bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from A Randomized Phase II Study Comparing Nivolumab with Carboplatin–Pemetrexed for EGFR-Mutated NSCLC with Resistance to EGFR Tyrosine Kinase Inhibitors (WJOG8515L)
Authors: Hayashi Hidetoshi , Sugawara Shunichi , Fukuda Yasushi , Fujimoto Daichi , Miura Satoru , Ota Keiichi , Ozawa Yuichi , Hara Satoshi , Tanizaki Junko , Azuma Koichi , Omori Shota , Tachihara Motoko , Nishino Kazumi , Bessho Akihiro , Chiba Yasutaka , Haratani Koji , Sakai Kazuko , Nishio Kazuto , Yamamoto Nobuyuki , Nakagawa Kazuhiko
Published: April 2023

AbstractPurpose:
Although the efficacy of programmed cell death–1 (PD-1) blockade is generally poor for non–small cell lung cancer (NSCLC) with activating mutations of the epidermal growth factor receptor (EGFR) gene, EGFR tyrosine kinase inhibitors (TKIs) may improve the tumor immune microenvironment. We performed a randomized study to assess whether nivolumab improves outcome compared with chemotherapy in such patients previously treated with EGFR-TKIs.
Patients and Methods:
Patients with EGFR-mutated NSCLC who acquired EGFR-TKI resistance not due to a secondary T790M mutation of EGFR were randomized 1:1 to nivolumab (n = 52) or carboplatin–pemetrexed (n = 50). The primary endpoint was progression-free survival (PFS).
Results:
Median PFS and 1-year PFS probability were 1.7 months and 9.6% for nivolumab versus 5.6 months and 14.0% for carboplatin–pemetrexed [log-rank P < 001; hazard ratio (HR) of 1.92, with a 60% confidence interval (CI) of 1.61–2.29]. Overall survival was 20.7 and 19.9 months [HR, 0.88 (95% CI, 0.53–1.47)], and response rate was 9.6% and 36.0% for nivolumab and carboplatin–pemetrexed, respectively. No subgroup including patients with a high tumor mutation burden showed a substantially longer PFS with nivolumab than with carboplatin-pemetrexed. The T-cell–inflamed gene expression profile score (0.11 vs. −0.17, P = 0.036) and expression of genes related to cytotoxic T lymphocytes or their recruitment were higher in tumors that showed a benefit from nivolumab.
Conclusions:
Nivolumab did not confer a longer PFS compared with carboplatin-pemetrexed in the study patients. Gene expression profiling identified some cases with a favorable tumor immune microenvironment that was associated with nivolumab efficacy.
Data from Persistence of ctDNA in Patients with Breast Cancer During Neoadjuvant Treatment Is a Significant Predictor of Poor Tumor Response
Authors: Zhou Qing , Gampenrieder Simon P. , Frantal Sophie , Rinnerthaler Gabriel , Singer Christian F. , Egle Daniel , Pfeiler Georg , Bartsch Rupert , Wette Viktor , Pichler Angelika , Petru Edgar , Dubsky Peter C. , Bago-Horvath Zsuzsanna , Fesl Christian , Rudas Margaretha , Ståhlberg Anders , Graf Ricarda , Weber Sabrina , Dandachi Nadia , Filipits Martin , Gnant Michael , Balic Marija , Heitzer Ellen
Published: April 2023

AbstractPurpose:
Accurate response assessment during neoadjuvant systemic treatment (NST) poses a clinical challenge. Therefore, a minimally invasive assessment of tumor response based on cell-free circulating tumor DNA (ctDNA) may be beneficial to guide treatment decisions.
Experimental Design:
We profiled 93 genes in tissue from 193 patients with early breast cancer. Patient-specific assays were designed for 145 patients to track ctDNA during NST in plasma. ctDNA presence and levels were correlated with complete pathological response (pCR) and residual cancer burden (RCB) as well as clinicopathologic characteristics of the tumor to identify potential proxies for ctDNA release.
Results:
At baseline, ctDNA could be detected in 63/145 (43.4%) patients and persisted in 25/63 (39.7%) patients at mid-therapy (MT) and 15/63 (23.8%) patients at the end of treatment. ctDNA detection at MT was significantly associated with higher RCB (OR = 0.062; 95% CI, 0.01–0.48; P = 0.0077). Of 31 patients with detectable ctDNA at MT, 30 patients (96.8%) were nonresponders (RCB II, n = 8; RCB III, n = 22) and only one patient responded to the treatment (RCB I). Considering all 145 patients with baseline (BL) plasma, none of the patients with RCB 0 and only 6.7% of patients with RCB I had ctDNA detectable at MT, whereas 30.6% and 29.6% of patients with RCB II/III, respectively, had a positive ctDNA result.
Conclusions:
Overall, our results demonstrate that the detection and persistence of ctDNA at MT may have the potential to negatively predict response to neoadjuvant treatment and identify patients who will not achieve pCR or be classified with RCB II/III.
Data from A Phase Ib/II Study of Sabizabulin, a Novel Oral Cytoskeleton Disruptor, in Men with Metastatic Castration-resistant Prostate Cancer with Progression on an Androgen Receptor–targeting Agent
Authors: Markowski Mark C. , Tutrone Ronald , Pieczonka Christopher , Barnette K. Gary , Getzenberg Robert H. , Rodriguez Domingo , Steiner Mitchell S. , Saltzstein Daniel R. , Eisenberger Mario A. , Antonarakis Emmanuel S.
Published: April 2023

