bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Identification of a RAS-activating TMEM87A–RASGRF1 Fusion in an Exceptional Responder to Sunitinib with Non–Small Cell Lung Cancer
Authors: Cooper Alissa J. , Kobayashi Yoshihisa , Kim Dewey , Clifford Sarah E. , Kravets Sasha , Dahlberg Suzanne E. , Chambers Emily S. , Li Jiaqi , Rangachari Deepa , Nguyen Tom , Costa Daniel B. , Rabin Michael S. , Wagle Nikhil , Sholl Lynette M. , Jänne Pasi A , Oxnard Geoffrey R.
Published: April 2023

AbstractPurpose:
We pursued genomic analysis of an exceptional responder with non–small cell lung cancer (NSCLC) through a multi-platform effort to discover novel oncogenic targets.
Experimental Design:
In this open-label, single-arm phase II study (NCT01829217), an enriched cohort of patients with advanced NSCLC was treated with the multi-kinase inhibitor sunitinib. The primary endpoint was objective response rate. Tissue was collected for multi-platform genomic analysis of responders, and a candidate oncogene was validated using in vitro models edited by CRISPR-Cas9.
Results:
Of 13 patients enrolled, 1 patient (8%), a never smoker, had a partial response lasting 33 months. Genomic analysis of the responder identified no oncogenic variant using multi-platform DNA analysis including hotspot allelotyping, massively parallel hybrid-capture next-generation sequencing, and whole-exome sequencing. However, bulk RNA-sequencing (RNA-seq) revealed a novel fusion, TMEM87A–RASGRF1, with high overexpression of the fusion partners. RASGRF1 encodes a guanine exchange factor which activates RAS from GDP-RAS to GTP-RAS. Oncogenicity was demonstrated in NIH/3T3 models with intrinsic TMEM87A–RASGRF1 fusion. In addition, activation of MAPK was shown in PC9 models edited to express this fusion, although sensitivity to MAPK inhibition was seen without apparent sensitivity to sunitinib.
Conclusions:
Sunitinib exhibited limited activity in this enriched cohort of patients with advanced NSCLC. Nonetheless, we find that RNA-seq of exceptional responders represents a potentially underutilized opportunity to identify novel oncogenic targets including oncogenic activation of RASGRF1.
Data from Noninvasive Detection of Urothelial Carcinoma by Cost-effective Low-coverage Whole-genome Sequencing from Urine-Exfoliated Cell DNA
Authors: Zeng Shuxiong , Ying Yidie , Xing Naidong , Wang Baiyun , Qian Ziliang , Zhou Zunlin , Zhang Zhensheng , Xu Weidong , Wang Huiqing , Dai Lihe , Gao Li , Zhou Tie , Ji Jiatao , Xu Chuanliang
Published: April 2023

AbstractPurpose:
Urothelial carcinoma is a malignant cancer with frequent chromosomal aberrations. Here, we investigated the application of a cost-effective, low-coverage whole-genome sequencing technology in detecting all chromosomal aberrations.
Experimental Design:
Patients with urothelial carcinomas and nontumor controls were prospectively recruited in clinical trial NCT03998371. Urine-exfoliated cell DNA was analyzed by Illumina HiSeq XTen, followed by genotyping with a customized bioinformatics workflow named Urine Exfoliated Cells Copy Number Aberration Detector (UroCAD).
Results:
In the discovery phase, urine samples from 126 patients with urothelial carcinomas and 64 nontumor disease samples were analyzed. Frequent chromosome copy-number changes were found in patients with tumor as compared with nontumor controls. A novel diagnosis model, UroCAD, was built by incorporating all the autosomal chromosomal changes. The model reached performance of AUC = 0.92 (95% confidence interval, 89.4%–97.3%). At the optimal cutoff, |Z| ≥ 3.21, the sensitivity, specificity, and accuracy were 82.5%, 96.9%, and 89.0%, respectively. The prediction positivity was found correlated with tumor grade (P = 0.01). In the external validation cohort of 95 participants, the UroCAD assay identified urothelial carcinomas with an overall sensitivity of 80.4%, specificity of 94.9%, and AUC of 0.91. Meanwhile, UroCAD assay outperformed cytology tests with significantly improved sensitivity (80.4% vs. 33.9%; P < 0.001) and comparable specificity (94.9% vs. 100%; P = 0.49).
Conclusions:
UroCAD could be a robust urothelial carcinoma diagnostic method with improved sensitivity and similar specificity as compared with cytology tests. It may be used as a noninvasive approach for diagnosis and recurrence surveillance in urothelial carcinoma prior to the use of cystoscopy, which would largely reduce the burden on patients.
Data from Advanced Age Increases Immunosuppression in the Brain and Decreases Immunotherapeutic Efficacy in Subjects with Glioblastoma
Authors: Ladomersky Erik , Zhai Lijie , Lauing Kristen L. , Bell April , Xu Jiahui , Kocherginsky Masha , Zhang Bin , Wu Jennifer D. , Podojil Joseph R. , Platanias Leonidas C. , Mochizuki Aaron Y. , Prins Robert M. , Kumthekar Priya , Raizer Jeffrey J. , Dixit Karan , Lukas Rimas V. , Horbinski Craig , Wei Min , Zhou Changyou , Pawelec Graham , Campisi Judith , Grohmann Ursula , Prendergast George C. , Munn David H. , Wainwright Derek A.
Published: April 2023

