bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Long-Term Efficacy, Survival, and Safety of [177Lu-DOTA0,Tyr3]octreotate in Patients with Gastroenteropancreatic and Bronchial Neuroendocrine Tumors
Authors: Brabander Tessa , van der Zwan Wouter A. , Teunissen Jaap J.M. , Kam Boen L.R. , Feelders Richard A. , de Herder Wouter W. , van Eijck Casper H.J. , Franssen Gaston J.H. , Krenning Eric P. , Kwekkeboom Dik J.
Published: April 2023

Abstract
Purpose: Bronchial and gastroenteropancreatic neuroendocrine tumors (NET) are slow-growing tumors, which frequently express somatostatin receptors on their cell membranes. These receptors are targets for therapy with Lutetium-177–labeled somatostatin analogues. We have treated over 1,200 patients with peptide receptor radionuclide therapy (PRRT) with [177Lu-DOTA0,Tyr3]octreotate (177Lu-DOTATATE) since the year 2000 and present the results on efficacy, survival, and toxicity of this therapy.

Experimental Design: For safety analysis, 610 patients treated with a cumulative dose of at least 100 mCi (3.7 GBq) 177Lu-DOTATATE were included. A subgroup of 443 Dutch patients who were treated with a cumulative dose of at least 600 mCi (22.2 GBq) 177Lu-DOTATATE before 2013 was further analyzed for efficacy and survival.

Results: The objective response rate of the total group of patients was 39%. Stable disease was reached in 43% of patients. Progression-free survival (PFS) and overall survival (OS) for all NET patients were 29 months [95% confidence interval (CI), 26–33 months] and 63 months (95% CI, 55–72 months). Long-term toxicity included acute leukemia in four patients (0.7%) and myelodysplastic syndrome in nine patients (1.5%). No therapy-related long-term renal or hepatic failure occurred.

Conclusions: PRRT with 177Lu-DOTATATE is a favorable therapeutic option in patients with metastatic bronchial and gastroenteropancreatic NETs that express somatostatin receptors. PRRT with 177Lu-DOTATATE is safe with few side-effects and shows good response rates with PFS of 29 months and OS of 63 months. Clin Cancer Res; 23(16); 4617–24. ©2017 AACR.
Data from Tumor BRCA1 Reversion Mutation Arising during Neoadjuvant Platinum-Based Chemotherapy in Triple-Negative Breast Cancer Is Associated with Therapy Resistance
Authors: Afghahi Anosheh , Timms Kirsten M. , Vinayak Shaveta , Jensen Kristin C. , Kurian Allison W. , Carlson Robert W. , Chang Pei-Jen , Schackmann Elizabeth , Hartman Anne-Renee , Ford James M. , Telli Melinda L.
Published: April 2023

Abstract
Purpose: In germline BRCA1 or BRCA2 (BRCA1/2) mutation carriers, restoration of tumor BRCA1/2 function by a secondary mutation is recognized as a mechanism of resistance to platinum and PARP inhibitors, primarily in ovarian cancer. We evaluated this mechanism of resistance in newly diagnosed patients with BRCA1/2-mutant breast cancer with poor response to neoadjuvant platinum-based therapy.

Experimental Design: PrECOG 0105 was a phase II neoadjuvant study of gemcitabine, carboplatin, and iniparib in patients with stage I–IIIA triple-negative or BRCA1/2 mutation–associated breast cancer (n = 80). All patients underwent comprehensive BRCA1/2 genotyping. For mutation carriers with moderate or extensive residual disease after neoadjuvant therapy, BRCA1/2 status was resequenced in the residual surgical breast tumor tissue.

Results: Nineteen patients had a deleterious germline BRCA1/2 mutation, and four had moderate residual disease at surgery. BRCA1/2 sequencing of residual tissue was performed on three patients. These patients had BRCA1 1479delAG, 3374insGA, and W1712X mutations, respectively, with LOH at these loci in the pretreatment tumors. In the first case, a new BRCA1 mutation was detected in the residual disease. This resulted in a 14–amino acid deletion and restoration of the BRCA1 reading frame. A local relapse biopsy 4 months later revealed the identical reversion mutation, and the patient subsequently died from metastatic breast cancer.

