bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Electronic DNA Analysis of CSF Cell-free Tumor DNA to Quantify Multi-gene Molecular Response in Pediatric High-grade Glioma
Authors: Bruzek Amy K. , Ravi Karthik , Muruganand Ashwath , Wadden Jack , Babila Clarissa May , Cantor Evan , Tunkle Leo , Wierzbicki Kyle , Stallard Stefanie , Dickson Robert P. , Wolfe Ian , Mody Rajen , Schwartz Jonathan , Franson Andrea , Robertson Patricia L. , Muraszko Karin M. , Maher Cormac O. , Garton Hugh J.L. , Qin Tingtin , Koschmann Carl
Published: April 2023

AbstractPurpose:
Pediatric high-grade glioma (pHGG) diagnosis portends poor prognosis and therapeutic monitoring remains difficult. Tumors release cell-free tumor DNA (cf-tDNA) into cerebrospinal fluid (CSF), allowing for potential detection of tumor-associated mutations by CSF sampling. We hypothesized that direct, electronic analysis of cf-tDNA with a handheld platform (Oxford Nanopore MinION) could quantify patient-specific CSF cf-tDNA variant allele fraction (VAF) with improved speed and limit of detection compared with established methods.
Experimental Design:
We performed ultra-short fragment (100–200 bp) PCR amplification of cf-tDNA for clinically actionable alterations in CSF and tumor samples from patients with pHGG (n = 12) alongside nontumor CSF (n = 6). PCR products underwent rapid amplicon-based sequencing by Oxford Nanopore Technology (Nanopore) with quantification of VAF. Additional comparison to next-generation sequencing (NGS) and droplet digital PCR (ddPCR) was performed.
Results:
Nanopore demonstrated 85% sensitivity and 100% specificity in CSF samples (n = 127 replicates) with 0.1 femtomole DNA limit of detection and 12-hour results, all of which compared favorably with NGS. Multiplexed analysis provided concurrent analysis of H3.3A (H3F3A) and H3C2 (HIST1H3B) mutations in a nonbiopsied patient and results were confirmed by ddPCR. Serial CSF cf-tDNA sequencing by Nanopore demonstrated correlation of radiological response on a clinical trial, with one patient showing dramatic multi-gene molecular response that predicted long-term clinical response.
Conclusions:
Nanopore sequencing of ultra-short pHGG CSF cf-tDNA fragments is feasible, efficient, and sensitive with low-input samples thus overcoming many of the barriers restricting wider use of CSF cf-tDNA diagnosis and monitoring in this patient population.
Data from Safety and Feasibility of PARP1/2 Imaging with 18F-PARPi in Patients with Head and Neck Cancer
Authors: Schöder Heiko , França Paula Demétrio De Souza , Nakajima Reiko , Burnazi Eva , Roberts Sheryl , Brand Christian , Grkovski Milan , Mauguen Audrey , Dunphy Mark P. , Ghossein Ronald A. , Lyashchenko Serge K. , Lewis Jason S. , O'Donoghue Joseph A. , Ganly Ian , Patel Snehal G. , Lee Nancy Y. , Reiner Thomas
Published: April 2023

AbstractPurpose:
We performed a first-in-human clinical trial. The aim of this study was to determine safety and feasibility of PET imaging with 18F-PARPi in patients with head and neck cancer.
Patients and Methods:
Eleven patients with newly diagnosed or recurrent oral and oropharyngeal cancer were injected with 18F-PARPi (331 ± 42 MBq), and dynamic PET/CT imaging was performed between 0 and 25 minutes postinjection. Static PET/CT scans were obtained at 30, 60, and 120 minutes postinjection. Blood samples for tracer concentration and metabolite analysis were collected. Blood pressure, ECG, oxygen levels, clinical chemistry, and complete blood count were obtained before and after tracer administration.
Results:
18F-PARPi was well-tolerated by all patients without any safety concerns. Of the 11 patients included in the analysis, 18F-PARPi had focal uptake in all primary lesions (n = 10, SUVmax = 2.8 ± 1.2) and all 18F-FDG–positive lymph nodes (n = 34). 18F-PARPi uptake was seen in 18F-FDG–negative lymph nodes of 3 patients (n = 6). Focal uptake of tracer in primary and metastatic lesions was corroborated by CT alone or in combination with 18F-FDG. The overall effective dose with 18F-PARPi PET was 3.9 mSv – 5.2 mSv, contrast was high [SUVmax(lesion)/SUVmax(trapezius muscle) = 4.5] and less variable than 18F-FDG when compared with the genioglossus muscle (1.3 vs. 6.0, P = 0.001).
Conclusions:
Imaging of head and neck cancer with 18F-PARPi is feasible and safe. 18F-PARPi detects primary and metastatic lesions, and retention in tumors is longer than in healthy tissues.
Data from Impact of Neoadjuvant Durvalumab with or without Tremelimumab on CD8+ Tumor Lymphocyte Density, Safety, and Efficacy in Patients with Oropharynx Cancer: CIAO Trial Results
Authors: Ferrarotto Renata , Bell Diana , Rubin Maria L. , Hutcheson Katherine A. , Johnson Jason M. , Goepfert Ryan P. , Phan Jack , Elamin Yasir Y. , Torman Danice K. , Warneke Carla L. , Hessel Amy C. , Garden Adam S. , Myers Jeffrey N. , Johnson Faye M. , Lee J. Jack , Sikora Andrew G. , Gillison Maura L. , Glisson Bonnie S. , Gross Neil D.
Published: April 2023

