bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Genomic Signatures Predict the Immunogenicity of BRCA-Deficient Breast Cancer
Authors: Kraya Adam A. , Maxwell Kara N. , Wubbenhorst Bradley , Wenz Brandon M. , Pluta John , Rech Andrew J. , Dorfman Liza M. , Lunceford Nicole , Barrett Amanda , Mitra Nandita , Morrissette Jennifer J.D. , Feldman Michael , Nayak Anupma , Domchek Susan M. , Vonderheide Robert H. , Nathanson Katherine L.
Published: April 2023

AbstractPurpose:
Breast cancers with BRCA1/2 alterations have a relatively high mutational load, suggesting that immune checkpoint blockade may be a potential treatment option. However, the degree of immune cell infiltration varies widely, and molecular features contributing to this variability remain unknown.
Experimental Design:
We hypothesized that genomic signatures might predict immunogenicity in BRCA1/2 breast cancers. Using The Cancer Genome Atlas (TCGA) genomic data, we compared breast cancers with (89) and without (770) either germline or somatic BRCA1/2 alterations. We also studied 35 breast cancers with germline BRCA1/2 mutations from Penn using WES and IHC.
Results:
We found that homologous recombination deficiency (HRD) scores were negatively associated with expression-based immune indices [cytolytic index (P = 0.04), immune ESTIMATE (P = 0.002), type II IFN signaling (P = 0.002)] despite being associated with a higher mutational/neoantigen burden, in BRCA1/2 mutant breast cancers. Further, absence of allele-specific loss of heterozygosity (LOH negative; P = 0.01) or subclonality (P = 0.003) of germline and somatic BRCA1/2 mutations, respectively, predicted for heightened cytolytic activity. Gene set analysis found that multiple innate and adaptive immune pathways that converge on NF-κB may contribute to this heightened immunogenicity. IHC of Penn breast cancers demonstrated increased CD45+ (P = 0.039) and CD8+ infiltrates (P = 0.037) and increased PDL1 expression (P = 0.012) in HRD-low or LOH-negative cancers. Triple-negative cancers with low HRD had far greater CD8+ T cells (P = 0.0011) and Perforin 1 expression (P = 0.014) compared with hormone receptor-positive HRD-high cancers.
Conclusions:
HRD scores and hormone receptor subtype are predictive of immunogenicity in BRCA1/2 breast cancers and may inform the design of optimal immune therapeutic strategies.
Data from Serum miRNA–based Prediction of Axillary Lymph Node Metastasis in Breast Cancer
Authors: Shiino Sho , Matsuzaki Juntaro , Shimomura Akihiko , Kawauchi Junpei , Takizawa Satoko , Sakamoto Hiromi , Aoki Yoshiaki , Yoshida Masayuki , Tamura Kenji , Kato Ken , Kinoshita Takayuki , Kitagawa Yuko , Ochiya Takahiro
Published: April 2023

AbstractPurpose:
Sentinel lymph node biopsy (SLNB) is the gold-standard procedure for evaluating axillary lymph node (ALN) status in patients with breast cancer. However, the morbidity of SLNB is not negligible, and the procedure is invasive for patients without ALN metastasis. Here, we developed a diagnostic model for evaluating ALN status using a combination of serum miRNAs and clinicopathologic factors as a novel less-invasive biomarker.

Experimental Design: Preoperative serum samples were collected from patients who underwent surgery for primary breast cancer or breast benign diseases between 2008 and 2014. A total of 958 serum samples (921 cases of primary breast cancer, including 630 cases in the no ALN metastasis group and 291 cases in the ALN metastasis group, and 37 patients with benign breast diseases) were analyzed by miRNA microarray. Samples were randomly divided into training and test sets. Logistic LASSO regression analysis was used to construct diagnostic models in the training set, which were validated in the test set.
Results:
An optimal diagnostic model was identified using a combination of two miRNAs (miR-629-3p and miR-4710) and three clinicopathologic factors (T stage, lymphovascular invasion, and ultrasound findings), which showed a sensitivity of 0.88 (0.84–0.92), a specificity of 0.69 (0.61–0.76), an accuracy of 0.818, and an area under the receiver operating characteristic curve of 0.86 in the test set.
Conclusions:
Serum miRNA profiles may be useful for the diagnosis of ALN metastasis before surgery in a less-invasive manner than SLNB.
Data from Whole–Genome Sequencing of Childhood Cancer Survivors Treated with Cranial Radiation Therapy Identifies 5p15.33 Locus for Stroke: A Report from the St. Jude Lifetime Cohort Study
Authors: Sapkota Yadav , Cheung Yin Ting , Moon Wonjong , Shelton Kyla , Wilson Carmen L. , Wang Zhaoming , Mulrooney Daniel A. , Zhang Jinghui , Armstrong Gregory T. , Hudson Melissa M. , Robison Leslie L. , Krull Kevin R. , Yasui Yutaka
Published: April 2023

AbstractPurpose:
To identify genetic factors associated with risk of stroke among survivors of childhood cancer treated with cranial radiotherapy (CRT).
Experimental Design:
We analyzed whole-genome sequencing (36.8-fold) data of 686 childhood cancer survivors of European ancestry [median (range), 40.4 (12.4–64.7) years old; 54% male] from the St. Jude Lifetime Cohort study treated with CRT, of whom 116 (17%) had clinically diagnosed stroke. Association analyses (single-variant and Burden/SKAT tests) were performed, adjusting for demographic characteristics and childhood cancer treatment exposures.
Results:
We identified a genome-wide significant association between 5p15.33 locus and stroke [rs112896372: HR = 2.55; P = 1.42 × 10–8], with a stronger association (HR = 3.68) among survivors treated with CRT dose 25–50 Gray (Gy) and weaker associations among those treated with CRT doses <20 or 20–25 or >50 Gy (HRs = 2.14, 2.40, and 2.28). The association was replicated in 90 CRT-exposed African survivors (HR = 3.05; P = 0.034). In CRT-exposed Europeans, rs112896372 significantly (P < 0.001) improved predictive ability (AUC = 0.717) for determining stroke risk than nongenetic factors alone (AUC = 0.663) at 30 years since diagnosis, with significant improvement among African survivors (P = 0.047). SNP rs112896372 was further evaluated in three independent datasets including 1,641 European (HR = 1.54; P = 0.055) and 316 African survivors (HR = 1.88; P = 0.283) not treated with CRT, and 166,988 males in the UK Biobank (OR = 1.0012; P = 0.042).
Conclusions:
A novel locus 5p15.33 is associated with stroke risk among childhood cancer survivors, with a possible CRT dose-specific effect. The locus is of potential clinical utility in characterizing individuals who may benefit from surveillance and intervention strategies.
Data from Therapeutic Targeting of Non-oncogene Dependencies in High-risk Neuroblastoma
Authors: Huang Chen-Tsung , Hsieh Chiao-Hui , Lee Wen-Chi , Liu Yen-Lin , Yang Tsai-Shan , Hsu Wen-Ming , Oyang Yen-Jen , Huang Hsuan-Cheng , Juan Hsueh-Fen
Published: April 2023