AbstractPurpose:
Sabizabulin, an oral cytoskeleton disruptor, was tested in a phase Ib/II clinical study in men with metastatic castration-resistant prostate cancer (mCRPC).
Patients and Methods:
The phase Ib portion utilized a 3+3 design with escalating daily oral doses of 4.5–81 mg and increasing schedule in 39 patients with mCRPC treated with one or more androgen receptor–targeting agents. Prior taxane chemotherapy was allowed. The phase II portion tested a daily dose of 63 mg in 41 patients with no prior chemotherapy. Efficacy was assessed using PCWG3 and RECIST 1.1 criteria.
Results:
The MTD was not defined in the phase Ib and the recommended phase II dose was set at 63 mg/day. The most common adverse events (>10% frequency) at the 63 mg oral daily dosing (combined phase Ib/II data) were predominantly grade 1–2 events. Grade ≥3 events included diarrhea (7.4%), fatigue (5.6%), and alanine aminotransferase/aspartate aminotransferase elevations (5.6% and 3.7%, respectively). Neurotoxicity and neutropenia were not observed. Preliminary efficacy data in patients treated with ≥1 continuous cycle of 63 mg or higher included objective response rate in 6 of 29 (20.7%) patients with measurable disease (1 complete, 5 partial) and 14 of 48 (29.2%) patients had PSA declines. The Kaplan–Meier median radiographic progression-free survival was estimated to be 11.4 months (n = 55). Durable responses lasting >2.75 years were observed.
Conclusions:
This clinical trial demonstrated that chronic oral daily dosing of sabizabulin has a favorable safety profile with preliminary antitumor activity. These data support the ongoing phase III VERACITY trial of sabizabulin in men with mCRPC.
Data from Phase Ib Study of the BET Inhibitor GS-5829 as Monotherapy and Combined with Enzalutamide in Patients with Metastatic Castration-Resistant Prostate Cancer
Authors: Aggarwal Rahul , Starodub Alexander N. , Koh Brian D. , Xing Guan , Armstrong Andrew J. , Carducci Michael A.
Published: April 2023

AbstractPurpose:
A phase Ib study (1604) was conducted to evaluate the safety and efficacy of GS-5829, an oral bromodomain and extraterminal inhibitor, alone and in combination with enzalutamide in metastatic castration-resistant prostate cancer (mCRPC). A phase I study (1599) in solid tumors/lymphoma was also conducted.
Patients and Methods:
Men with confirmed mCRPC and disease progression despite abiraterone and/or enzalutamide treatment were enrolled in a 3 + 3 dose escalation paradigm starting at 2 mg daily with GS-5829 alone and in combination with 160 mg daily enzalutamide. The primary efficacy endpoint was nonprogression rate at week 24; secondary endpoints included prostate-specific antigen reduction from baseline, progression-free survival, and GS-5829 pharmacokinetics (PK). PK and safety were also evaluated in Study 1599.
Results:
Thirty-one men, with a median of five prior regimens, received at least 1 dose of study drug in Study 1604. Treatment-emergent adverse events (TEAE) were reported in 94% of patients; 16% discontinued for TEAEs. There were no dose-dependent increases in the AUCtau or Cmax after once-daily administration of GS-5829 2 to 9 mg, and biomarkers CCR2 inhibition and HEXIM1 induction were increased only at higher doses of monotherapy. A high degree of interpatient variability existed across all doses in PK and pharmacodynamic parameters. The proportion with nonprogression at week 24, estimated by Kaplan–Meier model, was 25% (95% confidence interval, 10–42) for all treated patients.
Conclusions:
GS-5829 was generally tolerated but demonstrated limited efficacy and lack of dose proportional increases in plasma concentrations in patients with mCRPC.
Data from Detecting Neuroendocrine Prostate Cancer Through Tissue-Informed Cell-Free DNA Methylation Analysis
Authors: Berchuck Jacob E. , Baca Sylvan C. , McClure Heather M. , Korthauer Keegan , Tsai Harrison K. , Nuzzo Pier Vitale , Kelleher Kaitlin M. , He Monica , Steinharter John A. , Zacharia Soumya , Spisak Sandor , Seo Ji-Heui , Conteduca Vincenza , Elemento Olivier , Auh Joonghoon , Sigouros Michael , Corey Eva , Hirsch Michelle S. , Taplin Mary-Ellen , Choueiri Toni K. , Pomerantz Mark M. , Beltran Himisha , Freedman Matthew L.
Published: April 2023

AbstractPurpose:
Neuroendocrine prostate cancer (NEPC) is a resistance phenotype that emerges in men with metastatic castration-resistant prostate adenocarcinoma (CR-PRAD) and has important clinical implications, but is challenging to detect in practice. Herein, we report a novel tissue–informed epigenetic approach to noninvasively detect NEPC.
Experimental Design:
We first performed methylated immunoprecipitation and high-throughput sequencing (MeDIP-seq) on a training set of tumors, identified differentially methylated regions between NEPC and CR-PRAD, and built a model to predict the presence of NEPC (termed NEPC Risk Score). We then performed MeDIP-seq on cell-free DNA (cfDNA) from two independent cohorts of men with NEPC or CR-PRAD and assessed the accuracy of the model to predict the presence NEPC.
Results:
The test cohort comprised cfDNA samples from 48 men, 9 with NEPC and 39 with CR-PRAD. NEPC Risk Scores were significantly higher in men with NEPC than CR-PRAD (P = 4.3 × 10–7) and discriminated between NEPC and CR-PRAD with high accuracy (AUROC 0.96). The optimal NEPC Risk Score cutoff demonstrated 100% sensitivity and 90% specificity for detecting NEPC. The independent, multi-institutional validation cohort included cfDNA from 53 men, including 12 with NEPC and 41 with CR-PRAD. NEPC Risk Scores were significantly higher in men with NEPC than CR-PRAD (P = 7.5×10–12) and perfectly discriminated NEPC from CR-PRAD (AUROC 1.0). Applying the predefined NEPC Risk Score cutoff to the validation cohort resulted in 100% sensitivity and 95% specificity for detecting NEPC.
Conclusions:
Tissue-informed cfDNA methylation analysis is a promising approach for noninvasive detection of NEPC in men with advanced prostate cancer.
Data from Nivolumab Retreatment in Non–Small Cell Lung Cancer Patients Who Responded to Prior Immune Checkpoint Inhibitors and Had ICI-Free Intervals (WJOG9616L)
Authors: Akamatsu Hiroaki , Teraoka Shunsuke , Takamori Shinkichi , Miura Satoru , Hayashi Hidetoshi , Hata Akito , Toi Yukihiro , Shiraishi Yoshimasa , Mamesaya Nobuaki , Sato Yuki , Furuya Naoki , Oyanagi Jun , Koh Yasuhiro , Misumi Toshihiro , Yamamoto Nobuyuki , Nakagawa Kazuhiko
Published: April 2023