AbstractPurpose:
In oropharyngeal squamous cell carcinoma (OPC), high CD8+ tumor-infiltrating lymphocyte (CD8+TIL) density confers improved prognosis. We compared neoadjuvant durvalumab (PD-L1 inhibitor) with durvalumab + tremelimumab (CTLA-4 inhibitor) in terms of impact on CD8+TIL density, safety, and efficacy in patients with OPC.
Patients and Methods:
Patients with newly diagnosed stage II–IVA OPC or locoregionally recurrent OPC amenable to resection were included. Patients were randomized to two cycles of durvalumab or durvalumab + tremelimumab before surgery. The primary endpoint was change between baseline and resection specimen in CD8+TIL density between arms. Secondary endpoints included safety, response rate per RECIST, major pathologic response (MPR; ≤10% viable tumor cells) rate, and patient-reported outcomes.
Results:
Of 28 eligible patients (14/arm), 20 (71%) had newly diagnosed OPC, and 24 (86%) were p16-positive. The posttreatment to pretreatment median CD8+TIL density ratio was 1.31 for durvalumab and 1.15 for combination treatment (P = 0.97; 95% CI: −1.07–2.28). In each group, 6 patients (43%, 95% CI: 17.66–71.14) had a response. Eight patients (29%) had a MPR at the primary tumor and/or nodal metastases. Neither baseline CD8+TIL density nor PD-L1 expression level correlated with overall response, but a trend toward greater CD8+TIL change in patients with a MPR was seen (P = 0.059; 95% CI: −0.33–3.46). Four patients (14%) had grade ≥3 adverse events. At median follow-up time of 15.79 months, all patients were alive, and one had an additional recurrence.
Conclusions:
Durvalumab + tremelimumab did not increase CD8+TIL density more than durvalumab alone did. The observed safety and activity support further investigation of neoadjuvant checkpoint inhibitor for OPC.
Data from Palbociclib and Trastuzumab in HER2-Positive Advanced Breast Cancer: Results from the Phase II SOLTI-1303 PATRICIA Trial
Authors: Ciruelos Eva , Villagrasa Patricia , Pascual Tomás , Oliveira Mafalda , Pernas Sonia , Paré Laia , Escrivá-de-Romaní Santiago , Manso Luis , Adamo Barbara , Martínez Eduardo , Cortés Javier , Vazquez Silvia , Perelló Antonia , Garau Isabel , Melé Mireia , Martínez Noelia , Montaño Alvaro , Bermejo Begoña , Morales Serafin , Echarri María J. , Vega Estela , González-Farré Blanca , Martínez Débora , Galván Patricia , Canes Jordi , Nuciforo Paolo , Gonzalez Xavier , Prat Aleix
Published: April 2023

AbstractPurpose:
To assess palbociclib in combination with trastuzumab with or without endocrine therapy in patients with HER2-positive advanced breast cancer.
Patients and Methods:
PATRICIA is a prospective, open-label, multicenter phase II trial. Patients had received 2–4 prior lines of anti-HER2–based regimens. Treatment consisted of palbociclib 200 mg daily for 2 weeks and 1 week off plus trastuzumab. The study was based on a Simon two-stage design comprising three cohorts: estrogen receptor (ER)-negative (cohort A), ER-positive (cohort B1), and ER-positive with letrozole (cohort B2). ER-positive patients were randomized to cohorts B1 or B2. Primary endpoint was progression-free survival rate at 6 months (PFS6). Secondary objectives included safety and evaluation of the PAM50 intrinsic subtypes.
Results:
Seventy-one patients were recruited (n = 15 in cohort A and 28 in each cohort B). The PFS6 rate in cohorts A, B1, and B2 was 33.3% (5/15), 42.8% (12/28), and 46.4% (13/28), respectively. Regarding safety, grade 1–2 and 3–4 toxicities occurred in 97.7% and 84.4% of patients, respectively. The most common grade 3–4 toxicities were neutropenia (66.4%) and thrombocytopenia (11.3%). Regarding PAM50, 59 (83.1%) tumors were profiled. Luminal disease defined by PAM50 was found independently associated with longer PFS compared with non-luminal disease (10.6 vs. 4.2 months median PFS; adjusted hazard ratio = 0.40; P = 0.003).
Conclusions:
Palbociclib in combination with trastuzumab is safe and exhibits promising survival outcomes in trastuzumab pretreated ER-positive/HER2-positive advanced breast cancer with a PAM50 Luminal A or B subtype. The enrollment was stopped prematurely, and a new randomized cohort was opened in this population.
Data from Preclinical and Dose-Finding Phase I Trial Results of Combined Treatment with a TORC1/2 Inhibitor (TAK-228) and Aurora A Kinase Inhibitor (Alisertib) in Solid Tumors
Authors: Davis S. Lindsey , Ionkina Anastasia A. , Bagby Stacey M. , Orth James D. , Gittleman Brian , Marcus Joshua M. , Lam Elaine T. , Corr Bradley R. , O'Bryant Cindy L. , Glode Ashley E. , Tan Aik-Choon , Kim Jihye , Tentler John J. , Capasso Anna , Lopez Kyrie L. , Gustafson Daniel L. , Messersmith Wells A. , Leong Stephen , Eckhardt S. Gail , Pitts Todd M. , Diamond Jennifer R.
Published: April 2023

AbstractPurpose:
The purpose of this study was to evaluate the rational combination of TORC1/2 inhibitor TAK-228 and Aurora A kinase inhibitor alisertib in preclinical models of triple-negative breast cancer (TNBC) and to conduct a phase I dose escalation trial in patients with advanced solid tumors.
Experimental Design:
TNBC cell lines and patient-derived xenograft (PDX) models were treated with alisertib, TAK-228, or the combination and evaluated for changes in proliferation, cell cycle, mTOR pathway modulation, and terminal cellular fate, including apoptosis and senescence. A phase I clinical trial was conducted in patients with advanced solid tumors treated with escalating doses of alisertib and TAK-228 using a 3+3 design to determine the maximum tolerated dose (MTD).
Results:
The combination of TAK-228 and alisertib resulted in decreased proliferation and cell-cycle arrest in TNBC cell lines. Treatment of TNBC PDX models resulted in significant tumor growth inhibition and increased apoptosis with the combination. In the phase I dose escalation study, 18 patients with refractory solid tumors were enrolled. The MTD was alisertib 30 mg b.i.d. days 1 to 7 of a 21-day cycle and TAK-228 2 mg daily, continuous dosing. The most common treatment-related adverse events were neutropenia, fatigue, nausea, rash, mucositis, and alopecia.
Conclusions:
The addition of TAK-228 to alisertib potentiates the antitumor activity of alisertib in vivo, resulting in increased cell death and apoptosis. The combination is tolerable in patients with advanced solid tumors and should be evaluated further in expansion cohorts with additional pharmacodynamic assessment.
Data from First-in-Man Phase I Trial of the Selective MET Inhibitor Tepotinib in Patients with Advanced Solid Tumors
Authors: Falchook Gerald S. , Kurzrock Razelle , Amin Hesham M. , Xiong Wenyuan , Fu Siqing , Piha-Paul Sarina A. , Janku Filip , Eskandari Ghazaleh , Catenacci Daniel V. , Klevesath Manfred , Bruns Rolf , Stammberger Uz , Johne Andreas , Bladt Friedhelm , Friese-Hamim Manja , Girard Pascal , El Bawab Samer , Hong David S.
Published: April 2023

