bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from The Immunosuppressive Niche of Soft-Tissue Sarcomas is Sustained by Tumor-Associated Macrophages and Characterized by Intratumoral Tertiary Lymphoid Structures
Authors: Chen Lingling , Oke Teniola , Siegel Nicholas , Cojocaru Gady , Tam Ada J. , Blosser Richard L. , Swailes Jessica , Ligon John A. , Lebid Andriana , Morris Carol , Levin Adam , Rhee Daniel S. , Johnston Fabian M. , Greer Jonathan B. , Meyer Christian F. , Ladle Brian H. , Thompson Elizabeth D. , Montgomery Elizabeth A. , Choi Woonyoung , McConkey David J. , Anders Robert A. , Pardoll Drew M. , Llosa Nicolas J.
Published: April 2023

AbstractPurpose:
Clinical trials with immune checkpoint inhibition in sarcomas have demonstrated minimal response. Here, we interrogated the tumor microenvironment (TME) of two contrasting soft-tissue sarcomas (STS), rhabdomyosarcomas and undifferentiated pleomorphic sarcomas (UPS), with differing genetic underpinnings and responses to immune checkpoint inhibition to understand the mechanisms that lead to response.
Experimental Design:
Utilizing fresh and formalin-fixed, paraffin-embedded tissue from patients diagnosed with UPS and rhabdomyosarcomas, we dissected the TME by using IHC, flow cytometry, and comparative transcriptomic studies.
Results:
Our results demonstrated both STS subtypes to be dominated by tumor-associated macrophages and infiltrated with immune cells that localized near the tumor vasculature. Both subtypes had similar T-cell densities, however, their in situ distribution diverged. UPS specimens demonstrated diffuse intratumoral infiltration of T cells, while rhabdomyosarcomas samples revealed intratumoral T cells that clustered with B cells near perivascular beds, forming tertiary lymphoid structures (TLS). T cells in UPS specimens were comprised of abundant CD8+ T cells exhibiting high PD-1 expression, which might represent the tumor reactive repertoire. In rhabdomyosarcomas, T cells were limited to TLS, but expressed immune checkpoints and immunomodulatory molecules which, if appropriately targeted, could help unleash T cells into the rest of the tumor tissue.
Conclusions:
Our work in STS revealed an immunosuppressive TME dominated by myeloid cells, which may be overcome with activation of T cells that traffic into the tumor. In rhabdomyosarcomas, targeting T cells found within TLS may be key to achieve antitumor response.
Data from Impact of Prior Bevacizumab Treatment on VEGF-A and PlGF Levels and Outcome Following Second-Line Aflibercept Treatment: Biomarker Post Hoc Analysis of the VELOUR Trial
Authors: Van Cutsem Eric , Paccard Caroline , Chiron Marielle , Tabernero Josep
Published: April 2023

AbstractPurpose:
Aflibercept is a targeted anti-VEGF therapy used to treat patients with metastatic colorectal cancer (mCRC) following progression on oxaliplatin-based regimens. This post hoc study evaluated the effect of prior bevacizumab treatment and growth factor levels on patient outcomes associated with aflibercept in the VELOUR phase III trial.
Experimental Design:
Baseline biomarker plasma concentrations were measured using a bead-based multiplex assay. Patients were grouped according to prior bevacizumab treatment, second‐line treatment, and serum biomarker concentrations, and analyzed for overall survival (OS) and progression-free survival (PFS).
Results:
Plasma samples were available for 553 patients (placebo n = 265; aflibercept n = 288), of which 169 had received prior bevacizumab. Nine biomarkers implicated in angiogenesis or bevacizumab resistance correlated with prior bevacizumab therapy. VEGF-A and placental growth factor (PlGF) were the most significantly increased in patients who had received prior bevacizumab compared with those who had not received prior bevacizumab. In the placebo group, patients with high VEGF-A (>144 pg/mL) levels at baseline had worse OS and PFS compared with patients with lower levels at baseline (9.6 vs. 12.9 months). This was also seen in patients who received placebo and had high baseline PlGF (>8 pg/mL; 9.7 vs. 11.7 months). In the aflibercept group, prolonged OS and PFS were observed regardless of baseline VEGF-A or PlGF levels.
Conclusions:
High VEGF-A and PlGF serum levels may underlie development of resistance to bevacizumab in patients with mCRC. Aflibercept retains its activity regardless of baseline VEGF-A and PlGF levels and may be an effective second-line treatment for patients with bevacizumab-induced resistance.
Data from A Phase Ib/IIa Study of the Pan-BET Inhibitor ZEN-3694 in Combination with Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer
Authors: Aggarwal Rahul R. , Schweizer Michael T. , Nanus David M. , Pantuck Allan J. , Heath Elisabeth I. , Campeau Eric , Attwell Sarah , Norek Karen , Snyder Margo , Bauman Lisa , Lakhotia Sanjay , Feng Felix Y. , Small Eric J. , Abida Wassim , Alumkal Joshi J.
Published: April 2023

AbstractPurpose:
ZEN-3694 is a bromodomain extraterminal inhibitor (BETi) with activity in androgen-signaling inhibitor (ASI)-resistant models. The safety and efficacy of ZEN-3694 plus enzalutamide was evaluated in a phase Ib/IIa study in metastatic castration-resistant prostate cancer (mCRPC).
Patients and Methods:
Patients had progressive mCRPC with prior resistance to abiraterone and/or enzalutamide. 3+3 dose escalation was followed by dose expansion in parallel cohorts (ZEN-3694 at 48 and 96 mg orally once daily, respectively).
Results:
Seventy-five patients were enrolled (N = 26 and 14 in dose expansion at low- and high-dose ZEN-3694, respectively). Thirty (40.0%) patients were resistant to abiraterone, 34 (45.3%) to enzalutamide, and 11 (14.7%) to both. ZEN-3694 dosing ranged from 36 to 144 mg daily without reaching an MTD. Fourteen patients (18.7%) experienced grade ≥3 toxicities, including three patients with grade 3 thrombocytopenia (4%). An exposure-dependent decrease in whole-blood RNA expression of BETi targets was observed (up to fourfold mean difference at 4 hours post–ZEN-3694 dose; P ≤ 0.0001). The median radiographic progression-free survival (rPFS) was 9.0 months [95% confidence interval (CI), 4.6–12.9] and composite median radiographic or clinical progression-free survival (PFS) was 5.5 months (95% CI, 4.0–7.8). Median duration of treatment was 3.5 months (range, 0–34.7+). Lower androgen receptor (AR) transcriptional activity in baseline tumor biopsies was associated with longer rPFS (median rPFS 10.4 vs. 4.3 months).
Conclusions:
ZEN-3694 plus enzalutamide demonstrated acceptable tolerability and potential efficacy in patients with ASI-resistant mCRPC. Further prospective study is warranted including in mCRPC harboring low AR transcriptional activity.
Data from Impact of DNA Damage Response and Repair (DDR) Gene Mutations on Efficacy of PD-(L)1 Immune Checkpoint Inhibition in Non–Small Cell Lung Cancer
Authors: Ricciuti Biagio , Recondo Gonzalo , Spurr Liam F. , Li Yvonne Y. , Lamberti Giuseppe , Venkatraman Deepti , Umeton Renato , Cherniack Andrew D. , Nishino Mizuki , Sholl Lynette M. , Shapiro Geoffrey I. , Awad Mark M. , Cheng Michael L.
Published: April 2023