Conclusions: We report a BRCA1 reversion mutation in a patient newly diagnosed with triple-negative breast cancer that developed over 18 weeks of platinum-based neoadjuvant therapy. This was associated with poor therapy response, early relapse, and death. Clin Cancer Res; 23(13); 3365–70. ©2017 AACR.
Data from An Open-Label, Dose–Escalation Phase I Study of Anti-TYRP1 Monoclonal Antibody IMC-20D7S for Patients with Relapsed or Refractory Melanoma
Authors: Khalil Danny N. , Postow Michael A. , Ibrahim Nageatte , Ludwig Dale L. , Cosaert Jan , Kambhampati Siva Rama Prasad , Tang Shande , Grebennik Dmitri , Kauh John Sae Wook , Lenz Heinz-Josef , Flaherty Keith T. , Hodi F. Stephen , Lawrence Donald P. , Wolchok Jedd D.
Published: April 2023

Abstract
Purpose: Tyrosinase-related protein-1 (TYRP1) is a transmembrane glycoprotein that is specifically expressed in melanocytes and melanoma cells. Preclinical data suggest that mAbs targeting TYRP1 confer antimelanoma activity. IMC-20D7S is a recombinant human IgG1 mAb targeting TYRP1. Here, we report the first-in-human phase I/Ib trial of IMC-20D7S.

Experimental Design: The primary objective of this study was to establish the safety profile and the MTD of IMC-20D7S. Patients with advanced melanoma who progressed after or during at least one line of treatment or for whom standard therapy was not indicated enrolled in this standard 3 + 3 dose–escalation, open-label study. IMC-20D7S was administered intravenously every 2 or 3 weeks.

Results: Twenty-seven patients were enrolled. The most common adverse events were fatigue and constipation experienced by nine (33%) and eight (30%) patients, respectively. There were no serious adverse events related to treatment, no discontinuations of treatment due to adverse events, and no treatment-related deaths. Given the absence of dose-limiting toxicities, an MTD was not defined, but a provisional MTD was established at the 20 mg/kg every 2-week dose based on serum concentration and safety data. One patient experienced a complete response. A disease control rate, defined as stable disease or better, of 41% was observed.

Conclusion: IMC-20D7S is well tolerated among patients with advanced melanoma with evidence of antitumor activity. Further investigation of this agent as monotherapy in selected patients or as part of combination regimens is warranted. Clin Cancer Res; 22(21); 5204–10. ©2016 AACR.
Data from Tumor-Specific Uptake of Fluorescent Bevacizumab–IRDye800CW Microdosing in Patients with Primary Breast Cancer: A Phase I Feasibility Study
Authors: Lamberts Laetitia E. , Koch Maximillian , de Jong Johannes S. , Adams Arthur L.L. , Glatz Jürgen , Kranendonk Mariëtte E.G. , Terwisscha van Scheltinga Anton G.T. , Jansen Liesbeth , de Vries Jakob , Lub-de Hooge Marjolijn N. , Schröder Carolien P. , Jorritsma-Smit Annelies , Linssen Matthijs D. , de Boer Esther , van der Vegt Bert , Nagengast Wouter B. , Elias Sjoerd G. , Oliveira Sabrina , Witkamp Arjen J. , Mali Willem P.Th.M. , Van der Wall Elsken , van Diest Paul J. , de Vries Elisabeth G.E. , Ntziachristos Vasilis , van Dam Gooitzen M.
Published: April 2023

Abstract
Purpose: To provide proof of principle of safety, breast tumor–specific uptake, and positive tumor margin assessment of the systemically administered near-infrared fluorescent tracer bevacizumab–IRDye800CW targeting VEGF-A in patients with breast cancer.

Experimental Design: Twenty patients with primary invasive breast cancer eligible for primary surgery received 4.5 mg bevacizumab–IRDye800CW as intravenous bolus injection. Safety aspects were assessed as well as tracer uptake and tumor delineation during surgery and ex vivo in surgical specimens using an optical imaging system. Ex vivo multiplexed histopathology analyses were performed for evaluation of biodistribution of tracer uptake and coregistration of tumor tissue and healthy tissue.

