICIs. There were 60 NSCLC, 10 melanoma, 4 RCC, and 19 other solid tumors. 49 pts received nivolumab, 27 pembrolizumab, 10 atezolizumab, and 7 ipilimumab and nivolumab. All 93 patients were categorized into three groups: good- DNLR < 0 AND NLR < 5, intermediate- DNLR < 0 OR NLR < 5, poor- DNLR≥0 AND NLR≥5. We also classified the pts according to their TMB: high [≥ 20 m/Mb (mutations per megabase)], intermediate (6-19 m/Mb) and low (≤5 m/Mb). We evaluated the overall survival (OS) and progression free survival (PFS). Results: The median follow-up was 15.8 months (M) (95% CI:14.0-17.6). The number of patients for good, intermediate, and poor groups were 16 (17.2%), 58 (62.3%), and 19 (20.4%) patients, respectively. The median OS for the good, intermediate, and poor groups were 23.9 (18.3-29.6), 19.7 (16.1-23.2), and 6.9 (3.6-10.2) M, respectively. Log-rank test for OS was significant (p = 0.00003). The median OS for the good group was not reached. The median OS for the intermediate, and low group were 16.7 (8.8-24.5), and 5.7 (2.6-8.8) M, respectively. We identified 11, 42 and 40 patients with high, intermediate and low TMB. There were no differences of PFS (p = 0.281) or OS (p = 0.619) across all three TMB groups. Conclusions: In this retrospective single institutional cohort, TMB did not correlate with clinical outcomes in this diverse and heterogenous group of solid tumor patients treated with ICIs. The combination of NLR and DNLR was a better predictor of OS regardless of the tumor types. This suggests that recruitment of reactive neutrophils may be potentially used as an indicator of poorer prognosis in patients treated with ICIs.
Abstract 16238: Apixaban versus Warfarin in the Evaluation of Progression of Atherosclerotic Calcification and Vulnerable Plaque (A Prospective Randomized Trial)
Authors: Theingi Tiffany Win, Rine Nakanishi, Kazuhiro Osawa, Dong Li, Shriraj Susaria, Eranthi Jayawardena, Sajad Hamal, Michael Kim, Alexander Broersen, Pieter Kitslaar, Christopher Dailing, Matthew J Budoff
Journal: Circulation (2017)

Background: Warfarin, a vitamin K antagonist (VKA) and one of the most commonly used anticoagulants, has been showed to increase vascular calcification leading to increased cardiovascular (CV) even...
Effect of intravenous contrast on renal function in advanced and metastatic renal cell carcinoma.
Authors: Sagar Shashi Patel, Chad Christian Cherington, Mark Tyson, Erik P. Castle, Thai Huu Ho
Journal: Journal of Clinical Oncology (2016)

e16071 Chronic kidney disease (CKD) after serial intravenous contrast exposure in patients who have had nephrectomy for kidney tumors.Background: Risk of CKD after long-term repetitive intravenous contrast imaging is not well described in post-nephrectomy or metastatic kidney cancer. Patients with reduced nephrons are at increased risk of CKD and often require serial contrast imaging placing them at risk for Contrast-induced nephropathy (CIN) and potential CKD. Methods: This is a retrospective review of 290 patients, of whom 271 had a partial or radical nephrectomy (PN or RN) for kidney tumors at Mayo Clinic-Arizona or Mayo Clinic-Florida from 2010 through 2014 and 19 patients did not have nephrectomy, but were considered in the setting of metastatic Renal Cell Carcinoma (RCC). Results: We found 209 patients received at least one contrast scan, of whom 99 had metastatic RCC, 105 had local RCC and 5 had oncocytoma compared to the 81 patients without contrast had metastatic RCC in 22, local RCC in 50 and oncocytoma in 9 patients. Median age was 61 years old with a male to female ratio of 232:58 and median follow up of 26 months (range 1-96). Median baseline glomerular filtration rate (GFR) was 61 ml/min with a median decline post-nephrectomy of 17.18 ml/min for RN and +2 ml/min for PN. Median baseline GFR in the 81 patients who did not receive contrast was 68 ml/min with a median decline post-nephrectomy of 16.98 ml/min for RN and 3 ml/min for PN. The median contrast exposure scans were 4 (range 1-30 scans) with a median follow up of 26 months (range 1-96 months. There were 8 (8/209 = 4%) CIN events, 6 had a RN and 1 with PN and 1 aborted nephrectomy (p value 0.37). Conclusions: In this retrospective analysis, patients with chronic contrast exposure had a similar decline in median GFR compared to those without serial contrast exposure over the median follow up time. Analysis of major risk factors for CKD show that the prevalence of these factors are similar in our contrast and non-contrast groups. The limitations are follow up time, and uncertainty on whether patients in the non-contrast exposure group received contrast scans outside of Mayo Clinic. Longer follow-up, prospective control and larger sample size may help answer this question in future studies.
TBX20 Regulates Angiogenesis Through the Prokineticin 2–Prokineticin Receptor 1 Pathway
Authors: Shu Meng, Qilin Gu, Xiaojie Yang, Jie Lv, Iris Owusu, Gianfranco Matrone, Kaifu Chen, John P. Cooke, Longhou Fang
Journal: Circulation (2018)