AbstractPurpose:
Neuroblastoma is a pediatric malignancy of the sympathetic nervous system with diverse clinical behaviors. Genomic amplification of MYCN oncogene has been shown to drive neuroblastoma pathogenesis and correlate with aggressive disease, but the survival rates for those high-risk tumors carrying no MYCN amplification remain equally dismal. The paucity of mutations and molecular heterogeneity has hindered the development of targeted therapies for most advanced neuroblastomas. We use an alternative method to identify potential drugs that target nononcogene dependencies in high-risk neuroblastoma.
Experimental Design:
By using a gene expression–based integrative approach, we identified prognostic signatures and potentially effective single agents and drug combinations for high-risk neuroblastoma.
Results:
Among these predictions, we validated in vitro efficacies of some investigational and marketed drugs, of which niclosamide, an anthelmintic drug approved by the FDA, was further investigated in vivo. We also quantified the proteomic changes during niclosamide treatment to pinpoint nucleoside diphosphate kinase 3 (NME3) downregulation as a potential mechanism for its antitumor activity.
Conclusions:
Our results establish a gene expression–based strategy to interrogate cancer biology and inform drug discovery and repositioning for high-risk neuroblastoma.
Data from Molecular Characterization of Locally Relapsed Head and Neck Cancer after Concomitant Chemoradiotherapy
Authors: de Roest Reinout H. , Mes Steven W. , Poell Jos B. , Brink Arjen , van de Wiel Mark A. , Bloemena Elisabeth , Thai Elena , Poli Tito , Leemans C. René , Brakenhoff Ruud H.
Published: April 2023

AbstractPurpose:
To investigate the pathobiological origin of local relapse after chemoradiotherapy, we studied genetic relationships of primary tumors (PT) and local relapses (LR) of patients treated with chemoradiotherapy.
Experimental Design:
First, low-coverage whole genome sequencing was performed on DNA from 44 biopsies of resected head and neck squamous cell carcinoma (HNSCC) specimens (median 3 biopsies/tumor) to assess suitability of copy number alterations (CNAs) as biomarker for genetic relationships. CNAs were compared within and between tumors and an algorithm was developed to assess genetic relationships with consideration of intratumor heterogeneity. Next, this CNA-based algorithm was combined with target enrichment sequencing of genes frequently mutated in HNSCC to assess the genetic relationships of paired tumors and LRs of patients treated with chemoradiotherapy.
Results:
Genetic relationship analysis using CNAs could accurately (96%) predict tumor biopsy pairs as patient-matched or independent. However, subsequent CNA analysis of PTs and LRs after chemoradiotherapy suggested genetic relationships in only 20% of cases, and absence in 80%. Target enrichment sequencing for mutations confirmed absence of any genetic relationship in half of the paired PTs and LRs.
Conclusions:
There are minor variations in CNA profiles within different areas of HNSCC tumors and many between independent tumors, suggesting that CNA profiles could be exploited as a marker of genetic relationship. Using CNA profiling and mutational analysis of cancer driver genes, relapses after chemoradiotherapy appear to be partially genetically related to the corresponding PTs, but seem often genetically unrelated. This remarkable observation warrants further studies and will impact therapeutic innovations and prognostic modeling when using index tumor characteristics.
Data from Metastatic Breast Carcinoma–Associated Fibroblasts Have Enhanced Protumorigenic Properties Related to Increased IGF2 Expression
Authors: Gui Yirui , Aguilar-Mahecha Adriana , Krzemien Urszula , Hosein Abdel , Buchanan Marguerite , Lafleur Josiane , Pollak Michael , Ferrario Cristiano , Basik Mark
Published: April 2023

AbstractPurpose:
The microenvironment of metastatic breast cancer is incompletely characterized, despite prior evidence that it plays a key role in the biology of metastasis. A major component of the tumor stroma is the carcinoma-associated fibroblast (CAF), which has been shown to communicate with other stromal and cancer cells to create a protumorigenic milieu. Our study was designed to characterize human CAFs from different metastatic sites.
Experimental Design:
We collected eight carcinoma-associated fibroblasts (mCAFs) from different metastatic sites and compared them with CAFs from primary tumors (pCAFs) and with normal breast fibroblasts (NFs). Molecular profiles and effects on breast cancer cell growth, on response to doxorubicin and on T-cell proliferation were compared.
Results:
We observed marked differences in mCAFs compared with pCAFs and NFs with respect to in vitro proliferation and effects on breast cancer cell migration, spheroid growth, invasion, response to doxorubicin, and in vivo tumor growth. We found marked transcriptomic differences between mCAFs and pCAFs, including increased expression of IFN-related genes and IGF2 in the former. Cluster analysis revealed two groups of mCAFs, with the liver mCAFs clustering together, with increased PDGFA expression. Treatment with an antibody against insulin-like growth factors (BI836845) inhibited growth of mixed mCAF-tumor cell xenografts in vivo. Also, mCAFs had a suppressive effect on T-cell proliferation.
Conclusions:
This is the first comparative analysis of a set of CAFs from metastatic sites in breast cancer. It revealed a marked protumorigenic effect in these mCAFs, which occurs in part through increased expression of IGF2.
Data from Prostate-Specific Membrane Antigen Ligand Positron Emission Tomography in Men with Nonmetastatic Castration-Resistant Prostate Cancer
Authors: Fendler Wolfgang P. , Weber Manuel , Iravani Amir , Hofman Michael S. , Calais Jérémie , Czernin Johannes , Ilhan Harun , Saad Fred , Small Eric J. , Smith Matthew R. , Perez Paola M. , Hope Thomas A. , Rauscher Isabel , Londhe Anil , Lopez-Gitlitz Angela , Cheng Shinta , Maurer Tobias , Herrmann Ken , Eiber Matthias , Hadaschik Boris
Published: April 2023

