bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from A Novel Pharmacologic Activity of Ketorolac for Therapeutic Benefit in Ovarian Cancer Patients
Authors: Guo Yuna , Kenney S. Ray , Cook Linda , Adams Sarah F. , Rutledge Teresa , Romero Elsa , Oprea Tudor I. , Sklar Larry A. , Bedrick Edward , Wiggins Charles L. , Kang Huining , Lomo Lesley , Muller Carolyn Y. , Wandinger-Ness Angela , Hudson Laurie G.
Published: April 2023

Abstract
Purpose: We previously identified the R-enantiomer of ketorolac as an inhibitor of the Rho-family GTPases Rac1 and Cdc42. Rac1 and Cdc42 regulate cancer-relevant functions, including cytoskeleton remodeling necessary for tumor cell adhesion and migration. This study investigated whether administration of racemic (R,S) ketorolac after ovarian cancer surgery leads to peritoneal distribution of R-ketorolac, target GTPase inhibition in cells retrieved from the peritoneal cavity, and measureable impact on patient outcomes.

Experimental Design: Eligible patients had suspected advanced-stage ovarian, fallopian tube or primary peritoneal cancer. Secondary eligibility was met when ovarian cancer was confirmed and optimally debulked, an intraperitoneal port was placed, and there were no contraindications for ketorolac administration. R- and S-ketorolac were measured in serum and peritoneal fluid, and GTPase activity was measured in peritoneal cells. A retrospective study correlated perioperative ketorolac and ovarian cancer–specific survival in ovarian cancer cases.

Results: Elevated expression and activity of Rac1 and Cdc42 was detected in ovarian cancer patient tissues, confirming target relevance. Ketorolac in peritoneal fluids was enriched in the R-enantiomer and peritoneal cell GTPase activity was inhibited after ketorolac administration when R-ketorolac was at peak levels. After adjusting for age, AJCC stage, completion of chemotherapy, and neoadjuvant therapy, women given perioperative ketorolac had a lower hazard of death (HR, 0.30; 95% confidence interval, 0.11–0.88).

Conclusions: Ketorolac has a novel pharmacologic activity conferred by the R-enantiomer and R-ketorolac achieves sufficient levels in the peritoneal cavity to inhibit Rac1 and Cdc42, potentially contributing to the observed survival benefit in women who received ketorolac. Clin Cancer Res; 21(22); 5064–72. ©2015 AACR.
Data from A Phase II, Randomized, Placebo-Controlled Study of Vismodegib as Maintenance Therapy in Patients with Ovarian Cancer in Second or Third Complete Remission
Authors: Kaye Stanley B. , Fehrenbacher Louis , Holloway Robert , Amit Amnon , Karlan Beth , Slomovitz Brian , Sabbatini Paul , Fu Ling , Yauch Robert L. , Chang Ilsung , Reddy Josina C.
Published: April 2023

Abstract
Purpose: Hedgehog pathway inhibition has been suggested as a potential maintenance treatment approach in ovarian cancer through disruption of tumor–stromal interactions. Vismodegib is an orally available Hedgehog pathway inhibitor with clinical activity in advanced basal cell carcinoma and medulloblastoma. This phase II, randomized, double-blind, placebo-controlled trial was designed to provide a preliminary estimate of efficacy in patients with ovarian cancer in second or third complete remission (CR).

Experimental Design: Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in second or third CR were randomized 1:1 to vismodegib (GDC-0449; 150 mg daily) or placebo three to 14 weeks after completing chemotherapy. Treatment continued until radiographic progression or toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS).

Results: One hundred four patients were randomized to vismodegib (n = 52) or placebo (n = 52); median PFS was 7.5 months and 5.8 months, respectively [HR 0.79; 95% confidence interval (CI), 0.46–1.35]. The HR was 0.66 (95% CI, 0.36–1.20) for second CR patients (n = 84) and 1.79 (95% CI, 0.50–6.48) for third CR patients (n = 20). The most common adverse events in the vismodegib arm were dysgeusia/ageusia, muscle spasms, and alopecia. Grade 3/4 adverse events occurred in 12 patients (23.1%) with vismodegib and six (11.5%) with placebo. Hedgehog expression was detected in 13.5% of archival tissues.

Conclusions: In this study, the sought magnitude of increase in PFS was not achieved for vismodegib maintenance versus placebo in patients with ovarian cancer in second or third CR. The frequency of Hedgehog ligand expression was lower than expected. Clin Cancer Res; 18(23); 6509–18. ©2012 AACR.
Data from Genetically Defined Subsets of Human Pancreatic Cancer Show Unique In Vitro Chemosensitivity
Authors: Cui Yunfeng , Brosnan Jacqueline A. , Blackford Amanda L. , Sur Surojit , Hruban Ralph H. , Kinzler Kenneth W. , Vogelstein Bert , Maitra Anirban , Diaz Luis A. , Iacobuzio-Donahue Christine A. , Eshleman James R.
Published: April 2023

Abstract
Purpose: Pancreatic cancer is the fourth cause of death from cancer in the western world. Majority of patients present with advanced unresectable disease responding poorly to most chemotherapeutic agents. Chemotherapy for pancreatic cancer might be improved by adjusting it to individual genetic profiles. We attempt to identify genetic predictors of chemosensitivity to broad classes of anticancer drugs.

Experimental Design: Using a panel of genetically defined human pancreatic cancer cell lines, we tested gemcitabine (antimetabolite), docetaxel (antimicrotubule), mitomycin C (MMC; alkylating), irinotecan (topoisomerase I inhibitor), cisplatin (crosslinking), KU0058948 (Parp1 inhibitor), triptolide (terpenoid drug), and artemisinin (control).

Results: All pancreatic cancer cell lines were sensitive to triptolide and docetaxel. Most pancreatic cancer cells were also sensitive to gemcitabine and MMC. The vast majority of pancreatic cancer cell lines were insensitive to cisplatin, irinotecan, and a Parp1 inhibitor. However, individual cell lines were often sensitive to these compounds in unique ways. We found that DPC4/SMAD4 inactivation sensitized pancreatic cancer cells to cisplatin and irinotecan by 2- to 4-fold, but they were modestly less sensitive to gemcitabine. Pancreatic cancer cells were all sensitive to triptolide and 18% were sensitive to the Parp1 inhibitor. P16/CDKN2A-inactivated pancreatic cancer cells were 3- to 4-fold less sensitive to gemcitabine and MMC.

