bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Evaluation of Progression-Free Survival as a Surrogate Endpoint for Survival in Chemotherapy and Targeted Agent Metastatic Colorectal Cancer Trials
Authors: Sidhu Roger , Rong Alan , Dahlberg Steve
Published: April 2023

Abstract
Pooled analyses of chemotherapy trials in metastatic colorectal cancer (mCRC) have suggested that progression-free survival (PFS) is a surrogate endpoint for overall survival (OS). However, this has not been evaluated under current standard-of-care regimens of chemotherapy in combination with targeted therapies. We conducted an analysis of published mCRC trials of chemotherapy and targeted therapies from 2000 to evaluate the surrogacy of PFS and response rate (RR) for OS. Study-level data was pooled from 24 randomized mCRC trials that evaluated fluoropyrimidine-based regimens and included trials conducted with targeted agents (panitumumab, cetuximab, bevacizumab, and aflibercept). A total of 69 treatment arms with a sample size of 20,438 patients was included. Linear regression analysis was carried out to estimate the correlation of PFS and RR with OS. The correlation coefficient between PFS HRs and OS HRs was 0.86 for all trials, 0.89 for 12 phase III trials of targeted agents in combination with chemotherapy, 0.95 for 8 first-line phase III trials of targeted agents, and 0.83 for 9 trials of anti-EGFR-targeted agents. In all cases, correlation coefficients between RR and OS HRs were lower than those between PFS HRs and OS HRs (range, 0.42–0.81). In this study-level analysis of randomized mCRC trials of chemotherapy and targeted agents, improvements in PFS are strongly correlated with improvements in OS. This suggests that PFS remains a valid surrogate endpoint for OS with current treatment regimens in the mCRC setting. Clin Cancer Res; 19(5); 969–76. ©2012 AACR.
Data from Improved Survival with HPV among African Americans with Oropharyngeal Cancer
Authors: Worsham Maria J. , Stephen Josena K. , Chen Kang Mei , Mahan Meredith , Schweitzer Vanessa , Havard Shaleta , Divine George
Published: April 2023

Abstract
Purpose: A major limitation of studies reporting a lower prevalence rate of human papilloma virus (HPV) in African American patients with oropharyngeal squamous cell cancer (OPSCC) than Caucasian Americans, with corresponding worse outcomes, was adequate representation of HPV-positive African American patients. This study examined survival outcomes in HPV-positive and HPV-negative African Americans with OPSCC.

Experimental Design: The study cohort of 121 patients with primary OPSCC had 42% African Americans. Variables of interest included age, race, gender, HPV status, stage, marital status, smoking, treatment, and date of diagnosis.

Results: Caucasian Americans are more likely to be HPV positive (OR = 3.28; P = 0.035), as are younger age (age < 50 OR = 7.14; P = 0.023 compared with age > 65) or being married (OR = 3.44; P = 0.016). HPV positivity and being unmarried were associated with being late stage (OR = 3.10; P = 0.047 and OR = 3.23; P = 0.038, respectively). HPV-negative patients had 2.7 times the risk of death as HPV-positive patients (P = 0.004). Overall, the HPV-race groups differed (log-rank P < 0.001), with significantly worse survival for HPV-negative African Americans versus (i) HPV-positive African Americans (HR = 3.44; P = 0.0012); (ii) HPV-positive Caucasian Americans (HR = 3.11; P = < 0.049); and (iii) HPV-negative Caucasian Americans (HR = 2.21; P = 0.049).

Conclusions: HPV has a substantial impact on overall survival in African American patients with OPSCC. Among African American patients with OPSCC, HPV-positive patients had better survival than HPV negative. HPV-negative African Americans also did worse than both HPV-positive Caucasian Americans and HPV-negative Caucasian Americans. This study adds to the mounting evidence of HPV as a racially linked sexual behavior life style risk factor impacting survival outcomes for both African American and Caucasian American patients with OPSCC. Clin Cancer Res; 19(9); 2486–92. ©2013 AACR.
Data from MUC4-Mediated Regulation of Acute Phase Protein Lipocalin 2 through HER2/AKT/NF-κB Signaling in Pancreatic Cancer
Authors: Kaur Sukhwinder , Sharma Neil , Krishn Shiv Ram , Lakshmanan Imay , Rachagani Satyanarayana , Baine Michael J. , Smith Lynette M. , Lele Subodh M. , Sasson Aaron R. , Guha Sushovan , Mallya Kavita , Anderson Judy M. , Hollingsworth Michael A. , Batra Surinder K.
Published: April 2023

Abstract
Purpose: MUC4 shows aberrant expression in early pancreatic lesions and a high specificity for pancreatic cancer. It thus has a high potential to be a sensitive and specific biomarker. Unfortunately, its low serum level limits its diagnostic/prognostic potential. We here report that a multifaceted acute phase protein lipocalin 2, regulated by MUC4, could be a potential diagnostic/prognostic marker for pancreatic cancer.

Experimental Designs and Results: Overexpression/knockdown, luciferase reporter and molecular inhibition studies revealed that MUC4 regulates lipocalin 2 by stabilizing HER2 and stimulating AKT, which results in the activation of NF-κB. Immunohistochemical analyses of lipocalin 2 and MUC4 showed a significant positive correlation between MUC4 and lipocalin 2 in primary, metastatic tissues (Spearman correlation coefficient 0.71, P = 0.002) from rapid autopsy tissue sample from patients with pancreatic cancer as well as in serum and tissue samples from spontaneous KRASG12D mouse pancreatic cancer model (Spearman correlation coefficient 0.98, P < 0.05). Lipocalin 2 levels increased progressively with disease advancement (344.2 ± 22.8 ng/mL for 10 weeks to 3067.2 ± 572.6 for 50 weeks; P < 0.0001). In human pancreatic cancer cases, significantly elevated levels of lipocalin 2 were observed in patients with pancreatic cancer (148 ± 13.18 ng/mL) in comparison with controls (73.27 ± 4.9 ng/mL, P = 0.014). Analyses of pre- and postchemotherapy patients showed higher lipocalin 2 levels in prechemotherapy patients [121.7 ng/mL; 95% confidence interval (CI), 98.1–150.9] in comparison with the postchemotherapy (92.6 ng/mL; 95% CI, 76.7–111.6; P = 0.06) group.