AbstractPurpose:
Tepotinib is an oral, potent, highly selective MET inhibitor. This first-in-man phase I trial investigated the MTD of tepotinib to determine the recommended phase II dose (RP2D).
Patients and Methods:
Patients received tepotinib orally according to one of three dose escalation regimens (R) on a 21-day cycle: R1, 30–400 mg once daily for 14 days; R2, 30–315 mg once daily 3 times/week; or R3, 300–1,400 mg once daily. After two cycles, treatment could continue in patients with stable disease until disease progression or unacceptable toxicity. The primary endpoint was incidence of dose-limiting toxicity (DLT) and treatment-emergent adverse events (TEAE). Secondary endpoints included safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor effects.
Results:
One hundred and forty-nine patients received tepotinib (R1: n = 42; R2: n = 45; R3: n = 62). Although six patients reported DLTs [one patient in R1 (115 mg), three patients in R2 (60, 100, 130 mg), two patients in R3 (1,000, 1,400 mg)], the MTD was not reached at the highest tested dose of 1,400 mg daily. The RP2D of tepotinib was established as 500 mg once daily, supported by translational modeling data as sufficient to achieve ≥95% MET inhibition in ≥90% of patients. Treatment-related TEAEs were mostly grade 1 or 2 fatigue, peripheral edema, decreased appetite, nausea, vomiting, and lipase increase. The best overall response in R3 was partial response in two patients, both with MET overexpression.
Conclusions:
Tepotinib was well tolerated with clinical activity in MET-dysregulated tumors. The RP2D of tepotinib was established as 500 mg once daily. MET abnormalities can drive tumorigenesis. This first-in-man trial demonstrated that the potent, highly selective MET inhibitor tepotinib can reduce or stabilize tumor burden and is well tolerated at doses up to 1,400 mg once daily. An RP2D of 500 mg once daily, as determined from translational modeling and simulation integrating human population pharmacokinetic and pharmacodynamic data in tumor biopsies, is being used in ongoing clinical trials.
Data from Phase I Study of Lysine-Specific Demethylase 1 Inhibitor, CC-90011, in Patients with Advanced Solid Tumors and Relapsed/Refractory Non-Hodgkin Lymphoma
Authors: Hollebecque Antoine , Salvagni Stefania , Plummer Ruth , Isambert Nicolas , Niccoli Patricia , Capdevila Jaume , Curigliano Giuseppe , Moreno Victor , Martin-Romano Patricia , Baudin Eric , Arias Marina , Mora Sheila , de Alvaro Juan , Di Martino Jorge , Parra-Palau Josep L. , Sánchez-Pérez Tania , Aronchik Ida , Filvaroff Ellen H. , Lamba Manisha , Nikolova Zariana , de Bono Johann S.
Published: April 2023

AbstractPurpose:
Lysine-specific demethylase 1 (LSD1) is implicated in multiple tumor types, and its expression in cancer stem cells is associated with chemoresistance. CC-90011 is a potent, selective, and reversible oral LSD1 inhibitor. We examined CC-90011 in advanced solid tumors and relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL).
Patients and Methods:
CC-90011-ST-001 (NCT02875223; 2015-005243-13) is a phase I, multicenter, first-in-human dose-escalation study. Nine dose levels of CC-90011 (1.25–120 mg) given once per week were explored. Primary objectives were to determine safety, maximum tolerated dose (MTD), and/or recommended phase II dose (RP2D). Secondary objectives were to evaluate preliminary efficacy and pharmacokinetics.
Results:
Fifty patients were enrolled, 49 with solid tumors (27 neuroendocrine tumors/carcinomas) and 1 with R/R NHL. Median age was 61 years (range, 22–75). Patients received a median of three (range, 1–9) prior anticancer regimens. The RP2D was 60 mg once per week; the nontolerated dose (NTD) and MTD were 120 mg once per week and 80 mg once per week, respectively. Grade 3/4 treatment-related toxicities were thrombocytopenia (20%; an on-target effect unassociated with clinically significant bleeding), neutropenia (8%; in the context of thrombocytopenia at the highest doses), and fatigue (2%). The patient with R/R NHL had a complete response, currently ongoing in cycle 34, and 8 patients with neuroendocrine tumors/carcinomas had stable disease ≥6 months, including bronchial neuroendocrine tumors, kidney tumor, and paraganglioma.
Conclusions:
CC-90011 is well tolerated, with the RP2D established as 60 mg once per week. The MTD and NTD were determined to be 80 mg once per week and 120 mg once per week, respectively. Further evaluation of CC-90011 is warranted.
Data from Cobomarsen, an Oligonucleotide Inhibitor of miR-155, Slows DLBCL Tumor Cell Growth In Vitro and In Vivo
Authors: Anastasiadou Eleni , Seto Anita G. , Beatty Xuan , Hermreck Melanie , Gilles Maud-Emmanuelle , Stroopinsky Dina , Pinter-Brown Lauren C. , Pestano Linda , Marchese Cinzia , Avigan David , Trivedi Pankaj , Escolar Diana M. , Jackson Aimee L. , Slack Frank J.
Published: April 2023