AbstractPurpose:
Systemic androgen-signaling inhibition added to ongoing androgen-deprivation therapy (ADT) improved clinical outcomes in patients with nonmetastatic castration-resistant prostate cancer without detectable metastases by conventional imaging (nmCRPC). Prostate-specific membrane antigen ligand positron emission tomography (PSMA-PET) detects prostate cancer with superior sensitivity to conventional imaging, but its performance in nmCRPC remains largely unknown. We characterized cancer burden in high-risk patients with nmCRPC using PSMA-PET.
Experimental Design:
We retrospectively included 200 patients with nmCRPC, prostate-specific antigen (PSA) >2 ng/mL, and high risk for metastatic disease [PSA doubling time (PSADT) of ≤10 months and/or Gleason score of ≥8] from six high-volume PET centers. We centrally reviewed PSMA-PET detection rate for pelvic disease and distant metastases (M1). We further evaluated SPARTAN patients stratified by risk factors for PSMA-PET-detected M1 disease.
Results:
PSMA-PET was positive in 196 of 200 patients. Overall, 44% had pelvic diseases, including 24% with local prostate bed recurrence, and 55% had M1 disease despite negative conventional imaging. Interobserver agreement was very high (κ: 0.81–0.91). PSA ≥ 5.5 ng/mL, locoregional nodal involvement determined by pathology (pN1), prior primary radiation, and prior salvage radiotherapy independently predicted M1 disease (all P < 0.05).
Conclusions:
PSMA-PET detected any disease in nearly all patients and M1 disease in 55% of patients previously diagnosed with nmCRPC, including subgroups with PSADT of ≤10 months and Gleason score of ≥8. The value of PSMA-PET imaging for treatment guidance should be tested in future studies.
Data from Early Modeled Longitudinal CA-125 Kinetics and Survival of Ovarian Cancer Patients: A GINECO AGO MRC CTU Study
Authors: Colomban Olivier , Tod Michel , Leary Alexandra , Ray-Coquard Isabelle , Lortholary Alain , Hardy-Bessard Anne Claire , Pfisterer Jacobus , Du Bois Andreas , Kurzeder Christian , Burges Alexander , Péron Julien , Freyer Gilles , You Benoit
Published: April 2023

AbstractPurpose:
Regarding cancer antigen 125 (CA-125) longitudinal kinetics during chemotherapy, the actual predictive value of the Gynecologic Cancer Intergroup (GCIG) CA-125 response criterion is questioned. The modeled CA-125 elimination rate constant KELIM exhibited higher prognostic value in patients with recurrent ovarian cancer enrolled in the CALYPSO trial. The objective was to validate the higher predictive and prognostic values of KELIM during first-line treatments.
Experimental Design:
Data from three large phase III trials were analyzed: AGO OVAR 9 [learning set: carboplatin-paclitaxel (CP) ± gemcitabine; n = 1,288]; AGO OVAR 7 (validation set: CP ± topotecan; n = 192); and ICON7 (validation set: CP ± bevacizumab; n = 1,388). The CA-125 profiles were fit with a nonlinear mixed-effect model during the first 100 days, and the individual KELIM were calculated. KELIM prognostic and predictive values for survival were assessed against GCIG criterion and other prognostic factors in univariate/multivariate analyses.
Results:
The GCIG CA-125 endpoint provided no meaningful predictive/prognostic information. C-index analyses confirmed the higher predictive value of KELIM compared with GCIG criterion for progression-free survival and overall survival (OS). KELIM provided reproducible prognostic information. Patients with favorable KELIM ≥ upper tercile (0.0711 per days) consistently experienced better OS, with HRs between 0.44 and 0.58 (e.g., median OS >65 months vs. <35 months).
Conclusions:
Modeled KELIM provides higher predictive and prognostic information based on CA-125 longitudinal kinetics compared with GCIG response criteria during first-line chemotherapy. Integration of this endpoint in guidelines may be considered. Individual KELIM and survival simulations can be calculated at http://www.biomarker-kinetics.org/. Further assessment of the surrogate value of KELIM treatment–related variations in a GCIG meta-analysis is warranted.

See related commentary by Maitland et al., p. 5182
Data from B7-H3 Expression in Merkel Cell Carcinoma–Associated Endothelial Cells Correlates with Locally Aggressive Primary Tumor Features and Increased Vascular Density
Authors: Aung Phyu P. , Parra Edwin Roger , Barua Souptik , Sui Dawen , Ning Jing , Mino Barbara , Ledesma Debora Alejandra , Curry Jonathan L. , Nagarajan Priyadharsini , Torres-Cabala Carlos A. , Efstathiou Eleni , Hoang Anh G. , Wong Michael K. , Wargo Jennifer A. , Lazar Alexander J. , Rao Arvind , Prieto Victor G. , Wistuba Ignacio , Tetzlaff Michael T.
Published: April 2023

AbstractPurpose:
Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy whose pathogenesis and prognosis are related to the integrity of the host immune system. Despite promising clinical responses to immune-checkpoint blockade, response and resistance remain unpredictable, underscoring a critical need to delineate novel prognostic biomarkers and/or therapeutic targets for this disease.