Conclusions: This study delineates the association and the downstream mechanisms of MUC4-regulated elevation of lipocalin-2 (via HER2/AKT/NF-κB) and its clinical significance for prognosis of pancreatic cancer. Clin Cancer Res; 20(3); 688–700. ©2013 AACR.
Data from Predictive Value of Phase I Trials for Safety in Later Trials and Final Approved Dose: Analysis of 61 Approved Cancer Drugs
Authors: Jardim Denis L. , Hess Kenneth R. , LoRusso Patricia , Kurzrock Razelle , Hong David S.
Published: April 2023

Abstract
Phase I trials use a small number of patients to define a maximum tolerated dose (MTD) and the safety of new agents. We compared data from phase I and registration trials to determine whether early trials predicted later safety and final dose. We searched the U.S. Food and Drug Administration (FDA) website for drugs approved in nonpediatric cancers (January 1990–October 2012). The recommended phase II dose (R2PD) and toxicities from phase I were compared with doses and safety in later trials. In 62 of 85 (73%) matched trials, the dose from the later trial was within 20% of the RP2D. In a multivariable analysis, phase I trials of targeted agents were less predictive of the final approved dose (OR, 0.2 for adopting ± 20% of the RP2D for targeted vs. other classes; P = 0.025). Of the 530 clinically relevant toxicities in later trials, 70% (n = 374) were described in phase I. A significant relationship (P = 0.0032) between increasing the number of patients in phase I (up to 60) and the ability to describe future clinically relevant toxicities was observed. Among 28,505 patients in later trials, the death rate that was related to drug was 1.41%. In conclusion, dosing based on phase I trials was associated with a low toxicity-related death rate in later trials. The ability to predict relevant toxicities correlates with the number of patients on the initial phase I trial. The final dose approved was within 20% of the RP2D in 73% of assessed trials. Clin Cancer Res; 20(2); 281–8. ©2013 AACR.
Data from Steroidogenic Germline Polymorphism Predictors of Prostate Cancer Progression in the Estradiol Pathway
Authors: Lévesque Éric , Laverdière Isabelle , Audet-Walsh Étienne , Caron Patrick , Rouleau Mélanie , Fradet Yves , Lacombe Louis , Guillemette Chantal
Published: April 2023

Abstract
Purpose: Reliable biomarkers that predict prostate cancer outcomes are urgently needed to improve and personalize treatment approaches. With this goal in mind, we individually and collectively appraised common genetic polymorphisms related to estradiol metabolic pathways to find prostate cancer prognostic markers.

Methods: The genetic profiles of 526 men with organ-confined prostate cancer were examined to find common genetic polymorphisms related to estradiol metabolic pathways and these findings were replicated in a cohort of 213 men with more advanced disease (follow-up time for both cohorts, >7.4 years). Specifically, we examined 71 single-nucleotide polymorphisms (SNP) in SULT2A1, SULT2B1, CYP1B1, COMT, CYP3A4, CYP3A5, CYP3A43, NQO1, and NQO2 and assessed the impact of the SNPs alone and in combination on prostate cancer progression and on circulating hormone levels.

Results: According to a multivariate analysis, CYP1B1 (rs1800440), COMT (rs16982844), and SULT2B1 (rs12460535, rs2665582, rs10426628) were significantly associated with prostate cancer progression and hormone levels. Remarkably, by combining the SNP information with previously identified HSD17B2 markers, the patients could be stratified into four distinct prognostic subgroups. The most prominent association was observed for the eight-marker combination [CYP1B1 (rs1800440), SULT2B1 (rs12460535, rs2665582, and rs10426628), and HSD17B2 (rs4243229, rs1364287, rs2955162, and rs1119933)].

Conclusion: This study identified specific germline variations in estradiol metabolism–related pathways, namely CYP1B1, SULT2B1, and HSD17B2, as novel prognostic markers that are cumulatively associated with increased risk of prostate cancer progression. This panel of markers warrants additional investigation and validation to help stratify patients according to their risk of progression. Clin Cancer Res; 20(11); 2971–83. ©2014 AACR.
Data from Acute Infection Induces a Metastatic Niche: A Double Menace for Cancer Patients
Authors: Smith Heath A. , Kang Yibin
Published: April 2023

Abstract
Tumor-derived factors can induce a premetastatic niche, yet little is known about how metastatic microenvironments are influenced by external insults, such as acute infections commonly seen in patients with cancer. New findings reveal increased metastasis to the lung after acute bacterial infection via the CXCR4/ubiquitin axis, suggesting new targets for antimetastasis therapeutics. Clin Cancer Res; 19(17); 4547–9. ©2013 AACR.
Data from Serum Antibodies to Blood Group A Predict Survival on PROSTVAC-VF
Authors: Campbell Christopher T. , Gulley James L. , Oyelaran Oyindasola , Hodge James W. , Schlom Jeffrey , Gildersleeve Jeffrey C.
Published: April 2023

Abstract
Purpose: There is evidence that therapeutic cancer vaccines can lengthen survival for some patients with cancer, but responses vary widely from one person to another. Methods to predict clinical outcomes will advance the field and provide new insights into critical determinants of in vivo efficacy.

Experimental Design: This retrospective study included 141 subjects from phase II trials of PROSTVAC-VF, a poxvirus-based cancer vaccine currently in phase III clinical trials for advanced prostate cancer. A glycan microarray was used to profile prevaccination antiglycan antibody populations in sera as potential biomarkers for PROSTVAC-VF. The screen for predictive biomarkers identified antiglycan antibodies that consistently stratified subjects into groups with different Kaplan–Meier survival estimates. Because of the potential for overfitting, a permutation test was used to estimate the false discovery rate.