AbstractPurpose:
miRNA-155 is an oncogenic miRNA highly expressed in B-cell malignancies, particularly in the non–germinal center B-cell or activated B-cell subtype of diffuse large B-cell lymphoma (ABC-DLBCL), where it is considered a potential diagnostic and prognostic biomarker. Thus, miR-155 inhibition represents an important therapeutic strategy for B-cell lymphomas. In this study, we tested the efficacy and pharmacodynamic activity of an oligonucleotide inhibitor of miR-155, cobomarsen, in ABC-DLBCL cell lines and in corresponding xenograft mouse models. In addition, we assessed the therapeutic efficacy and safety of cobomarsen in a patient diagnosed with aggressive ABC-DLBCL.
Experimental Design:
Preclinical studies included the delivery of cobomarsen to highly miR-155–expressing ABC-DLBCL cell lines to assess any phenotypic changes, as well as intravenous injections of cobomarsen in NSG mice carrying ABC-DLBCL xenografts, to study tumor growth and pharmacodynamics of the compound over time. To begin to test its safety and therapeutic efficacy, a patient was recruited who underwent five cycles of cobomarsen treatment.
Results:
Cobomarsen decreased cell proliferation and induced apoptosis in ABC-DLBCL cell lines. Intravenous administration of cobomarsen in a xenograft NSG mouse model of ABC-DLBCL reduced tumor volume, triggered apoptosis, and derepressed direct miR-155 target genes. Finally, the compound reduced and stabilized tumor growth without any toxic effects for the patient.
Conclusions:
Our findings support the potential therapeutic application of cobomarsen in ABC-DLBCL and other types of lymphoma with elevated miR-155 expression.
Data from Molecular Mechanisms of Acquired Resistance to MET Tyrosine Kinase Inhibitors in Patients with MET Exon 14–Mutant NSCLC
Authors: Recondo Gonzalo , Bahcall Magda , Spurr Liam F. , Che Jianwei , Ricciuti Biagio , Leonardi Giulia C. , Lo Ying-Chun , Li Yvonne Y. , Lamberti Giuseppe , Nguyen Tom , Milan Marina S.D. , Venkatraman Deepti , Umeton Renato , Paweletz Cloud P. , Albayrak Adem , Cherniack Andrew D. , Price Kristin S. , Fairclough Stephen R. , Nishino Mizuki , Sholl Lynette M. , Oxnard Geoffrey R. , Jänne Pasi A. , Awad Mark M.
Published: April 2023

AbstractPurpose:
Molecular mechanisms of acquired resistance to MET tyrosine kinase inhibitors (TKI) are poorly understood. We aimed to characterize the genomic mechanisms of resistance to type I and type II MET TKIs and their impact on sequential MET TKI therapy outcomes in patients with metastatic MET exon 14–mutant NSCLC.
Experimental Design:
Genomic alterations occurring at the time of progression on MET TKIs were studied using plasma and tissue next-generation sequencing (NGS).
Results:
A total of 20 patients had tissue or plasma available for analysis at the time of acquired resistance to a MET TKI. Genomic alterations known or suspected to be mechanisms of resistance were detected in 15 patients (75%). On-target acquired mechanisms of resistance, including single and polyclonal MET kinase domain mutations in codons H1094, G1163, L1195, D1228, Y1230, and high levels of amplification of the MET exon 14–mutant allele, were observed in 7 patients (35%). A number of off-target mechanisms of resistance were detected in 9 patients (45%), including KRAS mutations and amplifications in KRAS, EGFR, HER3, and BRAF; one case displayed both on- and off-target mechanisms of resistance. In 2 patients with on-target resistant mutations, switching between type I and type II MET TKIs resulted in second partial responses.
Conclusions:
On-target secondary mutations and activation of bypass signaling drive resistance to MET TKIs. A deeper understanding of these molecular mechanisms can support the development of sequential or combinatorial therapeutic strategies to overcome resistance.
Data from The Oxford Classic Links Epithelial-to-Mesenchymal Transition to Immunosuppression in Poor Prognosis Ovarian Cancers
Authors: Hu Zhiyuan , Cunnea Paula , Zhong Zhe , Lu Haonan , Osagie Oloruntoba I. , Campo Leticia , Artibani Mara , Nixon Katherine , Ploski Jennifer , Santana Gonzalez Laura , Alsaadi Abdulkhaliq , Wietek Nina , Damato Stephen , Dhar Sunanda , Blagden Sarah P. , Yau Christopher , Hester Joanna , Albukhari Ashwag , Aboagye Eric O. , Fotopoulou Christina , Ahmed Ahmed
Published: April 2023

AbstractPurpose:
Using RNA sequencing, we recently developed the 52-gene–based Oxford classifier of carcinoma of the ovary (Oxford Classic, OxC) for molecular stratification of serous ovarian cancers (SOCs) based on the molecular profiles of their cell of origin in the fallopian tube epithelium. Here, we developed a 52-gene NanoString panel for the OxC to test the robustness of the classifier.
Experimental Design:
We measured the expression of the 52 genes in an independent cohort of prospectively collected SOC samples (n = 150) from a homogenous cohort who were treated with maximal debulking surgery and chemotherapy. We performed data mining of published expression profiles of SOCs and validated the classifier results on tissue arrays comprising 137 SOCs.
Results:
We found evidence of profound nongenetic heterogeneity in SOCs. Approximately 20% of SOCs were classified as epithelial-to-mesenchymal transition–high (EMT-high) tumors, which were associated with poor survival. This was independent of established prognostic factors, such as tumor stage, tumor grade, and residual disease after surgery (HR, 3.3; P = 0.02). Mining expression data of 593 patients revealed a significant association between the EMT scores of tumors and the estimated fraction of alternatively activated macrophages (M2; P < 0.0001), suggesting a mechanistic link between immunosuppression and poor prognosis in EMT-high tumors.
Conclusions:
The OxC-defined EMT-high SOCs carry particularly poor prognosis independent of established clinical parameters. These tumors are associated with high frequency of immunosuppressive macrophages, suggesting a potential therapeutic target to improve clinical outcome.
Data from Clinical Validation of a Machine-learning–derived Signature Predictive of Outcomes from First-line Oxaliplatin-based Chemotherapy in Advanced Colorectal Cancer
Authors: Abraham Jim P. , Magee Daniel , Cremolini Chiara , Antoniotti Carlotta , Halbert David D. , Xiu Joanne , Stafford Phillip , Berry Donald A. , Oberley Matthew J. , Shields Anthony F. , Marshall John L. , Salem Mohamed E. , Falcone Alfredo , Grothey Axel , Hall Michael J. , Venook Alan P. , Lenz Heinz-Josef , Helmstetter Anthony , Korn W. Michael , Spetzler David B.
Published: April 2023

