bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from INTRAVENOUS N-ACETYLCYSTEINE TO PREVENT CISPLATIN-INDUCED HEARING LOSS IN CHILDREN: A NONRANDOMIZED CONTROLLED PHASE 1 TRIAL
Authors: Orgel Etan , Knight Kristin R. , Chi Yueh-Yun , Malvar Jemily , Rushing Teresa , Mena Victoria , Eisenberg Laurie S. , Rassekh Shahrad R. , Ross Colin JD. , Scott Erika N. , Neely Michael , Neuwelt Edward A. , Muldoon Leslie L. , Freyer David R.
Published: September 2024

Abstract
Purpose: Cisplatin-induced hearing loss (CIHL) is common and permanent. As compared to earlier otoprotectants, we hypothesized N-acetylcysteine (NAC) offers potential for stronger otoprotection through stimulation of glutathione production. This study tested the optimal dose, safety, and efficacy of NAC to prevent CIHL. Patients and Methods: In this nonrandomized, controlled Phase 1a/1b trial, children and adolescents newly diagnosed with non-metastatic, cisplatin-treated tumors received NAC intravenously four hours post-cisplatin. The trial performed dose-escalation across three dose levels to establish a safe dose that exceeded the targeted peak serum NAC concentration of 1.5 mM (as identified from preclinical models). Patients with metastatic disease or otherwise ineligible were enrolled in an observation-only/control arm. To evaluate efficacy, serial age-appropriate audiology assessments were performed. Integrated biology examined genes involved in glutathione metabolism and post-NAC glutathione concentrations. Results: Of 52 patients enrolled, 24 received NAC and 28 were in the control arm. The maximum tolerated dose was not reached; analysis of peak [NAC] identified 450 mg/kg as the recommended Phase 2 dose (RP2D). Infusion-related reactions were common. No severe adverse events occurred. Compared to the control arm, NAC decreased likelihood of CIHL at end of cisplatin therapy (odds ratio [OR] 0.13, 95% confidence interval [CI] 0.021-0.847, p=0.033) and recommendations for hearing intervention at end of study (OR 0.082, 95%CI 0.011-0.60, p=0.014). NAC increased glutathione; GSTP1 influenced risk for CIHL and NAC otoprotection. Conclusion: NAC was safe at the RP2D with strong evidence for efficacy to prevent CIHL, warranting further development as a next-generation otoprotectant. Trial number: NCT02094625
Data from Metastatic Prostate Cancers with BRCA2 versus ATM Mutations Exhibit Divergent Molecular Features and Clinical Outcomes
Authors: Hwang Justin , Shi Xiaolei , Elliott Andrew , Arnoff Taylor E. , McGrath Julie , Xiu Joanne , Walker Phillip , Bergom Hannah E. , Day Abderrahman , Ahmed Shihab , Tape Sydney , Makovec Allison , Ali Atef , Shaker Rami M. , Toye Eamon , Passow Rachel , Lozada John R. , Wang Jinhua , Lou Emil , Mouw Kent W. , Carneiro Benedito A. , Heath Elisabeth I. , McKay Rana R. , Korn W. Michael , Nabhan Chadi , Ryan Charles J. , Antonarakis Emmanuel S.
Published: September 2024

Abstract
Purpose: In metastatic prostate cancer (mPC) patients, ATM and BRCA2 mutations dictate differences in PARP inhibitor response and other therapies. We interrogated the molecular features of ATM- and BRCA2-mutated mPC to explain the divergent clinical outcomes and inform future treatment decisions. Experimental design: We examined a novel set of 1187 mPCs after excluding microsatellite unstable (MSI) tumors. We stratified these based on ATM (n = 88) or BRCA2 (n = 98) mutations. As control groups, mPCs with mutations in 12 other HRR genes were considered non-BRCA2/ATM HRR-deficient (HRDother, n = 193), whereas lack of any HRR mutations were considered HRR-proficient (HRP) (n = 808). Gene expression analyses were performed using Limma. Real-world overall survival was determined from insurance claims data. Results: In non-castrate mPCs, only BRCA2 mutated mPCs exhibited worse clinical outcomes to AR-targeted therapies. In castrate mPCs, both ATM and BRCA2 mutations exhibited worse clinical outcomes to AR-targeted therapies. ATM-mutated mPCs had reduced TP53 mutations, and harbored co-amplification of 11q13 genes including CCND1 and genes in the FGF family. BRCA2-mutated tumors showed elevated genomic loss-of-heterozygosity scores and were often TMB-high. BRCA2-mutated mPCs had upregulation of cell cycle genes and were enriched in cell cycle signaling programs. This was distinct from ATM-mutated tumors. Conclusions: Tumoral ATM and BRCA2 mutations are associated with differential clinical outcomes when patients are stratified by treatments including hormonal or taxanes therapies. ATM- and BRCA2-mutated tumors exhibited differences in co-occurring molecular features. These unique molecular features may inform therapeutic decisions and development of novel therapies.
Data from Efficacy of nivolumab in pediatric cancers with high mutation burden and mismatch-repair deficiency
Authors: Das Anirban , Tabori Uri , Sambira Nahum Lauren C. , Collins Natalie B. , Deyell Rebecca , Dvir Rina , Faure-Conter Cecile , Hassall Timothy E. , Minturn Jane E. , Edwards Melissa , Brookes Elissa , Bianchi Vanessa , Levine Adrian , Stone Simone C. , Sudhaman Sumedha , Sanchez-Ramirez Santiago , Ercan Ayse B. , Stengs Lucie , Chung Jiil , Negm Logine , Getz Gad , Maruvka Yosef E. , Ertl-Wagner Birgit , Ohashi Pamela S. , Pugh Trevor , Hawkins Cynthia , Bouffet Eric , Morgenstern Daniel A.
Published: September 2024