Results: Prevaccination antibody levels to blood group A trisaccharide (BG-Atri) were found to have a statistically significant correlation with survival. Long-term survival was approximately doubled in subjects with abundant anti-BG-Atri immunoglobulin M (IgM) relative to subjects with little or no preexisting IgM for BG-Atri. This survival correlation was specific to vaccine treatment, as no correlation was observed in control patients immunized with wild-type poxviruses lacking the key tumor antigen, prostate-specific antigen (PSA). Moreover, anti-BG-Atri IgM levels were not correlated with general measures of disease severity, such as PSA levels, Gleason score, or Halabi predicted survival.

Conclusion: In addition to reporting a new potentially predictive biomarker for PROSTVAC-VF, this study highlights the use of glycan microarray technology for improving our understanding of vaccine immunology. Clin Cancer Res; 19(5); 1290–9. ©2012 AACR.
Data from Accessory Cells of the Microenvironment Protect Multiple Myeloma from T-Cell Cytotoxicity through Cell Adhesion-Mediated Immune Resistance
Authors: de Haart Sanne J. , van de Donk Niels W.C.J. , Minnema Monique C. , Huang Julie H. , Aarts-Riemens Tineke , Bovenschen Niels , Yuan Huipin , Groen Richard W.J. , McMillin Douglas W. , Jakubikova Jana , Lokhorst Henk M. , Martens Anton C. , Mitsiades Constantine S. , Mutis Tuna
Published: April 2023

Abstract
Purpose: Cellular immunotherapy frequently fails to induce sustained remissions in patients with multiple myeloma, indicating the ability of multiple myeloma cells to evade cellular immunity. Toward a better understanding and effective therapeutic modulation of multiple myeloma immune evasion mechanisms, we here investigated the role of the tumor microenvironment in rendering multiple myeloma cells resistant to the cytotoxic machinery of T cells.

Experimental Design: Using a compartment-specific, bioluminescence imaging-based assay system, we measured the lysis of luciferase-transduced multiple myeloma cells by CD4+ or CD8+ CTLs in the presence versus absence of adherent accessory cells of the bone marrow microenvironment. We simultaneously determined the level of CTL activation by measuring the granzyme B release in culture supernatants.

Results: Bone marrow stromal cells from patients with multiple myeloma and healthy individuals, as well as vascular endothelial cells, significantly inhibited the lysis of multiple myeloma cells in a cell–cell contact-dependent manner and without substantial T-cell suppression, thus showing the induction of a cell adhesion-mediated immune resistance (CAM-IR) against CTL lysis. Further analyses revealed that adhesion to accessory cells downregulated Fas and upregulated the caspase-3 inhibitor survivin in multiple myeloma cells. Reconstitution of Fas expression with bortezomib enhanced the CTL-mediated lysis of multiple myeloma cells. Repressing survivin with the small-molecule YM155 synergized with CTLs and abrogated CAM-IR in vitro and in vivo.

Conclusion: These results reveal the cell adhesion-mediated induction of apoptosis resistance as a novel immune escape mechanism and provide a rationale to improve the efficacy of cellular therapies by pharmacologic modulation of CAM-IR. Clin Cancer Res; 19(20); 5591–601. ©2013 AACR.
Data from Chimeric Rat/Human HER2 Efficiently Circumvents HER2 Tolerance in Cancer Patients
Authors: Occhipinti Sergio , Sponton Laura , Rolla Simona , Caorsi Cristiana , Novarino Anna , Donadio Michela , Bustreo Sara , Satolli Maria Antonietta , Pecchioni Carla , Marchini Cristina , Amici Augusto , Cavallo Federica , Cappello Paola , Pierobon Daniele , Novelli Francesco , Giovarelli Mirella
Published: April 2023

Abstract
Purpose: Despite the great success of HER2 vaccine strategies in animal models, effective clinical results have not yet been obtained. We studied the feasibility of using DNA coding for chimeric rat/human HER2 as a tool to break the unresponsiveness of T cells from patients with HER2-overexpressing tumors (HER2-CP).

Experimental Design: Dendritic cells (DCs) generated from patients with HER2-overexpressing breast (n = 28) and pancreatic (n = 16) cancer were transfected with DNA plasmids that express human HER2 or heterologous rat sequences in separate plasmids or as chimeric constructs encoding rat/human HER2 fusion proteins and used to activate autologous T cells. Activation was evaluated by IFN-γ ELISPOT assay, perforin expression, and ability to halt HER2+ tumor growth in vivo.

Results: Specific sustained proliferation and IFN-γ production by CD4 and CD8 T cells from HER2-CP was observed after stimulation with autologous DCs transfected with chimeric rat/human HER2 plasmids. Instead, T cells from healthy donors (n = 22) could be easily stimulated with autologous DCs transfected with any human, rat, or chimeric rat/human HER2 plasmid. Chimeric HER2-transfected DCs from HER2-CP were also able to induce a sustained T-cell response that significantly hindered the in vivo growth of HER2+ tumors. The efficacy of chimeric plasmids in overcoming tumor-induced T-cell dysfunction relies on their ability to circumvent suppressor effects exerted by regulatory T cells (Treg) and/or interleukin (IL)-10 and TGF-β1.

