bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Inherited Germline Cancer Susceptibility Gene Variants in Individuals with Non–Muscle-Invasive Bladder Cancer
Authors: Pietzak Eugene J. , Whiting Karissa , Srinivasan Preethi , Bandlamudi Chaitanya , Khurram Aliya , Joseph Vijai , Walasek Aleksandra , Bochner Emily , Clinton Timothy , Almassi Nima , Truong Hong , de Jesus Escano Manuel R. , Wiseman Michal , Mandelker Diana , Kemel Yelena , Zhang Liying , Walsh Michael F. , Cadoo Karen A. , Coleman Jonathan A. , Al-Ahmadie Hikmat , Rosenberg Jonathan E. , Iyer Gopakumar V. , Solit David B. , Ostrovnaya Irina , Offit Kenneth , Robson Mark E. , Stadler Zsofia K. , Berger Michael F. , Bajorin Dean F. , Carlo Maria , Bochner Bernard H.
Published: April 2023

AbstractPurpose:
Identification of inherited germline variants can guide personalized cancer screening, prevention, and treatment. Pathogenic and likely pathogenic (P/LP) germline variants in cancer predisposition genes are frequent among patients with locally advanced or metastatic urothelial carcinoma, but their prevalence and significance in patients with non–muscle-invasive bladder cancer (NMIBC), the most common form of urothelial carcinoma, is understudied.
Experimental Design:
Germline analysis was conducted on paired tumor/normal sequencing results from two distinct cohorts of patients initially diagnosed with NMIBC. Associations between clinicopathologic features and clinical outcomes with the presence of P/LP germline variants in ≥76 hereditary cancer predisposition genes were analyzed.
Results:
A similar frequency of P/LP germline variants were seen in our two NMIBC cohorts [12% (12/99) vs. 8.7% (10/115), P = 0.4]. In the combined analysis, P/LP germline variants were found only in patients with high-grade NMIBC (22/163), but none of the 46 patients with low-grade NMIBC (13.5% vs. 0%, P = 0.005). Fifteen (9.2%) patients with high-grade NMIBC had P/LP variants in DNA damage response genes, most within the nucleotide excision repair (ERCC2/3) and homologous recombination repair (BRCA1, NBN, RAD50) pathways. Contrary to prior reports in patients with NMIBC not receiving Bacillus Calmette-Guerin (BCG), P/LP germline variants were not associated with worse recurrence-free or progression-free survival in patients treated with BCG or with risk of developing upper tract urothelial carcinoma.
Conclusions:
Our results support offering germline counseling and testing for all patients with high-grade bladder cancer, regardless of initial tumor stage. Therapeutic strategies that target impaired DNA repair may benefit patients with high-grade NMIBC.
Data from miR-196b–TLR7/8 Signaling Axis Regulates Innate Immune Signaling and Myeloid Maturation in DNMT3A-Mutant AML
Authors: Gamlen Holly A. , Romer-Seibert Jennifer S. , Lawler Michael E. , Versace Amanda M. , Goetz Melanie L. , Feng Yang , Guryanova Olga A. , Palmisiano Neil , Meyer Sara E.
Published: April 2023

AbstractPurpose:
DNMT3A mutations confer a poor prognosis in acute myeloid leukemia (AML), but the molecular mechanisms downstream of DNMT3A mutations in disease pathogenesis are not completely understood, limiting targeted therapeutic options. The role of miRNA in DNMT3A-mutant AML pathogenesis is understudied.
Experimental Design:
DNA methylation and miRNA expression was evaluated in human AML patient samples and in Dnmt3a/Flt3-mutant AML mice. The treatment efficacy and molecular mechanisms of TLR7/8-directed therapies on DNMT3A-mutant AML were evaluated in vitro on human AML patient samples and in Dnmt3a/Flt3-mutant AML mice.
Results:
miR-196b is hypomethylated and overexpressed in DNMT3A-mutant AML and is associated with poor patient outcome. miR-196b overexpression in DNMT3A-mutant AML is important to maintain an immature state and leukemic cell survival through repression of TLR signaling. The TLR7/8 agonist resiquimod induces dendritic cell–like differentiation with costimulatory molecule expression in DNMT3A-mutant AML cells and provides a survival benefit to Dnmt3a/Flt3-mutant AML mice. The small molecule bryostatin-1 augments resiquimod-mediated AML growth inhibition and differentiation.
Conclusions:
DNMT3A loss-of-function mutations cause miRNA locus-specific hypomethylation and overexpression important for mutant DNMT3A–mediated pathogenesis and clinical outcomes. Specifically, the overexpression of miR-196b in DNMT3A-mutant AML creates a novel therapeutic vulnerability by controlling sensitivity to TLR7/8-directed therapies.
Data from Safety and Efficacy of Intraventricular Immunovirotherapy with Oncolytic HSV-1 for CNS Cancers
Authors: Kang Kyung-Don , Bernstock Joshua D. , Totsch Stacie K. , Gary Sam E. , Rocco Abbey , Nan Li , Li Rong , Etminan Tina , Han Xiaosi , Beierle Elizabeth A. , Eisemann Tanja , Wechsler-Reya Robert J. , Bae Sejong , Whitley Richard , Gillespie G. Yancey , Markert James M. , Friedman Gregory K.
Published: April 2023

