bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Pan-Cancer Molecular Classes Transcending Tumor Lineage Across 32 Cancer Types, Multiple Data Platforms, and over 10,000 Cases
Authors: Chen Fengju , Zhang Yiqun , Gibbons Don L. , Deneen Benjamin , Kwiatkowski David J. , Ittmann Michael , Creighton Chad J.
Published: April 2023

Abstract
Purpose: The Cancer Genome Atlas data resources represent an opportunity to explore commonalities across cancer types involving multiple molecular levels, but tumor lineage and histology can represent a barrier in moving beyond differences related to cancer type.

Experimental Design: On the basis of gene expression data, we classified 10,224 cancers, representing 32 major types, into 10 molecular-based “classes.” Molecular patterns representing tissue or histologic dominant effects were first removed computationally, with the resulting classes representing emergent themes across tumor lineages.

Results: Key differences involving mRNAs, miRNAs, proteins, and DNA methylation underscored the pan-cancer classes. One class expressing neuroendocrine and cancer-testis antigen markers represented ∼4% of cancers surveyed. Basal-like breast cancers segregated into an exclusive class, distinct from all other cancers. Immune checkpoint pathway markers and molecular signatures of immune infiltrates were most strongly manifested within a class representing ∼13% of cancers. Pathway-level differences involving hypoxia, NRF2-ARE, Wnt, and Notch were manifested in two additional classes enriched for mesenchymal markers and miR200 silencing.

Conclusions: All pan-cancer molecular classes uncovered here, with the important exception of the basal-like breast cancer class, involve a wide range of cancer types and would facilitate understanding the molecular underpinnings of cancers beyond tissue-oriented domains. Numerous biological processes associated with cancer in the laboratory setting were found here to be coordinately manifested across large subsets of human cancers. The number of cancers manifesting features of neuroendocrine tumors may be much higher than previously thought, which disease is known to occur in many different tissues. Clin Cancer Res; 24(9); 2182–93. ©2018 AACR.
Data from A Coclinical Radiogenomic Validation Study: Conserved Magnetic Resonance Radiomic Appearance of Periostin-Expressing Glioblastoma in Patients and Xenograft Models
Authors: Zinn Pascal O. , Singh Sanjay K. , Kotrotsou Aikaterini , Hassan Islam , Thomas Ginu , Luedi Markus M. , Elakkad Ahmed , Elshafeey Nabil , Idris Tagwa , Mosley Jennifer , Gumin Joy , Fuller Gregory N. , de Groot John F. , Baladandayuthapani Veera , Sulman Erik P. , Kumar Ashok J. , Sawaya Raymond , Lang Frederick F. , Piwnica-Worms David , Colen Rivka R.
Published: April 2023

AbstractPurpose:
Radiomics is the extraction of multidimensional imaging features, which when correlated with genomics, is termed radiogenomics. However, radiogenomic biological validation is not sufficiently described in the literature. We seek to establish causality between differential gene expression status and MRI-extracted radiomic-features in glioblastoma.
Experimental Design:
Radiogenomic predictions and validation were done using the Cancer Genome Atlas and Repository of Molecular Brain Neoplasia Data glioblastoma patients (n = 93) and orthotopic xenografts (OX; n = 40). Tumor phenotypes were segmented, and radiomic-features extracted using the developed radiome-sequencing pipeline. Patients and animals were dichotomized on the basis of Periostin (POSTN) expression levels. RNA and protein levels confirmed RNAi-mediated POSTN knockdown in OX. Total RNA of tumor cells isolated from mouse brains (knockdown and control) was used for microarray-based expression profiling. Radiomic-features were utilized to predict POSTN expression status in patient, mouse, and interspecies.
Results:
Our robust pipeline consists of segmentation, radiomic-feature extraction, feature normalization/selection, and predictive modeling. The combination of skull stripping, brain-tissue focused normalization, and patient-specific normalization are unique to this study, providing comparable cross-platform, cross-institution radiomic features. POSTN expression status was not associated with qualitative or volumetric MRI parameters. Radiomic features significantly predicted POSTN expression status in patients (AUC: 76.56%; sensitivity/specificity: 73.91/78.26%) and OX (AUC: 92.26%; sensitivity/specificity: 92.86%/91.67%). Furthermore, radiomic features in OX were significantly associated with patients with similar POSTN expression levels (AUC: 93.36%; sensitivity/specificity: 82.61%/95.74%; P = 02.021E−15).
Conclusions:
We determined causality between radiomic texture features and POSTN expression levels in a preclinical model with clinical validation. Our biologically validated radiomic pipeline also showed the potential application for human–mouse matched coclinical trials.
Data from STAG2 Is a Biomarker for Prediction of Recurrence and Progression in Papillary Non–Muscle-Invasive Bladder Cancer
Authors: Lelo Alana , Prip Frederik , Harris Brent T. , Solomon David , Berry Deborah L. , Chaldekas Krysta , Kumar Anagha , Simko Jeffry , Jensen Jørgen Bjerggaard , Bhattacharyya Pritish , Mannion Ciaran , Kim Jung-Sik , Philips George , Dyrskjøt Lars , Waldman Todd
Published: April 2023

Abstract
Purpose: Most bladder cancers are early-stage tumors known as papillary non–muscle-invasive bladder cancer (NMIBC). After resection, up to 70% of NMIBCs recur locally, and up to 20% of these recurrences progress to muscle invasion. There is an unmet need for additional biomarkers for stratifying tumors based on their risk of recurrence and progression. We previously identified STAG2 as among the most commonly mutated genes in NMIBC and provided initial evidence in a pilot cohort that STAG2-mutant tumors recurred less frequently than STAG2 wild-type tumors. Here, we report a STAG2 biomarker validation study using two independent cohorts of clinically annotated papillary NMIBC tumors from the United States and Europe.