AbstractPurpose:
To explore the efficacy of retreatment with immune checkpoint inhibitors (ICI) in patients with advanced non–small cell lung cancer (NSCLC) who responded to prior ICI and had adequate ICI-free interval.
Patients and Methods:
Patients with advanced NSCLC who had achieved complete response (CR), partial response (PR), or stable disease for ≥6 months with prior ICI therapy preceding progression were prospectively enrolled. All patients should have had ICI-free interval ≥60 days before registration. Patients were treated with nivolumab (240 mg) every 2 weeks until progression. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival, and safety (Trial Identifier, UMIN000028561).
Results:
Sixty-one patients were enrolled during October 2017 to February 2020, with 59 analyzed for efficacy. Regarding prior ICI, 41 patients had CR or PR. Median treatment on ICI and median ICI-free intervals were 8.1 months and 9.2 months, respectively. Twenty patients experienced immune-related adverse events (irAE) that required discontinuation of prior ICI. Nivolumab retreatment demonstrated ORR of 8.5% [95% confidence interval (CI), 2.8–18.7%] and median PFS of 2.6 months (95% CI, 1.6–2.8 months) while 5 responders had 11.1 months of median PFS. In the multivariate analysis, ICI-free interval was the only predictive factor of PFS (HR, 2.02; P = 0.02), while prior efficacy or history of irAE was not. Common adverse events were skin disorders (23%), malaise (20%), and hypoalbuminemia (15%).
Conclusions:
Even in patients who initially responded to prior ICI and had ICI-free interval, once resistance occurred, retreatment with nivolumab had limited efficacy.
Data from Osimertinib plus Selumetinib in EGFR-Mutated Non–Small Cell Lung Cancer After Progression on EGFR-TKIs: A Phase Ib, Open-Label, Multicenter Trial (TATTON Part B)
Authors: Yang James Chih-Hsin , Ohe Yuichiro , Chiu Chao-Hua , Ou Xiaoling , Cantarini Mireille , Jänne Pasi A. , Hartmaier Ryan J. , Ahn Myung Ju
Published: April 2023

AbstractPurpose:
MEK/ERK inhibition can overcome acquired resistance to osimertinib in preclinical models. Osimertinib [EGFR–tyrosine kinase inhibitor (TKI)] plus selumetinib (MEK1/2 inhibitor) was assessed in the global TATTON study.
Patients and Methods:
This multicenter, open-label, phase Ib study expansion cohort enrolled patients (aged ≥18 years) with MET-negative, EGFRm advanced NSCLC who had progressed on EGFR-TKIs. Patients were assigned to one of two cohorts by prior first- or second-generation or T790M-directed EGFR-TKI and received osimertinib 80 mg every day and intermittent selumetinib 75 mg twice a day orally. Safety and tolerability (primary objective) and antitumor activity determined by objective response rate (ORR), and progression-free survival (PFS) using RECIST v1.1 were assessed. Data cutoff: March 4, 2020.
Results:
Forty-seven patients received treatment (prior first- or second-generation EGFR-TKI, n = 12; prior T790M-directed EGFR-TKI, n = 35). Forty-four (94%) patients were Asian; 30 (64%) had baseline exon 19 deletion. Most common AEs were diarrhea (89%), decreased appetite (40%), and stomatitis (32%); 11/47 patients (23%) had an AE Grade ≥3 possibly causally selumetinib-related. ORR was 66.7% [95% confidence interval (CI), 34.9–90.1] in the prior first- or second-generation EGFR-TKI group, 22.9% (95% CI, 10.4–40.1) in the prior T790M-directed EGFR-TKI group, and 34.0% (95% CI, 20.9–49.3) overall; median PFS was 15.0 (95% CI, 2.7–33.0), 2.8 (95% CI, 1.6–5.5), and 4.2 months (95% CI, 2.7–7.2), respectively.
Conclusions:
In this small study, AEs and tolerability of osimertinib plus selumetinib were as expected, on the basis of previous studies. The combination demonstrated antitumor activity supportive of further investigation in patients with MET-negative, EGFRm advanced NSCLC who had progressed on a previous EGFR-TKI.
Data from A Mesenchymal Tumor Cell State Confers Increased Dependency on the BCL-XL Antiapoptotic Protein in Kidney Cancer
Authors: Grubb Treg , Maganti Smruthi , Krill-Burger John Michael , Fraser Cameron , Stransky Laura , Radivoyevitch Tomas , Sarosiek Kristopher A. , Vazquez Francisca , Kaelin William G. , Chakraborty Abhishek A.
Published: April 2023

AbstractPurpose:
Advanced/metastatic forms of clear-cell renal cell carcinomas (ccRCC) have limited therapeutic options. Genome-wide genetic screens have identified cellular dependencies in many cancers. Using the Broad Institute/Novartis combined short hairpin RNA (shRNA) dataset, and cross-validation with the CRISPR/Cas9 DepMap (21Q3) dataset, we sought therapeutically actionable dependencies in kidney lineage cancers.
Experimental Design:
We identified preferential genetic dependencies in kidney cancer cells versus other lineages. BCL2L1, which encodes the BCL-XL antiapoptotic protein, scored as the top actionable dependency. We validated this finding using genetic and pharmacologic tools in a panel of ccRCC cell lines. Select BCL-XL–dependent (versus independent) cell lines were then transcriptionally profiled to identify biomarkers and mechanistic drivers of BCL-XL dependence. Cell-based studies (in vitro and in vivo) and clinical validations were used to address physiologic relevance.
Results:
Inactivation of BCL-XL, but not BCL-2, led to fitness defects in renal cancer cells, and sensitized them to chemotherapeutics. Transcriptomic profiling identified a “BCL-XL dependency” signature, including an elevated mesenchymal gene signature. A mesenchymal state was both necessary and sufficient to confer increased BCL-XL dependence. The “BCL-XL dependency” signature was observed in approximately 30% of human ccRCCs, which were also associated with worse clinical outcomes. Finally, an orally bioavailable BCL-XL inhibitor, A-1331852, showed antitumor efficacy in vivo.
Conclusions:
Our studies uncovered an unexpected link between cell state and BCL-XL dependence in ccRCC. Therapeutic agents that specifically target BCL-XL are available. Our work justifies testing the utility of BCL-XL blockade to target, likely, a clinically aggressive subset of human kidney cancers.