AbstractPurpose:
Wild-type isocitrate dehydrogenase–expressing glioblastoma (GBM) is the most common and aggressive primary brain tumor with a median age at diagnosis of ≥65 years. It accounts for approximately 90% of all GBMs and has a median overall survival (OS) of <15 months. Although immune checkpoint blockade (ICB) therapy has achieved remarkable survival benefits in a variety of aggressive malignancies, similar success has yet to be achieved for GBM among phase III clinical trials to date. Our study aimed to understand the relationship between subject age and immunotherapeutic efficacy as it relates to survival from glioma.
Experimental Design:
(i) Clinical data: GBM patient datasets from The Cancer Genome Atlas, Northwestern Medicine Enterprise Data Warehouse, and clinical studies evaluating ICB were stratified by age and compared for OS. (ii) Animal models: young, middle-aged, and older adult wild-type and indoleamine 2,3 dioxygenase (IDO)-knockout syngeneic mice were intracranially engrafted with CT-2A or GL261 glioma cell lines and treated with or without CTLA-4/PD-L1 mAbs, or radiation, anti–PD-1 mAb, and/or a pharmacologic IDO enzyme inhibitor.
Results:
Advanced age was associated with decreased GBM patient survival regardless of treatment with ICB. The advanced age–associated increase of brain IDO expression was linked to the suppression of immunotherapeutic efficacy and was not reversed by IDO enzyme inhibitor treatment.
Conclusions:
Immunosuppression increases in the brain during advanced age and inhibits antiglioma immunity in older adults. Going forward, it will be important to fully understand the factors and mechanisms in the elderly brain that contribute to the decreased survival of older patients with GBM during treatment with ICB.
Data from Microtubule Engagement with Taxane Is Altered in Taxane-Resistant Gastric Cancer
Authors: Galletti Giuseppe , Zhang Chao , Gjyrezi Ada , Cleveland Kyle , Zhang Jiaren , Powell Sarah , Thakkar Prashant V. , Betel Doron , Shah Manish A. , Giannakakou Paraskevi
Published: April 2023

AbstractPurpose:
Although taxane-based therapy is standard treatment for advanced gastric cancer, a majority of patients exhibit intrinsic resistance to taxanes. Here, we aim to identify the molecular basis of taxane resistance in gastric cancer.
Experimental Design:
We performed a post hoc analysis of the TAX-325 clinical trial and molecular interrogation of gastric cancer cell lines to assess the benefit of docetaxel in diffuse (DIF-GC) versus intestinal (INT-GC) gastric cancer. We assessed drug-induced microtubule stabilization in gastric cancer cells and in biopsies of patients with gastric cancer treated with taxanes. We performed transcriptome analysis in taxane-treated gastric cancer cells and patients to identify molecular drivers of taxane resistance.
Results:
Patients with DIF-GC did not derive a clinical benefit from taxane treatment suggesting intrinsic taxane resistance. DIF-GC cell lines displayed intrinsic resistance specific to taxanes because of impaired drug-induced microtubule stabilization, in the absence of tubulin mutations or decreased drug accumulation. Using taxane-treated gastric cancer patient biopsies, we demonstrated that absence of drug–target engagement was correlated with clinical taxane resistance. Taxane-sensitive cell lines displayed faster microtubule dynamics at baseline, implicating proteins that regulate cytoskeletal dynamics in intrinsic taxane resistance. Differential gene expression analysis of untreated and docetaxel-treated gastric cancer lines and patient samples identified kinesins to be associated with taxane sensitivity in vitro and in patient samples.
Conclusions:
Our data reveal that taxane resistance is more prevalent in patients with DIF-GC, support assessment of drug–target engagement as an early read-out of taxane clinical efficacy, and encourage the investigation of kinesins and other microtubule-associated proteins as potentially targetable mediators of taxane resistance in gastric cancer.
Data from Changes in Peripheral and Local Tumor Immunity after Neoadjuvant Chemotherapy Reshape Clinical Outcomes in Patients with Breast Cancer
Authors: Axelrod Margaret L. , Nixon Mellissa J. , Gonzalez-Ericsson Paula I. , Bergman Riley E. , Pilkinton Mark A. , McDonnell Wyatt J. , Sanchez Violeta , Opalenik Susan R. , Loi Sherene , Zhou Jing , Mackay Sean , Rexer Brent N. , Abramson Vandana G. , Jansen Valerie M. , Mallal Simon , Donaldson Joshua , Tolaney Sara M. , Krop Ian E. , Garrido-Castro Ana C. , Marotti Jonathan D. , Shee Kevin , Miller Todd W. , Sanders Melinda E. , Mayer Ingrid A. , Salgado Roberto , Balko Justin M.
Published: April 2023

AbstractPurpose:
The recent approval of anti-programmed death-ligand 1 immunotherapy in combination with nab-paclitaxel for metastatic triple-negative breast cancer (TNBC) highlights the need to understand the role of chemotherapy in modulating the tumor immune microenvironment (TIME).
Experimental Design:
We examined immune-related gene expression patterns before and after neoadjuvant chemotherapy (NAC) in a series of 83 breast tumors, including 44 TNBCs, from patients with residual disease (RD). Changes in gene expression patterns in the TIME were tested for association with recurrence-free (RFS) and overall survival (OS). In addition, we sought to characterize the systemic effects of NAC through single-cell analysis (RNAseq and cytokine secretion) of programmed death-1–high (PD-1HI) CD8+ peripheral T cells and examination of a cytolytic gene signature in whole blood.
Results:
In non-TNBC, no change in expression of any single gene was associated with RFS or OS, while in TNBC upregulation of multiple immune-related genes and gene sets were associated with improved long-term outcome. High cytotoxic T-cell signatures present in the peripheral blood of patients with breast cancer at surgery were associated with persistent disease and recurrence, suggesting active antitumor immunity that may indicate ongoing disease burden.
Conclusions:
We have characterized the effects of NAC on the TIME, finding that TNBC is uniquely sensitive to the immunologic effects of NAC, and local increases in immune genes/sets are associated with improved outcomes. However, expression of cytotoxic genes in the peripheral blood, as opposed to the TIME, may be a minimally invasive biomarker of persistent micrometastatic disease ultimately leading to recurrence.
Data from The Outcome of TGFβ Antagonism in Metastatic Breast Cancer Models In Vivo Reflects a Complex Balance between Tumor-Suppressive and Proprogression Activities of TGFβ
Authors: Yang Yuan , Yang Howard H. , Tang Binwu , Wu Alex Man Lai , Flanders Kathleen C. , Moshkovich Nellie , Weinberg Douglas S. , Welsh Michael A. , Weng Jia , Ochoa Humberto J. , Hu Tiffany Y. , Herrmann Michelle A. , Chen Jinqiu , Edmondson Elijah F. , Simpson R. Mark , Liu Fang , Liu Huaitian , Lee Maxwell P. , Wakefield Lalage M.
Published: April 2023

