bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Theranostic Targeting of CUB Domain Containing Protein 1 (CDCP1) in Pancreatic Cancer
Authors: Moroz Anna , Wang Yung-Hua , Sharib Jeremy M. , Wei Junnian , Zhao Ning , Huang Yangjie , Chen Zhuo , Martinko Alexander J. , Zhuo Jie , Lim Shion A. , Zhang Lydia H. , Seo Youngho , Carlin Sean , Leung Kevin K. , Collisson Eric A. , Kirkwood Kimberly S. , Wells James A. , Evans Michael J.
Published: April 2023

AbstractPurpose:
The recent emergence of radioligand therapies for cancer treatment has increased enthusiasm for developing new theranostic strategies coupling both imaging and cytotoxicity in the same entity. In this study, we evaluated whether CUB domain containing protein 1 (CDCP1), a single-pass transmembrane protein highly overexpressed in diverse human cancers, might be a target for cancer theranostics.
Experimental Design:
The ectodomain of CDCP1 was targeted using radiolabeled forms of 4A06, a potent and specific recombinant human antibody that we developed. Imaging and antitumor assessment studies were performed in animal models of pancreatic cancer, including two patient-derived xenograft models we developed for this study. For antitumor assessment studies, the endpoints were death due to tumor volume >3,000 mm3 or ≥20% loss in body weight. Specific tracer binding or antitumor effects were assessed with an unpaired, two-tailed Student t test and survival advantages were assessed with a log rank (Mantel–Cox) test. Differences at the 95% confidence level were interpreted to be significant.
Results:
89Zr-4A06 detected a broad dynamic range of full length or cleaved CDCP1 expression on seven human pancreatic cancer tumors (n = 4/tumor). Treating mice with single or fractionated doses of 177Lu-4A06 significantly reduced pancreatic cancer tumor volume compared with mice receiving vehicle or unlabeled 4A06 (n = 8; P < 0.01). A single dose of 225Ac-4A06 also inhibited tumor growth, although the effect was less profound compared with 177Lu-4A06 (n = 8; P < 0.01). A significant survival advantage was imparted by 225Ac-4A06 (HR = 2.56; P < 0.05).
Conclusions:
These data establish that CDCP1 can be exploited for theranostics, a finding with widespread implications given its breadth of overexpression in cancer.
Data from Whole-Exome Sequencing Analysis of the Progression from Non–Low-Grade Ductal Carcinoma In Situ to Invasive Ductal Carcinoma
Authors: Pareja Fresia , Brown David N. , Lee Ju Youn , Da Cruz Paula Arnaud , Selenica Pier , Bi Rui , Geyer Felipe C. , Gazzo Andrea , da Silva Edaise M. , Vahdatinia Mahsa , Stylianou Anthe A. , Ferrando Lorenzo , Wen Hannah Y. , Hicks James B. , Weigelt Britta , Reis-Filho Jorge S.
Published: April 2023

AbstractPurpose:
Ductal carcinoma in situ (DCIS) is a nonobligate precursor of invasive breast cancer. Here, we sought to investigate the level of intralesion genetic heterogeneity in DCIS and the patterns of clonal architecture changes in the progression from DCIS to invasive disease.
Experimental Design:
Synchronous DCIS (n = 27) and invasive ductal carcinomas of no special type (IDC-NSTs; n = 26) from 25 patients, and pure DCIS (n = 7) from 7 patients were microdissected separately and subjected to high-depth whole-exome (n = 56) or massively parallel sequencing targeting ≥410 key cancer-related genes (n = 4). Somatic genetic alterations, mutational signatures, clonal composition, and phylogenetic analyses were defined using validated computational methods.
Results:
DCIS revealed genetic alterations similar to those of synchronously diagnosed IDC-NSTs and of non-related IDC-NSTs from The Cancer Genome Atlas (TCGA), whereas pure DCIS lacked PIK3CA mutations. Clonal decomposition and phylogenetic analyses based on somatic mutations and copy number alterations revealed that the mechanisms of progression of DCIS to invasive carcinoma are diverse, and that clonal selection might have constituted the mechanism of progression from DCIS to invasive disease in 28% (7/25) of patients. DCIS displaying a pattern of clonal selection in the progression to invasive cancer harbored higher levels of intralesion genetic heterogeneity than DCIS where no clonal selection was observed.
Conclusions:
Intralesion genetic heterogeneity is a common feature in DCIS synchronously diagnosed with IDC-NST. DCIS is a nonobligate precursor of IDC-NST, whose mechanisms of progression to invasive breast cancer are diverse and vary from case to case.
Data from Therapeutic Targeting of SDHB-Mutated Pheochromocytoma/Paraganglioma with Pharmacologic Ascorbic Acid
Authors: Liu Yang , Pang Ying , Zhu Boqun , Uher Ondrej , Caisova Veronika , Huynh Thanh-Truc , Taieb David , Hadrava Vanova Katerina , Ghayee Hans Kumar , Neuzil Jiri , Levine Mark , Yang Chunzhang , Pacak Karel
Published: April 2023

AbstractPurpose:
Pheochromocytomas and paragangliomas (PCPG) are usually benign neuroendocrine tumors. However, PCPGs with mutations in the succinate dehydrogenase B subunit (SDHB) have a poor prognosis and frequently develop metastatic lesions. SDHB-mutated PCPGs exhibit dysregulation in oxygen metabolic pathways, including pseudohypoxia and formation of reactive oxygen species, suggesting that targeting the redox balance pathway could be a potential therapeutic approach.
Experimental Design:
We studied the genetic alterations of cluster I PCPGs compared with cluster II PCPGs, which usually present as benign tumors. By targeting the signature molecular pathway, we investigated the therapeutic effect of ascorbic acid on PCPGs using in vitro and in vivo models.
Results:
By investigating PCPG cells with low SDHB levels, we show that pseudohypoxia resulted in elevated expression of iron transport proteins, including transferrin (TF), transferrin receptor 2 (TFR2), and the divalent metal transporter 1 (SLC11A2; DMT1), leading to iron accumulation. This iron overload contributed to elevated oxidative stress. Ascorbic acid at pharmacologic concentrations disrupted redox homeostasis, inducing DNA oxidative damage and cell apoptosis in PCPG cells with low SDHB levels. Moreover, through a preclinical animal model with PCPG allografts, we demonstrated that pharmacologic ascorbic acid suppressed SDHB-low metastatic lesions and prolonged overall survival.
Conclusions:
The data here demonstrate that targeting redox homeostasis as a cancer vulnerability with pharmacologic ascorbic acid is a promising therapeutic strategy for SDHB-mutated PCPGs.
Data from sFRP2 Supersedes VEGF as an Age-related Driver of Angiogenesis in Melanoma, Affecting Response to Anti-VEGF Therapy in Older Patients
Authors: Fane Mitchell E. , Ecker Brett L. , Kaur Amanpreet , Marino Gloria E. , Alicea Gretchen M. , Douglass Stephen M. , Chhabra Yash , Webster Marie R. , Marshall Andrea , Colling Richard , Espinosa Olivia , Coupe Nicholas , Maroo Neera , Campo Leticia , Middleton Mark R. , Corrie Pippa , Xu Xiaowei , Karakousis Giorgos C. , Weeraratna Ashani T.
Published: April 2023