AbstractPurpose:
DNA damage response and repair (DDR) gene alterations are associated with increased tumor-infiltrating lymphocytes, higher genomic instability, and higher tumor mutational burden (TMB) in cancer. Whether DDR alterations are associated with clinical outcomes to programmed death ligand 1 [PD-(L)1] blockade in non–small cell lung cancer (NSCLC) is unknown.
Experimental Design:
Tumors from patients treated with PD-(L)1 inhibitors were analyzed using targeted next-generation sequencing (NGS). Cancers were categorized on the basis of the presence or absence of deleterious mutations across a panel of 53 DDR genes. Clinical outcomes to PD-(L)1 inhibitors were evaluated according to DDR mutation status.
Results:
Of 266 patients with successful NGS who received PD-(L)1 inhibitors, 132 (49.6%) were identified as having deleterious DDR mutations (DDR-positive). DDR-positive and DDR-negative groups were similar in terms of baseline clinicopathologic characteristics. The median TMB was significantly higher in the DDR-positive group compared with the DDR-negative group (12.1 vs. 7.6 mutations/megabase; P < 0.001). Compared with DDR-negative patients (N = 134), DDR-positive patients had a significantly higher objective response rate (30.3% vs. 17.2%; P = 0.01), longer median progression-free survival [PFS; 5.4 vs. 2.2 months; HR, 0.58 (95% confidence interval (CI), 0.45–0.76); P < 0.001], and longer median overall survival [OS; 18.8 vs. 9.9 months; HR, 0.57 (95% CI, 0.42–0.77); P < 0.001] with PD-(L)1 therapy. After adjusting for PD-L1, TMB, performance status, tobacco use, and line of therapy, DDR-positive status was associated with a significantly longer PFS [HR, 0.68 (95% CI, 0.51–0.92); P = 0.01] and OS [HR, 0.60 (95% CI, 0.43–0.85); P = 0.004] in multivariate analysis.
Conclusions:
Deleterious DDR mutations are frequent in NSCLC and are associated with improved clinical outcomes in patients with NSCLC treated with PD-(L)1 blockade.
Data from Immunotherapy of Ipilimumab and Nivolumab in Patients with Advanced Neuroendocrine Tumors: A Subgroup Analysis of the CA209-538 Clinical Trial for Rare Cancers
Authors: Klein Oliver , Kee Damien , Markman Ben , Michael Michael , Underhill Craig , Carlino Matteo S. , Jackett Louise , Lum Caroline , Scott Clare , Nagrial Adnan , Behren Andreas , So Jane Y. , Palmer Jodie , Cebon Jonathan
Published: April 2023

AbstractPurpose:
Combination immunotherapy with anti–CTLA-4 and anti–PD-1 blockade has demonstrated significant clinical activity across several tumor types. Neuroendocrine tumors (NET) are a heterogeneous group of rare tumors with limited treatment options. CA209-538 is a clinical trial of combination immunotherapy with ipilimumab and nivolumab in rare cancers, including advanced NETs.
Patients and Methods:
CA209-538 is a prospective multicenter clinical trial in patients with advanced rare cancers. Patients received treatment with nivolumab at a dose of 3 mg/kg and ipilimumab at 1 mg/kg every three weeks for four doses, followed by nivolumab 3 mg/kg every two weeks and continued for up to 96 weeks, until disease progression or the development of unacceptable toxicity. Response was assessed every 12 weeks by RECIST 1.1. The primary endpoint was clinical benefit rate (CBR; complete remission + partial remission + stable disease).
Results:
Twenty-nine patients with advanced NETs received treatment. Three (10%) patients had low-, 13 (45%) had intermediate-, and 13 (45%) had high-grade tumors; lung was the most common primary site (39%). The objective response rate was 24% with a CBR of 72%; 43% of patients with pancreatic neuroendocrine neoplasms (NEN), and 33% of patients with atypical bronchial carcinoid achieved an objective response. The median progression-free survival was 4.8 months [95% confidence interval (CI): 2.7–10.5] and overall survival was 14.8 months (95% CI: 4.1–21.3). Immune-related toxicity was reported in 66% of patients with 34% experiencing grade 3/4 events.
Conclusions:
Combination immunotherapy with ipilimumab and nivolumab demonstrated significant clinical activity in subgroups of patients with advanced NETs including patients with atypical bronchial carcinoid and high-grade pancreatic NENs.
Data from A Prospective, Phase 1 Trial of Nivolumab, Ipilimumab, and Radiotherapy in Patients with Advanced Melanoma
Authors: Postow Michael A. , Knox Susan J. , Goldman Debra A. , Elhanati Yuval , Mavinkurve Vikram , Wong Phillip , Halpenny Darragh , Reddy Sunil K. , Vado Kenya , McCabe Danielle , Ramirez Kristen Aufiero , Macri Mary , Schwarzenberger Paul , Ricciardi Toni , Ryan Aileen , Venhaus Ralph , Momtaz Parisa , Shoushtari Alexander N. , Callahan Margaret K. , Chapman Paul B. , Wolchok Jedd D. , Subrahmanyam Priyanka B. , Maecker Holden T. , Panageas Katherine S. , Barker Christopher A.
Published: April 2023