Experimental Design: The value of STAG2 immunostaining for prediction of recurrence was initially evaluated in a cohort of 82 patients with papillary NMIBC (“Georgetown cohort”). Next, the value of STAG2 immunostaining for prediction of progression to muscle invasion was evaluated in a progressor-enriched cohort of 253 patients with papillary NMIBC (“Aarhus cohort”).

Results: In the Georgetown cohort, 52% of NMIBC tumors with intact STAG2 expression recurred, whereas 25% of STAG2-deficient tumors recurred (P = 0.02). Multivariable analysis identified intact STAG2 expression as an independent predictor of recurrence (HR = 2.4; P = 0.05). In the progressor-enriched Aarhus cohort, 38% of tumors with intact STAG2 expression progressed within 5 years, versus 16% of STAG2-deficient tumors (P < 0.01). Multivariable analysis identified intact STAG2 expression as an independent predictor of progression (HR = 1.86; P = 0.05).

Conclusions: STAG2 IHC is a simple, binary, new assay for risk stratification in papillary NMIBC. Clin Cancer Res; 24(17); 4145–53. ©2018 AACR.
Data from Antigen-Specific CD8 Lytic Phenotype Induced by Sipuleucel-T in Hormone-Sensitive or Castration-Resistant Prostate Cancer and Association with Overall Survival
Authors: Antonarakis Emmanuel S. , Small Eric J. , Petrylak Daniel P. , Quinn David I. , Kibel Adam S. , Chang Nancy N. , Dearstyne Erica , Harmon Matt , Campogan Dwayne , Haynes Heather , Vu Tuyen , Sheikh Nadeem A. , Drake Charles G.
Published: April 2023

Abstract
Purpose: Sipuleucel-T is FDA approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC) based on the IMPACT trial showing a 4.1-month benefit in median overall survival (OS) for patients receiving sipuleucel-T versus control. Although efficacy of sipuleucel-T is well established, its mechanism remains incompletely understood.

Patients and Methods: Patient samples from three sipuleucel-T trials were assessed for peripheral cellular immune responses to the immunogen PA2024 and the target antigen prostatic acid phosphatase (PAP). PAP- and PA2024-specific proliferative and cytolytic responses were characterized to delineate sipuleucel-T–induced immune responses. To quantify potential cytotoxic T lymphocyte (CTL) activity, cell-surface CD107a expression on PAP- or PA2024-specific CD8+ T cells was measured in sipuleucel-T–treated patient and healthy volunteer samples.

Results: Increased PA2024-specific CD4+ (P = 0.030) and CD8+ (P = 0.052) T-cell proliferation from baseline to week 6 was observed (N = 14) post–sipuleucel-T, with greater magnitude of PA2024-specific responses compared with PAP. PAP- and PA2024-CTL activity (CD107a positivity) significantly increased at weeks 6 and 26 after sipuleucel-T treatment (P < 0.0001; N = 22). At 26 weeks post–sipuleucel-T, OS correlated with the magnitude of PAP (Pearson R, 0.52; P = 0.013) or PA2024 (Pearson R, 0.67; P = 0.0006) CTL activity. Higher PA2024-CTL activity at week 26 was significantly associated with longer OS using tertile analysis (P = 0.0005; N = 22), with PA2024 responses correlating with PAP responses at week 26 (R = 0.90; P = 1.53E−08).

Conclusions: This study is the first to report PAP-specific CD8+ T-cell responses elicited by sipuleucel-T treatment. Increased and persistent potential PA2024-specific CTL activity correlated with PAP-specific CTL activity and associated with improved OS following sipuleucel-T treatment. Clin Cancer Res; 24(19); 4662–71. ©2018 AACR.
Data from Development and External Validation of Prediction Models for 10-Year Survival of Invasive Breast Cancer. Comparison with PREDICT and CancerMath
Authors: Karapanagiotis Solon , Pharoah Paul D.P. , Jackson Christopher H. , Newcombe Paul J.
Published: April 2023

Abstract
Purpose: To compare PREDICT and CancerMath, two widely used prognostic models for invasive breast cancer, taking into account their clinical utility. Furthermore, it is unclear whether these models could be improved.

Experimental Design: A dataset of 5,729 women was used for model development. A Bayesian variable selection algorithm was implemented to stochastically search for important interaction terms among the predictors. The derived models were then compared in three independent datasets (n = 5,534). We examined calibration, discrimination, and performed decision curve analysis.

Results: CancerMath demonstrated worse calibration performance compared with PREDICT in estrogen receptor (ER)–positive and ER-negative tumors. The decline in discrimination performance was −4.27% (−6.39 to −2.03) and −3.21% (−5.9 to −0.48) for ER-positive and ER-negative tumors, respectively. Our new models matched the performance of PREDICT in terms of calibration and discrimination, but offered no improvement. Decision curve analysis showed predictions for all models were clinically useful for treatment decisions made at risk thresholds between 5% and 55% for ER-positive tumors and at thresholds of 15% to 60% for ER-negative tumors. Within these threshold ranges, CancerMath provided the lowest clinical utility among all the models.

Conclusions: Survival probabilities from PREDICT offer both improved accuracy and discrimination over CancerMath. Using PREDICT to make treatment decisions offers greater clinical utility than CancerMath over a range of risk thresholds. Our new models performed as well as PREDICT, but no better, suggesting that, in this setting, including further interaction terms offers no predictive benefit. Clin Cancer Res; 24(9); 2110–5. ©2018 AACR.
Data from Magnetic Resonance Imaging of Tumor-Associated Macrophages: Clinical Translation
Authors: Aghighi Maryam , Theruvath Ashok J. , Pareek Anuj , Pisani Laura L. , Alford Raphael , Muehe Anne M. , Sethi Tarsheen K. , Holdsworth Samantha J. , Hazard Florette K. , Gratzinger Dita , Luna-Fineman Sandra , Advani Ranjana , Spunt Sheri L. , Daldrup-Link Heike E.
Published: April 2023

Abstract
Purpose: Tumor-associated macrophages (TAMs) in malignant tumors have been linked to tumor aggressiveness and represent a new target for cancer immunotherapy. As new TAM-targeted immunotherapies are entering clinical trials, it is important to detect and quantify TAM with noninvasive imaging techniques. The purpose of this study was to determine if ferumoxytol-enhanced MRI can detect TAM in lymphomas and bone sarcomas of pediatric patients and young adults.