See related commentary by Wang et al., p. 4600
Data from Pilot Study of ONCOS-102 and Pembrolizumab: Remodeling of the Tumor Microenvironment and Clinical Outcomes in Anti–PD-1–Resistant Advanced Melanoma
Authors: Shoushtari Alexander N. , Olszanski Anthony J. , Nyakas Marta , Hornyak Thomas J. , Wolchok Jedd D. , Levitsky Victor , Kuryk Lukasz , Hansen Thomas B. , Jäderberg Magnus
Published: April 2023

AbstractPurpose:
Intratumoral oncolytic virotherapy may overcome anti–PD(L)-1 resistance by triggering pro-inflammatory remodeling of the tumor microenvironment. This pilot study investigated ONCOS-102 (oncolytic adenovirus expressing GM-CSF) plus anti–programmed cell death protein 1 (PD)-1 therapy in anti–PD-1–resistant melanoma.
Patients and Methods:
Patients with advanced melanoma progressing after prior PD-1 blockade received intratumoral ONCOS-102 either as priming with 3 doses (3 × 1011 viral particles) during Week 1 [Part 1 (sequential treatment)] or as 4-dose priming and 8 booster doses every 3 weeks [Part 2 (combination treatment)]. From Week 3, all patients received pembrolizumab every 3 weeks (≤8 doses). The primary endpoint was safety. Objective response rate (ORR), progression-free survival, and immunologic activation in repeat biopsies were also investigated.
Results:
In 21 patients (Part 1, n = 9; Part 2, n = 12) ONCOS-102 plus pembrolizumab was well tolerated: most adverse events (AE) were mild/moderate in severity. Pyrexia (43%), chills (43%), and nausea (28%) were the most common ONCOS-102–related AEs. There were no dose-limiting toxicities. ORR was 35% [response evaluation in solid tumors (RECIST) 1.1, irRECIST]. Reduction in size of ≥1 non-injected lesions observed in 53% patients indicated a systemic effect. In injected tumors, persistent immune-related gene expression and T-cell infiltration were associated with clinical benefit. Viral persistence and efficacy in injected and non-injected lesions without additional toxicity supported Part 2 dosing regimen in future studies.
Conclusions:
ONCOS-102 plus pembrolizumab was well tolerated and led to objective responses in patients with anti–PD-1–resistant advanced melanoma. ONCOS-102 promoted T-cell infiltration, particularly cytotoxic CD8+ T cells, which persisted at Week 9, driving clinical benefit. Further investigation of ONCOS-102 plus PD-1 blockade is warranted.

See related commentary by Levi and Boland, p. 3
Data from Lenalidomide and Eltrombopag for Treatment of Low- or Intermediate-Risk Myelodysplastic Syndrome: Result of a Phase II Clinical Trial
Authors: Gonzalez-Lugo Jesus D. , Kambhampati Suman , Yacoub Abdulraheem , Donnellan William B. , Berdeja Jesus , Bhagat Prafulla , Fehn Karen , Remy Cassady , Jasra Sakshi , Kazemi Mohammed , Pradhan Kith , Kim Mimi , Mantzaris Ioannis , Sica R. Alejandro , Shah Nishi , Goldfinger Mendel , Kornblum Noah , Gritsman Kira , Braunschweig Ira , Steidl Ulrich , Will Britta , Shastri Aditi , Verma Amit
Published: April 2023

AbstractPurpose:
Thrombocytopenia is a serious complication of myelodysplastic syndromes (MDS) associated with an increased bleeding risk and worse prognosis. Eltrombopag (ELT), a thrombopoietin receptor agonist, can increase platelet counts and reverse anti-megakaryopoietic effects of lenalidomide (LEN) in preclinical studies. We hypothesized ELT would reduce the incidence of thrombocytopenia in MDS.
Patients and Methods:
We conducted a Phase II multicenter trial of ELT and LEN in adult patients with low- or intermediate-1–risk MDS with symptomatic or transfusion-dependent anemia or thrombocytopenia (NCT01772420). Thrombocytopenic patients were started on ELT and subsequently treated with LEN after platelets were increased. Patients without thrombocytopenia were started on LEN monotherapy and treated with ELT if they became thrombocytopenic.
Results:
Fifty-two patients were enrolled; mean age was 71 years (range 34–93). Overall response rate (ORR) in the intention-to-treat population was 35% (18/52). ELT monotherapy led to ORR of 33.3% (7/21), 29% achieving hematologic improvement (HI)-Platelets, and 24% bilineage responses. LEN monotherapy had 38% ORR (6/16) with all responders achieving HI-Erythroid. Fifteen patients received both ELT and LEN with ORR of 33.3%, 20% achieved HI-Erythroid, and 20% HI-Platelets with 13% bilineage responses. Median duration of response was 40 weeks for ELT (range 8–ongoing), 41 weeks (25–ongoing) for LEN, and 88 weeks (8.3–ongoing) for ELT/LEN. Non-hematologic grade 3–4 treatment-related adverse events were infrequent. Among patients on ELT, 2 had major bleeding events, 1 had a reversible increase in peripheral blasts, and 1 developed marrow fibrosis after 6 years on ELT.
Conclusions:
ELT and LEN are well tolerated and effective in achieving hematologic improvement in patients with low-/intermediate-risk MDS.
Data from Blood-Based Diagnosis and Risk Stratification of Patients with Pancreatic Intraductal Papillary Mucinous Neoplasm (IPMN)
Authors: Zhang Chaoyang , Al-Shaheri Fawaz N. , Alhamdani Mohamed Saiel Saeed , Bauer Andrea S. , Hoheisel Jörg D. , Schenk Miriam , Hinz Ulf , Goedecke Philipp , Al-Halabi Karam , Büchler Markus W. , Giese Nathalia A. , Hackert Thilo , Roth Susanne
Published: April 2023