Conclusions: These results provide the proof of concept that chimeric rat/human HER2 plasmids can be used as effective vaccines for any HER2-CP with the advantage of being not limited to specific MHC. Clin Cancer Res; 20(11); 2910–21. ©2014 AACR.
Data from Phase II Study of Cediranib in Patients with Advanced Gastrointestinal Stromal Tumors or Soft-Tissue Sarcoma
Authors: Judson Ian , Scurr Michelle , Gardner Kate , Barquin Elizabeth , Marotti Marcelo , Collins Barbara , Young Helen , Jürgensmeier Juliane M. , Leahy Michael
Published: April 2023

Abstract
Purpose: Cediranib is a potent VEGF signaling inhibitor with activity against all three VEGF receptors and KIT. This phase II study evaluated the antitumor activity of cediranib in patients with metastatic gastrointestinal stromal tumor (GIST) resistant/intolerant to imatinib, or metastatic soft-tissue sarcomas (STS; ClinicalTrials.gov, NCT00385203).

Experimental Design: Patients received cediranib 45 mg/day. Primary objective was to determine the antitumor activity of cediranib according to changes in 2[18F]fluoro-2-deoxy-D-glucose positron emission tomography (18FDG-PET) tumor uptake in patients with GIST using maximum standardized uptake values (SUVmax). Secondary objectives included objective tumor response and tolerability in patients with GIST/STS.

Results: Thirty-four of 36 enrolled patients were treated (GIST n = 24; STS n = 10). At day 29, five patients had confirmed decreases in SUVmax (≥10% from day 8) and two had confirmed partial metabolic responses (≥25% decrease), but arithmetic mean percentage changes in SUVmax, averaged across the cohort, were not significant at day 8 [6.8%; 95% confidence interval (CI), 19.95–33.54) or day 29 (4.6%; 95% CI, 8.05–17.34). Eleven patients with GIST achieved a best objective tumor response of stable disease; eight achieved stable disease ≥16 weeks. In patients with STS, four of six with alveolar soft-part sarcoma (ASPS) achieved confirmed and durable partial responses. The commonest adverse events were diarrhea (85%), fatigue (74%), and hypertension (68%).

Conclusions: In patients progressing on imatinib/sunitinib, cediranib 45 mg/day demonstrated evidence of activity by 18FDG-PET, but did not reduce average SUVmax. Evidence of antitumor activity was seen in ASPS. Clin Cancer Res; 20(13); 3603–12. ©2014 AACR.
Data from Uncovering the Molecular Secrets of Inflammatory Breast Cancer Biology: An Integrated Analysis of Three Distinct Affymetrix Gene Expression Datasets
Authors: Van Laere Steven J. , Ueno Naoto T. , Finetti Pascal , Vermeulen Peter , Lucci Anthony , Robertson Fredika M. , Marsan Melike , Iwamoto Takayuki , Krishnamurthy Savitri , Masuda Hiroko , van Dam Peter , Woodward Wendy A. , Viens Patrice , Cristofanilli Massimo , Birnbaum Daniel , Dirix Luc , Reuben James M. , Bertucci François
Published: April 2023

Abstract
Background: Inflammatory breast cancer (IBC) is a poorly characterized form of breast cancer. So far, the results of expression profiling in IBC are inconclusive due to various reasons including limited sample size. Here, we present the integration of three Affymetrix expression datasets collected through the World IBC Consortium allowing us to interrogate the molecular profile of IBC using the largest series of IBC samples ever reported.

Experimental Design: Affymetrix profiles (HGU133-series) from 137 patients with IBC and 252 patients with non-IBC (nIBC) were analyzed using unsupervised and supervised techniques. Samples were classified according to the molecular subtypes using the PAM50-algorithm. Regression models were used to delineate IBC-specific and molecular subtype-independent changes in gene expression, pathway, and transcription factor activation.

Results: Four robust IBC-sample clusters were identified, associated with the different molecular subtypes (P < 0.001), all of which were identified in IBC with a similar prevalence as in nIBC, except for the luminal A subtype (19% vs. 42%; P < 0.001) and the HER2-enriched subtype (22% vs. 9%; P < 0.001). Supervised analysis identified and validated an IBC-specific, molecular subtype-independent 79-gene signature, which held independent prognostic value in a series of 871 nIBCs. Functional analysis revealed attenuated TGF-β signaling in IBC.

Conclusion: We show that IBC is transcriptionally heterogeneous and that all molecular subtypes described in nIBC are detectable in IBC, albeit with a different frequency. The molecular profile of IBC, bearing molecular traits of aggressive breast tumor biology, shows attenuation of TGF-β signaling, potentially explaining the metastatic potential of IBC tumor cells in an unexpected manner. Clin Cancer Res; 19(17); 4685–96. ©2013 AACR.
Data from Long-lasting Disease Stabilization in the Absence of Toxicity in Metastatic Lung Cancer Patients Vaccinated with an Epitope Derived from Indoleamine 2,3 Dioxygenase
Authors: Iversen Trine Zeeberg , Engell-Noerregaard Lotte , Ellebaek Eva , Andersen Rikke , Larsen Stine Kiaer , Bjoern Jon , Zeyher Claus , Gouttefangeas Cécile , Thomsen Birthe Moerk , Holm Bente , thor Straten Per , Mellemgaard Anders , Andersen Mads Hald , Svane Inge Marie
Published: April 2023

Abstract
Purpose: To investigate targeting of indoleamine 2,3 dioxygenase (IDO) enzyme using a synthetic peptide vaccine administered to patients with metastatic non–small cell lung cancer (NSCLC).

Experimental Design: In a clinical phase I study, we treated 15 HLA-A2–positive patients with stage III–IV NSCLC in disease stabilization after standard chemotherapy. Patients were treated with imiquimod ointment and subcutaneous vaccinations (100 μg IDO5 peptide, sequence ALLEIASCL, formulated in 900 μL Montanide). Primary endpoint was toxicity. Clinical benefit and immunity were assessed as secondary endpoints.

