bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Initial Whole-Genome Sequencing of Plasma Cell Neoplasms in First Responders and Recovery Workers Exposed to the World Trade Center Attack of September 11, 2001
Authors: Maura Francesco , Diamond Benjamin , Maclachlan Kylee H. , Derkach Andriy , Yellapantula Venkata D. , Rustad Even H. , Hultcrantz Malin , Shah Urvi A. , Hong Jessica , Landau Heather J. , Iacobuzio-Donahue Christine A. , Papaemmanuil Elli , Irby Shani , Crowley Laura , Crane Michael , Webber Mayris P. , Goldfarb David G. , Zeig-Owens Rachel , Giricz Orsi , Verma Amit , Prezant David J. , Dogan Ahmet , Shah Sohrab P. , Zhang Yanming , Landgren Ola
Published: April 2023

AbstractPurpose:
The World Trade Center (WTC) attack of September 11, 2001 created an unprecedented environmental exposure to known and suspected carcinogens. High incidence of multiple myeloma and precursor conditions has been reported among first responders to the WTC disaster. To expand on our prior screening studies, and to characterize the genomic impact of the exposure to known and potential carcinogens in the WTC debris, we were motivated to perform whole-genome sequencing (WGS) of WTC first responders and recovery workers who developed a plasma cell disorder after the attack.
Experimental Design:
We performed WGS of nine CD138-positive bone marrow mononuclear samples from patients who were diagnosed with plasma cell disorders after the WTC disaster.
Results:
No significant differences were observed in comparing the post-WTC driver and mutational signature landscapes with 110 previously published WGSs from 56 patients with multiple myeloma and the CoMMpass WGS cohort (n = 752). Leveraging constant activity of the single-base substitution mutational signatures 1 and 5 over time, we estimated that tumor-initiating chromosomal gains were windowed to both pre- and post-WTC exposure.
Conclusions:
Although limitations in sample size preclude any definitive conclusions, our findings suggest that the observed increased incidence of plasma cell neoplasms in this population is due to complex and heterogeneous effects of the WTC exposure that may have initiated or contributed to progression of malignancy.
Data from Predictive Significance of an Optimized Panel for Basal-like Breast Cancer: Results from the Canadian Cancer Trials Group MA.5 and MA.12 Phase III Clinical Trials
Authors: Asleh Karama , Tu Dongsheng , Gao Dongxia , Bramwell Vivien , Levine Mark N. , Pritchard Kathleen I. , Shepherd Lois E. , Nielsen Torsten O.
Published: April 2023

AbstractPurpose:
Accurate IHC biomarkers incorporating nestin positivity or inositol polyphosphate-4-phosphate (INPP4B) loss have recently been optimized to identify the basal-like intrinsic breast cancer subtype regardless of estrogen, progesterone, or Her2 status. We examined the predictive capacity of these basal biomarkers in the CCTG MA.5 chemotherapy and MA.12 endocrine therapy trials.
Experimental Design:
Formalin-fixed paraffin embedded blocks of primary tumors from patients randomized in the two trials were used to build tissue microarrays. IHC staining for nestin and INPP4B followed published methods and REMARK criteria. A prespecified statistical plan tested the hypothesis that patients with basal breast cancer (nestin+ or INPP4B−) would not benefit from anthracycline substitution in MA.5 or from tamoxifen in MA.12.
Results:
Nestin positivity or INPP4B loss was observed in 110/453 (24%) interpretable samples from MA.5 and 47/366 (13%) from MA.12, and was associated with high grade, younger age, estrogen receptor negativity, triple-negative, core basal, and PAM50 basal-like subtypes. In the MA.5 trial, patients assigned as basal experienced lower benefit from anthracycline versus nonanthracycline adjuvant chemotherapy [HR, 1.49; 95% confidence interval (CI), 0.72–3.10] when compared with non-basal (nestin− and INPP4B+) cases where there was a higher benefit from anthracyclines (HR, 0.75; 95% CI, 0.54–1.04; Pinteraction = 0.01). In the MA.12 trial, patients assigned as basal did not demonstrate a benefit from adjuvant tamoxifen versus placebo (HR, 0.48; 95% CI, 0.12–1.86; P = 0.29), whereas nonbasal cases displayed significant benefit (HR, 0.66; 95% CI, 0.45–0.98; P = 0.04), although the interaction test was not significant.
Conclusions:
The nestin/INPP4B IHC panel identifies women with basal breast cancers who benefit from nonanthracycline chemotherapy but not endocrine adjuvant treatments.
Data from A Randomized Phase II Study of Anti-CSF1 Monoclonal Antibody Lacnotuzumab (MCS110) Combined with Gemcitabine and Carboplatin in Advanced Triple-Negative Breast Cancer
Authors: Kuemmel Sherko , Campone Mario , Loirat Delphine , Lopez Rafael Lopez , Beck J. Thaddeus , De Laurentiis Michelino , Im Seock-Ah , Kim Sung-Bae , Kwong Ava , Steger Guenther G. , Adelantado Esther Zamora , Duhoux Francois P. , Greil Richard , Kuter Irene , Lu Yen-Shen , Tibau Ariadna , Özgüroğlu Mustafa , Scholz Christian W. , Singer Christian F. , Vega Estela , Wimberger Pauline , Zamagni Claudio , Couillebault Xuan-Mai , Fan Liqiong , Guerreiro Nelson , Mataraza Jennifer , Sand-Dejmek Janna , Chan Arlene
Published: April 2023