Angiogenesis is integral for embryogenesis, and targeting angiogenesis improves the outcome of many pathological conditions in patients. TBX20 is a crucial transcription factor for embryonic development, and its deficiency is associated with congenital heart disease. However, the role of TBX20 in angiogenesis has not been described.Loss- and gain-of-function approaches were used to explore the role of TBX20 in angiogenesis both in vitro and in vivo. Angiogenesis gene array was used to identify key downstream targets of TBX20.Unbiased gene array survey showed that TBX20 knockdown profoundly reduced angiogenesis-associated PROK2 (prokineticin 2) gene expression. Indeed, loss of TBX20 hindered endothelial cell migration and in vitro angiogenesis. In a murine angiogenesis model using subcutaneously implanted Matrigel plugs, we observed that TBX20 deficiency markedly reduced PROK2 expression and restricted intraplug angiogenesis. Furthermore, recombinant PROK2 administration enhanced angiogenesis and blood flow recovery in murine hind-limb ischemia. In zebrafish, transient knockdown of tbx20 by morpholino antisense oligos or genetic disruption of tbx20 by CRISPR/Cas9 impaired angiogenesis. Furthermore, loss of prok2 or its cognate receptor prokr1a also limited angiogenesis. In contrast, overexpression of prok2 or prokr1a rescued the impaired angiogenesis in tbx20-deficient animals.Our study identifies TBX20 as a novel transcription factor regulating angiogenesis through the PROK2-PROKR1 (prokineticin receptor 1) pathway in both development and disease and reveals a novel mode of angiogenic regulation whereby the TBX20-PROK2-PROKR1 signaling cascade may act as a "biological capacitor" to relay and sustain the proangiogenic effect of vascular endothelial growth factor. This pathway may be a therapeutic target in the treatment of diseases with dysregulated angiogenesis.
A phase I dose-finding study of metformin in combination with concurrent cisplatin and radiation in patients with locally advanced head and neck squamous cell carcinoma.
Authors: Shuchi Gulati, Benyamin Yaniv, Sarah Palackdharry, Vinita Takiar, Michelle Lynn Mierzwa, Muhammad Kashif Riaz, John Charles Morris, Changchun Xie, J. Silvio Gutkind, Pankaj B Desai, Nooshin Hashemi Sadraei, Trisha Michel Wise-Draper
Journal: Journal of Clinical Oncology (2018)

6074 Background: Up to 60% of HNSCC present as locally advanced disease (LAHNSCC). Although prognosis has improved significantly, 3 year PFS and OS remain at 62%, and 73% respectively (RTOG 0522) despite definitive cisplatin (Cis) based chemo-radiation (CRT), underscoring the need for improved regimens. Metformin (MET) is hypothesized to suppress tumor cell growth by mTOR pathway inhibition, which mediates the phosphoinositide 3-kinase/Akt signaling pathway (frequently deregulated in HNSCC). Retrospective studies suggest that MET improves survival in HNSCC patients (pts). Therefore, we conducted a phase I open-label single site dose escalation study combining MET with CRT in LAHNSCC (NCT02325401). Methods: Previously untreated LAHNSCC (Stage III/IV) pts were enrolled to receive escalating doses of MET with a 7-14 day lead-in prior to CRT based on modified toxicity probability interval design. Starting dose of MET was 2000mg daily in addition to Cis (100mg/m2 days 1, 22 and 43) and standard radiation (70Gy) (Table 1). Adverse events were categorized per CTCAE v4.03. Results: 20 pts were enrolled, (2 replaced due to withdrawal of consent during lead-in period). Most common grade ≥ 2 toxicities were nausea (25%), vomiting (25%), diarrhea (20%), and AKI (15%). Dose limiting toxicity (DLT) included Grade 3 diarrhea (cohort 3) and AKI (cohort 2). MTD was established at 2550mg daily in combination with CRT. Median age was 55 (46-65); majority pts were male (95%), Caucasian (95%), tobacco users (70%), and HPV positive (70%). After a median follow up of 18 months (range 1-26), 1-year PFS, and OS remain at 94%. 1 death was reported (sudden cardiac, unrelated, occurred > 8 weeks after stopping MET). Pharmacokinetic data showed that Cis did not affect MET steady state. Conclusions: For the first time, MET is shown to be safe and tolerable in combination with CRT with an impressive impact on survival in LAHNSCC pts. This warrants further investigation in a phase II trial, with the established MTD of 2550 mg as the recommended dose. Clinical trial information: NCT02325401.Dose-escalation schedule. Dose Level Dose Met Daily (divided doses) Level -1 1500mg Level 1 2000mg Level 2 2550mg Level 3 3000mg Expansion MTD
Characterization of CTCs isolated from patients with recurrent ovarian cancer using an antibody-free CTC isolation device.
Authors: Alpa Manchandia Nick, Geoff Copper, Weiguo Wu, Cherie Dantone, Asifa Haider, Bryan Fellman, Darren W. Davis, Anil Sood
Journal: Journal of Clinical Oncology (2016)