Experimental Design: In a first-in-patient, Institutional Review Board–approved prospective clinical trial, 25 pediatric and young adult patients with lymphoma or bone sarcoma underwent ferumoxytol-enhanced MRI. To confirm ferumoxytol enhancement, five pilot patients (two lymphoma and three bone sarcoma) underwent pre- and postcontrast MRI. Subsequently, 20 patients (10 lymphoma and 10 bone sarcoma) underwent ferumoxytol-enhanced MRI 24 to 48 hours after i.v. injection, followed by tumor biopsy/resection and macrophage staining. To determine if ferumoxytol-MRI can differentiate tumors with different TAM content, we compared T2* relaxation times of lymphomas and bone sarcomas. Tumor T2* values of 20 patients were correlated with CD68+ and CD163+ TAM quantities on histopathology.

Results: Significant ferumoxytol tumor enhancement was noted on postcontrast scans compared with precontrast scans (P = 0.036). Bone sarcomas and lymphomas demonstrated significantly different MRI enhancement and TAM density (P < 0.05). Within each tumor group, T2* signal enhancement on MR images correlated significantly with the density of CD68+ and CD163+ TAM (P < 0.05).

Conclusions: Ferumoxytol-enhanced MRI is immediately clinically applicable and could be used to stratify patients with TAM-rich tumors to immune-targeted therapies and to monitor tumor response to these therapies. Clin Cancer Res; 24(17); 4110–8. ©2018 AACR.
Data from A Model of Overall Survival Predicts Treatment Outcomes with Atezolizumab versus Chemotherapy in Non–Small Cell Lung Cancer Based on Early Tumor Kinetics
Authors: Claret Laurent , Jin Jin Y. , Ferté Charles , Winter Helen , Girish Sandhya , Stroh Mark , He Pei , Ballinger Marcus , Sandler Alan , Joshi Amita , Rittmeyer Achim , Gandara David , Soria Jean-Charles , Bruno René
Published: April 2023

Abstract
Purpose: Standard endpoints often poorly predict overall survival (OS) with immunotherapies. We investigated the predictive performance of model-based tumor growth inhibition (TGI) metrics using data from atezolizumab clinical trials in patients with non–small cell lung cancer.

Patients and Methods: OS benefit with atezolizumab versus docetaxel was observed in both POPLAR (phase II) and OAK (phase III), although progression-free survival was similar between arms. A multivariate model linking baseline patient characteristics and on-treatment tumor growth rate constant (KG), estimated using time profiles of sum of longest diameters (RECIST 1.1) to OS, was developed using POPLAR data. The model was evaluated to predict OAK outcome based on estimated KG at TGI data cutoffs ranging from 10 to 122 weeks.

Results: In POPLAR, TGI profiles in both arms crossed at 25 weeks, with more shrinkage with docetaxel and slower KG with atezolizumab. A log-normal OS model, with albumin and number of metastatic sites as independent prognostic factors and estimated KG, predicted OS HR in subpopulations of patients with varying baseline PD-L1 expression in both POPLAR and OAK: model-predicted OAK HR (95% prediction interval), 0.73 (0.63–0.85), versus 0.73 observed. The POPLAR OS model predicted greater than 97% chance of success of OAK (significant OS HR, P < 0.05) from the 40-week data cutoff onward with 50% of the total number of tumor assessments when a successful study was predicted from 70 weeks onward based on observed OS.

Conclusions: KG has potential as a model-based early endpoint to inform decisions in cancer immunotherapy studies. Clin Cancer Res; 24(14); 3292–8. ©2018 AACR.
Data from A Phase II Study of Alisertib in Children with Recurrent/Refractory Solid Tumors or Leukemia: Children's Oncology Group Phase I and Pilot Consortium (ADVL0921)
Authors: Mossé Yael P. , Fox Elizabeth , Teachey David T. , Reid Joel M. , Safgren Stephanie L. , Carol Hernan , Lock Richard B. , Houghton Peter J. , Smith Malcolm A. , Hall David , Barkauskas Donald A. , Krailo Mark , Voss Stephan D. , Berg Stacey L. , Blaney Susan M. , Weigel Brenda J.
Published: April 2023

AbstractPurpose:
Aurora A kinase (AAK) plays an integral role in mitotic entry, DNA damage checkpoint recovery, and centrosome and spindle maturation. Alisertib (MLN8237) is a potent and selective AAK inhibitor. In pediatric preclinical models, antitumor activity was observed in neuroblastoma, acute lymphoblastic leukemia, and sarcoma xenografts. We conducted a phase 2 trial of alisertib in pediatric patients with refractory or recurrent solid tumors or acute leukemias (NCT01154816).
Patients and Methods:
Alisertib (80 mg/m2/dose) was administered orally, daily for 7 days every 21 days. Pharmacogenomic (PG) evaluation for polymorphisms in the AURK gene and drug metabolizing enzymes (UGT1A1*28), and plasma pharmacokinetic studies (PK) were performed. Using a 2-stage design, patients were enrolled to 12 disease strata (10 solid tumor and 2 acute leukemia). Response was assessed after cycle 1, then every other cycle.
Results:
A total of 139 children and adolescents (median age, 10 years) were enrolled, 137 were evaluable for response. Five objective responses were observed (2 complete responses and 3 partial responses). The most frequent toxicity was myelosuppression. The median alisertib trough concentration on day 4 was 1.3 μmol/L, exceeding the 1 μmol/L target trough concentration in 67% of patients. No correlations between PG or PK and toxicity were observed.
Conclusions:
Despite alisertib activity in pediatric xenograft models and cogent pharmacokinetic-pharmacodynamic relationships in preclinical models and adults, the objective response rate in children and adolescents receiving single-agent alisertib was less than 5%.
Data from TP53, STK11, and EGFR Mutations Predict Tumor Immune Profile and the Response to Anti–PD-1 in Lung Adenocarcinoma
Authors: Biton Jérôme , Mansuet-Lupo Audrey , Pécuchet Nicolas , Alifano Marco , Ouakrim Hanane , Arrondeau Jennifer , Boudou-Rouquette Pascaline , Goldwasser François , Leroy Karen , Goc Jeremy , Wislez Marie , Germain Claire , Laurent-Puig Pierre , Dieu-Nosjean Marie-Caroline , Cremer Isabelle , Herbst Ronald , Blons Hélène , Damotte Diane
Published: April 2023

