bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence for selective silencing of MHC-binding neoepitopes to avoid immune surveillance.
Authors: Parulkar Rahul , Nguyen Andrew , Sanborn J Zachary , Vaske Charles Joseph , Benz Stephen Charles , Reddy Sandeep K. , Kato Shumei , Kurzrock Razelle , Szeto Christopher
Published: May 2019

2591

Background: Overall response rates to immune checkpoint inhibition (ICI) are < 50% even in TMB-high patients (e.g. Checkmate-227), suggesting other mechanisms of immune escape exist beyond expressing checkpoints. At least 18% of somatic-specific exonic DNA variants are not expressed into mRNA (Rabizadeh, 2018), yet the selection criteria for which variants to silence remains unclear. We sought to determine if immunogenicity of variants factors into their suppression. Methods: Somatic-specific single nucleotide variants (SNVs) were identified from paired tumor/normal whole-exome sequencing (WES), and annotated as expressed if observed in > = 2 RNAseq reads. MHC1 binding affinity for 9-mer neoepitope peptides resulting from said SNVs were predicted using NetMHC within presented HLA-types. Cases with > 200 non-synonymous exonic mutations were designated as TMB-high in accordance with Rizvi et al, 2015. Tumor immune activity was inferred by RNAseq expression of 6 checkpoint/TME markers, as well as by estimating immune infiltration using RNAseq deconvolution of immune genesets (Bindea et al 2013). Significant associations between TMB, neoantigen-load, expressed neoepitope binding affinities, and immune activity were analyzed. Results: Within a clinical database of 1,363 cases with T/N/R sequencing, a total of 147,015 potential neoepitopes were identified. A small but significant enrichment was observed for silencing neoepitopes that are predicted to bind MHC1 (OR = 1.22, p = 2.4e-78 one-sided Fishers test). The silencing rate was similar between the 17% of patients with high TMB vs others, but was increased in 35% of all patients with high inferred immune infiltration (N = 490, OR = 1.30, p = 1.8e-31). A further silencing enrichment was observed in 19% of all patients displaying high immune activity but low PDL1 expression (N = 263, OR = 1.44, p = 4.0e-45). Conclusions: We observe significant preferential silencing of MHC binding neoepitopes. Specifically, when tumor infiltrating immune cells are activated, silencing neoepitopes may be an alternative to checkpoint expression for avoiding an immune cascade. Patients with TILs and silenced neoepitopes may benefit from epigenetic priming therapy prior to ICI therapy.
Association of an inflammatory gene signature with CD8 expression by immunohistochemistry (IHC) in multiple tumor types.
Authors: Szabo Peter M , Qi Zhenhao , Zerba Kim , Ely Scott , Edwards Robin , Lu James , Cooley James , Navratil Marian , Dalgliesh Gillian L , Adya Neeraj
Published: May 2019

2593

Background: A multiparameter tumor inflammation assay based on gene expression profiling (TIA-GEP) can extend the utility of IHC to interrogate the tumor microenvironment (TME). Using CD8 expression assessed by IHC (CD8-IHC) as a surrogate for inflammation, statistical modelling was used to develop a specific gene signature on the TIA-GEP panel to predict CD8-IHC. The correlation between TIA-GEP and CD8-IHC and the prevalence of inflammation were explored across multiple tumor types. Methods: Levels of inflammation were measured by CD8-IHC and TIA-GEP on 1778 procured samples across 12 tumor types. Quality control metrics involved sample input quality, technical errors, and inter-run variability. Generalized linear models were used to identify an inflammation score that predicts the CD8-IHC score in melanoma and SCCHN tissue. The predictive accuracy of this signature was also examined in 10 additional tumor types. Results: Assessment of TME inflammation by CD8-IHC was consistent with that observed by TIA-GEP in multiple tumor types. The range of inflammation varied across different tumor types, with relatively lower inflammation range and scores in SCLC, ovarian, and prostate cancers, and higher values in NSCLC, melanoma, SCCHN, and gastric cancers. R2 x 100 values reflecting percent variation in CD8-IHC associated with TIA-GEP ranged from 62.4% to 79.2% ( P < 0.0001) for all tumor types except prostate cancer (32.5%). Low correlation in prostate cancer may be a result of low prevalence of inflammation by CD8-IHC. Estimated linear regression slopes between CD8-IHC and TIA-GEP ranged from 0.74 in SCLC to 1.27 in gastric cancer. Conclusions: The results suggest that the inflammation signature is a robust potential diagnostic tool predicting inflammation in the TME. The inflammation signature not only correlates with CD8-IHC for multiple tumor types, but also leverages the alternative benefits associated with TIA-GEP, which include information related to tumor inflammation-associated biomarkers and flexibility in exploring the value of other genomic signatures.
Application of artificial intelligence to predict a new class of novel synthetic lethal targets.
Authors: Mousses Spyro , Schneider David , Kiefer Jeff , Derdeyn Pieter , Douglas Kendyl , Kothari Abhishek , Von Hoff Daniel D. , Yoo Chris
Published: May 2019