Experimental Design: Expression of immune-regulatory markers (PD-L2, B7-H3, B7-H4, IDO-1, ICOS, TIM3, LAG3, VISTA, and OX-40) was assessed using singlet chromogenic IHC in 10 primary MCCs. Multiplex immunofluorescence quantified CD31 and B7-H3 expression in 52 primary and 25 metastatic MCCs. B7-H3 and CD31 expressions were tabulated as a series of independent (X,Y) cell centroids. A spatial G-function, calculated based on the distribution of distances of B7-H3+ (X,Y) cell centroids around the CD31+ (X,Y) cell centroids, was used to estimate a colocalization index equivalent to the percentage of CD31-positive cell centroids that overlap with a B7-H3–positive cell centroid.
Results:
Primary and metastatic MCCs exhibit a dynamic range of colocalized CD31 and B7-H3 expression. Increasing colocalized expression of B7-H3 with CD31 significantly associated with increased tumor size (P = 0.0060), greater depth of invasion (P = 0.0110), presence of lymphovascular invasion (P = 0.0453), and invasion beyond skin (P = 0.0428) in primary MCC. Consistent with these findings, increasing colocalized expression of B7-H3 and CD31 correlated with increasing vascular density in primary MCC, but not metastatic MCC.
Conclusions:
Our results demonstrate that colocalized expression of B7-H3/CD31 is a poor prognostic indicator and suggest therapies targeting B7-H3 may represent an effective approach to augmenting immune-activating therapies for MCC.
Data from Results from a Phase IIb, Randomized, Multicenter Study of GVAX Pancreas and CRS-207 Compared with Chemotherapy in Adults with Previously Treated Metastatic Pancreatic Adenocarcinoma (ECLIPSE Study)
Authors: Le Dung T. , Picozzi Vincent J. , Ko Andrew H. , Wainberg Zev A. , Kindler Hedy , Wang-Gillam Andrea , Oberstein Paul , Morse Michael A. , Zeh Herbert J. , Weekes Colin , Reid Tony , Borazanci Erkut , Crocenzi Todd , LoConte Noelle K. , Musher Benjamin , Laheru Dan , Murphy Aimee , Whiting Chan , Nair Nitya , Enstrom Amanda , Ferber Sandy , Brockstedt Dirk G. , Jaffee Elizabeth M.
Published: April 2023

AbstractPurpose:
Limited options exist for patients with advanced pancreatic cancer progressing after 1 or more lines of therapy. A phase II study in patients with previously treated metastatic pancreatic cancer showed that combining GVAX pancreas (granulocyte-macrophage colony-stimulating factor-secreting allogeneic pancreatic tumor cells) with cyclophosphamide (Cy) and CRS-207 (live, attenuated Listeria monocytogenes expressing mesothelin) resulted in median overall survival (OS) of 6.1 months, which compares favorably with historical OS achieved with chemotherapy. In the current study, we compared Cy/GVAX + CRS-207, CRS-207 alone, and standard chemotherapy in a three-arm, randomized, controlled phase IIb trial.
Patients and Methods:
Patients with previously treated metastatic pancreatic adenocarcinoma were randomized 1:1:1 to receive Cy/GVAX + CRS-207 (arm A), CRS-207 (arm B), or physician's choice of single-agent chemotherapy (arm C). The primary cohort included patients who had failed ≥2 prior lines of therapy, including gemcitabine. The primary objective compared OS between arms A and C in the primary cohort. The second-line cohort included patients who had received 1 prior line of therapy. Additional objectives included OS between all treatment arms, safety, and tumor responses.
Results:
The study did not meet its primary efficacy endpoint. At the final study analysis, median OS [95% confidence interval (CI)] in the primary cohort (N = 213) was 3.7 (2.9–5.3), 5.4 (4.2–6.4), and 4.6 (4.2–5.7) months in arms A, B, and C, respectively, showing no significant difference between arm A and arm C [P = not significant (NS), HR = 1.17; 95% CI, 0.84–1.64]. The most frequently reported adverse events in all treatment groups were chills, pyrexia, fatigue, and nausea. No treatment-related deaths occurred.
Conclusions:
The combination of Cy/GVAX + CRS-207 did not improve survival over chemotherapy. (ClinicalTrials.gov ID: NCT02004262)

See related commentary by Salas-Benito et al., p. 5435
Data from Phase I Trial of Well-Differentiated Neuroendocrine Tumors (NETs) with Radiolabeled Somatostatin Antagonist 177Lu-Satoreotide Tetraxetan
Authors: Reidy-Lagunes Diane , Pandit-Taskar Neeta , O'Donoghue Joseph A. , Krebs Simone , Staton Kevin D. , Lyashchenko Serge K. , Lewis Jason S. , Raj Nitya , Gönen Mithat , Lohrmann Christian , Bodei Lisa , Weber Wolfgang A.
Published: April 2023

AbstractPurpose:
Radiolabeled somatostatin receptor 2 (SSTR2) antagonists have shown higher tumor uptake and tumor-to-organ ratios than somatostatin agonists in preclinical models of neuroendocrine tumors (NETs). We performed a phase I study to evaluate the safety and efficacy of SSTR2 antagonist 177Lu-satoreotide tetraxetan.
Patients and Methods:
Twenty patients with advanced SSTR2-positive NETs were treated with 177Lu-satoreotide tetraxetan. Patients first underwent a dosimetry study with 177Lu-satoreotide tetraxetan to determine the therapeutic activity that could be safely administered. This activity was split into two equal cycles to be delivered 3 months apart. The maximum activity was 7.4 GBq per cycle.
Results:
Of 20 patients with NETs (one lung, seven small bowel, nine pancreatic, one gastric, one rectal, one kidney; mean prior treatments: three), six received one cycle of 177Lu- satoreotide tetraxetan and 14 received two cycles. Hematologic toxicity after cycle 1 was mild-moderate and reversed before cycle 2. However, grade 4 hematologic toxicity occurred in four of seven (57%) patients after cycle 2 of 177Lu-satoreotide tetraxetan. The study was suspended, and the protocol modified to limit the cumulative absorbed bone marrow dose to 1 Gy and to reduce prescribed activity for cycle 2 by 50%. The best overall response rate was 45% [5% complete response (1/20), 40% partial response (8/20)]; with 40% stable disease (8/20) and 15% progression of disease (3/20). Median progression-free survival (PFS) was 21.0 months (95% CI, 13.6–NR).
Conclusions:
In this trial of heavily treated NETs, preliminary data are promising for the use of 177Lu-satoreotide tetraxetan. Additional studies are ongoing to determine optimal therapeutic dose/schedule.
Data from Discovery, Validation, and Application of Novel Methylated DNA Markers for Detection of Esophageal Cancer in Plasma
Authors: Qin Yi , Wu Chung W. , Taylor William R. , Sawas Tarek , Burger Kelli N. , Mahoney Douglas W. , Sun Zhifu , Yab Tracy C. , Lidgard Graham P. , Allawi Hatim T. , Buttar Navtej S. , Smyrk Thomas C. , Iyer Prasad G. , Katzka David A. , Ahlquist David A. , Kisiel John B.
Published: April 2023