Results: No severe toxicity was observed. One patient developed a partial response (PR) after one year of vaccine treatment, whereas long-lasting stable disease (SD) ≥ 8.5 months was demonstrated in another six patients. The median overall survival (OS) was 25.9 months. Patients demonstrated significant improved OS (P = 0.03) when compared with the group of patients excluded because of HLA-A2 negativity. IDO-specific CD8+ T-cell immunity was demonstrated by IFN-γ Elispot and Tetramer staining. Fluorescence-activated cell sorting analyses demonstrated a significant reduction of the Treg population (P = 0.03) after the sixth vaccine (2.5 months) compared with pretreatment levels. Furthermore, expression of IDO was detected in nine of ten tumor biopsies by immunohistochemistry. High-performance liquid chromatography analyses of kynurenine/tryptophan (Kyn/Trp) ratio in sera were performed. In long-term analyses of two clinical responding patients, the ratio of Kyn/Trp remained stable.

Conclusions: The vaccine was well tolerated with no severe toxicity occurring. A median OS of 25.9 months was demonstrated and long-lasting PR+SD was seen in 47% of the patients. Clin Cancer Res; 20(1); 221–32. ©2013 AACR.
Data from Identification of FGFR4 as a Potential Therapeutic Target for Advanced-Stage, High-Grade Serous Ovarian Cancer
Authors: Zaid Tarrik M. , Yeung Tsz-Lun , Thompson Melissa S. , Leung Cecilia S. , Harding Tom , Co Ngai-Na , Schmandt Rosie S. , Kwan Suet-Ying , Rodriguez-Aguay Cristian , Lopez-Berestein Gabriel , Sood Anil K. , Wong Kwong-Kwok , Birrer Michael J. , Mok Samuel C.
Published: April 2023

Abstract
Purpose: To evaluate the prognostic value of fibroblast growth factor receptor 4 (FGFR4) protein expression in patients with advanced-stage, high-grade serous ovarian cancer, delineate the functional role of FGFR4 in ovarian cancer progression, and evaluate the feasibility of targeting FGFR4 in serous ovarian cancer treatment.

Experimental Design: Immunolocalization of FGFR4 was conducted on 183 ovarian tumor samples. The collected FGFR4 expression data were correlated with overall survival using Kaplan–Meier and Cox regression analyses. The effects of FGFR4 silencing on ovarian cancer cell growth, survival, invasiveness, apoptosis, and FGF1-mediated signaling pathway activation were evaluated by transfecting cells with FGFR4-specific siRNAs. An orthotopic mouse model was used to evaluate the effect of injection of FGFR4-specific siRNAs and FGFR4 trap protein encapsulated in nanoliposomes on ovarian tumor growth in vivo.

Results: Overexpression of FGFR4 protein was significantly associated with decreased overall survival durations. FGFR4 silencing significantly decreased the proliferation, survival, and invasiveness and increased apoptosis of ovarian cancer cells. Also, downregulation of FGFR4 significantly abrogated the mitogen-activated protein kinase (MAPK), nuclear factor-κB (NF-κB), and WNT signaling pathways, which are activated by FGF1. Targeting FGFR4 with the FGFR4-specific siRNAs and FGFR4 trap protein significantly decreased ovarian tumor growth in vivo.

Conclusions: FGFR4 is a prognostic marker for advanced-stage, high-grade serous ovarian carcinoma. Silencing FGFR4 and inhibiting ligand-receptor binding significantly decrease ovarian tumor growth both in vitro and in vivo, suggesting that targeting ovarian cancer cells with high levels of FGFR4 protein expression is a new therapeutic modality for this disease and will improve survival of it. Clin Cancer Res; 19(4); 809–20. ©2012 AACR.
Data from Discrete Molecular Classes of Ovarian Cancer Suggestive of Unique Mechanisms of Transformation and Metastases
Authors: Gardi Nilesh L. , Deshpande Tejaswini U. , Kamble Swapnil C. , Budhe Sagar R. , Bapat Sharmila A.
Published: April 2023

Abstract
Purpose: Tumor heterogeneity and subsistence of high-grade serous ovarian adenocarcinoma (HGSC) classes can be speculated from clinical incidences suggesting passive tumor dissemination versus active invasion and metastases.

Experimental Design: We explored this theme toward tumor classification through two approaches of gene expression pattern clustering: (i) derivation of a core set of metastases-associated genes and (ii) resolution of independent weighted correlation networks. Further identification of appropriate cell and xenograft models was carried out for resolution of class-specific biologic functions.

Results: Both clustering approaches achieved resolution of three distinct tumor classes, two of which validated in other datasets. Networks of enriched gene modules defined biologic functions of quiescence, cell division-differentiation-lineage commitment, immune evasion, and cross-talk with niche factors. Although deviant from normal homeostatic mechanisms, these class-specific profiles are not totally random. Preliminary validation of these suggests that Class 1 tumors survive, metastasize in an epithelial–mesenchymal transition (EMT)-independent manner, and are associated with a p53 signature, aberrant differentiation, DNA damage, and genetic instability. These features supported by association of cell-specific markers, including PAX8, PEG3, and TCF21, led to the speculation of their origin being the fimbrial fallopian tube epithelium. On the other hand, Class 2 tumors activate extracellular matrix–EMT–driven invasion programs (Slug, SPARC, FN1, THBS2 expression), IFN signaling, and immune evasion, which are prospectively suggestive of ovarian surface epithelium associated wound healing mechanisms. Further validation of these etiologies could define a new therapeutic framework for disease management. Clin Cancer Res; 20(1); 87–99. ©2013 AACR.
Data from αB-Crystallin: A Novel Regulator of Breast Cancer Metastasis to the Brain
Authors: Malin Dmitry , Strekalova Elena , Petrovic Vladimir , Deal Allison M. , Al Ahmad Abraham , Adamo Barbara , Miller C. Ryan , Ugolkov Andrey , Livasy Chad , Fritchie Karen , Hamilton Erika , Blackwell Kimberly , Geradts Joseph , Ewend Matt , Carey Lisa , Shusta Eric V. , Anders Carey K. , Cryns Vincent L.
Published: April 2023

Abstract
Purpose: Basal-like breast tumors are typically (ER/PR/HER2) triple-negative and are associated with a high incidence of brain metastases and poor clinical outcomes. The molecular chaperone αB-crystallin is predominantly expressed in triple-negative breast cancer (TNBC) and contributes to an aggressive tumor phenotype in preclinical models. We investigated the potential role of αB-crystallin in brain metastasis in TNBCs.

