bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Tumor-Associated Fibroblasts Promote HER2-Targeted Therapy Resistance through FGFR2 Activation
Authors: Fernández-Nogueira Patricia , Mancino Mario , Fuster Gemma , López-Plana Anna , Jauregui Patricia , Almendro Vanesa , Enreig Estel , Menéndez Silvia , Rojo Federico , Noguera-Castells Aleix , Bill Anke , Gaither L. Alex , Serrano Laia , Recalde-Percaz Leire , Moragas Núria , Alonso Raul , Ametller Elisabet , Rovira Ana , Lluch Ana , Albanell Joan , Gascon Pere , Bragado Paloma
Published: April 2023

AbstractPurpose:
Despite the therapeutic success of existing HER2-targeted therapies, tumors invariably relapse. This study aimed at identifying new mechanisms responsible for HER2-targeted therapy resistance.
Experimental Design:
We have used a platform of HER2-targeted therapy–resistant cell lines and primary cultures of healthy and tumor-associated fibroblasts (TAF) to identify new potential targets related to tumor escape from anti-HER2 therapies.
Results:
We have shown that TAFs promote resistance to HER2-targeted therapies. TAFs produce and secrete high levels of FGF5, which induces FGFR2 activation in the surrounding breast cancer cells. FGFR2 transactivates HER2 via c-Src, leading to resistance to HER2-targeted therapies. In vivo, coinoculating nonresistant cell lines with TAFs results in more aggressive and resistant tumors. Resistant cells activate fibroblasts and secrete FGFR ligands, creating a positive feedback loop that fuels resistance. FGFR2 inhibition not only inhibits HER2 activation, but also induces apoptosis in cells resistant to HER2-targeted therapies. In vivo, inhibitors of FGFR2 reverse resistance and resensitize resistant cells to HER2-targeted therapies. In HER2 patients' samples, α-SMA, FGF5, and FGFR2 contribute to poor outcome and correlate with c-Src activation. Importantly, expression of FGF5 and phospho-HER2 correlated with a reduced pathologic complete response rate in patients with HER2-positive breast cancer treated with neoadjuvant trastuzumab, which highlights the significant role of TAFs/FGF5 in HER2 breast cancer progression and resistance.
Conclusions:
We have identified the TAF/FGF5/FGFR2/c-Src/HER2 axis as an escape pathway responsible for HER2-targeted therapy resistance in breast cancer, which can be reversed by FGFR inhibitors.
Data from Comprehensive Transcriptomic Profiling Identifies Breast Cancer Patients Who May Be Spared Adjuvant Systemic Therapy
Authors: Sjöström Martin , Chang S. Laura , Fishbane Nick , Davicioni Elai , Hartman Linda , Holmberg Erik , Feng Felix Y. , Speers Corey W. , Pierce Lori J. , Malmström Per , Fernö Mårten , Karlsson Per
Published: April 2023

AbstractPurpose:
There is currently no molecular signature in clinical use for adjuvant endocrine therapy omission in breast cancer. Given the unique trial design of SweBCG91-RT, where adjuvant endocrine and chemotherapy were largely unadministered, we sought to evaluate the potential of transcriptomic profiling for identifying patients who may be spared adjuvant endocrine therapy.
Experimental Design:
We performed a whole-transcriptome analysis of SweBCG91-RT, a randomized phase III trial of ± radiotherapy after breast-conserving surgery for node-negative stage I–IIA breast cancer. Ninety-two percent of patients were untreated by both adjuvant endocrine therapy and chemotherapy. We calculated 15 transcriptomic signatures from the literature and combined them into an average genomic risk, which was further used to derive a novel 141-gene signature (MET141). All signatures were then independently examined in SweBCG91-RT and in the publicly available METABRIC cohort.
Results:
In SweBCG91-RT, 454 patients were node-negative, postmenopausal, and systemically untreated with ER-positive, HER2-negative cancers, which constitutes a low-risk subgroup and potential candidates for therapy omission. Most transcriptomic signatures were highly prognostic for distant metastasis, but considerable discordance was observed on the individual patient level. Within the MET141 low-risk subgroup (lowest 25th percentile of scores), 95% of patients were free of metastasis at 15 years, even in the absence of adjuvant endocrine therapy. In a clinically low-risk subgroup of the METABRIC cohort not treated with systemic therapy, no breast cancer death occurred among the MET141 low-risk patients.
Conclusions:
Transcriptomic profiling identifies patients with an excellent outcome without any systemic adjuvant therapy in clinically low-risk patients of the SweBCG91-RT and METABRIC cohorts.
Data from Cooperative Immune-Mediated Mechanisms of the HDAC Inhibitor Entinostat, an IL15 Superagonist, and a Cancer Vaccine Effectively Synergize as a Novel Cancer Therapy
Authors: Hicks Kristin C. , Knudson Karin M. , Lee Karin L. , Hamilton Duane H. , Hodge James W. , Figg William D. , Ordentlich Peter , Jones Frank R. , Rabizadeh Shahrooz , Soon-Shiong Patrick , Schlom Jeffrey , Gameiro Sofia R.
Published: April 2023