AbstractPurpose:
The burden of esophageal cancer continues to rise, and noninvasive screening tools are needed. Methylated DNA markers (MDM) assayed from plasma show promise in detection of other cancers. For esophageal cancer detection, we aimed to discover and validate MDMs in tissue, and determine their feasibility when assayed from plasma.
Experimental Design:
Whole-methylome sequencing was performed on DNA extracted from 37 tissues (28 EC; 9 normal esophagus) and 8 buffy coat samples. Top MDMs were validated by methylation specific PCR on tissue from 76 EC (41 adeno, 35 squamous cell) and 17 normal esophagus. Quantitative allele-specific real-time target and signal amplification was used to assay MDMs in plasma from 183 patients (85 EC, 98 controls). Recursive partitioning (rPART) identified MDM combinations predictive of esophageal cancer. Validation was performed in silico by bootstrapping.
Results:
From discovery, 23 candidate MDMs were selected for independent tissue validation; median area under the receiver operating curve (AUC) for individual MDMs was 0.93. Among 12 MDMs advanced to plasma testing, rPART modeling selected a 5 MDM panel (FER1L4, ZNF671, ST8SIA1, TBX15, ARHGEF4) which achieved an AUC of 0.93 (95% CI, 0.89–0.96) on best-fit and 0.81 (95% CI, 0.75–0.88) on cross-validation. At 91% specificity, the panel detected 74% of esophageal cancer overall, and 43%, 64%, 77%, and 92% of stages I, II, III, and IV, respectively. Discrimination was not affected by age, sex, smoking, or body mass index.
Conclusions:
Novel MDMs assayed from plasma detect esophageal cancer with moderate accuracy. Further optimization and clinical testing are warranted.
Data from Tissue 2-Hydroxyglutarate as a Biomarker for Isocitrate Dehydrogenase Mutations in Gliomas
Authors: Sim Hao-Wen , Nejad Romina , Zhang Wenjiang , Nassiri Farshad , Mason Warren , Aldape Kenneth D. , Zadeh Gelareh , Chen Eric X.
Published: April 2023

AbstractPurpose:
Isocitrate dehydrogenase (IDH) mutations are common in low-grade gliomas and the IDH mutation status is now integrated into the WHO classification of gliomas. IDH mutations lead to preferential accumulation of the R- relative to the S-enantiomer of 2-hydroxyglutarate (2-HG). We investigated the utility of tissue total 2-HG, R-2-HG, and the R-2-HG/S-2-HG ratio (rRS) as diagnostic and prognostic biomarkers for IDH mutations in gliomas.

Experimental Design: Glioma tissue and blood samples from 87 patients were analyzed with HPLC-MS/MS coupled with a CHIROBIOTIC column to quantify both enantiomers of 2-HG. ROC analysis was conducted to evaluate the sensitivity and specificity of 2-HG, R-2-HG, and rRS. The feasibility of real-time determination of IDH status was evaluated in 11 patients intraoperatively. The prognostic value of rRS was evaluated using the Kaplan–Meier method.
Results:
The rRS in glioma tissues clearly distinguished patients with IDH-mutant versus wild-type tumors (P < 0.001). Sensitivity and specificity using an rRS cut-off value of 32.26 were 97% and 100%, respectively. None of total 2-HG, R-2-HG, or rRS was elevated in serum samples. Among patients with IDH-mutant tumors, tissue rRS stratifies overall survival. The duration of tissue analysis is approximately 60 minutes.
Conclusions:
Our study demonstrates that rRS is a reliable biomarker of IDH mutation status. This technique can be used to determine IDH mutation status intraoperatively, and to guide treatment decisions based on IDH mutation status in real time. Finally, rRS values may provide additional prognostic information and further validation is required.
Data from A Phase I Study of ASTX660, an Antagonist of Inhibitors of Apoptosis Proteins, in Adults with Advanced Cancers or Lymphoma
Authors: Mita Monica M. , LoRusso Patricia M. , Papadopoulos Kyriakos P. , Gordon Michael S. , Mita Alain C. , Ferraldeschi Roberta , Keer Harold , Oganesian Aram , Su Xiang Yao , Jueliger Simone , Tolcher Anthony W.
Published: April 2023

AbstractPurpose:
This first-in-human, phase I study evaluated ASTX660, an oral, small-molecule antagonist of cellular/X-linked inhibitors of apoptosis proteins in patients with advanced solid tumors or lymphoma.
Patients and Methods:
ASTX660 was administered orally once daily on a 7-day-on/7-day-off schedule in a 28-day cycle. Dose escalation followed a standard 3+3 design to determine the MTD and recommended phase II dose (RP2D). Dose expansion was conducted at the RP2D.
Results:
Forty-five patients received ASTX660 (range 15–270 mg/day). Dose-limiting toxicity of grade 3 increased lipase with or without increased amylase occurred in 3 patients at 270 mg/day and 1 patient at 210 mg/day. The MTD was determined to be 210 mg/day and the RP2D 180 mg/day. Common treatment-related adverse events included fatigue (33%), vomiting (31%), and nausea (27%). Grade ≥3 treatment-related adverse events occurred in 7 patients, most commonly anemia (13%), increased lipase (11%), and lymphopenia (9%). ASTX660 was rapidly absorbed, with maximum concentration achieved at approximately 0.5–1.0 hour. An approximately 2-fold accumulation in AUC exposures was observed on day 7 versus 1. ASTX660 suppressed cellular inhibitor of apoptosis protein-1 in peripheral blood mononuclear cells, which was maintained into the second cycle beyond the off-therapy week at the 180-mg/day RP2D and above. Clinical activity was seen in a patient with cutaneous T-cell lymphoma.
Conclusions:
ASTX660 demonstrated a manageable safety profile and exhibited evidence of pharmacodynamic and preliminary clinical activity at the 180-mg/day RP2D. The phase II part of the study is ongoing.
Data from Lucitanib for the Treatment of HR+/HER2− Metastatic Breast Cancer: Results from the Multicohort Phase II FINESSE Study
Authors: Hui Rina , Pearson Alex , Cortes Javier , Campbell Christine , Poirot Camille , Azim Hatem A. , Fumagalli Debora , Lambertini Matteo , Daly Fergus , Arahmani Amal , Perez-Garcia José , Aftimos Philippe , Bedard Philippe L. , Xuereb Laura , Scheepers Elsemieke D. , Vicente Malou , Goulioti Theodora , Loibl Sibylle , Loi Sherene , Pierrat Marie-Jeanne , Turner Nicholas C. , Andre Fabrice , Curigliano Giuseppe
Published: April 2023