AbstractPurpose:
Preclinical data suggest that radiotherapy (RT) is beneficial in combination with immune checkpoint blockade. Clinical trials have explored RT with single-agent immune checkpoint blockade, but no trials have reported RT with the combination of nivolumab and ipilimumab.
Patients and Methods:
We conducted a phase 1 study of patients with stage IV melanoma receiving nivolumab and ipilimumab with two different dose-fractionation schemes of RT. Patients had at least one melanoma metastasis that would benefit from palliative RT and one metastasis that would not be irradiated. Nivolumab 1 mg/kg + ipilimumab 3 mg/kg and extracranial RT with a dose of 30 Gy in 10 fractions was administered in Cohort A, and then 27 Gy in 3 fractions was administered in Cohort B. The primary outcome was safety.
Results:
Twenty patients were treated (10 in each cohort). The rates of treatment-related grade 3–4 adverse events in Cohort A and B were 40% and 30%, respectively. There were no grade ≥3 adverse events attributed to RT. Patients responded to treatment outside of the irradiated volume (Cohort A 5/10; Cohort B 1/9). No evaluable patients had progression of irradiated metastases. Immunologic changes were seen in the peripheral blood with increases in T-cell receptor diversity in some responding patients.
Conclusions:
RT with nivolumab and ipilimumab was safe compared with historical data of nivolumab and ipilimumab alone. Immunologic effects were observed in the peripheral blood. Randomized studies are ongoing to assess whether RT increases the efficacy of nivolumab and ipilimumab.
Data from Population-based Screening for BRAFV600E in Metastatic Colorectal Cancer Reveals Increased Prevalence and Poor Prognosis
Authors: Chu Jenny E. , Johnson Benny , Kugathasan Laveniya , Morris Van K. , Raghav Kanwal , Swanson Lucas , Lim Howard J. , Renouf Daniel J. , Gill Sharlene , Wolber Robert , Karsan Aly , Kopetz Scott , Schaeffer David F. , Loree Jonathan M.
Published: April 2023

AbstractPurpose:
BRAFV600E mutations portend poor prognosis in metastatic colorectal cancer (mCRC); however, the true prevalence and prognosis are unknown, as unwell patients may not undergo BRAF sequencing.
Experimental Design:
We reviewed a population-based cohort of 1,898 patients with colorectal cancer that underwent reflexive IHC mismatch repair (MMR) and BRAFV600E testing. Outcomes among IHC-detected BRAFV600E mCRC (BRAFIHC) were compared with patients with next-generation sequencing (NGS)–identified BRAFV600E-mutated mCRC from two institutions (BRAFNGS) with patients spanning from 2004 to 2018.
Results:
All-stage population prevalence of BRAFV600E was 12.5% (238/1,898) and did not differ between early and metastatic stages (P = 0.094). Prevalence among mCRC was 10.6% (61/575), of whom 51 (83.6%) were referred to oncology and 26 (42.6%) had NGS testing. BRAFIHC had worse median overall survival (mOS) than BRAFNGS [5.5 vs. 20.4 months; HR, 2.90; 95% confidence interval (CI), 1.89–4.45; P < 0.0001], which persisted in multivariate analysis (P < 0.0001). Across a combined NGS and IHC cohort, BRAFV600E tumors with deficient MMR showed worse mOS compared with MMR proficient tumors (8.9 vs. 17.2 months; HR, 1.46; 95% CI, 0.96–2.27; P = 0.043). In this combined cohort, first-line progression-free survival was 5.9 months, with minimal differences between regimens. Within the population-based cohort, attrition between treatment lines was high with only 60.7% receiving first-line chemotherapy and 26.2% receiving second line.
Conclusions:
Patients with BRAFV600E-mutated mCRC have a worse prognosis than previously suggested, potentially arising from referral bias for testing. High attrition between lines of therapy suggests efficacious therapies need to be prioritized early for patients to benefit.
Data from Therapeutic Efficacy of Immune Stimulatory Thymidine Kinase and fms-like Tyrosine Kinase 3 Ligand (TK/Flt3L) Gene Therapy in a Mouse Model of High-Grade Brainstem Glioma
Authors: Mendez Flor , Kadiyala Padma , Nunez Felipe J. , Carney Stephen , Nunez Fernando M. , Gauss Jessica C. , Ravindran Ramya , Pawar Sheeba , Edwards Marta , Garcia-Fabiani Maria Belen , Haase Santiago , Lowenstein Pedro R. , Castro Maria G.
Published: April 2023

AbstractPurpose:
Diffuse intrinsic pontine glioma (DIPG) bears a dismal prognosis. A genetically engineered brainstem glioma model harboring the recurrent DIPG mutation, Activin A receptor type I (ACVR1)-G328V (mACVR1), was developed for testing an immune-stimulatory gene therapy.
Experimental Design:
We utilized the Sleeping Beauty transposase system to generate an endogenous mouse model of mACVR1 brainstem glioma. Histology was used to characterize and validate the model. We performed RNA-sequencing analysis on neurospheres harboring mACVR1. mACVR1 neurospheres were implanted into the pons of immune-competent mice to test the therapeutic efficacy and toxicity of immune-stimulatory gene therapy using adenoviruses expressing thymidine kinase (TK) and fms-like tyrosine kinase 3 ligand (Flt3L). mACVR1 neurospheres expressing the surrogate tumor antigen ovalbumin were generated to investigate whether TK/Flt3L treatment induces the recruitment of tumor antigen–specific T cells.
Results:
Histologic analysis of mACVR1 tumors indicates that they are localized in the brainstem and have increased downstream signaling of bone morphogenetic pathway as demonstrated by increased phospho-smad1/5 and Id1 levels. Transcriptome analysis of mACVR1 neurosphere identified an increase in the TGFβ signaling pathway and the regulation of cell differentiation. Adenoviral delivery of TK/Flt3L in mice bearing brainstem gliomas resulted in antitumor immunity, recruitment of antitumor-specific T cells, and increased median survival (MS).
Conclusions:
This study provides insights into the phenotype and function of the tumor immune microenvironment in a mouse model of brainstem glioma harboring mACVR1. Immune-stimulatory gene therapy targeting the hosts' antitumor immune response inhibits tumor progression and increases MS of mice bearing mACVR1 tumors.
Data from Human Cancers Express TRAILshort, a Dominant Negative TRAIL Splice Variant, Which Impairs Immune Effector Cell Killing of Tumor Cells
Authors: Aboulnasr Fatma , Krogman Ashton , Graham Rondell P. , Cummins Nathan W. , Misra Anisha , Garcia-Rivera Enrique , Anderson Jeff R. , Natesampillai Sekar , Kogan Nicole , Aravamudan Murali , Nie Zilin , Chung Thomas D.Y. , Buick Richard , Feldman Andrew L. , King Rebecca L. , Novak Anne J. , Ansell Stephen M. , Kenderian Saad , Badley Andrew D.
Published: April 2023