e17056 Background: Elucidating the molecular pathways that drive progression or metastases of ovarian cancer may provide insight into prognosis and potentially treatment of advanced or recurrent ovarian cancer. Reports have shown that EpCAM based methods detect only a fraction of CTCs and miss the heterogenous subpopulations related to epithelial to mesenchymal transition (EMT) which is considered a hallmark of cellular invasion and metastases. The objective of this work was to isolate CTCs using an antibody-free CTC isolation device. Methods: Blood samples from 25 recurrent ovarian cancer patients were collected and processed using an antibody-free CTC isolation device. Isolated cells were immunophenotyped using a multiplexed immunofluorescence assay for epithelial [CK, EpCAM, E-Cadherin, CA125], CD45, DAPI and mesenchymal [Vimentin, N-Cadherin, CD44, TWIST], CD45, DAPI cell populations. Laser scanning cytometry analysis was applied to identify subsets of cells for the expression and distribution of epithelial and EMT markers. CTC populations were then correlated with clinical prognostic factors and patient outcomes. Results: The majority of patients had advanced stage disease (Stage III [76%], Stage IV [20%]), high grade (83.3%), serous histology (88%), underwent optimal tumor reductive surgery (68%), and were considered platinum sensitive at the time of blood collection (60% vs. 40%). EPI+/CD45- CTC’s were detected in 21/25 (84%) patients and EMT+/CD45- CTC’s were detected in 21/25 (85%) patients. CTC counts ranged from 0-115/mL (median = 6) for the EPI+ phenotype and 0-180/mL (median = 6) for the EMT+ phenotype. Although there was no significant correlation between CTC cell counts and clinical prognostic factors, there appears to be a trend towards higher number of EMT+/CD45- cells in patients with high grade (81% vs. 19%) tumors of serous histology (90 vs. 10%). Conclusions: This antibody-free CTC isolation device isolated cells from blood of ovarian cancer patients with phenotypic characteristics of CTCs. Further study is warranted to determine the prognostic impact of EMT positive CTCs and their impact on survival.
Objective response rate (ORR) and time to treatment failure (TTF) for BRAF v600 mutated metastatic melanoma (BRAF+ MM) patients receiving first-line (1L) treatment with dabrafenib/trametinib (D+T) v ipilimumab/nivolumab (I+N) and nivolumab or pembrolizumab (N/P) monotherapy at US-based community oncology practices.
Authors: Bruce A. Feinberg, Jonathan Kish, Sameer R. Ghate, Briana Ndife, Choo Hyung Lee, Lindsay McAllister, Sonam Mehta, Antonio Reis Nakasato, Jason J. Luke
Journal: Journal of Clinical Oncology (2018)