AbstractPurpose:
Immunotherapy has demonstrated clinical efficacy in subsets of patients with solid carcinomas. Multimodal therapies using agents that can affect different arms of the immune system and/or tumor microenvironment (TME) might increase clinical responses.
Experimental Design:
We demonstrate that entinostat, a class I histone deacetylase inhibitor, enhances the antitumor efficacy of the IL15 superagonist N-803 plus vaccine in 4T1 triple-negative breast and MC38-CEA colon murine carcinoma models. A comprehensive immune and gene-expression analysis was performed in the periphery and/or TME of MC38-CEA tumor–bearing mice.
Results:
Although N-803 plus vaccine induced peripheral CD8+ T-cell activation and cytokine production, there was no reduction in tumor burden and poor tumor infiltration of CD8+ T cells with minimal levels of granzyme B. For the first time, we demonstrate that the addition of entinostat to N-803 plus vaccine promoted significant tumor control, correlating with increased expression of genes associated with tumor inflammation, enhanced infiltration of activated CD8+ T cells with maximal granzyme B, T-cell responses to multiple tumor-associated antigens, increased serum IFNγ, reduction of regulatory T cells in the TME, and decreased expression of the checkpoint V-domain Ig suppressor of T-cell activation (VISTA) on multiple immune subsets.
Conclusions:
Collectively, these data demonstrate that the synergistic combination of entinostat, N-803, and vaccine elicits potent antitumor activity by generating a more inflamed TME. These findings thus form the rationale for the use of this combination of agents for patients harboring poorly or noninflamed solid carcinomas.
Data from Prognostic Score and Cytogenetic Risk Classification for Chronic Lymphocytic Leukemia Patients: Center for International Blood and Marrow Transplant Research Report
Authors: Kim Haesook T. , Ahn Kwang Woo , Hu Zhen-Huan , Davids Matthew S. , Volpe Virginia O. , Antin Joseph H. , Sorror Mohamed L. , Shadman Mazyar , Press Oliver , Pidala Joseph , Hogan William , Negrin Robert , Devine Steven , Uberti Joseph , Agura Edward , Nash Richard , Mehta Jayesh , McGuirk Joseph , Forman Stephen , Langston Amelia , Giralt Sergio A. , Perales Miguel-Angel , Battiwalla Minoo , Hale Gregory A. , Gale Robert Peter , Marks David I. , Hamadani Mehdi , Ganguly Sid , Bacher Ulrike , Lazarus Hillard , Reshef Ran , Hildebrandt Gerhard C. , Inamoto Yoshihiro , Cahn Jean-Yves , Solh Melhem , Kharfan-Dabaja Mohamed A. , Ghosh Nilanjan , Saad Ayman , Aljurf Mahmoud , Schouten Harry C. , Hill Brian T. , Pawarode Attaphol , Kindwall-Keller Tamila , Saba Nakhle , Copelan Edward A. , Nathan Sunita , Beitinjaneh Amer , Savani Bipin N. , Cerny Jan , Grunwald Michael R. , Yared Jean , Wirk Baldeep M. , Nishihori Taiga , Chhabra Saurabh , Olsson Richard F. , Bashey Asad , Gergis Usama , Popat Uday , Sobecks Ronald , Alyea Edwin , Saber Wael , Brown Jennifer R.
Published: April 2023

AbstractPurpose:
To develop a prognostic model and cytogenetic risk classification for previously treated patients with chronic lymphocytic leukemia (CLL) undergoing reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT).
Experimental Design:
We performed a retrospective analysis of outcomes of 606 patients with CLL who underwent RIC allogeneic HCT between 2008 and 2014 reported to the Center for International Blood and Marrow Transplant Research.
Results:
On the basis of multivariable models, disease status, comorbidity index, lymphocyte count, and white blood cell count at HCT were selected for the development of prognostic model. Using the prognostic score, we stratified patients into low-, intermediate-, high-, and very-high-risk [4-year progression-free survival (PFS) 58%, 42%, 33%, and 25%, respectively, P < 0.0001; 4-year overall survival (OS) 70%, 57%, 54%, and 38%, respectively, P < 0.0001]. We also evaluated karyotypic abnormalities together with del(17p) and found that del(17p) or ≥5 abnormalities showed inferior PFS. Using a multivariable model, we classified cytogenetic risk into low, intermediate, and high (P < 0.0001). When the prognostic score and cytogenetic risk were combined, patients with low prognostic score and low cytogenetic risk had prolonged PFS (61% at 4 years) and OS (75% at 4 years).
Conclusions:
In this large cohort of patients with previously treated CLL who underwent RIC HCT, we developed a robust prognostic scoring system of HCT outcomes and a novel cytogenetic-based risk stratification system. These prognostic models can be used for counseling patients, comparing data across studies, and providing a benchmark for future interventions. For future study, we will further validate these models for patients receiving targeted therapies prior to HCT.
Data from Antigen Experienced T Cells from Peripheral Blood Recognize p53 Neoantigens
Authors: Malekzadeh Parisa , Yossef Rami , Cafri Gal , Paria Biman C. , Lowery Frank J. , Jafferji Mohammad , Good Meghan L. , Sachs Abraham , Copeland Amy R. , Kim Sanghyun P. , Kivitz Scott , Parkhurst Maria R. , Robbins Paul F. , Ray Satyajit , Xi Liqiang , Raffeld Mark , Yu Zhiya , Restifo Nicholas P. , Somerville Robert P.T. , Rosenberg Steven A. , Deniger Drew C.
Published: April 2023

AbstractPurpose:
The purpose of this study was to evaluate antigen experienced T cells in peripheral blood lymphocytes (PBL) for responses to p53 neoantigens.
Experimental Design:
PBLs from patients with a mutated TP53 tumor were sorted for antigen-experienced T cells and in vitro stimulation (IVS) was performed with p53 neoantigens. The IVS cultures were stimulated with antigen-presenting cells expressing p53 neoantigens, enriched for 41BB/OX40 and grown with rapid expansion protocol.
Results:
T-cell responses were not observed in the PBLs of 4 patients who did not have tumor-infiltrating lymphocyte (TIL) responses to mutated TP53. In contrast, 5 patients with TIL responses to mutated TP53 also had similar T-cell responses in their PBLs, indicating that the PBLs and TILs were congruent in p53 neoantigen reactivity. CD4+ and CD8+ T cells were specific for p53R175H, p53Y220C, or p53R248W neoantigens, including a 78% reactive T-cell culture against p53R175H and HLA-A*02:01. Tracking TCRB clonotypes (clonality, top ranked, and TP53 mutation-specific) supported the enrichment of p53 neoantigen–reactive T cells from PBLs. The same T-cell receptor (TCR) from the TIL was found in the IVS cultures in three cases and multiple unique TCRs were found in another patient. TP53 mutation–specific T cells also recognized tumor cell lines bearing the appropriate human leukocyte antigen restriction element and TP53 mutation, indicating these T cells could recognize processed and presented p53 neoantigens.
Conclusions:
PBL was a noninvasive source of T cells targeting TP53 mutations for cell therapy and can provide a window into intratumoral p53 neoantigen immune responses.

