tbuckley/cabot-search huggingface dataset:
Inhibition of glucose metabolism through treatment of BRAF mutated metastatic melanoma with vemurafenib.
Authors: Govind Warrier, Lilibeth Lanceta, Yoannis Imbert-Fernandez, Jason Alan Chesney
Journal: Journal of Clinical Oncology (2019)

e21005 Background: Increased glucose metabolism is a hallmark of neoplastic cells that allows self-promotion of growth and survival. The enzyme 6-phosphofructo-2-kinase (PFKFB3) is an integral controller of glycolysis by promoting the synthesis of fructose 2,6-bisphosphonate (F2,6BP) which activates 6-phoshofructo-1-kinase (PFK-1), a rate-limiting enzyme and essential control point in the glycolytic pathway. Additionally, mitogen-activated protein kinase (MAPK) is a key signaling pathway in a number of cancers with mutations of the BRAF component, described most commonly in melanoma, resulting in constitutive activation of the MAPK pathway. We aim to demonstrate that vemurafenib, a BRAF inhibitor, has antiglycolytic activity in sensitive melanoma cell lines which may help guide development of future therapies with specific attention to PFKFB3 as a potential enzymatic target to decrease glycolytic flux thereby inhibiting tumor growth and survival. Methods: Vemurafenib sensitive and resistant variants of two separate human metastatic melanoma cell lines (451Lu and WM983) were treated with 3 mM Vemurafenib for 24 and 48 hours. Additionally, cells from aforementioned lines were probed for PFKFB3 after 24 hours of treatment with vemurafenib. Glycolysis was measured by incubating cells in complete media containing 1 mCi [5- 3 H]glucose for 60 minutes. [ 3 H]H 2 O produced by glycolysis through enolase was measured. Results: A decrease in PFKFB3 protein expression was found in vemurafenib sensitive cells compared to controls but not in resistant cells after 24h treatment with 3 mM vemurafenib in both 451Lu and WM983 metastatic melanoma cell lines (n = 2). Treatment with vemurafenib led to decrease in glycolysis compared to untreated controls in both vemurafenib sensitive metastatic melanoma cell lines but not in resistant cell lines (n = 5). Additionally, there was a significant reduction in glycolysis in vemurafenib resistant WM983 at 48 hours compared to resistant untreated control. Conclusions: BRAF mutated metastatic melanoma cells showed decrease in PFKFB3 protein expression and decreased glycolysis after treatment with BRAF inhibitor vemurafenib. Future studies will focus on assessing metastatic melanoma cell viability and glycolytic activity after treatment with combination BRAF inhibition and PFKFB3 specific inhibition.
A sequential dual cohort phase II clinical trial on adjuvant low-dose nivolumab with or without low-dose ipilimumab as adjuvant therapy following the resection of melanoma macrometastases (MM).