Conclusions: Chemosensitivity of pancreatic cancer cells correlated with some specific genetic profiles. These results support the hypothesis that genetic subsets of pancreatic cancer exist, and these genetic backgrounds may permit one to personalize the chemotherapy of pancreatic cancer in the future. Further work will need to confirm these responses and determine their magnitude in vivo. Clin Cancer Res; 18(23); 6519–30. ©2012 AACR.
Data from Dual Block with Lapatinib and Trastuzumab Versus Single-Agent Trastuzumab Combined with Chemotherapy as Neoadjuvant Treatment of HER2-Positive Breast Cancer: A Meta-analysis of Randomized Trials
Authors: Clavarezza Matteo , Puntoni Matteo , Gennari Alessandra , Paleari Laura , Provinciali Nicoletta , D'Amico Mauro , DeCensi Andrea
Published: April 2023

Abstract
Purpose: (Neo)adjuvant treatment with chemotherapy plus trastuzumab reduces recurrence and death risk in HER2-positive (HER2+) breast cancer. Randomized trials assessed HER2 dual block by adding lapatinib to trastuzumab and chemotherapy in the neoadjuvant setting using pathologic complete response (pCR) as the outcome measure. We conducted a meta-analysis of randomized trials testing neoadjuvant dual block with lapatinib and trastuzumab versus trastuzumab alone in HER2+ breast cancer.

Experimental Design: Trials were identified by Medline (PubMed), ISI Web of Science (Science Citation Index Expanded), Embase, Cochrane library, and reference lists of published studies, review articles, editorials, and by hand-searched reports from major cancer meeting reports.

Results: Six randomized trials including 1,155 patients were identified, of whom 483 (41.8%) were hormone receptor–negative, 672 (58.2%) hormone receptor–positive, 534 (46.2%) received taxanes alone, and 621 (53.8%) anthracyclines plus taxanes or the docetaxel–carboplatin regimen. Overall, the dual block was associated with a significant 13% absolute improvement in pCR rate compared with single-agent trastuzumab (summary risk difference, SRD 0.13; 95% CI, 0.08–0.19). The activity was greater in hormone receptor–negative patients who received chemotherapy with taxanes alone (SRD 0.25; 95% CI, 0.13–0.37), compared to hormone receptor–positive or hormone receptor–negative disease treated with anthracyclines plus taxanes or the docetaxel–carboplatin regimen (SRD 0.09; 95% CI, 0.02–0.15; Pinteraction = 0.05).

Conclusions: On the basis of ΔpCR data, the dual block with trastuzumab and lapatinib plus chemotherapy is a very active treatment only in HER2+ and hormone receptor–negative breast cancer treated with taxane monochemotherapy. Clin Cancer Res; 22(18); 4594–603. ©2016 AACR.
Data from Serum C-Telopeptide Collagen Crosslinks and Plasma Soluble VEGFR2 as Pharmacodynamic Biomarkers in a Trial of Sequentially Administered Sunitinib and Cilengitide
Authors: O'Donnell Peter H. , Karovic Sanja , Karrison Theodore G. , Janisch Linda , Levine Matthew R. , Harris Pamela J. , Polite Blase N. , Cohen Ezra E.W. , Fleming Gini F. , Ratain Mark J. , Maitland Michael L.
Published: April 2023

Abstract
Purpose: Fit-for-purpose pharmacodynamic biomarkers could expedite development of combination antiangiogenic regimens. Plasma sVEGFR2 concentrations ([sVEGFR2]) mark sunitinib effects on the systemic vasculature. We hypothesized that cilengitide would impair microvasculature recovery during sunitinib withdrawal and could be detected through changes in [sVEGFR2].

Experimental Design: Advanced solid tumor patients received 50 mg sunitinib daily for 14 days. For the next 14 days, patients were randomized to arm A (cilengitide 2,000 mg administered intravenously twice weekly) or arm B (no treatment). The primary endpoint was change in [sVEGFR2] between days 14 and 28. A candidate pharmacodynamic biomarker of cilengitide inhibition of integrin αvβ3, serum c-telopeptide collagen crosslinks (CTx), was also measured.

Results: Of 21 patients, 14 (7 per arm) received all treatments without interruption and had all blood samples available for analysis. The mean change and SD of [sVEGFR2] for all sunitinib-treated patients was consistent with previous data. There was no significant difference in the mean change in [sVEGFR2] from days 14 to 28 between the arms [arm A: 2.8 ng/mL; 95% confidence interval (CI), 2.1–3.6 vs. arm B: 2.0 ng/mL; 95% CI, 0.72–3.4; P = 0.22, 2-sample t test]. Additional analyses suggested (i) prior bevacizumab therapy to be associated with unusually low baseline [sVEGFR2] and (ii) sunitinib causes measurable changes in CTx.

Conclusions: Cilengitide had no measurable effects on any circulating biomarkers. Sunitinib caused measurable declines in serum CTx. The properties of [sVEGFR2] and CTx observed in this study inform the design of future combination antiangiogenic therapy trials. Clin Cancer Res; 21(22); 5092–9. ©2015 AACR.
Data from MRI-Based Liver Iron Content Predicts for Nonrelapse Mortality in MDS and AML Patients Undergoing Allogeneic Stem Cell Transplantation
Authors: Wermke Martin , Schmidt Anne , Middeke Jan Moritz , Sockel Katja , von Bonin Malte , Schönefeldt Claudia , Mair Sabine , Plodeck Verena , Laniado Michael , Weiss Günter , Schetelig Johannes , Ehninger Gerhard , Theurl Igor , Bornhäuser Martin , Platzbecker Uwe
Published: April 2023

Abstract
Purpose: Retrospective, surrogate marker–based studies have found inconsistent associations between systemic iron overload (SIO) and adverse outcome in patients undergoing allogeneic stem cell transplantation (allo-SCT). As a consequence, the impact of SIO in this context remains under debate. The aim of this study was to test whether the objective pretransplant quantification of liver-iron content (LIC) by magnetic resonance imaging (MRI) could circumvent these limitations and conclusively define the prognostic relevance of SIO.