AbstractPurpose:
TGFβs are overexpressed in many advanced cancers and promote cancer progression through mechanisms that include suppression of immunosurveillance. Multiple strategies to antagonize the TGFβ pathway are in early-phase oncology trials. However, TGFβs also have tumor-suppressive activities early in tumorigenesis, and the extent to which these might be retained in advanced disease has not been fully explored.
Experimental Design:
A panel of 12 immunocompetent mouse allograft models of metastatic breast cancer was tested for the effect of neutralizing anti-TGFβ antibodies on lung metastatic burden. Extensive correlative biology analyses were performed to assess potential predictive biomarkers and probe underlying mechanisms.
Results:
Heterogeneous responses to anti-TGFβ treatment were observed, with 5 of 12 models (42%) showing suppression of metastasis, 4 of 12 (33%) showing no response, and 3 of 12 (25%) showing an undesirable stimulation (up to 9-fold) of metastasis. Inhibition of metastasis was immune-dependent, whereas stimulation of metastasis was immune-independent and targeted the tumor cell compartment, potentially affecting the cancer stem cell. Thus, the integrated outcome of TGFβ antagonism depends on a complex balance between enhancing effective antitumor immunity and disrupting persistent tumor-suppressive effects of TGFβ on the tumor cell. Applying transcriptomic signatures derived from treatment-naïve mouse primary tumors to human breast cancer datasets suggested that patients with breast cancer with high-grade, estrogen receptor–negative disease are most likely to benefit from anti-TGFβ therapy.
Conclusions:
Contrary to dogma, tumor-suppressive responses to TGFβ are retained in some advanced metastatic tumors. Safe deployment of TGFβ antagonists in the clinic will require good predictive biomarkers.
Data from Circulating Tumor DNA Analysis to Assess Risk of Progression after Long-term Response to PD-(L)1 Blockade in NSCLC
Authors: Hellmann Matthew D. , Nabet Barzin Y. , Rizvi Hira , Chaudhuri Aadel A. , Wells Daniel K. , Dunphy Mark P.S. , Chabon Jacob J. , Liu Chih Long , Hui Angela B. , Arbour Kathryn C. , Luo Jia , Preeshagul Isabel R. , Moding Everett J. , Almanza Diego , Bonilla Rene F. , Sauter Jennifer L. , Choi Hyejin , Tenet Megan , Abu-Akeel Mohsen , Plodkowski Andrew J. , Perez Johnston Rocio , Yoo Christopher H. , Ko Ryan B. , Stehr Henning , Gojenola Linda , Wakelee Heather A. , Padda Sukhmani K. , Neal Joel W. , Chaft Jamie E. , Kris Mark G. , Rudin Charles M. , Merghoub Taha , Li Bob T. , Alizadeh Ash A. , Diehn Maximilian
Published: April 2023

AbstractPurpose:
Treatment with PD-(L)1 blockade can produce remarkably durable responses in patients with non–small cell lung cancer (NSCLC). However, a significant fraction of long-term responders ultimately progress and predictors of late progression are unknown. We hypothesized that circulating tumor DNA (ctDNA) analysis of long-term responders to PD-(L)1 blockade may differentiate those who will achieve ongoing benefit from those at risk of eventual progression.
Experimental Design:
In patients with advanced NSCLC achieving long-term benefit from PD-(L)1 blockade (progression-free survival ≥ 12 months), plasma was collected at a surveillance timepoint late during/after treatment to interrogate ctDNA by Cancer Personalized Profiling by Deep Sequencing. Tumor tissue was available for 24 patients and was profiled by whole-exome sequencing (n = 18) or by targeted sequencing (n = 6).
Results:
Thirty-one patients with NSCLC with long-term benefit to PD-(L)1 blockade were identified, and ctDNA was analyzed in surveillance blood samples collected at a median of 26.7 months after initiation of therapy. Nine patients also had baseline plasma samples available, and all had detectable ctDNA prior to therapy initiation. At the surveillance timepoint, 27 patients had undetectable ctDNA and 25 (93%) have remained progression-free; in contrast, all 4 patients with detectable ctDNA eventually progressed [Fisher P < 0.0001; positive predictive value = 1, 95% confidence interval (CI), 0.51–1; negative predictive value = 0.93 (95% CI, 0.80–0.99)].
Conclusions:
ctDNA analysis can noninvasively identify minimal residual disease in patients with long-term responses to PD-(L)1 blockade and predict the risk of eventual progression. If validated, ctDNA surveillance may facilitate personalization of the duration of immune checkpoint blockade and enable early intervention in patients at high risk for progression.
Data from Circulating Tumor Cell Subtypes and T-cell Populations as Prognostic Biomarkers to Combination Immunotherapy in Patients with Metastatic Genitourinary Cancer
Authors: Chalfin Heather J. , Pramparo Tiziano , Mortazavi Amir , Niglio Scot A. , Schonhoft Joseph D. , Jendrisak Adam , Chu Yen-Lin , Richardson Robin , Krupa Rachel , Anderson Amanda K.L. , Wang Yipeng , Dittamore Ryan , Pal Sumanta K. , Lara Primo N. , Stein Mark N. , Quinn David I. , Steinberg Seth M. , Cordes Lisa M. , Ley Lisa , Mallek Marissa , Sierra Ortiz Olena , Costello Rene , Cadena Jacqueline , Diaz Carlos , Gulley James L. , Dahut William L. , Streicher Howard , Wright John J. , Trepel Jane B. , Bottaro Donald P. , Apolo Andrea B.
Published: April 2023