Authors: Julia Katharina Schwarze, Valerie Vandersleyen, Gil Awada, Yanina Jansen, Teofila Seremet, Bart Neyns
Journal: Journal of Clinical Oncology (2019)

9585 Background: Optimal dosing and duration of adjuvant treatment with anti-PD-1 checkpoint inhibitors, e.g. nivolumab (NIVO), following complete resection of melanoma (MEL) lymph node metastases has not been established. We investigated a regimen of low-dose NIVO with/without low-dose ipilimumab (IPI) as adjuvant therapy in MEL pts. Methods: After complete resection of MM, pts were treated with IPI 50mg (fixed dose, 1x) plus NIVO 10mg (fixed dose, Q2w x4) (Cohort-A), or NIVO 10mg (Q2w x9, Q8w x4) (Cohort-B). One-year relapse-free survival (RFS) rate served as primary endpoint. Sample size (34 pts) was calculated according to a Fleming one-stage clinical trial design. Recruitment to Cohort-B was closed prematurely following registration of NIVO in the adjuvant setting by EMA. Secondary endpoints were safety, distant metastasis-free survival (DMFS) and overall survival (OS). Quantitative measurement of BRAF/ NRAS mutant circulating tumor DNA (ctDNA), as well as tumor gene expression profiling were performed. Results: 34 pts (15M/19F, 31 stage III/3 stage IV) and 22 pts (12M/10F, 21 stage III/1 stage IV) were enrolled in Cohort-A/-B, respectively. After a median follow-up of 86w for Cohort-A and 36w for Cohort-B, estimated 12 months (m) RFS-rate was respectively 55% (95% CI, 39–72) and 78% (95% CI, 73-82), 12m OS-rate was 97% (95% CI, 94-100) and 100%, and 12m DMFS-rate was 79% (95% CI, 92-65), no distant metastases occurred in Cohort-B. Median RFS for Cohort-A was 84w (95%, CI 28-139), not-reached in -B. Median DMFS and OS had not been reached at time of analysis in either cohort. All grade treatment-related adverse events were observed in 21 (61%)/17 (77%) with 3 (8%)/1 (4%) grade 3 irAE in Cohort-A/-B, respectively. One patient in Cohort-A had a detectable level of ctDNA at baseline and relapsed 33w after initiating treatment. Tumor profiling is ongoing at time of submission. Conclusions: The investigated adjuvant low-dose regimens have an acceptable safety profile. Survival rates resemble those of standard regimens. These regimens could be economically advantageous alternatives for pts without access to standard regimens. Clinical trial information: NCT02941744.
Next Generation Sequencing in Salivary Gland Carcinomas: Do Actionable Mutations Lead to a Therapeutic Advantage? A Multicenter Experience.
Authors: Assaf Moore, Orit Gutfeld, Salem Billan, Yael Bar, Corinne Maurice Dror, Inna Ospovat, Noa Gordon, Aron Popovitzer
Journal: Journal of Clinical Oncology (2019)

e17582 Background: Salivary gland cancers (SGCs) are rare tumors. The approach to recurrent or metastatic patients is histology dependent, as the clinical course is highly variable. Response rates to chemotherapy are modest and no second-line therapies have proven to be effective. The rarity and heterogeneity of SGCs make conducting clinical trials challenging. Recent reports of Next Generation Sequencing (NGS) in SGCs have identified unique genetic attributes of certain histological classes. However, despite the elaborate work done with genetic characterization, there is very little evidence on whether these findings translate to tumor control. In this study, we aimed to explore the treatment outcomes of patients with advanced SGCs who underwent a commercially available NGS. Methods: A retrospective analysis of all patients with histologically confirmed SGC treated in three major Israeli cancer centers who underwent NGS. Results: Twenty-seven patients were included. Eighteen patients were male (66.6%). The median age was 59 (range 38-81). Histologic type was adenoid cystic carcinoma in 11 (40.7%) patients, 8 (29.6%) mucoepidermoid carcinomas, 5 (18.5%) adenocarcinomas, 2 (7.4%) salivary duct carcinomas and 1 (3.7%) acinic cell carcinoma. Twenty-five (92.6%) had recurrent disease after initial curative treatment and 2 were initially diagnosed with metastatic disease. Median time to recurrence was 24.3 months. The median number of systemic treatment lines was 1 (range 0-5). Thirteen patients (48%) had targetable findings in NGS, including: 5 ERBB2 amplifications, 3 PIK3CA mutation, 1 TRIM33-RET fusion, 1 FGFR3-TACC3 fusion, 1 MSI-high and 2 high mutational burden. Nine patients were treated accordingly; 5 in the second-line and 4 as first-line treatment. Median progression-free survival for targeted treatment was 8.4 months. Of 4 patients who achieved durable responses to anti-RET/HER2 agents and immunotherapy of 8.4 – 31.1 months, two are ongoing. The median overall survival for all patients was 101.75 months, was not reached for patients receiving targeted treatment and was 40.4 months for patients treated conventionally (p = 0.26). Conclusions: In the absence of a well-established therapeutic approach, NGS may detect clinically significant genetic alterations and benefit patients with advanced SGCs.