AbstractPurpose:
FOLFOX, FOLFIRI, or FOLFOXIRI chemotherapy with bevacizumab is considered standard first-line treatment option for patients with metastatic colorectal cancer (mCRC). We developed and validated a molecular signature predictive of efficacy of oxaliplatin-based chemotherapy combined with bevacizumab in patients with mCRC.
Experimental Design:
A machine-learning approach was applied and tested on clinical and next-generation sequencing data from a real-world evidence (RWE) dataset and samples from the prospective TRIBE2 study resulting in identification of a molecular signature, FOLFOXai. Algorithm training considered time-to-next treatment (TTNT). Validation studies used TTNT, progression-free survival, and overall survival (OS) as the primary endpoints.
Results:
A 67-gene signature was cross-validated in a training cohort (N = 105) which demonstrated the ability of FOLFOXai to distinguish FOLFOX-treated patients with mCRC with increased benefit from those with decreased benefit. The signature was predictive of TTNT and OS in an independent RWE dataset of 412 patients who had received FOLFOX/bevacizumab in first line and inversely predictive of survival in RWE data from 55 patients who had received first-line FOLFIRI. Blinded analysis of TRIBE2 samples confirmed that FOLFOXai was predictive of OS in both oxaliplatin-containing arms (FOLFOX HR, 0.629; P = 0.04 and FOLFOXIRI HR, 0.483; P = 0.02). FOLFOXai was also predictive of treatment benefit from oxaliplatin-containing regimens in advanced esophageal/gastro-esophageal junction cancers, as well as pancreatic ductal adenocarcinoma.
Conclusions:
Application of FOLFOXai could lead to improvements of treatment outcomes for patients with mCRC and other cancers because patients predicted to have less benefit from oxaliplatin-containing regimens might benefit from alternative regimens.
Data from Comparison of Haploidentical Bone Marrow versus Matched Unrelated Donor Peripheral Blood Stem Cell Transplantation with Posttransplant Cyclophosphamide in Patients with Acute Leukemia
Authors: Nagler Arnon , Labopin Myriam , Dholaria Bhagirathbhai , Angelucci Emanuele , Afanasyev Boris , Cornelissen Jan J. , Sica Simona , Meijer Ellen , Ciceri Fabio , Van Gorkom Gwendolyn , Kröger Nicolaus , Martin Hans , Pioltelli Pietro , Risitano Antonio , Canaani Jonathan , Savani Bipin N. , Sanz Jaime , Mohty Mohamad
Published: April 2023

AbstractPurpose:
Posttransplant cyclophosphamide (PTCy) is increasingly being utilized as a principle GvHD prophylaxis strategy in allogeneic hematopoietic cell transplantation (allo-HCT). A haploidentical (haplo) or matched unrelated donor (UD) is a valid option in the absence of a matched related donor.
Experimental Design:
We compared the outcomes of patients with acute leukemia who underwent haplo bone marrow (haplo-BM, N = 401) versus UD mobilized peripheral blood stem cells (UD-PB, N = 192) transplantation in the setting of PTCy.
Results:
The median follow-up duration was 36 months in the haplo-BM group and 16.6 months in the UD-PB group, respectively (P < 0.01). Myeloablative conditioning was used in 64.6% and 42.7% of haplo-BM and UD-PB patients, respectively (P < 0.01). Cumulative incidence of neutrophil engraftment at day 30 was 87% in haplo-BM versus 94% in UD-PB, respectively (P = 0.21). In the multivariate analysis, the risk of grade 2–4 acute GvHD (HR = 0.53, P = 0.01) and chronic GvHD (HR = 0.50, P = 0.02) was significantly lower in the haplo-BM group compared with the UD-PB group. There was no significant difference between the study groups with respect to relapse incidence, nonrelapse mortality, leukemia-fee survival, overall survival, or GvHD-free and relapse-free survival.
Conclusions:
The use of a haplo donor with a BM graft resulted in a lower incidence of GvHD compared with a UD-PB stem cell graft in the setting of PTCy for patients with acute leukemia. However, differences in GvHD did not translate into a difference in survival outcomes. Based upon these data, UD-PB or haplo-BM should be considered equally acceptable sources for allo-HCT.
Data from Genomic, Transcriptomic, and Proteomic Profiling of Metastatic Breast Cancer
Authors: Akcakanat Argun , Zheng Xiaofeng , Cruz Pico Christian X. , Kim Tae-Beom , Chen Ken , Korkut Anil , Sahin Aysegul , Holla Vijaykumar , Tarco Emily , Singh Gopal , Damodaran Senthil , Mills Gordon B. , Gonzalez-Angulo Ana Maria , Meric-Bernstam Funda
Published: April 2023

AbstractPurpose:
Metastatic breast cancer (MBC) is not curable and there is a growing interest in personalized therapy options. Here we report molecular profiling of MBC focusing on molecular evolution in actionable alterations.
Experimental Design:
Sixty-two patients with MBC were included. An analysis of DNA, RNA, and functional proteomics was done, and matched primary and metastatic tumors were compared when feasible.
Results:
Targeted exome sequencing of 41 tumors identified common alterations in TP53 (21; 51%) and PIK3CA (20; 49%), as well as alterations in several emerging biomarkers such as NF1 mutations/deletions (6; 15%), PTEN mutations (4; 10%), and ARID1A mutations/deletions (6; 15%). Among 27 hormone receptor–positive patients, we identified MDM2 amplifications (3; 11%), FGFR1 amplifications (5; 19%), ATM mutations (2; 7%), and ESR1 mutations (4; 15%). In 10 patients with matched primary and metastatic tumors that underwent targeted exome sequencing, discordances in actionable alterations were common, including NF1 loss in 3 patients, loss of PIK3CA mutation in 1 patient, and acquired ESR1 mutations in 3 patients. RNA sequencing in matched samples confirmed loss of NF1 expression with genomic NF1 loss. Among 33 patients with matched primary and metastatic samples that underwent RNA profiling, 14 actionable genes were differentially expressed, including antibody–drug conjugate targets LIV-1 and B7-H3.
Conclusions:
Molecular profiling in MBC reveals multiple common as well as less frequent but potentially actionable alterations. Genomic and transcriptional profiling demonstrates intertumoral heterogeneity and potential evolution of actionable targets with tumor progression. Further work is needed to optimize testing and integrated analysis for treatment selection.
Data from Prognostic Value of ER and PgR Expression and the Impact of Multi-clonal Expression for Recurrence in Ductal Carcinoma in situ: Results from the UK/ANZ DCIS Trial
Authors: Thorat Mangesh A. , Levey Pauline M. , Jones J. Louise , Pinder Sarah E. , Bundred Nigel J. , Fentiman Ian S. , Cuzick Jack
Published: April 2023