Abstract
Purpose: Checkpoint-inhibitors have limited efficacy for children with unselected solid and brain tumors. We report the first prospective pediatric trial (NCT02992964) using nivolumab exclusively for refractory non-hematological cancers harboring tumor mutation burden (TMB) ≥5 mutations/megabase (mut/Mb) and/or mismatch-repair deficiency (MMRD). Patients and methods: Twenty patients were screened, and ten ultimately included in the response cohort of whom nine had TMB >10mut/Mb (three initially eligible based on MMRD) and one patient had TMB between 5-10 mut/Mb. Results: Delayed immune responses contributed to best overall response of 50%, improving on initial objective responses (20%) and leading to 2-year overall survival (OS) of 50% (95% CI; 27, 93). Four children, including three with refractory malignant gliomas are in complete remission at a median follow-up of 37-months (range: 32.4-60), culminating in 2-year OS of 43% (95% CI; 18.2, 100). Biomarker analyses confirmed benefit in children with germline MMRD, microsatellite instability, higher activated and lower regulatory circulating T-cells. Stochastic mutation accumulation driven by underlying germline MMRD impacted the tumor microenvironment, contributing to delayed responses. No benefit was observed in the single patient with a MMR-proficient tumour and TMB 7.4 mut/Mb. Conclusions: Nivolumab resulted in durable responses and prolonged survival for the first time in a pediatric trial of refractory hypermutated cancers including malignant gliomas. Novel biomarkers identified here need to be translated rapidly to clinical care to identify children who can benefit from checkpoint-inhibitors, including for upfront management of their cancers.
Data from Monitoring sarcoma response to immune checkpoint inhibition and local cryotherapy with circulating tumor DNA analysis
Authors: Bui Nam Q. , Nemat-Gorgani Neda , Subramanian Ajay , Torres Ileana A. , Lohman Marta , Sears Timothy J. , van de Rijn Matt , Charville Gregory W. , Becker Hans-Christoph , Wang David S. , Hwang Gloria L. , Ganjoo Kristen N. , Moding Everett J.
Published: September 2024

Abstract
Purpose: Immune checkpoint inhibition has led to promising responses in soft tissue sarcomas (STSs), but the majority of patients do not respond and biomarkers of response will be crucial. Local ablative therapies may augment systemic responses to immunotherapy. We evaluated circulating tumor DNA (ctDNA) as a biomarker of response in patients treated on a trial combining immunotherapy with local cryotherapy for advanced STSs. Experimental Design: We enrolled 30 patients with unresectable or metastatic STS to a phase 2 clinical trial. Patients received ipilimumab and nivolumab for 4 doses followed by nivolumab alone with cryoablation performed between cycles 1 and 2. The primary endpoint was objective response rate (ORR) by 14 weeks. Personalized ctDNA analysis using bespoke panels was performed on blood samples collected prior to each immunotherapy cycle. Results: ctDNA was detected in at least one sample for 96% of patients. Pre-treatment ctDNA allele fraction was negatively associated with treatment response, progression-free survival (PFS), and overall survival (OS). ctDNA increased in 90% of patients from pre-treatment to post-cryotherapy, and patients with a subsequent decrease in ctDNA or undetectable ctDNA after cryotherapy had significantly better PFS. Of the 27 evaluable patients, the ORR was 4% by RECIST and 11% by irRECIST. Median PFS and OS were 2.7 and 12.0 months, respectively. No new safety signals were observed. Conclusions: ctDNA represents a promising biomarker for monitoring response to treatment in advanced STS, warranting future prospective studies. Combining cryotherapy and immune checkpoint inhibitors did not increase the response rate of STSs to immunotherapy.
Data from Trimodality Therapy Improves Disease Control in Radiation-Associated Angiosarcoma of the Breast
Authors: Degnim Amy C. , Siontis Brittany L. , Ahmed Safia K. , Hoskin Tanya L. , Hieken Tina J. , Jakub James W. , Baum Christian L. , Day Courtney , Schrup Sarah E. , Smith Lauren , Carter Jodi M. , Sae-Kho Tiffany M. , Glazebrook Katrina N. , Vijayasekaran Aparna , Okuno Scott H. , Petersen Ivy A.
Published: September 2024

Abstract
Purpose: To evaluate the impact of trimodality treatment versus mono- or dual-therapy for radiation-associated angiosarcoma of the breast (RAASB) after prior breast cancer treatment. Experimental Design: With IRB approval, we identified patients diagnosed with RAASB and abstracted data on disease presentation, treatment, and oncologic outcomes. Trimodality therapy included 1) taxane induction, 2) concurrent taxane/radiation, and then 3) surgical resection with wide margins. Results: 38 patients (median age 69 years) met inclusion criteria. Sixteen received trimodality therapy and 22 mono/dual-therapy. Skin involvement and disease extent were similar in both groups. All trimodality patients required reconstructive procedures for wound closure/coverage, compared to 48% of mono/dual-therapy patients (p<0.001). Twelve of 16 (75%) patients receiving trimodality therapy had a pathologic complete response (pCR). With median follow-up of 5.6 years, none had local recurrence, 1 patient (6%) had distant recurrence, and no patients died. Among 22 patients in the mono/dual-therapy group, 10 (45%) had local recurrence, 8 (36%) had distant recurrence, and 7 (32%) died of disease. Trimodality therapy demonstrated significantly better 5-year RFS (93.8% vs 42.9%, p=0.004, HR 7.6 (95% CI: 1.3-44.2)). Combining all RAASB patients regardless of treatment, local recurrence was associated with subsequent distant recurrence (HR 9.0, p=0.002); distant recurrence developed in 3/28 (11%) patients without local recurrence compared to 6/10 (60%) with local recurrence. The trimodality group had more surgical complications that required reoperation or prolonged healing. Conclusions: Trimodality therapy for RAASB was more toxic but is promising with a high rate of pCR, durable local control, and improved RFS.
Data from Autocrine 17-β-estradiol/estrogen receptor-α loop determines the response to immune-checkpoint inhibitors in non-small cell lung cancer
Authors: Anobile Dario P. , Salaroglio Iris C. , Tabbò Fabrizio , La Vecchia Sofia , Akman Muhlis , Napoli Francesca , Bungaro Maristella , Benso Federica , Aldieri Elisabetta , Bironzo Paolo , Kopecka Joanna , Passiglia Francesco , Righi Luisella , Novello Silvia , Scagliotti Giorgio V. , Riganti Chiara
Published: September 2024