AbstractPurpose:
The FGFR1 gene is amplified in 14% of patients with HR+/HER2− breast cancer. Efficacy and safety of lucitanib, an inhibitor of VEGFR1-3, FGFR1-3, and PDGFRα/β, were assessed.
Patients and Methods:
Patients with HR+/HER2− metastatic breast cancer (MBC) received oral lucitanib in three centrally confirmed cohorts: (i) FGFR1 amplified, (ii) FGFR1 nonamplified, 11q13 amplified, and (iii) FGFR1 and 11q13 nonamplified. Key inclusion criteria included Eastern Cooperative Oncology Group Performance Status ≤2, ≥1 line of anticancer therapy, but ≤2 lines of chemotherapy. Primary endpoint was overall response rates (ORR) by RECIST1.1. Simon's two-stage design was used: If ≥2 patients responded among 21 patients, 20 additional patients could be enrolled in each cohort. FGFR1 copy-number variation (CNV) was determined by FISH and droplet digital PCR, whereas FGFR1 expression was determined by IHC.
Results:
Seventy-six patients (32/18/26 in cohorts 1/2/3) from nine countries were enrolled. The prespecified primary endpoint was met in cohort 1 with ORR of 19% [95% confidence interval (CI), 9%–35%], but not in cohorts 2 and 3 with ORR of 0% (95% CI, 0%–18%) and 15% (95% CI, 6%–34%), respectively. Frequent adverse events included hypertension (87%), hypothyroidism (45%), nausea (33%), and proteinuria (32%). Exploratory biomarker analyses suggested higher ORR in patients with high FGFR1 amplification (≥4 CNV) than those without high amplification (22% vs. 9%). ORR in patients with FGFR1-high tumors (IHC, H-score ≥50) was 25% versus 8% in FGFR1-low cancers.
Conclusions:
Lucitanib had modest antitumor activity and significant hypertension-related toxicity in patients with HR+/HER2− MBC. Although based on small sample sizes, exploratory biomarker analyses suggested that patients with high FGFR1 amplification or expression might derive greater benefit.
Data from Genetic Ancestry–dependent Differences in Breast Cancer–induced Field Defects in the Tumor-adjacent Normal Breast
Authors: Nakshatri Harikrishna , Kumar Brijesh , Burney Heather N. , Cox Mary L. , Jacobsen Max , Sandusky George E. , D'Souza-Schorey Crislyn , Storniolo Anna Maria V.
Published: April 2023

AbstractPurpose:
Genetic ancestry influences evolutionary pathways of cancers. However, whether ancestry influences cancer-induced field defects is unknown. The goal of this study was to utilize ancestry-mapped true normal breast tissues as controls to identify cancer-induced field defects in normal tissue adjacent to breast tumors (NATs) in women of African American (AA) and European (EA) ancestry.
Experimental Design:
A tissue microarray comprising breast tissues of ancestry-mapped 100 age-matched healthy women from the Komen Tissue Bank (KTB) at Indiana University (Indianapolis, IN) and tumor-NAT pairs from 100 women (300 samples total) was analyzed for the levels of ZEB1, an oncogenic transcription factor that is central to cell fate, mature luminal cell–enriched estrogen receptor alpha (ERα), GATA3, FOXA1, and for immune cell composition.
Results:
ZEB1+ cells, which were localized surrounding the ductal structures of the normal breast, were enriched in the KTB-normal of AA compared with KTB-normal of EA women. In contrast, in EA women, both NATs and tumors compared with KTB-normal contained higher levels of ZEB1+ cells. FOXA1 levels were lower in NATs compared with KTB-normal in AA but not in EA women. We also noted variations in the levels of GATA3, CD8+ T cells, PD1+ immune cells, and PDL1+ cell but not CD68+ macrophages in NATs of AA and EA women. ERα levels did not change in any of our analyses, pointing to the specificity of ancestry-dependent variations.
Conclusions:
Genetic ancestry–mapped tissues from healthy individuals are required for proper assessment and development of cancer-induced field defects as early cancer detection markers. This finding is significant in light of recent discoveries of influence of genetic ancestry on both normal biology and tumor evolution.
Data from Clonality, Antigen Recognition, and Suppression of CD8+ T Cells Differentially Affect Prognosis of Breast Cancer Subtypes
Authors: Hammerl Dora , Massink Maarten P.G. , Smid Marcel , van Deurzen Carolien H.M. , Meijers-Heijboer Hanne E.J. , Waisfisz Quinten , Debets Reno , Martens John W.M.
Published: April 2023

AbstractPurpose:
In breast cancer, response rates to immune therapies are generally low and differ significantly across molecular subtypes, urging a better understanding of immunogenicity and immune evasion.
Experimental Design:
We interrogated large gene-expression data sets including 867 node-negative, treatment-naïve breast cancer patients (microarray data) and 347 breast cancer patients (whole-genome sequencing and transcriptome data) according to parameters of T cells as well as immune microenvironment in relation to patient survival.
Results:
We developed a 109–immune gene signature that captures abundance of CD8 tumor-infiltrating lymphocytes (TIL) and is prognostic in basal-like, her2, and luminal B breast cancer, but not in luminal A or normal-like breast cancer. Basal-like and her2 are characterized by highest CD8 TIL abundance, highest T-cell clonality, highest frequencies of memory T cells, and highest antigenicity, yet only the former shows highest expression level of immune and metabolic checkpoints and highest frequency of myeloid suppressor cells. Also, luminal B shows a high antigenicity and T-cell clonality, yet a low abundance of CD8 TILs. In contrast, luminal A and normal-like both show a low antigenicity, and notably, a low and high abundance of CD8 TILs, respectively, which associates with T-cell influx parameters, such as expression of adhesion molecules.
Conclusions:
Collectively, our data argue that not only CD8 T-cell presence itself, but rather T-cell clonality, T-cell subset distribution, coinhibition, and antigen presentation reflect occurrence of a CD8 T-cell response in breast cancer subtypes, which have been aborted by distinct T-cell–suppressive mechanisms, providing a rationale for subtype-specific combination immune therapies.
Data from Clinical Response of Live-Attenuated, Listeria monocytogenes Expressing Mesothelin (CRS-207) with Chemotherapy in Patients with Malignant Pleural Mesothelioma
Authors: Hassan Raffit , Alley Evan , Kindler Hedy , Antonia Scott , Jahan Thierry , Honarmand Somayeh , Nair Nitya , Whiting Chan C. , Enstrom Amanda , Lemmens Ed , Tsujikawa Takahiro , Kumar Sushil , Choe Gina , Thomas Anish , McDougall Katherine , Murphy Aimee L. , Jaffee Elizabeth , Coussens Lisa M. , Brockstedt Dirk G.
Published: April 2023