Results: None of the patients experienced adverse events. Tracer levels in primary tumor tissue were higher compared with those in the tumor margin (P < 0.05) and healthy tissue (P < 0.0001). VEGF-A tumor levels also correlated with tracer levels (r = 0.63, P < 0.0002). All but one tumor showed specific tracer uptake. Two of 20 surgically excised lumps contained microscopic positive margins detected ex vivo by fluorescent macro- and microscopy and confirmed at the cellular level.

Conclusions: Our study shows that systemic administration of the bevacizumab–IRDye800CW tracer is safe for breast cancer guidance and confirms tumor and tumor margin uptake as evaluated by a systematic validation methodology. The findings are a step toward a phase II dose-finding study aimed at in vivo margin assessment and point to a novel drug assessment tool that provides a detailed picture of drug distribution in the tumor tissue. Clin Cancer Res; 23(11); 2730–41. ©2016 AACR.
Data from Density, Distribution, and Composition of Immune Infiltrates Correlate with Survival in Merkel Cell Carcinoma
Authors: Feldmeyer Laurence , Hudgens Courtney W. , Ray-Lyons Genevieve , Nagarajan Priyadharsini , Aung Phyu P. , Curry Jonathan L. , Torres-Cabala Carlos A. , Mino Barbara , Rodriguez-Canales Jaime , Reuben Alexandre , Chen Pei-Ling , Ko Jennifer S. , Billings Steven D. , Bassett Roland L. , Wistuba Ignacio I. , Cooper Zachary A. , Prieto Victor G. , Wargo Jennifer A. , Tetzlaff Michael T.
Published: April 2023

Abstract
Purpose: Merkel cell carcinoma (MCC) is an aggressive cancer with frequent metastasis and death with few effective therapies. Because programmed death ligand-1 (PD-L1) is frequently expressed in MCC, immune checkpoint blockade has been leveraged as treatment for metastatic disease. There is therefore a critical need to understand the relationships between MCPyV status, immune profiles, and patient outcomes.

Experimental Design: IHC for CD3, CD8, PD-1, PD-L1, and MCPyV T-antigen (to determine MCPyV status) was performed on 62 primary MCCs with annotated clinical outcomes. Automated image analysis quantified immune cell density (positive cells/mm2) at discrete geographic locations (tumor periphery, center, and hotspot). T-cell receptor sequencing (TCRseq) was performed in a subset of MCCs.

Results: No histopathologic variable associated with overall survival (OS) or disease-specific survival (DSS), whereas higher CD3+ (P = 0.004) and CD8+ (P = 0.037) T-cell density at the tumor periphery associated with improved OS. Higher CD8+ T-cell density at the tumor periphery associated with improved DSS (P = 0.049). Stratifying MCCs according to MCPyV status, higher CD3+ (P = 0.026) and CD8+ (P = 0.015) T-cell density at the tumor periphery associated with improved OS for MCPyV+ but not MCPyV− MCC. TCRseq revealed clonal overlap among MCPyV+ samples, suggesting an antigen-specific response against a unifying antigen.

Conclusions: These findings establish the tumor-associated immune infiltrate at the tumor periphery as a robust prognostic indicator in MCC and provide a mechanistic rationale to further examine whether the immune infiltrate at the tumor periphery is relevant as a biomarker for response in ongoing and future checkpoint inhibitor trials in MCC. Clin Cancer Res; 22(22); 5553–63. ©2016 AACR.
Data from RIP1–HAT1–SIRT Complex Identification and Targeting in Treatment and Prevention of Cancer
Authors: Carafa Vincenzo , Nebbioso Angela , Cuomo Francesca , Rotili Dante , Cobellis Gilda , Bontempo Paola , Baldi Alfonso , Spugnini Enrico P. , Citro Gennaro , Chambery Angela , Russo Rosita , Ruvo Menotti , Ciana Paolo , Maravigna Luca , Shaik Jani , Radaelli Enrico , De Antonellis Pasquale , Tarantino Domenico , Pirolli Adele , Ragno Rino , Zollo Massimo , Stunnenberg Hendrik G. , Mai Antonello , Altucci Lucia
Published: April 2023

Abstract
Purpose: Alteration in cell death is a hallmark of cancer. A functional role regulating survival, apoptosis, and necroptosis has been attributed to RIP1/3 complexes.