AbstractPurpose:
Angiogenesis is thought to be critical for tumor metastasis. However, inhibiting angiogenesis using antibodies such as bevacizumab (Avastin), has had little impact on melanoma patient survival. We have demonstrated that both angiogenesis and metastasis are increased in older individuals, and therefore sought to investigate whether there was an age-related difference in response to bevacizumab, and if so, what the underlying mechanism could be.
Experimental Design:
We analyzed data from the AVAST-M trial of 1,343 patients with melanoma treated with bevacizumab to determine whether there is an age-dependent response to bevacizumab. We also examined the age-dependent expression of VEGF and its cognate receptors in patients with melanoma, while using syngeneic melanoma animal models to target VEGF in young versus old mice. We also examined the age-related proangiogenic factor secreted frizzled-related protein 2 (sFRP2) and whether it could modulate response to anti-VEGF therapy.
Results:
We show that older patients respond poorly to bevacizumab, whereas younger patients show improvement in both disease-free survival and overall survival. We find that targeting VEGF does not ablate angiogenesis in an aged mouse model, while sFRP2 promotes angiogenesis in vitro and in young mice. Targeting sFRP2 in aged mice successfully ablates angiogenesis, while the effects of targeting VEGF in young mice can be overcome by increasing sFRP2.
Conclusions:
VEGF is decreased during aging, thereby reducing response to bevacizumab. Despite the decrease in VEGF, angiogenesis is increased because of an increase in sFRP2 in the aged tumor microenvironment. These results stress the importance of considering age as a factor for designing targeted therapies.
Data from Multimodal CEA-Targeted Image-Guided Colorectal Cancer Surgery using 111In-Labeled SGM-101
Authors: de Gooyer Jan Marie , Elekonawo Fortuné M.K. , Bos Desirée L. , van der Post Rachel S. , Pèlegrin André , Framery Bérénice , Cailler Françoise , Vahrmeijer Alexander L. , de Wilt Johannes H.W. , Rijpkema Mark
Published: April 2023

AbstractPurpose:
Intraoperative image guidance may aid in clinical decision-making during surgical treatment of colorectal cancer. We developed the dual-labeled carcinoembryonic antigen–targeting tracer, [111In]In-DTPA-SGM-101, for pre- and intraoperative imaging of colorectal cancer. Subsequently, we investigated the tracer in preclinical biodistribution and multimodal image-guided surgery studies, and assessed the clinical feasibility on patient-derived colorectal cancer samples, paving the way for rapid clinical translation.
Experimental Design:
SGM-101 was conjugated with p-isothiocyanatobenzyl–diethylenetriaminepentaacetic acid (DTPA) and labeled with Indium-111 (111In). The biodistribution of 3, 10, 30, and 100 μg [111In]In-DTPA-SGM-101 was assessed in a dose escalation study in BALB/c nude mice with subcutaneous LS174T human colonic tumors, followed by a study to determine the optimal timepoint for imaging. Mice with intraperitoneal LS174T tumors underwent micro-SPECT/CT imaging and fluorescence image–guided resection. In a final translational experiment, we incubated freshly resected human tumor specimens with the tracer and assessed the tumor-to-adjacent tissue ratio of both signals.
Results:
The optimal protein dose of  [111In]In-DTPA-SGM-101 was 30 μg (tumor-to-blood ratio, 5.8 ± 1.1) and the optimal timepoint for imaging was 72 hours after injection (tumor-to-blood ratio, 5.1 ± 1.0). In mice with intraperitoneal tumors, [111In]In-DTPA-SGM-101 enabled preoperative SPECT/CT imaging and fluorescence image–guided resection. After incubation of human tumor samples, overall fluorescence and radiosignal intensities were higher in tumor areas compared with adjacent nontumor tissue (P < 0.001).
Conclusions:
[111In]In-DTPA-SGM-101 showed specific accumulation in colorectal tumors, and enabled micro-SPECT/CT imaging and fluorescence image–guided tumor resection. Thus, [111In]In-DTPA-SGM-101 could be a valuable tool for preoperative SPECT/CT imaging and intraoperative radio-guided localization and fluorescence image–guided resection of colorectal cancer.
Data from ESR1 Mutations and Overall Survival on Fulvestrant versus Exemestane in Advanced Hormone Receptor–Positive Breast Cancer: A Combined Analysis of the Phase III SoFEA and EFECT Trials
Authors: Turner Nicholas C. , Swift Claire , Kilburn Lucy , Fribbens Charlotte , Beaney Matthew , Garcia-Murillas Isaac , Budzar Aman U. , Robertson John F.R. , Gradishar William , Piccart Martine , Schiavon Gaia , Bliss Judith M. , Dowsett Mitch , Johnston Stephen R.D. , Chia Stephen K.
Published: April 2023