AbstractPurpose:
Circulating tumor cells (CTC) are under investigation as a minimally invasive liquid biopsy that may improve risk stratification and treatment selection. CTCs uniquely allow for digital pathology of individual malignant cell morphology and marker expression. We compared CTC features and T-cell counts with survival endpoints in a cohort of patients with metastatic genitourinary cancer treated with combination immunotherapy.
Experimental Design:
Markers evaluated included pan-CK/CD45/PD-L1/DAPI for CTCs and CD4/CD8/Ki-67/DAPI for T cells. ANOVA was used to compare CTC burden and T-cell populations across timepoints. Differences in survival and disease progression were evaluated using the maximum log-rank test.
Results:
From December 2016 to January 2019, 183 samples from 81 patients were tested. CTCs were found in 75% of patients at baseline. CTC burden was associated with shorter overall survival (OS) at baseline (P = 0.022), but not on-therapy. Five morphologic subtypes were detected, and the presence of two specific subtypes with unique cellular features at baseline and on-therapy was associated with worse OS (0.9–2.3 vs. 28.2 months; P < 0.0001–0.013). Increasing CTC heterogeneity on-therapy had a trend toward worse OS (P = 0.045). PD-L1+ CTCs on-therapy were associated with worse OS (P < 0.01, cycle 2). Low baseline and on-therapy CD4/CD8 counts were also associated with poor OS and response category.
Conclusions:
Shorter survival may be associated with high CTC counts at baseline, presence of specific CTC morphologic subtypes, PD-L1+ CTCs, and low �4/8 T cells in patients with metastatic genitourinary cancer. A future study is warranted to validate the prognostic utility of CTC heterogeneity and detection of specific CTC morphologies.
Data from Association of Fusobacterium nucleatum with Specific T-cell Subsets in the Colorectal Carcinoma Microenvironment
Authors: Borowsky Jennifer , Haruki Koichiro , Lau Mai Chan , Dias Costa Andressa , Väyrynen Juha P. , Ugai Tomotaka , Arima Kota , da Silva Annacarolina , Felt Kristen D. , Zhao Melissa , Gurjao Carino , Twombly Tyler S. , Fujiyoshi Kenji , Väyrynen Sara A. , Hamada Tsuyoshi , Mima Kosuke , Bullman Susan , Harrison Tabitha A. , Phipps Amanda I. , Peters Ulrike , Ng Kimmie , Meyerhardt Jeffrey A. , Song Mingyang , Giovannucci Edward L. , Wu Kana , Zhang Xuehong , Freeman Gordon J. , Huttenhower Curtis , Garrett Wendy S. , Chan Andrew T. , Leggett Barbara A. , Whitehall Vicki L.J. , Walker Neal , Brown Ian , Bettington Mark , Nishihara Reiko , Fuchs Charles S. , Lennerz Jochen K. , Giannakis Marios , Nowak Jonathan A. , Ogino Shuji
Published: April 2023

AbstractPurpose:
While evidence indicates that Fusobacterium nucleatum (F. nucleatum) may promote colorectal carcinogenesis through its suppressive effect on T-cell–mediated antitumor immunity, the specific T-cell subsets involved remain uncertain.
Experimental Design:
We measured F. nucleatum DNA within tumor tissue by quantitative PCR on 933 cases (including 128 F. nucleatum–positive cases) among 4,465 incident colorectal carcinoma cases in two prospective cohorts. Multiplex immunofluorescence combined with digital image analysis and machine learning algorithms for CD3, CD4, CD8, CD45RO (PTPRC isoform), and FOXP3 measured various T-cell subsets. We leveraged data on Bifidobacterium, microsatellite instability (MSI), tumor whole-exome sequencing, and M1/M2-type tumor-associated macrophages [TAM; by CD68, CD86, IRF5, MAF, and MRC1 (CD206) multimarker assay]. Using the 4,465 cancer cases and inverse probability weighting method to control for selection bias due to tissue availability, multivariable-adjusted logistic regression analysis assessed the association between F. nucleatum and T-cell subsets.
Results:
The amount of F. nucleatum was inversely associated with tumor stromal CD3+ lymphocytes [multivariable OR, 0.47; 95% confidence interval (CI), 0.28–0.79, for F. nucleatum–high vs. -negative category; Ptrend = 0.0004] and specifically stromal CD3+CD4+CD45RO+ cells (corresponding multivariable OR, 0.52; 95% CI, 0.32–0.85; Ptrend = 0.003). These relationships did not substantially differ by MSI status, neoantigen load, or exome-wide tumor mutational burden. F. nucleatum was not significantly associated with tumor intraepithelial T cells or with M1 or M2 TAMs.
Conclusions:
The amount of tissue F. nucleatum is associated with lower density of stromal memory helper T cells. Our findings provide evidence for the interactive pathogenic roles of microbiota and specific immune cells.
Data from Development of Highly Optimized Antibody–Drug Conjugates against CD33 and CD123 for Acute Myeloid Leukemia
Authors: Han Yoon-Chi , Kahler Jennifer , Piché-Nicholas Nicole , Hu Wenyue , Thibault Stephane , Jiang Fan , Leal Mauricio , Katragadda Madan , Maderna Andreas , Dushin Russell , Prashad Nadira , Charati Manoj B. , Clark Tracey , Tumey L. Nathan , Tan Xingzhi , Giannakou Andreas , Rosfjord Edward , Gerber Hans-Peter , Tchistiakova Lioudmila , Loganzo Frank , O'Donnell Christopher J. , Sapra Puja
Published: April 2023