Experimental Design: The correlation between pretransplant LIC and surrogate parameters as well as the impact of SIO on posttransplant outcome was assessed within an observational study of patients (n = 88) with either myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) undergoing allo-SCT.

Results: Ferritin levels of 1,000 ng/mL or more provided only poor specificity (31.8%) for predicting elevated LIC (≥125 μmol/g) and even higher thresholds (≥2,500 ng/mL) lacked an association with nonrelapse mortality (NRM). In contrast, LIC 125 μmol/g or more was a significant risk factor for NRM in uni- and multivariate analysis (HR = 2.98; P = 0.016). Multivariate Cox-regression further showed that LIC 125 μmol/g or more was associated with a decreased overall survival (HR = 2.24, P = 0.038), whereas ferritin or transfusion burden were not.

Conclusions: SIO reflected by LIC is an independent negative prognostic factor for posttransplant outcome in patients with AML and MDS undergoing allo-SCT. Therefore, MRI-based LIC, and not interference-prone serum markers such as ferritin, should be preferred for pretransplant risk stratification and patient selection in future clinical trials. Clin Cancer Res; 18(23); 6460–8. ©2012 AACR.
Data from Bevacizumab Preconditioning Followed by Etoposide and Cisplatin Is Highly Effective in Treating Brain Metastases of Breast Cancer Progressing from Whole-Brain Radiotherapy
Authors: Lu Yen-Shen , Chen Tom Wei-Wu , Lin Ching-Hung , Yeh Dah-Cherng , Tseng Ling-Ming , Wu Pei-Fang , Rau Kun-Ming , Chen Bang-Bin , Chao Ta-Chung , Huang Shu-Min , Huang Chiun-Sheng , Shih Tiffany Ting-Fang , Cheng Ann-Lii
Published: April 2023

Abstract
Purpose: We hypothesized that a window period between bevacizumab and cytotoxic agents may enhance drug delivery into tumor tissue through bevacizumab-induced vascular normalization in patients with brain metastases of breast cancer (BMBC).

Experimental Design: A single-arm phase II study was conducted in which BMBC patients refractory to whole-brain radiotherapy (WBRT) were enrolled. In a 21-day cycle, patients received bevacizumab (15 mg/kg) on day 1, which, with a 1-day window period, was followed by etoposide (70 mg/m2/day; days 2–4) and cisplatin (70 mg/m2; day 2; BEEP regimen). The BEEP regimen was administered for a maximum of 6 cycles. The primary endpoint was the central nervous system (CNS)–objective response rate according to volumetric response criteria.

Results: A total of 35 patients were enrolled between January 2011 and January 2013. The median age was 54.3 years (range, 33–75); 19 patients (54.3%) had an Eastern Cooperative Oncology Group performance status of 2 or 3. Twenty-seven patients [77.1%; 95% confidence interval (CI), 59.9–89.6] achieved a CNS-objective response, including 13 patients (37.1%) with a ≥80% volumetric reduction of CNS lesions. With a median follow-up of 16.1 months, the median CNS progression-free survival and overall survival times were 7.3 months (95% CI, 6.5–8.1) and 10.5 months (95% CI, 7.8–13.2), respectively. Common grade 3 or 4 toxicities included neutropenia (30.8%) and infection (21.3%).

Conclusions: By administering bevacizumab 1 day before etoposide and cisplatin, the BEEP regimen appeared highly effective in BMBC refractory to WBRT. Further study of vascular normalization window concept is warranted. Clin Cancer Res; 21(8); 1851–8. ©2015 AACR.
Data from Effects of Tumor Microenvironment Heterogeneity on Nanoparticle Disposition and Efficacy in Breast Cancer Tumor Models
Authors: Song Gina , Darr David B. , Santos Charlene M. , Ross Mark , Valdivia Alain , Jordan Jamie L. , Midkiff Bentley R. , Cohen Stephanie , Nikolaishvili-Feinberg Nana , Miller C. Ryan , Tarrant Teresa K. , Rogers Arlin B. , Dudley Andrew C. , Perou Charles M. , Zamboni William C.
Published: April 2023

Abstract
Purpose: Tumor cells are surrounded by a complex microenvironment. The purpose of our study was to evaluate the role of heterogeneity of the tumor microenvironment in the variability of nanoparticle (NP) delivery and efficacy.

Experimental Designs:C3(1)-T-Antigen genetically engineered mouse model (C3-TAg) and T11/TP53Null orthotopic syngeneic murine transplant model (T11) representing human breast tumor subtypes basal-like and claudin-low, respectively, were evaluated. For the pharmacokinetic studies, non-liposomal doxorubicin (NL-doxo) or polyethylene glycol tagged (PEGylated) liposomal doxorubicin (PLD) was administered at 6 mg/kg i.v. x1. Area under the concentration versus time curve (AUC) of doxorubicin was calculated. Macrophages, collagen, and the amount of vasculature were assessed by IHC. Chemokines and cytokines were measured by multiplex immunochemistry. NL-doxo or PLD was administered at 6 mg/kg i.v. weekly x6 in efficacy studies. Analyses of intermediary tumor response and overall survival were performed.

Results: Plasma AUC of NL-doxo and PLD encapsulated and released doxorubicin was similar between two models. However, tumor sum total AUC of PLD was 2-fold greater in C3-TAg compared with T11 (P < 0.05). T11 tumors showed significantly higher expression of CC chemokine ligand (CCL) 2 and VEGF-a, greater vascular quantity, and decreased expression of VEGF-c compared with C3-TAg (P < 0.05). PLD was more efficacious compared with NL-doxo in both models.

Conclusion: The tumor microenvironment and/or tumor cell features of breast cancer affected NP tumor delivery and efficacy, but not the small-molecule drug. Our findings reveal the role of the tumor microenvironment in variability of NP delivery and therapeutic outcomes. Clin Cancer Res; 20(23); 6083–95. ©2014 AACR.
Data from Intrinsic Resistance to JAK2 Inhibition in Myelofibrosis
Authors: Kalota Anna , Jeschke Grace R. , Carroll Martin , Hexner Elizabeth O.
Published: April 2023

Abstract
Purpose: Recent results have shown that myeloproliferative neoplasms (MPN) are strongly associated with constitutive activation of the Janus-activated kinase (JAK)2 tyrosine kinase. However, JAK2 inhibitors currently approved or under development for treating myeloproliferative neoplasms do not selectively deplete the malignant clone, and the inhibition of activity of the drug target (JAK2) has not been rigorously evaluated in the clinical studies. Therefore, in this study we developed an in vitro assay to gain insight into how effectively JAK2 activity is inhibited in the samples of patients.