AbstractPurpose:
Oncolytic virotherapy with herpes simplex virus-1 (HSV) has shown promise for the treatment of pediatric and adult brain tumors; however, completed and ongoing clinical trials have utilized intratumoral/peritumoral oncolytic HSV (oHSV) inoculation due to intraventricular/intrathecal toxicity concerns. Intratumoral delivery requires an invasive neurosurgical procedure, limits repeat injections, and precludes direct targeting of metastatic and leptomeningeal disease. To address these limitations, we determined causes of toxicity from intraventricular oHSV and established methods for mitigating toxicity to treat disseminated brain tumors in mice.
Experimental Design:
HSV-sensitive CBA/J mice received intraventricular vehicle, inactivated oHSV, or treatment doses (1×107 plaque-forming units) of oHSV, and toxicity was assessed by weight loss and IHC. Protective strategies to reduce oHSV toxicity, including intraventricular low-dose oHSV or interferon inducer polyinosinic-polycytidylic acid (poly I:C) prior to oHSV treatment dose, were evaluated and then utilized to assess intraventricular oHSV treatment of multiple models of disseminated CNS disease.
Results:
A standard treatment dose of intraventricular oHSV damaged ependymal cells via virus replication and induction of CD8+ T cells, whereas vehicle or inactivated virus resulted in no toxicity. Subsequent doses of intraventricular oHSV caused little additional toxicity. Interferon induction with phosphorylation of eukaryotic initiation factor-2α (eIF2α) via intraventricular pretreatment with low-dose oHSV or poly I:C mitigated ependyma toxicity. This approach enabled the safe delivery of multiple treatment doses of clinically relevant oHSV G207 and prolonged survival in disseminated brain tumor models.
Conclusions:
Toxicity from intraventricular oHSV can be mitigated, resulting in therapeutic benefit. These data support the clinical translation of intraventricular G207.
Data from A Sequential Targeting Strategy Interrupts AKT-Driven Subclone-Mediated Progression in Glioblastoma
Authors: Kebir Sied , Ullrich Vivien , Berger Pia , Dobersalske Celia , Langer Sarah , Rauschenbach Laurèl , Trageser Daniel , Till Andreas , Lorbeer Franziska K. , Wieland Anja , Wilhelm-Buchstab Timo , Ahmad Ashar , Fröhlich Holger , Cima Igor , Prasad Shruthi , Matschke Johann , Jendrossek Verena , Remke Marc , Grüner Barbara M. , Roesch Alexander , Siveke Jens T. , Herold-Mende Christel , Blau Tobias , Keyvani Kathy , van Landeghem Frank K.H. , Pietsch Torsten , Felsberg Jörg , Reifenberger Guido , Weller Michael , Sure Ulrich , Brüstle Oliver , Simon Matthias , Glas Martin , Scheffler Björn
Published: April 2023

AbstractPurpose:
Therapy resistance and fatal disease progression in glioblastoma are thought to result from the dynamics of intra-tumor heterogeneity. This study aimed at identifying and molecularly targeting tumor cells that can survive, adapt, and subclonally expand under primary therapy.
Experimental Design:
To identify candidate markers and to experimentally access dynamics of subclonal progression in glioblastoma, we established a discovery cohort of paired vital cell samples obtained before and after primary therapy. We further used two independent validation cohorts of paired clinical tissues to test our findings. Follow-up preclinical treatment strategies were evaluated in patient-derived xenografts.
Results:
We describe, in clinical samples, an archetype of rare ALDH1A1+ tumor cells that enrich and acquire AKT-mediated drug resistance in response to standard-of-care temozolomide (TMZ). Importantly, we observe that drug resistance of ALDH1A1+ cells is not intrinsic, but rather an adaptive mechanism emerging exclusively after TMZ treatment. In patient cells and xenograft models of disease, we recapitulate the enrichment of ALDH1A1+ cells under the influence of TMZ. We demonstrate that their subclonal progression is AKT-driven and can be interfered with by well-timed sequential rather than simultaneous antitumor combination strategy.
Conclusions:
Drug-resistant ALDH1A1+/pAKT+ subclones accumulate in patient tissues upon adaptation to TMZ therapy. These subclones may therefore represent a dynamic target in glioblastoma. Our study proposes the combination of TMZ and AKT inhibitors in a sequential treatment schedule as a rationale for future clinical investigation.
Data from PD-1T TILs as a Predictive Biomarker for Clinical Benefit to PD-1 Blockade in Patients with Advanced NSCLC
Authors: Hummelink Karlijn , van der Noort Vincent , Muller Mirte , Schouten Robert D. , Lalezari Ferry , Peters Dennis , Theelen Willemijn S.M.E. , Koelzer Viktor H. , Mertz Kirsten D. , Zippelius Alfred , van den Heuvel Michel M. , Broeks Annegien , Haanen John B.A.G. , Schumacher Ton N. , Meijer Gerrit A. , Smit Egbert F. , Monkhorst Kim , Thommen Daniela S.
Published: April 2023

AbstractPurpose:
Durable clinical benefit to PD-1 blockade in non–small cell lung cancer (NSCLC) is currently limited to a small fraction of patients, underlining the need for predictive biomarkers. We recently identified a tumor-reactive tumor-infiltrating T lymphocyte (TIL) pool, termed PD-1T TILs, with predictive potential in NSCLC. Here, we examined PD-1T TILs as biomarker in NSCLC.
Experimental Design:
PD-1T TILs were digitally quantified in 120 baseline samples from advanced NSCLC patients treated with PD-1 blockade. Primary outcome was disease control (DC) at 6 months. Secondary outcomes were DC at 12 months and survival. Exploratory analyses addressed the impact of lesion-specific responses, tissue sample properties, and combination with other biomarkers on the predictive value of PD-1T TILs.
Results:
PD-1T TILs as a biomarker reached 77% sensitivity and 67% specificity at 6 months, and 93% and 65% at 12 months, respectively. Particularly, a patient group without clinical benefit was reliably identified, indicated by a high negative predictive value (NPV) (88% at 6 months, 98% at 12 months). High PD-1T TILs related to significantly longer progression-free (HR 0.39, 95% CI, 0.24–0.63, P < 0.0001) and overall survival (HR 0.46, 95% CI, 0.28–0.76, P < 0.01). Predictive performance was increased when lesion-specific responses and samples obtained immediately before treatment were assessed. Notably, the predictive performance of PD-1T TILs was superior to PD-L1 and tertiary lymphoid structures in the same cohort.
Conclusions:
This study established PD-1T TILs as predictive biomarker for clinical benefit to PD-1 blockade in patients with advanced NSCLC. Most importantly, the high NPV demonstrates an accurate identification of a patient group without benefit.