e21538 Background: D+T, I+N, N and P are approved for the treatment of BRAF+ MM. Without head to head trials of D+T v. I+N or N/P comparative effectiveness of real world outcomes are needed to better inform treatment decisions. Methods: Physicians from the Cardinal Health Oncology Provider Extended Network identified BRAF+ MM patients initiating 1L with D+T, I+N, or N/P after 01/01/2014 through 6/31/2017. Treatment and clinical data (including target lesion measurements) were entered into electronic case-report forms which were validated by clinical research staff. 1L ORR using RECIST v1.1 and TTF was compared between D+T and I+N, N/P. Odds ratio (OR) for objective response (complete or partial) using multivariate logistic regression and hazard ratio (HR) for TTF using a Cox proportional hazards models adjusted for patient factors were calculated. Results: 53 providers contributed 345 patients. Patient characteristics, ORR, median TTF, and model estimates are shown in the table. ORR was significantly lower in N/P than in D+T (42.3% v 60.6%, p=0.01); adjusted OR was not significantly different. Median TTF was significantly longer in D+T versus I+N (11.4 v 4.6 mo, p<0.001) but not N/P (12.0 mo, p=0.26). Risk of treatment failure was 3.2 times greater (HR=3.2; 95% CI: 2.3-4.6) among I+N v D+T. Conclusions: In the largest community-based study of 1L outcomes for BRAF+ MM the ORR was greatest for 1L D+T. TTF for 1L D+T was longer than I+N but similar to N/P. Adjusting for LDH/liver metastases, a potential community provider selection bias, results in a non-significant difference in ORR but lower risk of TTF for D+T v I+N remained. D+T N=188 I+N N=86 N/P N=71 Median Age (Yr) 61 56* 69* Female (%) 38.8 38.4 45.1 LDH Normal (%) 38.8 45.3 59.2* Sites of Metastases (%) Lung 69.7 67.4 73.2 Liver 45.2 37.2 32.4 Brain 8.5 8.1 11.3 ORR (%) 60.6 48.8 42.3* Adjusted OR; 95% CI REF 0.69; 0.37-1.30 0.53; 0.26-1.06 Median TTF (mo) 11.4; 10.5-13.1 4.6*; 3.6-7.9 12.0; 7.1-13.2 Adjusted HR: 95% CI REF 3.2*; 2.3-4.6 1.0; 0.68-1.5 * p<0.05 v D+T
Cisplatin-induced ototoxicity in head and neck squamous cell carcinoma (HNSCC) patients treated with chemoradiation: The role of WFS1 and ABCC2 heritable variants.
Authors: Mary Mahler, Yiwen Zhang, Katrina Hueniken, M. Catherine Brown, Zhuo Chen, Maryam Mirshams, Jennifer Wang, Lillian L. Siu, Anna Spreafico, Daniel Adam Breadner, Wendy A. Teft, Richard B. Kim, Eric Winquist, Carolyn Falls, Fei Fei Liu, David Paul Goldstein, Scott Victor Bratman, Wei Xu, Andrew Hope, Geoffrey Liu
Journal: Journal of Clinical Oncology (2018)

6048 Background: Ototoxicity is a common adverse drug reaction associated with cisplatin therapy and with radiation to the HN region. We evaluated the differential effect on hearing impairment in HNSCC patients by candidate polymorphisms of genes associated with either hearing loss or cisplatin function. Methods: In this observational study of locally-advanced HNSCC patients treated with cisplatin chemoradiation, hearing impairment attributed to treatment was defined as ≥grade 2 audiometric change from baseline to post-treatment, evaluated within 18 months of completing therapy (CTCAE v4.02). Patients were genotyped for 30 polymorphisms using Sequenom. Logistic regression evaluated associations between genetic variants and ototoxicity. Cox regression assessed relationships between genetic variants and locoregional control (LRC), distant control (DC), disease free survival (DFS) and overall survival (OS). Results: Of 246 patients who had audiometric testing pre- and post-chemoradiation, 79% were male; 76%, oropharyngeal cancers; 11%, oral cavity cancers; 8%, laryngeal cancer; 91%, stage IV; 58% had hearing loss. Two polymorphisms had significant associations with hearing loss post treatment: WFS1 rs62283056 and ABCC2 rs3740066. In an additive inheritance model, individuals with WFS1 variants had a significantly decreased risk of ototoxicity (P = 0.012; adjusted odds ratio (aOR) = 0.56; 95% CI, 0.4-0.9, per increase in one minor allele), while the minor allele of ABCC2 was associated with greater risk of ototoxicity (P = 0.016; aOR = 1.68; 95% CI, 1.1-2.6). In contrast, the same genetic variants were not associated with LRC, DC, DFS or OS in a larger cohort of 642 HNSCC patients. Conclusions: WFS1 genetic variant is associated with differential hearing loss in LA-HNSCC patients. An ABCC2 variant, involved with removal of cisplatin from cells, is associated with increased cisplatin-induced ototoxicity. The same genetic variants were not associated with any efficacy outcomes. This information could be useful in the development of predictive models for cisplatin-induced ototoxicity.