AbstractPurpose:
Mortality due to acute myeloid leukemia (AML) remains high, and the management of relapsed or refractory AML continues to be therapeutically challenging. The reapproval of Mylotarg, an anti-CD33–calicheamicin antibody–drug conjugate (ADC), has provided a proof of concept for an ADC-based therapeutic for AML. Several other ADCs have since entered clinical development of AML, but have met with limited success. We sought to develop a next-generation ADC for AML with a wide therapeutic index (TI) that overcomes the shortcomings of previous generations of ADCs.
Experimental Design:
We compared the TI of our novel CD33-targeted ADC platform with other currently available CD33-targeted ADCs in preclinical models of AML. Next, using this next-generation ADC platform, we performed a head-to-head comparison of two attractive AML antigens, CD33 and CD123.
Results:
Our novel ADC platform offered improved safety and TI when compared with certain currently available ADC platforms in preclinical models of AML. Differentiation between the CD33- and CD123-targeted ADCs was observed in safety studies conducted in cynomolgus monkeys. The CD33-targeted ADC produced severe hematologic toxicity, whereas minimal hematologic toxicity was observed with the CD123-targeted ADC at the same doses and exposures. The improved toxicity profile of an ADC targeting CD123 over CD33 was consistent with the more restricted expression of CD123 in normal tissues.
Conclusions:
We optimized all components of ADC design (i.e., leukemia antigen, antibody, and linker-payload) to develop an ADC that has the potential to translate into an effective new therapy against AML.
Data from Clinical Efficacy and Molecular Response Correlates of the WEE1 Inhibitor Adavosertib Combined with Cisplatin in Patients with Metastatic Triple-Negative Breast Cancer
Authors: Keenan Tanya E. , Li Tianyu , Vallius Tuulia , Guerriero Jennifer L. , Tayob Nabihah , Kochupurakkal Bose , Davis Janae , Pastorello Ricardo , Tahara Rie K. , Anderson Leilani , Conway Jake , He Meng X. , Shannon Erin , Godin Robert E. , Sorger Peter K. , D'Andrea Alan , Overmoyer Beth , Winer Eric P. , Mittendorf Elizabeth A. , Van Allen Eliezer M. , Shapiro Geoffrey I. , Tolaney Sara M.
Published: April 2023

AbstractPurpose:
We report results from a phase II study assessing the efficacy of the WEE1 inhibitor adavosertib with cisplatin in metastatic triple-negative breast cancer (mTNBC).
Patients and Methods:
Patients with mTNBC treated with 0–1 prior lines of chemotherapy received cisplatin 75 mg/m2 i.v. followed 21 days later by cisplatin plus adavosertib 200 mg oral twice daily for five doses every 21 days. The study had 90% power to detect the difference between null (20%) and alternative (40%) objective response rates (ORR) with a one-sided type I error of 0.1: an ORR >30% was predefined as making the regimen worthy of further study. RNA sequencing and multiplex cyclic immunofluorescence on pre- and post-adavosertib tumor biopsies, as well as targeted next-generation sequencing on archival tissue, were correlated with clinical benefit, defined as stable disease ≥6 months or complete or partial response.
Results:
A total of 34 patients initiated protocol therapy; median age was 56 years, 2 patients (6%) had BRCA2 mutations, and 14 (41%) had one prior chemotherapy. ORR was 26% [95% confidence interval (CI), 13–44], and median progression-free survival was 4.9 months (95% CI, 2.3–5.7). Treatment-related grade 3–5 adverse events occurred in 53% of patients, most commonly diarrhea in 21%. One death occurred because of sepsis, possibly related to study therapy. Tumors from patients with clinical benefit demonstrated enriched immune gene expression and T-cell infiltration.
Conclusions:
Among patients with mTNBC treated with 0–1 prior lines, adavosertib combined with cisplatin missed the prespecified ORR cutoff of >30%. The finding of immune-infiltrated tumors in patients with clinical benefit warrants validation.
Data from Proteogenomic Analysis of Salivary Adenoid Cystic Carcinomas Defines Molecular Subtypes and Identifies Therapeutic Targets
Authors: Ferrarotto Renata , Mitani Yoshitsugu , McGrail Daniel J. , Li Kaiyi , Karpinets Tatiana V. , Bell Diana , Frank Steven J. , Song Xingzhi , Kupferman Michael E. , Liu Bin , Lee J. Jack , Glisson Bonnie S. , Zhang Jianhua , Aster Jon C. , Lin Shiaw-Yih , Futreal P. Andrew , Heymach John V. , El-Naggar Adel K.
Published: April 2023

AbstractPurpose:
Salivary gland adenoid cystic carcinoma (ACC) has heterogeneous clinical behavior. Currently, all patients are treated uniformly, and no standard-of-care systemic therapy exists for metastatic ACC. We conducted an integrated proteogenomic analyses of ACC tumors to identify dysregulated pathways and propose a classification with therapeutic implications.
Experimental Design:
RNA/DNA sequencing of 54 flash-frozen salivary ACCs and reverse phase protein array (RPPA) in 38 specimens were performed, with validation by Western blotting and/or IHC. Three independent ACC cohorts were used for validation.
Results:
Both unbiased RNA sequencing (RNA-seq) and RPPA analysis revealed two molecular subtypes: ACC-I (37%) and ACC-II (63%). ACC-I had strong upregulation of MYC, MYC target genes, and mRNA splicing, enrichment of NOTCH-activating mutations, and dramatically worse prognosis. ACC-II exhibited upregulation of TP63 and receptor tyrosine kinases (AXL, MET, and EGFR) and less aggressive clinical course. TP63 and MYC were sufficient to assign tumors to ACC subtypes, which was validated in one independent cohort by IHC and two additional independent cohorts by RNA-seq. Furthermore, IHC staining for MYC and P63 protein levels can be used to identify ACC subtypes, enabling rapid clinical deployment to guide therapeutic decisions. Our data suggest a model in which ACC-I is driven by MYC signaling through either NOTCH mutations or direct amplification, which in turn suppress P63 signaling observed in ACC-II, producing unique therapeutic vulnerabilities for each subtype.
Conclusions:
Cooccurrence of multiple actionable protein/pathways alterations in each subtype indicates unique therapeutic vulnerabilities and opportunities for optimal combination therapy for this understudied and heterogeneous disease.
Data from Randomized Phase II and Biomarker Study of Pembrolizumab plus Bevacizumab versus Pembrolizumab Alone for Patients with Recurrent Glioblastoma
Authors: Nayak Lakshmi , Molinaro Annette M. , Peters Katherine , Clarke Jennifer L. , Jordan Justin T. , de Groot John , Nghiemphu Leia , Kaley Thomas , Colman Howard , McCluskey Christine , Gaffey Sarah , Smith Timothy R. , Cote David J. , Severgnini Mariano , Yearley Jennifer H. , Zhao Qing , Blumenschein Wendy M. , Duda Dan G. , Muzikansky Alona , Jain Rakesh K. , Wen Patrick Y. , Reardon David A.
Published: April 2023