Abstract
Purpose: The response to immune checkpoint inhibitors (ICI) often differs between genders in non-small cell lung cancer (NSCLC), but metanalyses results are controversial, and no clear mechanisms are defined. We aim at clarifying the molecular circuitries explaining the differential gender-related response to anti-PD1/anti-PD-L1 agents in NSCLC. Experimental Design: We prospectively analyzed a cohort of patients with NSCLC treated with ICI as a first-line approach and we identified the molecular mechanisms determining the differential efficacy of ICI in 29 NSCLC cell lines of both genders, recapitulating patients’ phenotype. We validated new immunotherapy strategies in mice bearing NSCLC patient-derived xenografts and human reconstituted immune system (“immune-PDXs”). Results: In patients, we found that estrogen receptor α (ERα) was a predictive factor of response to pembrolizumab, stronger than gender and PD-L1 levels, and was directly correlated with PD-L1 expression, particularly in female patients. ERα transcriptionally upregulated CD274/PD-L1 gene, more in females than in males. This axis was activated by 17-β-estradiol, autocrinely produced by intratumor aromatase, and by the EGFR-downstream effectors Akt and ERK1/2 that activated ERα. The efficacy of pembrolizumab in immune-PDXs was significantly improved by the aromatase inhibitor letrozole, which reduced PD-L1 and increased the percentage of anti-tumor CD8+T-lymphocytes, NK cells and Vγ9Vδ2 T-lymphocytes, producing durable control and even tumor regression after continuous administration, with maximal benefit in 17-β-estradiol/ERα high female immune-xenografts. Conclusions: Our work unveils that 17-β-estradiol/ERα status predicts the response to pembrolizumab in NSCLC patients. Secondly, we propose aromatase inhibitors as new gender-tailored immune-adjuvants in NSCLC.
Data from A multiparameter molecular classifier to predict response to neoadjuvant lapatinib plus trastuzumab without chemotherapy in HER2+ breast cancer
Authors: Veeraraghavan Jamunarani , Gutierrez Carolina , De Angelis Carmine , Davis Robert , Wang Tao , Pascual Tomas , Selenica Pier , Sanchez Katherine , Nitta Hiroaki , Kapadia Monesh , Pavlick Anne C. , Galván Patricia , Rexer Brent , Forero-Torres Andres , Nanda Rita , Storniolo Anna M. , Krop Ian E. , Goetz Matthew P. , Nangia Julie R. , Wolff Antonio C. , Weigelt Britta , Reis-Filho Jorge S. , Hilsenbeck Susan G. , Prat Aleix , Osborne C. Kent , Schiff Rachel , Rimawi Mothaffar F.
Published: September 2024

Abstract
Background: Clinical trials reported 25-30% pathologic complete response (pCR) rates in HER2+ breast cancer (BC) patients treated with anti-HER2 therapies without chemotherapy. We hypothesize that a multiparameter classifier can identify patients with HER2 “addicted” tumors who may benefit from a chemotherapy-sparing strategy. Patients and Methods: Baseline HER2+ BC specimens from TBCRC023 and PAMELA trials of neoadjuvant lapatinib+trastuzumab (plus endocrine therapy in ER+ tumors) were used. HER2 protein and gene amplification (ratio), HER2-enriched (HER2-E), and PIK3CA mutation status were assessed by dual gene protein assay (GPA), research-based PAM50, and targeted DNA-sequencing. GPA cutoffs and classifier of response were constructed in TBCRC023 using a decision tree algorithm, then validated in PAMELA. Results: In TBCRC023, 72 BCs had GPA, PAM50, and sequencing data, of which 15 had pCR. Recursive partitioning identified cutoffs of HER2 ratio≥4.6 and %3+ IHC-staining≥97.5%. With PAM50 and sequencing data, the model added HER2-E and PIK3CA wild-type (wt). For clinical implementation, the classifier was locked as HER2 ratio≥4.5 and %3+ IHC-staining≥90% and PIK3CA-wt and HER2-E, yielding 55% and 94% positive (PPV) and negative (NPV) predictive values, respectively. Independent validation using 44 PAMELA cases with all three biomarkers yielded 47% PPV and 82% NPV. Importantly, our classifier’s high NPV signifies its strength in accurately identifying patients who may not be good candidates for treatment de-escalation. Conclusions: Our multiparameter classifier differentially identifies patients who may benefit from HER2-targeted therapy alone from those who need chemotherapy and predicts pCR to anti-HER2 therapy alone comparable to chemotherapy plus dual anti-HER2 therapy in unselected patients.
Data from Association of Antifolate Response Signature Status and Clinical Activity of Pemetrexed-Platinum Chemotherapy in Non-Small Cell Lung Cancer - The Piedmont Study
Authors: Eisner Joel R. , Mayhew Gregory M. , Davison James M. , Beebe Kirk D. , Shibata Yoichiro , Guo Yuelong , Farhangfar Carol , Farhangfar Farhang , Uronis Joshua M. , Conroy Jeffrey M. , Milburn Michael V. , Hayes David Neil. , Mileham Kathryn F.
Published: September 2024

Abstract
Purpose: The Piedmont study is a prospectively designed retrospective evaluation of a new 48-gene antifolate response signature (AF-PRS) in patients with locally advanced/metastatic NS-NSCLC treated with pemetrexed-containing platinum doublet chemotherapy (PMX-PDC). The study tested the hypothesis that AF-PRS selects for patients with NS-NSCLC that preferentially respond to PMX-PDC, with a goal of providing clinical support for AF-PRS as potential diagnostic test. Experimental Design: Residual pre-treatment FFPE tumor samples and clinical data were analyzed from 105 patients treated with 1st-line (1L) PMX-PDC. 95 patients had sufficient RNA sequencing (RNAseq) data quality and clinical annotation for inclusion in the analysis. Associations between AF-PRS status and associate genes, and outcome measures including progression-free survival (PFS) and clinical response were evaluated. Results: Overall, 53% of patients were AF-PRS(+), which was associated with extended PFS, but not OS, vs. AF-PRS(-) (16.6 vs. 6.6 mo; p = 0.025). In patients who were Stage I-III patients at time of treatment, PFS was further extended in AF-PRS(+) vs. AF-PRS(-) (36.2 vs. 9.3 mo; p = 0.03). Complete response (CR) to therapy was noted in 14 of 95 patients. AF-PRS(+) preferentially selected a majority (79%) of CRs, which were evenly split between patients Stage I-III (6 of 7) and Stage IV (5 of 7) at time of treatment. Conclusions: AF-PRS identified a significant population of patients with extended PFS and/or clinical response following PMX-PDC treatment. AF-PRS may be a useful diagnostic test for patients indicated for systemic chemotherapy, especially when determining the optimal PDC regimen for locally advanced disease.
Data from Activin A-mediated polarization of cancer-associated fibroblasts and macrophages confers resistance to checkpoint immunotherapy in skin cancer
Authors: Pich-Bavastro Christine , Yerly Laura , Di Domizio Jeremy , Tissot-Renaud Stéphanie , Gilliet Michel , Kuonen François
Published: September 2024