See related commentary by Anagnostou and Luke, p. 4835
Data from Mutational Signature 3 Detected from Clinical Panel Sequencing is Associated with Responses to Olaparib in Breast and Ovarian Cancers
Authors: Batalini Felipe , Gulhan Doga C. , Mao Victor , Tran Antuan , Polak Madeline , Xiong Niya , Tayob Nabihah , Tung Nadine M. , Winer Eric P. , Mayer Erica L. , Knappskog Stian , Lønning Per E. , Matulonis Ursula A. , Konstantinopoulos Panagiotis A. , Solit David B. , Won Helen , Eikesdal Hans P. , Park Peter J. , Wulf Gerburg M.
Published: April 2023

AbstractPurpose:
The identification of patients with homologous recombination deficiency (HRD) beyond BRCA1/2 mutations is an urgent task, as they may benefit from PARP inhibitors. We have previously developed a method to detect mutational signature 3 (Sig3), termed SigMA, associated with HRD from clinical panel sequencing data, that is able to reliably detect HRD from the limited sequencing data derived from gene-focused panel sequencing.
Experimental Design:
We apply this method to patients from two independent datasets: (i) high-grade serous ovarian cancer and triple-negative breast cancer (TNBC) from a phase Ib trial of the PARP inhibitor olaparib in combination with the PI3K inhibitor buparlisib (BKM120; NCT01623349), and (ii) TNBC patients who received neoadjuvant olaparib in the phase II PETREMAC trial (NCT02624973).
Results:
We find that Sig3 as detected by SigMA is positively associated with improved progression-free survival and objective responses. In addition, comparison of Sig3 detection in panel and exome-sequencing data from the same patient samples demonstrated highly concordant results and superior performance in comparison with the genomic instability score.
Conclusions:
Our analyses demonstrate that HRD can be detected reliably from panel-sequencing data that are obtained as part of routine clinical care, and that this approach can identify patients beyond those with germline BRCA1/2mut who might benefit from PARP inhibitors. Prospective clinical utility testing is warranted.
Data from Genomic Characteristics and Single-Cell Profiles After Immunotherapy in Fumarate Hydratase-Deficient Renal Cell Carcinoma
Authors: Dong Pei , Zhang Xinyue , Peng Yulu , Zhang Yijun , Liu Ruiqi , Li Yilin , Pan Qiwen , Wei Wensu , Guo Shengjie , Zhang Zhiling , Han Hui , Zhou Fangjian , Liu Yang , He Liru
Published: April 2023

AbstractPurpose:
Fumarate hydratase–deficient renal cell carcinoma (FHRCC) is highly malignant, but the urgent need for effective treatment remains unmet. We aimed to analyze the genomic characteristics and microenvironment of FHRCC and the cause of heterogeneous response to immune checkpoint inhibitor (ICI)-based treatment at single-cell level.
Experimental Design:
Whole-exome sequencing and IHC staining analyses were performed in 30 advanced FHRCC patients. Single-cell RNA sequencing following ICI-based treatment was conducted in 4 patients. The clinical characteristics, therapeutic effect, and follow-up data were analyzed.
Results:
The median tumor mutation burden was only 0.14 mutations per megabase. IHC staining showed an immune-active tumor microenvironment characterized by extensive CD8+ T-cell infiltration. ATM expression was inversely correlated with percentage of tumor-infiltrating CD8+ T cells. Trajectory analysis indicated gradually upregulated exhausted markers and an increased apoptotic trend of CD8+ T cells despite continuous exposure to ICI-based treatment. ICI-based treatment was associated with improved overall response rate (17.6% vs. 0%, P = 0.046) and disease control rate (DCR; 64.7% vs. 12.5%, P = 0.004) compared with tyrosine kinase inhibitor. Among patients with germline mutation, the ORR (16.7% vs. 0%, P = 0.086) and the DCR (66.7% vs. 14.3%, P = 0.011) were higher after ICI-based treatment.
Conclusions:
Immune infiltration is frequent in FHRCC. ICI-based treatment is a promising regimen, and treatment response depends on the functional status of tumor-infiltrating lymphocytes. ICI-based treatment cannot reverse the exhaustion of CD8+ T cells in patients with progressive disease, highlighting the need for additional therapeutic strategies.
Data from A Phase II Trial of Guadecitabine in Children and Adults with SDH-Deficient GIST, Pheochromocytoma, Paraganglioma, and HLRCC-Associated Renal Cell Carcinoma
Authors: Ligon John A. , Sundby R. Taylor , Wedekind Mary F. , Arnaldez Fernanda I. , Del Rivero Jaydira , Wiener Lori , Srinivasan Ramaprasad , Spencer Melissa , Carbonell Amanda , Lei Haiyan , Shern John , Steinberg Seth M. , Figg William D. , Peer Cody J. , Zimmerman Sara , Moraly Josquin , Xu Xia , Fox Stephen , Chan King , Barbato Michael I. , Andresson Thorkell , Taylor Naomi , Pacak Karel , Killian J. Keith , Dombi Eva , Linehan W. Marston , Miettinen Markku , Piekarz Richard , Helman Lee J. , Meltzer Paul , Widemann Brigitte , Glod John
Published: April 2023