AbstractPurpose:
The prognostic value of estrogen receptor (ER)/progesterone receptor (PgR) expression in ductal carcinoma in situ (DCIS) is unclear. We observed multi-clonality when evaluating ER/PgR expression in the UK/ANZ DCIS trial, therefore, we investigated the prognostic role of both uni-clonal and multi-clonal ER/PgR expression in DCIS.
Experimental Design:
Formalin-fixed paraffin embedded tissues were collected from UK/ANZ DCIS trial participants (n = 755), and ER/PgR expression was evaluated by IHC in 181 cases (with recurrence) matched to 362 controls by treatment arm and age. Assays were scored by the Allred method and by a newly devised clonal method—analyses categorizing multi-clonal DCIS as ER/PgR-positive as per current practice (Standard) and as ER/PgR-negative (clonal) were performed.
Results:
ER expression was multi-clonal in 11% (39/356) of ER-positive (70.6%, 356/504) patients. Ipsilateral breast event (IBE) risk was similarly higher in ER-multi-clonal and ER-negative DCIS as compared with DCIS with uni-clonal ER expression. ER-negative DCIS (clonal) had a higher risk of in situ IBE [OR 4.99; 95% confidence interval (CI), 2.66–9.36; P < 0.0001], but the risk of invasive IBE was not significantly higher (OR 1.72; 95% CI, 0.84–3.53; P = 0.14), Pheterogeneity = 0.03. ER was an independent predictor in multivariate analyses (OR 2.66; 95% CI, 1.53–4.61). PgR status did not add to the prognostic information provided by ER.
Conclusions:
ER expression is a strong predictor of ipsilateral recurrence risk in DCIS. ER-positive DCIS with distinct ER-negative clones has a recurrence risk similar to ER-negative DCIS. ER should be routinely assessed in DCIS, and ER scoring should take clonality of expression into account.
Data from First-in-Human Phase I Study of ABBV-085, an Antibody–Drug Conjugate Targeting LRRC15, in Sarcomas and Other Advanced Solid Tumors
Authors: Demetri George D. , Luke Jason J. , Hollebecque Antoine , Powderly John D. , Spira Alexander I. , Subbiah Vivek , Naumovski Louie , Chen Chris , Fang Hua , Lai Dominic W. , Yue Huibin , Polepally Akshanth R. , Purcell James W. , Robinson Randy , Sharma Padmanee , Allison James P. , Tolcher Anthony , Villalobos Victor M.
Published: April 2023

AbstractPurpose:
Leucine-rich repeat containing 15 (LRRC15) is expressed on stromal fibroblasts in the tumor microenvironment of multiple solid tumor types and may represent an interesting target for therapy, particularly in patients with sarcomas where LRRC15 is also expressed by malignant cells. ABBV-085 is a monomethyl auristatin-E antibody–drug conjugate that targets LRRC15 and showed antineoplastic efficacy in preclinical experiments. Herein, we report findings of ABBV-085 monotherapy or combination therapy in adult patients with sarcomas and other advanced solid tumors.
Patients and Methods:
This first-in-human phase I study (NCT02565758) assessed ABBV-085 safety, pharmacokinetics/pharmacodynamics, and preliminary antitumor activity. The study consisted of two parts: dose escalation and dose expansion. ABBV-085 was administered by intravenous infusion at 0.3 to 6.0 mg/kg every 14 days.
Results:
In total, 85 patients were enrolled; 45 patients received the recommended expansion dose of 3.6 mg/kg ABBV-085 monotherapy, including 10 with osteosarcoma and 10 with undifferentiated pleomorphic sarcoma (UPS). Most common treatment-related adverse events were fatigue, nausea, and decreased appetite. The overall response rate for patients with osteosarcoma/UPS treated at 3.6 mg/kg was 20%, including four confirmed partial responses. No monotherapy responses were observed for other advanced cancers treated at 3.6 mg/kg. One patient treated with ABBV-085 plus gemcitabine achieved partial response.
Conclusions:
ABBV-085 appeared safe and tolerable at a dose of 3.6 mg/kg every 14 days, with preliminary antitumor activity noted in patients with osteosarcoma and UPS. Given the high unmet need in these orphan malignancies, further investigation into targeting LRRC15 in these sarcomas may be warranted.
Data from Gene Expression Signatures Identify Novel Therapeutics for Metastatic Pancreatic Neuroendocrine Tumors
Authors: Scott Aaron T. , Weitz Michelle , Breheny Patrick J. , Ear Po Hien , Darbro Benjamin , Brown Bart J. , Braun Terry A. , Li Guiying , Umesalma Shaikamjad , Kaemmer Courtney A. , Maharjan Chandra K. , Quelle Dawn E. , Bellizzi Andrew M. , Chandrasekharan Chandrikha , Dillon Joseph S. , O'Dorisio Thomas M. , Howe James R.
Published: April 2023