AbstractPurpose:
ESR1 mutations are acquired frequently in hormone receptor–positive metastatic breast cancer after prior aromatase inhibitors. We assessed the clinical utility of baseline ESR1 circulating tumor DNA (ctDNA) analysis in the two phase III randomized trials of fulvestrant versus exemestane.
Experimental Design:
The phase III EFECT and SoFEA trials randomized patients with hormone receptor–positive metastatic breast cancer who had progressed on prior nonsteroidal aromatase inhibitor therapy, between fulvestrant 250 mg and exemestane. Baseline serum samples from 227 patients in EFECT, and baseline plasma from 161 patients in SoFEA, were analyzed for ESR1 mutations by digital PCR. The primary objectives were to assess the impact of ESR1 mutation status on progression-free (PFS) and overall survival (OS) in a combined analysis of both studies.
Results:
ESR1 mutations were detected in 30% (151/383) baseline samples. In patients with ESR1 mutation detected, PFS was 2.4 months [95% confidence interval (CI), 2.0–2.6] on exemestane and 3.9 months (95% CI, 3.0–6.0) on fulvestrant [hazard ratio (HR), 0.59; 95% CI, 0.39–0.89; P = 0.01). In patients without ESR1 mutations detected, PFS was 4.8 months (95% CI, 3.7–6.2) on exemestane and 4.1 months (95% CI, 3.6–5.5) on fulvestrant (HR, 1.05; 95% CI, 0.81–1.37; P = 0.69). There was an interaction between ESR1 mutation and treatment (P = 0.02). Patients with ESR1 mutation detected had 1-year OS of 62% (95% CI, 45%–75%) on exemestane and 80% (95% CI, 68%–87%) on fulvestrant (P = 0.04; restricted mean survival analysis). Patients without ESR1 mutations detected had 1-year OS of 79% (95% CI, 71%–85%) on exemestane and 81% (95% CI, 74%–87%) on fulvestrant (P = 0.69).
Conclusions:
Detection of ESR1 mutations in baseline ctDNA is associated with inferior PFS and OS in patients treated with exemestane versus fulvestrant.
Data from Biomarkers Associated with Beneficial PD-1 Checkpoint Blockade in Non–Small Cell Lung Cancer (NSCLC) Identified Using High-Plex Digital Spatial Profiling
Authors: Zugazagoitia Jon , Gupta Swati , Liu Yuting , Fuhrman Kit , Gettinger Scott , Herbst Roy S. , Schalper Kurt A. , Rimm David L.
Published: April 2023

AbstractPurpose:
Only a minority of patients with advanced non–small cell lung cancer (NSCLC) truly benefits from single-agent PD-1 checkpoint blockade, and more robust predictive biomarkers are needed.
Experimental Design:
We assessed tumor samples from 67 immunotherapy-treated NSCLC cases represented in a tissue microarray, 53 of whom had pretreatment samples and received monotherapy. Using GeoMx Digital Spatial Profiling System (NanoString Technologies), we quantified 39 immune parameters simultaneously in four tissue compartments defined by fluorescence colocalization [tumor (panCK+), leucocytes (CD45+), macrophages (CD68+), and nonimmune stroma].
Results:
A total of 156 protein variables were generated per case. In the univariate unadjusted analysis, we found 18 markers associated with outcome in spatial context, five of which remained significant after multiplicity adjustment. In the multivariate analysis, high levels of CD56 and CD4 measured in the CD45 compartment were the only markers that were predictive for all clinical outcomes, including progression-free survival (PFS, HR: 0.24, P = 0.006; and HR: 0.31, P = 0.011, respectively), and overall survival (OS, HR: 0.26, P = 0.014; and HR: 0.23, P = 0.007, respectively). Then, using an orthogonal method based on multiplex immunofluorescence and cell counting (inForm), we validated that high CD56+ immune cell counts in the stroma were associated with PFS and OS in the same cohort.
Conclusions:
This pilot scale discovery study shows the potential of the digital spatial profiling technology in the identification of spatially informed biomarkers of response to PD-1 checkpoint blockade in NSCLC. We identified a number of relevant candidate immune predictors in spatial context that deserve validation in larger independent cohorts.
Data from STAT3 Antisense Oligonucleotide Remodels the Suppressive Tumor Microenvironment to Enhance Immune Activation in Combination with Anti–PD-L1
Authors: Proia Theresa A. , Singh Maneesh , Woessner Richard , Carnevalli Larissa , Bommakanti Gayathri , Magiera Lukasz , Srinivasan Srimathi , Grosskurth Shaun , Collins Mike , Womack Chris , Griffin Matthew , Ye Minwei , Cantin Susan , Russell Deanna , Xie Mingchao , Hughes Adina , Deng Nanhua , Mele Deanna A. , Fawell Stephen , Barry Simon , Reimer Corinne , Barrett J. Carl , McCoon Patricia
Published: April 2023

AbstractPurpose:
Danvatirsen is a therapeutic antisense oligonucleotide (ASO) that selectively targets STAT3 and has shown clinical activity in two phase I clinical studies. We interrogated the clinical mechanism of action using danvatirsen-treated patient samples and conducted back-translational studies to further elucidate its immunomodulatory mechanism of action.
Experimental Design:
Paired biopsies and blood samples from danvatirsen-treated patients were evaluated using immunohistochemistry and gene-expression analysis. To gain mechanistic insight, we used mass cytometry, flow cytometry, and immunofluorescence analysis of CT26 tumors treated with a mouse surrogate STAT3 ASO, and human immune cells were treated in vitro with danvatirsen.
Results:
Within the tumors of treated patients, danvatirsen uptake was observed mainly in cells of the tumor microenvironment (TME). Gene expression analysis comparing baseline and on-treatment tumor samples showed increased expression of proinflammatory genes. In mouse models, STAT3 ASO demonstrated partial tumor growth inhibition and enhanced the antitumor activity when combined with anti–PD-L1. Immune profiling revealed reduced STAT3 protein in immune and stromal cells, and decreased suppressive cytokines correlating with increased proinflammatory macrophages and cytokine production. These changes led to enhanced T-cell abundance and function in combination with anti–PD-L1.
Conclusions:
STAT3 ASO treatment reverses a suppressive TME and promotes proinflammatory gene expression changes in patients' tumors and mouse models. Preclinical data provide evidence that ASO-mediated inhibition of STAT3 in the immune compartment is sufficient to remodel the TME and enhance the activity of checkpoint blockade without direct STAT3 inhibition in tumor cells. Collectively, these data provide a rationale for testing this combination in the clinic.
Data from Immunomodulatory Activity of a Colony-stimulating Factor-1 Receptor Inhibitor in Patients with Advanced Refractory Breast or Prostate Cancer: A Phase I Study
Authors: Autio Karen A. , Klebanoff Christopher A. , Schaer David , Kauh John Sae Wook , Slovin Susan F. , Adamow Matthew , Blinder Victoria S. , Brahmachary Manisha , Carlsen Michelle , Comen Elizabeth , Danila Daniel C. , Doman Thompson N. , Durack Jeremy C. , Fox Josef J. , Gluskin Jill S. , Hoffman David M. , Kang Suhyun , Kang Praneet , Landa Jonathan , McAndrew Philomena F. , Modi Shanu , Morris Michael J. , Novosiadly Ruslan , Rathkopf Dana E. , Sanford Rachel , Chapman Sonya C. , Tate Courtney M. , Yu Danni , Wong Phillip , McArthur Heather L.
Published: April 2023