Experimental Design: We have investigated the role of RIP1 and the effects of MC2494 in cell death induction, using different methods as flow cytometry, transcriptome analysis, immunoprecipitation, enzymatic assays, transfections, mutagenesis, and in vivo studies with different mice models.

Results: Here, we show that RIP1 is highly expressed in cancer, and we define a novel RIP1/3–SIRT1/2–HAT1/4 complex. Mass spectrometry identified five acetylations in the kinase and death domain of RIP1. The novel characterized pan-SIRT inhibitor, MC2494, increases RIP1 acetylation at two additional sites in the death domain. Mutagenesis of the acetylated lysine decreases RIP1-dependent cell death, suggesting a role for acetylation of the RIP1 complex in cell death modulation. Accordingly, MC2494 displays tumor-selective potential in vitro, in leukemic blasts ex vivo, and in vivo in both xenograft and allograft cancer models. Mechanistically, MC2494 induces bona fide tumor-restricted acetylated RIP1/caspase-8–mediated apoptosis. Excitingly, MC2494 displays tumor-preventive activity by blocking 7,12-dimethylbenz(α)anthracene–induced mammary gland hyperproliferation in vivo.

Conclusions: These preventive features might prove useful in patients who may benefit from a recurrence-preventive approach with low toxicity during follow-up phases and in cases of established cancer predisposition. Thus, targeting the newly identified RIP1 complex may represent an attractive novel paradigm in cancer treatment and prevention. Clin Cancer Res; 24(12); 2886–900. ©2018 AACR.
Data from Interferon-Stimulated Genes Are Involved in Cross-resistance to Radiotherapy in Tamoxifen-Resistant Breast Cancer
Authors: Post Annemarie E.M. , Smid Marcel , Nagelkerke Anika , Martens John W.M. , Bussink Johan , Sweep Fred C.G.J. , Span Paul N.
Published: April 2023

Abstract
Purpose: Treatment resistance is the main cause of adverse disease outcome in breast cancer patients. Here, we aimed to investigate common features in tamoxifen-resistant and radioresistant breast cancer, as tamoxifen-resistant breast cancer cells are cross-resistant to irradiation in vitro.

Experimental Design: RNA sequencing of tamoxifen-resistant and radioresistant breast cancer cells was performed and validated by quantitative PCR. Pathways were further investigated in vitro and in breast cancer patient cohorts to establish their relation with treatment resistance.

Results: Both tamoxifen-resistant and radioresistant breast cancer cells had increased expression levels of genes involved in type I IFN signaling compared with nonresistant cells. IFN-stimulated genes (ISG) were induced in a dose-dependent and time-dependent manner after tamoxifen treatment and irradiation. Tamoxifen treatment also led to ssDNA presence in the cytoplasm, which is known to induce expression of ISGs, a phenomenon that has already been described for irradiation. Moreover, in a breast cancer patient cohort, high expression levels of ISGs were found in the primary tumor in around half of the patients. This was associated with a tumor-infiltrating lymphocyte (TIL) expression signature, although the ISGs were also expressed by the tumor cells themselves. Importantly, the expression of ISGs correlated with outcome in breast cancer patients treated with adjuvant tamoxifen or radiotherapy, but not in systemically untreated patients or chemotherapy-treated patients.

Conclusions: Our data indicate that expression of ISGs by tumor cells is involved in acquired, treatment-induced resistance to tamoxifen and radiotherapy, and might play a role in intrinsic resistance via interaction with TILs. Clin Cancer Res; 24(14); 3397–408. ©2018 AACR.
Data from Reactivation of cAMP Pathway by PDE4D Inhibition Represents a Novel Druggable Axis for Overcoming Tamoxifen Resistance in ER-positive Breast Cancer
Authors: Mishra Rasmi R. , Belder Nevin , Ansari Suhail A. , Kayhan Merve , Bal Hilal , Raza Umar , Ersan Pelin G. , Tokat Ünal M. , Eyüpoğlu Erol , Saatci Özge , Jandaghi Pouria , Wiemann Stefan , Üner Ayşegül , Cekic Caglar , Riazalhosseini Yasser , Şahin Özgür
Published: April 2023

Abstract
Purpose: Tamoxifen remains an important hormonal therapy for ER-positive breast cancer; however, development of resistance is a major obstacle in clinics. Here, we aimed to identify novel mechanisms of tamoxifen resistance and provide actionable drug targets overcoming resistance.