Abstract
Purpose: By unlocking antitumor immunity, antibodies targeting programmed cell death 1 (PD-1) exhibit impressive clinical results in non–small cell lung cancer, underlining the strong interactions between tumor and immune cells. However, factors that can robustly predict long-lasting responses are still needed.

Experimental Design: We performed in-depth immune profiling of lung adenocarcinoma using an integrative analysis based on immunohistochemistry, flow-cytometry, and transcriptomic data. Tumor mutational status was investigated using next-generation sequencing. The response to PD-1 blockers was analyzed from a prospective cohort according to tumor mutational profiles and PD-L1 expression, and a public clinical database was used to validate the results obtained.

Results: We showed that distinct combinations of STK11, EGFR, and TP53 mutations were major determinants of the tumor immune profile (TIP) and of the expression of PD-L1 by malignant cells. Indeed, the presence of TP53 mutations without co-occurring STK11 or EGFR alterations (TP53-mut/STK11-EGFR-WT), independently of KRAS mutations, identified the group of tumors with the highest CD8 T-cell density and PD-L1 expression. In this tumor subtype, pathways related to T-cell chemotaxis, immune cell cytotoxicity, and antigen processing were upregulated. Finally, a prolonged progression-free survival (PFS: HR = 0.32; 95% CI, 0.16–0.63, P < 0.001) was observed in anti–PD-1-treated patients harboring TP53-mut/STK11-EGFR-WT tumors. This clinical benefit was even more remarkable in patients with associated strong PD-L1 expression.

Conclusions: Our study reveals that different combinations of TP53, EGFR, and STK11 mutations, together with PD-L1 expression by tumor cells, represent robust parameters to identify best responders to PD-1 blockade. Clin Cancer Res; 24(22); 5710–23. ©2018 AACR.
Data from Cell-Free DNA Modification Dynamics in Abiraterone Acetate-Treated Prostate Cancer Patients
Authors: Gordevičius Juozas , Kriščiūnas Algimantas , Groot Daniel E. , Yip Steven M. , Susic Miki , Kwan Andrew , Kustra Rafal , Joshua Anthony M. , Chi Kim N. , Petronis Art , Oh Gabriel
Published: April 2023

Abstract
Purpose: Primary resistance to abiraterone acetate (AA), a key medication for the treatment of metastatic castration-resistant prostate cancer, occurs in 20% to 40% of patients. We aim to identify predictive biomarkers for AA-treatment response and understand the mechanisms related to treatment resistance.

Experimental Design: We used the Infinium Human Methylation 450K BeadChip to monitor modification profiles of cell-free circulating DNA (cfDNA) in 108 plasma samples collected from 33 AA-treated patients.

Results: Thirty cytosines showed significant modification differences (FDR Q < 0.05) between AA-sensitive and AA-resistant patients during the treatment, of which 21 cytosines were differentially modified prior to treatment. In addition, AA-sensitive patients, but not AA-resistant patients, lost interindividual variation of cfDNA modification shortly after starting AA treatment, but such variation returned to initial levels in the later phases of treatment.

Conclusions: Our findings provide a list of potential biomarkers for predicting AA-treatment response, highlight the prognostic value of using cytosine modification variance as biomarkers, and shed new insights into the mechanisms of prostate cancer relapse in AA-sensitive patients. Clin Cancer Res; 24(14); 3317–24. ©2018 AACR.
Data from High-Resolution Bisulfite-Sequencing of Peripheral Blood DNA Methylation in Early-Onset and Familial Risk Breast Cancer Patients
Authors: Chen Justin , Haanpää Maria K. , Gruber Joshua J. , Jäger Natalie , Ford James M. , Snyder Michael P.
Published: April 2023

AbstractPurpose:
Understanding and explaining hereditary predisposition to cancer has focused on the genetic etiology of the disease. However, mutations in known genes associated with breast cancer, such as BRCA1 and BRCA2, account for less than 25% of familial cases of breast cancer. Recently, specific epigenetic modifications at BRCA1 have been shown to promote hereditary breast cancer, but the broader potential for epigenetic contribution to hereditary breast cancer is not yet well understood.
Experimental Design:
We examined DNA methylation through deep bisulfite sequencing of CpG islands and known promoter or regulatory regions in peripheral blood DNA from 99 patients with familial or early-onset breast or ovarian cancer, 6 unaffected BRCA mutation carriers, and 49 unaffected controls.
Results:
In 9% of patients, we observed altered methylation in the promoter regions of genes known to be involved in cancer, including hypermethylation at the tumor suppressor PTEN and hypomethylation at the proto-oncogene TEX14. These alterations occur in the form of allelic methylation that span up to hundreds of base pairs in length.
Conclusions:
Our observations suggest a broader role for DNA methylation in early-onset, familial risk breast cancer. Further studies are warranted to clarify these mechanisms and the benefits of DNA methylation screening for early risk prediction of familial cancers.
Data from Enhanced Therapeutic Activity of Non-Internalizing Small-Molecule-Drug Conjugates Targeting Carbonic Anhydrase IX in Combination with Targeted Interleukin-2
Authors: Cazzamalli Samuele , Ziffels Barbara , Widmayer Fontaine , Murer Patrizia , Pellegrini Giovanni , Pretto Francesca , Wulhfard Sarah , Neri Dario
Published: April 2023

Abstract
Purpose: Antibody–drug conjugates and small-molecule-drug conjugates have been proposed as alternatives to conventional anticancer cytotoxic agents, with the potential to deliver bioactive payloads to the site of disease, helping spare normal tissues.