AbstractPurpose:
Malignant pleural mesothelioma (MPM) is an aggressive cancer associated with poor prognosis. CRS-207 is a live-attenuated Listeria monocytogenes engineered to express mesothelin, a tumor-associated antigen highly expressed in MPM. CRS-207 induces antitumor immune responses and increases susceptibility of neoplastic cells to immune-mediated killing.
Patients and Methods:
Patients with unresectable MPM, ECOG 0 or 1, and adequate organ and pulmonary function were enrolled in this multicenter, open-label phase Ib study. They received two priming infusions of 1 × 109 CFU CRS-207, followed by pemetrexed/cisplatin chemotherapy, and CRS-207 booster infusions. Primary objectives were safety and induction of immune response. Secondary/exploratory objectives included tumor response, progression-free survival (PFS), overall survival (OS), immune subset analysis, and gene-expression profiling of tumor.
Results:
Of 35 evaluable patients, 89% (31/35) had disease control with one complete response (3%), 19 partial responses (54%), and 10 stable disease (29%). The estimated median duration of response was 5.0 months (95% CI, 3.9–11.5). The median PFS and OS were 7.5 (95% CI, 7.0–9.9) and 14.7 (95% CI, 11.2–21.9) months, respectively. Tumor size reduction was observed post–CRS-207 infusion prior to chemotherapy in 11 of 35 (31%) patients. No unexpected treatment-related serious adverse events or deaths were observed. IHC analysis of pre- and post–CRS-207 treatment tumor biopsies revealed possible reinvigoration and proliferation of T cells, increased infiltration of dendritic and natural killer cells, increased CD8:Treg ratio, and a shift from immunosuppressive M2-like to proinflammatory M1-like macrophages following CRS-207 administration.
Conclusions:
Combination of CRS-207 and chemotherapy induced significant changes in the local tumor microenvironment and objective tumor responses in a majority of treated patients.
Data from A First-in-Human Phase I Study of INVAC-1, an Optimized Human Telomerase DNA Vaccine in Patients with Advanced Solid Tumors
Authors: Teixeira Luis , Medioni Jacques , Garibal Julie , Adotevi Olivier , Doucet Ludovic , Durey Marie-Agnès Dragon , Ghrieb Zineb , Kiladjian Jean-Jacques , Brizard Mara , Laheurte Caroline , Wehbe Maria , Pliquet Elodie , Escande Marie , Defrance Rémy , Culine Stephane , Oudard Stephane , Wain-Hobson Simon , Doppler Valérie , Huet Thierry , Langlade-Demoyen Pierre
Published: April 2023

AbstractPurpose:
Human telomerase reverse transcriptase (hTERT) is highly expressed in >85% of human tumors and is thus considered as a good tumor-associated antigen candidate for vaccine development. We conducted a phase I study to investigate the safety, tolerability, clinical response, and immunogenicity of INVAC-1, a DNA plasmid encoding a modified hTERT protein in patients with relapsed or refractory solid tumors.
Patients and Methods:
INVAC-1 was either administered by intradermal route followed by electroporation or by Tropis, a needle-free injection system. Safety and tolerability were monitored by clinical and laboratory assessments. Progression-free survival and overall survival were reported using Kaplan–Meier survival analysis. Immunogenicity was studied by ELISpot, Luminex, and Flow Cytometry.
Results:
Twenty-six patients were treated with INVAC-1 administered at three dose levels (100, 400, and 800 μg). Vaccination was well tolerated and no dose-limiting toxicity was reported. One treatment-related grade 3 SAE was reported. Fifty-eight percent of patients experienced disease stabilization. PFS was 2.7 months, median OS was 15 months, and 1-year survival was reached for 65% of patients. INVAC-1 vaccination stimulated specific anti-hTERT CD4 T-cell response as well as cytotoxic CD8 T-cell response. No evidence of peripheral vaccine-induced immunosuppression was observed.
Conclusions:
INVAC-1 vaccination was safe, well tolerated, and immunogenic when administered intradermally at the three tested doses in patients with relapsed or refractory cancers. Disease stabilization was observed for the majority of patients (58%) during the treatment period and beyond.

See related commentary by Slingluff Jr, p. 529
Data from Ganetespib in Combination with Pemetrexed–Platinum Chemotherapy in Patients with Pleural Mesothelioma (MESO-02): A Phase Ib Trial
Authors: Fennell Dean A. , Danson Sarah , Woll Penella J. , Forster Martin , Talbot Denis , Child Jennifer , Farrelly Laura , Sharkey Annabel , Busacca Sara , Ngai Yenting , Hackshaw Allan , Wheeler Graham M.
Published: April 2023