Abstract
Purpose: Cemiplimab is approved for the treatment of locally advanced basal cell carcinomas (BCCs), however with mitigated results. We sought to interrogate the cellular and molecular transcriptional reprogramming underlying BCC resistance to immunotherapy. Experimental Design: Here, we combined spatial and single-cell transcriptomics to deconvolute the spatial heterogeneity of the tumor microenvironment in regard with response to immunotherapy, in a cohort of both naive and resistant BCCs. Results: We identified subsets of intermingled cancer-associated fibroblasts (CAFs) and macrophages contributing the most to CD8 T cells exclusion and immunosuppression. Within this spatially-resolved peritumoral immunosuppressive niche, CAFs and adjacent macrophages were found to display Activin A-mediated transcriptional reprogramming towards extracellular matrix remodeling, suggesting active participation to CD8 T cells exclusion. In independent datasets of human skin cancers, Activin A-conditioned CAFs and macrophages were associated with resistance to immune checkpoint inhibitors (ICI). Conclusions: Altogether, our data identify the cellular and molecular plasticity of TME and the pivotal role of Activin A in polarizing the TME towards immune suppression and ICI resistance.
Data from Associations between AI-assisted tumor amphiregulin and epiregulin IHC and outcomes from anti-EGFR therapy in the routine management of metastatic colorectal cancer
Authors: Williams Christopher J.M. , Elliott Faye , Sapanara Nancy , Aghaei Faranak , Zhang Liping , Muranyi Andrea , Yan Dongyao , Bai Isaac , Zhao Zuo , Shires Michael , Wood Henry M. , Richman Susan D. , Hemmings Gemma , Hale Michael , Bottomley Daniel , Galvin Leanne , Cartlidge Caroline , Dance Sarah , Bacon Chris M. , Mansfield Laura , Young-Zvandasara Kathe , Sudan Ajay , Lambert Katy , Bibby Irena , Coupland Sarah E. , Montazeri Amir , Kipling Natalie , Hughes Kathryn , Cross Simon S. , Dewdney Alice , Pheasey Leanne , Leng Cathryn , Gochera Tatenda , Mangham D Chas , Saunders Mark , Pritchard Martin , Stott Helen , Mukherjee Abhik , Ilyas Mohammad , Silverman Rafael , Hyland Georgina , Sculthorpe Declan , Thornton Kirsty , Gould Imogen , O'Callaghan Ann , Brown Nicholas , Turnbull Samantha , Shaw Lisa , Seymour Matthew T. , West Nicholas P. , Seligmann Jenny F. , Singh Shalini , Shanmugam Kandavel , Quirke Philip
Published: September 2024

Abstract
Purpose: High tumor production of the EGFR ligands, amphiregulin (AREG) and epiregulin (EREG), predicted benefit from anti-EGFR therapy for metastatic colorectal cancer (mCRC) in a retrospective analysis of clinical trial data. Here, AREG/EREG immunohistochemistry (IHC) was analyzed in a cohort of patients who received anti-EGFR therapy as part of routine care, including key clinical contexts not investigated in the previous analysis. Experimental Design: Patients who received panitumumab or cetuximab ± chemotherapy for treatment of RAS wild-type mCRC at eight UK cancer centers were eligible. Archival FFPE tumor tissue was analyzed for AREG and EREG IHC in six regional laboratories using previously developed artificial intelligence technologies. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Results: 494 of 541 patients (91.3%) had adequate tissue for analysis. 45 were excluded after central extended RAS testing, leaving 449 patients in the primary analysis population. After adjustment for additional prognostic factors, high AREG/EREG expression (n=360; 80.2%) was associated with significantly prolonged PFS (median: 8.5 vs 4.4 months; HR 0.73; 95% CI, 0.56-0.95; p=0.02) and OS (median: 16.4 vs 8.9 months; HR 0.66 [0.50-0.86]; p=0.002). The significant OS benefit was maintained among patients with right primary tumor location (PTL), those receiving cetuximab or panitumumab, those with an oxaliplatin- or irinotecan-based chemotherapy backbone, and those with tumor tissue obtained by biopsy or surgical resection. Conclusions: High tumor AREG/EREG expression was associated with superior survival outcomes from anti-EGFR therapy in mCRC, including in right PTL disease. AREG/EREG IHC assessment could aid therapeutic decisions in routine practice.
Data from Safety, Efficacy, and Biomarker Analyses of Dostarlimab in Patients with Endometrial Cancer: Interim Results of the Phase I GARNET Study
Authors: Oaknin Ana , Pothuri Bhavana , Gilbert Lucy , Sabatier Renaud , Brown Jubilee , Ghamande Sharad , Mathews Cara , O'Malley David M. , Kristeleit Rebecca , Boni Valentina , Gravina Adriano , Banerjee Susana , Miller Rowan , Pikiel Joanna , Mirza Mansoor R. , Dewal Ninad , Antony Grace , Dong Yuping , Zografos Eleftherios , Veneris Jennifer , Tinker Anna V.
Published: September 2024