Experimental Design: Here, we describe a novel small-molecule-drug conjugate, based on a high-affinity ligand specific to carbonic anhydrase IX. The product featured a peptidic linker, suitable for cleavage in the tumor extracellular environment, and monomethyl auristatin E as cytotoxic payload.

Results: A potent anticancer activity was observed in nude mice bearing SKRC-52 renal cell carcinoma xenografts, but no durable complete responses could be observed in this model. However, when the product was administered together with L19-IL2 (a clinical-stage fusion protein capable of delivering IL2 to the tumor neovasculature), all treated mice in the combination group could be rendered tumor free, in a process that favored the influx of natural killer cells into the tumor mass. The combination of L19-IL2 and the new small-molecule-drug conjugate also eradicated cancer in 100% of immunocompetent mice, bearing subcutaneously grafted CT26 colorectal cancer cells, which stably expressed carbonic anhydrase IX.

Conclusions: These findings may be of clinical significance, because carbonic anhydrase IX is overexpressed in the majority of clear cell renal cell carcinomas and in approximately 30% of colorectal cancers. The targeted delivery of IL2 helps potentiate the action of targeted cytotoxics, leading to cancer eradication in models that cannot be cured by conventional chemotherapy. Clin Cancer Res; 24(15); 3656–67. ©2018 AACR.
Data from Clinical Utility of Prospective Molecular Characterization in Advanced Endometrial Cancer
Authors: Soumerai Tara E. , Donoghue Mark T.A. , Bandlamudi Chaitanya , Srinivasan Preethi , Chang Matthew T. , Zamarin Dmitriy , Cadoo Karen A. , Grisham Rachel N. , O'Cearbhaill Roisin E. , Tew William P. , Konner Jason A. , Hensley Martee L. , Makker Vicky , Sabbatini Paul , Spriggs David R. , Troso-Sandoval Tiffany A. , Charen Alexandra Snyder , Friedman Claire , Gorsky Mila , Schweber Sarah J. , Middha Sumit , Murali Rajmohan , Chiang Sarah , Park Kay J. , Soslow Robert A. , Ladanyi Marc , Li Bob T. , Mueller Jennifer , Weigelt Britta , Zehir Ahmet , Berger Michael F. , Abu-Rustum Nadeem R. , Aghajanian Carol , DeLair Deborah F. , Solit David B. , Taylor Barry S. , Hyman David M.
Published: April 2023

AbstractPurpose:
Advanced-stage endometrial cancers have limited treatment options and poor prognosis, highlighting the need to understand genetic drivers of therapeutic vulnerabilities and/or prognostic predictors. We examined whether prospective molecular characterization of recurrent and metastatic disease can reveal grade and histology-specific differences, facilitating enrollment onto clinical trials.
Experimental Design:
We integrated prospective clinical sequencing and IHC data with detailed clinical and treatment histories for 197 tumors, profiled by MSK-IMPACT from 189 patients treated at Memorial Sloan Kettering Cancer Center.
Results:
Patients had advanced disease and high-grade histologies, with poor progression-free survival on first-line therapy (PFS1). When matched for histology and grade, the genomic landscape was similar to that of primary untreated disease profiled by TCGA. Using multiple complementary genomic and mutational signature-based methods, we identified patients with microsatellite instability (MSI), even when standard MMR protein IHC staining failed. Tumor and matched normal DNA sequencing identified rare pathogenic germline mutations in BRCA2 and MLH1. Clustering the pattern of DNA copy-number alterations revealed a novel subset characterized by heterozygous losses across the genome and significantly worse outcomes compared with other clusters (median PFS1 9.6 months vs. 17.0 and 17.4 months; P = 0.006). Of the 68% of patients harboring potentially actionable mutations, 27% were enrolled to matched clinical trials, of which 47% of these achieved clinical benefit.
Conclusions:
Prospective clinical sequencing of advanced endometrial cancer can help refine prognosis and aid treatment decision making by simultaneously detecting microsatellite status, germline predisposition syndromes, and potentially actionable mutations. A small overall proportion of all patients tested received investigational, genomically matched therapy as part of clinical trials.
Data from Vitamin D Supplementation and Survival of Patients with Non–small Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial
Authors: Akiba Tadashi , Morikawa Toshiaki , Odaka Makoto , Nakada Takeo , Kamiya Noriki , Yamashita Makoto , Yabe Mitsuo , Inagaki Takuya , Asano Hisatoshi , Mori Shohei , Tsukamoto Yo , Urashima Mitsuyoshi
Published: April 2023

Abstract
Purpose: Higher serum 25-hydroxyvitamin D (25(OH)D) levels are reportedly associated with better survival in early-stage non–small cell lung cancer (NSCLC). Therefore, whether vitamin D supplementation can improve the prognosis of patients with NSCLC was examined (UMIN000001869).

Patients and Methods: A randomized, double-blind trial comparing vitamin D supplements (1,200 IU/day) with placebo for 1 year after operation was conducted. The primary and secondary outcomes were relapse-free survival (RFS) and overall survival (OS), respectively. Prespecified subgroup analyses were performed with stratification by stage (early vs. advanced), pathology (adenocarcinoma vs. others), and 25(OH)D levels (low, <20 ng/mL vs. high, ≥20 ng/mL). Polymorphisms of vitamin D receptor (VDR) and vitamin D–binding protein (DBP) and survival were also examined.