AbstractPurpose:
This phase II study determined the efficacy of lacnotuzumab added to gemcitabine plus carboplatin (gem-carbo) in patients with advanced triple-negative breast cancer (TNBC).
Patients and Methods:
Female patients with advanced TNBC, with high levels of tumor-associated macrophages not amenable to curative treatment by surgery or radiotherapy were enrolled. Lacnotuzumab was dosed at 10 mg/kg every 3 weeks, ± a dose on cycle 1, day 8. Gemcitabine (1,000 mg/m2) and carboplatin (dose in mg calculated by area under the curve [mg/mL/min] × (glomerular filtration rate [mL/min] + 25 [mL/min]) were dosed every 3 weeks. Treatment continued until unacceptable toxicity, disease progression, or discontinuation by physician/patient.
Results:
Patients received lacnotuzumab + gem-carbo (n = 34) or gem-carbo (n = 15). Enrollment was halted due to recruitment challenges owing to rapid evolution of the therapeutic landscape; formal hypothesis testing of the primary endpoint was therefore not performed. Median progression-free survival was 5.6 months [90% confidence interval (CI), 4.47–8.64] in the lacnotuzumab + gem-carbo arm and 5.5 months (90% CI, 3.45–7.46) in the gem-carbo arm. Hematologic adverse events were common in both treatment arms; however, patients treated with lacnotuzumab experienced more frequent aspartate aminotransferase, alanine aminotransferase, and creatine kinase elevations. Pharmacokinetic results showed that free lacnotuzumab at 10 mg/kg exhibited a typical IgG pharmacokinetic profile and target engagement of circulating colony-stimulating factor 1 ligand.
Conclusions:
Despite successful target engagement and anticipated pharmacokinetic profile, lacnotuzumab + gem-carbo showed comparable antitumor activity to gem-carbo alone, with slightly poorer tolerability. However, the data presented in this article would be informative for future studies testing agents targeting the CSF1–CSF1 receptor pathway in TNBC.
Data from DOT1L Is a Novel Cancer Stem Cell Target for Triple-Negative Breast Cancer
Authors: Kurani Hetakshi , Razavipour Seyedeh Fatemeh , Harikumar Kuzhuvelil B. , Dunworth Matthew , Ewald Andrew J. , Nasir Apsra , Pearson Gray , Van Booven Derek , Zhou Zhiqun , Azzam Diana , Wahlestedt Claes , Slingerland Joyce
Published: April 2023

AbstractPurpose:
Although chemotherapies kill most cancer cells, stem cell–enriched survivors seed metastasis, particularly in triple-negative breast cancers (TNBC). TNBCs arise from and are enriched for tumor stem cells. Here, we tested if inhibition of DOT1L, an epigenetic regulator of normal tissue stem/progenitor populations, would target TNBC stem cells.
Experimental Design:
Effects of DOT1L inhibition by EPZ-5676 on stem cell properties were tested in three TNBC lines and four patient-derived xenograft (PDX) models and in isolated cancer stem cell (CSC)-enriched ALDH1+ and ALDH1− populations. RNA sequencing compared DOT1L regulated pathways in ALDH1+ and ALDH1− cells. To test if EPZ-5676 decreases CSC in vivo, limiting dilution assays of EPZ-5676/vehicle pretreated ALDH1+ and ALDH1− cells were performed. Tumor latency, growth, and metastasis were evaluated. Antitumor activity was also tested in TNBC PDX and PDX-derived organoids.
Results:
ALDH1+ TNBC cells exhibit higher DOT1L and H3K79me2 than ALDH1−. DOT1L maintains MYC expression and self-renewal in ALDH1+ cells. Global profiling revealed that DOT1L governs oxidative phosphorylation, cMyc targets, DNA damage response, and WNT activation in ALDH1+ but not in ALDH1− cells. EPZ-5676 reduced tumorspheres and ALDH1+ cells in vitro and decreased tumor-initiating stem cells and metastasis in xenografts generated from ALDH1+ but not ALDH1− populations in vivo. EPZ-5676 significantly reduced growth in vivo of one of two TNBC PDX tested and decreased clonogenic 3D growth of two other PDX-derived organoid cultures.
Conclusions:
DOT1L emerges as a key CSC regulator in TNBC. Present data support further clinical investigation of DOT1L inhibitors to target stem cell–enriched TNBC.
Data from Molecular Features of Cancer-associated Fibroblast Subtypes and their Implication on Cancer Pathogenesis, Prognosis, and Immunotherapy Resistance
Authors: Galbo Phillip M. , Zang Xingxing , Zheng Deyou
Published: April 2023

AbstractPurpose:
Cancer-associated fibroblasts (CAFs) are an important component of the tumor microenvironment, but a systematic investigation of their molecular characteristics and clinical relevance are lacking. Here, we sought to compare CAFs across multiple cancer types to identify critical molecular pathways activated in CAF subtypes, which may contribute to clinical outcome, disease progression, and immunotherapy resistance.
Experimental Design:
We performed integrated analysis of CAFs from melanoma, head and neck squamous cell carcinoma, and lung cancer, and identified the molecular characteristics that are distinctly active in each CAF subtype. Gene signatures for individual CAF subtypes were identified and used to study the association of subtype abundance with clinical outcome and immunotherapy resistance.
Results:
We identified six CAF subtypes (pan-CAF) shared across cancer types and uncovered the molecular characteristics and genetic pathways distinguishing them. Interestingly, these CAF subtypes express distinct immunosuppressive factors, such as CXCL12 and CXLC14, and stem cell–promoting factor IL6. In addition, we identified novel transcriptional drivers (MEF2C, TWIST1, NR1H3, RELB, and FOXM1) key to CAF heterogeneity. Furthermore, we showed that CAF subtypes were associated with different clinical outcomes and uncovered key molecular pathways that could activate or suppress cancer progression or were involved in resistance to anti-PD1 or anti–PD-L1 immunotherapy.
Conclusions:
Our study identifies the molecular characteristics of CAF subtypes shared across several cancer types, implicates cancer types that may benefit from CAF subtype targeted therapies, and identifies specific CAF subtypes associated with immunotherapy resistance.
Data from Response to Rucaparib in BRCA-Mutant Metastatic Castration-Resistant Prostate Cancer Identified by Genomic Testing in the TRITON2 Study
Authors: Loehr Andrea , Patnaik Akash , Campbell David , Shapiro Jeremy , Bryce Alan H. , McDermott Ray , Sautois Brieuc , Vogelzang Nicholas J. , Bambury Richard M. , Voog Eric , Zhang Jingsong , Piulats Josep M. , Hussain Arif , Ryan Charles J. , Merseburger Axel S. , Daugaard Gedske , Heidenreich Axel , Fizazi Karim , Higano Celestia S. , Krieger Laurence E. , Sternberg Cora N. , Watkins Simon P. , Despain Darrin , Simmons Andrew D. , Dowson Melanie , Golsorkhi Tony , Chowdhury Simon , Abida Wassim
Published: April 2023