Abstract
Purpose: This interim report of the GARNET phase I trial presents efficacy and safety of dostarlimab in patients with advanced or recurrent endometrial cancer (EC), with an analysis of tumor biomarkers as prognostic indicators. Patients and Methods: A total of 153 patients with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) and 161 patients with mismatch repair proficient (MMRp)/microsatellite stable (MSS) EC were enrolled and dosed. Patients received 500 mg dostarlimab every 3 weeks for 4 cycles, then 1000 mg every 6 weeks until progression. Primary endpoints were objective response rate (ORR) and duration of response (DOR). Results: A total of 143 patients with dMMR/MSI-H EC and 156 patients with MMRp/MSS EC were evaluated for efficacy. ORR was 45.5% (n = 65) and 15.4% (n = 24) for dMMR/MSI-H EC and MMRp/MSS EC, respectively. Median DOR for dMMR/MSI-H EC was not met (median follow-up, 27.6 months); median DOR for MMRp/MSS EC was 19.4 months. The ORRs by combined positive score (CPS) ≥1 status were 54.9% and 21.7% for dMMR/MSI-H EC and MMRp/MSS EC, respectively. ORRs by high tumor mutational burden (≥10 mutations/Mb) were 47.8% (43/90) and 45.5% (5/11) for dMMR/MSI-H EC and MMRp/MSS EC, respectively. ORR in TP53mut or POLεmut molecular subgroups was 18.1% (17/94) and 40.0% (2/5), respectively. The safety profile of dostarlimab was consistent with previous reports. Conclusions: Dostarlimab demonstrated durable antitumor activity and safety in patients with dMMR/MSI-H EC. Biomarkers associated with EC may identify patients likely to respond to dostarlimab. Trial Registration: ClinicalTrials.gov NCT02715284
Data from Caveolin gene expression predicts clinical outcomes for early-stage HER2-negative breast cancer treated with paclitaxel-based chemotherapy in the GeparSepto trial
Authors: Williams Terence M. , Schneeweiss Andreas , Jackisch Christian , Shen Changxian , Weber Karsten E. , Fasching Peter A. , Denkert Carsten , Furlanetto Jenny , Heinmöller Ernst , Schmatloch Sabine , Karn Thomas , Szeto Christopher W. , van Mackelenbergh Marion T. , Nekljudova Valentina , Stickeler Elmar , Soon-Shiong Patrick , Schem Christian , Mairinger Thomas , Müller Volkmar , Marme Frederik , Untch Michael , Loibl Sibylle
Published: September 2024

Abstract
Background: Caveolin-1 and -2 (CAV1/2) dysregulation are implicated in driving cancer progression and may predict response to nab-paclitaxel. We explored the prognostic and predictive potential of CAV1/2 expression for early-stage HER2-negative (HER-) breast cancer (BC) patients receiving neoadjuvant paclitaxel-based chemotherapy regimens. Patients and Methods: We correlated tumor CAV1/2 RNA expression with pathologic complete response (pCR), disease-free survival (DFS) and overall survival (OS) in the GeparSepto trial, which randomized patients to neoadjuvant paclitaxel- versus nab-paclitaxel-based chemotherapy. Results: RNA-Seq data was available for 279 patients, of which 74 (26.5%) were hormone receptor (HR)-negative, thus triple-negative BC (TNBC). Patients treated with nab-paclitaxel with high CAV1/2 had higher probability of obtaining a pCR (CAV1 odds ratio (OR) = 4.92, 95% CI 1.70-14.22, p=0.003; CAV2 OR=5.39, 95%CI 1.76-16.47, p=0.003) as compared to patients with high CAV1/2 treated with solvent-based paclitaxel (CAV1 OR=0.33, 95%CI 0.11-0.95, p=0.040; CAV2 OR=0.37, 95%CI 0.12-1.13, p=0.082). High CAV1 expression was significantly associated with worse DFS and OS in paclitaxel-treated patients (DFS HR=2.29, 95%CI 1.08-4.87, p=0.030; OS HR=4.97, 95%CI 1.73-14.31, p=0.003). High CAV2 was associated with worse DFS and OS in all patients (DFS HR=2.12, p=0.006; OS HR=2.51, p=0.013), in paclitaxel-treated patients (DFS HR=2.47, p=0.025; OS HR=4.24, p=0.007) and in patients with TNBC (DFS HR=4.68, p=0.009; OS HR=10.43, p=0.032). Conclusions: Our findings indicate high CAV1/2 expression is associated with worse DFS and OS in paclitaxel-treated patients. Conversely, in nab-paclitaxel-treated patients, high CAV1/2 expression is associated with increased pCR and no significant detriment to DFS or OS compared to low CAV1/2 expression.
Data from Phase 1 Study of JNJ-64619178, a Protein Arginine Methyltransferase 5 Inhibitor, in Advanced Solid Tumors
Authors: Vieito Maria , Moreno Victor , Spreafico Anna , Brana Irene , Wang Judy S. , Preis Meir , Hernandez-Guerrero Tatiana , Genta Sofia , Hansen Aaron R. , Doger Bernard , Galvao Vladimir , Lenox Laurie , Brown Regina J. , Kalota Anna , Mehta Jaydeep , Pastore Friederike , Patel Bharvin , Mistry Pankaj , Gu Junchen , Lauring Josh , Patel Manish R.
Published: September 2024

Abstract
Purpose: In this first-in-human, Phase 1, open-label, multicenter study, we evaluated JNJ-64619178, a selective and potent PRMT5 inhibitor, in patients with advanced malignant solid tumors or non-Hodgkin lymphomas. The primary objective was to evaluate the safety and to identify a recommended Phase 2 dose (RP2D) of JNJ-64619178. Patients and Methods: Adult patients with treatment-refractory advanced solid tumors or non-Hodgkin lymphomas and measurable disease received escalating doses of JNJ-64619178 following two schedules (Schedule A: 14 days on/7 days off; Schedule B: every day on a 21-day cycle). Safety, pharmacokinetics (PK), pharmacodynamics, and clinical activity were evaluated. Results: Ninety patients received JNJ-64619178. Thrombocytopenia was identified as the only dose-limiting toxicity. JNJ-64619178 showed dose-proportional PK and robust target engagement, as measured by plasma symmetric dimethylarginine, across all dose levels. The objective response rate was 5.6% (5 of 90). Patients with adenoid cystic carcinoma (ACC) had an ORR of 11.5% (3 of 26) and a median progression-free survival of 19.1 months. Conclusions: JNJ-64619178 demonstrated manageable dose-dependent toxicity and preliminary evidence of antitumor activity in ACC and other tumor types. Plasma exposure was dose dependent, and target inhibition was maintained with intermittent and continuous dosing. Based on safety, clinical activity, PK, and PD findings, two provisional RP2Ds were selected: 1.5 mg intermittently and 1.0 mg once daily. Aside from ACC, clinical benefit was limited, and biomarkers to enrich for responsiveness to PRMT5 inhibition will be needed for further development.
Data from Randomized Phase II Trial of Dendritic Cell/Myeloma Fusion Vaccine with Lenalidomide Maintenance after Upfront Autologous Hematopoietic Cell Transplantation for Multiple Myeloma: BMT CTN 1401
Authors: Chung David J. , Shah Nina , Wu Juan , Logan Brent , Bisharat Lina , Callander Natalie , Cheloni Giulia , Anderson Kenneth , Chodon Thinle , Dhakal Binod , Devine Steve , Somaiya Dutt Poorvi , Efebera Yvonne , Geller Nancy , Ghiasuddin Haider , Hematti Peiman , Holmberg Leona , Howard Alan , Johnson Bryon , Karagkouni Dimitra , Lazarus Hillard M. , Malek Ehsan , McCarthy Philip , McKenna David , Mendizabal Adam , Nooka Ajay , Munshi Nikhil , O'Donnell Lynn , Rapoport Aaron P. , Reese Jane , Rosenblatt Jacalyn , Soiffer Robert , Stroopinsky Dina , Uhl Lynne , Vlachos Ioannis S. , Waller Edmund K. , Young James W. , Pasquini Marcelo C. , Avigan David
Published: September 2024