2598

Background: Synthetic lethal targets are proteins that are contextually vulnerable. Inhibitors of PARP1, for example, selectively produce a lethal phenotype in the context of cancer cells which have lost BRCA1 or BRCA2 function. As a high mutation rate is a hallmark of many cancers, targeting synthetic lethal interactions to selectively inhibit cancer cells with altered genetic backgrounds may increase the specificity and efficacy of therapeutics. Recently, clinical trials have targeted synthetic lethal pairs such as EGFR and BRAF, TP53 and BCL2, and PTEN and CHD1. Previous attempts to identify synthetic lethal targets have relied on empirical results from published studies of biological pathways perturbed in cancer cells. Developing strategies to rapidly identify synthetic lethals by combining multiple experimental and computational approaches would result in a new class of potential cancer drug targets beyond the existing efforts that rely on single experimental or computational methods alone. Methods: Here we present Expansive AI, an artificial intelligence augmented knowledge network that enables rapid hypothesis generation for accelerated discovery research. Using a purpose-built, hypergraph database of massive, integrated genomic and biomedical data, we can query all synthetic lethals and their component genes, as well as a wealth of data related to these genes. The database of biological data includes 11,000+ cancer genomes from TCGA, prior knowledge resources such as gene ontology and pathway resources, and experimental data including chemical and protein interaction and patent data. The hypergraph’s architecture allows for linking and nesting data, enabling efficient extraction of biologically-relevant features. Results: Using these features, a neural network classified 540 new candidate pairs that have previously not been reported. The candidate pairs were filtered to include only known oncogenes and least-studied genes. This produced a list of gene pairs which may represent the most novel class of synthetic lethal target candidates identified to date. Conclusions: We highlight the results of this AI-based approach and discuss validation efforts of the predicted interactions in specific cancer contexts.
Immune profiling of tumor-infiltrating T cells using mass cytometry.
Authors: Roumanes David , Newell Evan , Fehlings Michael
Published: May 2019

2607

Background: Immunotherapy recent successes have opened new avenues for the treatment of cancer and the presence of tumor-specific CD8+ T cells in tumor-bearing individuals offer a promising therapeutic target. However, the detection and profiling of such T cells are challenging due to the need to detect rare antigen-specific T cell subpopulations in patient samples that are limited in size thus making it difficult to exploit these parameters for predictive signatures of clinical response. Moreover, the identification and analysis of neoantigen-specific CD8+ T-cells in tumor-bearing individuals is challenging due to the small pool of such cells. Methods: In order to identify therapy-relevant tumor antigens and to facilitate a concurrent in-depth characterization of cells directed towards these targets, immunoSCAPE leverages the high-dimensional immune profiling capabilities of cytometry by time of flight (CyTOF) combined with a unique technology allowing the identification rare antigen-specific T-cell subsets. Results: We applied this technology to patient tumor-infiltrating lymphocytes from human cancer samples and tumor-derived neoantigens recognized by T-cells were identified and characterized. Interestingly, the majority of patient-derived tumor infiltrates consisted of tumor-unrelated T-cells characterized by a diverse phenotype. Strikingly, the expression of CD39 was absent from these bystander cells, suggesting that CD39 could be a useful biomarker for the identification of putative tumor-reactive T cells. Conclusions: Simultaneous immune profiling revealed that tumor-unrelated, bystander CD8+ T-cells are phenotypically different in human tumor infiltrates and identified CD39 as a putative marker of neoantigen-specific T-cells. By providing insights into the nature, frequency and phenotype of antigen-specific T-cells, immunoSCAPE’s unique target discovery and high-dimensional immune profiling platform is a valuable tool for the development of novel diagnostic and therapeutic strategies in immunotherapy.
Pan-tumor prognostic value of multiple immune protein expressions.
Authors: Lambert Tiphaine , Verlingue Loic , Colmet-Daage Léo , Rauby Brice , Sanchez-Escobar Aladro Nicolas , Kerisit Marie , Champiat Stephane , Wartelle Muriel , Lion Francois , Besse Benjamin , Angevin Eric , Hollebecque Antoine , Soria Jean-Charles , Scoazec Jean-Yves , Massard Christophe
Published: May 2019

2618

Background: Using multiple immune-checkpoint proteins (ICP) screening in clinical routine could improve the evaluation of patients’ prognosis and ultimately tailor their treatment choice. We have evaluated this hypothesis in the context of early drug clinical trials. Methods: Patients included in MOSCATO-02 trial had refractory cancers and were candidate for phase 1 study. They were proposed to have a biopsy on an accessible tumor site for the analysis of four proteins by immunohistochemistry (IHC) and RNAseq: PD-L1, CD3, CD8 and FOXP3. Quantification of IHC staining was separated between intratumoral, intersitial and stromal by semi-quantitative method. Their relations to prognosis have been evaluated by survival Random Forest and compared to classical prognosis clinical variables, such as age and RMH score (calculated by the number of metastatic sites, lactate dehydrogenase (LDH) and serum albumin). Results: From April 2016 to September 2017, 228 patients included in MOSCATO-02 had a successful biopsy procedure with available IHC expression analysis. The main tumor subtypes were gastro-intestinal, urological, head and neck, breast and lung. RNAseq analyzes were performed for two thirds of the patients (N=170). Median overall survival was 8.1 months (CI95% 7.79 – 10, 65). We found that, in a cohort of phase I patients, RMH score was the most important variable used to estimate prognosis. Prognosis value of immune proteins were considerably inferior compared to clinical criteria. Among those proteins, the percentage of PD-L1 low score (1+) and average staining intensity of CD3 were the most valuables for prognosis evaluation. Variables with very few importance to prognosis estimation were CD8 and FOXP3 IHC scores, biopsy site and cancer types, subsequent treatments by immunotherapies or targeted therapies. Conclusions: In this cohort of patients with refractory cancers, the RMH score is confirmed as highly prognosis. Immune proteins could be used as a support to guide patient’s selection but does not constitute effective prognosis criteria.
Baseline tumor-immune signatures associated with response to bempegaldesleukin (NKTR-214) and nivolumab.
Authors: Hurwitz Michael E. , Cho Daniel C. , Balar Arjun Vasant , Curti Brendan D. , Siefker-Radtke Arlene O. , Sznol Mario , Kluger Harriet M. , Bernatchez Chantale , Fanton Christie , Iacucci Ernesto , Liu Yi , Nguyen Tuan , Overwijk Willem , Zalevsky Jonathan , Tagliaferri Mary Ann , Hoch Ute , Diab Adi
Published: May 2019