Experimental Design: We treated primary cells from normal donors and patients with MPN with JAK2 inhibitors and measured phosphorylation of downstream targets STAT5 and STAT3 by flow cytometry. Obtained results were next correlated with JAK2 V617F allele burden and plasma cytokine level.

Results: We observed a dose-dependent decrease in pSTAT5 and pSTAT3 in ex vivo treated granulocytes. However, phosphorylation of STAT3 and STAT5 in cells from patients with myelofibrosis was significantly less inhibited when compared with cells from patients with polycythemia vera, essential thrombocythemia, and normal donors. Sensitivity to inhibition did not correlate with JAK2 V617F clonal burden. Mixing studies using plasma from patients with myelofibrosis did not transfer resistance to sensitive cells. Likewise, no single cytokine measured seemed to account for the observed pattern of resistance.

Conclusions:Taken together, these observations suggest that there are cell intrinsic mechanisms that define a priori resistance to JAK2 inhibition in myelofibrosis, and the lesion is localized upstream of STAT3 and STAT5. Clin Cancer Res; 19(7); 1729–39. ©2013 AACR.
Data from Noninvasive Diagnosis of Actionable Mutations by Deep Sequencing of Circulating Free DNA in Lung Cancer from Never-Smokers: A Proof-of-Concept Study from BioCAST/IFCT-1002
Authors: Couraud Sébastien , Vaca-Paniagua Felipe , Villar Stéphanie , Oliver Javier , Schuster Tibor , Blanché Hélène , Girard Nicolas , Trédaniel Jean , Guilleminault Laurent , Gervais Radj , Prim Nathalie , Vincent Michel , Margery Jacques , Larivé Sébastien , Foucher Pascal , Duvert Bernard , Vallee Maxime , Le Calvez-Kelm Florence , McKay James , Missy Pascale , Morin Franck , Zalcman Gérard , Olivier Magali , Souquet Pierre-Jean
Published: April 2023

Abstract
Purpose: Tumor somatic mutation analysis is part of the standard management of metastatic lung cancer. However, physicians often have to deal with small biopsies and consequently with challenging mutation testing. Circulating free DNA (cfDNA) is a promising tool for accessing the tumor genome as a liquid biopsy. Here, we evaluated next-generation sequencing (NGS) on cfDNA samples obtained from a consecutive series of patients for the screening of a range of clinically relevant mutations.

Experimental Design: A total of 107 plasma samples were collected from the BioCAST/IFCT-1002 lung cancer study (never-smokers cohort). Matched tumor DNA (tDNA) was obtained for 68 cases. Multiplex PCR-based assays were designed to target specific coding regions in EGFR, KRAS, BRAF, ERBB2, and PI3KCA genes, and amplicon sequencing was performed at deep coverage on the cfDNA/tDNA pairs using the NGS IonTorrent Personal Genome Machine Platform.

Results: CfDNA concentration in plasma was significantly associated with both stage and number of metastatic sites. In tDNA, 50 mutations (36 EGFR, 5 ERBB2, 4 KRAS, 3 BRAF, and 2 PIK3CA) were identified, of which 26 were detected in cfDNA. Sensitivity of the test was 58% (95% confidence interval, 43%–71%) and the estimated specificity was 87% (62%–96%).

Conclusion: These data demonstrate the feasibility and potential utility of mutation screening in cfDNA using IonTorrent NGS for the detection of a range of tumor biomarkers in patients with metastatic lung cancer. Clin Cancer Res; 20(17); 4613–24. ©2014 AACR.
Data from Evaluation of Diffusion-Weighted MRI for Pretherapeutic Assessment and Staging of Lymphoma: Results of a Prospective Study in 140 Patients
Authors: Mayerhoefer Marius E. , Karanikas Georgios , Kletter Kurt , Prosch Helmut , Kiesewetter Barbara , Skrabs Cathrin , Porpaczy Edit , Weber Michael , Pinker-Domenig Katja , Berzaczy Dominik , Hoffmann Martha , Sillaber Christian , Jaeger Ulrich , Müllauer Leonhard , Simonitsch-Klupp Ingrid , Dolak Werner , Gaiger Alexander , Ubl Philipp , Lukas Julius , Raderer Markus
Published: April 2023

Abstract
Purpose: To determine the value of diffusion-weighted MRI (DWI-MRI) for pretherapeutic imaging of fluorodeoxyglucose (FDG)-avid lymphoma and lymphoma with variable FDG avidity.

Experimental Design: Treatment-naïve patients with lymphoma who were referred for whole-body staging were included in this prospective study. Group A included patients with FDG-avid lymphoma (e.g., Hodgkin, diffuse large B-cell, and follicular lymphoma), whereas Group B included patients with lymphoma of variable FDG avidity [e.g., extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT)]. All patients underwent DWI-MRI and 18F-FDG- positron emission tomography/computed tomography (PET/CT). Region-based sensitivity and agreement with Ann Arbor staging, relative to the reference standard, were calculated for DWI-MRI, and, in Group B, also 18F-FDG-PET/CT and contrast-enhanced (CE-) CT.

Results: In Group A (100 patients), DWI-MRI had a region-based sensitivity of 97%, and with regard to staging, agreed with the reference standard in 94 of 100 patients (κ, 0.92). In Group B (40 patients; 38 MALT lymphomas and 2 small lymphocytic lymphomas/chronic lymphocytic leukemias), DWI-MRI, 18F-FDG-PET/CT, and CE-CT had region-based sensitivities of 94.4%, 60.9%, and 70.7%, respectively. With regard to staging in Group B, DWI-MRI, 18F-FDG-PET/CT, and CE-CT agreed with the reference standard in 37 of 40, 26 of 40, and 24 of 40 patients, with κ values of 0.89, 0.52, and 0.43, respectively.