AbstractPurpose:
Vaccination with dendritic cell (DC)/multiple myeloma (MM) fusions has been shown to induce the expansion of circulating multiple myeloma–reactive lymphocytes and consolidation of clinical response following autologous hematopoietic cell transplant (auto-HCT).
Patients and Methods:
In this randomized phase II trial (NCT02728102), we assessed the effect of DC/MM fusion vaccination, GM-CSF, and lenalidomide maintenance as compared with control arms of GM-CSF and lenalidomide or lenalidomide maintenance alone on clinical response rates and induction of multiple myeloma–specific immunity at 1-year posttransplant.
Results:
The study enrolled 203 patients, with 140 randomized posttransplantation. Vaccine production was successful in 63 of 68 patients. At 1 year, rates of CR were 52.9% (vaccine) and 50% (control; P = 0.37, 80% CI 44.5%, 61.3%, and 41.6%, 58.4%, respectively), and rates of VGPR or better were 85.3% (vaccine) and 77.8% (control; P = 0.2). Conversion to CR at 1 year was 34.8% (vaccine) and 27.3% (control; P = 0.4). Vaccination induced a statistically significant expansion of multiple myeloma–reactive T cells at 1 year compared with before vaccination (P = 0.024) and in contrast to the nonvaccine arm (P = 0.026). Single-cell transcriptomics revealed clonotypic expansion of activated CD8 cells and shared dominant clonotypes between patients at 1-year posttransplant.
Conclusions:
DC/MM fusion vaccination with lenalidomide did not result in a statistically significant increase in CR rates at 1 year posttransplant but was associated with a significant increase in circulating multiple myeloma–reactive lymphocytes indicative of tumor-specific immunity. Site-specific production of a personalized cell therapy with centralized product characterization was effectively accomplished in the context of a multicenter cooperative group study.

See related commentary by Qazilbash and Kwak, p. 4703
Data from Multiomic mapping of acquired chromosome 1 copy number and structural variants to identify therapeutic vulnerabilities in multiple myeloma.
Authors: Boyle Eileen M. , Blaney Patrick , Stoeckle James H. , Wang Yubao , Ghamlouch Hussein , Gagler Dylan , Braunstein Marc , Williams Louis , Tenenbaum Avital , Siegel Ariel , Chen Xiaoyi , Varma Gaurav , Avigan Jason , Li Alexander , Jinsi Monica , Kaminetzky David , Arbini Arnaldo , Montes Lydia , Corre Jill , Rustad Even H. , Landgren Ola , Maura Francesco , Walker Brian A. , Bauer Michael , Bruno Benedetto , Tsirigos Aristotelis , Davies Faith E. , Morgan Gareth J.
Published: September 2024

Abstract
Purpose: Chromosome 1 (chr1) copy number abnormalities (CNAs) and structural variants (SV) are frequent in newly diagnosed multiple myeloma (NDMM) and associate with a heterogeneous impact on outcome the drivers of which are largely unknown. Experimental Design: A multiomic approach comprising CRISPR, gene mapping of CNA and SV, methylation, expression, and mutational analysis was used to document the extent of chr1 molecular variants and their impact on pathway utilisation. Results: We identified two distinct groups of gain(1q): focal gains associated with limited gene expression changes and a neutral prognosis, and whole-arm gains, which associate with substantial gene expression changes, complex genetics and an adverse prognosis. CRISPR identified a number of dependencies on chr1 but only limited variants associated with acquired CNAs. We identified seven regions of deletion, nine of gain, three of chromothripsis (CT) and two of templated-insertion (TI), which contain a number of potential drivers. An additional mechanism involving hypomethylation of genes at 1q may contribute to the aberrant gene expression of a number of genes. Expression changes associated with whole-arm gains were substantial and gene set enrichment analysis identified metabolic processes, apoptotic resistance, signaling via the MAPK pathway, and upregulation of transcription factors as being key drivers of the adverse prognosis associated with these variants. Conclusions: Multiple layers of genetic complexity impact the phenotype associated with CNAs on chr1 to generate its associated clinical phenotype. Whole-arm gains of 1q are the critically important prognostic group that deregulate multiple pathways, which may offer therapeutic vulnerabilities.
Data from Safety and Efficacy of Anlotinib Hydrochloride Plus Temozolomide in Patients with Recurrent Glioblastoma
Authors: Xu Qingsheng , Huang Kaiyuan , Meng Xiangqi , Weng Yuxiang , Zhang Luyuan , Bu Linghao , Zheng Xiujue , Cai Jinquan , Zhan Renya , Chen Qun
Published: September 2024