2623

Background: PIVOT-02 is an ongoing phase 1/2 study of bempegaldesleukin (NKTR-214), a CD122-preferential IL-2 pathway agonist, plus nivolumab in patients with advanced solid tumors. Bempegaldesleukin (NKTR-214) increases proliferative tumor infiltrating lymphocytes (TIL) and cell surface PD-1 on immune cells and PD-L1 on tumor cells, demonstrating potential synergy with anti-PD-1 therapy. Pre-treatment tumor biopsies from metastatic 1L melanoma (MEL) and urothelial carcinoma (UC) patients were analyzed to correlate baseline immune phenotype to response. Methods: Pre-treatment TIL (CD8+ T cells/mm2 and %CD3+ by IHC; 29 MEL; 22 UC) were measured and divided into high and low groups based on median values. PD-L1 (% PD-L1 on tumor cells by IHC [28-8 PharmDx]; 33 MEL; 23 UC) was scored negative (<1%) or positive (≥1%). Interferon gamma gene score (IFNG; 11 MEL) was scored as high or low based on median p value of <0.1 for 15 genes (EdgeSeq). High and low groups were correlated with responses per RECIST 1.1. Results: Baseline demographics and prognostic factors were balanced in the biomarker subgroups. Response rates for response evaluable MEL and UC were 53% (SITC 2018) and 48% (ASCO-GU 2019), respectively. In MEL, median values of CD3-TIL and CD8-TIL were 19% and 203 cells/mm2, respectively. Response rate correlations were 67% and 20% with IFNG high and low, 79% and 29% with CD3-TIL high and low, 79% and 33% with CD8-TIL high and low, and 68% and 43% with PD-L1 positive and negative. Most importantly, responses were observed in patients with the least favorable tumor microenvironment, characterized as both PD-L1 negative and TIL low, with responses of 17% (1/6 CD8-TIL), and 25% (2/8 CD3-TIL), respectively. Similar correlative trends were observed in UC, with 50% (4/8 CD8-TIL) and 38% (3/8 CD3-TIL) responses in patients with least favorable microenvironment. Conclusions: The biomarker program included in PIVOT-02 identified baseline immune signatures correlated with response for MEL and UC. The response rates observed in both the favorable and unfavorable tumor microenvironments indicate the potential of this combination and support its broad development. Clinical trial information: NCT02983045.
Comparison between whole exome sequencing (WES) and single nucleotide polymorphism (SNP)-based tumor mutation burden analysis.
Authors: Timms Kirsten , Zharkikh Andrey , Perry Michael , Birkbak Nicolai , Szallasi Zoltan , Gutin Alexander , Richardson Andrea , Lanchbury Jerry
Published: May 2019

2634

Background: Immune checkpoint inhibitors (ICI) block proteins which enable cancer cells to evade the immune system. Recent studies have shown that the higher the tumor mutation burden (TMB) the greater the likelihood of response to ICI therapy. Analysis of TMB has focused on WES of paired tumor and normal samples. This study tests the feasibility of measuring TMB from a SNP-based resequencing assay (myChoice HRD Plus). Methods: WES and myChoice HRD Plus were performed on matched tumor and normal DNA from 44 breast and 12 colon tumors. myChoice HRD Plus combines homologous recombination deficiency analysis with resequencing of 108 genes and microsatellite instability analysis. WES-based TMB was calculated by identifying all variants in paired samples, and subtracting germline variants. Two SNP-based TMB (SbTMB) methods were utilized to calculate TMB. The first used germline subtraction similar to the WES-based method. The second utilized an algorithm which removed background germline variants. Median sequence length to calculate TMB was 9.7 Mb for WES, 4.6 Mb for SbTMB (germline subtraction), and 1.9 Mb for SbTMB (algorithm). Results: Correlation coefficients for WES vs. SbTMB (germline subtraction) and SbTMB (algorithm) were 0.895 and 0.908, respectively. The two SbTMB methods had a correlation coefficient of 0.834. SbTMB measures of TMB were generally higher than WES-based TMB with a mean increase in score of 1.6 variants/Mb for SbTMB (germline subtraction; p = 4.6x10-6) and 1.5 variants/MB for SbTMB (algorithm; p = 1.2x10-5). No significant difference in magnitude of TMB score between the SbTMB measures was observed (0.04 variants/Mb; p = 0.88). Conclusions: SNP-based methods for calculating TMB produced highly concordant scores compared to WES-based methods. SbTMB assays produced elevated TMB scores, consistent with selective pressure against mutations in coding regions of genes, necessitating a higher score threshold for when using a SbTMB assay. This SbTMB analysis expands the utility of myChoice HRD Plus, and provides a method for calculation of TMB without sequencing a germline comparator.
Electrostatic human leukocyte antigen-neoantigen interactions and durable benefit in non-small cell lung cancer patients treated with immunotherapy.
Authors: Cummings Amy Lauren , Gukasyan Jaklin , Lu Henry , Bachrach Benji , Madrigal John , Carroll James M. , Akingbemi Wisdom O , Noor Zorawar Singh , Lisberg Aaron Elliott , Garon Edward B.
Published: May 2019