AbstractPurpose:
TNF-related apoptosis inducing ligand (TRAIL) expression by immune cells contributes to antitumor immunity. A naturally occurring splice variant of TRAIL, called TRAILshort, antagonizes TRAIL-dependent cell killing. It is unknown whether tumor cells express TRAILshort and if it impacts antitumor immunity.
Experimental Design:
We used an unbiased informatics approach to identify TRAILshort expression in primary human cancers, and validated those results with IHC and ISH. TRAILshort-specific mAbs were used to determine the effect of TRAILshort on tumor cell sensitivity to TRAIL, and to immune effector cell dependent killing of autologous primary tumors.
Results:
As many as 40% of primary human tumors express TRAILshort by both RNA sequencing and IHC analysis. By ISH, TRAILshort expression is present in tumor cells and not bystander cells. TRAILshort inhibition enhances cancer cell lines sensitivity to TRAIL-dependent killing both in vitro and in immunodeficient xenograft mouse models. Immune effector cells isolated from patients with B-cell malignancies killed more autologous tumor cells in the presence compared with the absence of TRAILshort antibody (P < 0.05).
Conclusions:
These results identify TRAILshort in primary human malignancies, and suggest that TRAILshort blockade can augment the effector function of autologous immune effector cells.

See related commentary by de Miguel and Pardo, p. 5546
Data from Pediatric PK/PD Phase I Trial of Pexidartinib in Relapsed and Refractory Leukemias and Solid Tumors Including Neurofibromatosis Type I–Related Plexiform Neurofibromas
Authors: Boal Lauren H. , Glod John , Spencer Melissa , Kasai Miki , Derdak Joanne , Dombi Eva , Ahlman Mark , Beury Daniel W. , Merchant Melinda S. , Persenaire Christianne , Liewehr David J. , Steinberg Seth M. , Widemann Brigitte C. , Kaplan Rosandra N.
Published: April 2023

AbstractPurpose:
Simultaneously targeting the tumor and tumor microenvironment may hold promise in treating children with refractory solid tumors. Pexidartinib, an oral inhibitor of tyrosine kinases including colony stimulating factor 1 receptor (CSF-1R), KIT, and FLT3, is FDA approved in adults with tenosynovial giant cell tumor. A phase I trial was conducted in pediatric and young adult patients with refractory leukemias or solid tumors including neurofibromatosis type 1–related plexiform neurofibromas.
Patients and Methods:
A rolling six design with dose levels (DL) of 400 mg/m2, 600 mg/m2, and 800 mg/m2 once daily for 28-day cycles (C) was used. Response was assessed at regular intervals. Pharmacokinetics and population pharmacokinetics were analyzed during C1.
Results:
Twelve patients (4 per DL, 9 evaluable) enrolled on the dose-escalation phase and 4 patients enrolled in the expansion cohort: median (lower, upper quartile) age 16 (14, 16.5) years. No dose-limiting toxicities were observed. Pharmacokinetics appeared linear over three DLs. Pharmacokinetic modeling and simulation determined a weight-based recommended phase II dose (RP2D). Two patients had stable disease and 1 patient with peritoneal mesothelioma (C49+) had a sustained partial response (67% RECIST reduction). Pharmacodynamic markers included a rise in plasma macrophage CSF (MCSF) levels and a decrease in absolute monocyte count.
Conclusions:
Pexidartinib in pediatric patients was well tolerated at all DL tested, achieved target inhibition, and resulted in a weight-based RPD2 dose.
Data from Amphiregulin Expression Is a Predictive Biomarker for EGFR Inhibition in Metastatic Colorectal Cancer: Combined Analysis of Three Randomized Trials
Authors: Stahler Arndt , Stintzing Sebastian , Modest Dominik P. , Ricard Ingrid , Giessen-Jung Clemens , Kapaun Christine , Ivanova Boryana , Kaiser Florian , Fischer von Weikersthal Ludwig , Moosmann Nicolas , Schalhorn Andreas , Stauch Martina , Kiani Alexander , Held Swantje , Decker Thomas , Moehler Markus , Neumann Jens , Kirchner Thomas , Jung Andreas , Heinemann Volker
Published: April 2023

AbstractPurpose:
Amphiregulin (AREG) and epiregulin (EREG) are ligands of EGFR. Predictive information for anti-EGFR treatment in metastatic colorectal cancer (mCRC) was observed, but data for other agents is limited.
Experimental Design:
Ligand mRNA expression; RAS, BRAF, PIK3CA mutations; and EGFR expression were assessed by qRT-PCR, pyrosequencing, and IHC, respectively, in mCRC tumor tissue of patients participating in the randomized controlled trials FIRE-1, CIOX, and FIRE-3. Normalized mRNA expression was dichotomized using median and third quartile. Overall (OS) and progression-free survival (PFS) were estimated by Kaplan–Meier method including univariate and multivariate Cox regression analyses. Penalized spline regression analysis tested interaction of mRNA expression and outcome.
Results:
Of 688 patients with available material, high AREG expression was detected in 343 (>median) and 172 (>3rd quartile) patients. High AREG expression was associated with significantly higher OS [26.2 vs. 21.5 months, HR = 0.80; 95% confidence interval (CI), 0.68–0.94; P = 0.007], PFS (10.0 vs. 8.1 months, HR = 0.74; 95% CI, 0.63–0.86; P = 0.001), and objective response rate (63.1% vs. 51.6%, P = 0.004) compared to low expression at both threshold values. This effect remained significant in multivariate Cox regression analysis (OS: P = 0.01, PFS: P = 0.002). High AREG mRNA expression interacted significantly with the efficacy of cetuximab compared with bevacizumab (OS: P = 0.02, PFS: P = 0.04) in RAS WT mCRC.
Conclusions:
High AREG mRNA expression is a favorable prognostic biomarker for mCRC which interacted significantly with efficacy of anti-EGFR treatment.
Data from Gene Networks Constructed Through Simulated Treatment Learning can Predict Proteasome Inhibitor Benefit in Multiple Myeloma
Authors: Ubels Joske , Sonneveld Pieter , van Vliet Martin H. , de Ridder Jeroen
Published: April 2023