AbstractPurpose:
The PARP inhibitor rucaparib is approved in the United States for patients with metastatic castration-resistant prostate cancer (mCRPC) and a deleterious germline and/or somatic BRCA1 or BRCA2 (BRCA) alteration. While sequencing of tumor tissue is considered the standard for identifying patients with BRCA alterations (BRCA+), plasma profiling may provide a minimally invasive option to select patients for rucaparib treatment. Here, we report clinical efficacy in patients with BRCA+ mCRPC identified through central plasma, central tissue, or local genomic testing and enrolled in TRITON2.
Patients and Methods:
Patients had progressed after next-generation androgen receptor–directed and taxane-based therapies for mCRPC and had BRCA alterations identified by central sequencing of plasma and/or tissue samples or local genomic testing. Concordance of plasma/tissue BRCA status and objective response rate and prostate-specific antigen (PSA) response rates were summarized.
Results:
TRITON2 enrolled 115 patients with BRCA+ identified by central plasma (n = 34), central tissue (n = 37), or local (n = 44) testing. Plasma/tissue concordance was determined in 38 patients with paired samples and was 47% in 19 patients with a somatic BRCA alteration. No statistically significant differences were observed between objective and PSA response rates to rucaparib across the 3 assay groups. Patients unable to provide tissue samples and tested solely by plasma assay responded at rates no different from patients identified as BRCA+ by tissue testing.
Conclusions:
Plasma, tissue, and local testing of mCRPC patients can be used to identify men with BRCA+ mCRPC who can benefit from treatment with the PARP inhibitor rucaparib.
Data from Functional Mapping of AKT Signaling and Biomarkers of Response from the FAIRLANE Trial of Neoadjuvant Ipatasertib plus Paclitaxel for Triple-Negative Breast Cancer
Authors: Shi Zhen , Wulfkuhle Julia , Nowicka Malgorzata , Gallagher Rosa I. , Saura Cristina , Nuciforo Paolo G. , Calvo Isabel , Andersen Jay , Passos-Coelho José Luis , Gil-Gil Miguel J. , Bermejo Begoña , Pratt Debra A. , Ciruelos Eva M. , Villagrasa Patricia , Wongchenko Matthew J. , Petricoin Emanuel F. , Oliveira Mafalda , Isakoff Steven J.
Published: April 2023

AbstractPurpose:
Despite extensive genomic and transcriptomic profiling, it remains unknown how signaling pathways are differentially activated and how tumors are differentially sensitized to certain perturbations. Here, we aim to characterize AKT signaling activity and its association with other genomic or IHC-based PI3K/AKT pathway biomarkers as well as the clinical activity of ipatasertib (AKT inhibitor) in the FAIRLANE trial.
Experimental Design:
In FAIRLANE, 151 patients with early triple-negative breast cancer (TNBC) were randomized 1:1 to receive paclitaxel with ipatasertib or placebo for 12 weeks prior to surgery. Adding ipatasertib did not increase pathologic complete response rate and numerically improved overall response rate by MRI. We used reverse-phase protein microarrays (RPPA) to examine the total level and/or phosphorylation states of over 100 proteins in various signaling or cell processes including PI3K/AKT and mTOR signaling. One hundred and twenty-five baseline and 127 on-treatment samples were evaluable by RPPA, with 110 paired samples at both time points.
Results:
Tumors with genomic/protein alterations in PIK3CA/AKT1/PTEN were associated with higher levels of AKT phosphorylation. In addition, phosphorylated AKT (pAKT) levels exhibited a significant association with enriched clinical benefit of ipatasertib, and identified patients who received benefit in the absence of PIK3CA/AKT1/PTEN alterations. Ipatasertib treatment led to a downregulation of AKT/mTORC1 signaling, which was more pronounced among the tumors with PIK3CA/AKT1/PTEN alterations or among the responders to the treatment.
Conclusions:
We showed that the high baseline pAKT levels are associated with the alterations of PI3K/AKT pathway components and enriched benefit of ipatasertib in TNBC.
Data from Bias Reduction through Analysis of Competing Events (BRACE) Correction to Address Cancer Treatment Selection Bias in Observational Data
Authors: Williamson Casey W. , Nelson Tyler J. , Thompson Caroline A. , Vitzthum Lucas K. , Zakeri Kaveh , Riviere Paul J. , Bryant Alex K. , Sharabi Andrew B. , Zou Jingjing , Mell Loren K.
Published: April 2023

AbstractPurpose:
Cancer treatments can paradoxically appear to reduce the risk of noncancer mortality in observational studies, due to residual confounding. Here we introduce a method, Bias Reduction through Analysis of Competing Events (BRACE), to reduce bias in the presence of residual confounding.
Experimental Design:
BRACE is a novel method for adjusting for bias from residual confounding in proportional hazards models. Using standard simulation methods, we compared BRACE with Cox proportional hazards regression in the presence of an unmeasured confounder. We examined estimator distributions, bias, mean squared error (MSE), and coverage probability. We then estimated treatment effects of high versus low intensity treatments in 36,630 prostate cancer, 4,069 lung cancer, and 7,117 head/neck cancer patients, using the Veterans Affairs database. We analyzed treatment effects on cancer-specific mortality (CSM), noncancer mortality (NCM), and overall survival (OS), using conventional multivariable Cox and propensity score (adjusted using inverse probability weighting) models, versus BRACE-adjusted estimates.
Results:
In simulations with residual confounding, BRACE uniformly reduced both bias and MSE. In the absence of bias, BRACE introduced bias toward the null, albeit with lower MSE. BRACE markedly improved coverage probability, but with a tendency toward overcorrection for effective but nontoxic treatments. For each clinical cohort, more intensive treatments were associated with significantly reduced hazards for CSM, NCM, and OS. BRACE attenuated OS estimates, yielding results more consistent with findings from randomized trials and meta-analyses.
Conclusions:
BRACE reduces bias and MSE when residual confounding is present and represents a novel approach to improve treatment effect estimation in nonrandomized studies.
Data from A Clinical PET Imaging Tracer ([18F]DASA-23) to Monitor Pyruvate Kinase M2–Induced Glycolytic Reprogramming in Glioblastoma
Authors: Beinat Corinne , Patel Chirag B. , Haywood Tom , Murty Surya , Naya Lewis , Castillo Jessa B. , Reyes Samantha T. , Phillips Megan , Buccino Pablo , Shen Bin , Park Jun Hyung , Koran Mary Ellen I. , Alam Israt S. , James Michelle L. , Holley Dawn , Halbert Kim , Gandhi Harsh , He Joy Q. , Granucci Monica , Johnson Eli , Liu Daniel Dan , Uchida Nobuko , Sinha Rahul , Chu Pauline , Born Donald E. , Warnock Geoffrey I. , Weissman Irving , Hayden-Gephart Melanie , Khalighi Mehdi , Massoud Tarik F. , Iagaru Andrei , Davidzon Guido , Thomas Reena , Nagpal Seema , Recht Lawrence D. , Gambhir Sanjiv Sam
Published: April 2023