AbstractPurpose:
Tumor-associated macrophages correlate with increased invasiveness, growth, and immunosuppression. Activation of the colony-stimulating factor-1 receptor (CSF-1R) results in proliferation, differentiation, and migration of monocytes/macrophages. This phase I study evaluated the immunologic and clinical activity, and safety profile of CSF-1R inhibition with the mAb LY3022855.
Patients and Methods:
Patients with advanced refractory metastatic breast cancer (MBC) or metastatic castration-resistant prostate cancer (mCRPC) were treated with LY3022855 intravenously in 6-week cycles in cohorts: (A) 1.25 mg/kg every 2 weeks (Q2W); (B) 1.0 mg/kg on weeks 1, 2, 4, and 5; (C) 100 mg once weekly; (D)100 mg Q2W. mCRPC patients were enrolled in cohorts A and B; patients with MBC were enrolled in all cohorts. Efficacy was assessed by RECIST and Prostate Cancer Clinical Trials Working Group 2 criteria.
Results:
Thirty-four patients (22 MBC; 12 mCRPC) received ≥1 dose of LY3022855. At day 8, circulating CSF-1 levels increased and proinflammatory monocytes CD14DIMCD16BRIGHT decreased. Best RECIST response was stable disease in five patients with MBC (23%; duration, 82–302 days) and three patients with mCRPC (25%; duration, 50–124 days). Two patients with MBC (cohort A) had durable stable disease >9 months and a third patient with MBC had palpable reduction in a nontarget neck mass. Immune-related gene activation in tumor biopsies posttreatment was observed. Common any grade treatment-related adverse events were fatigue, decreased appetite, nausea, asymptomatic increased lipase, and creatine phosphokinase.
Conclusions:
LY3022855 was well tolerated and showed evidence of immune modulation. Clinically meaningful stable disease >9 months was observed in two patients with MBC.
Data from Clinical Outcome–Related Mutational Signatures Identified by Integrative Genomic Analysis in Nasopharyngeal Carcinoma
Authors: Dai Wei , Chung Dittman Lai-Shun , Chow Larry Ka-Yue , Yu Valen Zhuoyou , Lei Lisa Chan , Leong Merrin Man-Long , Chan Candy King-Chi , Ko Josephine Mun-Yee , Lung Maria Li
Published: April 2023

AbstractPurpose:
Investigation of biological mechanisms underlying genetic alterations in cancer can assist the understanding of etiology and identify the potential prognostic biomarkers.
Experimental Design:
We performed an integrative genomic analysis for a total of 731 nasopharyngeal carcinoma cases from five independent nasopharyngeal carcinoma cohorts to identify the genetic events associated with clinical outcomes.
Results:
In addition to the known mutational signatures associated with aging, APOBEC and mismatch repair (MMR), a new signature for homologous recombination deficiency (BRCAness) was discovered in 64 of 216 (29.6%) cases in the discovery set including three cohorts. This signature appeared more frequently in the recurrent and metastatic tumors and significantly correlated with shorter overall survival (OS) in the primary tumors. Independent prognostic value of MMR and BRCAness signatures was revealed by multivariable Cox analysis after adjustment for clinical parameters and stratification by studies. The cases with both signatures had much worse clinical outcome than those without these signatures [hazard ratio (HR), 12.4; P = 0.002]. This correlation was confirmed in the validation set (HR, 8.9; P = 0.003). The BRCAness signature is highly associated with BRCA2 pathogenic germline or somatic alterations (7.8% vs. 0%; P = 0.002). Targeted sequencing results from a prospective nasopharyngeal carcinoma cohort (N = 402) showed that the cases carrying BRCA2 germline rare variants are more likely to have poor OS and progression-free survival.
Conclusions:
Our study highlights importance of defects of DNA repair machinery in nasopharyngeal carcinoma pathogenesis and their prognostic values for clinical implications. These signatures will be useful for patient stratification to evaluate conventional and new treatment for precision medicine in nasopharyngeal carcinoma.
Data from Characterization and Clinical Outcomes of DNA Mismatch Repair–deficient Small Bowel Adenocarcinoma
Authors: Latham Alicia , Shia Jinru , Patel Zalak , Reidy-Lagunes Diane L. , Segal Neil H. , Yaeger Rona , Ganesh Karuna , Connell Louise , Kemeny Nancy E. , Kelsen David P. , Hechtman Jaclyn F. , Nash Garrett M. , Paty Philip B. , Zehir Ahmet , Tkachuk Kaitlin A. , Sheikh Rania , Markowitz Arnold J. , Mandelker Diana , Offit Kenneth , Berger Michael F. , Cercek Andrea , Garcia-Aguilar Julio , Saltz Leonard B. , Weiser Martin R. , Stadler Zsofia K.
Published: April 2023