Experimental Design: αB-crystallin expression in primary breast carcinomas and brain metastases was analyzed by immunohistochemistry among patients with breast cancer with brain metastases. αB-crystallin was overexpressed or silenced in two different TNBC cell lines. The effects on cell adhesion to human brain microvascular endothelial cells (HBMEC) or extracellular matrix proteins, transendothelial migration, and transmigration across a HBMEC/astrocyte coculture blood–brain barrier (BBB) model were examined. In addition, the effects of overexpressing or silencing αB-crystallin on brain metastasis in vivo were investigated using orthotopic TNBC models.

Results: In a cohort of women with breast cancer brain metastasis, αB-crystallin expression in primary breast carcinomas was associated with poor overall survival and poor survival after brain metastasis, even among patients with TNBC. Stable overexpression of αB-crystallin in TNBC cells enhanced adhesion to HBMECs, transendothelial migration, and BBB transmigration in vitro, whereas silencing αB-crystallin inhibited these events. αB-crystallin promoted adhesion of TNBC cells to HBMECs, at least in part, through an α3β1 integrin–dependent mechanism. αB-crystallin overexpression promoted brain metastasis, whereas silencing αB-crystallin inhibited brain metastasis in orthotopic TNBC models.

Conclusion: αB-crystallin is a novel regulator of brain metastasis in TNBC and represents a potential biomarker and drug target for this aggressive disease. Clin Cancer Res; 20(1); 56–67. ©2013 AACR.
Data from PI3K Pathway Activation in High-Grade Ductal Carcinoma In Situ—Implications for Progression to Invasive Breast Carcinoma
Authors: Sakr Rita A. , Weigelt Britta , Chandarlapaty Sarat , Andrade Victor P. , Guerini-Rocco Elena , Giri Dilip , Ng Charlotte K.Y. , Cowell Catherine F. , Rosen Neal , Reis-Filho Jorge S. , King Tari A.
Published: April 2023

Abstract
Purpose: To assess the prevalence of phosphoinositide 3-kinase (PI3K) pathway alterations in pure high-grade ductal carcinoma in situ (DCIS) and DCIS associated with invasive breast cancer (IBC), and to determine whether DCIS and adjacent IBCs harbor distinct PI3K pathway aberrations.

Experimental Design: Eighty-nine cases of pure high-grade DCIS and 119 cases of high-grade DCIS associated with IBC were characterized according to estrogen receptor (ER) and HER2 status, subjected to immunohistochemical analysis of PTEN, INPP4B, phosphorylated (p)AKT and pS6 expression, and to microdissection followed by Sequenom genotyping of PIK3CA and AKT1 hotspot mutations.

Results: Alterations affecting the PI3K pathway were found in a subset of pure DCIS and DCIS adjacent to IBC. A subtype-matched comparison of pure DCIS and DCIS adjacent to IBC revealed that PIK3CA hotspot mutations and pAKT expression were significantly more prevalent in ER-positive/HER2-negative DCIS adjacent to IBC (P values, 0.005 and 0.043, respectively), and that in ER-negative/HER2-positive cases INPP4B loss of expression was more frequently observed in pure DCIS (a P value of 0.013). No differences in the parameters analyzed were observed in a pairwise comparison of the in situ and invasive components of cases of DCIS and adjacent IBC. Analysis of the PIK3CA-mutant allelic frequencies in DCIS and synchronous IBC revealed cases in which PIK3CA mutations were either restricted to the DCIS or to the invasive components.

Conclusion: Molecular aberrations affecting the PI3K pathway may play a role in the progression from high-grade DCIS to IBC in a subset of cases (e.g., a subgroup of ER-positive/HER2-negative lesions). Clin Cancer Res; 20(9); 2326–37. ©2014 AACR.
Data from Impact of c-MYC Protein Expression on Outcome of Patients with Early-Stage HER2+ Breast Cancer Treated with Adjuvant Trastuzumab NCCTG (Alliance) N9831
Authors: Dueck Amylou C. , Reinholz Monica M. , Geiger Xochiquetzal J. , Tenner Kathleen , Ballman Karla , Jenkins Robert B. , Riehle Darren , Chen Beiyun , McCullough Ann E. , Davidson Nancy E. , Martino Silvana , Sledge George W. , Kaufman Peter A. , Kutteh Leila A. , Gralow Julie , Harris Lyndsay N. , Ingle James N. , Lingle Wilma L. , Perez Edith A.
Published: April 2023

Abstract
Purpose: This study investigated the association between tumor MYC protein expression and disease-free survival (DFS) of patients randomized to receive chemotherapy alone (Arm A) or chemotherapy with sequential (Arm B) or concurrent trastuzumab (Arm C) in the N9831 (Alliance) adjuvant HER2+ trastuzumab breast cancer trial.

Experimental Design: This analysis included 1,736 patients randomized to Arms A, B, and C on N9831. Nuclear MYC protein expression was determined in tissue microarray sections containing three biopsies per patient or whole tissue sections using standard immunohistochemistry (clone 9E10). A tumor was considered positive for MYC protein overexpression (MYC+) if the nuclear 3+ staining percentage was more than 30%.