AbstractPurpose:
VEGF is upregulated in glioblastoma and may contribute to immunosuppression. We performed a phase II study of pembrolizumab alone or with bevacizumab in recurrent glioblastoma.
Patients and Methods:
Eighty bevacizumab-naïve patients with recurrent glioblastoma were randomized to pembrolizumab with bevacizumab (cohort A, n = 50) or pembrolizumab monotherapy (cohort B, n = 30). The primary endpoint was 6-month progression-free survival (PFS-6). Assessed biomarkers included evaluation of tumor programmed death-ligand 1 expression, tumor-infiltrating lymphocyte density, immune activation gene expression signature, and plasma cytokines. The neurologic assessment in neuro-oncology (NANO) scale was used to prospectively assess neurologic function.
Results:
Pembrolizumab alone or with bevacizumab was well tolerated but of limited benefit. For cohort A, PFS-6 was 26.0% [95% confidence interval (CI), 16.3–41.5], median overall survival (OS) was 8.8 months (95% CI, 7.7–14.2), objective response rate (ORR) was 20%, and median duration of response was 48 weeks. For cohort B, PFS-6 was 6.7% (95% CI, 1.7–25.4), median OS was 10.3 months (95% CI, 8.5–12.5), and ORR was 0%. Tumor immune markers were not associated with OS, but worsened OS correlated with baseline dexamethasone use and increased posttherapy plasma VEGF (cohort A) and mutant IDH1, unmethylated MGMT, and increased baseline PlGF and sVEGFR1 levels (cohort B). The NANO scale contributed to overall outcome assessment.
Conclusions:
Pembrolizumab was ineffective as monotherapy and with bevacizumab for recurrent glioblastoma. The infrequent radiographic responses to combinatorial therapy were durable. Tumor immune biomarkers did not predict outcome. Baseline dexamethasone use and tumor MGMT warrant further study as potential biomarkers in glioblastoma immunotherapy trials.
Data from Investigation of Antigen-Specific T-Cell Receptor Clusters in Human Cancers
Authors: Zhang Hongyi , Liu Longchao , Zhang Jian , Chen Jiahui , Ye Jianfeng , Shukla Sachet , Qiao Jian , Zhan Xiaowei , Chen Hao , Wu Catherine J. , Fu Yang-Xin , Li Bo
Published: April 2023

AbstractPurpose:
Cancer antigen–specific T cells are key components in antitumor immune response, yet their identification in the tumor microenvironment remains challenging, as most cancer antigens are unknown. Recent advance in immunology suggests that similar T-cell receptor (TCR) sequences can be clustered to infer shared antigen specificity. This study aims to identify antigen-specific TCRs from the tumor genomics sequencing data.
Experimental Design:
We used the TRUST (Tcr Repertoire Utilities for Solid Tissue) algorithm to assemble the TCR hypervariable CDR3 regions from 9,700 bulk tumor RNA-sequencing (RNA-seq) samples, and developed a computational method, iSMART, to group similar TCRs into antigen-specific clusters. Integrative analysis on the TCR clusters with multi-omics datasets was performed to profile cancer-associated T cells and to uncover novel cancer antigens.
Results:
Clustered TCRs are associated with signatures of T-cell activation after antigen encounter. We further elucidated the phenotypes of clustered T cells using single-cell RNA-seq data, which revealed a novel subset of tissue-resident memory T-cell population with elevated metabolic status. An exciting application of the TCR clusters is to identify novel cancer antigens, exemplified by our identification of a candidate cancer/testis gene, HSFX1, through integrated analysis of HLA alleles and genomics data. The target was further validated using vaccination of humanized HLA-A*02:01 mice and ELISpot assay. Finally, we showed that clustered tumor-infiltrating TCRs can differentiate patients with early-stage cancer from healthy donors, using blood TCR repertoire sequencing data, suggesting potential applications in noninvasive cancer detection.
Conclusions:
Our analysis on the antigen-specific TCR clusters provides a unique resource for alternative antigen discovery and biomarker identification for cancer immunotherapies.
Data from Integrative Genomic Analysis of Gemcitabine Resistance in Pancreatic Cancer by Patient-derived Xenograft Models
Authors: Yang Gang , Guan Wenfang , Cao Zhe , Guo Wenbo , Xiong Guangbing , Zhao Fangyu , Feng Mengyu , Qiu Jiangdong , Liu Yueze , Zhang Michael Q. , You Lei , Zhang Taiping , Zhao Yupei , Gu Jin
Published: April 2023

AbstractPurpose:
Gemcitabine is most commonly used for pancreatic cancer. However, the molecular features and mechanisms of the frequently occurring resistance remain unclear. This work aims at exploring the molecular features of gemcitabine resistance and identifying candidate biomarkers and combinatorial targets for the treatment.
Experimental Design:
In this study, we established 66 patient-derived xenografts (PDXs) on the basis of clinical pancreatic cancer specimens and treated them with gemcitabine. We generated multiomics data (including whole-exome sequencing, RNA sequencing, miRNA sequencing, and DNA methylation array) of 15 drug-sensitive and 13 -resistant PDXs before and after the gemcitabine treatment. We performed integrative computational analysis to identify the molecular networks related to gemcitabine intrinsic and acquired resistance. Then, short hairpin RNA–based high-content screening was implemented to validate the function of the deregulated genes.
Results:
The comprehensive multiomics analysis and functional experiment revealed that MRPS5 and GSPT1 had strong effects on cell proliferation, and CD55 and DHTKD1 contributed to gemcitabine resistance in pancreatic cancer cells. Moreover, we found miR-135a-5p was significantly associated with the prognosis of patients with pancreatic cancer and could be a candidate biomarker to predict gemcitabine response. Comparing the molecular features before and after the treatment, we found that PI3K-Akt, p53, and hypoxia-inducible factor-1 pathways were significantly altered in multiple patients, providing candidate target pathways for reducing the acquired resistance.
Conclusions:
This integrative genomic study systematically investigated the predictive markers and molecular mechanisms of chemoresistance in pancreatic cancer and provides potential therapy targets for overcoming gemcitabine resistance.
Data from Blocking IL1 Beta Promotes Tumor Regression and Remodeling of the Myeloid Compartment in a Renal Cell Carcinoma Model: Multidimensional Analyses
Authors: Aggen David H. , Ager Casey R. , Obradovic Aleksandar Z. , Chowdhury Nivedita , Ghasemzadeh Ali , Mao Wendy , Chaimowitz Matthew G. , Lopez-Bujanda Zoila A. , Spina Catherine S. , Hawley Jessica E. , Dallos Matthew C. , Zhang Cheng , Wang Vinson , Li Hu , Guo Xinzheng V. , Drake Charles G.
Published: April 2023