Experimental Design: Whole-transcriptome sequencing, downstream pathway analysis, and drug repositioning approaches were used to identify novel modulators [here: phosphodiesterase 4D (PDE4D)] of tamoxifen resistance. Clinical data involving tamoxifen-treated patients with ER-positive breast cancer were used to assess the impact of PDE4D in tamoxifen resistance. Tamoxifen sensitization role of PDE4D was tested in vitro and in vivo. Cytobiology, biochemistry, and functional genomics tools were used to elucidate the mechanisms of PDE4D-mediated tamoxifen resistance.

Results: PDE4D, which hydrolyzes cyclic AMP (cAMP), was significantly overexpressed in both MCF-7 and T47D tamoxifen-resistant (TamR) cells. Higher PDE4D expression predicted worse survival in tamoxifen-treated patients with breast cancer (n = 469, P = 0.0036 for DMFS; n = 561, P = 0.0229 for RFS) and remained an independent prognostic factor for RFS in multivariate analysis (n = 132, P = 0.049). Inhibition of PDE4D by either siRNAs or pharmacologic inhibitors (dipyridamole and Gebr-7b) restored tamoxifen sensitivity. Sensitization to tamoxifen is achieved via cAMP-mediated induction of unfolded protein response/ER stress pathway leading to activation of p38/JNK signaling and apoptosis. Remarkably, acetylsalicylic acid (aspirin) was predicted to be a tamoxifen sensitizer using a drug repositioning approach and was shown to reverse resistance by targeting PDE4D/cAMP/ER stress axis. Finally, combining PDE4D inhibitors and tamoxifen suppressed tumor growth better than individual groups in vivo.

Conclusions: PDE4D plays a pivotal role in acquired tamoxifen resistance via blocking cAMP/ER stress/p38-JNK signaling and apoptosis. Clin Cancer Res; 24(8); 1987–2001. ©2018 AACR.
Data from A First-in-Human Study of the New Oral Selective Estrogen Receptor Degrader AZD9496 for ER+/HER2− Advanced Breast Cancer
Authors: Hamilton Erika P. , Patel Manish R. , Armstrong Anne C. , Baird Richard D. , Jhaveri Komal , Hoch Matthias , Klinowska Teresa , Lindemann Justin P.O. , Morgan Shethah R. , Schiavon Gaia , Weir Hazel M. , Im Seock-Ah
Published: April 2023

Abstract
Purpose: AZD9496 is an oral nonsteroidal, small-molecule inhibitor of estrogen receptor alpha (ERα) and a potent and selective antagonist and degrader of ERα. This first-in-human phase I study determined the safety and tolerability of ascending doses of oral AZD9496 in women with estrogen receptor (ER)+/HER2− advanced breast cancer, characterized its pharmacokinetic (PK) profile, and made preliminary assessment of antitumor activity.

Patients and Methods: Forty-five patients received AZD9496 [20 mg once daily (QD) to 600 mg twice daily (BID)] in a dose-escalation, dose-expansion “rolling 6” design. Safety, tolerability, and PK activity in each cohort were reviewed before escalating to the next dose. PK was determined by mass spectrometry. Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Objective tumor response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

Results: Most common causally related AEs were diarrhea (35.6%), fatigue (31.1%), and nausea (22.2%), and seven patients had grade ≥3 AEs. Three patients experienced a dose-limiting toxicity: one each at 150 mg BID (abnormal hepatic function), 400 mg BID (diarrhea and elevated liver function tests), and 600 mg BID (diarrhea), and all were reversible. The maximum tolerated dose was not reached. Partial response was confirmed in one patient, who also had decreased tumor marker Ca15.3. Four patients had stable disease at 12 months' follow-up.