2635

Background: Human leukocyte antigen (HLA) binding relies on energy from the interaction of B-pocket residues with anchor amino acids (AA). Among HLA class I supertypes, only HLA-B has distinct electrostatic B-pocket specificities, and of 7 HLA-B supertypes, B08, B27, and B44 feature binding pockets with preferences for charged AAs (Lund Immunogen). Whether electrostatic interactions in HLA-neoepitope binding would identify superior neoantigens and associate with survival in NSCLC patients treated with immunotherapy was unknown. Methods: Forty patients with advanced NSCLC treated with single agent pembrolizumab on a clinical trial with at least 5 years follow-up underwent paired tumor-normal whole-exome sequencing (WES) with Illumina HiSeq 2000/3000. HLA typing used normal (germline) WES from peripheral blood mononuclear cells analyzed with BWA-ALN and Athlates software (Liu Nuc Acids Res); supertype was determined by 2008 criteria (Sidney BMC Immunol). Tumor nonsynonymous coding mutations were identified with GATK v3.8, annotated with Ensembl-VEP, and passed through pVAC-Seq using a NetMHC 4.0 algorithm to identify potential neoepitopes 9 AAs in length (Hundal Genome Med). Neoepitopes were characterized based on mutant AA charge (D/E negative, H/K/R positive) and position. High affinity neoepitopes (HAN) were defined as those an with IC50 < 50 nM with wildtype IC50 > 50 nM (Ghorani Annals Oncol) and a mutation to a known B-pocket supermotif (K in position 3 or 5 for B08, R in position 2 for B27, E in position 2 for B44) (Lund Immunogen). Progression-free survival (PFS) was compared with logrank tests and proportional hazards (JMPv14, Cary, NC). Results: Of the 40 patients, 29 (72.5%) had at least one B08, B27, or B44 allele. One or more supertype-matched HAN were found in 10 of the 29 (34.5%), including 6/7 with PFS > 2 years, 3 of whom continue on therapy beyond 5 years. Median PFS in those with HAN was 26.7 months (m) vs 4.3 m in those without (HR 0.34, 95% CI 0.11-0.88, p = 0.024). Conclusions: Electrostatic charge may serve as a mechanism for enhanced binding affinity in HLA-B supertypes with a preference for charged AA in their B-pockets. Identification of favorable HLA-matched neoepitopes may identify distinct prognostic groups and potentially durable responders to immunotherapy in NSCLC.
Dabrafenib and trametinib in patients with tumors with BRAF V600E/K mutations: Results from the molecular analysis for therapy choice (MATCH) Arm H.
Authors: Salama April K.S. , Li Shuli , Macrae Erin Renee , Park Jong-In , Mitchell Edith P. , Zwiebel James A. , Chen Helen X. , Gray Robert James , McShane Lisa , Rubinstein Lawrence , Patton David , Williams Paul M. , Hamilton Stanley R. , Armstrong Deborah Kay , Conley Barbara A. , Arteaga Carlos L. , Harris Lyndsay , O'Dwyer Peter J. , Chen Alice P. , Flaherty Keith
Published: May 2019

3002

Background: The NCI-MATCH precision medicine trial assigns patients (pts) with solid tumors, lymphomas, or multiple myeloma with progression on prior treatment to a targeted therapy based on genetic alterations identified in pre-treatment biopsies. Arm H (EAY131-H) evaluated the combination of the BRAF inhibitor (inh) dabrafenib (DAB), and the MEK inh, trametinib (TRM), in pts with BRAF V600E/K mutations. Methods: Pts with melanoma, thyroid, or colorectal cancer were excluded. Pts with NSCLC were excluded after the U.S. Food and Drug Administration (FDA) approved DAB/TRM for this indication. Pts received DAB 150 mg po BID and TRM 2 mg PO daily on 28 day cycles until disease progression or intolerable toxicity; restaging was performed every 2 cycles. The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS), 6-month PFS, and overall survival (OS). Results: A total of 35 pts were enrolled from 1/2016-2/2018; 2 were ineligible (CrCl below criteria; labs out of window). Over 17 distinct tumor histologies were represented. 58% of pts were female, median age was 63 (range 21-85), 94% were Caucasian, and 48% of pts had received at least 3 prior therapies (range 1- 8). The confirmed ORR was 33.3% (90% CI 19.9%, 49.1%), with a median duration of response (DoR) of 12 months (mon). Varied histologies had a DoR of > 12 mon: histiocytic sarcoma, cholangiocarcinoma and mixed adenoneuroendocrine carcinoma of unknown primary, among others. Median PFS was 9.4 mon; the 6 mon PFS rate was 70.6% (90% CI 58.2%-85.5%), and an additional 10 pts had a PFS > 5.5 mon. Median OS has not been reached. At the time of data cutoff (12/2018) 11 pts continue on treatment. Adverse events (AE) were comparable to previously reported profiles of DAB/TRM; no new AEs were identified. The most frequent grade 3 AEs were fatigue, neutropenia, hyponatremia, hypophosphatemia, and urinary tract infection; there was 1 grade 4 sepsis; no grade 5 AEs. Conclusions: In this pre-treated, mixed histology cohort, DAB and TRM showed promising activity outside of currently approved FDA indications warranting further investigations. Correlative analyses are planned. Clinical trial information: NCT02465060.
First-in-human phase 1 study of ABBV-085, an antibody-drug conjugate (ADC) targeting LRRC15, in sarcomas and other advanced solid tumors.
Authors: Demetri George D. , Luke Jason J. , Hollebecque Antoine , Powderly John D. , Spira Alexander I. , Subbiah Vivek , Lai Dominic W. , Yue Huibin , Kasichayanula Sreeneeranj , Gulbranson Scott , Purcell James , Myzak Melinda , Robinson Randy , Villalobos Victor Manuel , Tolcher Anthony W.
Published: May 2019