See related commentary by Olivera et al., p. 1203
Data from A Phase I Dose-Escalation Trial of BN-CV301, a Recombinant Poxviral Vaccine Targeting MUC1 and CEA with Costimulatory Molecules
Authors: Gatti-Mays Margaret E. , Strauss Julius , Donahue Renee N. , Palena Claudia , Del Rivero Jaydira , Redman Jason M. , Madan Ravi A. , Marté Jennifer L. , Cordes Lisa M. , Lamping Elizabeth , Orpia Alanvin , Burmeister Andrea , Wagner Eva , Pico Navarro Cesar , Heery Christopher R. , Schlom Jeffrey , Gulley James L.
Published: April 2023

AbstractPurpose:
BN-CV301 is a poxviral-based vaccine comprised of recombinant (rec.) modified vaccinia Ankara (MVA-BN-CV301; prime) and rec. fowlpox (FPV-CV301; boost). Like its predecessor PANVAC, BN-CV301 contains transgenes encoding tumor-associated antigens MUC1 and CEA as well as costimulatory molecules (B7.1, ICAM-1, and LFA-3). PANVAC was reengineered to make it safer and more antigenic.
Patients and Methods:
This open-label, 3+3 design, dose-escalation trial evaluated three dose levels (DL) of MVA-BN-CV301: one, two, or four subcutaneous injections of 4 × 108 infectious units (Inf.U)/0.5 mL on weeks 0 and 4. All patients received FPV-CV301 subcutaneously at 1 × 109 Inf.U/0.5 mL every 2 weeks for 4 doses, then every 4 weeks. Clinical and immune responses were evaluated.
Results:
There were no dose-limiting toxicities. Twelve patients enrolled on trial [dose level (DL) 1 = 3, DL2 = 3, DL3 = 6). Most side effects were seen with the prime doses and lessened with subsequent boosters. All treatment-related adverse events were temporary, self-limiting, grade 1/2, and included injection-site reactions and flu-like symptoms. Antigen-specific T cells to MUC1 and CEA, as well as to a cascade antigen, brachyury, were generated in most patients. Single-agent BN-CV301 produced a confirmed partial response (PR) in 1 patient and prolonged stable disease (SD) in multiple patients, most notably in KRAS-mutant gastrointestinal tumors. Furthermore, 2 patients with KRAS-mutant colorectal cancer had prolonged SD when treated with an anti-PD-L1 antibody following BN-CV301.
Conclusions:
The BN-CV301 vaccine can be safely administered to patients with advanced cancer. Further studies of the vaccine in combination with other agents are planned.

See related commentary by Repáraz et al., p. 4871
Data from Circulating miRNAs and PD-L1 Tumor Expression Are Associated with Survival in Advanced NSCLC Patients Treated with Immunotherapy: a Prospective Study
Authors: Boeri Mattia , Milione Massimo , Proto Claudia , Signorelli Diego , Lo Russo Giuseppe , Galeone Carlotta , Verri Carla , Mensah Mavis , Centonze Giovanni , Martinetti Antonia , Sottotetti Elisa , Pastorino Ugo , Garassino Marina Chiara , Sozzi Gabriella
Published: April 2023

AbstractPurpose:
Immune-checkpoint inhibitors (ICI) have improved the survival of patients with non–small cell lung cancer (NSCLC). However, only a subset of patients benefit from ICIs, and the role of PD-L1 as predictive biomarker is still debated. A plasma immune-related miRNA-signature classifier (MSC) was established in lung cancer screening settings to identify the lethal form of the disease in early stages. In this exploratory study, we tested the efficacy of the MSC as prognostic marker in patients with advanced NSCLC treated with ICIs.
Experimental Design:
The MSC risk level was prospectively assessed in a consecutive series of 140 patients with NSCLC before starting treatment with ICIs. Overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) in strata of PD-L1 and MSC alone or combined were considered as endpoints. Multiple plasma samples to monitor MSC risk level during treatment were also profiled.
Results:
Adequate tissue and plasma samples were available from 111 (79%) and 104 (75%) patients with NSCLC, respectively. MSC risk level was associated with ORR (P = 0.0009), PFS [multivariate HR = 0.31; 95% confidence interval (CI), 0.17–0.56; P = 0.0001], and OS (multivariate HR = 0.33; 95% CI, 0.18–0.59; P = 0.0002). The combination of MSC and PD-L1 stratified patients into three risk groups having 39%–18%–0% 1-year PFS (P < 0.0001) and 88%–44%–0% 1-year OS (P < 0.0001), according to the presence of 2–1–0 favorable markers. During treatment, MSC risk level decreased or remained low until tumor progression in patients with responsive or stable disease.
Conclusions:
The plasma MSC test could supplement PD-L1 tumor expression to identify a subgroup of patients with advanced lung cancer with worse ORR, PFS, and OS in immunotherapy regimens.
Data from TAp73 Modifies Metabolism and Positively Regulates Growth of Cancer Stem–Like Cells in a Redox-Sensitive Manner
Authors: Sharif Tanveer , Dai Cathleen , Martell Emma , Ghassemi-Rad Mohammad Saleh , Hanes Mark Robert , Murphy Patrick J. , Kennedy Barry E. , Venugopal Chitra , Subapanditha Minomi , Giacomantonio Carman A. , Marcato Paola , Singh Sheila K. , Gujar Shashi
Published: April 2023

AbstractPurpose:
Stem-like cancer cells, with characteristic self-renewal abilities, remain highly refractory to various clinical interventions. As such, stemness-inhibiting entities, such as tumor suppressor p53, are therapeutically pursued for their anticancer activities. Interestingly, similar implications for tumor suppressor TAp73 in regulating stemness features within stem-like cancer cells remain unknown.