Conclusions: AZD9496 is well tolerated with an acceptable safety profile, showing evidence of prolonged disease stabilization in heavily pretreated patients with ER+/HER2− advanced breast cancer. Clin Cancer Res; 24(15); 3510–8. ©2018 AACR.

See related commentary by Jordan, p. 3480
Data from Targeting Merkel Cell Carcinoma by Engineered T Cells Specific to T-Antigens of Merkel Cell Polyomavirus
Authors: Gavvovidis Ioannis , Leisegang Matthias , Willimsky Gerald , Miller Natalie , Nghiem Paul , Blankenstein Thomas
Published: April 2023

Abstract
Purpose: The causative agent of most cases of Merkel cell carcinoma (MCC) has been identified as the Merkel cell polyomavirus (MCV). MCV-encoded T antigens (Tag) are essential not only for virus-mediated tumorigenesis but also for maintaining MCC cell lines in vitro. MCV Tags are thus an appealing target for viral oncoprotein-directed T-cell therapy for MCC. With this study, we aimed to isolate and characterize Tag-specific T-cell receptors (TCR) for potential use in gene therapy clinical trials.

Experimental Design: T-cell responses against MCV Tag epitopes were investigated by immunizing transgenic mice that express a diverse human TCR repertoire restricted to HLA-A2. Human lymphocytes genetically engineered to express Tag-specific TCRs were tested for specific reactivity against MCC cell lines. The therapeutic potential of Tag-specific TCR gene therapy was tested in a syngeneic cancer model.

Results: We identified naturally processed epitopes of MCV Tags and isolated Tag-specific TCRs. T cells expressing these TCRs were activated by HLA-A2–positive cells loaded with cognate peptide or cells that stably expressed MCV Tags. We showed cytotoxic potential of T cells engineered to express these TCRs in vitro and demonstrated regression of established tumors in a mouse model upon TCR gene therapy.

Conclusions: Our findings demonstrate that MCC cells can be targeted by MCV Tag-specific TCRs. Although recent findings suggest that approximately half of MCC patients benefit from PD-1 pathway blockade, additional patients may benefit if their endogenous T-cell response can be augmented by infusion of transgenic MCV-specific T cells such as those described here. Clin Cancer Res; 24(15); 3644–55. ©2018 AACR.
Data from Resistance Mechanisms to Targeted Therapies in ROS1+ and ALK+ Non–small Cell Lung Cancer
Authors: McCoach Caroline E. , Le Anh T. , Gowan Katherine , Jones Kenneth , Schubert Laura , Doak Andrea , Estrada-Bernal Adriana , Davies Kurtis D. , Merrick Daniel T. , Bunn Paul A. , Purcell W. Tom , Dziadziuszko Rafal , Varella-Garcia Marileila , Aisner Dara L. , Camidge D. Ross , Doebele Robert C.
Published: April 2023

Abstract
Purpose: Despite initial benefit from tyrosine kinase inhibitors (TKIs), patients with advanced non–small cell lung cancer (NSCLC) harboring ALK (ALK+) and ROS1 (ROS1+) gene fusions ultimately progress. Here, we report on the potential resistance mechanisms in a series of patients with ALK+ and ROS1+ NSCLC progressing on different types and/or lines of ROS1/ALK–targeted therapy.

Experimental Design: We used a combination of next-generation sequencing (NGS), multiplex mutation assay, direct DNA sequencing, RT-PCR, and FISH to identify fusion variants/partners and copy-number gain (CNG), kinase domain mutations (KDM), and copy-number variations (CNVs) in other cancer-related genes. We performed testing on 12 ROS1+ and 43 ALK+ patients.

Results: One of 12 ROS1+ (8%) and 15 of 43 (35%) ALK+ patients harbored KDM. In the ROS1+ cohort, we identified KIT and β-catenin mutations and HER2-mediated bypass signaling as non-ROS1–dominant resistance mechanisms. In the ALK+ cohort, we identified a novel NRG1 gene fusion, a RET fusion, 2 EGFR, and 3 KRAS mutations, as well as mutations in IDH1, RIT1, NOTCH, and NF1. In addition, we identified CNV in multiple proto-oncogenes genes including PDGFRA, KIT, KDR, GNAS, K/HRAS, RET, NTRK1, MAP2K1, and others.