AbstractPurpose:
Ganetespib, a highly potent, small-molecule Heatshock protein 90 inhibitor, has potential efficacy in malignant pleural mesothelioma (MPM) via activity on critical survival pathways and known synergies with antifolates and platinum chemotherapy. We conducted a dose-escalation study to identify the maximum tolerated dose (MTD) of ganetespib in patients with chemotherapy-naïve MPM.
Patients and Methods:
MESO-02 (ClinicalTrials.gov: NCT01590160) was a nonrandomized, multicenter, phase Ib trial of 3-weekly ganetespib (100 mg/m2, 150 mg/m2, 200 mg/m2; days 1 and 15) with pemetrexed (500 mg/m2; day 1) and cisplatin (75 mg/m2; day 1) or carboplatin (area under concentration–time curve 5; day 1) in patients with MPM. Dose escalation was performed using the 3 + 3 design (cisplatin) and accelerated titration design (carboplatin). Secondary endpoints included best response, progression-free survival (PFS), and pharmacogenomic analyses.
Results:
Of 27 patients enrolled (cisplatin, n = 16; carboplatin, n = 11), 3 experienced dose-limiting toxicities: grade 3 nausea (cisplatin, n = 1; carboplatin, n = 1) and grade 2 infusion-related reaction (carboplatin, n = 1). Ganetespib's MTD was 200 mg/m2. Partial response was observed in 14 of 27 patients (52%; 61% in 23 response-evaluable patients) and 13 of 21 (62%) with epithelioid histology. At the MTD, 10 of 18 patients (56%) had partial response, 15 of 18 (83%) had disease control, and median PFS was 6.3 months (95% CI, 5.0–10.0). One responder exhibited disease control beyond 50 months. Global loss of heterozygosity was associated with shorter time to progression (HR 1.12; 95% CI, 1.02–1.24; P = 0.018).
Conclusions:
Ganetespib can be combined safely with pemetrexed and platinum chemotherapy to treat patients with MPM. This class of agent should be investigated in larger randomized studies.
Data from Abemaciclib, a Selective CDK4/6 Inhibitor, Enhances the Radiosensitivity of Non–Small Cell Lung Cancer In Vitro and In Vivo
Authors: Naz Sarwat , Sowers Anastasia , Choudhuri Rajani , Wissler Maria , Gamson Janet , Mathias Askale , Cook John A. , Mitchell James B.
Published: April 2023

Abstract
Purpose: To characterize the ionizing radiation (IR) enhancing effects and underlying mechanisms of the CDK4/6 inhibitor abemaciclib in non–small cell lung cancer (NSCLC) cells in vitro and in vivo.

Experimental Design: IR enhancement by abemaciclib in a variety of NSCLC cell lines was assessed by in vitro clonogenic assay, flow cytometry, and target inhibition verified by immunoblotting. IR-induced DNA damage repair was evaluated by γH2AX analysis. Global metabolic alterations by abemaciclib and IR combination were evaluated by LC/MS mass spectrometry and YSI bioanalyzer. Effects of abemaciclib and IR combination in vivo were studied by xenograft tumor regrowth delay, xenograft lysate immunoblotting, and tissue section immunohistochemistry.

Results: Abemaciclib enhanced the radiosensitivity of NSCLC cells independent of RAS or EGFR status. Enhancement of radiosensitivity was lost in cell lines deficient for functional p53 and RB protein. After IR, abemaciclib treatment inhibited DNA damage repair as measured by γH2AX. Mechanistically, abemaciclib inhibited RB phosphorylation, leading to cell-cycle arrest. It also inhibited mTOR signaling and reduced intracellular amino acid pools, causing nutrient stress. In vivo, abemaciclib, when administered in an adjuvant setting for the second week after fractionated IR, further inhibited vasculogenesis and tumor regrowth, with sustained inhibition of RB/E2F activity, mTOR pathway, and HIF-1 expression. In summary, our study signifies inhibiting the CDK4/6 pathway by abemaciclib in combination with IR as a promising therapeutic strategy to treat NSCLC.

Conclusions: Abemaciclib in combination with IR enhances NSCLC radiosensitivity in preclinical models, potentially providing a novel biomarker-driven combination therapeutic strategy for patients with NSCLC. Clin Cancer Res; 24(16); 3994–4005. ©2018 AACR.
Data from Ad5NULL-A20: A Tropism-Modified, αvβ6 Integrin-Selective Oncolytic Adenovirus for Epithelial Ovarian Cancer Therapies
Authors: Uusi-Kerttula Hanni , Davies James A. , Thompson Jill M. , Wongthida Phonphimon , Evgin Laura , Shim Kevin G. , Bradshaw Angela , Baker Alexander T. , Rizkallah Pierre J. , Jones Rachel , Hanna Louise , Hudson Emma , Vile Richard G. , Chester John D. , Parker Alan L.
Published: April 2023

Abstract
Purpose: Virotherapies are maturing in the clinical setting. Adenoviruses (Ad) are excellent vectors for the manipulability and tolerance of transgenes. Poor tumor selectivity, off-target sequestration, and immune inactivation hamper clinical efficacy. We sought to completely redesign Ad5 into a refined, tumor-selective virotherapy targeted to αvβ6 integrin, which is expressed in a range of aggressively transformed epithelial cancers but nondetectable in healthy tissues.

Experimental Design: Ad5NULL-A20 harbors mutations in each major capsid protein to preclude uptake via all native pathways. Tumor-tropism via αvβ6 targeting was achieved by genetic insertion of A20 peptide (NAVPNLRGDLQVLAQKVART) within the fiber knob protein. The vector's selectivity in vitro and in vivo was assessed.

Results: The tropism-ablating triple mutation completely blocked all native cell entry pathways of Ad5NULL-A20 via coxsackie and adenovirus receptor (CAR), αvβ3/5 integrins, and coagulation factor 10 (FX). Ad5NULL-A20 efficiently and selectively transduced αvβ6+ cell lines and primary clinical ascites-derived EOC ex vivo, including in the presence of preexisting anti-Ad5 immunity. In vivo biodistribution of Ad5NULL-A20 following systemic delivery in non–tumor-bearing mice was significantly reduced in all off-target organs, including a remarkable 107-fold reduced genome accumulation in the liver compared with Ad5. Tumor uptake, transgene expression, and efficacy were confirmed in a peritoneal SKOV3 xenograft model of human EOC, where oncolytic Ad5NULL-A20–treated animals demonstrated significantly improved survival compared with those treated with oncolytic Ad5.

Conclusions: Oncolytic Ad5NULL-A20 virotherapies represent an excellent vector for local and systemic targeting of αvβ6-overexpressing cancers and exciting platforms for tumor-selective overexpression of therapeutic anticancer modalities, including immune checkpoint inhibitors. Clin Cancer Res; 24(17); 4215–24. ©2018 AACR.