AbstractPurpose:
Proteasome inhibitors are widely used in treating multiple myeloma, but can cause serious side effects and response varies among patients. It is, therefore, important to gain more insight into which patients will benefit from proteasome inhibitors.
Experimental Design:
We introduce simulated treatment learned signatures (STLsig), a machine learning method to identify predictive gene expression signatures. STLsig uses genetically similar patients who have received an alternative treatment to model which patients will benefit more from proteasome inhibitors than from an alternative treatment. STLsig constructs gene networks by linking genes that are synergistic in their ability to predict benefit.
Results:
In a dataset of 910 patients with multiple myeloma, STLsig identified two gene networks that together can predict benefit to the proteasome inhibitor, bortezomib. In class “benefit,” we found an HR of 0.47 (P = 0.04) in favor of bortezomib, while in class “no benefit,” the HR was 0.91 (P = 0.68). Importantly, we observed a similar performance (HR class benefit, 0.46; P = 0.04) in an independent patient cohort. Moreover, this signature also predicts benefit for the proteasome inhibitor, carfilzomib, indicating it is not specific to bortezomib. No equivalent signature can be found when the genes in the signature are excluded from the analysis, indicating that they are essential. Multiple genes in the signature are linked to working mechanisms of proteasome inhibitors or multiple myeloma disease progression.
Conclusions:
STLsig can identify gene signatures that could aid in treatment decisions for patients with multiple myeloma and provide insight into the biological mechanism behind treatment benefit.
Data from Genomic Profiling of Prostate Cancers from Men with African and European Ancestry
Authors: Koga Yusuke , Song Hanbing , Chalmers Zachary R. , Newberg Justin , Kim Eejung , Carrot-Zhang Jian , Piou Daphnee , Polak Paz , Abdulkadir Sarki A. , Ziv Elad , Meyerson Matthew , Frampton Garrett M. , Campbell Joshua D. , Huang Franklin W.
Published: April 2023

AbstractPurpose:
African American (AFR) men have the highest mortality rate from prostate cancer (PCa) compared with men of other racial/ancestral groups. Differences in the spectrum of somatic genome alterations in tumors between AFR men and other populations have not been well-characterized due to a lack of inclusion of significant numbers in genomic studies.
Experimental Design:
To identify genomic alterations associated with race, we compared the frequencies of somatic alterations in PCa obtained from four publicly available datasets comprising 250 AFR and 611 European American (EUR) men and a targeted sequencing dataset from a commercial platform of 436 AFR and 3018 EUR men.
Results:
Mutations in ZFHX3 as well as focal deletions in ETV3 were more frequent in tumors from AFR men. TP53 mutations were associated with increasing Gleason score. MYC amplifications were more frequent in tumors from AFR men with metastatic PCa, whereas deletions in PTEN and rearrangements in TMPRSS2-ERG were less frequent in tumors from AFR men. KMT2D truncations and CCND1 amplifications were more frequent in primary PCa from AFR men. Genomic features that could impact clinical decision making were not significantly different between the two groups including tumor mutation burden, MSI status, and genomic alterations in select DNA repair genes, CDK12, and in AR.
Conclusions:
Although we identified some novel differences in AFR men compared with other populations, the frequencies of genomic alterations in current therapeutic targets for PCa were similar between AFR and EUR men, suggesting that existing precision medicine approaches could be equally beneficial if applied equitably.
Data from Early Intervention with Lenalidomide in Patients with High-risk Chronic Lymphocytic Leukemia
Authors: Thangavadivel Shanmugapriya , Zhao Qiuhong , Epperla Narendranath , Rike Lindsey , Mo Xiaokui , Badawi Mohamed , Bystry Darlene M. , Phelps Mitch A. , Andritsos Leslie A. , Rogers Kerry A. , Jones Jeffrey , Woyach Jennifer A. , Byrd John C. , Awan Farrukh T.
Published: April 2023

AbstractPurpose:
Infectious complications constitute a leading cause of morbidity and mortality in chronic lymphocytic leukemia (CLL). Patients respond poorly to vaccines, particularly pneumococcal polysaccharide and influenza vaccines. In addition, patients with genetically high-risk disease are at increased risk for early disease progression and death. Lenalidomide, an oral immunomodulatory agent with demonstrated clinical activity in CLL, can potentially restore immune system dysfunction associated with CLL while improving disease outcomes.
Patients and Methods:
Phase II study randomized 49 patients with genetically high-risk CLL or small lymphocytic lymphoma [SLL; defined as unmutated Ig heavy chain variable region, deletion(17p) or (11q), and/or complex abnormal karyotype], to receive lenalidomide either concurrent (arm A) or sequential to (arm B) two doses of 13-valent protein-conjugated pneumococcal vaccine (PCV13) administered 2 months apart, in patients not meeting International Workshop on Chronic Lymphocytic Leukemia treatment criteria.
Results:
Four serotypes (3, 4, 5, 6B) achieved the additional seroprotection definition of a fourfold increase in arm A, and six serotypes (3, 4, 5, 6B, 19A, 19F) in arm B. All patients achieved the defined concentration of 0.35 μg/mL for at least one serotype tested. No significant difference was observed with the addition of lenalidomide. At median time on treatment of 3.6 years, median progression-free survival (PFS) was 5.8 years [95% confidence interval (CI), 3.1—not reached]. PFS at 1, 2, and 3 years was 85% (95% CI, 72–93), 79% (95% CI, 64–88), and 72% (95% CI, 57–83), respectively.
Conclusions:
Lenalidomide is efficacious with manageable toxicities as an early intervention strategy in patients with high-risk CLL, but did not enhance humoral response to PCV13 vaccine.
Data from Baseline Characteristics, Treatment Patterns, and Outcomes in Patients with HER2-Positive Metastatic Breast Cancer by Hormone Receptor Status from SystHERs
Authors: Cobleigh Melody , Yardley Denise A. , Brufsky Adam M. , Rugo Hope S. , Swain Sandra M. , Kaufman Peter A. , Tripathy Debu , Hurvitz Sara A. , O'Shaughnessy Joyce , Mason Ginny , Antao Vincent , Li Haocheng , Chu Laura , Jahanzeb Mohammad
Published: April 2023