AbstractPurpose:
Succinate dehydrogenase (dSDH)-deficient tumors, including pheochromocytoma/paraganglioma, hereditary leiomyomatosis and renal cell cancer–associated renal cell carcinoma (HLRCC-RCC), and gastrointestinal stromal tumors (GIST) without KIT or platelet-derived growth factor receptor alpha mutations are often resistant to cytotoxic chemotherapy, radiotherapy, and many targeted therapies. We evaluated guadecitabine, a dinucleotide containing the DNA methyltransferase inhibitor decitabine, in these patient populations.
Patients and Methods:
Phase II study of guadecitabine (subcutaneously, 45 mg/m2/day for 5 consecutive days, planned 28-day cycle) to assess clinical activity (according to RECISTv.1.1) across three strata of patients with dSDH GIST, pheochromocytoma/paraganglioma, or HLRCC-RCC. A Simon optimal two-stage design (target response rate 30% rule out 5%) was used. Biologic correlates (methylation and metabolites) from peripheral blood mononuclear cells (PBMC), serum, and urine were analyzed.
Results:
Nine patients (7 with dSDH GIST, 1 each with paraganglioma and HLRCC-RCC, 6 females and 3 males, age range 18–57 years) were enrolled. Two patients developed treatment-limiting neutropenia. No partial or complete responses were observed (range 1–17 cycles of therapy). Biologic activity assessed as global demethylation in PBMCs was observed. No clear changes in metabolite concentrations were observed.
Conclusions:
Guadecitabine was tolerated in patients with dSDH tumors with manageable toxicity. Although 4 of 9 patients had prolonged stable disease, there were no objective responses. Thus, guadecitabine did not meet the target of 30% response rate across dSDH tumors at this dose, although signs of biologic activity were noted.
Data from Defactinib, Pembrolizumab, and Gemcitabine in Patients with Advanced Treatment Refractory Pancreatic Cancer: A Phase I Dose Escalation and Expansion Study
Authors: Wang-Gillam Andrea , Lim Kian-Huat , McWilliams Robert , Suresh Rama , Lockhart Albert C. , Brown Amberly , Breden Marcus , Belle Jad I. , Herndon John , Bogner Savannah J. , Pedersen Katrina , Tan Benjamin , Boice Nicholas , Acharya Abhi , Abdiannia Mina , Gao Feng , Yoon Harry H. , Zhu Mojun , Trikalinos Nikolaos A. , Ratner Lee , Aranha Olivia , Hawkins William G. , Herzog Brett H. , DeNardo David G.
Published: April 2023

AbstractPurpose:
Targeting focal adhesion kinase (FAK) renders checkpoint immunotherapy effective in pancreatic ductal adenocarcinoma (PDAC) mouse model. Defactinib is a highly potent oral FAK inhibitor that has a tolerable safety profile.
Patients and Methods:
We conducted a multicenter, open-label, phase I study with dose escalation and expansion phases. In dose escalation, patients with refractory solid tumors were treated at five escalating dose levels of defactinib and gemcitabine to identify a recommended phase II dose (RP2D). In expansion phase, patients with metastatic PDAC who progressed on frontline treatment (refractory cohort) or had stable disease (SD) after at least 4 months of standard gemcitabine/nab-paclitaxel (maintenance cohort) were treated at RP2D. Pre- and posttreatment tumor biopsies were performed to evaluate tumor immunity.
Results:
The triple drug combination was well-tolerated, with no dose-limiting toxicities. Among 20 treated patients with refractory PDAC, the disease control rate (DCR) was 80%, with one partial response (PR) and 15 SDs, and the median progression-free survival (PFS) and overall survival (OS) were 3.6 and 7.8 months, respectively. Among 10 evaluable patients in the maintenance cohort, DCR was 70% with one PR and six SDs. Three patients with SD came off study due to treatment- or disease-related complications. The median PFS and OS on study treatment were 5.0 and 8.3 months, respectively.
Conclusions:
The combination of defactinib, pembrolizumab, and gemcitabine was well-tolerated and safe, had promising preliminary efficacy, and showed biomarker activity in infiltrative T lymphocytes. Efficacy of this strategy may require incorporation of more potent chemotherapy in future studies.
Data from Combination of the STING Agonist MIW815 (ADU-S100) and PD-1 Inhibitor Spartalizumab in Advanced/Metastatic Solid Tumors or Lymphomas: An Open-Label, Multicenter, Phase Ib Study
Authors: Meric-Bernstam Funda , Sweis Randy F. , Kasper Stefan , Hamid Omid , Bhatia Shailender , Dummer Reinhard , Stradella Agostina , Long Georgina V. , Spreafico Anna , Shimizu Toshio , Steeghs Neeltje , Luke Jason J. , McWhirter Sarah M. , Müller Thomas , Nair Nitya , Lewis Nancy , Chen Xinhui , Bean Andrew , Kattenhorn Lisa , Pelletier Marc , Sandhu Shahneen
Published: April 2023

AbstractPurpose:
The stimulator of IFN genes (STING) is a transmembrane protein that plays a role in the immune response to tumors. Single-agent STING agonist MIW815 (ADU-S100) has demonstrated immune activation but limited antitumor activity. This phase Ib, multicenter, dose-escalation study assessed the safety and tolerability of MIW815 plus spartalizumab (PDR001), a humanized IgG4 antibody against PD-1, in 106 patients with advanced solid tumors or lymphomas.
Patients and Methods:
Patients were treated with weekly intratumoral injections of MIW815 (50–3,200 μg) on a 3-weeks-on/1-week-off schedule or once every 4 weeks, plus a fixed dose of spartalizumab (400 mg) intravenously every 4 weeks.
Results:
Common adverse events were pyrexia (n = 23; 22%), injection site pain (n = 21; 20%), and diarrhea (n = 12; 11%). Overall response rate was 10.4%. The MTD was not reached. Pharmacodynamic biomarker analysis demonstrated on-target activity.
Conclusions:
The combination of MIW815 and spartalizumab was well tolerated in patients with advanced/metastatic cancers, including in patients with anti-PD-1 refractory disease. Minimal antitumor responses were seen.
Data from A Phase II Randomized Trial of Chemoradiation with or without Metformin in Locally Advanced Cervical Cancer
Authors: Han Kathy , Fyles Anthony , Shek Tina , Croke Jennifer , Dhani Neesha , D'Souza David , Lee Ting-Yim , Chaudary Naz , Bruce Jeffrey , Pintilie Melania , Cairns Rob , Vines Douglass , Pakbaz Sara , Jaffray David , Metser Ur , Rouzbahman Marjan , Milosevic Michael , Koritzinsky Marianne
Published: April 2023