Abstract
Background: Glioblastoma (GBM) is a highly vascularized tumor with few treatment options after disease recurrence. Here, we report the efficacy and safety of anlotinib hydrochloride plus temozolomide in patients with recurrent GBM. Methods: Patients with first definite postsurgical progression of histologically confirmed GBM preceded by standard radiotherapy and temozolomide chemotherapy were eligible for inclusion. All patients received temozolomide (150-200mg/m2, orally, QD, d1-5/4wks) and anlotinib (10mg, orally, QD, d1-14/3wks) until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed 6-month PFS rate by RANO criteria. Result: Twenty-one patients were enrolled between May 2020 and July 2021, with a median age of 55 (range 27-68) years old. According to the RANO criteria, tumor response occurred in 17 patients, of which 9 patients had a complete response, and the objective response rate was 81.0% (95% CI 62.6-99.3). The disease control rate was 95.2% (95% CI 76.2-99.9), with three additional patients achieving a stable disease without tumor progression. The median PFS was 7.3 months (95% CI 4.9-9.7), and the 6-month PFS rate was 61.9% (95% CI 39.3-84.6). The median overall OS was 16.9 months (95% CI 7.8-26.0). The most common adverse events were leukocytopenia (66.7%), thrombocytopenia (38.1%), and hypertriglyceridemia (38.1%). Five patients had nine grade 3 adverse events, with a 23.8% incidence rate. Two patients discontinued therapy due to ischemic stroke (grade 3) and wound dehiscence (grade 1) respectively. No grade 4 or treatment-related deaths occurred in this study. Conclusions: Anlotinib combined with temozolomide is efficacious and tolerated in recurrent GBM patients.
Data from Comprehensive analysis of tumor microenvironment reveals prognostic ceRNA network related to immune infiltration in sarcoma
Authors: Leng Dongliang , Yang Ziyi , Sun Heng , Song Chengcheng , Huang Chen , Ip Ka U. , Chen Guokai , Deng Chu-Xia , Zhang Xiaohua Douglas. , Zhao Qi
Published: September 2024

Abstract
Purpose:Sarcoma (SARC) is the second most common solid tumor type in children and adolescents. The high level of tumor heterogeneity as well as aggressive behavior of SARCs bring serious difficulties to developing effective therapeutic strategies for clinical application. Therefore, it’s of great importance to identify accurate biomarkers for early detection and prognostic prediction of SARCs. Experimental Design:In this study, we characterized three subtypes of SARCs based on tumor immune infiltration levels (TIILs), and constructed a prognosis-related competing endogenous RNA (ceRNA) network to investigate molecular regulations in the sarcoma tumor microenvironment (TME). We further built a subnetwork consisting of mRNAs and lncRNAs which are targets of key miRNAs and strongly correlated with each other in the ceRNA network. After validation using public data and experiments in vivo and in vitro, we deeply dug the biological role of the miRNAs and lncRNAs in a subnetwork and their impact on TME. Results:Altogether, 5 miRNAs (hsa-mir-125b-2, hsa-mir-135a-1, hsa-mir92a-2, hsa-mir-181a-2, and hsa-mir-214), 3 lncRNAs (LINC00641, LINC01146, and LINC00892), and 10 mRNAs (AGO2, CXCL10, CD86, CASP1, IKZF1, CD27, CD247, CD69, CCR2, and CSF2RB) in the subnetwork were identified as vital regulators to shape the TME. Based on the systematic network, we identified that Trichostatin A, a pan-HDAC inhibitor, could potentially regulate the TME of sarcoma thereby inhibiting the tumor growth. Conclusions:Our study identifies a ceRNA network as promising biomarker for SARC. This system provides a more comprehensive understanding and a novel perspective of how ceRNAs are involving in shaping sarcoma TME.
Data from A Population of Tumor-Infiltrating CD4+ T-cells Co-expressing CD38 and CD39 is Associated with Checkpoint Inhibitor Resistance
Authors: Mitra Ankita , Thompson Brian , Strange Ann , Amato Carol M. , Vassallo Melinda , Dolgalev Igor , Hester-McCullough Jonathan , Muramatsu Tomoaki , Kimono Diana , Puranik Amrutesh S. , Weber Jeffrey S. , Woods David
Published: September 2024

Abstract
Purpose: We previously showed that elevated frequencies of peripheral blood CD3+CD4+CD127-GARP-CD38+CD39+ T-cells was associated with checkpoint immunotherapy resistance in metastatic melanoma patients. In the present study we sought to further investigate this population of ectoenzyme expressing T-cells (Teee). Expeirmental Design: Teee derived from the peripheral blood of metastatic melanoma patients were evaluated by bulk RNA-seq and flow cytometry. The presence of Teee in the tumor microenviroment was assessed using publically available single-cell RNA-seq datasets of melanoma, lung, and bladder cancer along with multispectral immunofluorescent imaging of melanoma patient FFPE specimens. Suppressive function of Teee was determined by an in vitro autologous suppression assay. Results: Teee had phenotypes associated with proliferation, apoptosis, exhaustion, and high expression of inhibitory molecules. Cells with a Teee gene signature were present in melanoma, lung cancer and bladder cancer patients’ tumors. CD4+ T-cells co-expressing CD38 and CD39 in the tumor microenvironment were preferentially associated with Ki67- CD8+ T-cells. Co-culture of patient Teee with autologous T-cells resulted in decreased proliferation of target T-cells. High baseline intra-tumoral frequencies of Teee were associated with checkpoint immunotherapy resistance and poor overall survival in metastatic melanoma patients. Conclusions: These results demonstrate that a novel population of CD4+ T-cells co-expressing CD38 and CD39 is found both in the peripheral blood and tumor of melanoma patients and is associated with checkpoint immunotherapy resistance.
Data from Therapeutic Vaccination against Human Papillomavirus Type 16 for the Treatment of Anal Intraepithelial Neoplasia in HIV+ Men
Authors: Gosens Karien C.M. , van der Burg Sjoerd H. , Welters Marij J.P. , Boekestijn Sanne , Loof Nikki M. , Quint Wim G.V. , van Noesel Carel J.M. , van der Wal Allard C. , Richel Olivier , Krebber Wilhelmus J.T.A. , Melief Cornelis J.M. , de Vries Henry J.C. , Prins Jan M.
Published: September 2024