AbstractPurpose:
We report treatments and outcomes in a contemporary patient population with HER2-positive metastatic breast cancer (MBC) by hormone receptor (HR) status from the Systemic Therapies for HER2-positive Metastatic Breast Cancer Study (SystHERs).
Experimental Design:
SystHERs (NCT01615068) was an observational, prospective registry study of U.S.-based patients with newly diagnosed HER2-positive MBC. Endpoints included treatment patterns and clinical outcomes.
Results:
Of 977 eligible patients (enrolled from 2012 to 2016), 70.1% (n = 685) had HR-positive and 29.9% (n = 292) had HR-negative disease. Overall, 59.1% (405/685) of patients with HR-positive disease received any first-line endocrine therapy (with or without HER2-targeted therapy or chemotherapy); 34.9% (239/685) received HER2-targeted therapy + chemotherapy + sequential endocrine therapy. Patients with HR-positive versus HR-negative disease had longer median overall survival (OS; 53.0 vs 43.4 months; hazard ratio, 0.70; 95% confidence interval, 0.56–0.87). Compared with patients with high HR-positive staining (10%–100%, n = 550), those with low HR-positive staining (1%–9%, n = 60) received endocrine therapy less commonly (64.2% vs 33.3%) and had shorter median OS (53.8 vs 40.1 months). Similar median OS (43.4 vs 40.1 months) was observed in patients with HR-negative versus low HR-positive tumors (1%–9%).
Conclusions:
Despite evidence that first-line HER2-targeted therapy, chemotherapy, and sequential endocrine therapy improves survival in patients with HR-positive, HER2-positive disease, only 34.9% of patients in this real-world setting received such treatment. Patients with low tumor HR positivity (1%–9%) had lower endocrine therapy use and worse survival than those with high tumor HR positivity (10%–100%).
Data from Single-Cell Circulating Tumor Cell Analysis Reveals Genomic Instability as a Distinctive Feature of Aggressive Prostate Cancer
Authors: Malihi Paymaneh D. , Graf Ryon P. , Rodriguez Angel , Ramesh Naveen , Lee Jerry , Sutton Ramsay , Jiles Rhett , Ruiz Velasco Carmen , Sei Emi , Kolatkar Anand , Logothetis Christopher , Navin Nicholas E. , Corn Paul , Aparicio Ana M. , Dittamore Ryan , Hicks James , Kuhn Peter , Zurita Amado J.
Published: April 2023

AbstractPurpose:
Aggressive variant prostate cancer (AVPC) represents a clinical subset distinguished by therapy resistance and poor prognosis, linked to combined losses of the tumor suppressor genes (TSG) PTEN, RB1, and TP53. Circulating tumor cells (CTC) provide a minimally invasive opportunity for identification and molecular characterization of AVPC. We aimed to evaluate the incidence and clinical significance of compound (2+)TSG losses and genomic instability in prostate cancer CTC, and to expand the set genomic biomarkers relevant to AVPC.
Experimental Design:
Genomic analysis of chromosomal copy-number alterations (CNA) at single-cell resolution was performed in CTC from patients with and without AVPC before initiating chemotherapy with cabazitaxel or cabazitaxel and carboplatin. We evaluated associations between single-CTC genomics and clinical features, progression-free survival, and overall survival.
Results:
A total of 257 individual CTC were sequenced from 47 patients (1–22 CTC/patient). Twenty patients (42.6%) had concurrent 2+TSG losses in at least one CTC in association with poor survival and increased genomic instability, inferred by high large-scale transitions scores. Higher LST in CTC were independent of CTC enumerated, clinically more indicative of aggressive behavior than co-occurring TSG losses, and molecularly associated with gains in chromosomal regions including PTK2, Myc, and NCOA2; increased androgen receptor expression; and BRCA2 loss. In 57 patients with matched cell-free tumor DNA data, CTC were more frequently detectable and evaluable for CNA analysis (in 73.7% vs. 42.1%, respectively).
Conclusions:
Our findings suggest that genomic instability in CTC is a hallmark of advanced prostate cancer aggressiveness, and support single-CTC sequencing as a compelling tool to noninvasively characterize cancer heterogeneity.
Data from Single-Cell–Derived Primary Rectal Carcinoma Cell Lines Reflect Intratumor Heterogeneity Associated with Treatment Response
Authors: Braun Rüdiger , Anthuber Lena , Hirsch Daniela , Wangsa Darawalee , Lack Justin , McNeil Nicole E. , Heselmeyer-Haddad Kerstin , Torres Irianna , Wangsa Danny , Brown Markus A. , Tubbs Anthony , Auslander Noam , Gertz E. Michael , Brauer Philip R. , Cam Margaret C. , Sackett Dan L. , Habermann Jens K. , Nussenzweig Andre , Ruppin Eytan , Zhang Zhongqiu , Rosenberg Daniel W. , Ried Thomas
Published: April 2023