AbstractPurpose:
Intraductal papillary mucinous neoplasm (IPMN) is a precursor of pancreatic ductal adenocarcinoma. Low-grade dysplasia has a relatively good prognosis, whereas high-grade dysplasia and IPMN invasive carcinoma require surgical intervention. However, diagnostic distinction is difficult. We aimed to identify biomarkers in peripheral blood for accurate discrimination.
Experimental Design:
Sera were obtained from 302 patients with IPMNs and 88 healthy donors. For protein biomarkers, serum samples were analyzed on microarrays made of 2,977 antibodies. A support vector machine (SVM) algorithm was applied to define classifiers, which were validated on a separate sample set. For microRNA biomarkers, a PCR-based screen was performed for discovery. Biomarker candidates confirmed by quantitative PCR were used to train SVM classifiers, followed by validation in a different sample set. Finally, a combined SVM classifier was established entirely independent of the earlier analyses, again using different samples for training and validation.
Results:
Panels of 26 proteins or seven microRNAs could distinguish high- and low-risk IPMN with an AUC value of 95% and 94%, respectively. Upon combination, a panel of five proteins and three miRNAs yielded an AUC of 97%. These values were much better than those obtained in the same patient cohort by using the guideline criteria for discrimination. In addition, accurate discrimination was achieved between other patient subgroups.
Conclusions:
Protein and microRNA biomarkers in blood allow precise diagnosis and risk stratification of IPMN cases, which should improve patient management and thus the prognosis of IPMN patients.
Data from Monitoring of Circulating Tumor DNA Predicts Response to Treatment and Early Progression in Follicular Lymphoma: Results of a Prospective Pilot Study
Authors: Fernández-Miranda Ismael , Pedrosa Lucía , Llanos Marta , Franco Fernando F. , Gómez Sagrario , Martín-Acosta Paloma , García-Arroyo Francisco R. , Gumá Josep , Horcajo Beatriz , Ballesteros Ana K. , Gálvez Laura , Martínez Natividad , Marín Miguel , Sequero Silvia , Navarro Marta , Yanguas-Casás Natalia , Calvo Virginia , Rueda-Domínguez Antonio , Provencio Mariano , Sánchez-Beato Margarita
Published: April 2023

AbstractPurpose:
Follicular lymphoma (FL) is the most frequent indolent non-Hodgkin lymphoma. Around 20% of patients suffer early disease progression within 24 months (POD24) of diagnosis. This study examined the significance of circulating tumor DNA (ctDNA) in predicting response to therapy and POD24 in patients with FL.
Experimental Design:
We collected 100 plasma samples, before and during the treatment, from 36 patients with FL prospectively enrolled in 8 Spanish hospitals. They were treated with a chemotherapy-rituximab regimen and followed up for a median of 3.43 years. We performed targeted deep sequencing in cell-free DNA (cfDNA) and tumor genomic DNA from 31 diagnostic biopsy samples.
Results:
Of the alterations detected in the diagnostic tissue samples, 73% (300/411) were also identified in basal cfDNA. The mean numbers of alterations per basal cfDNA sample in patients who suffered progression of disease within 24 months (POD24-pos) or did not achieve complete response (non-CR) were significantly higher than in POD24-neg or CR patients (unpaired samples t test, P = 0.0001 and 0.001, respectively). Pretreatment ctDNA levels, as haploid genome equivalents per milliliter of plasma, were higher in patients without CR (P = 0.02) and in POD24-pos patients compared with POD24-neg patients (P < 0.001). Dynamic analysis showed that ctDNA levels decreased dramatically after treatment, although the reduction was more significant in patients with CR and POD24-neg patients.
Conclusions:
Basal ctDNA levels are associated with the risk of early progression and response to treatment in FL. cfDNA monitoring and genotyping during treatment and follow-up predict response to treatment and early progression.
Data from Detection of BRCA1, BRCA2, and ATM Alterations in Matched Tumor Tissue and Circulating Tumor DNA in Patients with Prostate Cancer Screened in PROfound
Authors: Chi Kim N. , Barnicle Alan , Sibilla Caroline , Lai Zhongwu , Corcoran Claire , Barrett J. Carl , Adelman Carrie A. , Qiu Ping , Easter Ashley , Dearden Simon , Oxnard Geoffrey R. , Agarwal Neeraj , Azad Arun , de Bono Johann , Mateo Joaquin , Olmos David , Thiery-Vuillemin Antoine , Harrington Elizabeth A.
Published: April 2023

AbstractPurpose:
Not all patients with metastatic castration-resistant prostate cancer (mCRPC) have sufficient tumor tissue available for multigene molecular testing. Furthermore, samples may fail because of difficulties within the testing procedure. Optimization of screening techniques may reduce failure rates; however, a need remains for additional testing methods to detect cancers with alterations in homologous recombination repair genes. We evaluated the utility of plasma-derived circulating tumor DNA (ctDNA) in identifying deleterious BRCA1, BRCA2 (BRCA), and ATM alterations in screened patients with mCRPC from the phase III PROfound study.
Patients and Methods:
Tumor tissue samples were sequenced prospectively at Foundation Medicine, Inc. (FMI) using an investigational next-generation sequencing (NGS) assay based on FoundationOne®CDx to inform trial eligibility. Matched ctDNA samples were retrospectively sequenced at FMI, using an investigational assay based on FoundationOne®Liquid CDx.
Results:
81% (503/619) of ctDNA samples yielded an NGS result, of which 491 had a tumor tissue result. BRCA and ATM status in tissue compared with ctDNA showed 81% positive percentage agreement and 92% negative percentage agreement, using tissue as reference. At variant-subtype level, using tissue as reference, concordance was high for nonsense (93%), splice (87%), and frameshift (86%) alterations but lower for large rearrangements (63%) and homozygous deletions (27%), with low ctDNA fraction being a limiting factor.
Conclusions:
We demonstrate that ctDNA can greatly complement tissue testing in identifying patients with mCRPC and BRCA or ATM alterations who are potentially suitable for receiving targeted PARP inhibitor treatments, particularly patients with no or insufficient tissue for genomic analyses.
Data from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes
Authors: Bolton Kelly L. , Chen Denise , Corona de la Fuente Rosario , Fu Zhuxuan , Murali Rajmohan , Köbel Martin , Tazi Yanis , Cunningham Julie M. , Chan Irenaeus C.C. , Wiley Brian J. , Moukarzel Lea A. , Winham Stacey J. , Armasu Sebastian M. , Lester Jenny , Elishaev Esther , Laslavic Angela , Kennedy Catherine J. , Piskorz Anna , Sekowska Magdalena , Brand Alison H. , Chiew Yoke-Eng , Pharoah Paul , Elias Kevin M. , Drapkin Ronny , Churchman Michael , Gourley Charlie , DeFazio Anna , Karlan Beth , Brenton James D. , Weigelt Britta , Anglesio Michael S. , Huntsman David , Gayther Simon , Konner Jason , Modugno Francesmary , Lawrenson Kate , Goode Ellen L. , Papaemmanuil Elli
Published: April 2023