Abstract
Purpose: Anal cancer is increasing in HIV-positive men who have sex with men (MSM). Treatment options for its precursor, high-grade anal intraepithelial neoplasia (HGAIN), are suboptimal. In this phase I-II dose-finding study we assessed the safety and efficacy of the human papillomavirus type 16 (HPV16) synthetic long peptide vaccine (SLP-HPV-01®) in HIV-positive MSM with HPV16-positive HGAIN. Patients and Methods: Four dosage schedules (1-5-10; 5-10-20; 10-20-40 and 40-40-40-40 mg) of SLP-HPV-01® were administered intradermally with a three-week interval in 10 patients per dose level. In each dose group, five patients also received 1 µg/kg pegylated interferon-alpha-2b subcutaneously. Primary endpoints were safety and regression of HGAIN at 3,6 and 12 months. Results: Eighty-one of 134 screened patients (60%) had HPV16-negative HGAIN lesions, leaving 53 eligible patients. Thirteen patients were excluded, leaving 40 men. The vaccine was well tolerated. One patient developed a generalized rash. The highest dosage level induced the strongest immune responses. There was no indication for stronger reactivity in the IFN-α groups. Up to 18 months of follow-up, 8/38 intention-to-treat patients had a complete clinical and histological response (CR) and one had a partial response (PR) (in total 9/38, 23.7%). At the highest dosage level the clinical response was 4/10 (40%). Stronger immune responses were detected among clinical responders. Conclusions: The highest dose level is safe, immunogenic and associated with clinical responses to HPV16-induced lesions. However, as the majority of HGAIN is caused by the other HPV types, further studies should aim at pan-HPV vaccination to prevent or treat HGAIN.
Data from Immune marker spatial distribution and clinical outcome after PD-1 blockade in mismatch repair-deficient, advanced colorectal carcinomas
Authors: Saberzadeh-Ardestani Bahar , Graham Rondell P. , McMahon Sara , Ahanonu Eze , Shi Qian , Williams Crystal , Hubbard Antony , Zhang Wenjun , Muranyi Andrea , Yan Dongyao , Jin Zhaohui , Shanmugam Kandavel , Sinicrope Frank A.
Published: September 2024

Abstract
Purpose: Targeting the PD-1/PD-L1 interaction has led to durable responses in fewer than half of patients with mismatch repair-deficient (MMR-d) advanced colorectal cancers (CRC). Immune contexture, including spatial distribution of immune cells in the tumor microenvironment, may predict immunotherapy outcome. Patients and Methods: Immune contexture and spatial distribution, including cell-to-cell distance measurements, were analyzed by multiplex immunofluorescence in primary CRCs with d-MMR (N=33) from patients treated with anti-PD-1 antibodies. By digital image analysis, density, ratio, intensity, and spatial distribution of PD-L1, PD-1, CD8, CD3, CD68, LAG3, TGFβR2, MHC-I, CD14, B2M, and pan-cytokeratin were computed. Feature selection was performed by regularized Cox regression with LASSO, and a proportional hazards model was fitted to predict progression-free survival (PFS). Results: For predicting survival among patients with MMR-d advanced CRC receiving PD-1 blockade, cell-to-cell distance measurements, but not cell densities or ratios, achieved statistical significance univariately. By multivariable feature selection, only mean number of PD-1+ cells within 10μm of a PD-L1+ cell was significantly predictive of progression-free survival (PFS). Dichotomization of this variable revealed that those with high versus low values had significantly prolonged PFS [median not reached (>83 months) vs 8.5 months (95% CI: 4.7-NR)] with a median PFS of 28.4 months for all patients [HRadj= 0.14, 95% CI: 0.04, 0.56; p=0.005]. Expression of PD-1 was observed on CD8+ T-cells; PD-L1 on CD3+ and CD8+ T-lymphocytes, macrophages (CD68+) and tumor cells. Conclusions: In d-MMR CRCs, PD-1+ to PD-L1+ receptor to ligand proximity is a potential predictive biomarker for the effectiveness of PD-1 blockade.
Clinical and Genomic Features of Classical and Basal Transcriptional Subtypes in Pancreatic Cancer
Authors: Singh Harshabad , Xiu Joanne , Kapner Kevin S. , Yuan Chen , Narayan Raja R. , Oberley Matthew , Farrell Alex , Surana Rishi , Huffman Brandon M. , Perez Kimberly , Cleary James M. , Jordan Alexander C. , Dias Costa Andressa , Williams Hannah L. , Raghavan Srivatsan , Weinberg Benjamin , Pishvaian Michael J. , Shroff Rachna T. , Goel Sanjay , Dougan Stephanie K. , Nowak Jonathan A. , Spetzler David , Sledge George , Wolpin Brian M. , Aguirre Andrew J.
Published: September 2024

Purpose:

Transcriptional profiling of pancreatic cancers has defined two main transcriptional subtypes: classical and basal. Initial data suggest shorter survival for patients with basal tumors and differing treatment sensitivity to FOLFIRINOX and gemcitabine plus nab-paclitaxel by transcriptional subtype.

Experimental Design:

We examined 8,743 patients with RNA sequencing from pancreatic cancers performed at Caris Life Sciences. Classical and basal subtypes were identified using purity independent subtyping algorithm on RNA sequencing, and two cohorts were analyzed: (i) the biomarker cohort included patients with complete molecular profiling data (n = 7,250) and (ii) the outcome cohort included patients with metastatic disease with available survival outcomes (n = 5,335). A total of 3,842 patients were shared between the two cohorts. Kaplan–Meier curves and Cox proportional hazards regression were used to assess patient survival.

Results:

In the biomarker cohort, 3,063 tumors (42.2%) were strongly classical (SC) and 2,015 tumors (27.8%) were strongly basal (SB). SC and SB tumors showed strong associations with histologic phenotypes and biopsy sites. SB tumors had higher rates of KRAS, TP53, and ARID1A mutations, lower rates of SMAD4 mutation, and transcriptional evidence of epithelial-mesenchymal transition. Sixty of 77 cases (78%) maintained their transcriptional subtype between temporally and/or spatially disparate lesions. In the outcome cohort, the SB subtype was associated with shorter overall survival time, regardless of whether they received FOLFIRINOX or gemcitabine plus nab-paclitaxel as first-line chemotherapy. The mutant KRAS allele type was prognostic of outcomes; however, this impact was restricted to SC tumors, whereas all mutant KRAS alleles had similarly poor outcomes in SB tumors.

Conclusions:

The SB subtype is a strong independent predictor of worse outcomes, regardless of the up-front chemotherapy regimen used. Clinical trials should further investigate pancreatic cancer transcriptional subtypes as a prognostic and predictive biomarker.