Conclusions: In patients with FDG-avid lymphoma, DWI-MRI seems to be only slightly inferior to 18F-FDG-PET/CT with regard to pretherapeutic regional assessment and staging. In patients with lymphoma subtypes that show a variable FDG avidity (e.g., MALT lymphoma), DWI-MRI seems to be superior to both 18F-FDG-PET/CT and CE-CT. Clin Cancer Res; 20(11); 2984–93. ©2014 AACR.
Data from OX40+ Regulatory T Cells in Cutaneous Squamous Cell Carcinoma Suppress Effector T-Cell Responses and Associate with Metastatic Potential
Authors: Lai Chester , August Suzannah , Albibas Amel , Behar Ramnik , Cho Shin-Young , Polak Marta E. , Theaker Jeffrey , MacLeod Amanda S. , French Ruth R. , Glennie Martin J. , Al-Shamkhani Aymen , Healy Eugene
Published: April 2023

Abstract
Purpose: Cutaneous squamous cell carcinoma (cSCC) is the most common human cancer with metastatic potential. Despite T cells accumulating around cSCCs, these tumors continue to grow and persist. To investigate reasons for failure of T cells to mount a protective response in cSCC, we focused on regulatory T cells (Tregs) as this suppressive population is well represented among the infiltrating lymphocytes.

Experimental Design: Flow cytometry was conducted on cSCC lymphocytes and in vitro functional assays were performed using sorted tumoral T cells. Lymphocyte subsets in primary cSCCs were quantified immunohistochemically.

Results: FOXP3+ Tregs were more frequent in cSCCs than in peripheral blood (P < 0.0001, n = 86 tumors). Tumoral Tregs suppressed proliferation of tumoral effector CD4+ (P = 0.005, n = 10 tumors) and CD8+ T cells (P = 0.043, n = 9 tumors) and inhibited IFNγ secretion by tumoral effector T cells (P = 0.0186, n = 11 tumors). The costimulatory molecule OX40 was expressed predominantly on tumoral Tregs (P < 0.0001, n = 15 tumors) and triggering OX40 with an agonist anti-OX40 antibody overcame the suppression exerted by Tregs, leading to increased tumoral effector CD4+ lymphocyte proliferation (P = 0.0098, n = 10 tumors). Tregs and OX40+ lymphocytes were more abundant in primary cSCCs that metastasized than in primary cSCCs that had not metastasized (n = 48 and n = 49 tumors, respectively).

Conclusions: Tregs in cSCCs suppress effector T-cell responses and are associated with subsequent metastasis, suggesting a key role for Tregs in cSCC development and progression. OX40 agonism reversed the suppressive effects of Tregs in vitro, suggesting that targeting OX40 could benefit the subset of cSCC patients at high risk of metastasis. Clin Cancer Res; 22(16); 4236–48. ©2016 AACR.
Data from Enumeration and Molecular Characterization of Tumor Cells in Lung Cancer Patients Using a Novel In Vivo Device for Capturing Circulating Tumor Cells
Authors: Gorges Tobias M. , Penkalla Nicole , Schalk Thomas , Joosse Simon A. , Riethdorf Sabine , Tucholski Johannes , Lücke Klaus , Wikman Harriet , Jackson Stephen , Brychta Nora , von Ahsen Oliver , Schumann Christian , Krahn Thomas , Pantel Klaus
Published: April 2023

Abstract
Purpose: The use of circulating tumor cells (CTC) as “liquid biopsy” is limited by the very low yield of CTCs available for subsequent analyses. Most in vitro approaches rely on small sample volumes (5–10 mL).

Experimental Design: Here, we used a novel approach, the GILUPI CellCollector, which enables an in vivo isolation of CTCs from peripheral blood. In total, 50 lung cancer patients were screened in two subsequent device applications before and after therapy (n = 185 applications).

Results: By in vivo isolation, 58% (108/185) of the patients were positive for ≥1 CTC (median, 5 CTCs; range, 1–56 cells) as compared with 27% (23/84; range, 1–300 cells) using the FDA-cleared CellSearch system. Furthermore, we could show that treatment response during therapy was associated with significant decreases in CTC counts (P = 0.001). By dPCR, mutations in the KRAS and EGFR genes relevant for treatment decisions could be detected in CTCs captured by in vivo isolation and confirmed in the primary tumors of the same patients.

Conclusions: In vivo isolation of CTCs overcomes blood volume limitations of other approaches, which might help to implement CTC-based “liquid biopsies” into clinical decision making. Clin Cancer Res; 22(9); 2197–206. ©2015 AACR.
Data from A Phase I Study of the Anti-Activin Receptor-Like Kinase 1 (ALK-1) Monoclonal Antibody PF-03446962 in Patients with Advanced Solid Tumors
Authors: Goff Laura W. , Cohen Roger B. , Berlin Jordan D. , de Braud Filippo G. , Lyshchik Andrej , Noberasco Cristina , Bertolini Francesco , Carpentieri Marina , Stampino Corrado Gallo , Abbattista Antonello , Wang Erjan , Borghaei Hossein
Published: April 2023

Abstract
Purpose: Objectives of this dose-finding study were to determine the MTD and recommended phase II dose (RP2D) of the first-in-class anti-activin receptor-like kinase 1 (ALK-1) monoclonal antibody PF-03446962, and assess safety and antitumor activity in patients with advanced solid tumors.

Experimental Design: This open-label, multicenter study was based on a 3+3 design. PF-03446962 was administered biweekly by intravenous infusion, at doses ranging from 0.5 to 15 mg/kg.

Results: Forty-four patients received treatment with PF-03446962. Dose-limiting toxicities observed during dose escalation included grade 3 increased amylase, grade 3/4 increased lipase, and grade 3/4 thrombocytopenia. The MTD was determined to be 10 mg/kg. The RP2D was set at 7 mg/kg for patients with advanced solid tumors, based on the observed safety, pharmacokinetics, and antitumor activity. The most-frequent treatment-related, all-grade adverse events included thrombocytopenia (20.5%), fatigue (15.9%), and nausea, increased amylase, and increased lipase (each 11.4%). Treatment-related telangiectasia was noted in 7% of patients, suggesting in vivo inhibition of the ALK-1 pathway. None of the deaths was deemed to be treatment-related. Three (6.8%) patients with advanced hepatocellular carcinoma, renal cell carcinoma, or non–small cell lung cancer achieved a partial response, and 12 (27.3%) patients had stable disease, across dose levels. Contrast-enhanced ultrasound analysis of tumor vascularity showed reduction in tumor perfusion in 2 patients with stable disease following treatment with PF-03446962.