AbstractPurpose:
Tumor hypoxia is associated with poor response to radiation (RT). We previously discovered a novel mechanism of metformin: enhancing tumor RT response by decreasing tumor hypoxia. We hypothesized that metformin would decrease tumor hypoxia and improve cervical cancer response to RT.
Patients and Methods:
A window-of-opportunity, phase II randomized trial was performed in stage IB–IVA cervical cancer. Patients underwent screening positron emission tomography (PET) imaging with hypoxia tracer fluoroazomycin arabinoside (FAZA). Only patients with FAZA uptake (hypoxic tumor) were included and randomized 2:1 to receive metformin in combination with chemoRT or chemoRT alone. A second FAZA-PET/CT scan was performed after 1 week of metformin or no intervention (control). The primary endpoint was a change in fractional hypoxic volume (FHV) between FAZA-PET scans, compared using the Wilcoxon signed-rank test. The study was closed early due to FAZA availability and the COVID-19 pandemic.
Results:
Of the 20 consented patients, 6 were excluded due to no FAZA uptake and 1 withdrew. FHV of 10 patients in the metformin arm decreased by an average of 10.2% (44.4%–34.2%) ± SD 16.9% after 1 week of metformin, compared with an average increase of 4.7% (29.1%–33.8%) ± 11.5% for the 3 controls (P = 0.027). Those with FHV reduction after metformin had significantly lower MATE2 expression. With a median follow-up of 2.8 years, the 2-year disease-free survival was 67% for the metformin arm versus 33% for controls (P = 0.09).
Conclusions:
Metformin decreased cervical tumor hypoxia in this trial that selected for patients with hypoxic tumor.

See related commentary by Lyng et al., p. 5233
Data from Combined MEK/PD-L1 Inhibition Alters Peripheral Cytokines and Lymphocyte Populations Correlating with Improved Clinical Outcomes in Advanced Biliary Tract Cancer
Authors: Ruggieri Amanda N. , Yarchoan Mark , Goyal Subir , Liu Yuan , Sharon Elad , Chen Helen X. , Olson Brian M. , Paulos Chrystal M. , El-Rayes Bassel F. , Maithel Shishir K. , Azad Nilofer S. , Lesinski Gregory B.
Published: April 2023

AbstractPurpose:
Biliary tract cancers (BTC) are aggressive malignancies refractory to chemotherapy and immunotherapy. MEK inhibition (MEKi)-based regimens may have utility in this disease when combined with PD-L1 blockade. We hypothesize that dual MEK/PD-L1 inhibition alters circulating soluble and cellular immune mediators to improve clinical outcomes in patients with advanced BTC.
Experimental Design:
We examined immune features in peripheral blood from 77 patients with advanced BTC enrolled in a phase II clinical trial investigating atezolizumab with or without cobimetinib. Plasma and peripheral blood mononuclear cells (PBMC) were isolated from whole blood to evaluate soluble factors and immune cell populations. Baseline blood samples were additionally compared with healthy donors to identify immune signatures unique to BTC.
Results:
At baseline, the soluble factors platelet-derived growth factor B (PDGF)-BB, placental growth factor (PlGF)-1, IL5, and IL17A were elevated in patients with BTC compared with healthy adult donors, and higher baseline frequencies of CD8+BTLA+ T cells correlated with better overall survival (OS) in this trial. There were also significant treatment-related alterations in several factors, including decreased PDGF-BB following combination treatment, that correlated with improved OS and progression-free survival (PFS). Higher baseline levels of IL23 and RANTES corresponded to improved clinical outcomes following combination treatment. Dual MEK/PD-L1 inhibition increased populations of CD4+TIM3+ and decreased CD8+VISTA+ T cells, correlating with worse OS and better PFS, respectively.
Conclusions:
This work represents a comprehensive analysis of peripheral immune features in patients with BTC and systemic responses to dual MEK/PD-L1 inhibition. These data support further investigation to understand how MEKi combines with immunotherapeutic approaches to improve clinical outcomes for patients with advanced BTC.
Data from Comprehensive Molecular Characterization of Gallbladder Carcinoma and Potential Targets for Intervention
Authors: Giraldo Nicolas A. , Drill Esther , Satravada Baby A. , Dika Imane El , Brannon A. Rose , Dermawan Josephine , Mohanty Abhinita , Ozcan Kerem , Chakravarty Debyani , Benayed Ryma , Vakiani Efsevia , Abou-Alfa Ghassan K. , Kundra Ritika , Schultz Nikolaus , Li Bob T. , Berger Michael F. , Harding James J. , Ladanyi Marc , O'Reilly Eileen M. , Jarnagin William , Vanderbilt Chad , Basturk Olca , Arcila Maria E.
Published: April 2023

AbstractPurpose:
Gallbladder carcinoma (GBC) is an uncommon and aggressive disease, which remains poorly defined at a molecular level. Here, we aimed to characterize the molecular landscape of GBC and identify markers with potential prognostic and therapeutic implications.
Experimental Design:
GBC samples were analyzed using the MSK-IMPACT (Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets) platform (targeted NGS assay that analyzes 505 cancer-associated genes). Variants with therapeutic implications were identified using OncoKB database. The associations between recurrent genetic alterations and clinicopathologic characteristics (Fisher exact tests) or overall survival (univariate Cox regression) were evaluated. P values were adjusted for multiple testing.
Results:
Overall, 244 samples (57% primary tumors and 43% metastases) from 233 patients were studied (85% adenocarcinomas, 10% carcinomas with squamous differentiation, and 5% neuroendocrine carcinomas). The most common oncogenic molecular alterations appeared in the cell cycle (TP53 63% and CDKN2A 21%) and RTK_RAS pathways (ERBB2 15% and KRAS 11%). No recurrent structural variants were identified. There were no differences in the molecular landscape of primary and metastasis samples. Variants in SMAD4 and STK11 independently associated with reduced survival in patients with metastatic disease. Alterations considered clinically actionable in GBC or other solid tumor types (e.g., NTRK1 fusions or oncogenic variants in ERBB2, PIK3CA, or BRCA1/2) were identified in 35% of patients; 18% of patients with metastatic disease were treated off-label or enrolled in a clinical trial based on molecular findings.
Conclusions:
GBC is a genetically diverse malignancy. This large-scale genomic analysis revealed alterations with potential prognostic and therapeutic implications and provides guidance for the development of targeted therapies.
Data from Family History of Prostate and Breast Cancer Integrated with a Polygenic Risk Score Identifies Men at Highest Risk of Dying from Prostate Cancer before Age 75 Years
Authors: Plym Anna , Zhang Yiwen , Stopsack Konrad H. , Jee Yon Ho , Wiklund Fredrik , Kibel Adam S. , Kraft Peter , Giovannucci Edward , Penney Kathryn L. , Mucci Lorelei A.
Published: April 2023