Searching for a link between Ki-67 values and HER2 absence in 297 patients with triple-negative breast cancer.
Authors: Sven Kurbel, Ana Tecic Vuger, Robert Separovic, Branko Dmitrovic, Damir Vrbanec
Journal: Journal of Clinical Oncology (2019)

e12551 Background: Based on the report that in ER- invasive breast cancer (IBC) patients, the absence of HER2 might be linked to their Ki-67 values ( Kurbel et al. BMC Cancer 2017;17:231), this relation was searched in 297 consecutive IBC patients with triple negative tumors, treated at two Croatian hospitals. Methods: All 297 patients had ER and PgR negative IBC, The HER2 expression was IHC absent in 211 pts.; IHC 1+ in 62 pts.: IHC 2+ &amp; ISH negative in 24 pts. Based on the cited reference that the Expectation maximization clustering (EM) of the pooled IBC Ki-67 values detects three clusters, regardless of the tumor type, the same approach was used. Differences in the distribution of HER2 values were tested by the χ2 test. Results: Three EM clusters were detected among the pooled Ki67 values: LMA (low mitotic activity) cluster: 109 cases with Ki-67 &lt; 44%; IMA (intermediate mitotic activity) cluster: 96 cases, Ki-67 from 44 to 70% and HMA (high mitotic activity) cluster: 92 cases, Ki-67 &gt; 70%. Beside the Ki-67, distribution of HER2 values was dependent on the age (Chi-square: 25.0309, df = 12, p = 0.014677), as shown here: In patients younger than 46, the HMA cluster was 32% larger than expected. Out of 29 HMA pts, 24 had HER2 absent tumors (53% more than expected). In patients aged 46 to 55, the IMA cluster was 27% larger than expected and out of 30 IMA, 24 had HER2 absent tumors (43% more than expected). In patients older than 55, the LMA cluster was 21% larger than expected, due to more patients with tumors positive for HER2. Out of 68 LMA pts., 22 pts. had tumors with HER2 expression (1+/2+), 40% more than expected. Conclusions: HER2 absent triple negative IBCs might be biologically different from the triple negative and HER2 1+/2+ tumors. The former were linked to pts younger than 55 and Ki-67 values &gt; 43%. The latter showed opposite affinities, age above 55 and Ki-67 &lt; 44%. Based on this, the absence of HER2 in triple negative IBC seems a valid target for future research.[Table: see text]
Benefits of MEDPED Treatment Support Program (TSP) for Patients with Familial Hypercholesterolemia
Authors: Paul N. Hopkins, Susan H. Stephenson, Stacey Larrinaga-Shum
Journal: Circulation (2001)

P93 As prior experience had shown treatment of heterozygous FH was often unsatisfactory, the U.S. MEDPED (Make Early Diagnoses to Prevent Early Deaths) team developed the TSP to empower FH patients to ensure the adequacy of their own care. The TSP consisted of mailed educational materials, baseline and follow-up questionnaires on lipids and medications, and individualized mailed feedback on NCEP goals and medications. There were 386 patients reporting 2 or more lipid levels. There were 6.03 contacts per patient including the baseline, 7.6 months apart. 40% of patients had initial total cholesterol under 240 mg/dl. These showed little additional benefit with follow-up. For the remainder, benefits of TSP participation were substantial as shown in the table. In repeated measures analysis, major determinants of lipid change were baseline level (p &lt;0.0001), number of contacts with TSP staff (p &lt;0.0001) and an interaction term between these two variables (p=0.05 total-C; p&lt;0.0001 LDL-C) such that patients with higher baseline values saw greater benefit with more contacts. There was a 39% to 45% reduction of total or LDL cholesterol (p &lt;0.0001) in those with the highest quintiles of initial total cholesterol (mean 388 mg/dl) and number of contacts (8 or more). Table 1.