AbstractPurpose:
Pyruvate kinase M2 (PKM2) catalyzes the final step in glycolysis, a key process of cancer metabolism. PKM2 is preferentially expressed by glioblastoma (GBM) cells with minimal expression in healthy brain. We describe the development, validation, and translation of a novel PET tracer to study PKM2 in GBM. We evaluated 1-((2-fluoro-6-[18F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([18F]DASA-23) in cell culture, mouse models of GBM, healthy human volunteers, and patients with GBM.
Experimental Design:
[18F]DASA-23 was synthesized with a molar activity of 100.47 ± 29.58 GBq/μmol and radiochemical purity >95%. We performed initial testing of [18F]DASA-23 in GBM cell culture and human GBM xenografts implanted orthotopically into mice. Next, we produced [18F]DASA-23 under FDA oversight, and evaluated it in healthy volunteers and a pilot cohort of patients with glioma.
Results:
In mouse imaging studies, [18F]DASA-23 clearly delineated the U87 GBM from surrounding healthy brain tissue and had a tumor-to-brain ratio of 3.6 ± 0.5. In human volunteers, [18F]DASA-23 crossed the intact blood–brain barrier and was rapidly cleared. In patients with GBM, [18F]DASA-23 successfully outlined tumors visible on contrast-enhanced MRI. The uptake of [18F]DASA-23 was markedly elevated in GBMs compared with normal brain, and it identified a metabolic nonresponder within 1 week of treatment initiation.
Conclusions:
We developed and translated [18F]DASA-23 as a new tracer that demonstrated the visualization of aberrantly expressed PKM2 for the first time in human subjects. These results warrant further clinical evaluation of [18F]DASA-23 to assess its utility for imaging therapy–induced normalization of aberrant cancer metabolism.
Data from DNMT3A Harboring Leukemia-Associated Mutations Directs Sensitivity to DNA Damage at Replication Forks
Authors: Venugopal Kartika , Feng Yang , Nowialis Pawel , Xu Huanzhou , Shabashvili Daniil E. , Berntsen Cassandra M. , Kaur Prabhjot , Krajcik Kathryn I. , Taragjini Christina , Zaroogian Zachary , Casellas Román Heidi L. , Posada Luisa M. , Gunaratne Chamara , Li Jianping , Dupéré-Richer Daphné , Bennett Richard L. , Pondugula Santhi , Riva Alberto , Cogle Christopher R. , Opavsky Rene , Law Brian K. , Bhaduri-McIntosh Sumita , Kubicek Stefan , Staber Philipp B. , Licht Jonathan D. , Bird Jonathan E. , Guryanova Olga A.
Published: April 2023

AbstractPurpose:
In acute myeloid leukemia (AML), recurrent DNA methyltransferase 3A (DNMT3A) mutations are associated with chemoresistance and poor prognosis, especially in advanced-age patients. Gene-expression studies in DNMT3A-mutated cells identified signatures implicated in deregulated DNA damage response and replication fork integrity, suggesting sensitivity to replication stress. Here, we tested whether pharmacologically induced replication fork stalling, such as with cytarabine, creates a therapeutic vulnerability in cells with DNMT3A(R882) mutations.
Experimental Design:
Leukemia cell lines, genetic mouse models, and isogenic cells with and without DNMT3A(mut) were used to evaluate sensitivity to nucleoside analogues such as cytarabine in vitro and in vivo, followed by analysis of DNA damage and signaling, replication restart, and cell-cycle progression on treatment and after drug removal. Transcriptome profiling identified pathways deregulated by DNMT3A(mut) expression.
Results:
We found increased sensitivity to pharmacologically induced replication stress in cells expressing DNMT3A(R882)-mutant, with persistent intra–S-phase checkpoint activation, impaired PARP1 recruitment, and elevated DNA damage, which was incompletely resolved after drug removal and carried through mitosis. Pulse-chase double-labeling experiments with EdU and BrdU after cytarabine washout demonstrated a higher rate of fork collapse in DNMT3A(mut)-expressing cells. RNA-seq studies supported deregulated cell-cycle progression and p53 activation, along with splicing, ribosome biogenesis, and metabolism.
Conclusions:
Together, our studies show that DNMT3A mutations underlie a defect in recovery from replication fork arrest with subsequent accumulation of unresolved DNA damage, which may have therapeutic tractability. These results demonstrate that, in addition to its role in epigenetic control, DNMT3A contributes to preserving genome integrity during replication stress.