AbstractPurpose:
Family history of prostate cancer is one of the few universally accepted risk factors for prostate cancer. How much an assessment of inherited polygenic risk for prostate cancer adds to lifetime risk stratification beyond family history is unknown.
Experimental Design:
We followed 10,120 men in the Health Professionals Follow-up Study with existing genotype data for risk of prostate cancer and prostate cancer–specific death. We assessed to what extent family history of prostate or breast cancer, combined with a validated polygenic risk score (PRS) including 269 prostate cancer risk variants, identifies men at risk of prostate cancer and prostate cancer death across the age span.
Results:
During 20 years of follow-up, 1,915 prostate cancer and 166 fatal prostate cancer events were observed. Men in the top PRS quartile with a family history of prostate or breast cancer had the highest rate of both prostate cancer and prostate cancer–specific death. Compared with men at lowest genetic risk (bottom PRS quartile and no family history), the HR was 6.95 [95% confidence interval (CI), 5.57–8.66] for prostate cancer and 4.84 (95% CI, 2.59–9.03) for prostate cancer death. Men in the two upper PRS quartiles (50%–100%) or with a family history of prostate or breast cancer (61.8% of the population) accounted for 97.5% of prostate cancer deaths by age 75 years.
Conclusions:
Our study shows that prostate cancer risk stratification on the basis of family history and inherited polygenic risk can identify men at highest risk of dying from prostate cancer before age 75 years.
Data from Gene Expression Profiling Identifies Two Chordoma Subtypes Associated with Distinct Molecular Mechanisms and Clinical Outcomes
Authors: Bai Jiwei , Shi Jianxin , Zhang Yazhuo , Li Chuzhong , Xiong Yujia , Koka Hela , Wang Difei , Zhang Tongwu , Song Lei , Luo Wen , Zhu Bin , Hicks Belynda , Hutchinson Amy , Kirk Erin , Troester Melissa A. , Li Mingxuan , Shen Yutao , Ma Tianshun , Wang Junmei , Liu Xing , Wang Shuai , Gui Songbai , McMaster Mary L. , Chanock Stephen J. , Parry Dilys M. , Goldstein Alisa M. , Yang Xiaohong R.
Published: April 2023

AbstractPurpose:
Chordoma is a rare bone tumor with a high recurrence rate and limited treatment options. The aim of this study was to identify molecular subtypes of chordoma that may improve clinical management.
Experimental Design:
We conducted RNA sequencing in 48 tumors from patients with Chinese skull-base chordoma and identified two major molecular subtypes. We then replicated the classification using a NanoString panel in 48 patients with chordoma from North America.
Results:
Tumors in one subtype were more likely to have somatic mutations and reduced expression in chromatin remodeling genes, such as PBRM1 and SETD2, whereas the other subtype was characterized by the upregulation of genes in epithelial–mesenchymal transition and Sonic Hedgehog pathways. IHC staining of top differentially expressed genes between the two subtypes in 312 patients with Chinese chordoma with long-term follow-up data showed that the expression of some markers such as PTCH1 was significantly associated with survival outcomes.
Conclusions:
Our findings may improve the understanding of subtype-specific tumorigenesis of chordoma and inform clinical prognostication and targeted options.
Data from A Phase II Study of Nivolumab plus Gemcitabine in Patients with Recurrent or Metastatic Nasopharyngeal Carcinoma (KCSG HN17–11)
Authors: Jung Hyun Ae , Park Keon-Uk , Cho Sanghee , Lim Jinyeong , Lee Keun-Wook , Hong Min Hee , Yun Tak , An Ho Jung , Park Woong-Yang , Pereira Sergio , Ock Chan-Young , Keam Bhumsuk
Published: April 2023

AbstractPurpose:
Although programmed death 1/programmed death ligand 1 (PD-1/PD-L1) inhibitors are promising agents for recurrent or metastatic nasopharyngeal carcinoma (NPC), PD-1/PD-L1 inhibitor monotherapy has shown modest efficacy. This study evaluated the efficacy and safety of nivolumab plus gemcitabine in patients with NPC who failed prior platinum-based chemotherapy.
Patients and Methods:
This is a phase II, multicenter, open-label, single-arm study. Patients with recurrent or metastatic NPC received nivolumab 3 mg/kg and gemcitabine 1,250 mg/m2 every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). The secondary endpoints included objective response rate (ORR), overall survival (OS), and safety. To identify potential biomarkers, whole-exome sequencing, whole-transcriptome sequencing, and immune phenotype analysis based on Lunit SCOPE IO, an artificial intelligence–powered spatial tumor-infiltrating lymphocyte analyzer, were performed.
Results:
Thirty-six patients were enrolled between June 2018 and June 2019. The ORR was 36.1% and disease control rate was 97.2%. With median follow-up of 22.0 months, median PFS was 13.8 months [95% confidence interval (CI), 8.6–16.8 months]. Median OS was not reached, and OS rate at 6 months was 97.0% (95% CI, 80.4%–99.6%). The grade ≥3 treatment-related adverse events were hypertension (2.8%) and anemia (2.8%). In multivariate analysis of mutation of chromatin modifier gene, tumor mutational burden (≥ 2.1 mut/Mb), and somatic copy-number alteration (SCNA) level, the group with high SCNA (> 3 points; HR, 7.0; 95% CI, 1.3–37.9; P = 0.02) had independently associated with poor PFS. Immune phenotype analysis showed that tumors with high proportion of immune-excluded immune phenotype was significantly correlated with poor PFS (HR, 4.4; 95% CI, 1.2–16.2; P = 0.018).
Conclusions:
Nivolumab plus gemcitabine showed promising efficacy with favorable toxicity profiles in patients with advanced NPC in whom platinum-based combination chemotherapy failed.
Data from Phenotype, Function, and Clinical Significance of CD26+ and CD161+Tregs in Splenic Marginal Zone Lymphoma
Authors: Tang Xinyi , Yang Zhi-Zhang , Kim Hyo Jin , Anagnostou Theodora , Yu Yue , Wu Xiaosheng , Chen Jun , Krull Jordan E. , Wenzl Kerstin , Mondello Patrizia , Bhardwaj Vaishali , Wang Junwen , Novak Anne J. , Ansell Stephen M.
Published: April 2023