Conclusions: We identified a putative TKI resistance mechanism in six of 12 (50%) ROS1+ patients and 37 of 43 (86%) ALK+ patients. Our data suggest that a focus on KDMs will miss most resistance mechanisms; broader gene testing strategies and functional validation is warranted to devise new therapeutic strategies for drug resistance. Clin Cancer Res; 24(14); 3334–47. ©2018 AACR.
Data from Modifying the Clinical Research Infrastructure at a Dedicated Clinical Trials Unit: Assessment of Trial Development, Activation, and Participant Accrual
Authors: Tang Chad , Hess Kenneth R. , Sanders Dwana , Davis Suzanne E. , Buzdar Aman U. , Kurzrock Razelle , Lee J. Jack , Meric-Bernstam Funda , Hong David S.
Published: April 2023

Abstract
Purpose: Information on processes for trials assessing investigational therapeutics is sparse. We assessed the trial development processes within the Department of Investigational Cancer Therapeutics (ICT) at MD Anderson Cancer Center (Houston, TX) and analyzed their effects on the trial activation timeline and enrolment.

Experimental Design: Data were from a prospectively maintained registry that tracks all clinical studies at MD Anderson. From this database, we identified 2,261 activated phase I–III trials; 221 were done at the ICT. ICT trials were matched to trials from other MD Anderson departments by phase, sponsorship, and submission year. Trial performance metrics were compared with paired Wilcoxon signed rank tests.

Results: We identified three facets of the ICT research infrastructure: parallel processing of trial approval steps; a physician-led research team; and regular weekly meetings to foster research accountability. Separate analyses were conducted stratified by sponsorship [industry (133 ICT and 133 non-ICT trials) or institutional (68 ICT and 68 non-ICT trials)]. ICT trial development was faster from IRB approval to activation (median difference of 1.1 months for industry-sponsored trials vs. 2.3 months for institutional) and from activation to first enrolment (median difference of 0.3 months for industry vs. 1.2 months for institutional; all matched P < 0.05). ICT trials also accrued more patients (median difference of 8 participants for industry vs. 33.5 for institutional) quicker (median difference 4.8 participants/year for industry vs. 11.1 for institutional; all matched P < 0.05).

Conclusions: Use of a clinical research–focused infrastructure within a large academic cancer center was associated with efficient trial development and participant accrual. Clin Cancer Res; 23(6); 1407–13. ©2016 AACR.
Data from DICER1 and Associated Conditions: Identification of At-risk Individuals and Recommended Surveillance Strategies
Authors: Schultz Kris Ann P. , Williams Gretchen M. , Kamihara Junne , Stewart Douglas R. , Harris Anne K. , Bauer Andrew J. , Turner Joyce , Shah Rachana , Schneider Katherine , Schneider Kami Wolfe , Carr Ann Garrity , Harney Laura A. , Baldinger Shari , Frazier A. Lindsay , Orbach Daniel , Schneider Dominik T. , Malkin David , Dehner Louis P. , Messinger Yoav H. , Hill D. Ashley
Published: April 2023

Abstract
Pathogenic germline DICER1 variants cause a hereditary cancer predisposition syndrome with a variety of manifestations. In addition to conferring increased cancer risks for pleuropulmonary blastoma (PPB) and ovarian sex cord–stromal tumors, particularly Sertoli–Leydig cell tumor, individuals with pathogenic germline DICER1 variants may also develop lung cysts, cystic nephroma, renal sarcoma and Wilms tumor, nodular hyperplasia of the thyroid, nasal chondromesenchymal hamartoma, ciliary body medulloepithelioma, genitourinary embryonal rhabdomyosarcoma, and brain tumors including pineoblastoma and pituitary blastoma. In May 2016, the International PPB Registry convened the inaugural International DICER1 Symposium to develop consensus testing and surveillance and treatment recommendations. Attendees from North America, Europe, and Russia provided expert representation from the disciplines of pediatric oncology, endocrinology, genetics, genetic counseling, radiology, pediatric surgery, pathology, and clinical research. Recommendations are provided for genetic testing; prenatal management; and surveillance for DICER1-associated pulmonary, renal, gynecologic, thyroid, ophthalmologic, otolaryngologic, and central nervous system tumors and gastrointestinal polyps. Risk for most DICER1-associated neoplasms is highest in early childhood and decreases in adulthood. Individual and caregiver education and judicious imaging-based surveillance are the primary recommended approaches. These testing and surveillance recommendations reflect a consensus of expert opinion and current literature. As DICER1 research expands, guidelines for screening and treatment will continue to be updated. Clin Cancer Res; 24(10); 2251–61. ©2018 AACR.
Data from Skeletal Muscle Measures as Predictors of Toxicity, Hospitalization, and Survival in Patients with Metastatic Breast Cancer Receiving Taxane-Based Chemotherapy
Authors: Shachar Shlomit Strulov , Deal Allison M. , Weinberg Marc , Nyrop Kirsten A. , Williams Grant R. , Nishijima Tomohiro F. , Benbow Julia M. , Muss Hyman B.
Published: April 2023