Conclusions: The clinical activity demonstrated in this study points to PF-03446962 as a novel approach to antiangiogenic therapy, with manageable safety profile and single-agent, antitumor activity in patients with advanced solid tumors. Clin Cancer Res; 22(9); 2146–54. ©2015 AACR.
Data from A Phase Ib/II Study of Afatinib in Combination with Nimotuzumab in Non–Small Cell Lung Cancer Patients with Acquired Resistance to Gefitinib or Erlotinib
Authors: Lee Ji Yun , Sun Jong-Mu , Lim Sung Hee , Kim Hae Su , Yoo Kwai Han , Jung Ki Sun , Song Haa-Na , Ku Bo Mi , Koh Jiae , Bae Yeon-Hee , Lee Se-Hoon , Ahn Jin Seok , Park Keunchil , Ahn Myung-Ju
Published: April 2023

Abstract
Purpose: In this phase Ib/II study, we aimed to assess the safety and efficacy of afatinib plus nimotuzumab (N) in advanced non–small cell lung cancer (NSCLC) patients with acquired resistance to gefitinib or erlotinib.

Experimental Design: In phase Ib stage, patients received afatinib (40 mg or 30 mg once daily) plus nimotuzumab (100 mg or 200 mg once weekly) for 28-day cycles to determine the recommended phase II dose (RPIID). The safety and efficacy of RPIID dose was evaluated in phase II stage.

Results: In total, 50 patients were enrolled (13 to phase Ib and 37 to phase II). In the first dose-finding cohort (afatinib 40 mg plus nimotuzumab 100 mg), one patient experienced dose-limiting toxicity (DLT) of grade 3 diarrhea and in the subsequent cohort (afatinib 40 mg plus nimotuzumab 200 mg), two DLTs (grade 3 diarrhea and grade 3 neutropenia) occurred in 2 of 6 patients. Accordingly, RPIID was determined as afatinib 40 mg plus nimotuzumab 100 mg. In 44 patients treated with RPIID, 7 (16%) patients had grade 3 toxicities; skin rash (7%), diarrhea (5%), acne (2%), and fatigue (2%). The overall response rate was 23% and the median duration of response was 4.3 months (range, 0.7–16.2 months). The median progression-free survival and overall survival were 4.0 months [95% confidence interval (CI), 2.3–5.7 months] and 11.7 months (95% CI, 9.4–14.0 months), respectively.

Conclusions: Combination treatment of afatinib and nimotuzumab demonstrated an acceptable safety profile and encouraging antitumor activity in advanced NSCLC patients with acquired resistance to gefitinib or erlotinib. Larger phase III trial is warranted to confirm its efficacy and safety. Clin Cancer Res; 22(9); 2139–45. ©2015 AACR.
Data from A Novel Carcinoembryonic Antigen T-Cell Bispecific Antibody (CEA TCB) for the Treatment of Solid Tumors
Authors: Bacac Marina , Fauti Tanja , Sam Johannes , Colombetti Sara , Weinzierl Tina , Ouaret Djamila , Bodmer Walter , Lehmann Steffi , Hofer Thomas , Hosse Ralf J. , Moessner Ekkehard , Ast Oliver , Bruenker Peter , Grau-Richards Sandra , Schaller Teilo , Seidl Annette , Gerdes Christian , Perro Mario , Nicolini Valeria , Steinhoff Nathalie , Dudal Sherri , Neumann Sebastian , von Hirschheydt Thomas , Jaeger Christiane , Saro Jose , Karanikas Vaios , Klein Christian , Umaña Pablo
Published: April 2023

Abstract
Purpose: CEA TCB is a novel IgG-based T-cell bispecific (TCB) antibody for the treatment of CEA-expressing solid tumors currently in phase I clinical trials (NCT02324257). Its format incorporates bivalent binding to CEA, a head-to-tail fusion of CEA- and CD3e-binding Fab domains and an engineered Fc region with completely abolished binding to FcγRs and C1q. The study provides novel mechanistic insights into the activity and mode of action of CEA TCB.

Experimental Design: CEA TCB activity was characterized on 110 cell lines in vitro and in xenograft tumor models in vivo using NOG mice engrafted with human peripheral blood mononuclear cells.

Results: Simultaneous binding of CEA TCB to tumor and T cells leads to formation of immunologic synapses, T-cell activation, secretion of cytotoxic granules, and tumor cell lysis. CEA TCB activity strongly correlates with CEA expression, with higher potency observed in highly CEA-expressing tumor cells and a threshold of approximately 10,000 CEA-binding sites/cell, which allows distinguishing between high- and low-CEA–expressing tumor and primary epithelial cells, respectively. Genetic factors do not affect CEA TCB activity confirming that CEA expression level is the strongest predictor of CEA TCB activity. In vivo, CEA TCB induces regression of CEA-expressing xenograft tumors with variable amounts of immune cell infiltrate, leads to increased frequency of activated T cells, and converts PD-L1 negative into PD-L1–positive tumors.

Conclusions: CEA TCB is a novel generation TCB displaying potent antitumor activity; it is efficacious in poorly infiltrated tumors where it increases T-cell infiltration and generates a highly inflamed tumor microenvironment. Clin Cancer Res; 22(13); 3286–97. ©2016 AACR.
Data from A HGF/cMET Autocrine Loop Is Operative in Multiple Myeloma Bone Marrow Endothelial Cells and May Represent a Novel Therapeutic Target
Authors: Ferrucci Arianna , Moschetta Michele , Frassanito Maria Antonia , Berardi Simona , Catacchio Ivana , Ria Roberto , Racanelli Vito , Caivano Antonella , Solimando Antonio Giovanni , Vergara Daniele , Maffia Michele , Latorre Dominga , Rizzello Antonia , Zito Alfredo , Ditonno Paolo , Maiorano Eugenio , Ribatti Domenico , Vacca Angelo
Published: April 2023

Abstract
Purpose: The aim of this study was to investigate the angiogenic role of the hepatocyte growth factor (HGF)/cMET pathway and its inhibition in bone marrow endothelial cells (EC) from patients with multiple myeloma versus from patients with monoclonal gammopathy of undetermined significance (MGUS) or benign anemia (control group).