AbstractPurpose:
To identify molecular subclasses of clear cell ovarian carcinoma (CCOC) and assess their impact on clinical presentation and outcomes.
Experimental Design:
We profiled 421 primary CCOCs that passed quality control using a targeted deep sequencing panel of 163 putative CCOC driver genes and whole transcriptome sequencing of 211 of these tumors. Molecularly defined subgroups were identified and tested for association with clinical characteristics and overall survival.
Results:
We detected a putative somatic driver mutation in at least one candidate gene in 95% (401/421) of CCOC tumors including ARID1A (in 49% of tumors), PIK3CA (49%), TERT (20%), and TP53 (16%). Clustering of cancer driver mutations and RNA expression converged upon two distinct subclasses of CCOC. The first was dominated by ARID1A-mutated tumors with enriched expression of canonical CCOC genes and markers of platinum resistance; the second was largely comprised of tumors with TP53 mutations and enriched for the expression of genes involved in extracellular matrix organization and mesenchymal differentiation. Compared with the ARID1A-mutated group, women with TP53-mutated tumors were more likely to have advanced-stage disease, no antecedent history of endometriosis, and poorer survival, driven by their advanced stage at presentation. In women with ARID1A-mutated tumors, there was a trend toward a lower rate of response to first-line platinum-based therapy.
Conclusions:
Our study suggests that CCOC consists of two distinct molecular subclasses with distinct clinical presentation and outcomes, with potential relevance to both traditional and experimental therapy responsiveness.

See related commentary by Lheureux, p. 4838
Data from Ewing Sarcoma and Osteosarcoma Have Distinct Immune Signatures and Intercellular Communication Networks
Authors: Cillo Anthony R. , Mukherjee Elina , Bailey Nathanael G. , Onkar Sayali , Daley Jessica , Salgado Claudia , Li Xiang , Liu Dongyan , Ranganathan Sarangarajan , Burgess Melissa , Sembrat John , Weiss Kurt , Watters Rebecca , Bruno Tullia C. , Vignali Dario A.A. , Bailey Kelly M.
Published: April 2023

AbstractPurpose:
Ewing sarcoma and osteosarcoma are primary bone sarcomas occurring most commonly in adolescents. Metastatic and relapsed disease are associated with dismal prognosis. Although effective for some soft tissue sarcomas, current immunotherapeutic approaches for the treatment of bone sarcomas have been largely ineffective, necessitating a deeper understanding of bone sarcoma immunobiology.
Experimental Design:
Multiplex immunofluorescence analysis of immune infiltration in relapsed versus primary disease was conducted. To better understand immune states and drivers of immune infiltration, especially during disease progression, we performed single-cell RNA sequencing (scRNAseq) of immune populations from paired blood and bone sarcoma tumor samples.
Results:
Our multiplex immunofluorescence analysis revealed increased immune infiltration in relapsed versus primary disease in both Ewing sarcoma and osteosarcoma. scRNAseq analyses revealed terminally exhausted CD8+ T cells expressing co-inhibitory receptors in osteosarcoma and an effector T-cell subpopulation in Ewing sarcoma. In addition, distinct subsets of CD14+CD16+ macrophages were present in Ewing sarcoma and osteosarcoma. To determine pathways driving tumor immune infiltration, we conducted intercellular communication analyses and uncovered shared mechanisms of immune infiltration driven by CD14+CD16+ macrophages and unique pathways of immune infiltration driven by CXCL10 and CXCL12 in osteosarcoma.
Conclusions:
Our study provides preclinical rationale for future investigation of specific immunotherapeutic targets upon relapse and provides an invaluable resource of immunologic data from bone sarcomas.
Data from Phase I Study of Niraparib in Combination with Radium-223 for the Treatment of Metastatic Castrate-Resistant Prostate Cancer
Authors: Quinn Zachary , Leiby Benjamin , Sonpavde Guru , Choudhury Atish D. , Sweeney Christopher , Einstein David , Szmulewitz Russell , Sartor Oliver , Knudsen Karen , Yang Eddy Shih-Hsin , Kelly Wm. Kevin
Published: April 2023

AbstractPurpose:
To identify the safety of niraparib, a PARP inhibitor, in combination with Radium-223 for the treatment of metastatic castrate-resistant prostate cancer (mCRPC) in men without known BRCA mutations.
Patients and Methods:
Men with progressive mCPRC following ≥1 line of androgen receptor (AR)-targeted therapy and bone metastases but no documented BRCA-1 or BRCA-2 alterations or bulky visceral disease were included. Niraparib dose was escalated in combination with standard dosing of Radium-223 using a time-to-event continual reassessment method. The highest dose level with a DLT probability <20% was defined as MTD. Secondary endpoints included PSA change and progression-free survival. Exploratory analyses included assessing DNA mutations found in ctDNA as well as gene expression changes assessed in whole blood samples.
Results:
Thirty patients were treated with niraparib and radium-223: 13 patients received 100 mg, 12 received 200 mg, and 5 patients received 300 mg of niraparib. There were six DLT events: two (13%) for neutropenia, two (13%) for thrombocytopenia, whereas fatigue and nausea each occurred once (3%). Anemia (2/13%) and neutropenia (2/13%) were the most common grade 3 adverse events. For patients with prior chemotherapy exposure, the MTD was 100 mg, whereas the MTD for chemotherapy naïve patients was 200 mg. Whole blood gene expression of PAX5 and CD19 was higher in responders and ARG-1, IL2R, and FLT3 expression was higher in nonresponders.
Conclusions:
Combining niraparib with Radium-223 in patients with mCRPC was safe; however, further studies incorporating biomarkers will better elucidate the role of combinations of PARP inhibitors with DNA damaging and other agents.
Data from A Single-Arm Phase Ib/II Study of Lenvatinib plus Eribulin in Advanced Liposarcoma and Leiomyosarcoma
Authors: Chen Tom Wei-Wu , Hsu Chia-Lang , Hong Ruey-Long , Lee Jen-Chieh , Chang Koping , Yu Chih-Wei , Chen San-Chi , Guo Jhe-Cyuan , Chen Mei-Lu , Hsu Meng-Chi , Kung Ting-Fang , Cheng Ann-Lii , Yen Chueh-Chuan
Published: April 2023