Results: Patients with NSCLC (n = 155) were randomly assigned to receive vitamin D (n = 77) or placebo (n = 78) and followed for a median of 3.3 years. Relapse and death occurred in 40 (28%) and 24 (17%) patients, respectively. In the total study population, no significant difference in either RFS or OS was seen with vitamin D compared with the placebo group. However, by restricting the analysis to the subgroup with early-stage adenocarcinoma with low 25(OH)D, the vitamin D group showed significantly better 5-year RFS (86% vs. 50%, P = 0.04) and OS (91% vs. 48%, P = 0.02) than the placebo group. Among the examined polymorphisms, DBP1 (rs7041) TT and CDX2 (rs11568820) AA/AG genotypes were markers of better prognosis, even with multivariate adjustment.

Conclusions: In patients with NSCLC, vitamin D supplementation may improve survival of patients with early-stage lung adenocarcinoma with lower 25(OH)D levels. Clin Cancer Res; 24(17); 4089–97. ©2018 AACR.
Data from p95HER2 Methionine 611 Carboxy-Terminal Fragment Is Predictive of Trastuzumab Adjuvant Treatment Benefit in the FinHer Trial
Authors: Sperinde Jeff , Huang Weidong , Vehtari Aki , Chenna Ahmed , Kellokumpu-Lehtinen Pirkko-Liisa , Winslow John , Bono Petri , Lie Yolanda S. , Petropoulos Christos J. , Weidler Jodi , Joensuu Heikki
Published: April 2023

Abstract
Purpose: Expression of p95HER2 (p95), a truncated form of the HER2 receptor, which lacks the trastuzumab binding site but retains kinase activity, has been reported as a prognostic biomarker for poor outcomes in patients with trastuzumab-treated HER2-positive metastatic breast cancer. The impact of p95 expression on trastuzumab treatment efficacy in early HER2-positive breast cancer is less clear. In the current study, p95 was tested as a predictive marker of trastuzumab treatment benefit in the HER2-positive subset of the FinHer adjuvant phase III trial.

Experimental Design: In the FinHer trial, 232 patients with HER2-positive early breast cancer were randomized to receive chemotherapy plus 9 weeks of trastuzumab or no trastuzumab treatment. Quantitative p95 protein expression was measured in formalin-fixed paraffin-embedded samples using the p95 VeraTag assay (Monogram Biosciences), specific for the M611 form of p95. Quantitative HER2 protein expression was measured using the HERmark assay (Monogram Biosciences). Distant disease-free survival (DDFS) was used as the primary outcome measure.

Results: In the arm receiving chemotherapy only, increasing log10(p95) correlated with shorter DDFS (HR, 2.0; P = 0.02). In the arm receiving chemotherapy plus trastuzumab (N = 95), increasing log10(p95) was not correlated with a shorter DDFS. In a combined analysis of both treatment arms, high breast tumor p95 content was significantly correlated with trastuzumab treatment benefit in multivariate models (interaction P = 0.01).

Conclusions: A high p95HER2/HER2 ratio identified patients with metastatic breast cancer with poor outcomes on trastuzumab-based therapies. Further investigation of the p95HER2/HER2 ratio as a potential prognostic or predictive biomarker for HER2-targeted therapy is warranted. Clin Cancer Res; 24(13); 3046–52. ©2018 AACR.
Data from A Pan-cancer Landscape of Interactions between Solid Tumors and Infiltrating Immune Cell Populations
Authors: Tamborero David , Rubio-Perez Carlota , Muiños Ferran , Sabarinathan Radhakrishnan , Piulats Josep M. , Muntasell Aura , Dienstmann Rodrigo , Lopez-Bigas Nuria , Gonzalez-Perez Abel
Published: April 2023

Abstract
Purpose: Throughout their development, tumors are challenged by the immune system, and they acquire features to evade its surveillance. A systematic view of these traits, which shed light on how tumors respond to immunotherapies, is still lacking.

Experimental Design: Here, we computed the relative abundance of an array of immune cell populations to measure the immune infiltration pattern of 9,174 tumors of 29 solid cancers. We then clustered tumors with similar infiltration pattern to define immunophenotypes. Finally, we identified genomic and transcriptomic traits associated to these immunophenotypes across cancer types.

Results: In highly cytotoxic immunophenotypes, we found tumors with low clonal heterogeneity enriched for alterations of genes involved in epigenetic regulation, ubiquitin-mediated proteolysis, antigen presentation, and cell–cell communication, which may drive resistance in combination with the ectopic expression of negative immune checkpoints. Tumors with immunophenotypes of intermediate cytotoxicity are characterized by an upregulation of processes involved in neighboring tissue invasion and remodeling that may foster the recruitment of immunosuppressive cells. Tumors with poorly cytotoxic immunophenotype tend to be of more advanced stages and bear a greater burden of copy number alterations and frequent alterations of cell cycle, hedgehog, β-catenin, and TGFβ pathways, which may cause immune depletion.

Conclusions: We provide a comprehensive landscape of the characteristics of solid tumors that may influence (or be influenced by) the characteristics of their immune infiltrate. These results may help interpret the response of solid tumors to immunotherapies and guide the development of novel drug combination strategies. Clin Cancer Res; 24(15); 3717–28. ©2018 AACR.
Data from Comprehensive Molecular Profiling of Intrahepatic and Extrahepatic Cholangiocarcinomas: Potential Targets for Intervention
Authors: Lowery Maeve A. , Ptashkin Ryan , Jordan Emmet , Berger Michael F. , Zehir Ahmet , Capanu Marinela , Kemeny Nancy E. , O'Reilly Eileen M. , El-Dika Imane , Jarnagin William R. , Harding James J. , D'Angelica Michael I. , Cercek Andrea , Hechtman Jaclyn F. , Solit David B. , Schultz Nikolaus , Hyman David M. , Klimstra David S. , Saltz Leonard B. , Abou-Alfa Ghassan K.
Published: April 2023

Abstract
Purpose: Various genetic driver aberrations have been identified among distinct anatomic and clinical subtypes of intrahepatic and extrahepatic cholangiocarcinoma, and these molecular alterations may be prognostic biomarkers and/or predictive of drug response.