3004

Background: ABBV-085 is an ADC (conjugated to monomethyl auristatin E, drug:antibody ratio of 2:1) directed against leucine-rich repeat containing 15 (LRRC15), a type 1 transmembrane protein highly expressed on the surface of sarcomas and cancer-associated fibroblasts in stroma of many other cancers. ABBV-085 induced antitumor activity in both in vitro and xenograft models of sarcoma. This phase 1, first-in-human, 2-part study assessed the safety/tolerability of ABBV-085 in patients (pts) with advanced solid tumors (NCT02565758). Methods: Eligible pts (≥18 yr; advanced solid tumors) received ABBV-085 intravenously in a 3+3 dose-escalation (DE) design; 0.3- to 4.8-mg/kg doses every 2 wk (8 cohorts). Pharmacokinetics (PK) were assessed in cycle 1 and cycle 3. Results: As of Dec 2018, 78 pts were enrolled in monotherapy DE and dose-expansion (EXP) cohorts (≤2.7 mg/kg, n = 21; 3.6 mg/kg, n = 45; 4.2 mg/kg, n = 6; 4.8 mg/kg, n = 6); median age: 58 yr (range 21–84); median treatment (Tx) duration: 6.2 wk (range 0.3–54.4). Overall, 77 (98.7%) pts reported ≥1 Tx-emergent adverse events (TEAEs). Fatigue (48.7%) was most common; 19 (24.4%) pts reported grade 1/2 blurred vision (reversible on study discontinuation). Grade ≥3 TEAEs were reported in 56 (71.8%) pts; anemia (14.1%) was the most common. Dose-limiting toxicities occurred at 3.6 mg/kg (n = 1; anemia), 4.2 mg/kg (n = 1; hypertriglyceridemia), and 4.8 mg/kg (n = 2; ileus and nausea); 3.6 mg/kg was chosen as the recommended phase 1b dose (RP1bD). PK exhibited dose-proportional increase in the area under the curve after single-dose administration; half-life was 2.84 days at the RP1bD. Of the 27 sarcoma pts (DE [n = 8]/EXP [n = 19] cohorts; undifferentiated pleomorphic sarcoma [n = 10], osteosarcoma [n = 10], and other sarcomas [n = 7]) treated at the RP1bD, 4 (14.8%) had confirmed partial response (PR; 2 [7.4%] unconfirmed), 8 (29.6%) had stable disease, 11 (40.7%) had progressive disease; 2 (7.4%) were not evaluable. The median duration of response (confirmed responders) was 7.6 mo (95% CI: 5.6–9.2). Updated safety and efficacy data will be reported. Conclusions: ABBV-085 was well tolerated with durable PR observed in pts with advanced sarcomas. Clinical trial information: NCT02565758.
First-in-human trial of the oral ataxia telangiectasia and Rad3-related (ATR) inhibitor BAY 1895344 in patients (pts) with advanced solid tumors.
Authors: De Bono Johann S. , Tan David Shao Peng , Caldwell Reece , Terbuch Angelika , Goh Boon C. , Heong Valerie , Haris Noor Md , Bashir Saira , Hong David S. , Meric-Bernstam Funda , Bordia Sonal , Liu LI , Wilkinson Gary , Hreiki Joseph , Wengner Antje , Fischer Kerstin , Boix Oliver , Lagkadinou Eleni , Plummer Elizabeth , Yap Timothy A
Published: May 2019

3007

Background: The ATR kinase is a key regulator of the DNA damage response (DDR) machinery, activated by DNA damage and replication stress. BAY 1895344 is a novel, potent, and selective ATR inhibitor with anti-tumor activity in preclinical models with DDR defects. Methods: Pts with advanced metastatic solid tumors resistant or refractory to standard treatment, with and without DDR defects, received BAY 1895344 BID, 3 days (d) on/4 d off continuously in 3-weekly cycles. Results: As of December 20, 2018, 18 pts with colorectal (4), breast (3), prostate (2), and ovarian (2) cancers were enrolled across 6 cohorts (5 mg, 10 mg, 20 mg, 40 mg, 60 mg, and 80 mg BID). Median prior lines of treatment was 5. No dose-limiting toxicities (DLTs) were reported in the 5-40 mg cohorts. 2/3 pts had DLTs in the 80 mg cohort (grade [G] 4 neutropenia, G4 neutropenia and G4 thrombocytopenia) and 2/7 had DLTs in the 60 mg cohort (G4 neutropenia, G2 fatigue). 40 mg BID 3 on/4 off was defined as the maximum tolerated dose. Most common treatment-emergent adverse events included anemia, neutropenia, nausea, and fatigue. Pharmacokinetics appeared dose proportional. Pharmacodynamic analyses showed modulation of pH2AX and/or pKAP1 in paired tumor biopsies at exposures associated with preclinical anti-tumor activity. In 13 pts with and without DDR defects treated at dose levels ≥40 mg BID, the objective response rate was 30.7%, including 2/2 pts at 40 mg (appendix and urothelial cancer), 1/8 pts at 60 mg (breast), and 1/3 pts at 80 mg (endometrial). All responders had ATM protein loss of expression and/or ATM mutation; median treatment duration was 347 d (range 293-364 d). A BRCA1-mutant, olaparib-resistant ovarian cancer pt (60 mg) had a CA125 response and stable disease >10 months. 41 additional pts have been enrolled in ongoing expansion cohorts in cancers with DDR defects (prostate, breast, gynecologic, colorectal) or ATM protein loss (all comers) with responses observed. Conclusions: The ATR inhibitor BAY 1895344 is tolerated at biologically active doses with anti-tumor activity against cancers with certain DDR defects, including ATM protein loss. Clinical trial information: NCT03188965.
Multimodality liquid biopsy for early monitoring and outcome prediction in first-line metastatic HER2-negative breast cancer: Final results of the prospective cohort from the French Breast Cancer InterGroup Unicancer (UCBG)— COMET study.
Authors: Pierga Jean-Yves , Silveira Amanda , Tredan Olivier , Tanguy Marie-Laure , Lorgis Veronique , Dubot Coraline , Jacot William , Goncalves Anthony , Debled Marc , Levy Christelle , Ferrero Jean-Marc , Jouannaud Christelle , Mouret-Reynier Marie-Ange , Dalenc Florence , Lemonnier Jerome , Berger Frederique , Proudhon Charlotte , Bidard Francois Clement
Published: May 2019