See related commentary by Viny, p. 573
Data from Clinico-Genomic Characterization of Patients with Metastatic Urothelial Carcinoma in Real-World Practice Identifies a Novel Bladder Immune Performance Index (BIPI)
Authors: Szabados Bernadett , Ponz-Sarvisé Mariano , Machado Robson , Saldana Diego , Kadel Edward E. , Banchereau Romain , Bouquet Fanny , Garmhausen Marius , Powles Thomas , Schröder Carsten
Published: April 2023

AbstractPurpose:
This retrospective analysis of the largest available clinico-genomic database used de-identified patient-level electronic health record–derived real-world data (RWD) combined with FoundationOne comprehensive genomic profiling (CGP) to characterize patients with metastatic urothelial carcinoma (mUC) treated in the real-world setting, detect potential biomarkers, and develop a bladder immune performance index (BIPI).
Experimental Design:
Patients with mUC who started front-line single-agent immune checkpoint inhibitors (ICI) and an unmatched group treated with front-line platinum-based chemotherapy between January 1, 2011, and September 30, 2019, were selected. Clinical and genomic data were correlated with overall survival (OS). A novel BIPI predicting outcome with ICIs was developed using machine learning methods and validated using data from a phase II trial (NCT02951767).
Results:
In ICI-treated patients (n = 118), high tumor mutational burden (≥10 mutations/megabase) was associated with improved OS (HR, 0.58; 95% CI, 0.35–0.95; P = 0.03). In chemotherapy-treated patients (n = 268), those with high APOBEC mutational signature had worse OS (HR, 1.43; 95% CI, 1.06–1.94; P = 0.02). Neither FGFR3 mutations nor DNA damage–repair pathway alterations were associated with OS. A novel BIPI combining clinical and genomic variables (nonmetastatic at initial diagnosis, normal or above normal albumin level at baseline, prior surgery for organ-confined disease, high tumor mutational burden) identified ICI-treated patients with longest OS and was validated in an independent dataset.
Conclusions:
Contemporary RWD including FoundationOne CGP can be used to characterize outcomes in real-world patients according to biomarkers beyond PD-L1. A validated, novel clinico-genomic BIPI demonstrated satisfactory prognostic performance for OS in patients with mUC receiving front-line ICI therapy.
Data from An Autologous Dendritic Cell Vaccine Promotes Anticancer Immunity in Patients with Ovarian Cancer with Low Mutational Burden and Cold Tumors
Authors: Fucikova Jitka , Hensler Michal , Kasikova Lenka , Lanickova Tereza , Pasulka Josef , Rakova Jana , Drozenova Jana , Fredriksen Tessa , Hraska Marek , Hrnciarova Tereza , Sochorova Klara , Rozkova Daniela , Sojka Ludek , Dundr Pavel , Laco Jan , Brtnicky Tomas , Praznovec Ivan , Halaska Michael J. , Rob Lukas , Ryska Ales , Coosemans An , Vergote Ignace , Cibula David , Bartunkova Jirina , Galon Jérôme , Galluzzi Lorenzo , Spisek Radek
Published: April 2023

AbstractPurpose:
The successful implementation of immune checkpoint inhibitors (ICI) in the clinical management of various solid tumors has raised considerable expectations for patients with epithelial ovarian carcinoma (EOC). However, EOC is poorly responsive to ICIs due to immunologic features including limited tumor mutational burden (TMB) and poor lymphocytic infiltration. An autologous dendritic cell (DC)-based vaccine (DCVAC) has recently been shown to be safe and to significantly improve progression-free survival (PFS) in a randomized phase II clinical trial enrolling patients with EOC (SOV01, NCT02107937).
Patients and Methods:
We harnessed sequencing, flow cytometry, multispectral immunofluorescence microscopy, and IHC to analyze (pretreatment) tumor and (pretreatment and posttreatment) peripheral blood samples from 82 patients enrolled in SOV01, with the aim of identifying immunologic biomarkers that would improve the clinical management of patients with EOC treated with DCVAC.
Results:
Although higher-than-median TMB and abundant CD8+ T-cell infiltration were associated with superior clinical benefits in patients with EOC receiving standard-of-care chemotherapy, the same did not hold true in women receiving DCVAC. Conversely, superior clinical responses to DCVAC were observed in patients with lower-than-median TMB and scarce CD8+ T-cell infiltration. Such responses were accompanied by signs of improved effector functions and tumor-specific cytotoxicity in the peripheral blood.
Conclusions:
Our findings suggest that while patients with highly infiltrated, “hot” EOCs benefit from chemotherapy, women with “cold” EOCs may instead require DC-based vaccination to jumpstart clinically relevant anticancer immune responses.
Data from Rapid Screening Using Pathomorphologic Interpretation to Detect BRAFV600E Mutation and Microsatellite Instability in Colorectal Cancer
Authors: Fujii Satoshi , Kotani Daisuke , Hattori Masahiro , Nishihara Masato , Shikanai Toshihide , Hashimoto Junji , Hama Yuki , Nishino Takuya , Suzuki Mizuto , Yoshidumi Ayatoshi , Ueno Makoto , Komatsu Yoshito , Masuishi Toshiki , Hara Hiroki , Esaki Taito , Nakamura Yoshiaki , Bando Hideaki , Yamada Tomoyuki , Yoshino Takayuki
Published: April 2023

AbstractPurpose:
Rapid decision-making is essential in precision medicine for initiating molecular targeted therapy for patients with cancer. This study aimed to extract pathomorphologic features that enable the accurate prediction of genetic abnormalities in cancer from hematoxylin and eosin images using deep learning (DL).
Experimental Design:
A total of 1,657 images (one representative image per patient) of thin formalin-fixed, paraffin-embedded tissue sections from either primary or metastatic tumors with next-generation sequencing–confirmed genetic abnormalities—including BRAFV600E and KRAS mutations, and microsatellite instability high (MSI-H)—that are directly relevant to therapeutic strategies for advanced colorectal cancer were obtained from the nationwide SCRUM-Japan GI-SCREEN project. The images were divided into three groups of 986, 248, and 423 images to create one training and two validation cohorts, respectively. Pathomorphologic feature-prediction DL models were first developed on the basis of pathomorphologic features. Subsequently, gene-prediction DL models were constructed for all possible combinations of pathomorphologic features that enabled the prediction of gene abnormalities based on images filtered by the combination of pathomorphologic feature-prediction models.
Results:
High accuracies were achieved, with AUCs > 0.90 and 0.80 for 12 and 27, respectively, of 33 analyzed pathomorphologic features, with high AUCs being yielded for both BRAFV600E (0.851 and 0.859) and MSI-H (0.923 and 0.862).
Conclusions:
These findings show that novel next-generation pathology methods can predict genetic abnormalities without the need for standard-of-care gene tests, and this novel next-generation pathology method can be applied for colorectal cancer treatment planning in the near future.
Data from Phase I Clinical Trial of DNA Methyltransferase Inhibitor Decitabine and PARP Inhibitor Talazoparib Combination Therapy in Relapsed/Refractory Acute Myeloid Leukemia
Authors: Baer Maria R. , Kogan Aksinija A. , Bentzen Søren M. , Mi Tian , Lapidus Rena G. , Duong Vu H. , Emadi Ashkan , Niyongere Sandrine , O'Connell Casey L. , Youngblood Benjamin A. , Baylin Stephen B. , Rassool Feyruz V.
Published: April 2023