Experimental Design: This study utilizes various in vitro molecular biology techniques, including immunoblotting, qRT-PCR, and mass spectrometry–based proteomics, and metabolomics approaches to study the role of TAp73 in human and murine embryonal carcinoma stem-like cells (ECSLC) as well as human breast cancer stem-like cells (BCSLC). These findings were confirmed using patient-derived brain tumor–initiating cells (BTIC) and in vivo xenograft models.
Results:
TAp73 inhibition decreases the expression of stem cell transcription factors Oct4, Nanog, and Sox-2, as well as tumorsphere formation capacity in ECSLCs. In vivo, TAp73-deficient ECSLCs and BCSLCs demonstrate decreased tumorigenic potential when xenografted in mice. Mechanistically, TAp73 modifies the proline regulatory axis through regulation of enzymes GLS, OAT, and PYCR1 involved in the interconversion of proline–glutamine–ornithine. Further, TAp73 deficiency exacerbates glutamine dependency, enhances accumulation of reactive oxygen species through reduced superoxide dismutase 1 (SOD1) expression, and promotes differentiation by arresting cell cycle and elevating autophagy. Most importantly, the knockdown of TAp73 in CD133HI BTICs, separated from three different glioblastoma patients, strongly decreases the expression of prosurvival factors Sox-2, BMI-1, and SOD1, and profoundly decreases their self-renewal capacity as evidenced through their reduced tumorsphere formation ability.
Conclusions:
Collectively, we reveal a clinically relevant aspect of cancer cell growth and stemness regulation through TAp73-mediated redox-sensitive metabolic reprogramming.
Data from High-Intensity Focused Ultrasound (HIFU) Triggers Immune Sensitization of Refractory Murine Neuroblastoma to Checkpoint Inhibitor Therapy
Authors: Eranki Avinash , Srinivasan Priya , Ries Mario , Kim AeRang , Lazarski Christopher A. , Rossi Christopher T. , Khokhlova Tatiana D. , Wilson Emmanuel , Knoblach Susan M. , Sharma Karun V. , Wood Bradford J. , Moonen Chrit , Sandler Anthony D. , Kim Peter C.W.
Published: April 2023

AbstractPurpose:
Immunotherapy promises unprecedented benefits to patients with cancer. However, the majority of cancer types, including high-risk neuroblastoma, remain immunologically unresponsive. High-intensity focused ultrasound (HIFU) is a noninvasive technique that can mechanically fractionate tumors, transforming immunologically “cold” tumors into responsive “hot” tumors.
Experimental Design:
We treated <2% of tumor volume in previously unresponsive, large, refractory murine neuroblastoma tumors with mechanical HIFU and assessed systemic immune response using flow cytometry, ELISA, and gene sequencing. In addition, we combined this treatment with αCTLA-4 and αPD-L1 to study its effect on the immune response and long-term survival.
Results:
Combining HIFU with αCTLA-4 and αPD-L1 significantly enhances antitumor response, improving survival from 0% to 62.5%. HIFU alone causes upregulation of splenic and lymph node NK cells and circulating IL2, IFNγ, and DAMPs, whereas immune regulators like CD4+Foxp3+, IL10, and VEGF-A are significantly reduced. HIFU combined with checkpoint inhibitors induced significant increases in intratumoral CD4+, CD8α+, and CD8α+CD11c+ cells, CD11c+ in regional lymph nodes, and decrease in circulating IL10 compared with untreated group. We also report significant abscopal effect following unilateral treatment of mice with large, established bilateral tumors using HIFU and checkpoint inhibitors compared with tumors treated with HIFU or checkpoint inhibitors alone (61.1% survival, P < 0.0001). This combination treatment significantly also induces CD4+CD44+hiCD62L+low and CD8α+CD44+hiCD62L+low population and is adoptively transferable, imparting immunity, slowing subsequent de novo tumor engraftment.
Conclusions:
Mechanical fractionation of tumors using HIFU can effectively induce immune sensitization in a previously unresponsive murine neuroblastoma model and promises a novel yet efficacious immunoadjuvant modality to overcome therapeutic resistance.
Data from Functional Properties of KIT Mutations Are Associated with Differential Clinical Outcomes and Response to Targeted Therapeutics in CBF Acute Myeloid Leukemia
Authors: Tarlock Katherine , Alonzo Todd A. , Wang Yi-Cheng , Gerbing Robert B. , Ries Rhonda , Loken Michael R. , Pardo Laura , Hylkema Tiffany , Joaquin Jason , Sarukkai Leela , Raimondi Susana C. , Hirsch Betsy , Sung Lillian , Aplenc Richard , Bernstein Irwin , Gamis Alan S. , Meshinchi Soheil , Pollard Jessica A.
Published: April 2023

AbstractPurpose:
KIT mutations (KIT+) are common in core binding factor (CBF) AML and have been associated with varying prognostic significance. We sought to define the functional and clinical significance of distinct KIT mutations in CBF pediatric AML.
Experimental Design:
Following transfection of exon 17 (E17) and exon 8 (E8) mutations into HEK293 and Ba/F3 cells, KIT phosphorylation, cytokine-independent growth, and response to tyrosine kinase inhibitors (TKI) were evaluated. Clinical outcomes of patients treated on COG AAML0531 (NCT01407757), a phase III study of gemtuzumab ozogamicin (GO), were analyzed according to mutation status [KIT+ vs. wild-type KIT (KIT−)] and mutation location (E8 vs. E17).
Results:
KIT mutations were detected in 63 of 205 patients (31%); 22 (35%) involved only E8, 32 (51%) only E17, 6 (10%) both exons, and 3 (5%) alternative exons. Functional studies demonstrated that E17, but not E8, mutations result in aberrant KIT phosphorylation and growth. TKI exposure significantly affected growth of E17, but not E8, transfected cells. Patients with KIT+ CBF AML had overall survival similar to those with KIT− (78% vs. 81%, P = 0.905) but higher relapse rates (RR = 43% vs. 21%; P = 0.005). E17 KIT+ outcomes were inferior to KIT− patients [disease-free survival (DFS), 51% vs. 73%, P = 0.027; RR = 21% vs. 46%, P = 0.007)], although gemtuzumab ozogamicin abrogated this negative prognostic impact. E8 mutations lacked significant prognostic effect, and GO failed to significantly improve outcome.
Conclusions:
E17 mutations affect prognosis in CBF AML, as well as response to GO and TKIs; thus, clinical trials using both agents should be considered for KIT+ patients.
Data from Extended 5-Year Follow-up Results of a Phase Ib Study (BRIM7) of Vemurafenib and Cobimetinib in BRAF-Mutant Melanoma
Authors: Ribas Antoni , Daud Adil , Pavlick Anna C. , Gonzalez Rene , Lewis Karl D. , Hamid Omid , Gajewski Thomas F. , Puzanov Igor , Wongchenko Matthew , Rooney Isabelle , Hsu Jessie J. , Yan Yibing , Park Erica , McArthur Grant A.
Published: April 2023