Experimental Design: The HGF/cMET pathway was evaluated in ECs from patients with multiple myeloma (multiple myeloma ECs) at diagnosis, at relapse after bortezomib- or lenalidomide-based therapies, or on refractory phase to these drugs; in ECs from patients with MGUS (MGECs); and in those patients from the control group. The effects of a selective cMET tyrosine kinase inhibitor (SU11274) on multiple myeloma ECs' angiogenic activities were studied in vitro and in vivo.

Results: Multiple myeloma ECs express more HGF, cMET, and activated cMET (phospho (p)-cMET) at both RNA and protein levels versus MGECs and control ECs. Multiple myeloma ECs are able to maintain the HGF/cMET pathway activation in absence of external stimulation, whereas treatment with anti-HGF and anti-cMET neutralizing antibodies (Ab) is able to inhibit cMET activation. The cMET pathway regulates several multiple myeloma EC activities, including chemotaxis, motility, adhesion, spreading, and whole angiogenesis. Its inhibition by SU11274 impairs these activities in a statistically significant fashion when combined with bortezomib or lenalidomide, both in vitro and in vivo.

Conclusions: An autocrine HGF/cMET loop sustains multiple myeloma angiogenesis and represents an appealing new target to potentiate the antiangiogenic management of patients with multiple myeloma. Clin Cancer Res; 20(22); 5796–807. ©2014 AACR.
Data from Phase II Study of Perifosine and Sorafenib Dual-Targeted Therapy in Patients with Relapsed or Refractory Lymphoproliferative Diseases
Authors: Guidetti Anna , Carlo-Stella Carmelo , Locatelli Silvia L. , Malorni Walter , Mortarini Roberta , Viviani Simonetta , Russo Domenico , Marchianò Alfonso , Sorasio Roberto , Dodero Anna , Farina Lucia , Giordano Laura , Di Nicola Massimo , Anichini Andrea , Corradini Paolo , Gianni Alessandro M.
Published: April 2023

Abstract
Purpose: To evaluate safety and activity of perifosine and sorafenib combination therapy in patients with lymphoproliferative diseases.

Experimental Design: Patients with relapsed and refractory lymphoproliferative diseases received perifosine (50 mg twice daily) for 1 month. Patients achieving less than partial response (PR) after perifosine alone were administered the combination therapy [perifosine plus sorafenib (400 mg twice daily)] until progressive disease (PD) or unacceptable toxicity occurred. The pERK and pAKT in peripheral blood lymphocytes as well as serum cytokine levels were investigated as predictive biomarkers of response.

Results: Forty patients enrolled in this study. After 1 month of perifosine alone, 36 who achieved less than PR went on to combination therapy, whereas four patients with chronic lymphocytic leukemia (CLL) who achieved PR continued with perifosine alone for a median of 10 months (range, 4–21). The most common drug-related toxicities were grade 1–2 anemia (17%), thrombocytopenia (9%), diarrhea (25%), joint pain (22%), and hand–foot skin reaction (25%). Three patients experienced grade 3 pneumonitis. Eight patients (22%) achieved PR, 15 (42%) achieved stable disease, and 13 (36%) experienced PD. A 28% PR rate was recorded for 25 patients with Hodgkin lymphoma. Among all patients, median overall survival and progression-free survival were 16 and 5 months, respectively. Early reductions in pERK and pAKT significantly correlated with the probability of clinical response.

Conclusions: Perifosine and sorafenib combination therapy is feasible with manageable toxicity and demonstrates promising activity in patients with Hodgkin lymphoma. The predictive value of pERK and pAKT should be confirmed in a larger patient cohort. Clin Cancer Res; 20(22); 5641–51. ©2014 AACR.
Data from Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer
Authors: Telli Melinda L. , Timms Kirsten M. , Reid Julia , Hennessy Bryan , Mills Gordon B. , Jensen Kristin C. , Szallasi Zoltan , Barry William T. , Winer Eric P. , Tung Nadine M. , Isakoff Steven J. , Ryan Paula D. , Greene-Colozzi April , Gutin Alexander , Sangale Zaina , Iliev Diana , Neff Chris , Abkevich Victor , Jones Joshua T. , Lanchbury Jerry S. , Hartman Anne-Renee , Garber Judy E. , Ford James M. , Silver Daniel P. , Richardson Andrea L.
Published: April 2023

Abstract
Purpose:BRCA1/2-mutated and some sporadic triple-negative breast cancers (TNBC) have DNA repair defects and are sensitive to DNA-damaging therapeutics. Recently, three independent DNA-based measures of genomic instability were developed on the basis of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST).

Experimental Design: We assessed a combined homologous recombination deficiency (HRD) score, an unweighted sum of LOH, TAI, and LST scores, in three neoadjuvant TNBC trials of platinum-containing therapy. We then tested the association of HR deficiency, defined as HRD score ≥42 or BRCA1/2 mutation, with response to platinum-based therapy.

Results: In a trial of neoadjuvant platinum, gemcitabine, and iniparib, HR deficiency predicted residual cancer burden score of 0 or I (RCB 0/I) and pathologic complete response (pCR; OR = 4.96, P = 0.0036; OR = 6.52, P = 0.0058). HR deficiency remained a significant predictor of RCB 0/I when adjusted for clinical variables (OR = 5.86, P = 0.012). In two other trials of neoadjuvant cisplatin therapy, HR deficiency predicted RCB 0/I and pCR (OR = 10.18, P = 0.0011; OR = 17.00, P = 0.0066). In a multivariable model of RCB 0/I, HR deficiency retained significance when clinical variables were included (OR = 12.08, P = 0.0017). When restricted to BRCA1/2 nonmutated tumors, response was higher in patients with high HRD scores: RCB 0/I P = 0.062, pCR P = 0.063 in the neoadjuvant platinum, gemcitabine, and iniparib trial; RCB 0/I P = 0.0039, pCR P = 0.018 in the neoadjuvant cisplatin trials.