AbstractPurpose:
Pancreatic neuroendocrine tumors (pNETs) are uncommon malignancies noted for their propensity to metastasize and comparatively favorable prognosis. Although both the treatment options and clinical outcomes have improved in the past decades, most patients will die of metastatic disease. New systemic therapies are needed.
Experimental Design:
Tissues were obtained from 43 patients with well-differentiated pNETs undergoing surgery. Gene expression was compared between primary tumors versus liver and lymph node metastases using RNA-Seq. Genes that were selectively elevated at only one metastatic site were filtered out to reduce tissue-specific effects. Ingenuity pathway analysis (IPA) and the Connectivity Map (CMap) identified drugs likely to antagonize metastasis-specific targets. The biological activity of top identified agents was tested in vitro using two pNET cell lines (BON-1 and QGP-1).
Results:
A total of 902 genes were differentially expressed in pNET metastases compared with primary tumors, 626 of which remained in the common metastatic profile after filtering. Analysis with IPA and CMap revealed altered activity of factors involved in survival and proliferation, and identified drugs targeting those pathways, including inhibitors of mTOR, PI3K, MEK, TOP2A, protein kinase C, NF-kB, cyclin-dependent kinase, and histone deacetylase. Inhibitors of MEK and TOP2A were consistently the most active compounds.
Conclusions:
We employed a complementary bioinformatics approach to identify novel therapeutics for pNETs by analyzing gene expression in metastatic tumors. The potential utility of these drugs was confirmed by in vitro cytotoxicity assays, suggesting drugs targeting MEK and TOP2A may be highly efficacious against metastatic pNETs. This is a promising strategy for discovering more effective treatments for patients with pNETs.
Data from Chromatin Accessibility Identifies Regulatory Elements Predictive of Gene Expression and Disease Outcome in Multiple Myeloma
Authors: Barwick Benjamin G. , Gupta Vikas A. , Matulis Shannon M. , Patton Jonathan C. , Powell Doris R. , Gu Yanyan , Jaye David L. , Conneely Karen N. , Lin Yin C. , Hofmeister Craig C. , Nooka Ajay K. , Keats Jonathan J. , Lonial Sagar , Vertino Paula M. , Boise Lawrence H.
Published: April 2023

AbstractPurpose:
Multiple myeloma is a malignancy of plasma cells. Extensive genetic and transcriptional characterization of myeloma has identified subtypes with prognostic and therapeutic implications. In contrast, relatively little is known about the myeloma epigenome.
Experimental Design:
CD138+CD38+ myeloma cells were isolated from fresh bone marrow aspirate or the same aspirate after freezing for 1–6 months. Gene expression and chromatin accessibility were compared between fresh and frozen samples by RNA sequencing (RNA-seq) and assay for transpose accessible chromatin sequencing (ATAC-seq). Chromatin accessible regions were used to identify regulatory RNA expression in more than 700 samples from newly diagnosed patients in the Multiple Myeloma Research Foundation CoMMpass trial (NCT01454297).
Results:
Gene expression and chromatin accessibility of cryopreserved myeloma recapitulated that of freshly isolated samples. ATAC-seq performed on a series of biobanked specimens identified thousands of chromatin accessible regions with hundreds being highly coordinated with gene expression. More than 4,700 of these chromatin accessible regions were transcribed in newly diagnosed myelomas from the CoMMpass trial. Regulatory element activity alone recapitulated myeloma gene expression subtypes, and in particular myeloma subtypes with immunoglobulin heavy chain translocations were defined by transcription of distal regulatory elements. Moreover, enhancer activity predicted oncogene expression implicating gene regulatory mechanisms in aggressive myeloma.
Conclusions:
These data demonstrate the feasibility of using biobanked specimens for retrospective studies of the myeloma epigenome and illustrate the unique enhancer landscapes of myeloma subtypes that are coupled to gene expression and disease progression.
Data from Multicenter Phase I/II Study of Nivolumab Combined with Paclitaxel Plus Ramucirumab as Second-line Treatment in Patients with Advanced Gastric Cancer
Authors: Nakajima Takako Eguchi , Kadowaki Shigenori , Minashi Keiko , Nishina Tomohiro , Yamanaka Takeharu , Hayashi Yuichiro , Izawa Naoki , Muro Kei , Hironaka Shuichi , Kajiwara Takeshi , Kawakami Yutaka
Published: April 2023

AbstractPurpose:
We conducted a phase I/II study to investigate the safety and efficacy of nivolumab with paclitaxel plus ramucirumab.
Patients and Methods:
Patients with advanced gastric cancer (AGC) refractory to first-line chemotherapy were included. Patients received nivolumab (3 mg/kg on days 1 and 15) combined with paclitaxel (80 mg/m2 on days 1, 8, and 15) and ramucirumab (8 mg/kg on days 1 and 15) every 4 weeks. After feasibility evaluation in six patients (phase I), 37 additional patients were enrolled in the phase II part with the primary endpoint of 6-month progression-free survival (PFS) rate with two-sided 80% confidence interval (CI). The combined positive score (CPS) was defined as the number of programmed death-ligand 1–positive cells divided by the total number of viable tumor cells multiplied by 100.
Results:
Forty-three patients were enrolled. Of these, 60.5% had CPS ≥ 1. Dose-limiting toxicities were observed in two patients, and the recommended dose was determined as level 1. Thirty-nine (90.7%) patients experienced treatment-related adverse events (AEs) grade ≥3 and 14 (32.6%) patients experienced immune-related AEs grade ≥3. The overall response rate was 37.2% (95% CI, 23.0%–53.5%) and the 6-month PFS rate was 46.5% (80% CI, 36.4%–55.8%; P = 0.067). Median survival time was 13.1 months (95% CI, 8.0–16.6 months): 13.8 months (95% CI, 8.0–19.5 months) in patients with CPS ≥ 1 and 8.0 months (95% CI, 4.8–24.1 months) in patients with CPS < 1.
Conclusions:
Nivolumab with paclitaxel plus ramucirumab demonstrated promising antitumor activity with manageable toxicities as second-line treatment for AGC.
Data from Defining the Comprehensive Genomic Landscapes of Pancreatic Ductal Adenocarcinoma Using Real-World Endoscopic Aspiration Samples
Authors: Semaan Alexander , Bernard Vincent , Lee Jaewon J. , Wong Justin W. , Huang Jonathan , Swartzlander Daniel B. , Stephens Bret M. , Monberg Maria E. , Weston Brian R. , Bhutani Manoop S. , Chang Kyle , Scheet Paul A. , Maitra Anirban , Jakubek Yasminka A. , Guerrero Paola A.
Published: April 2023