AbstractPurpose:
To report the 5-year overall survival (OS) landmark and the long-term safety profile of vemurafenib plus cobimetinib (BRAF plus MEK inhibition, respectively) in the BRIM7 study.
Patients and Methods:
This phase Ib, dose-finding, and expansion study evaluated combination treatment with vemurafenib and cobimetinib in two cohorts of patients with advanced BRAFV600-mutated melanoma: patients who were BRAF inhibitor (BRAFi)-naïve (n = 63) or patients who had progressed on prior treatment with BRAFi monotherapy [vemurafenib monotherapy–progressive disease (PD); n = 66]. Patients in the dose-escalation phase received vemurafenib at 720 or 960 mg twice daily in combination with cobimetinib at 60, 80, or 100 mg/d for 14 days on/14 days off, 21 days on/7 days off, or continuously. Two regimens were selected for expansion: vemurafenib (720 and 960 mg twice daily) and cobimetinib (60 mg/d 21/7).
Results:
Median OS was 31.8 months [95% confidence interval (CI), 24.5–not estimable] in the BRAFi-naïve cohort. The landmark OS rate plateaued at 39.2% at years 4 and 5 of follow-up. In the vemurafenib monotherapy–PD cohort, the median OS was 8.5 months (95% CI, 6.7–11.1), and the landmark OS rate plateaued at 14.0% from 3 years of follow-up. No increase was observed in the frequency and severity of adverse events with long-term follow-up. No new toxicities were detected, and there was no increase in the frequency of symptomatic MEK inhibitor class-effect adverse events.
Conclusions:
A subset of patients with advanced BRAFV600-mutated melanoma treated with a combination regimen of vemurafenib and cobimetinib achieve favorable long-term outcomes.
Data from A Phase I, Open-Label, Multicenter, Dose-escalation Study of the Oral Selective FGFR Inhibitor Debio 1347 in Patients with Advanced Solid Tumors Harboring FGFR Gene Alterations
Authors: Voss Martin H. , Hierro Cinta , Heist Rebecca S. , Cleary James M. , Meric-Bernstam Funda , Tabernero Josep , Janku Filip , Gandhi Leena , Iafrate A. John , Borger Darrell R. , Ishii Nobuya , Hu Youyou , Kirpicheva Yulia , Nicolas-Metral Valerie , Pokorska-Bocci Anna , Vaslin Chessex Anne , Zanna Claudio , Flaherty Keith T. , Baselga Jose
Published: April 2023

AbstractPurpose:
To investigate tolerability, efficacy, and pharmacokinetics/pharmacodynamics of Debio 1347, a selective FGFR inhibitor.
Patients and Methods:
This was a first-in-human, multicenter, open-label study in patients with advanced solid tumors harboring FGFR1–3 gene alterations. Eligible patients received oral Debio 1347 at escalating doses once daily until disease progression or intolerable toxicity. Dose-limiting toxicities (DLT) were evaluated during the first 4 weeks on treatment, pharmacokinetics/pharmacodynamics postfirst dose and after 4 weeks.
Results:
A total of 71 patients were screened and 58 treated with Debio 1347 at doses from 10 to 150 mg/day. Predominant tumor types were breast and biliary duct cancer, most common gene alterations were FGFR1 amplifications (40%) and mutations in FGFR2 (12%) and FGFR3 (17%); 12 patients (21%) showed FGFR fusions. Five patients at three dose levels had six DLTs (dry mouth/eyes, hyperamylasemia, hypercalcemia, hyperbilirubinemia, hyperphosphatemia, and stomatitis). The maximum tolerated dose was not reached, but dermatologic toxicity became sometimes dose limiting beyond the DLT period at ≥80 mg/day. Adverse events required dose modifications in 52% of patients, mostly due to dose-dependent, asymptomatic hyperphosphatemia (22%). RECIST responses were seen across tumor types and mechanisms of FGFR activation. Six patients, 3 with FGFR fusions, demonstrated partial responses, 10 additional patients' tumor size regressions of ≤30%. Plasma half-life was 11.5 hours. Serum phosphate increased with Debio 1347 plasma levels and confirmed target engagement at doses ≥60 mg/day.
Conclusions:
Preliminary efficacy was encouraging and tolerability acceptable up to 80 mg/day, which is now used in an extension part of the study.
Data from Proteogenomic Characterization of Patient-Derived Xenografts Highlights the Role of REST in Neuroendocrine Differentiation of Castration-Resistant Prostate Cancer
Authors: Flores-Morales Amilcar , Bergmann Tobias B. , Lavallee Charlotte , Batth Tanveer S. , Lin Dong , Lerdrup Mads , Friis Stine , Bartels Anette , Kristensen Gitte , Krzyzanowska Agnieszka , Xue Hui , Fazli Ladan , Hansen Klaus H. , Røder Martin A. , Brasso Klaus , Moreira José M. , Bjartell Anders , Wang Yuzhuo , Olsen Jesper V. , Collins Colin C. , Iglesias-Gato Diego
Published: April 2023

AbstractPurpose:
An increasing number of castration-resistant prostate cancer (CRPC) tumors exhibit neuroendocrine (NE) features. NE prostate cancer (NEPC) has poor prognosis, and its development is poorly understood.