Conclusions: HR deficiency identifies TNBC tumors, including BRCA1/2 nonmutated tumors more likely to respond to platinum-containing therapy. Clin Cancer Res; 22(15); 3764–73. ©2016 AACR.
Data from Relationship between Tumor Biomarkers and Efficacy in EMILIA, a Phase III Study of Trastuzumab Emtansine in HER2-Positive Metastatic Breast Cancer
Authors: Baselga José , Lewis Phillips Gail D. , Verma Sunil , Ro Jungsil , Huober Jens , Guardino Alice E. , Samant Meghna K. , Olsen Steve , de Haas Sanne L. , Pegram Mark D.
Published: April 2023

Abstract
Purpose: HER2-positive breast cancer is heterogeneous. Some tumors express mutations, like activating PIK3CA mutations or reduced PTEN expression, that negatively correlate with response to HER2-targeted therapies. In this exploratory analysis, we investigated whether the efficacy of trastuzumab emtansine (T-DM1), an antibody–drug conjugate comprised of the cytotoxic agent DM1 linked to the HER2-targeted antibody trastuzumab, was correlated with the expression of specific biomarkers in the phase III EMILIA study.

Experimental Design: Tumors were evaluated for HER2 (n = 866), EGFR (n = 832), and HER3 (n = 860) mRNA expression by quantitative reverse transcriptase PCR; for PTEN protein expression (n = 271) by IHC; and for PIK3CA mutations (n = 259) using a mutation detection kit. Survival outcomes were analyzed by biomarker subgroups. T-DM1 was also tested on cell lines and in breast cancer xenograft models containing PIK3CA mutations.

Results: Longer progression-free survival (PFS) and overall survival (OS) were observed with T-DM1 compared with capecitabine plus lapatinib in all biomarker subgroups. PIK3CA mutations were associated with shorter median PFS (mutant vs. wild type: 4.3 vs. 6.4 months) and OS (17.3 vs. 27.8 months) in capecitabine plus lapatinib–treated patients, but not in T-DM1–treated patients (PFS, 10.9 vs. 9.8 months; OS, not reached in mutant or wild type). T-DM1 showed potent activity in cell lines and xenograft models with PIK3CA mutations.

Conclusions: Although other standard HER2-directed therapies are less effective in tumors with PI3KCA mutations, T-DM1 appears to be effective in both PI3KCA-mutated and wild-type tumors. Clin Cancer Res; 22(15); 3755–63. ©2016 AACR.
Data from Phase II Study of Nilotinib in Melanoma Harboring KIT Alterations Following Progression to Prior KIT Inhibition
Authors: Carvajal Richard D. , Lawrence Donald P. , Weber Jeffrey S. , Gajewski Thomas F. , Gonzalez Rene , Lutzky Jose , O'Day Steven J. , Hamid Omid , Wolchok Jedd D. , Chapman Paul B. , Sullivan Ryan J. , Teitcher Jerrold B. , Ramaiya Nikhil , Giobbie-Hurder Anita , Antonescu Cristina R. , Heinrich Michael C. , Bastian Boris C. , Corless Christopher L. , Fletcher Jonathan A. , Hodi F. Stephen
Published: April 2023

Abstract
Purpose: Although durable responses can be achieved with tyrosine kinase inhibitors such as imatinib in melanomas harboring KIT mutations, the efficacy of alternative inhibitors after progression to imatinib and the activity of these agents on brain metastases are unknown.

Experimental Design: We conducted a phase II study of nilotinib 400 mg twice a day in two cohorts of patients with melanomas harboring KIT mutations or amplification: (A) those refractory or intolerant to a prior KIT inhibitor; and (B) those with brain metastases. The primary endpoint was 4-month disease control rate. Secondary endpoints included response rate, time-to-progression (TTP), and overall survival (OS). A Simon two-stage and a single-stage design was planned to assess for the primary endpoint in cohorts A and B, respectively.

Results: Twenty patients were enrolled and 19 treated (11 in cohort A; 8 in cohort B). Three patients on cohort A [27%; 95% confidence interval (CI), 8%–56%] and 1 on cohort B (12.5%; 90% CI, 0.6%–47%) achieved the primary endpoint. Two partial responses were observed in cohort A (18.2%; 90% CI, 3%–47%); none were observed in cohort B. The median TTP and OS was 3.3 (90% CI, 2.1–3.9 months) and 9.1 months (90% CI, 4.3–14.2 months), respectively, in all treated patients.

Conclusions: Nilotinib may achieve disease control in patients with melanoma harboring KIT alterations and whose disease progressed after imatinib therapy. The efficacy of this agent in KIT-altered melanoma with brain metastasis is limited. Clin Cancer Res; 21(10); 2289–96. ©2015 AACR.
Data from Are Doses and Schedules of Small-Molecule Targeted Anticancer Drugs Recommended by Phase I Studies Realistic?
Authors: Roda Desamparados , Jimenez Begoña , Banerji Udai
Published: April 2023

Abstract
Tolerability of molecularly targeted agents (MTA) used in cancer therapeutics is determined in phase I trials. We reviewed the reported incidence of toxicity in phase III trials at doses and schedules recommended by phase I trials to evaluate whether these recommendations are realistic when drugs are used in larger populations of patients. We systematically reviewed a safety profile of small molecule (SM-MTA) and mAb MTA (MA-MTA) approved by the FDA in the last 12 years. There was a significantly increased percentage of grade 3 or 4 adverse events reported with SM-MTA compared with MA-MTA [40% vs. 27%; RR 1.5; 95% confidence interval (CI), 1.10–2.25, P = 0.038] in phase III studies. Importantly, a substantial proportion of patients (45%) treated with SM-MTA required dose modifications due to drug-related toxicity in phase III trials. However, this toxicity was associated to a definitive study drug discontinuation in only 9%. Overall, 25% of SM-MTA declared recommended phase II doses below MTD based on pharmacokinetic–pharmacodynamic data and these trials were associated with a significantly reduced number of dose modifications in registration trials (32% vs. 50%; RR 0.64; 95% CI, 0.43–0.88, P = 0.01). Tolerability is going to come into further focus due to the need for combinations of SM-MTA and other anticancer agents. There was a higher incidence of grade 3–4 toxicity in phase III trials in combinations versus single-agent SM-MTAs (64% vs. 37%; RR 1.73; 95% CI, 1.3–2.3, P = 0.001). These results indicate that phase I studies underestimate toxicity while recommending doses of SM-MTA. Clin Cancer Res; 22(9); 2127–32. ©2015 AACR.