AbstractPurpose:
Regulatory T-cells (Treg) are essential to Tregs homeostasis and modulate the antitumor immune response in patients with lymphoma. However, the biology and prognostic impact of Tregs in splenic marginal zone lymphoma (SMZL) have not been studied.
Experimental Design:
Biopsy specimens from 24 patients with SMZL and 12 reactive spleens (rSP) from individuals without lymphoma were analyzed by using CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing), CyTOF (mass cytometry) analysis, and flow cytometry to explore the phenotype, transcriptomic profile, and clinical significance of intratumoral Tregs and their subsets. The biological characteristics and cell signaling pathways of intratumoral Treg subsets were confirmed by in vitro functional assays.
Results:
We found that Tregs are more abundant in SMZL patients' spleens than rSP, and Tregs from patients with SMZL and rSP can be separated into CD161+Treg and CD26+Treg subsets. CD161+Tregs are increased in SMZL but have dysregulated immune function. We found that CD161+Treg and CD26+Tregs have unique gene expression and phenotypic profiles and are differentially correlated with patient outcomes. Specifically, increased CD161+Tregs are significantly associated with a favorable prognosis in patients with SMZL, whereas CD26+Tregs are associated with a poor prognosis. Furthermore, activation of the IL2/STAT5 pathway contributes to the induction of CD26+Tregs and can be reversed by STAT5 inhibition.
Conclusions:
IL2/STAT5-mediated expansion of CD26+Tregs contributes to a poor clinical outcome in SMZL and may represent a therapeutic opportunity in this disease.
Data from Associations between Pretreatment Body Composition Features and Clinical Outcomes among Patients with Metastatic Clear Cell Renal Cell Carcinoma Treated with Immune Checkpoint Blockade
Authors: Ged Yasser , Sanchez Alejandro , Patil Sujata , Knezevic Andrea , Stein Emily , Petruzella Stacey , Weiss Kate , Duzgol Cihan , Chaim Joshua , Akin Oguz , Mourtzakis Marina , Paris Michael T. , Scott Jessica , Kuo Fengshen , Kotecha Ritesh , Hakimi A. Ari , Lee Chung-Han , Motzer Robert J. , Voss Martin H. , Furberg Helena
Published: April 2023

AbstractPurpose:
High body mass index (BMI) may lead to improved immune-checkpoint blockade (ICB) outcomes in metastatic clear cell renal cell carcinoma (mccRCC). However, BMI is a crude body size measure. We investigated BMI and radiographically assessed body composition (BC) parameters association with mccRCC ICB outcomes.
Experimental Design:
Retrospective study of ICB-treated patients with mccRCC. BMI and BC variables [skeletal muscle index (SMI) and multiple adiposity indexes] were determined using pretreatment CT scans. We examined the associations between BMI and BC variables with ICB outcomes. Therapeutic responses per RECIST v1.1 were determined. We compared whole-transcriptomic patterns with BC variables in a separate cohort of 62 primary tumor samples.
Results:
205 patients with mccRCC were included in the cohort (74% were male, 71% were overweight/obese, and 53% were classified as low SMI). High-BMI patients experienced longer overall survival (OS) than normal-weight patients [unadjusted HR, 0.66; 95% confidence interval (CI), 0.45–0.97; P = 0.035]. The only BC variable associated with OS was SMI [unadjusted HR comparing low vs. high SMI 1.65 (95% CI: 1.13–2.43); P = 0.009]. However, this OS association became nonsignificant after adjusting for International Metastatic Renal Cell Carcinoma Database Consortium score and line of therapy. No OS association was seen for adiposity and no BC variable was associated with progression-free survival or radiological responses. Tumors from patients with low SMI displayed increased angiogenic, inflammatory, and myeloid signals.
Conclusions:
Our findings highlight the relevance of skeletal muscle in the BMI paradox. Future studies should investigate if addressing low skeletal muscle in metastatic patients treated with ICB can improve survival.
Data from Phase Ia/b, Open-Label, Multicenter Study of AZD4635 (an Adenosine A2A Receptor Antagonist) as Monotherapy or Combined with Durvalumab, in Patients with Solid Tumors
Authors: Lim Emerson A. , Bendell Johanna C. , Falchook Gerald S. , Bauer Todd M. , Drake Charles G. , Choe Jennifer H. , George Daniel J. , Karlix Janet L. , Ulahannan Susanna , Sachsenmeier Kris F. , Russell Deanna L. , Moorthy Ganesh , Sidders Ben S. , Pilling Elizabeth A. , Chen Huifang , Hattersley Maureen M. , Das Mayukh , Kumar Rakesh , Pouliot Gayle P. , Patel Manish R.
Published: April 2023