AbstractPurpose:
Patients with acute myeloid leukemia (AML) unfit for, or resistant to, intensive chemotherapy are often treated with DNA methyltransferase inhibitors (DNMTi). Novel combinations may increase efficacy. In addition to demethylating CpG island gene promoter regions, DNMTis enhance PARP1 recruitment and tight binding to chromatin, preventing PARP-mediated DNA repair, downregulating homologous recombination (HR) DNA repair, and sensitizing cells to PARP inhibitor (PARPi). We previously demonstrated DNMTi and PARPi combination efficacy in AML in vitro and in vivo. Here, we report a phase I clinical trial combining the DNMTi decitabine and the PARPi talazoparib in relapsed/refractory AML.
Patients and Methods:
Decitabine and talazoparib doses were escalated using a 3 + 3 design. Pharmacodynamic studies were performed on cycle 1 days 1 (pretreatment), 5 and 8 blood blasts.
Results:
Doses were escalated in seven cohorts [25 patients, including 22 previously treated with DNMTi(s)] to a recommended phase II dose combination of decitabine 20 mg/m2 intravenously daily for 5 or 10 days and talazoparib 1 mg orally daily for 28 days, in 28-day cycles. Grade 3–5 events included fever in 19 patients and lung infections in 15, attributed to AML. Responses included complete remission with incomplete count recovery in two patients (8%) and hematologic improvement in three. Pharmacodynamic studies showed the expected DNA demethylation, increased PARP trapping in chromatin, increased γH2AX foci, and decreased HR activity in responders. γH2AX foci increased significantly with increasing talazoparib doses combined with 20 mg/m2 decitabine.
Conclusions:
Decitabine/talazoparib combination was well tolerated. Expected pharmacodynamic effects occurred, especially in responders.
Data from Multiphoton Phosphorescence Quenching Microscopy Reveals Kinetics of Tumor Oxygenation during Antiangiogenesis and Angiotensin Signaling Inhibition
Authors: Martin John D. , Lanning Ryan M. , Chauhan Vikash P. , Martin Margaret R. , Mousa Ahmed S. , Kamoun Walid S. , Han Hee-Sun , Lee Hang , Stylianopoulos Triantafyllos , Bawendi Moungi G. , Duda Dan G. , Brown Edward B. , Padera Timothy P. , Fukumura Dai , Jain Rakesh K.
Published: April 2023

AbstractPurpose:
The abnormal function of tumor blood vessels causes tissue hypoxia, promoting disease progression and treatment resistance. Although tumor microenvironment normalization strategies can alleviate hypoxia globally, how local oxygen levels change is not known because of the inability to longitudinally assess vascular and interstitial oxygen in tumors with sufficient resolution. Understanding the spatial and temporal heterogeneity should help improve the outcome of various normalization strategies.
Experimental Design:
We developed a multiphoton phosphorescence quenching microscopy system using a low-molecular-weight palladium porphyrin probe to measure perfused vessels, oxygen tension, and their spatial correlations in vivo in mouse skin, bone marrow, and four different tumor models. Further, we measured the temporal and spatial changes in oxygen and vessel perfusion in tumors in response to an anti-VEGFR2 antibody (DC101) and an angiotensin-receptor blocker (losartan).
Results:
We found that vessel function was highly dependent on tumor type. Although some tumors had vessels with greater oxygen-carrying ability than those of normal skin, most tumors had inefficient vessels. Further, intervessel heterogeneity in tumors is associated with heterogeneous response to DC101 and losartan. Using both vascular and stromal normalizing agents, we show that spatial heterogeneity in oxygen levels persists, even with reductions in mean extravascular hypoxia.
Conclusions:
High-resolution spatial and temporal responses of tumor vessels to two agents known to improve vascular perfusion globally reveal spatially heterogeneous changes in vessel structure and function. These dynamic vascular changes should be considered in optimizing the dose and schedule of vascular and stromal normalizing strategies to improve the therapeutic outcome.
Data from Immunostimulatory Cancer-Associated Fibroblast Subpopulations Can Predict Immunotherapy Response in Head and Neck Cancer
Authors: Obradovic Aleksandar , Graves Diana , Korrer Michael , Wang Yu , Roy Sohini , Naveed Abdullah , Xu Yaomin , Luginbuhl Adam , Curry Joseph , Gibson Michael , Idrees Kamran , Hurley Paula , Jiang Peng , Liu X. Shirley , Uppaluri Ravindra , Drake Charles G. , Califano Andrea , Kim Young J.
Published: April 2023