AbstractPurpose:
Intratumoral immunosuppression mediated by myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) represents a potential mechanism of immune checkpoint inhibitor (ICI) resistance in solid tumors. By promoting TAM and MDSC infiltration, IL1β may drive adaptive and innate immune resistance in renal cell carcinoma (RCC) and in other tumor types.
Experimental Design:
Using the RENCA model of RCC, we evaluated clinically relevant combinations of anti-IL1β plus either anti-PD-1 or the multitargeted tyrosine kinase inhibitor (TKI), cabozantinib. We performed comprehensive immune profiling of established RENCA tumors via multiparameter flow cytometry, tumor cytokine profiling, and single-cell RNA sequencing (RNA-seq). Similar analyses were extended to the MC38 tumor model.
Results:
Analyses via multiparameter flow cytometry, tumor cytokine profiling, and single-cell RNA-seq showed that anti-IL1β reduces infiltration of polymorphonuclear MDSCs and TAMs. Combination treatment with anti-IL1β plus anti-PD-1 or cabozantinib showed increased antitumor activity that was associated with decreases in immunosuppressive MDSCs and increases in M1-like TAMs.
Conclusions:
Single-cell RNA-seq analyses show that IL1β blockade and ICI or TKI remodel the myeloid compartment through nonredundant, relatively T-cell–independent mechanisms. IL1β is an upstream mediator of adaptive myeloid resistance and represents a potential target for kidney cancer immunotherapy.
Data from Targeted Therapy of TERT-Rearranged Neuroblastoma with BET Bromodomain Inhibitor and Proteasome Inhibitor Combination Therapy
Authors: Chen Jingwei , Nelson Christopher , Wong Matthew , Tee Andrew E. , Liu Pei Y. , La Ting , Fletcher Jamie I. , Kamili Alvin , Mayoh Chelsea , Bartenhagen Christoph , Trahair Toby N. , Xu Ning , Jayatilleke Nisitha , Wong Marie , Peng Hui , Atmadibrata Bernard , Cheung Belamy B. , Lan Qing , Bryan Tracy M. , Mestdagh Pieter , Vandesompele Jo , Combaret Valerie , Boeva Valentina , Wang Jenny Y. , Janoueix-Lerosey Isabelle , Cowley Mark J. , MacKenzie Karen L. , Dolnikov Alla , Li Jinyan , Polly Patsie , Marshall Glenn M. , Reddel Roger R. , Norris Murray D. , Haber Michelle , Fischer Matthias , Zhang Xu D. , Pickett Hilda A. , Liu Tao
Published: April 2023

AbstractPurpose:
TERT gene rearrangement with transcriptional superenhancers leads to TERT overexpression and neuroblastoma. No targeted therapy is available for clinical trials in patients with TERT-rearranged neuroblastoma.
Experimental Design:
Anticancer agents exerting the best synergistic anticancer effects with BET bromodomain inhibitors were identified by screening an FDA-approved oncology drug library. The synergistic effects of the BET bromodomain inhibitor OTX015 and the proteasome inhibitor carfilzomib were examined by immunoblot and flow cytometry analysis. The anticancer efficacy of OTX015 and carfilzomib combination therapy was investigated in mice xenografted with TERT-rearranged neuroblastoma cell lines or patient-derived xenograft (PDX) tumor cells, and the role of TERT reduction in the anticancer efficacy was examined through rescue experiments in mice.
Results:
The BET bromodomain protein BRD4 promoted TERT-rearranged neuroblastoma cell proliferation through upregulating TERT expression. Screening of an approved oncology drug library identified the proteasome inhibitor carfilzomib as the agent exerting the best synergistic anticancer effects with BET bromodomain inhibitors including OTX015. OTX015 and carfilzomib synergistically reduced TERT protein expression, induced endoplasmic reticulum stress, and induced TERT-rearranged neuroblastoma cell apoptosis which was blocked by TERT overexpression and endoplasmic reticulum stress antagonists. In mice xenografted with TERT-rearranged neuroblastoma cell lines or PDX tumor cells, OTX015 and carfilzomib synergistically blocked TERT expression, induced tumor cell apoptosis, suppressed tumor progression, and improved mouse survival, which was largely reversed by forced TERT overexpression.
Conclusions:
OTX015 and carfilzomib combination therapy is likely to be translated into the first clinical trial of a targeted therapy in patients with TERT-rearranged neuroblastoma.
Data from Tumor-Naïve Multimodal Profiling of Circulating Tumor DNA in Head and Neck Squamous Cell Carcinoma
Authors: Burgener Justin M. , Zou Jinfeng , Zhao Zhen , Zheng Yangqiao , Shen Shu Yi , Huang Shao Hui , Keshavarzi Sareh , Xu Wei , Liu Fei-Fei , Liu Geoffrey , Waldron John N. , Weinreb Ilan , Spreafico Anna , Siu Lillian L. , de Almeida John R. , Goldstein David P. , Hoffman Michael M. , De Carvalho Daniel D. , Bratman Scott V.
Published: April 2023