3019

Background: Circulating Tumor Cells (CTC) are independent markers of progression-free survival (PFS) and overall survival (OS) in patients (pts) with metastatic breast cancer (MBC). Monitoring circulating tumor DNA (ctDNA) can detect mutation associated with resistance to treatment and its variations reflect changes in tumor burden. We prospectively monitored CTC, Circulating Endothelial Cells (CEC), serum markers and ctDNA during first line chemotherapy for MBC. Methods: The French cohort COMET is a prospective study including first line HER2 negative pts receiving weekly paclitaxel and bevacizumab . Blood samples were obtained at baseline (BL) and before the second cycle of chemotherapy (C2).We present here the final planned analysis. Results: From 09/2012 to 11/2014, 286 patients were included: 198 for ctDNA, 251 for CEC and 283 for CTC. Median age was 56 years and 23% of pts had triple negative BC. At baseline, 71% of pts had ≥1 detectable CTC per 7.5 ml of blood (median 4 CTC, range 1- 30,000). With a threshold of ≥5 CTC, 49% of pts were positive at baseline and 22% at C2. For ctDNA, out of the first 196 pts analyzed, 147 had at least one somatic mutation (SNV) detected in plasma (75%). The average number of mutations per pt was 2.4 (range 1 to 9). Most commonly mutated genes were TP53 and GATA3. ESR1 was mutated in 10.6% of the pts and restricted to the ER+ subgroup. PIK3CA was mutated in 23.2% of the pts. Median Allelic Frequency was 9.1% . Only 68 pts (36%) had detectable ctDNA at C2. At baseline, CTC and ctDNA levels were correlated (r = 0.40, p < 0.0001). Despite no complete overlap, 24 pts (12%) had no CTC nor ctDNA detected at baseline. Median follow-up was 53 months and median OS was 32 months. Detectable CTC and ctDNA at baseline and at C2 were significantly associated with decreased PFS and OS. CEC and serum markers level had no prognostic value. At multivariate analysis, triple negative status, detectable ctDNA at C2, CTC ≥5 at C2 and grade 3 on primary tumor were independent prognostic factors. Conclusions: This is the largest prospective cohort assessing the respective prognostic values of early CTC and ctDNA changes in homogenously treated first line MBC pts. Early decrease of CTC and ctDNA after one cycle of chemotherapy are independent predictive markers of favorable outcome, with a stronger value for ctDNA compared to CTC. Clinical utility of early ctDNA variations monitoring and changes in mutation profile remain to be demonstrated. Clinical trial information: NCT01745757.
Exceptional responders to abexinostat (ABX) plus pazopanib (PAZ) in pretreated renal cell carcinoma (RCC) and other solid tumors: Long-term follow-up of a phase 1b study.
Authors: Aggarwal Rahul Raj , Thomas Scott , Pawlowska Nela , Grabowsky Jennifer A. , Calabrese Susan , Lam Phu , Comerford Kathleen , Bautista Daphne , Munster Pamela N.
Published: May 2019

3022

Background: We previously reported the initial phase 1b study results of PAZ + ABX, a potent pan-HDAC inhibitor, demonstrating acceptable toxicity profile and encouraging anti-tumor activity (Aggarwal et al. JCO 2017). We report the long-term follow up of exceptional responders and additional correlative analyses associated with clinical outcomes. Methods: Key efficacy endpoints included objective response rate and duration of response. Peripheral blood histone acetylation, HDAC expression, and plasma VEGF levels were analyzed and associated with clinical outcomes. Results: 51 pts (RCC subset; N = 22) were enrolled between June 2012 and October 2015. 10 pts (20%) had experienced disease progression on prior PAZ; 59% had received any prior VEGF-targeting therapy. 9 evaluable pts (18%) (N = 6 RCC; 2 thyroid; 1 mesothelioma) achieved partial tumor response (PR), of which 6 had prior progression on VEGF-targeting therapy. 7/10 (70%) of pts with prior disease progression on PAZ monotherapy had reduction in tumor burden on study. The median duration of response was 9.1 months (range 1.2 to 70+), and clinical benefit rate (PR or stable disease > 6 months) was 33%. Five treatment-refractory pts achieved durable PRs lasting for > 2 years duration, and one previously PAZ-refractory patient with RCC remains on treatment with ongoing PR for > 6 years. Higher HDAC2 expression was associated with prolonged progression-free survival (median PFS 5.9 vs. 3.5 months, log-rank p = 0.02). Induction of histone acetylation on ABX lead-in treatment was associated with subsequent time to progression (p = 0.002). On-treatment plasma VEGF levels were inversely correlated with PBMC histone acetylation (p = 0.02). Conclusions: Markedly durable responses with PAZ + ABX are achievable, including in pts with PAZ- and VEGF-refractory RCC and other solid tumor malignancies. Host factors including HDAC expression and acetylation status may identify those most likely to benefit. A randomized phase 3 study is underway of PAZ + ABX as a first- or second-line therapy in pts with locally advanced or metastatic RCC (RENAVIV; NCT03592472). Clinical trial information: NCT01543763.
A polymorphism within the mismatch repair gene predicts prognosis and adjuvant chemotherapy benefit in gastric cancer patients.
Authors: Wang Deqiang , Chen Deyu , Shen Bo , Chen Xiaofeng , Xiao Mingzhe , Li Xiaoqin , Shu Yongqian
Published: May 2019