AbstractPurpose:
To evaluate AZD4635, an adenosine A2A receptor antagonist, as monotherapy or in combination with durvalumab in patients with advanced solid tumors.
Patients and Methods:
In phase Ia (dose escalation), patients had relapsed/refractory solid tumors; in phase Ib (dose expansion), patients had checkpoint inhibitor–naïve metastatic castration-resistant prostate cancer (mCRPC) or colorectal carcinoma, non–small cell lung cancer with prior anti–PD-1/PD-L1 exposure, or other solid tumors (checkpoint-naïve or prior anti–PD-1/PD-L1 exposure). Patients received AZD4635 monotherapy (75–200 mg once daily or 125 mg twice daily) or in combination with durvalumab (AZD4635 75 or 100 mg once daily). The primary objective was safety; secondary objectives included antitumor activity and pharmacokinetics; exploratory objectives included evaluation of an adenosine gene signature in patients with mCRPC.
Results:
As of September 8, 2020, 250 patients were treated (AZD4635, n = 161; AZD4635+durvalumab, n = 89). In phase Ia, DLTs were observed with monotherapy (125 mg twice daily; n = 2) and with combination treatment (75 mg; n = 1) in patients receiving nanosuspension. The most common treatment-related adverse events included nausea, fatigue, vomiting, decreased appetite, dizziness, and diarrhea. The RP2D of the AZD4635 capsule formulation was 75 mg once daily, as monotherapy or in combination with durvalumab. The pharmacokinetic profile was dose-proportional, and exposure was adequate to cover target with 100 mg nanosuspension or 75 mg capsule once daily. In patients with mCRPC receiving monotherapy or combination treatment, tumor responses (2/39 and 6/37, respectively) and prostate-specific antigen responses (3/60 and 10/45, respectively) were observed. High versus low blood-based adenosine signature was associated with median progression-free survival of 21 weeks versus 8.7 weeks.
Conclusions:
AZD4635 monotherapy or combination therapy was well tolerated. Objective responses support additional phase II combination studies in patients with mCRPC.
Data from Neoadjuvant Chemotherapy Is Associated with Altered Immune Cell Infiltration and an Anti-Tumorigenic Microenvironment in Resected Pancreatic Cancer
Authors: Dias Costa Andressa , Väyrynen Sara A. , Chawla Akhil , Zhang Jinming , Väyrynen Juha P. , Lau Mai Chan , Williams Hannah L. , Yuan Chen , Morales-Oyarvide Vicente , Elganainy Dalia , Singh Harshabad , Cleary James M. , Perez Kimberly , Ng Kimmie , Freed-Pastor William , Mancias Joseph D. , Dougan Stephanie K. , Wang Jiping , Rubinson Douglas A. , Dunne Richard F. , Kozak Margaret M. , Brais Lauren , Reilly Emma , Clancy Thomas , Linehan David C. , Chang Daniel T. , Hezel Aram F. , Koong Albert C. , Aguirre Andrew J. , Wolpin Brian M. , Nowak Jonathan A.
Published: April 2023

AbstractPurpose:
Neoadjuvant chemotherapy is increasingly administered to patients with resectable or borderline resectable pancreatic ductal adenocarcinoma (PDAC), yet its impact on the tumor immune microenvironment is incompletely understood.
ExperimentalDesign:
We employed quantitative, spatially resolved multiplex immunofluorescence and digital image analysis to identify T-cell subpopulations, macrophage polarization states, and myeloid cell subpopulations in a multi-institution cohort of up-front resected primary tumors (n = 299) and in a comparative set of resected tumors after FOLFIRINOX-based neoadjuvant therapy (n = 36) or up-front surgery (n = 30). Multivariable-adjusted Cox proportional hazards models were used to evaluate associations between the immune microenvironment and patient outcomes.
Results:
In the multi-institutional resection cohort, immune cells exhibited substantial heterogeneity across patient tumors and were located predominantly in stromal regions. Unsupervised clustering using immune cell densities identified four main patterns of immune cell infiltration. One pattern, seen in 20% of tumors and characterized by abundant T cells (T cell–rich) and a paucity of immunosuppressive granulocytes and macrophages, was associated with improved patient survival. Neoadjuvant chemotherapy was associated with a higher CD8:CD4 ratio, greater M1:M2–polarized macrophage ratio, and reduced CD15+ARG1+ immunosuppressive granulocyte density. Within neoadjuvant-treated tumors, 72% showed a T cell–rich pattern with low immunosuppressive granulocytes and macrophages. M1-polarized macrophages were located closer to tumor cells after neoadjuvant chemotherapy, and colocalization of M1-polarized macrophages and tumor cells was associated with greater tumor pathologic response and improved patient survival.
Conclusions:
Neoadjuvant chemotherapy with FOLFIRINOX shifts the PDAC immune microenvironment toward an anti-tumorigenic state associated with improved patient survival.
Data from Genetic Heterogeneity and Tissue-specific Patterns of Tumors with Multiple PIK3CA Mutations
Authors: Sivakumar Smruthy , Jin Dexter X. , Rathod Ruchita , Ross Jeffrey , Cantley Lewis C. , Scaltriti Maurizio , Chen Jessica W. , Hutchinson Katherine E. , Wilson Timothy R. , Sokol Ethan S. , Vasan Neil
Published: April 2023

AbstractPurpose:
To comprehensively characterize tissue-specific and molecular subclasses of multiple PIK3CA (multi-PIK3CA) mutations and assess their impact on potential therapeutic outcomes.
Experimental Design:
We profiled a pan-cancer cohort comprised of 352,392 samples across 66 tumor types using a targeted hybrid capture-based next-generation sequencing panel covering at least 324 cancer-related genes. Molecularly defined subgroups, allelic configuration, clonality, and mutational signatures were identified and tested for association with PI3K inhibitor therapeutic response.
Results:
Multi-PIK3CA mutations are found in 11% of all PIK3CA-mutant tumors, including 9% of low tumor mutational burden (TMB) PIK3CA-mutant tumors, and are enriched in breast and gynecologic cancers. Multi-PIK3CA mutations are frequently clonal and in cis on the same allele and occur at characteristic positions across tumor types. These mutations tend to be mutually exclusive of mutations in other driver genes, and of genes in the PI3K pathway. Among PIK3CA-mutant tumors with a high TMB, 18% are multi-PIK3CA mutant and often harbor an apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC) mutational signature. Despite large differences in specific allele combinations comprising multi-PIK3CA mutant tumors, especially across cancer types, patients with different classes of multi-PIK3CA mutant estrogen receptor–positive, HER2-negative breast cancers respond similarly to PI3K inhibition.
Conclusions:
Our pan-tumor study provides biological insights into the genetic heterogeneity and tissue specificities of multi-PIK3CA mutations, with potential clinical utility to guide PI3K inhibition strategies.