Results: Five hundred and seventy-four (33%) tumors were MYC+. MYC+ was associated with hormone receptor positivity (χ2, P = 0.006), tumors 2 cm or more (χ2, P = 0.02), and a higher rate of nodal positivity (χ2, P < 0.001). HRs for DFS (median follow-up: 6.1 years) for Arm C versus A were 0.52 (P = 0.006) and 0.65 (P = 0.006) for patients with MYC+ and MYC− tumors, respectively (Pinteraction = 0.40). For Arm B versus A, HRs for patients with MYC+ and MYC− tumors were 0.79 (P = 0.21) and 0.74 (P = 0.04), respectively (Pinteraction = 0.71). For Arm C versus B, HRs for patients with MYC+ and MYC− tumors were 0.56 (P = 0.02) and 0.89 (P = 0.49), respectively (Pinteraction = 0.17).

Conclusions: Our data do not support an impact of tumor MYC protein expression on differential benefit from adjuvant trastuzumab. Clin Cancer Res; 19(20); 5798–807. ©2013 AACR.
Data from Plasma MicroRNA Are Disease Response Biomarkers in Classical Hodgkin Lymphoma
Authors: Jones Kimberley , Nourse Jamie P. , Keane Colm , Bhatnagar Atul , Gandhi Maher K.
Published: April 2023

Abstract
Purpose: Although microRNAs (miRNA) show potential as diagnostic biomarkers in cancer, their role as circulating cell-free disease response biomarkers remains unknown. Candidate circulating miRNA biomarkers for classical Hodgkin lymphoma (cHL) might arise from Hodgkin–Reed–Sternberg (HRS) cells and/or nonmalignant tumor-infiltrating cells. HRS cells are sparse within the diseased node, embedded within a benign microenvironment, the composition of which is distinct from that seen in healthy lymph nodes.

Experimental Design: Microarray profiling of more than 1,000 human miRNAs in 14 cHL primary tissues and eight healthy lymph nodes revealed a number of new disease node–associated miRNAs, including miR-494 and miR-1973. Using quantitative real-time PCR (qRT-PCR), we tested the utility of these, as well as previously identified disease node–associated plasma miRNAs (including miR-21 and miR-155), as disease response biomarkers in a prospective cohort of 42 patients with cHL. Blood samples were taken in conjunction with radiologic imaging at fixed time points before, during, and after therapy. Absolute quantification was used so as to facilitate implementation in diagnostic laboratories.

Results: Levels of miR-494, miR-1973, and miR-21 were higher in patients than control (n = 20) plasma (P = 0.004, P = 0.007, and P < 0.0001, respectively). MiR-494 and miR-21 associated with Hasenclever scores ≥3. Strikingly, all three miRNAs returned to normal at remission (P = 0.0006, P = 0.0002, and P < 0.0001 respectively). However, only miR-494 and miR-1973 reflected interim therapy response with reduction being more pronounced in patients achieving complete versus partial responses (P = 0.043 and P = 0.0012, respectively).

Conclusion: Our results demonstrate that in patients with cHL, circulating cell-free miRNAs can reflect disease response once therapy has commenced. Clin Cancer Res; 20(1); 253–64. ©2013 AACR.
Data from A Dose-Escalation Study of SAR3419, an Anti-CD19 Antibody Maytansinoid Conjugate, Administered by Intravenous Infusion Once Weekly in Patients with Relapsed/Refractory B-cell Non-Hodgkin Lymphoma
Authors: Ribrag Vincent , Dupuis Jehan , Tilly Herve , Morschhauser Franck , Laine Fabrice , Houot Roch , Haioun Corinne , Copie Christiane , Varga Andrea , Lambert John , Hatteville Laurence , Ziti-Ljajic Samira , Caron Anne , Payrard Sandrine , Coiffier Bertrand
Published: April 2023

Abstract
Purpose: To determine recommended dose, dose-limiting toxicity, safety profile, pharmacokinetics, preliminary antitumor activity, and exploratory pharmacodynamics of SAR3419, an antibody–drug conjugate targeting CD19, administered alone by intravenous infusion weekly (qw), in a dose-escalation phase I study in patients with refractory/relapsed (R/R) non-Hodgkin lymphoma (NHL).

Experimental Design: Patients with R/R CD19+ B-NHL were treated with escalating doses of SAR3419 repeated qw for eight to 12 doses. On the basis of clinical evidence of late or cumulative toxicities, the study protocol was amended to test an “optimized” administration schedule consisting of four qw doses followed by four biweekly (q2w) doses (qw/q2w) at the recommended dose with the intent of reducing drug accumulation.

Results: Forty-four patients were treated on seven dose levels ranging from 5 to 70 mg/m2. SAR3419 recommended dose was determined as 55 mg/m2 qw. Twenty-five patients received the qw/q2w schedule at 55 mg/m2, which showed an improved safety profile compared with the qw schedule. Antilymphoma activity was observed with both schedules in around 30% of patients with either indolent or aggressive diseases. SAR3419 displayed a long terminal half-life (approximately 7 days) and a low clearance (approximately 0.6 L/d), with no dose effect. The qw/q2w schedule allowed limiting accumulation with a decrease in SAR3419 plasma trough and average concentrations by around 1.4-fold compared with the qw schedule.

Conclusion: While administered weekly, SAR3419 is well tolerated and active. The qw/q2w schedule that shows an improved safety profile and preserves antilymphoma activity is selected for clinical phase II studies. Clin Cancer Res; 20(1); 213–20. ©2013 AACR.
Data from Prevailing Role of Contact Guidance in Intrastromal T-cell Trapping in Human Pancreatic Cancer
Authors: Hartmann Natalie , Giese Nathalia A. , Giese Thomas , Poschke Isabel , Offringa Rienk , Werner Jens , Ryschich Eduard
Published: April 2023

Abstract
Purpose: Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive collagen-rich stroma. T cells that infiltrate pancreatic cancers frequently become trapped in the stroma and do not contact tumor cells. Here, we aimed to analyze how chemokines and extracellular matrix (ECM) collagen interact in mediating T-cell infiltration in PDAC.

Experimental Design: T-cell distribution and ECM structure within tumors were analyzed. Chemokine concentrations in human PDAC were compared with the levels of immune cell infiltration. We assessed the influences of selected chemokines and collagen on directed and random T-cell movement using in vitro migration systems.