AbstractPurpose:
Satisfactory treatment options for advanced leiomyosarcoma and liposarcoma are limited. The LEADER study (NCT03526679) investigated the safety and efficacy of lenvatinib plus eribulin.
Patients andMethods:
LEADER is a multicenter phase Ib/II study for advanced leiomyosarcoma or liposarcoma. The phase Ib part enrolled 6 patients to determine the dose-limiting toxicity (DLT) and recommended phase II dose (RP2D) with the starting dose of lenvatinib 18 mg/day and eribulin 1.1 mg/m2 D1, D8 every 21 days. The primary endpoint of the phase II part was objective response rate (ORR) based on Response Evaluation Criteria in Solid Tumors 1.1, with phase Ib patients preplanned to be included in the efficacy analysis. Translational analyses were based on the transcriptomic data obtained from the NanoString nCounter platform.
Results:
Thirty patients were enrolled (leiomyosarcoma 21, liposarcoma 9); the median age was 59. One patient had to temporarily stop lenvatinib due to grade 2 arthritis in the first cycle, meeting DLT criteria. Four of 6 patients had to decrease the dose of lenvatinib to 14 mg between cycles two and three. RP2D was determined at lenvatinib 14 mg/day and eribulin 1.1 mg/m2. The confirmed ORR was 20%, and the ORR was not significantly different between phase Ib/II cohorts (P = 0.23). The median progression-free survival was 8.56 months (95% confidence interval, 4.40–not reached). Translational studies suggested increased dendritic cells in the tumor microenvironment (TME) after treatment.
Conclusions:
Lenvatinib plus eribulin has a manageable safety profile and exhibits promising efficacy for treating advanced leiomyosarcoma and liposarcoma.
Data from Single-Cell Transcriptomics Reveals Immune Reconstitution in R/R T-ALL/LBL Patients with Donor-Derived CD7 CAR-T Therapy
Authors: Chen Wei , Shi Hui , Liu Zhuojun , Yang Fan , Liu Jia , Zhang Leqiang , Wu Yajin , Xia Yuanshi , Ou Yuxuan , Li Ruiting , Zhang Ting , Zhang Jiecheng , Ke Xiaoyan , Hu Kai , Yu Jian
Published: April 2023

AbstractPurpose:
CD7 chimeric antigen receptor T (CAR-T) therapy has potent antitumor activity against relapsed/refractory (R/R) T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL), however, immune reconstitution after CAR-T remains largely unknown.
Experimental Design:
An open-label phase I clinical trial (ChiCTR2200058969) was initiated to evaluate safety and efficacy of donor-derived CD7 CAR-T cells in 7 R/R T-ALL/LBL patients. CAR-T cells were detected by flow cytometry and PCR. Cytokine levels were quantified by cytometric bead arrays. Single-cell RNA sequencing (scRNA-seq) was adopted to profile immune reconstitution.
Results:
Optimal complete remission (CR) was 100% on day 28, and median followed-up time was 4 months. Leukopenia, thrombocytopenia, and neutropenia were observed in 6 patients, and infections occurred in 5 patients. Two patients died of serious infection and one died of a brain hemorrhage. CAR-T cells expanded efficiently in all patients. CD7+ T cells were eliminated in peripheral blood on day 11 after infusion, and CD7− T cells dramatically expanded in all patients. scRNA-seq suggested that immunologic activities of CD7− T cells were stronger than those of T cells before infusion due to higher expression levels of T-cell function-related pathways, and major characters of such CD7− T cells were activation of autoimmune-related pathways. Monocyte loss was found in 2 patients who died of serious infections, indicating the main cause of the infections after infusion. S100A8 and S100A9 were identified as potential relapse markers due to their notable upregulation in leukocyte lineage in relapsed patients versus non-relapse controls.
Conclusions:
Our data revealed cellular level dynamics of immune homeostasis of CD7 CAR-T therapy, which is valuable for optimizing the treatment of R/R T-ALL/LBL.
Data from Targeting MET and FGFR in Relapsed or Refractory Acute Myeloid Leukemia: Preclinical and Clinical Findings, and Signal Transduction Correlates
Authors: Chen Evan C. , Gandler Helen , Tošić Isidora , Fell Geoffrey G. , Fiore Ashlee , Pozdnyakova Olga , DeAngelo Daniel J. , Galinsky Ilene , Luskin Marlise R. , Wadleigh Martha , Winer Eric S. , Leonard Rebecca , O'Day Kelsey , de Jonge Adrienne , Neuberg Donna , Look A. Thomas , Stone Richard M. , Frank David A. , Garcia Jacqueline S.
Published: April 2023