AbstractPurpose:
The prevalence and clinical characteristics of small bowel adenocarcinomas (SBA) in the setting of Lynch syndrome have not been well studied. We characterized SBA according to DNA mismatch repair and/or microsatellite instability (MMR/MSI) and germline mutation status and compared clinical outcomes.
Experimental Design:
A single-institution review identified 100 SBAs. Tumors were evaluated for MSI via MSIsensor and/or corresponding MMR protein expression via IHC staining. Germline DNA was analyzed for mutations in known cancer predisposition genes, including MMR (MLH1, MSH2, MSH6, PMS2, and EPCAM). Clinical variables were correlated with MMR/MSI status.
Results:
Twenty-six percent (26/100; 95% confidence interval, 18.4–35.4) of SBAs exhibited MMR deficiency (MMR-D). Lynch syndrome prevalence was 10% overall and 38.5% among MMR-D SBAs. Median age at SBA diagnosis was similar in non-Lynch syndrome MMR-D versus MMR-proficient (MMR-P) SBAs (65 vs. 61; P = 0.75), but significantly younger in Lynch syndrome (47.5 vs. 61; P = 0.03). The prevalence of synchronous/metachronous cancers was 9% (6/67) in MMR-P versus 34.6% (9/26) in MMR-D SBA, with 66.7% (6/9) of these in Lynch syndrome (P = 0.0002). In the MMR-P group, 52.2% (35/67) of patients presented with metastatic disease, compared with 23.1% (6/26) in the MMR-D group (P = 0.008). In MMR-P stage I/II patients, 88.2% (15/17) recurred, compared with 18.2% (2/11) in the MMR-D group (P = 0.0002).
Conclusions:
When compared with MMR-P SBA, MMR-D SBA was associated with earlier stage disease and lower recurrence rates, similar to observations in colorectal cancer. With a 38.5% prevalence in MMR-D SBA, germline Lynch syndrome testing in MMR-D SBA is warranted.
Data from Role of Tumor-Infiltrating B Cells in Clinical Outcome of Patients with Melanoma Treated With Dabrafenib Plus Trametinib
Authors: Brase Jan C. , Walter Robert F.H. , Savchenko Alexander , Gusenleitner Daniel , Garrett James , Schimming Tobias , Varaljai Renata , Castelletti Deborah , Kim Ju , Dakappagari Naveen , Schultz Ken , Robert Caroline , Long Georgina V. , Nathan Paul D. , Ribas Antoni , Flaherty Keith T. , Karaszewska Boguslawa , Schachter Jacob , Sucker Antje , Schmid Kurt W. , Zimmer Lisa , Livingstone Elisabeth , Gasal Eduard , Schadendorf Dirk , Roesch Alexander
Published: April 2023

AbstractPurpose:
Although patients with unresectable or metastatic melanoma can experience long-term survival with BRAF- and MEK-targeted agents or immune checkpoint inhibitors over 5 years, resistance develops in most patients. There is a distinct lack of pretherapeutic biomarkers to identify which patients are likely to benefit from each therapy type. Most research has focused on the predictive role of T cells in antitumor responses as opposed to B cells.
Patients and Methods:
We conducted prespecified exploratory biomarker analysis using gene expression profiling and digital pathology in 146 patients with previously untreated BRAF V600–mutant metastatic melanoma from the randomized, phase III COMBI-v trial and treated with dabrafenib plus trametinib who had available tumor specimens from screening.
Results:
Baseline cell-cycle gene expression signature was associated with progression-free survival (P = 0.007). Patients with high T-cell/low B-cell gene signatures had improved median overall survival (not reached [95% confidence interval (CI), 33.8 months–not reached]) compared with patients with high T-cell/high B-cell signatures (19.1 months; 95% CI, 13.4–38.6 months). Patients with high B-cell signatures had high B-cell infiltration into the tumor compartment, corresponding with decreased MAPK activity and increased expression of immunosuppressive markers.
Conclusions:
B cells may serve as a potential biomarker to predict clinical outcome in patients with advanced melanoma treated with dabrafenib plus trametinib. As separate studies have shown an opposite effect for B-cell levels and response to immunotherapy, B cells may serve as a potential biomarker to facilitate treatment selection. Further validation in a larger patient cohort is needed.
Data from The Anti-HER3 mAb Seribantumab Effectively Inhibits Growth of Patient-Derived and Isogenic Cell Line and Xenograft Models with Oncogenic NRG1 Fusions
Authors: Odintsov Igor , Lui Allan J.W. , Sisso Whitney J. , Gladstone Eric , Liu Zebing , Delasos Lukas , Kurth Renate I. , Sisso Exequiel M. , Vojnic Morana , Khodos Inna , Mattar Marissa S. , de Stanchina Elisa , Leland Shawn M. , Ladanyi Marc , Somwar Romel
Published: April 2023

AbstractPurpose:
Oncogenic fusions involving the neuregulin 1 (NRG1) gene are found in approximately 0.2% of cancers of diverse histologies. The resulting chimeric NRG1 proteins bind predominantly to HER3, leading to HER3-HER2 dimerization and activation of downstream growth and survival pathways. HER3 is, therefore, a rational target for therapy in NRG1 fusion–driven cancers.
Experimental Design:
We developed novel patient-derived and isogenic models of NRG1-rearranged cancers and examined the effect of the anti-HER3 antibody, seribantumab, on growth and activation of signaling networks in vitro and in vivo.
Results:
Seribantumab inhibited NRG1-stimulated growth of MCF-7 cells and growth of patient-derived breast (MDA-MB-175-VII, DOC4-NRG1 fusion) and lung (LUAD-0061AS3, SLC3A2-NRG1 fusion) cancer cells harboring NRG1 fusions or NRG1 amplification (HCC-95). In addition, seribantumab inhibited growth of isogenic HBEC cells expressing a CD74-NRG1 fusion (HBECp53-CD74-NRG1) and induced apoptosis in MDA-MB-175-VII and LUAD-0061AS3 cells. Induction of proapoptotic proteins and reduced expression of the cell-cycle regulator, cyclin D1, were observed in seribantumab-treated cells. Treatment of MDA-MB-175-VII, LUAD-0061AS3, and HBECp53-CD74-NRG1 cells with seribantumab reduced phosphorylation of EGFR, HER2, HER3, HER4, and known downstream signaling molecules, such as AKT and ERK1/2. Significantly, administration of seribantumab to mice bearing LUAD-0061AS3 patient-derived xenograft (PDX) and OV-10-0050 (ovarian cancer with CLU-NRG1 fusion) PDX tumors induced regression of tumors by 50%–100%. Afatinib was much less effective at blocking tumor growth.
Conclusions:
Seribantumab treatment blocked activation of the four ERBB family members and of downstream signaling, leading to inhibition of NRG1 fusion–dependent tumorigenesis in vitro and in vivo in breast, lung, and ovarian patient-derived cancer models.
Data from Independent Validation of the PAM50-Based Chemo-Endocrine Score (CES) in Hormone Receptor–Positive HER2-Positive Breast Cancer Treated with Neoadjuvant Anti–HER2-Based Therapy
Authors: Pascual Tomás , Fernandez-Martinez Aranzazu , Tanioka Maki , Dieci M. Vittoria , Pernas Sonia , Gavila Joaquin , Guarnieri Valentina , Cortes Javier , Villagrasa Patricia , Chic Núria , Vidal Maria , Adamo Barbara , Muñoz Montserrat , Griguolo Gaia , Llombart Antonio , Conte Pierfranco , Oliveira Mafalda , Conte Benedetta , Paré Laia , Galvan Patricia , Carey Lisa A. , Perou Charles M. , Prat Aleix
Published: April 2023