3025

Background: Radical surgery with subsequent adjuvant chemotherapy was effective treatment for early-stage gastric cancer (GC) patients. Unfortunately, after optimal multimodality therapy, up to 30% to 40% of patients undergoing resection will relapse within 5 years. There are no validated prognostic and predictive biomarkers for GC patients who receive adjuvant chemotherapy, and current patient selection is based mainly on postoperative pathological staging. Defective mismatch repair (MMR) or microsatellite instability (MSI) may affect GC outcome. Polymorphisms of MMR genes with a low-penetrant effect can cause heterogeneous MMR capability among individuals. It is not known about the impact of these polymorphisms on GC outcome. Methods: The polymorphisms rs1800734 in MLH1, rs2303428 and rs3732183 in MSH2, rs735943 in EXO1, and rs11797 in TREX1 were selected and analyzed in independent discovery and validation sets that included 167 and 593 patients, respectively. MSI was determined. Results: In the discovery set, both the rs2303428 TC+CC and the rs11797 GA+AA genotypes significantly correlated with poor overall survival (OS; P < 0.05). In the validation set, we confirmed the prognostic association for the rs2303428 TC+CC genotype (P = 0.036) but not for the rs11797 GA+AA genotype (P = 0.737). Furthermore, the prognostic role of the rs2303428 TC+CC genotype was observed in non-cardia (P = 0.005) but not in cardia GC (P = 0.934). The multivariate model showed that the rs2303428 TC+CC genotype was an independent predictor for OS in non-cardia patients (HR = 1.54; 95% CI: 1.02-2.32; P = 0.040). Moreover, fluoropyrimidines-based adjuvant chemotherapy significantly improved OS (HR = 0.29; 95% CI: 0.15-0.58; P < 0.001) for non-cardia patients with the rs2303428 TC+CC genotype but not for those with the rs2303428 TT genotype. The rs2303428 genotypes were not associated with MSI frequency. Conclusions: The rs2303428 TC+CC genotype may predict prognosis and adjuvant chemotherapy benefit in non-cardia GC patients independent of MSI. To our knowledge, our study is the first to report the prognostic and predictive roles of MMR genotype in GC. Although prospective validation is necessary, our findings have the potential to improve patient selection for adjuvant chemotherapy and spare large numbers of GC patients’ unnecessary therapy.
Phase I study of DFP-11207, a novel oral 5-FU with enhanced PK and improved tolerability, in patients with solid tumors.
Authors: Ajani Jaffer A. , Javle Milind M. , Eng Cathy , Fogelman David R. , Anderson Barry Douglas , Zhang Chun , Iizuka Kenzo
Published: May 2019

3034

Background: DFP-11207 combines a 5-fluorouracil (5-FU) pro-drug with a reversible dihydropyrimidine dehydrogenase inhibitor and a potent inhibitor of orotate phosphoribosyl transferase resulting in enhanced pharmacological activity of 5-FU with decreased gastrointestinal and myelosuppressive toxicity. Methods: Patients with advanced solid tumors were treated in this single arm, dose escalation study. Accelerated dose escalation using single pt cohorts was followed until drug-related Gr2 adverse events occurred; then a 3+3 design was followed to determine maximum tolerated dose (MTD). Pts were dosed daily in 28-day cycles until intolerable toxicity or disease progression. PK sampling was performed for DFP-11207 metabolites on all pts and a 6 pt cohort received DFP-11207 in fed and fasted states to determine drug bioavailability. Results: Primary tumors among the 23 enrolled pts included esophageal, colorectal, gastric, pancreatic and gallbladder. Seventeen pts were treated at 8 dose levels of oral DFP-11207 administered daily, ranging from 40 to 440 mg/m2/d. At 440 mg/m2/d one pt experienced drug-related Gr3 dehydration and mucosal inflammation, and Gr4 febrile neutropenia; a second pt experienced Gr4 febrile neutropenia. One DLT of Gr3 vomiting occurred among 6 pts treated at 330 mg/m2/d dosed q12hrs confirming the MTD. Six pts were administered 300 mg DFP-11207 q12 hrs in a fed or fasted state to determine drug bioavailability. Among all pts, the most frequently reported drug-related TEAEs were fatigue (47.8%), nausea (47.8%), decreased appetite (39.1%), diarrhea (26.1%), vomiting (21.7%), anemia (13.0%), dysgeusia (13.0%), mucosal inflammation (13.0%) and palmar-plantar erythrodysaesthesia syndrome (13.0%). PK analyses of pts treated at 330 and 440 mg/m2/d indicate 5-FU concentrations of ~20 ng/mL throughout the dose cycle. There was no substantial difference in DFP-11207 bioavailability among pts in a fed or fasted state. Out of 21 efficacy evaluable pts, 7 pts had stable disease (33.3%), of which 2 had prolonged stable disease of > 6 months. No pts achieved CR or PR. Conclusions: DFP-11207 at the dose of 330 mg/m2/d q12hrs is well-tolerated in pts with solid tumors with mild myelosuppressive and gastrointestinal side effects, and results in circulating 5-FU levels conducive to an anti-tumor effect. DFP-11207 can be explored as monotherapy or substitute for 5-FU, capecitabine or S-1 in combination treatment regimens. Clinical trial information: NCT02171221.
Progastrin, a novel ubiquitous cancer blood biomarker for early detection and monitoring.
Authors: You Benoit , Assenat Eric , Glehen Olivier , Maucort-Boulch Delphine , Payen Lea Francoise , Kepenekian Vahan , Dupuy Marie , Liaud Pierre , Mazard Thibault , Ferron Gwenael , Flaceliere Maud , Soulé Julien , Saywell Veronique , Tan Winston , Villeneuve Laurent , Ychou Marc , Beloin Fanny , Kohli Manish , Joubert Dominique , Prieur Alexandre
Published: May 2019