Evaluation of immunotherapy (I-O)-associated immune cell (IC) dynamics and PD-L1 expression using multispectral immunohistochemistry (mIHC) and single-cell hierarchical regression modeling in early-stage breast cancer (ESBC).
Authors: Katherine Sanchez, Maritza Martel, Shu-Ching Chang, Yaping Wu, Zhaoyu Sun, Richard Nyberg, William L Redmond, Joanna Pucilowska, Shaghayegh Aliabadi-Wahle, James Imatani, Alison Katherine Conlin, Brady Bernard, Monil Shah, Dottie Wadell, Deborah R. Laxague, Lu Wen, Qiao Li, Gregory T. Wolf, Walter John Urba, David B. Page
Journal: Journal of Clinical Oncology (2019)

e12070 Background: In triple negative breast cancer (TNBC), anti-PD-L1 is associated with gains in overall survival, however only in tumors with &gt; 1% PD-L1+ ICs. Locoregional cytokine therapy is being evaluated as a method of priming and redirecting ICs to tumors, which may increase I-O benefit particularly in PD-L1 negative tumors. We report a sensitive method of quantifying I-O-related changes in PD-L1 and ICs using mIHC and single-cell hierarchical regression, which controls for within-tumor and across-patient PD-L1/IC heterogeneity. Methods: Pre-treatment and resection tissues from a phase Ib trial of locoregional cytokines (IRX-2, n = 16 subjects) in ESBC were analyzed. IRX-2 contains immunostimulatory cytokines (GM-CSF, IL-2, IFN-α, INF-γ, and IL-12) and was injected in peri-areolar tissue, which communicates directly with tumor-draining lymphatics. Specimens were analyzed for 1) H&amp;E stromal TILs score; 2) clinical PD-L1 IC expression (Ventana SP142, 2 blinded pathologists); and 3) mIHC (PerkinElmer Vectra). InForm software was used to obtain geospatial outputs of tumor cells (CK+) and ICs (CD3, CD8, CD163) across multiple regions of interest (mean:18; range: 9-32). Mixed-effects modeling was used to evaluate for changes in PD-L1, ICs, and IC/tumor distance metrics. Results: PD-L1 and IC quantity by mIHC was highly concordant with clinical PD-L1 IC classification (JT test = 211, p &lt; .001) and TIL score (r = 0.77). Cytokine therapy was associated with higher PD-L1 IC classification in 9/13 tumors, and increased PD-L1 ICs by mIHC in 14/15 (+337%, 95% CI: 120,769%). After adjusting for heterogeneity, cytokine therapy increased CD3+CD8+ ICs (+173%, CI: 93,287%) and CD3+CD8- ICs (+120%, CI: 21,301%). Therapy was also associated with increased effector-helper T-cell clustering (nearest-neighbor distance, -40%, CI: -29,-50%) and effector cell tumor localization (stromal-tumor interface CD8+ density +90%, Cl: 74, 305%). Conclusions: Our method is concordant with clinical PD-L1 and sTILs scores, and can additionally quantify IC and IC distances. This assay may allow for comparative I-O assessments with increased resolution, and will be used in a randomized phase II trial of pembrolizumab, chemo +/- IRX-2 in stage II/III TNBC.
Phase 1 study of LY3022855, a colony-stimulating factor-1 receptor (CSF-1R) inhibitor, in patients with metastatic breast cancer (MBC) or metastatic castration-resistant prostate cancer (MCRPC).