AbstractPurpose:
Patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) have poor outcomes and require new therapies. In AML, autocrine production of hepatocyte growth factor (HGF) drives MET signaling that promotes myeloblast growth and survival, making MET an attractive therapeutic target. MET inhibition exhibits activity in AML preclinical studies, but HGF upregulation by the FGFR pathway is a common mechanism of resistance.
Patients and Methods:
We performed preclinical studies followed by a Phase I trial to investigate the safety and biological activity of the MET inhibitor merestinib in combination with the FGFR inhibitor LY2874455 for patients with R/R AML. Study Cohort 1 underwent a safety lead-in to determine a tolerable dose of single-agent merestinib. In Cohort 2, dose-escalation of merestinib and LY2874455 was performed following a 3+3 design. Correlative studies were conducted.
Results:
The primary dose-limiting toxicity (DLT) observed for merestinib alone or with LY2874455 was reversible grade 3 transaminase elevation, occurring in 2 of 16 patients. Eight patients had stable disease and one achieved complete remission (CR) without measurable residual disease. Although the MTD of combination therapy could not be determined due to drug supply discontinuation, single-agent merestinib administered at 80 mg daily was safe and biologically active. Correlative studies showed therapeutic plasma levels of merestinib, on-target attenuation of MET signaling in leukemic blood, and increased HGF expression in bone marrow aspirate samples of refractory disease.
Conclusions:
We provide prospective, preliminary evidence that MET and FGFR are biologically active and safely targetable pathways in AML.
Data from Overcoming Barriers to Tumor Genomic Profiling through Direct-to-Patient Outreach
Authors: Doe-Tetteh Seyram A. , Camp Sabrina Y. , Reales Dalicia , Crowdis Jett , Noronha Anne Marie , Wolff Bernadette , Alano Tina , Galle Jesse , Selcuklu S. Duygu , Viale Agnes , Socci Nicholas D. , Liu Ying L. , Tew William P. , Aghajanian Carol , Ladanyi Marc , He Meng Xiao , AlDubayan Saud H. , Mazor Roei David , Shpilberg Ofer , Hershkovitz-Rokah Oshrat , Riancho Jose A. , Hernandez Jose L. , Gonzalez-Vela M. Carmen , Buthorn Justin J. , Wilson Manda , Webber Amy E. , Yabe Mariko , Petrova-Drus Kseniya , Rosenblum Marc , Durham Benjamin H. , Abdel-Wahab Omar , Berger Michael F. , Donoghue Mark T.A. , Kung Andrew L. , Glade Bender Julia , Shukla Neerav N. , Funt Samuel A. , Dogan Ahmet , Soslow Robert A. , Al-Ahmadie Hikmat , Feldman Darren R. , Van Allen Eliezer M. , Diamond Eli L. , Solit David B.
Published: April 2023

AbstractPurpose:
To overcome barriers to genomic testing for patients with rare cancers, we initiated a program to offer free clinical tumor genomic testing worldwide to patients with select rare cancer subtypes.
Experimental Design:
Patients were recruited through social media outreach and engagement with disease-specific advocacy groups, with a focus on patients with histiocytosis, germ cell tumors (GCT), and pediatric cancers. Tumors were analyzed using the MSK-IMPACT next-generation sequencing assay with the return of results to patients and their local physicians. Whole-exome recapture was performed for female patients with GCTs to define the genomic landscape of this rare cancer subtype.
Results:
A total of 333 patients were enrolled, and tumor tissue was received for 288 (86.4%), with 250 (86.8%) having tumor DNA of sufficient quality for MSK-IMPACT testing. Eighteen patients with histiocytosis have received genomically guided therapy to date, of whom 17 (94%) have had clinical benefit with a mean treatment duration of 21.7 months (range, 6–40+). Whole-exome sequencing of ovarian GCTs identified a subset with haploid genotypes, a phenotype rarely observed in other cancer types. Actionable genomic alterations were rare in ovarian GCT (28%); however, 2 patients with ovarian GCTs with squamous transformation had high tumor mutational burden, one of whom had a complete response to pembrolizumab.
Conclusions:
Direct-to-patient outreach can facilitate the assembly of cohorts of rare cancers of sufficient size to define their genomic landscape. By profiling tumors in a clinical laboratory, results could be reported to patients and their local physicians to guide treatment.

See related commentary by Desai and Subbiah, p. 2339
Data from HER2 Copy Number and Resistance Mechanisms in Patients with HER2-positive Advanced Gastric Cancer Receiving Initial Trastuzumab-based Therapy in JACOB Trial
Authors: Pietrantonio Filippo , Manca Paolo , Bellomo Sara Erika , Corso Simona , Raimondi Alessandra , Berrino Enrico , Morano Federica , Migliore Cristina , Niger Monica , Castagnoli Lorenzo , Pupa Serenella Maria , Marchiò Caterina , Di Bartolomeo Maria , Restuccia Eleonora , Lambertini Chiara , Tabernero Josep , Giordano Silvia
Published: April 2023

AbstractPurpose:
In JACOB trial, pertuzumab added to trastuzumab-chemotherapy did not significantly improve survival of patients with HER2-positive metastatic gastric cancer, despite 3.3 months increase versus placebo. HER2 copy-number variation (CNV) and AMNESIA panel encompassing primary resistance alterations (KRAS/PIK3CA/MET mutations, KRAS/EGFR/MET amplifications) may improve patients’ selection for HER2 inhibition.
Experimental Design:
In a post hoc analysis of JACOB on 327 samples successfully sequenced by next-generation sequencing (NGS; Oncomine Focus DNA), HER2 CNV, HER2 expression by IHC, and AMNESIA were correlated with overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) by univariable/multivariable models.
Results:
Median HER2 CNV was 4.7 (interquartile range, 2.2–16.9). HER2 CNV-high versus low using the median as cutoff was associated with longer median PFS (10.5 vs. 6.4 months; HR = 0.48; 95% confidence interval: 0.38–0.62; P < 0.001) and OS (20.3 vs. 13.0 months; HR = 0.54; 0.42–0.72; P < 0.001). Combining HER2 CNV and IHC improved discriminative ability, with better outcomes restricted to HER2-high/HER2 3+ subgroup. AMNESIA positivity was found in 51 (16%), with unadjusted HR = 1.35 (0.98–1.86) for PFS; 1.43 (1.00–2.03) for OS.

In multivariable models, only HER2 CNV status remained significant for PFS (P < 0.001) and OS (P = 0.004). Higher ORR was significantly associated with IHC 3+ [61% vs. 34% in 2+; OR = 3.11 (1.89–5.17)] and HER2-high [59% vs. 43% in HER2-low; OR = 1.84 (1.16–2.94)], with highest OR in the top CNV quartile. These biomarkers were not associated with treatment effect of pertuzumab.
Conclusions:
HER2 CNV-high assessed by NGS may be associated with better ORR, PFS, and OS in a JACOB subgroup, especially if combined with HER2 3+. The negative prognostic role of AMNESIA requires further clinical validation.