3037

Background: The successes of recent publications on “multi-tumor” circulating markers highlight the relevance of novel universal diagnostic cancer serum biomarkers. Since the Wnt/ß-catenin/Tcf4 pathway, activated in many tumors, induces the GAST Gene encoding progastrin synthesis, we hypothesized that progastrin, easily measurable in the blood, might be a “multi-tumor” diagnostic biomarker. Methods: Progastrin levels were measured in the blood samples of 1319 patients with 12 different cancer origins, and compared to those of 557 asymptomatic 18-75 years old blood donors. Moreover the longitudinal kinetics of progastrin concentrations were serially assessed during treatments in 168 patients with ovarian cancers enrolled in the randomized CHIVA trial (NCT01583322, GINECO), 191 patients with peritoneal involvement from gastro-intestinal cancers enrolled in BIG-RENAPE trial (NCT03787056), and in 95 HCC patients. The progastrin was measured using an ELISA test developed by ECS Progastrin (Prilly, Switzerland). Results: Compared to healthy blood donors, progastrin was found at higher concentrations in the plasma of cancer patients: median 4.47 vs 0.20 pM, P < 0.0001; diagnostic discriminative power, ROC analysis AUC = 0.86 (95% CI, 0.83-0.89; P < 0.0001). Progastrin levels were found elevated in all cancer groups, regardless of disease stages, and of pathology origins: ROC AUCs ranged from 0.71 to 0.93, all P < 0.0001 (Table). The longitudinal progastrin changes during treatments, suggest relationships to tumor burden, and potential monitoring value. Conclusions: Progastrin is a novel ubiquitous cancer biomarker, easily detectable in the blood using an affordable ELISA test (CancerRead Lab test(R)). It may change the future paradigms about screening (in particular for populations at higher or lower risks of cancer), cancer diagnostic & monitoring. [Table: see text]
Mastocheck: Notable plasma protein biomarker for diagnosis of breast cancer in the real clinical practice by using multiple reaction monitoring-based mass spectrometry.
Authors: Kim Yumi , Kang Un-Beom , Kim Sungsoo , Lee Han-Byoel , Jung Jigwang , Kim Hong Kyu , Moon Hyeong-Gon , Han Wonshik , Noh Dong-Young
Published: May 2019

3044

Background: Breast cancer is the most frequently diagnosed cancer and the most leading cause of cancer-related deaths among women worldwide. Although screening mammography is available, there is an ongoing interest in improved early detection and prognosis. And also, serum tumor marker levels, such as CA 15-3 and others, may reflect disease progression and recurrence, they have not proven to be sensitive for early disease detection. Research investigating biomarkers for early detection, prognosis and the prediction of treatment responses in breast cancer is rapidly expanding. However, no validated biomarker currently exists for use in routine clinical practice, and breast cancer detection and management remains dependent on invasive procedures We aimed to develop biomarker for diagnosis of breast cancer in the real clinical practice by using proteomics technology. Methods: Based on our previous studies, we performed verification and validation of 124 candidate proteins by using proteomics approach. Among these 124 candidate proteins, the three proteins (neural cell adhesion molecule L1-like protein, apolipoprotein C-1, carbonic anhydrase-1) with highest statistical significance were selected. We created the performance algorithm of the 3-protein diagnostic model to predict of the breast cancer. We performed several experiments for establishment and validation of cut-off value. Furthermore we conducted test for acquisition of sample stability and more experiments to achieve the reproducibility and level of evidence, compared with other cancers (colon, thyroid, ovary, pancreas and lung cancer) and established effect of anesthesia. Results: Total 1226 samples (532 patients of breast cancer, 562 healthy women and 100 sample of other cancers) was analyzed. The sensitivity, specificity and accuracy from confirmation experiment was 71.58%, 85.25% and AUC 0.8323, respectively. The result of comparison with other cancers, there are no statistical significant difference and no relevance with effects of anesthesia. With these results, we recently got permission it to use for in vitro diagnostic use from Korea Food and Drug Administration. Conclusions: In this study, we developed a plasma protein biomarker that may help to diagnosis of breast cancer in the real clinical practice. By using MRM approach, the 3-protein biomarker was validated in an independent cohort with acceptable accuracy for early diagnosis of breast cancer.
Comprehensive genomic profiling of circulating cell-free DNA (cfDNA) distinguishes focal amplification (amp) from aneuploidy among MET amps in diverse advanced cancer types.
Authors: Kumaki Yuichi , Ikeda Sadakatsu , Rich Thereasa A. , Zhao Jing , Yoshino Takayuki , Cho Byoung Chul , Peled Nir , Han Ji-Youn , Shiotsu Yukimasa , Franovic Aleksandra , Raymond Victoria M. , Kurzrock Razelle , Lanman Richard B. , Lee Jeeyun , Mok Tony S. K.
Published: May 2019

3046

Background: MET amps can occur from focal gene copy number gain (e.g. MET-driven) or gain of chromosome 7 (e.g. aneuploidy); however, the contribution of each to MET amp is not well established. MET inhibitor-sensitive lung cancers harboring high-level MET amp have been reported in the absence of other sensitizing MET alterations (alts), e.g. exon 14 skipping, particularly among those with higher MET to chromosome 7 ratios. Methods: 3,114 samples from 2,902 Asian patients with advanced solid tumors were tested with a comprehensive cfDNA NGS panel (Guardant360) between Oct 2015-Dec 2018. This 70-73 gene assay evaluates single nucleotide variants (SNV), selected insertion-deletions (indels), fusions, and copy number gains. Focal amp was determined bioinformatically as having statistically higher copy number relative to other genes, such as BRAF, or CDK6, in the same chromosome arm. Results: MET alts associated with aberrant signaling were found in 223 pts (7.7%) with 18 different cancer types, most commonly lung (128/1,678), colorectal (36/349), and prostate (11/48). Among 223 pts, 189 pts (84.8%) had amps, 38(17.0%) had exon 14 skipping, and 8 (3.6%) had activating SNVs. 39.7% of MET amp was focal but differed by cancer type; highest prevalence was in gastroesophageal (80%) and lowest in prostate cancers (9%). Samples with focal MET amp had higher plasma copy number compared to those with non-focal MET amp (mean 5.8 vs. 2.5; p < 0.0001) and lower total number of alts per sample (8.8 vs. 11; p = 0.0122). Focal MET amp was more common than non-focal MET amp among 419 EGFR mutated samples (6.9% vs. 3.8%, p = 0.05) suggesting focal MET amp may be biologically more relevant as a mechanism of EGFR TKI resistance. Conclusions: This is the first study to use cfDNA to examine focal vs. non-focal MET amp. Focal MET amp accounted for ~40% of all MET amps, was found in 2.6% of pts with diverse cancers, was associated with higher plasma copy number, and found in a higher proportion of EGFR mutated lung cancer samples. The ability to differentiate may be clinically relevant given higher MET to chromosome 7 ratios have been associated with improved therapeutic response.