Authors: Karen A. Autio, Christopher Austin Klebanoff, David Schaer, John S. Kauh, Susan F. Slovin, Victoria Susana Blinder, Elizabeth Anne Comen, Daniel Costin Danila, David M. J. Hoffman, Suhyun Kang, Philomena McAndrew, Shanu Modi, Michael J. Morris, Dana E. Rathkopf, Rachel Ann Sanford, Sonya C. Tate, Danni Yu, Heather L. McArthur
Journal: Journal of Clinical Oncology (2019)

2548 Background: Tumor-associated macrophages (TAM) correlate with increased invasiveness, growth, and immunosuppression. Activation of CSF-1R results in proliferation, differentiation, and migration of monocytes/macrophages. CSF-1R inhibition with LY3022855 (LY), a human immunoglobulin G subclass 1 (IgG1) monoclonal antibody (mAB), may have favorable anti-tumor effects. We evaluated the safety and clinical response of LY monotherapy. Methods: Patients (pts) with advanced refractory MBC and MCRPC received LY intravenously in 6-week cycles in cohorts: A) 1.25 mg/kg every 2 weeks [Q2W]; B) 1.0 mg/kg on Weeks 1, 2, 4, and 5; C) 100 mg once weekly; D)100 mg Q2W. MCRPC pts were enrolled in cohorts A and B; MBC pts were enrolled in all cohorts. Anti-tumor activity was assessed using RECIST v1.1 by radiological imaging every 6 weeks. Results: Thirty-four pts (22 MBC; 12 MCRPC) received ≥1 dose of LY. Median age was 57.0 years (range: 32.0–81.0) for MBC pts and 72.5 years (range: 58.0–84.0) for MCRPC pts. Baseline Eastern Cooperative Oncology Group performance status was 0 (n = 13, 38.2%), 1 (n = 18, 52.9%), or 2 (n = 3, 8.8%). MBC pts were hormone receptor (HR) positive (n = 20), HR negative (n = 1), or unknown (n = 1); 3 MBC pts received concurrent hormone therapy. Common treatment-related adverse events of any grade were fatigue (38.2%), decreased appetite (26.5%), nausea (26.5%), increased lipase (23.5%), and increased creatine phosphokinase (20.6%). No complete or partial response was observed. Stable disease (SD) was observed in 5/22 MBC pts (duration 82–302 days) and 3/7 evaluable MCPRC pts (duration 50–124 days). Two MBC pts (9%; Cohort A) had durable SD &gt; 9 months and 1 pt had palpable reduction in a nontarget neck mass. Circulating CSF1 and IL-34 increased at Day 8 suggestive of target engagement. Pharmacokinetics of LY were consistent with other IgG1 mAbs. Conclusions: LY3022855 was well tolerated and showed evidence of target engagement. Clinically meaningful SD &gt; 9 months was observed in 2 MBC pts. Tumor biomarker analyses are underway. Clinical trial information: NCT02265536.
A novel subpopulation of circulating tumor cells in patients with cholangiocarcinoma.
Authors: Carolina Reduzzi, Marta Vismara, Marco Silvestri, Luigi Celio, Alessandra Raimondi, Martina Torchio, Sara Pusceddu, Monica Niger, Giorgia Peverelli, Filippo G. De Braud, Maria Grazia Daidone, Vera Cappelletti
Journal: Journal of Clinical Oncology (2019)

e15637 Background: In cholangiocarcinoma (CCA), molecular analysis during disease progression is rarely feasible due to low access to tissue. Circulating tumor cells (CTCs) could overcome this issue. Data on CTCs in CCA are presently insufficient to promote their use in clinical management due to their low detection rates. Improved methods to capture all CTC subpopulation are therefore needed. Methods: Peripheral blood (PB) was longitudinally collected from patients with metastatic/unresectable CCA (intrahepatic, extrahepatic and gallbladder). CTCs were enriched from PB (10mL) with Parsortix, labeled for epithelial and leukocyte markers, and analyzed in the DEPArray to collect i) single CTCs positive for epithelial markers (eCTC) and ii) single double negative cells (DNC) lacking epithelial and leukocyte markers. DNCs underwent WGA and low-pass WGS to detect copy number alterations. DNCs with aberrant genotype were defined as non-conventional CTCs (ncCTCs). Results: Forty-one