Results: PDAC overproduced several T-cell-active chemokines, but their levels were not correlated with intratumoral T-cell infiltration. In the absence of collagen, directed migration of activated T cells was induced by chemokines. Interestingly, collagen itself promoted high migratory activity of T cells, but completely abolished chemokine-guided movement. This effect was not altered by a β1-integrin blocking antibody. Activated T cells actively migrated in low-density collagen matrices, but migration was inhibited in dense collagen. Accordingly, T cells were heterogeneously distributed in the pancreatic cancer stroma, with the majority residing in areas of low-density collagen far from tumor clusters.

Conclusion: The excessive desmoplasia in PDAC promotes T-cell migration by contact guidance, which abrogates tumor cell–directed movement. Furthermore, dense collagen networks represent a physical barrier, additionally rearranging T-cell distribution to favor tumor stroma. These mechanisms are mainly responsible for intrastromal T-cell trapping in pancreatic cancer and may hinder the development of T-cell–based immunotherapies. Clin Cancer Res; 20(13); 3422–33. ©2014 AACR.
Data from Phase I Study of BIIB028, a Selective Heat Shock Protein 90 Inhibitor, in Patients with Refractory Metastatic or Locally Advanced Solid Tumors
Authors: Hong David , Said Rabih , Falchook Gerald , Naing Aung , Moulder Stacy , Tsimberidou Apostolia-Maria , Galluppi Gerald , Dakappagari Naveen , Storgard Chris , Kurzrock Razelle , Rosen Lee S.
Published: April 2023

Abstract
Purpose: Heat shot protein 90 (Hsp90) is a ubiquitous molecular chaperone involved in protein folding, activation, and assembly, including key mediators of signal transduction, cell-cycle control, and transcriptional regulation. We conducted a phase I dose-finding and pharmacokinetic/pharmacodynamic study of BIIB028, a prodrug designed to inhibit Hsp90 activity.

Experimental Design: Patients with advanced solid tumors were enrolled and received escalating doses of BIIB028 intravenously twice a week in 21-day cycles (3 + 3 design). Response was evaluated after two cycles.

Results: Forty-one patients received doses of 6 to 192 mg/m2. The maximum tolerated dose was 144 mg/m2. Dose-limiting toxicities were syncope (n = 1) and fatigue (n = 1). Common toxicities at least possibly related to drug were grades 1 to 2, including fatigue (46%), diarrhea (44%), nausea (44%), vomiting (29%), hot flushes (29%), and abnormal dreams (17%). The concentration–time curves for day 1 and day 18 for both prodrug and active metabolite (CF2772) showed a negligible difference. There was a dose-dependent increase in plasma exposure for BIIB028 (CF3647) and CF2772 with plasma half-life of 0.5 and 2.1 hours, respectively. Pharmacodynamic analyses showed significant increases in Hsp70 in peripheral blood mononuclear cells and significantly decreased circulating human EGF receptor-2 extracellular domain in all patients who received BIIB028 at dose levels of 48 mg/m2 or more. Stable disease for at least eight cycles (24 weeks) was achieved in 5 (12%) patients (for durations of 6, 6, 8, 12.5, and 19 months).

Conclusion: BIIB028 is a well-tolerated molecule that showed target impact and was associated with prolonged stable disease in two patients. Clin Cancer Res; 19(17); 4824–31. ©2013 AACR.
Data from A Genome-Wide Aberrant RNA Splicing in Patients with Acute Myeloid Leukemia Identifies Novel Potential Disease Markers and Therapeutic Targets
Authors: Adamia Sophia , Haibe-Kains Benjamin , Pilarski Patrick M. , Bar-Natan Michal , Pevzner Samuel , Avet-Loiseau Herve , Lode Laurence , Verselis Sigitas , Fox Edward A. , Burke John , Galinsky Ilene , Dagogo-Jack Ibiayi , Wadleigh Martha , Steensma David P. , Motyckova Gabriela , Deangelo Daniel J. , Quackenbush John , Stone Richard , Griffin James D.
Published: April 2023

Abstract
Purpose: Despite new treatments, acute myeloid leukemia (AML) remains an incurable disease. More effective drug design requires an expanded view of the molecular complexity that underlies AML. Alternative splicing of RNA is used by normal cells to generate protein diversity. Growing evidence indicates that aberrant splicing of genes plays a key role in cancer. We investigated genome-wide splicing abnormalities in AML and based on these abnormalities, we aimed to identify novel potential biomarkers and therapeutic targets.

Experimental Design: We used genome-wide alternative splicing screening to investigate alternative splicing abnormalities in two independent AML patient cohorts [Dana-Farber Cancer Institute (DFCI) (Boston, MA) and University Hospital de Nantes (UHN) (Nantes, France)] and normal donors. Selected splicing events were confirmed through cloning and sequencing analysis, and than validated in 193 patients with AML.

Results: Our results show that approximately 29% of expressed genes genome-wide were differentially and recurrently spliced in patients with AML compared with normal donors bone marrow CD34+ cells. Results were reproducible in two independent AML cohorts. In both cohorts, annotation analyses indicated similar proportions of differentially spliced genes encoding several oncogenes, tumor suppressor proteins, splicing factors, and heterogeneous-nuclear-ribonucleoproteins, proteins involved in apoptosis, cell proliferation, and spliceosome assembly. Our findings are consistent with reports for other malignances and indicate that AML-specific aberrations in splicing mechanisms are a hallmark of AML pathogenesis.

Conclusions: Overall, our results suggest that aberrant splicing is a common characteristic for AML. Our findings also suggest that splice variant transcripts that are the result of splicing aberrations create novel disease markers and provide potential targets for small molecules or antibody therapeutics for this disease. Clin Cancer Res; 20(5); 1135–45. ©2013 AACR.