Experimental Design: We applied mass spectrometry–based proteomics to a unique set of 17 prostate cancer patient–derived xenografts (PDX) to characterize the effects of castration in vivo, and the proteome differences between NEPC and prostate adenocarcinomas. Genome-wide profiling of REST-occupied regions in prostate cancer cells was correlated to the expression changes in vivo to investigate the role of the transcriptional repressor REST in castration-induced NEPC differentiation.
Results:
An average of 4,881 proteins were identified and quantified from each PDX. Proteins related to neurogenesis, cell-cycle regulation, and DNA repair were found upregulated and elevated in NEPC, while the reduced levels of proteins involved in mitochondrial functions suggested a prevalent glycolytic metabolism of NEPC tumors. Integration of the REST chromatin bound regions with expression changes indicated a direct role of REST in regulating neuronal gene expression in prostate cancer cells. Mechanistically, depletion of REST led to cell-cycle arrest in G1, which could be rescued by p53 knockdown. Finally, the expression of the REST-regulated gene secretagogin (SCGN) correlated with an increased risk of suffering disease relapse after radical prostatectomy.
Conclusions:
This study presents the first deep characterization of the proteome of NEPC and suggests that concomitant inhibition of REST and the p53 pathway would promote NEPC. We also identify SCGN as a novel prognostic marker in prostate cancer.
Data from Gene Expression Profiling Reveals Aberrant T-cell Marker Expression on Tumor Cells of Waldenström's Macroglobulinemia
Authors: Hao Mu , Barlogie Bart , Tricot Guido , Liu Lanting , Qiu Lugui , Shaughnessy John D. , Zhan Fenghuang
Published: April 2023

AbstractPurpose:
That the malignant clone of Waldenström's macroglobulinemia (WM) demonstrates significant intraclonal heterogeneity with respect to plasmacytoid differentiation indicates the mechanistic complexity of tumorigenesis and progression. Identification of WM genes by comparing different stages of B cells may provide novel druggable targets.
Experimental Design:
The gene expression signatures of CD19+ B cells (BC) and CD138+ plasma cells (PC) from 19 patients with WM were compared with those of BCs from peripheral blood and tonsil and to those of PCs from the marrow of healthy (N-PC) and multiple myeloma donors (MM-PC), as well as tonsil (T-PC). Flow cytometry and immunofluorescence were used to examine T-cell marker expression on WM tumor cells.
Results:
Consistent with defective differentiation, both BCs and PCs from WM cases expressed abnormal differentiation markers. Sets of 55 and 46 genes were differentially expressed in WM-BC and WM-PC, respectively; and 40 genes uniquely dysregulated in WM samples were identified. Dysregulated genes included cytokines, growth factor receptors, and oncogenes not previously implicated in WM or other plasma cell dyscrasias. Interestingly, strong upregulation of both IL6 and IL6R was confirmed. Supervised cluster analysis of PC revealed that marrow-derived WM-PC was either MM-PC–like or T-PC–like, but not N-PC–like. The aberrant expression of T-cell markers was confirmed at the protein level in WM-BC.
Conclusions:
We showed that comparative microarray profiles allowed gaining more comprehensive insights into the biology of WM. The data presented here have implications for the development of novel therapies, such as targeting aberrant T-cell markers in WM.
Data from Fusion Kinases Identified by Genomic Analyses of Sporadic Microsatellite Instability–High Colorectal Cancers
Authors: Sato Kazuhito , Kawazu Masahito , Yamamoto Yoko , Ueno Toshihide , Kojima Shinya , Nagae Genta , Abe Hiroyuki , Soda Manabu , Oga Takafumi , Kohsaka Shinji , Sai Eirin , Yamashita Yoshihiro , Iinuma Hisae , Fukayama Masashi , Aburatani Hiroyuki , Watanabe Toshiaki , Mano Hiroyuki
Published: April 2023

AbstractPurpose:
Colorectal cancers with microsatellite instability–high (MSI-H) status, due to mismatch repair deficiency, are associated with poor patient outcomes after relapse. We aimed to identify novel therapeutic targets for them.
Experimental Design:
We performed MSI analyses of over 2,800 surgically resected colorectal tumors obtained from consecutive patients treated in Japan from 1998 through June 2016. Whole-exome sequencing, transcriptome sequencing, and methylation analyses were performed on 149 of 162 tumors showing MSI in BAT25 and BAT26 loci. We analyzed patient survival times using Bonferroni-adjusted log-rank tests.
Results:
Sporadic MSI-H colorectal cancers with promoter methylation of MLH1 (called MM) had a clinicopathological profile that was distinct from that of colorectal cancers of patients with germline mutations (Lynch syndrome, LS-associated) or somatic, Lynch-like mutations in mismatch repair genes. MM tumors had more insertions and deletions and more recurrent mutations in BRAF and RNF43 than LS-associated or Lynch-like MSI-H tumors. Eleven fusion kinases were exclusively detected in MM MSI-H colorectal cancers lacking oncogenic KRAS/BRAF missense mutations and were associated with worse post-relapse prognosis. We developed a simple method to identify MM tumors and applied it to a validation cohort of 28 MSI-H colorectal cancers, identifying 16 MM tumors and 2 fusion kinases.
Conclusions:
We discovered that fusion kinases are frequently observed among sporadic MM MSI-H colorectal cancers. The new method to identify MM tumors enables us to straightforwardly group MSI-H patients into candidates of LS or fusion kinase carriers.
Data from Cell-free Circulating Tumor DNA Variant Allele Frequency Associates with Survival in Metastatic Cancer
Authors: Pairawan Seyed , Hess Kenneth R. , Janku Filip , Sanchez Nora S. , Mills Shaw Kenna R. , Eng Cathy , Damodaran Senthilkumar , Javle Milind , Kaseb Ahmed O. , Hong David S. , Subbiah Vivek , Fu Siqing , Fogelman David R. , Raymond Victoria M. , Lanman Richard B. , Meric-Bernstam Funda
Published: April 2023