AbstractPurpose:
We do not yet have validated biomarkers to predict response and outcome within hormone receptor–positive/HER2-positive (HR+/HER2+) breast cancer. The PAM50-based chemo-endocrine score (CES) predicts chemo-endocrine sensitivity in hormone receptor–positive/HER2-negative (HR+/HER2−) breast cancer. Here, we evaluate the relationship of CES with response and survival in HR+/HER2+ breast cancer.
Experimental Design:
Intrinsic subtype and clinicopathologic data were obtained from seven studies in which patients were treated with HER2-targeted therapy either with endocrine therapy (ET) or with chemotherapy (CTX). CES was evaluated as a continuous variable and categorically from low to high scores [CES-C (chemo-sensitive), CES-U (uncertain), and CES-E (endocrine-sensitive)]. We first analyzed each dataset individually, and then all combined. Multivariable analyses were used to test CES association with pathologic complete response (pCR) and disease-free survival (DFS).
Results:
A total of 457 patients were included (112 with ET and 345 with CTX). In the combined cohort, CES-C, CES-U, and CES-E were identified in 60%, 23%, and 17% of the patients, respectively. High CES (i.e., CES-E) was associated with a lower probability of achieving pCR independently of clinical characteristics, therapy, intrinsic subtype, and study (adjusted OR = 0.42; P = 0.016). A total of 295 patients were analyzed for DFS with a median follow-up of 66 months. High CES was also associated with better DFS (adjusted HR, 0.174; P = 0.003) independently of pCR, clinical characteristics and intrinsic subtype. In patients with residual disease, the adjusted DFS HR of CES was 0.160 (P = 0.012).
Conclusions:
In HER2+/HR+ breast cancer, CES is useful for predicting chemo-endocrine sensitivity and provides additional prognostication beyond intrinsic subtype and clinicopathologic characteristics.
Data from Diagnosis of Pseudoprogression Following Lomustine–Temozolomide Chemoradiation in Newly Diagnosed Glioblastoma Patients Using FET-PET
Authors: Werner Jan-Michael , Weller Johannes , Ceccon Garry , Schaub Christina , Tscherpel Caroline , Lohmann Philipp , Bauer Elena K. , Schäfer Niklas , Stoffels Gabriele , Baues Christian , Celik Eren , Marnitz Simone , Kabbasch Christoph , Gielen Gerrit H. , Fink Gereon R. , Langen Karl-Josef , Herrlinger Ulrich , Galldiks Norbert
Published: April 2023

AbstractPurpose:
The CeTeG/NOA-09 phase III trial demonstrated a significant survival benefit of lomustine–temozolomide chemoradiation in patients with newly diagnosed glioblastoma with methylated O6-methylguanine-DNA methyltransferase (MGMT) promoter. Following lomustine–temozolomide chemoradiation, late and prolonged pseudoprogression may occur. We here evaluated the value of amino acid PET using O-(2-[18F]fluoroethyl)-l-tyrosine (FET) for differentiating pseudoprogression from tumor progression.
Experimental Design:
We retrospectively identified patients (i) who were treated off-study according to the CeTeG/NOA-09 protocol, (ii) had equivocal MRI findings after radiotherapy, and (iii) underwent additional FET-PET imaging for diagnostic evaluation (number of scans, 1–3). Maximum and mean tumor-to-brain ratios (TBRmax, TBRmean) and dynamic FET uptake parameters (e.g., time-to-peak) were calculated. In patients with more than one FET-PET scan, relative changes of TBR values were evaluated, that is, an increase or decrease of >10% compared with the reference scan was considered as tumor progression or pseudoprogression. Diagnostic performances were evaluated using ROC curve analyses and Fisher exact test. Diagnoses were confirmed histologically or clinicoradiologically.
Results:
We identified 23 patients with 32 FET-PET scans. Within 5–25 weeks after radiotherapy (median time, 9 weeks), pseudoprogression occurred in 11 patients (48%). The parameter TBRmean calculated from the FET-PET performed 10 ± 7 days after the equivocal MRI showed the highest accuracy (87%) to identify pseudoprogression (threshold, <1.95; P = 0.029). The integration of relative changes of TBRmean further improved the accuracy (91%; P < 0.001). Moreover, the combination of static and dynamic parameters increased the specificity to 100% (P = 0.005).
Conclusions:
The data suggest that FET-PET parameters are of significant clinical value to diagnose pseudoprogression related to lomustine–temozolomide chemoradiation.
Data from Sex-Based Dimorphism of Anticancer Immune Response and Molecular Mechanisms of Immune Evasion
Authors: Conforti Fabio , Pala Laura , Pagan Eleonora , Bagnardi Vincenzo , De Pas Tommaso , Queirolo Paola , Pennacchioli Elisabetta , Catania Chiara , Cocorocchio Emilia , Ferrucci Pier Francesco , Saponara Maristella , Orsolini Gianmarco , Zagami Paola , Nicoló Eleonora , De Marinis Filippo , Tortora Giampaolo , Bria Emilio , Minucci Saverio , Joffe Hadine , Veronesi Paolo , Wargo Jennifer , Rosenthal Rachel , Swanton Charles , Mantovani Alberto , Gelber Richard D. , Viale Giuseppe , Goldhirsch Aron , Giaccone Giuseppe
Published: April 2023