Experimental Design: Tumor samples from patients with cholangiocarcinoma who consented prospectively were analyzed using the MSK-IMPACT platform, a targeted next-generation sequencing assay that analyzes all exons and selected introns of 410 cancer-associated genes. Fisher exact tests were performed to identify associations between clinical characteristics and genetic alterations.

Results: A total of 195 patients were studied: 78% intrahepatic and 22% extrahepatic cholangiocarcinoma. The most commonly altered genes in intrahepatic cholangiocarcinoma were IDH1 (30%), ARID1A (23%), BAP1 (20%), TP53 (20%), and FGFR2 gene fusions (14%). A tendency toward mutual exclusivity was seen between multiple genes in intrahepatic cholangiocarcinoma including TP53:IDH1, IDH1:KRAS, TP53:BAP1, and IDH1:FGFR2. Alterations in CDKN2A/B and ERBB2 were associated with reduced survival and time to progression on chemotherapy in patients with locally advanced or metastatic disease. Genetic alterations with potential therapeutic implications were identified in 47% of patients, leading to biomarker-directed therapy or clinical trial enrollment in 16% of patients.

Conclusions: Cholangiocarcinoma is a genetically diverse cancer. Alterations in CDKN2A/B and ERBB2 are associated with negative prognostic implications in patients with advanced disease. Somatic alterations with therapeutic implications were identified in almost half of patients. These prospective data provide a contemporary benchmark for guiding the development of targeted therapies in molecularly profiled cholangiocarcinoma, and support to the use of molecular profiling to guide therapy selection in patients with advanced biliary cancers. Clin Cancer Res; 24(17); 4154–61. ©2018 AACR.
Data from Combined Aurora Kinase A (AURKA) and WEE1 Inhibition Demonstrates Synergistic Antitumor Effect in Squamous Cell Carcinoma of the Head and Neck
Authors: Lee Jong Woo , Parameswaran Janaki , Sandoval-Schaefer Teresa , Eoh Kyung Jin , Yang Dong-hua , Zhu Fang , Mehra Ranee , Sharma Roshan , Gaffney Stephen G. , Perry Elizabeth B. , Townsend Jeffrey P. , Serebriiskii Ilya G. , Golemis Erica A. , Issaeva Natalia , Yarbrough Wendell G. , Koo Ja Seok , Burtness Barbara
Published: April 2023

AbstractPurpose:
Human papillomavirus (HPV)-negative head and neck squamous cell carcinomas (HNSCC) commonly bear disruptive mutations in TP53, resulting in treatment resistance. In these patients, direct targeting of p53 has not been successful, but synthetic lethal approaches have promise. Although Aurora A kinase (AURKA) is overexpressed and an oncogenic driver, its inhibition has only modest clinical effects in HPV-negative HNSCC. We explored a novel combination of AURKA and WEE1 inhibition to overcome intrinsic resistance to AURKA inhibition.

Experimental Design: AURKA protein expression was determined by fluorescence-based automated quantitative analysis of patient specimens and correlated with survival. We evaluated treatment with the AURKA inhibitor alisertib (MLN8237) and the WEE1 inhibitor adavosertib (AZD1775), alone or in combination, using in vitro and in vivo HNSCC models.
Results:
Elevated nuclear AURKA correlated with worse survival among patients with p16(−) HNSCC. Alisertib caused spindle defects, G2–M arrest and inhibitory CDK1 phosphorylation, and cytostasis in TP53 mutant HNSCC FaDu and UNC7 cells. Addition of adavosertib to alisertib instead triggered mitotic entry and mitotic catastrophe. Moreover, in FaDu and Detroit 562 xenografts, this combination demonstrated synergistic effects on tumor growth and extended overall survival compared with either vehicle or single-agent treatment.
Conclusions:
Combinatorial treatment with adavosertib and alisertib leads to synergistic antitumor effects in in vitro and in vivo HNSCC models. These findings suggest a novel rational combination, providing a promising therapeutic avenue for TP53-mutated cancers.
Data from Identification and Validation of a 3-Gene Methylation Classifier for HPV-Based Cervical Screening on Self-Samples
Authors: Verlaat Wina , Snoek Barbara C. , Heideman Daniëlle A.M. , Wilting Saskia M. , Snijders Peter J.F. , Novianti Putri W. , van Splunter Annina P. , Peeters Carel F.W. , van Trommel Nienke E. , Massuger Leon F.A.G. , Bekkers Ruud L.M. , Melchers Willem J.G. , van Kemenade Folkert J. , Berkhof Johannes , van de Wiel Mark A. , Meijer Chris J.L.M. , Steenbergen Renske D.M.
Published: April 2023

Abstract
Purpose: Offering self-sampling of cervico-vaginal material for high-risk human papillomavirus (hrHPV) testing is an effective method to increase the coverage in cervical screening programs. Molecular triage directly on hrHPV-positive self-samples for colposcopy referral opens the way to full molecular cervical screening. Here, we set out to identify a DNA methylation classifier for detection of cervical precancer (CIN3) and cancer, applicable to lavage and brush self-samples.

Experimental Design: We determined genome-wide DNA methylation profiles of 72 hrHPV-positive self-samples, using the Infinium Methylation 450K Array. The selected DNA methylation markers were evaluated by multiplex quantitative methylation-specific PCR (qMSP) in both hrHPV-positive lavage (n = 245) and brush (n = 246) self-samples from screening cohorts. Subsequently, logistic regression analysis was performed to build a DNA methylation classifier for CIN3 detection applicable to self-samples of both devices. For validation, an independent set of hrHPV-positive lavage (n = 199) and brush (n = 287) self-samples was analyzed.