AbstractPurpose:
Cancer-associated fibroblasts (CAF) have been implicated as potential mediators of checkpoint immunotherapy response. However, the extensive heterogeneity of these cells has precluded rigorous understanding of their immunoregulatory role in the tumor microenvironment.
Experimental Design:
We performed high-dimensional single-cell RNA sequencing (scRNA-seq) on four patient tumors pretreatment and posttreatment from a neoadjuvant trial of patients with advanced-stage head and neck squamous cell carcinoma that were treated with the αPD-1 therapy, nivolumab. The head and neck CAF (HNCAF) protein activity profiles, derived from this cohort of paired scRNA-seq, were used to perform protein activity enrichment analysis on the 28-patient parental cohort of clinically annotated bulk transcriptomic profiles. Ex vivo coculture assays were used to test functional relevance of HNCAF subtypes.
Results:
Fourteen distinct cell types were identified with the fibroblast population showing significant changes in abundance following nivolumab treatment. Among the fibroblast subtypes, HNCAF-0/3 emerged as predictive of nivolumab response, while HNCAF-1 was associated with immunosuppression. Functionally, HNCAF-0/3 were found to reduce TGFβ-dependent PD-1+TIM-3+ exhaustion of CD8 T cells, increase CD103+NKG2A+ resident memory phenotypes, and enhance the overall cytolytic profile of T cells.
Conclusions:
Our findings demonstrate the functional importance of distinct HNCAF subsets in modulating the immunoregulatory milieu of human HNSCC. In addition, we have identified clinically actionable HNCAF subtypes that can be used as a biomarker of response and resistance in future clinical trials.
Data from A Machine Learning Model Based on Tumor and Immune Biomarkers to Predict Undetectable MRD and Survival Outcomes in Multiple Myeloma
Authors: Guerrero Camila , Puig Noemi , Cedena Maria-Teresa , Goicoechea Ibai , Perez Cristina , Garcés Juan-José , Botta Cirino , Calasanz Maria-Jose , Gutierrez Norma C. , Martin-Ramos Maria-Luisa , Oriol Albert , Rios Rafael , Hernandez Miguel-Teodoro , Martinez-Martinez Rafael , Bargay Joan , de Arriba Felipe , Palomera Luis , Gonzalez-Rodriguez Ana Pilar , Mosquera-Orgueira Adrian , Gonzalez-Perez Marta-Sonia , Martinez-Lopez Joaquin , Lahuerta Juan-José , Rosiñol Laura , Blade Joan , Mateos Maria-Victoria , San-Miguel Jesus F. , Paiva Bruno
Published: April 2023

AbstractPurpose:
Undetectable measurable residual disease (MRD) is a surrogate of prolonged survival in multiple myeloma. Thus, treatment individualization based on the probability of a patient achieving undetectable MRD with a singular regimen could represent a new concept toward personalized treatment, with fast assessment of its success. This has never been investigated; therefore, we sought to define a machine learning model to predict undetectable MRD at the onset of multiple myeloma.
Experimental Design:
This study included 487 newly diagnosed patients with multiple myeloma. The training (n = 152) and internal validation cohorts (n = 149) consisted of 301 transplant-eligible patients with active multiple myeloma enrolled in the GEM2012MENOS65 trial. Two external validation cohorts were defined by 76 high-risk transplant-eligible patients with smoldering multiple myeloma enrolled in the Grupo Español de Mieloma(GEM)-CESAR trial, and 110 transplant-ineligible elderly patients enrolled in the GEM-CLARIDEX trial.
Results:
The most effective model to predict MRD status resulted from integrating cytogenetic [t(4;14) and/or del(17p13)], tumor burden (bone marrow plasma cell clonality and circulating tumor cells), and immune-related biomarkers. Accurate predictions of MRD outcomes were achieved in 71% of cases in the GEM2012MENOS65 trial (n = 214/301) and 72% in the external validation cohorts (n = 134/186). The model also predicted sustained MRD negativity from consolidation onto 2 years maintenance (GEM2014MAIN). High-confidence prediction of undetectable MRD at diagnosis identified a subgroup of patients with active multiple myeloma with 80% and 93% progression-free and overall survival rates at 5 years.
Conclusions:
It is possible to accurately predict MRD outcomes using an integrative, weighted model defined by machine learning algorithms. This is a new concept toward individualized treatment in multiple myeloma.

See related commentary by Pawlyn and Davies, p. 2482
Data from Health-Related Quality of Life Outcomes in Patients with Resected Epidermal Growth Factor Receptor–Mutated Non–Small Cell Lung Cancer Who Received Adjuvant Osimertinib in the Phase III ADAURA Trial
Authors: Majem Margarita , Goldman Jonathan W. , John Thomas , Grohe Christian , Laktionov Konstantin , Kim Sang-We , Kato Terufumi , Vu Huu Vinh , Lu Shun , Li Shanqing , Lee Kye Young , Akewanlop Charuwan , Yu Chong-Jen , de Marinis Filippo , Bonanno Laura , Domine Manuel , Shepherd Frances A. , Atagi Shinji , Zeng Lingmin , Kulkarni Dakshayini , Medic Nenad , Tsuboi Masahiro , Herbst Roy S. , Wu Yi-Long
Published: April 2023

AbstractPurpose:
In the phase III ADAURA trial, adjuvant treatment with osimertinib versus placebo, with/without prior adjuvant chemotherapy, resulted in a statistically significant and clinically meaningful disease-free survival benefit in completely resected stage IB–IIIA EGFR-mutated (EGFRm) non–small cell lung cancer (NSCLC). We report health-related quality of life (HRQoL) outcomes from ADAURA.
Patients and Methods:
Patients randomized 1:1 received oral osimertinib 80 mg or placebo for 3 years or until recurrence/discontinuation. HRQoL (secondary endpoint) was measured using the Short Form-36 (SF-36) health survey at baseline, 12, and 24 weeks, then every 24 weeks until recurrence or treatment completion/discontinuation. Exploratory analyses of SF-36 score changes from baseline until week 96 and time to deterioration (TTD) were performed in the overall population (stage IB–IIIA; N = 682). Clinically meaningful changes were defined using the SF-36 manual.
Results:
Baseline physical/mental component summary (PCS/MCS) scores were comparable between osimertinib and placebo (range, 46–47) and maintained to Week 96, with no clinically meaningful differences between arms; difference in adjusted least squares (LS) mean [95% confidence intervals (CI), −1.18 (−2.02 to −0.34) and −1.34 (−2.40 to −0.28), for PCS and MCS, respectively. There were no differences between arms for TTD of PCS and MCS; HR, 1.17 (95% CI, 0.82–1.67) and HR, 0.98 (95% CI, 0.70–1.39), respectively.
Conclusions:
HRQoL was maintained with adjuvant osimertinib in patients with stage IB–IIIA EGFRm NSCLC, who were disease-free after complete resection, with no clinically meaningful differences versus placebo, further supporting adjuvant osimertinib as a new treatment in this setting.