AbstractPurpose:
The standard treatment of patients with locally advanced rectal cancer consists of preoperative chemoradiotherapy (CRT) followed by surgery. However, the response of individual tumors to CRT is extremely diverse, presenting a clinical dilemma. This broad variability in treatment response is likely attributable to intratumor heterogeneity (ITH).
Experimental Design:
We addressed the impact of ITH on response to CRT by establishing single-cell–derived cell lines (SCDCL) from a treatment-naïve rectal cancer biopsy after xenografting.
Results:
Individual SCDCLs derived from the same tumor responded profoundly different to CRT in vitro. Clonal reconstruction of the tumor and derived cell lines based on whole-exome sequencing revealed nine separate clusters with distinct proportions in the SCDCLs. Missense mutations in SV2A and ZWINT were clonal in the resistant SCDCL, but not detected in the sensitive SCDCL. Single-cell genetic analysis by multiplex FISH revealed the expansion of a clone with a loss of PIK3CA in the resistant SCDCL. Gene expression profiling by tRNA-sequencing identified the activation of the Wnt, Akt, and Hedgehog signaling pathways in the resistant SCDCLs. Wnt pathway activation in the resistant SCDCLs was confirmed using a reporter assay.
Conclusions:
Our model system of patient-derived SCDCLs provides evidence for the critical role of ITH for treatment response in patients with rectal cancer and shows that distinct genetic aberration profiles are associated with treatment response. We identified specific pathways as the molecular basis of treatment response of individual clones, which could be targeted in resistant subclones of a heterogenous tumor.
Data from Copy-Number Alteration Burden Differentially Impacts Immune Profiles and Molecular Features of Hepatocellular Carcinoma
Authors: Bassaganyas Laia , Pinyol Roser , Esteban-Fabró Roger , Torrens Laura , Torrecilla Sara , Willoughby Catherine E. , Franch-Expósito Sebastià , Vila-Casadesús Maria , Salaverria Itziar , Montal Robert , Mazzaferro Vincenzo , Camps Jordi , Sia Daniela , Llovet Josep M.
Published: April 2023

AbstractPurpose:
Chromosomal instability is a hallmark of cancer that results in broad and focal copy-number alterations (CNAs), two events associated with distinct molecular, immunologic, and clinical features. In hepatocellular carcinoma (HCC), the role of CNAs has not been thoroughly assessed. Thus, we dissected the impact of CNA burdens on HCC molecular and immune features.
Experimental Design:
We analyzed SNP array data from 452 paired tumor/adjacent resected HCCs and 25 dysplastic nodules. For each sample, broad and focal CNA burdens were quantified using CNApp, and the resulting broad scores (BS) and focal scores (FS) were correlated with transcriptomic, mutational, and methylation profiles, tumor immune composition, and clinicopathologic data.
Results:
HCCs with low broad CNA burdens (defined as BS ≤ 4; 17%) presented high inflammation, active infiltrate signaling, high cytolytic activity, and enrichment of the “HCC immune class” and gene signatures related to antigen presentation. Conversely, tumors with chromosomal instability (high broad CNA loads, BS ≥ 11; 40%), displayed immune-excluded traits and were linked to proliferation, TP53 dysfunction, and DNA repair. Candidate determinants of the low cytotoxicity and immune exclusion features of high-BS tumors included alterations in antigen-presenting machinery (i.e., HLA), widespread hypomethylation, and decreased rates of observed/expected neoantigenic mutations. High FSs were independent of tumor immune features, but were related to proliferation, TP53 dysfunction, and progenitor cell traits.
Conclusions:
HCCs with high chromosomal instability exhibit features of immune exclusion, whereas tumors displaying low burdens of broad CNAs present an immune active profile. These CNA scores can be tested to predict response to immunotherapies.
Data from A Prognostic Model Based on PAM50 and Clinical Variables (PAM50MET) for Metastatic Hormone Receptor–positive HER2-negative Breast Cancer
Authors: Prat Aleix , Tsai Yi-Hsuan , Pascual Tomás , Paré Laia , Adamo Barbara , Vidal Maria , Brasó-Maristany Fara , Galván Patricia , Brase Jan Christoph , Rodrik-Outmezguine Vanessa , Johnston Stephen , Ciruelos Eva , Parker Joel S.
Published: April 2023

AbstractPurpose:
Predicting prognosis in HR+/HER2− metastatic breast cancer (MBC) might be clinically useful; however, no validated prognostic biomarkers exist in this setting to date.
Patients and Methods:
In phase III, EGF30008 trial, 484 patients with HER2− MBC who received letrozole and placebo or lapatinib were selected. PAM50 data, ECOG performance status, visceral disease, number of metastasis, biopsy type, and age were evaluated. A progression-free survival (PFS) Cox model was evaluated. The final model (PAM50MET) with a prespecified cutoff was validated in patients (n = 261) with HR+/HER2− advanced breast cancer (aBC) from BOLERO-2 (phase III trial that evaluated exemestane and placebo or everolimus).
Results:
In EGF30008, prognostic models with PAM50 plus clinical variables yielded higher C-index values versus models with only PAM50 or clinical variables. The PAM50MET model combined 21 variables: 2 PAM50 subtypes, basal signature, 14 genes, and 4 clinical variables. In EGF30008, the optimized cutoff was associated with PFS [HR = 0.37; 95% confidence interval (CI), 0.29–0.47; P < 0.0001] and overall survival (OS; HR = 0.37; 95% CI, 0.27–0.51; P < 0.0001). The median (months; 95% CI) PFS and OS were 22.24 (19.0–24.9) and not reached in PAM50MET-low versus 9.13 (8.15–11.0) and 33.0 (28.0–40.0) in PAM50MET-high groups, respectively. In BOLERO-2, the PAM50MET-low was associated with better PFS (HR = 0.72; 95% CI, 0.53–0.96; P = 0.028) and OS (HR = 0.51; 95% CI, 0.35–0.69; P < 0.0001). The median (months) (95% CI) PFS and OS were 6.93 (5.57–11.0) and 36.9 (33.4–NA) in PAM50MET-low versus 5.23 (4.2–6.8) and 23.5 (20.2–28.3) in PAM50MET-high groups, respectively.
Conclusions:
PAM50MET is prognostic in HR+/HER2− MBC, and further evaluation might help identify candidates for endocrine therapy only or novel therapies.
Data from A Three-Arm Randomized Phase II Study of Bendamustine/Rituximab with Bortezomib Induction or Lenalidomide Continuation in Untreated Follicular Lymphoma: ECOG-ACRIN E2408
Authors: Evens Andrew M. , Hong Fangxin , Habermann Thomas M. , Advani Ranjana H. , Gascoyne Randy D. , Witzig Thomas E. , Quon Andrew , Ranheim Erik A. , Ansell Stephen M. , Cheema Puneet Singh , Dy Philip A. , O'Brien Timothy E. , Winter Jane N. , Cescon Terrence P. , Chang Julie E. , Kahl Brad S.
Published: April 2023