AbstractPurpose:
Physicians are expected to assess prognosis both for patient counseling and for determining suitability for clinical trials. Increasingly, cell-free circulating tumor DNA (cfDNA) sequencing is being performed for clinical decision making. We sought to determine whether variant allele frequency (VAF) in cfDNA is associated with prognosis.
Experimental Design:
We performed a retrospective analysis of 298 patients with metastatic disease who underwent clinical comprehensive cfDNA analysis and assessed association between VAF and overall survival.
Results:
cfDNA mutations were detected in 240 patients (80.5%). Median overall survival (OS) was 11.5 months. cfDNA mutation detection and number of nonsynonymous mutations (NSM) significantly differed between tumor types, being lowest in appendiceal cancer and highest in colon cancer. Having more than one NSM detected was associated with significantly worse OS (HR = 2.3; P < 0.0001). VAF was classified by quartiles, Q1 lowest, Q4 highest VAF. Higher VAF levels were associated with a significantly worse overall survival (VAF Q3 HR 2.3, P = 0.0069; VAF Q4 HR = 3.8, P < 0.0001) on univariate analysis. On multivariate analysis, VAF Q4, male sex, albumin level <3.5 g/dL, number of nonvisceral metastatic sites >0 and number of prior therapies >4 were independent predictors of worse OS.
Conclusions:
Higher levels of cfDNA VAF and a higher number of NSMs were associated with worse OS in patients with metastatic disease. Further study is needed to determine optimal VAF thresholds for clinical decision making and the utility of cfDNA VAF as a prognostic marker in different tumor types.
Data from Validation of the OncoMasTR Risk Score in Estrogen Receptor–Positive/HER2-Negative Patients: A TransATAC study
Authors: Buus Richard , Sestak Ivana , Barron Stephen , Loughman Tony , Fender Bozena , Ruiz Cesar Lopez , Dynoodt Peter , Wang Chan-Ju Angel , O'Leary Des , Gallagher William M. , Dowsett Mitch , Cuzick Jack
Published: April 2023

AbstractPurpose:
To test the validity of OncoMasTR Molecular Score (OMm), OMclin1, and OncoMasTR Risk Score (OMclin2) prognostic scores for prediction of distant recurrence (DR) in estrogen receptor (ER)-positive/HER2-negative breast cancer treated with 5 years' endocrine therapy only and compare their performance with the Oncotype DX Recurrence Score (RS).
Experimental Design:
OMm incorporates three master transcription regulator genes. OMclin1 combines OMm, tumor size, grade, and nodal status; OMclin2 incorporates OMm, tumor size, and nodal status. OMclin1 and OMclin2 were evaluated for 646 postmenopausal patients with ER-positive/HER2-negative primary breast cancer with 0–3 involved lymph nodes in TransATAC. Patients were randomized to 5 years' anastrozole or tamoxifen without chemotherapy. RS was available in all cases. We used likelihood ratio-χ2, C-index, and Kaplan–Meier analyses to assess prognostic information.
Results:
OMm, OMclin1, and OMclin2 were highly prognostic for prediction of DR in years 0–10 among all patients [likelihood ratio (LR)-χ2 = 25.4, 48.7, and 45.0, respectively, all P < 0.001; C-index = 0.67, 0.71, and 0.71, respectively], compared with RS (LR-χ2 = 18.8; P < 0.001; C-index = 0.63). All three scores provided significant additional prognostic value beyond clinical treatment score, Nottingham Prognostic Index, and Ki67. OMclin1 and OMclin2 categorized 190 and 267 node-negative patients as low risk (DR rates: 2.9% and 4.9%, respectively). In comparison, RS categorized 296 node-negative patients as low-risk and 128 patients as intermediate-risk (DR rate: 6.6% and 17.3%, respectively).
Conclusions:
OMm, OMclin1, and OMclin2 were highly prognostic for early and late DR in women with early-stage ER-positive breast cancer receiving 5 years' endocrine therapy. In TransATAC, OMclin1 and the OncoMasTR Risk Score (OMclin2) were superior to RS in identifying patients at increased risk of DR.
Data from Pan-HDAC Inhibitors Restore PRDM1 Response to IL21 in CREBBP-Mutated Follicular Lymphoma
Authors: Desmots Fabienne , Roussel Mikaël , Pangault Céline , Llamas-Gutierrez Francisco , Pastoret Cédric , Guiheneuf Eric , Le Priol Jérôme , Camara-Clayette Valérie , Caron Gersende , Henry Catherine , Belaud-Rotureau Marc-Antoine , Godmer Pascal , Lamy Thierry , Jardin Fabrice , Tarte Karin , Ribrag Vincent , Fest Thierry
Published: April 2023

AbstractPurpose:
Follicular lymphoma arises from a germinal center B-cell proliferation supported by a bidirectional crosstalk with tumor microenvironment, in particular with follicular helper T cells (Tfh). We explored the relation that exists between the differentiation arrest of follicular lymphoma cells and loss-of-function of CREBBP acetyltransferase.

Experimental Design: The study used human primary cells obtained from either follicular lymphoma tumors characterized for somatic mutations, or inflamed tonsils for normal germinal center B cells. Transcriptome and functional analyses were done to decipher the B- and T-cell crosstalk. Responses were assessed by flow cytometry and molecular biology including ChIP-qPCR approaches.
Results:
Conversely to normal B cells, follicular lymphoma cells are unable to upregulate the transcription repressor, PRDM1, required for plasma cell differentiation. This defect occurs although the follicular lymphoma microenvironment is enriched in the potent inducer of PRDM1 and IL21, highly produced by Tfhs. In follicular lymphoma carrying CREBBP loss-of-function mutations, we found a lack of IL21-mediated PRDM1 response associated with an abnormal increased enrichment of the BCL6 protein repressor in PRDM1 gene. Moreover, in these follicular lymphoma cells, pan-HDAC inhibitor, vorinostat, restored their PRDM1 response to IL21 by lowering BCL6 bound to PRDM1. This finding was reinforced by our exploration of patients with follicular lymphoma treated with another pan-HDAC inhibitor. Patients showed an increase of plasma cell identity genes, mainly PRDM1 and XBP1, which underline the progression of follicular lymphoma B cells in the differentiation process.
Conclusions:
Our data uncover a new mechanism by which pan-HDAC inhibitors may act positively to treat patients with follicular lymphoma through the induction of the expression of plasma cell genes.
Data from Marrow-Infiltrating Regulatory T Cells Correlate with the Presence of Dysfunctional CD4+PD-1+ Cells and Inferior Survival in Patients with Newly Diagnosed Multiple Myeloma
Authors: Alrasheed Nouf , Lee Lydia , Ghorani Ehsan , Henry Jake Y. , Conde Lucia , Chin Melody , Galas-Filipowicz Daria , Furness Andrew J.S. , Chavda Selina J. , Richards Huw , De-Silva Dunnya , Cohen Oliver C. , Patel Dominic , Brooks Anthony , Rodriguez-Justo Manuel , Pule Martin , Herrero Javier , Quezada Sergio A. , Yong Kwee L.
Published: April 2023