AbstractPurpose:
Most patients with pancreatic ductal adenocarcinoma (PDAC) present with surgically unresectable cancer. As a result, endoscopic ultrasound–guided fine-needle aspiration (EUS-FNA) is the most common biospecimen source available for diagnosis in treatment-naïve patients. Unfortunately, these limited samples are often not considered adequate for genomic analysis, precluding the opportunity for enrollment on precision medicine trials.
Experimental Design:
Applying an epithelial cell adhesion molecule (EpCAM)-enrichment strategy, we show the feasibility of using real-world EUS-FNA for in-depth, molecular-barcoded, whole-exome sequencing (WES) and somatic copy-number alteration (SCNA) analysis in 23 patients with PDAC.
Results:
Potentially actionable mutations were identified in >20% of patients. Further, an increased mutational burden and higher aneuploidy in WES data were associated with an adverse prognosis. To identify predictive biomarkers for first-line chemotherapy, we developed an SCNA-based complexity score that was associated with response to platinum-based regimens in this cohort.
Conclusions:
Collectively, these results emphasize the feasibility of real-world cytology samples for in-depth genomic characterization of PDAC and show the prognostic potential of SCNA for PDAC diagnosis.
Data from Composition, Spatial Characteristics, and Prognostic Significance of Myeloid Cell Infiltration in Pancreatic Cancer
Authors: Väyrynen Sara A. , Zhang Jinming , Yuan Chen , Väyrynen Juha P. , Dias Costa Andressa , Williams Hannah , Morales-Oyarvide Vicente , Lau Mai Chan , Rubinson Douglas A. , Dunne Richard F. , Kozak Margaret M. , Wang Wenjia , Agostini-Vulaj Diana , Drage Michael G. , Brais Lauren , Reilly Emma , Rahma Osama , Clancy Thomas , Wang Jiping , Linehan David C. , Aguirre Andrew J. , Fuchs Charles S. , Coussens Lisa M. , Chang Daniel T. , Koong Albert C. , Hezel Aram F. , Ogino Shuji , Nowak Jonathan A. , Wolpin Brian M.
Published: April 2023

AbstractPurpose:
Although abundant myeloid cell populations in the pancreatic ductal adenocarcinoma (PDAC) microenvironment have been postulated to suppress antitumor immunity, the composition of these populations, their spatial locations, and how they relate to patient outcomes are poorly understood.
Experimental Design:
To generate spatially resolved tumor and immune cell data at single-cell resolution, we developed two quantitative multiplex immunofluorescence assays to interrogate myeloid cells (CD15, CD14, ARG1, CD33, HLA-DR) and macrophages [CD68, CD163, CD86, IFN regulatory factor 5, MRC1 (CD206)] in the PDAC tumor microenvironment. Spatial point pattern analyses were conducted to assess the degree of colocalization between tumor cells and immune cells. Multivariable-adjusted Cox proportional hazards regression was used to assess associations with patient outcomes.
Results:
In a multi-institutional cohort of 305 primary PDAC resection specimens, myeloid cells were abundant, enriched within stromal regions, highly heterogeneous across tumors, and differed by somatic genotype. High densities of CD15+ARG1+ immunosuppressive granulocytic cells and M2-polarized macrophages were associated with worse patient survival. Moreover, beyond cell density, closer proximity of M2-polarized macrophages to tumor cells was strongly associated with disease-free survival, revealing the clinical significance and biologic importance of immune cell localization within tumor areas.
Conclusions:
A diverse set of myeloid cells are present within the PDAC tumor microenvironment and are distributed heterogeneously across patient tumors. Not only the densities but also the spatial locations of myeloid immune cells are associated with patient outcomes, highlighting the potential role of spatially resolved myeloid cell subtypes as quantitative biomarkers for PDAC prognosis and therapy.
Data from MRI and 18FET-PET Predict Survival Benefit from Bevacizumab Plus Radiotherapy in Patients with Isocitrate Dehydrogenase Wild-type Glioblastoma: Results from the Randomized ARTE Trial
Authors: Wirsching Hans-Georg , Roelcke Ulrich , Weller Jonathan , Hundsberger Thomas , Hottinger Andreas F. , von Moos Roger , Caparrotti Francesca , Conen Katrin , Remonda Luca , Roth Patrick , Ochsenbein Adrian , Tabatabai Ghazaleh , Weller Michael
Published: April 2023

AbstractPurpose:
To explore a prognostic or predictive role of MRI and O-(2–18F-fluoroethyl)-L-tyrosine (18FET) PET parameters for outcome in the randomized multicenter trial ARTE that compared bevacizumab plus radiotherapy with radiotherpay alone in elderly patients with glioblastoma.
Patients and Methods:
Patients with isocitrate dehydrogenase wild-type glioblastoma ages 65 years or older were included in this post hoc analysis. Tumor volumetric and apparent diffusion coefficient (ADC) analyses of serial MRI scans from 67 patients and serial 18FET-PET tumor-to-brain intensity ratios (TBRs) from 31 patients were analyzed blinded for treatment arm and outcome. Multivariate Cox regression analysis was done to account for established prognostic factors and treatment arm.
Results:
Overall survival benefit from bevacizumab plus radiotherapy compared with radiotherapy alone was observed for larger pretreatment MRI contrast-enhancing tumor [HR per cm3 0.94; 95% confidence interval (CI), 0.89–0.99] and for higher ADC (HR 0.18; CI, 0.05–0.66). Higher 18FET-TBR on pretreatment PET scans was associated with inferior overall survival in both arms. Response assessed by standard MRI-based Response Assessment in Neuro-Oncology criteria was associated with overall survival in the bevacizumab plus radiotherapy arm by trend only (P = 0.09). High 18FET-TBR of noncontrast-enhancing tumor portions during bevacizumab therapy was associated with inferior overall survival on multivariate analysis (HR 5.97; CI, 1.16–30.8).
Conclusions:
Large pretreatment contrast-enhancing tumor mass and higher ADCs identify patients who may experience a survival benefit from bevacizumab plus radiotherapy. Persistent 18FET-PET signal of no longer contrast-enhancing tumor after concomitant bevacizumab plus radiotherapy suggests pseudoresponse and predicts poor outcome.