AbstractPurpose:
We sought to improve upon frontline bendamustine/rituximab (BR) induction therapy followed by rituximab maintenance in untreated high-risk follicular lymphoma (FL).
Patients and Methods:
Patients were randomized to BR induction followed by 2-year rituximab maintenance (BR-R), BR with bortezomib and rituximab maintenance (BVR-R), or BR followed by lenalidomide (1 year) with rituximab maintenance (BR-LR). Dual primary objectives were complete remission (CR) rate and 1-year disease-free survival (DFS); 289 patients enrolled (NCT01216683).
Results:
For induction, 92%, 87%, and 86% of patients randomized to BR-R, BVR-R, or BR-LR received six cycles, respectively. CR rate with BR versus BVR induction was 62% versus 75%, respectively (P = 0.04). One-year DFS rates with BR-R versus BR-LR were 85% versus 67%, respectively (P = 0.0009). This was due to an imbalance in CR rates post-BR induction and discontinuation due to adverse events (AEs). The most common grade 3–4 AEs for BVR versus BR were neutropenia and sensory neuropathy (12% vs <1%); 83% of the latter occurred with intravenous bortezomib. The most common grade 3–4 AEs related to LR versus rituximab maintenance were neutropenia 66% versus 21%, respectively (P < 0.0001), and febrile neutropenia 10% versus 2%, respectively (P = 0.05). The overall treatment-related mortality was 1.4%. With 5-year median follow-up, 3-year PFS rates for BR-R, BVR-R, and BR-LR were 77%, 82%, and 76%, respectively (P = 0.36) with OS rates of 87%, 90%, and 84%, respectively (P = 0.79). For prognostication, CR rate and POD-24 were associated with survival.
Conclusions:
Altogether, neither bortezomib added to BR induction nor lenalidomide added to rituximab maintenance immediately post-BR induction is recommended in untreated FL.
Data from OMTX705, a Novel FAP-Targeting ADC Demonstrates Activity in Chemotherapy and Pembrolizumab-Resistant Solid Tumor Models
Authors: Fabre Myriam , Ferrer Cristina , Domínguez-Hormaetxe Saioa , Bockorny Bruno , Murias Laura , Seifert Oliver , Eisler Stephan A. , Kontermann Roland E. , Pfizenmaier Klaus , Lee So Young , Vivanco María dM. , López-Casas Pedro P. , Perea Sofia , Abbas Muhammad , Richter Wolfgang , Simon Laureano , Hidalgo Manuel
Published: April 2023

AbstractPurpose:
The tumor microenvironment plays a key role in cancer development and progression and is involved in resistance to chemo- and immunotherapy. Cancer-associated fibroblast expressing fibroblast-activating protein α (FAPα) is one of the predominant stroma cell types and is involved in resistance to immunotherapy.
Experimental Design:
We generated OMTX705, a novel antibody–drug conjugate from a humanized anti-FAP antibody linked to a new cytolysin. Here, we studied its antineoplastic activity in vitro and in preclinical mouse models alone and in combination with chemotherapy as well as immunotherapy in PD-1–resistant tumors.
Results:
In Avatar models, OMTX705 showed a 100% tumor growth inhibition and prolonged tumor regressions as single agent and in combination with chemotherapy. Treatment rechallenge following treatment discontinuation induced additional tumor regression, suggesting lack of treatment resistance. In a mouse model with a humanized immune system resistant to PD-1 inhibition, OMTX705 increased tumor infiltration by CD8+ T cells, induced complete regressions, and delayed tumor recurrence.
Conclusions:
These data suggest that FAP targeting with OMTX705 represents a novel and potent strategy for cancer treatment, including tumors resistant to immunotherapy, and support its clinical development.
Data from Dual Blockade of c-MET and the Androgen Receptor in Metastatic Castration-resistant Prostate Cancer: A Phase I Study of Concurrent Enzalutamide and Crizotinib
Authors: Tripathi Abhishek , Supko Jeffrey G. , Gray Kathryn P. , Melnick Zachary J. , Regan Meredith M. , Taplin Mary-Ellen , Choudhury Atish D. , Pomerantz Mark M. , Bellmunt Joaquim , Yu Channing , Sun Zijie , Srinivas Sandy , Kantoff Philip W. , Sweeney Christopher J. , Harshman Lauren C.
Published: April 2023

AbstractPurpose:
Androgen receptor (AR) inhibition can upregulate c-MET expression, which may be a resistance mechanism driving progression of castration-resistant prostate cancer (CRPC). We conducted a phase I trial investigating the safety and pharmacokinetics of a potent c-MET inhibitor, crizotinib, with the AR antagonist, enzalutamide, in CRPC.
Patients and Methods:
Employing a 3+3 dose-escalation design, we tested three dose levels of crizotinib (250 mg daily, 200 mg twice a day, and 250 mg twice a day) with standard-dose enzalutamide (160 mg daily). The primary endpoint was rate of dose-limiting toxicities (DLTs). Tolerability and pharmacokinetics profile were secondary endpoints.
Results:
Twenty-four patients were enrolled in the dose-escalation (n = 16) and dose-expansion (n = 8) phases. Two DLTs occurred in dose escalation (grade 3 alanine aminotransferase elevation). The MTD of crizotinib was 250 mg twice a day. Most frequent treatment-related adverse events were fatigue (50%), transaminitis (38%), nausea (33%), and vomiting, constipation, and diarrhea (21% each). Grade ≥3 events (25%) included transaminitis (n = 2), fatigue (n = 1), hypertension (n = 1), pulmonary embolism (n = 1), and a cardiac event encompassing QTc prolongation/ventricular arrhythmia/cardiac arrest. Median progression-free survival was 5.5 months (95% confidence interval, 2.8–21.2). Pharmacokinetics analysis at the MTD (n = 12) revealed a mean Cmaxss of 104 ± 45 ng/mL and AUCτss of 1,000 ± 476 ng•h/mL, representing a 74% decrease in crizotinib systemic exposure relative to historical data (Cmaxss, 315 ng/mL and AUCτss, 3,817 ng•h/mL).
Conclusions:
Concurrent administration of enzalutamide and crizotinib resulted in a clinically significant 74% decrease in systemic crizotinib exposure. Further investigation of this combination in CRPC is not planned. Our results highlight the importance of evaluating pharmacokinetics interactions when evaluating novel combination strategies in CRPC.