AbstractPurpose:
Circulating tumor DNA (ctDNA) enables personalized treatment strategies in oncology by providing a noninvasive source of clinical biomarkers. In patients with low ctDNA abundance, tumor-naïve methods are needed to facilitate clinical implementation. Here, using locoregionally confined head and neck squamous cell carcinoma (HNSCC) as an example, we demonstrate tumor-naïve detection of ctDNA by simultaneous profiling of mutations and methylation.
Experimental Design:
We conducted CAncer Personalized Profiling by deep Sequencing (CAPP-seq) and cell-free Methylated DNA ImmunoPrecipitation and high-throughput sequencing (cfMeDIP-seq) for detection of ctDNA-derived somatic mutations and aberrant methylation, respectively. We analyzed 77 plasma samples from 30 patients with stage I–IVA human papillomavirus–negative HNSCC as well as plasma samples from 20 risk-matched healthy controls. In addition, we analyzed leukocytes from patients and controls.
Results:
CAPP-seq identified mutations in 20 of 30 patients at frequencies similar to that of The Tumor Genome Atlas (TCGA). Differential methylation analysis of cfMeDIP-seq profiles identified 941 ctDNA-derived hypermethylated regions enriched for CpG islands and HNSCC-specific methylation patterns. Both methods demonstrated an association between ctDNA abundance and shorter fragment lengths. In addition, mutation- and methylation-based ctDNA abundance was highly correlated (r > 0.85). Patients with detectable pretreatment ctDNA by both methods demonstrated significantly worse overall survival (HR = 7.5; P = 0.025) independent of clinical stage, with lack of ctDNA clearance post-treatment strongly correlating with recurrence. We further leveraged cfMeDIP-seq profiles to validate a prognostic signature identified from TCGA samples.
Conclusions:
Tumor-naïve detection of ctDNA by multimodal profiling may facilitate biomarker discovery and clinical use in low ctDNA abundance applications.
Data from FDA Approval Summary: Gilteritinib for Relapsed or Refractory Acute Myeloid Leukemia with a FLT3 Mutation
Authors: Pulte E. Dianne , Norsworthy Kelly J. , Wang Yaping , Xu Qing , Qosa Hisham , Gudi Ramadevi , Przepiorka Donna , Fu Wentao , Okusanya Olanrewaju O. , Goldberg Kirsten B. , De Claro R. Angelo , Farrell Ann T. , Pazdur Richard
Published: April 2023

Abstract
On November 28, 2018, the FDA approved gilteritinib (Xospata; Astellas), a small-molecule FMS-like tyrosine kinase 3 (FLT3) inhibitor, for treatment of relapsed or refractory acute myeloid leukemia with a FLT3 mutation as detected by an FDA-approved test. In the ADMIRAL study, patients were randomized 2:1 to receive gilteritinib or standard chemotherapy and stratified by response to first-line treatment and intensity of prespecified chemotherapy. Efficacy was established on interim analysis on the basis of complete remission (CR) + CR with partial hematologic recovery (CRh) rate, duration of CR + CRh, and conversion from transfusion dependence to transfusion independence in 138 patients in the gilteritinib arm. With median follow-up of 4.6 months [95% confidence interval (CI), 2.8–15.8 months] at interim analysis, the CR + CRh rate was 21% (95% CI, 15%–29%), median duration of CR + CRh was 4.6 months (range, 0.1–15.8+), and conversion from transfusion dependence to transfusion independence was 31%. Revised labeling approved on May 29, 2019 included the results of the final analysis, showing an improvement in overall survival (OS) with gilteritinib compared with chemotherapy (HR, 0.64; 95% CI, 0.49–0.83; one-sided P = 0.0004; median OS, 9.3 vs. 5.6 months). The OS benefit was observed in both high and low chemotherapy intensity subgroups. Labeling includes a boxed warning for differentiation syndrome and warnings for posterior reversible encephalopathy syndrome, QT prolongation, pancreatitis, and embryo-fetal toxicity. Safe use requires frequent monitoring of electrocardiograms and blood chemistries. Assessments of long-term safety are pending.
Data from Deep Learning for Fully Automated Prediction of Overall Survival in Patients with Oropharyngeal Cancer Using FDG-PET Imaging
Authors: Cheng Nai-Ming , Yao Jiawen , Cai Jinzheng , Ye Xianghua , Zhao Shilin , Zhao Kui , Zhou Wenlan , Nogues Isabella , Huo Yuankai , Liao Chun-Ta , Wang Hung-Ming , Lin Chien-Yu , Lee Li-Yu , Xiao Jing , Lu Le , Zhang Ling , Yen Tzu-Chen
Published: April 2023

AbstractPurpose:
Accurate prognostic stratification of patients with oropharyngeal squamous cell carcinoma (OPSCC) is crucial. We developed an objective and robust deep learning–based fully-automated tool called the DeepPET-OPSCC biomarker for predicting overall survival (OS) in OPSCC using [18F]fluorodeoxyglucose (FDG)-PET imaging.
Experimental Design:
The DeepPET-OPSCC prediction model was built and tested internally on a discovery cohort (n = 268) by integrating five convolutional neural network models for volumetric segmentation and ten models for OS prognostication. Two external test cohorts were enrolled—the first based on the Cancer Imaging Archive (TCIA) database (n = 353) and the second being a clinical deployment cohort (n = 31)—to assess the DeepPET-OPSCC performance and goodness of fit.
Results:
After adjustment for potential confounders, DeepPET-OPSCC was found to be an independent predictor of OS in both discovery and TCIA test cohorts [HR = 2.07; 95% confidence interval (CI), 1.31–3.28 and HR = 2.39; 95% CI, 1.38–4.16; both P = 0.002]. The tool also revealed good predictive performance, with a c-index of 0.707 (95% CI, 0.658–0.757) in the discovery cohort, 0.689 (95% CI, 0.621–0.757) in the TCIA test cohort, and 0.787 (95% CI, 0.675–0.899) in the clinical deployment test cohort; the average time taken was 2 minutes for calculation per exam. The integrated nomogram of DeepPET-OPSCC and clinical risk factors significantly outperformed the clinical model [AUC at 5 years: 0.801 (95% CI, 0.727–0.874) vs. 0.749 (95% CI, 0.649–0.842); P = 0.031] in the TCIA test cohort.
Conclusions:
DeepPET-OPSCC achieved an accurate OS prediction in patients with OPSCC and enabled an objective, unbiased, and rapid assessment for OPSCC prognostication.