AbstractPurpose:
We previously demonstrated that sex influences response to immune checkpoint inhibitors. In this article, we investigate sex-based differences in the molecular mechanisms of anticancer immune response and immune evasion in patients with NSCLC.
Experimental Design:
We analyzed (i) transcriptome data of 2,575 early-stage NSCLCs from seven different datasets; (ii) 327 tumor samples extensively characterized at the molecular level from the TRACERx lung study; (iii) two independent cohorts of 329 and 391 patients, respectively, with advanced NSCLC treated with anti–PD-1/anti–PD-L1 drugs.
Results:
As compared with men, the tumor microenvironment (TME) of women was significantly enriched for a number of innate and adaptive immune cell types, including specific T-cell subpopulations. NSCLCs of men and women exploited different mechanisms of immune evasion. The TME of females was characterized by significantly greater T-cell dysfunction status, higher expression of inhibitory immune checkpoint molecules, and higher abundance of immune-suppressive cells, including cancer-associated fibroblasts, MDSCs, and regulatory T cells. In contrast, the TME of males was significantly enriched for a T-cell–excluded phenotype. We reported data supporting impaired neoantigens presentation to immune system in tumors of men, as molecular mechanism explaining the findings observed. Finally, in line with our results, we showed significant sex-based differences in the association between TMB and outcome of patients with advanced NSCLC treated with anti–PD-1/PD-L1 drugs.
Conclusions:
We demonstrated meaningful sex-based differences of anticancer immune response and immune evasion mechanisms, that may be exploited to improve immunotherapy efficacy for both women and men.
Data from A Large-Scale Prospective Concordance Study of Plasma- and Tissue-Based Next-Generation Targeted Sequencing for Advanced Non–Small Cell Lung Cancer (LC-SCRUM-Liquid)
Authors: Sugimoto Akira , Matsumoto Shingo , Udagawa Hibiki , Itotani Ryo , Usui Yuko , Umemura Shigeki , Nishino Kazumi , Nakachi Ichiro , Kuyama Shoichi , Daga Haruko , Hara Satoshi , Miyamoto Shingo , Kato Terufumi , Sakakibara-Konishi Jun , Tabata Eriko , Nakagawa Taku , Kawaguchi Tomoya , Sakai Tetsuya , Shibata Yuji , Izumi Hiroki , Nosaki Kaname , Zenke Yoshitaka , Yoh Kiyotaka , Goto Koichi
Published: April 2023

AbstractPurpose:
We evaluated plasma cell-free DNA (cfDNA) and tissue-based sequencing concordance for comprehensive oncogenic driver detection in non–small cell lung cancer (NSCLC) using a large-scale prospective screening cohort (LC-SCRUM-Liquid).
Experimental Design:
Blood samples were prospectively collected within 4 weeks of corresponding tumor tissue sampling from patients with advanced NSCLC to investigate plasma cfDNA sequencing concordance for alterations in 8 oncogenes (EGFR, KRAS, BRAF, HER2, MET, ALK, RET, and ROS1) compared with tissue-based next-generation targeted sequencing.
Results:
Paired blood and tissue samples were obtained in 1,062/1,112 enrolled patients with NSCLC. Oncogenic alteration was detected by plasma cfDNA sequencing and tissue assay in 455 (42.8%) and 537 (50.5%) patients, respectively. The positive percent agreement of plasma cfDNA sequencing compared with tissue DNA and RNA assays were 77% (EGFR, 78%; KRAS, 75%; BRAF, 85%; HER2, 72%) and 47% (ALK, 46%; RET, 57%; ROS1, 18%; MET, 66%), respectively. Oncogenic drivers were positive for plasma cfDNA and negative for tissue due to unsuccessful genomic analysis from poor-quality tissue samples (70%), and were negative for plasma cfDNA and positive for tissue due to low sensitivity of cfDNA analysis (61%). In patients with positive oncogenic drivers by plasma cfDNA sequencing but negative by tissue assay, the response rate of genotype-matched therapy was 85% and median progression-free survival was 12.7 months.
Conclusions:
Plasma cfDNA sequencing in patients with advanced NSCLC showed relatively high sensitivity for detecting gene mutations but low sensitivity for gene fusions and MET exon 14 skipping. This may be an alternative only when tissue assay is unavailable due to insufficient DNA and RNA.
Data from ImmunoPET Imaging with 89Zr-Labeled Atezolizumab Enables In Vivo Evaluation of PD-L1 in Tumorgraft Models of Renal Cell Carcinoma
Authors: Mulgaonkar Aditi , Elias Roy , Woolford Layton , Guan Bing , Nham Kien , Kapur Payal , Christie Alana , Tcheuyap Vanina T. , Singla Nirmish , Bowman I. Alex , Stevens Christina , Hao Guiyang , Brugarolas James , Sun Xiankai
Published: April 2023

AbstractPurpose:
Immune checkpoint inhibitors (ICI) targeting the programmed cell death protein 1 and its ligand (PD-1/PD-L1) have transformed the treatment paradigm for metastatic renal cell carcinoma (RCC). However, response rates to ICIs as single agents or in combination vary widely and predictive biomarkers are lacking. Possibly related to the heterogeneity and dynamic nature of PD-L1 expression, tissue-based methods have shown limited value. Immuno–positron emission tomography (immunoPET) may enable noninvasive, comprehensive, and real-time PD-L1 detection. Herein, we systematically examined the performance of immunoPET for PD-L1 detection relative to IHC in an RCC patient-derived tumorgraft (TG) platform.
Experimental Design:
Eight independent RCC TGs with a wide range of PD-L1 expression (0%–85%) were evaluated by immunoPET. Uptake of 89Zr-labeled atezolizumab ([89Zr]Zr-DFO-ATZ) was compared with PD-L1 expression in tumors by IHC through double-blind analyses. Clinical outcomes of ICI-treated patients whose TGs were examined were analyzed to evaluate the clinical role of immunoPET in RCC.
Results:
ImmunoPET with [89Zr]Zr-DFO-ATZ (day 6/7 postinjection) revealed a statistically significant association with PD-L1 IHC assays (P = 0.0014; correlation ρXY = 0.78). Furthermore, immunoPET can be used to assess the heterogeneous distribution of PD-L1 expression. Finally, studies in the corresponding patients (n = 4) suggest that PD-L1 signal may influence ICI responsiveness.
Conclusions:
ImmunoPET with [89Zr]Zr-DFO-ATZ may enable a thorough and dynamic assessment of PD-L1 across sites of disease. The power of immunoPET to predict ICI response in RCC is being explored in an ongoing clinical trial (NCT04006522).
Data from Zinc Finger MYND-Type Containing 8 (ZMYND8) Is Epigenetically Regulated in Mutant Isocitrate Dehydrogenase 1 (IDH1) Glioma to Promote Radioresistance
Authors: Carney Stephen V. , Banerjee Kaushik , Mujeeb Anzar , Zhu Brandon , Haase Santiago , Varela Maria L. , Kadiyala Padma , Tronrud Claire E. , Zhu Ziwen , Mukherji Devarshi , Gorla Preethi , Sun Yilun , Tagett Rebecca , Núñez Felipe J. , Luo Maowu , Luo Weibo , Ljungman Mats , Liu Yayuan , Xia Ziyun , Schwendeman Anna , Qin Tingting , Sartor Maureen A. , Costello Joseph F. , Cahill Daniel P. , Lowenstein Pedro R. , Castro Maria G.
Published: April 2023