AbstractPurpose:
Immune dysregulation is described in multiple myeloma. While preclinical models suggest a role for altered T-cell immunity in disease progression, the contribution of immune dysfunction to clinical outcomes remains unclear. We aimed to characterize marrow-infiltrating T cells in newly diagnosed patients and explore associations with outcomes of first-line therapy.
Experimental Design:
We undertook detailed characterization of T cells from bone marrow (BM) samples, focusing on immune checkpoints and features of immune dysfunction, correlating with clinical features and progression-free survival.
Results:
We found that patients with multiple myeloma had greater abundance of BM regulatory T cells (Tregs) which, in turn, expressed higher levels of the activation marker CD25 compared with healthy donors. Patients with higher frequencies of Tregs had shorter PFS and a distinct Treg immune checkpoint profile (increased PD-1, LAG-3) compared with patients with lower frequencies of Tregs. Analysis of CD4 and CD8 effectors revealed that low CD4effector (CD4eff):Treg ratio and increased frequency of PD-1–expressing CD4eff cells were independent predictors of early relapse over and above conventional risk factors, such as genetic risk and depth of response. Ex vivo functional analysis and RNA sequencing revealed that CD4 and CD8 cells from patients with greater abundance of CD4effPD-1+ cells displayed transcriptional and secretory features of dysfunction.
Conclusions:
BM-infiltrating T-cell subsets, specifically Tregs and PD-1–expressing CD4 effectors, negatively influence clinical outcomes in newly diagnosed patients. Pending confirmation in larger cohorts and further mechanistic work, these immune parameters may inform new risk models, and present potential targets for immunotherapeutic strategies.
Data from Medium-throughput Drug Screening of Patient-derived Organoids from Colorectal Peritoneal Metastases to Direct Personalized Therapy
Authors: Narasimhan Vignesh , Wright Josephine A. , Churchill Michael , Wang Tongtong , Rosati Rachele , Lannagan Tamsin R.M. , Vrbanac Laura , Richardson Anne B. , Kobayashi Hiroki , Price Timothy , Tye Gayle X.Y. , Marker Julie , Hewett Peter J. , Flood Michael P. , Pereira Shalini , Whitney G. Adam , Michael Michael , Tie Jeanne , Mukherjee Siddhartha , Grandori Carla , Heriot Alexander G. , Worthley Daniel L. , Ramsay Robert G. , Woods Susan L.
Published: April 2023

AbstractPurpose:
Patients with colorectal cancer with peritoneal metastases (CRPMs) have limited treatment options and the lowest colorectal cancer survival rates. We aimed to determine whether organoid testing could help guide precision treatment for patients with CRPMs, as the clinical utility of prospective, functional drug screening including nonstandard agents is unknown.
Experimental Design:
CRPM organoids (peritonoids) isolated from patients underwent parallel next-generation sequencing and medium-throughput drug panel testing ex vivo to identify specific drug sensitivities for each patient. We measured the utility of such a service including: success of peritonoid generation, time to cultivate peritonoids, reproducibility of the medium-throughput drug testing, and documented changes to clinical therapy as a result of the testing.
Results:
Peritonoids were successfully generated and validated from 68% (19/28) of patients undergoing standard care. Genomic and drug profiling was completed within 8 weeks and a formal report ranking drug sensitivities was provided to the medical oncology team upon failure of standard care treatment. This resulted in a treatment change for two patients, one of whom had a partial response despite previously progressing on multiple rounds of standard care chemotherapy. The barrier to implementing this technology in Australia is the need for drug access and funding for off-label indications.
Conclusions:
Our approach is feasible, reproducible, and can guide novel therapeutic choices in this poor prognosis cohort, where new treatment options are urgently needed. This platform is relevant to many solid organ malignancies.
Data from Pharmacokinetics, Safety, and Antitumor Effect of Apalutamide with Abiraterone Acetate plus Prednisone in Metastatic Castration-Resistant Prostate Cancer: Phase Ib Study
Authors: Posadas Edwin M. , Chi Kim N. , de Wit Ronald , de Jonge Maja J.A. , Attard Gerhardt , Friedlander Terence W. , Yu Margaret K. , Hellemans Peter , Chien Caly , Abrams Charlene , Jiao Juhui J. , Saad Fred
Published: April 2023

AbstractPurpose:
Apalutamide is a next-generation androgen receptor (AR) inhibitor approved for patients with nonmetastatic castration-resistant prostate cancer (CRPC) and metastatic castration-sensitive prostate cancer. We evaluated the pharmacokinetics, safety, and antitumor activity of apalutamide combined with abiraterone acetate plus prednisone (AA-P) in patients with metastatic CRPC (mCRPC).
Patients and Methods:
Multicenter, open-label, phase Ib drug–drug interaction study conducted in 57 patients with mCRPC treated with 1,000 mg abiraterone acetate plus 10 mg prednisone daily beginning on cycle 1 day 1 (C1D1) and 240 mg apalutamide daily starting on C1D8 in 28-day cycles. Serial blood samples for pharmacokinetic analysis were collected on C1D7 and C2D8.
Results:
Systemic exposure to abiraterone, prednisone, and prednisolone decreased 14%, 61%, and 42%, respectively, when apalutamide was coadministered with AA-P. No increase in mineralocorticoid excess–related adverse events was observed. Patients without prior exposure to AR signaling inhibitors had longer median treatment duration and greater mean decrease in prostate-specific antigen (PSA) from baseline compared with those who had received prior therapy. Confirmed PSA reductions of ≥50% from baseline at any time were observed in 80% (12/15) of AR signaling inhibitor–naïve patients and 14% (6/42) of AR signaling inhibitor–treated patients.
Conclusions:
Treatment with apalutamide plus AA-P was well tolerated and showed evidence of antitumor activity in patients with mCRPC, including those with disease progression on AR signaling inhibitors. No clinically significant pharmacokinetic interaction was observed between abiraterone and apalutamide; however, apalutamide decreased exposure to prednisone. These data support development of 1,000 mg abiraterone acetate plus 10 mg prednisone daily with 240 mg apalutamide daily in patients with mCRPC.