See related commentary by Patil and Bunn, p. 2204
Data from Long-term Follow-up and Patterns of Response, Progression, and Hyperprogression in Patients after PD-1 Blockade in Advanced Sarcoma
Authors: Klemen Nicholas D. , Hwang Sinchun , Bradic Martina , Rosenbaum Evan , Dickson Mark A. , Gounder Mrinal M. , Kelly Ciara M. , Keohan Mary L. , Movva Sujana , Thornton Katherine A. , Chi Ping , Nacev Benjamin A. , Chan Jason E. , Bartlett Edmund K. , Richards Allison L. , Singer Samuel , Donoghue Mark T.A. , Tap William D. , D'Angelo Sandra P.
Published: April 2023

AbstractPurpose:
Programmed cell death protein 1 (PD-1) blockade can mediate objective responses in advanced sarcomas, but their durability has not been established and it is unclear if hyperprogressive disease (HPD) occurs in sarcomas treated with PD-1 inhibitors.
Experimental Design:
We pooled patients who were treated prospectively with nivolumab or pembrolizumab as monotherapy or with bempegaldesleukin, epacadostat, ipilimumab, or talimogene laherparepvec. We did a new independent assessment for HPD and analyzed clinical, pathologic, and genomic data from baseline tumor biopsies. Our primary endpoint was the incidence of HPD; secondary endpoints were clinical or genomic correlates of response or HPD.
Results:
We treated 134 patients with advanced sarcoma from 2015 to 2019. Twenty-one patients (16%) had a complete or partial response (CR/PR), and 30% of responses were durable for over 2 years. Forty-eight (36%) patients had stable disease (SD), 45 (34%) had progressive disease without HPD (PD), and 15 (11%) had HPD. Five patients (4%) were not evaluable for HPD. The sarcoma subtypes, sites of metastasis, clinical course, and genomic alterations in patients with PD and HPD were similar, except HPD tumors were smaller at baseline.
Conclusions:
In patients with advanced sarcoma, PD-1 blockade can mediate durable responses. HPD occurs in sarcoma at an incidence that is similar to what has been reported in other solid tumors, but patients with HPD were clinically and biologically similar to those who had PD. Further research is required to establish whether HPD is a biologically distinct phenomenon and whether a theoretical risk of HPD should influence patient management.
Data from Neoadjuvant Therapy Induces a Potent Immune Response to Sarcoma, Dominated by Myeloid and B Cells
Authors: Goff Peter H. , Riolobos Laura , LaFleur Bonnie J. , Spraker Matthew B. , Seo Y. David , Smythe Kimberly S. , Campbell Jean S. , Pierce Robert H. , Zhang Yuzheng , He Qianchuan , Kim Edward Y. , Schaub Stephanie K. , Kane Gabrielle M. , Mantilla Jose G. , Chen Eleanor Y. , Ricciotti Robert , Thompson Matthew J. , Cranmer Lee D. , Wagner Michael J. , Loggers Elizabeth T. , Jones Robin L. , Murphy Erin , Blumenschein Wendy M. , McClanahan Terrill K. , Earls Jon , Flanagan Kevin C. , LaFranzo Natalie A. , Kim Teresa S. , Pollack Seth M.
Published: April 2023

AbstractPurpose:
To characterize changes in the soft-tissue sarcoma (STS) tumor immune microenvironment induced by standard neoadjuvant therapy with the goal of informing neoadjuvant immunotherapy trial design.
Experimental Design:
Paired pre- and postneoadjuvant therapy specimens were retrospectively identified for 32 patients with STSs and analyzed by three modalities: multiplexed IHC, NanoString, and RNA sequencing with ImmunoPrism analysis.
Results:
All 32 patients, representing a variety of STS histologic subtypes, received neoadjuvant radiotherapy and 21 (66%) received chemotherapy prior to radiotherapy. The most prevalent immune cells in the tumor before neoadjuvant therapy were myeloid cells (45% of all immune cells) and B cells (37%), with T (13%) and natural killer (NK) cells (5%) also present. Neoadjuvant therapy significantly increased the total immune cells infiltrating the tumors across all histologic subtypes for patients receiving neoadjuvant radiotherapy with or without chemotherapy. An increase in the percentage of monocytes and macrophages, particularly M2 macrophages, B cells, and CD4+ T cells was observed postneoadjuvant therapy. Upregulation of genes and cytokines associated with antigen presentation was also observed, and a favorable pathologic response (≥90% necrosis postneoadjuvant therapy) was associated with an increase in monocytic infiltrate. Upregulation of the T-cell checkpoint TIM3 and downregulation of OX40 were observed posttreatment.
Conclusions:
Standard neoadjuvant therapy induces both immunostimulatory and immunosuppressive effects within a complex sarcoma microenvironment dominated by myeloid and B cells. This work informs ongoing efforts to incorporate immune checkpoint inhibitors and novel immunotherapies into the neoadjuvant setting for STSs.
Data from Breakthrough Therapy Designation Criteria Identify Drugs that Improve Clinical Outcomes for Patients: A Case for More Streamlined Coverage of Promising Therapies
Authors: Collins Grace , Stewart Mark , McKelvey Brittany , Stires Hillary , Allen Jeff
Published: April 2023

Abstract
The breakthrough therapy designation (BTD) process was created to expedite clinical development timelines for drugs intended to treat serious conditions and preliminary clinical evidence indicates the drug may demonstrate substantial improvement over existing therapies. This analysis demonstrates that BTD is a valuable tool for expediting approval of promising therapies in oncology. By comparing drugs indicated to treat non–small cell lung cancer (NSCLC) approved with BTD or without BTD between January 2013 and October 2021, BTD drugs reduced the risk of death by a median of 31% and progression by a median of 48%, while drugs never receiving BTD reduced the risk of death and progression by a median of 15% and 41.9%, respectively. These findings show that BTD criteria accurately identify drugs that improve long-term outcomes for patients with cancer and warrant coordinated efforts to ensure timely coverage decisions and access for patients.