blood samples were collected from 21 patients receiving gemcitabine and/or platinum-based regimens. We detected 18 eCTCs and 73 ncCTCs, respectively in 8/41 (19%, median number = 1.5, range 1-5) and 31/41 (76%, median number = 2, range 1-7) samples. By considering also ncCTCs, CTC-positivity increased by 4.4-fold (83% of CTC+ samples). All untreated patients were CTC+, and CTC- samples (n = 7) were collected only on-treatment. In 18 patients, the detection of eCTCs ( ≥1eCTC/10mL blood) at baseline was associated with a shorter overall survival than in eCTC- patients (7.0 vs 19 months, p = 0.03). CTC count fluctuations during treatment mirrored patient response. Indeed, in responding patients CTCs were not detectable. In some patients, CTC counts were more informative on treatment outcome than imaging and Ca19.9 levels. Conclusions: We developed a new single-cell protocol to detect two distinct CTC subpopulations (eCTC and ncCTC) in patients with CCA. Baseline eCTCs detected by our method inform prognosis whereas ncCTCs provide hints on treatment response. The possibility to collect and molecularly characterize CTC from all patients with our protocol, opens the way to future treatment planning based on CTC molecular asset.
The prevalence of hereditary pancreatitis mutations in families with pancreatic cancer.
Authors: Rino S. Seedor, Michelle J. Savage, Waleed Iqbal, Sanjeevani Arora, Kim Rainey, Andrea Forman, Steven Lincoln, John Garcia, Rebecca Truty, Edward D. Esplin, Elizabeth A. Handorf, Michael J. Hall
Journal: Journal of Clinical Oncology (2019)

e15728 Background: Germline pathogenic variants (PV) in hereditary cancer risk genes are found in ~10-15% of pancreatic adenocarcinomas/cancers (PC), but most cases of familial PC have no identifiable genetic cause. Chronic pancreatitis is an established risk factor for PC, with a lifetime risk of PC of 10-30%, and has been associated with germline mutations in several genes: PRSS1, SPINK1, CASR, CTRC, and CFTR. Few studies have examined the prevalence of PV in the pancreatitis risk genes among patients reporting a personal or family history (FHx) of PC. Methods: The FCCC Risk Assessment Program (RAP) database was queried to identify patients tested for PRSS1, SPINK1, CASR, CTRC, and CFTR as part of risk assessment. Pedigrees, demographic and cancer history data were reviewed. De-identified data from Invitae on patients found to be CFTR+ on hereditary pancreatitis testing were also reviewed for personal/FHx of PC. Results: 26 patients with PC and 48 patients with a FHx of PC underwent germline testing for the pancreatitis genes at FCCC. 7 of 26 (26.9%) patients with PC carried at least one CFTR mutation, while 3 of 48 (6.3%) patients with a FHx of PC carried a CFTR mutation. Interestingly, 8 patients carried an intronic variant in the CFTR gene. No patients with PC and 2 of 48 (4.2%) patients with a FHx of PC carried a SPINK1 mutation. The CFTR mutation rate in PC patients exceeded the expected carrier rate (2.6-3.6%)(p &lt; 0.001). The SPINK1 mutation rate in PC patients also exceeded the expected carrier rate but was not statistically significant (1.9%)(p = 0.23). CaSR, PRSS1, and CTRC mutations were not identified in our population. Personal/FHx data were available to review for 175 of the 496 CFTR+ patients tested through Invitae. 49 of 175 (28%) had a personal history of PC and 105 of 175 (60%) had a reported FHx of PC. Strikingly, 23% of CFTR+ patients carried pathogenic mutations in other genes (most commonly SPINK1). Conclusions: In our select sample, CFTR mutations, and in particular a known intronic variant, were highly enriched in a population of patients undergoing risk assessment for hereditary PC. Commercial data suggest a substantial minority of CFTR+ carriers with a personal/FHx of PC may also carry SPINK1 mutations.