Results: Genome-wide DNA methylation profiling revealed 12 DNA methylation markers for CIN3 detection. Multiplex qMSP analysis of these markers in large series of lavage and brush self-samples yielded a 3-gene methylation classifier (ASCL1, LHX8, and ST6GALNAC5). This classifier showed a very good clinical performance for CIN3 detection in both lavage (AUC = 0.88; sensitivity = 74%; specificity = 79%) and brush (AUC = 0.90; sensitivity = 88%; specificity = 81%) self-samples in the validation set. Importantly, all self-samples from women with cervical cancer scored DNA methylation–positive.

Conclusions: By genome-wide DNA methylation profiling on self-samples, we identified a highly effective 3-gene methylation classifier for direct triage on hrHPV-positive self-samples, which is superior to currently available methods. Clin Cancer Res; 24(14); 3456–64. ©2018 AACR.
Data from A Multi-center Phase I Trial of Ipilimumab in Patients with Myelodysplastic Syndromes following Hypomethylating Agent Failure
Authors: Zeidan Amer M. , Knaus Hanna A. , Robinson Tara M. , Towlerton Andrea M.H. , Warren Edus H. , Zeidner Joshua F. , Blackford Amanda L. , Duffield Amy S. , Rizzieri David , Frattini Mark G. , Levy Yair M. , Schroeder Mark A. , Ferguson Anna , Sheldon Katherine E. , DeZern Amy E. , Gojo Ivana , Gore Steven D. , Streicher Howard , Luznik Leo , Smith B. Douglas
Published: April 2023

Abstract
Purpose: After failure of hypomethylating agents (HMA), patients with myelodysplastic syndromes (MDS) have dismal survival and no approved treatment options.

Patients and Methods: We conducted a phase 1b investigator-initiated trial of ipilimumab in patients with higher risk MDS who have failed HMAs. Patients received monotherapy at two dose levels (DL; 3 and 10 mg/kg) with an induction followed by a maintenance phase. Toxicities and responses were evaluated with CTCAE.4 and IWG-2006 criteria, respectively. We also performed immunologic assays and T-cell receptor sequencing on serial samples.

Results: Twenty-nine patients from 7 centers were enrolled. In the initial DL1 (3 mg), 3 of 6 patients experienced grade 2–4 immune-related adverse events (IRAE) that were reversible with drug discontinuation and/or systemic steroids. In DL2, 4 of 5 patients experienced grade 2 or higher IRAE; thus, DL1 (3 mg/kg) was expanded with no grade 2–4 IRAEs reported in 18 additional patients. Best responses included marrow complete response (mCR) in one patient (3.4%). Prolonged stable disease (PSD) for ≥46 weeks occurred in 7 patients (24% of entire cohort and 29% of those treated with 3 mg/kg dose), including 3 patients with more than a year of SD. Five patients underwent allografting without excessive toxicity. Median survival for the group was 294 days (95% CI, 240–671+). Patients who achieved PSD or mCR had significantly higher frequency of T cells expressing ICOS (inducible T-cell co-stimulator).

Conclusions: Our findings suggest that ipilimumab dosed at 3 mg/kg in patients with MDS after HMA failure is safe but has limited efficacy as a monotherapy. Increased frequency of ICOS-expressing T cells might predict clinical benefit. Clin Cancer Res; 24(15); 3519–27. ©2018 AACR.
Data from Clinical and Pathological Characteristics of KEAP1- and NFE2L2-Mutated Non–Small Cell Lung Carcinoma (NSCLC)
Authors: Frank Rieke , Scheffler Matthias , Merkelbach-Bruse Sabine , Ihle Michaela A. , Kron Anna , Rauer Michael , Ueckeroth Frank , König Katharina , Michels Sebastian , Fischer Rieke , Eisert Anna , Fassunke Jana , Heydt Carina , Serke Monika , Ko Yon-Dschun , Gerigk Ulrich , Geist Thomas , Kaminsky Britta , Heukamp Lukas C. , Clement-Ziza Mathieu , Büttner Reinhard , Wolf Jürgen
Published: April 2023

Abstract
Purpose: KEAP1 and NFE2L2 mutations are associated with impaired prognosis in a variety of cancers and with squamous cell carcinoma formation in non–small cell lung cancer (NSCLC). However, little is known about frequency, histology dependence, molecular and clinical presentation as well as response to systemic treatment in NSCLC.

Experimental Design: Tumor tissue of 1,391 patients with NSCLC was analyzed using next-generation sequencing (NGS). Clinical and pathologic characteristics, survival, and treatment outcome of patients with KEAP1 or NFE2L2 mutations were assessed.

Results: KEAP1 mutations occurred with a frequency of 11.3% (n = 157) and NFE2L2 mutations with a frequency of 3.5% (n = 49) in NSCLC patients. In the vast majority of patients, both mutations did not occur simultaneously. KEAP1 mutations were found mainly in adenocarcinoma (AD; 72%), while NFE2L2 mutations were more common in squamous cell carcinoma (LSCC; 59%). KEAP1 mutations were spread over the whole protein, whereas NFE2L2 mutations were clustered in specific hotspot regions. In over 80% of the patients both mutations co-occurred with other cancer-related mutations, among them also targetable aberrations like activating EGFR mutations or MET amplification. Both patient groups showed different patterns of metastases, stage distribution and performance state. No patient with KEAP1 mutation had a response on systemic treatment in first-, second-, or third-line setting. Of NFE2L2-mutated patients, none responded to second- or third-line therapy.

Conclusions: KEAP1- and NFE2L2-mutated NSCLC patients represent a highly heterogeneous patient cohort. Both are associated with different histologies and usually are found together with other cancer-related, partly targetable, genetic aberrations. In addition, both markers seem to be predictive for chemotherapy resistance. Clin Cancer Res; 24(13); 3087–96. ©2018 AACR.