AbstractPurpose:
Mutant isocitrate dehydrogenase 1 (mIDH1) alters the epigenetic regulation of chromatin, leading to a hypermethylation phenotype in adult glioma. This work focuses on identifying gene targets epigenetically dysregulated by mIDH1 to confer therapeutic resistance to ionizing radiation (IR).
Experimental Design:
We evaluated changes in the transcriptome and epigenome in a radioresistant mIDH1 patient-derived glioma cell culture (GCC) following treatment with an mIDH1-specific inhibitor, AGI-5198. We identified Zinc Finger MYND-Type Containing 8 (ZMYND8) as a potential target of mIDH1 reprogramming. We suppressed ZMYND8 expression by shRNA knockdown and genetic knockout (KO) in mIDH1 glioma cells and then assessed cellular viability to IR. We assessed the sensitivity of mIDH1 GCCS to pharmacologic inhibition of ZMYND8-interacting partners: HDAC, BRD4, and PARP.
Results:
Inhibition of mIDH1 leads to an upregulation of gene networks involved in replication stress. We found that the expression of ZMYND8, a regulator of DNA damage response, was decreased in three patient-derived mIDH1 GCCs after treatment with AGI-5198. Knockdown of ZMYND8 expression sensitized mIDH1 GCCs to radiotherapy marked by decreased cellular viability. Following IR, mIDH1 glioma cells with ZMYND8 KO exhibit significant phosphorylation of ATM and sustained γH2AX activation. ZMYND8 KO mIDH1 GCCs were further responsive to IR when treated with either BRD4 or HDAC inhibitors. PARP inhibition further enhanced the efficacy of radiotherapy in ZMYND8 KO mIDH1 glioma cells.
Conclusions:
These findings indicate the impact of ZMYND8 in the maintenance of genomic integrity and repair of IR-induced DNA damage in mIDH1 glioma.
SALVO: Single-Arm Trial of Ipilimumab and Nivolumab as Adjuvant Therapy for Resected Mucosal Melanoma
Authors: Kottschade Lisa A. , Pond Gregory Russell , Olszanski Anthony J. , Zakharia Yousef , Domingo-Musibay Evidio , Hauke Ralph J. , Curti Brendan D. , Schober Sarah , Milhem Mohammed M. , Block Matthew Stephen , Hieken Tina , McWilliams Robert R.
Published: April 2023

Purpose:

Mucosal melanoma is a rare, aggressive form of melanoma with extremely high recurrence rates despite definitive surgical resection with curative intent. Currently there is no consensus on adjuvant therapy. Data on checkpoint inhibitors for adjuvant therapy are lacking.

Patients and Methods:

We performed a single-arm, multicenter clinical trial using “flip dose” ipilimumab (1 mg/kg q3w × 4 cycles), and nivolumab (3 mg/kg q3w × 4 cycles), then nivolumab 480 mg q4w × 11 cycles to complete a year of adjuvant therapy. Participants must have had R0/R1 resection ≤90 days before registration, no prior systemic therapy (adjuvant radiotherapy allowed), ECOG 0/1, and no uncontrolled autoimmune disease or other invasive cancer. Patients were recruited through the Midwest Melanoma Partnership/Hoosier Oncology Network.

Results:

From September 2017 to August 2021, 35 patients were enrolled. Of these, 29 (83%) had R0 resections, and 7 (20%) received adjuvant radiotherapy. Median age was 67 years, 21 (60.0%) female. Recurrence-free survival (RFS) rates at 1 and 2 years were 50% [95% confidence interval (CI), 31%–66%] and 37% (95% CI, 19%–55%), respectively. Overall survival rates at 1 and 2 years were 87% (95% CI, 68%–95%) and 68% (95% CI, 46%–83%), respectively. Median RFS was 10.3 months (95% CI, 5.7–25.8). Most common grade 3 toxicities were diarrhea (14%), hypertension (14%), and hyponatremia (11%), with no grade 4/5 toxicities.

Conclusions:

Flip-dose ipilimumab and nivolumab after resection of mucosal melanoma is associated with outcomes improved over that of surgical resection alone. Long-term follow-up, subgroup analyses and correlative studies are ongoing.
Data from Antitumor effect of dsRNA-induced p21WAF1/CIP1 gene activation in human bladder cancer cells
Authors: Chen Zhong , Place Robert F. , Jia Zhe-Jun , Pookot Deepa , Dahiya Rajvir , Li Long-Cheng
Published: April 2023

Abstract
We recently reported that synthetic dsRNAs targeting promoter regions can induce gene expression in a phenomenon referred to as dsRNA-induced gene activation/RNA activation (RNAa) [Li et al. Proc Natl Acad Sci U S A 2006;103:17337–42]. The present study investigates the in vitro antitumor activity RNAa can elicit through triggering the expression of cell cycle repressor protein p21WAF1/CIP1 (p21) in human bladder cancer cells. Transfection of a 21-nucleotide dsRNA targeting the p21 promoter (dsP21) was used to induce p21 expression in T24 and J82 bladder cancer cell lines. Reverse transcription-PCR and Western blot analysis accessed the increase p21 mRNA and protein levels, respectively, in transfected cells. In association to p21 induction, dsP21 transfection significantly inhibited bladder cancer cell proliferation and clonogenicity. Further analysis of cell viability and cell cycle distribution revealed that dsP21 transfection also enhanced apoptotic cell death and caused an accumulation in the G1 phase in both cell lines. In conclusion, p21 activation by RNAa has antitumor activity in vitro in bladder cancer cells. These results suggest that RNAa could be used for cancer treatment by targeted activation of tumor suppressor genes. [Mol Cancer Ther 2008;7(3):698–703]