Abstract
Purpose: Severe skeletal muscle (SM) loss (sarcopenia) is associated with poor cancer outcomes, including reduced survival and increased toxicity. This study investigates SM measures in metastatic breast cancer (MBC) patients receiving first-line taxane-based chemotherapy and evaluates associations with treatment toxicity and other outcomes.

Experimental Design: Using computerized tomography (CT) images taken for the evaluation of disease burden, skeletal muscle area (SMA), and density (SMD) were measured at the third lumbar vertebrae. Sarcopenia was defined as skeletal muscle index (SMI = SMA/height2) ≤ 41. Skeletal muscle gauge (SMG) was created by multiplying SMI × SMD. Fisher exact tests, t tests, the Kaplan–Meier method, and Cox regression modeling were used.

Results: MBC patients (N = 40), median age 55 (range, 34–80), 58% sarcopenic, median SMG 1296 AU (SD, 522). Grade 3–4 toxicity was found in 57% of sarcopenic versus 18% of non-sarcopenic patients (P = 0.02). Toxicity-related hospitalizations were also higher in sarcopenic patients (39% vs. 0%, P = 0.005) as were any adverse events—defined as any grade 3–4 toxicities, hospitalizations, dose reductions, or dose delay—(74% vs. 35%, P = 0.02). Low SMG was associated with grade 3–4 toxicity (P = 0.04), hospitalization (P = 0.01), and time to treatment failure (for progression or toxicity; P = 0.03). Low SMG had a borderline significant association with any adverse event (P = 0.06) and overall survival (P = 0.07).

Conclusions: SM measures are associated with toxicity outcomes and survival in MBC patients receiving first-line taxane-based chemotherapy. Further studies are needed to explore how routinely obtained CT scans can be used to individualize dosing and improve treatment planning. Clin Cancer Res; 23(3); 658–65. ©2016 AACR.
Data from Olaratumab Exerts Antitumor Activity in Preclinical Models of Pediatric Bone and Soft Tissue Tumors through Inhibition of Platelet-Derived Growth Factor Receptor α
Authors: Lowery Caitlin D. , Blosser Wayne , Dowless Michele , Knoche Shelby , Stephens Jennifer , Li Huiling , Surguladze David , Loizos Nick , Luffer-Atlas Debra , Oakley Gerard J. , Guo Qianxu , Iyer Seema , Rubin Brian P. , Stancato Louis
Published: April 2023

Abstract
Purpose: Platelet-derived growth factor receptor α (PDGFRα) is implicated in several adult and pediatric malignancies, where activated signaling in tumor cells and/or cells within the microenvironment drive tumorigenesis and disease progression. Olaratumab (LY3012207/IMC-3G3) is a human mAb that exclusively binds to PDGFRα and recently received accelerated FDA approval and conditional EMA approval for treatment of advanced adult sarcoma patients in combination with doxorubicin. In this study, we investigated olaratumab in preclinical models of pediatric bone and soft tissue tumors.

Experimental Design: PDGFRα expression was evaluated by qPCR and Western blot analysis. Olaratumab was investigated in in vitro cell proliferation and invasion assays using pediatric osteosarcoma and rhabdoid tumor cell lines. In vivo activity of olaratumab was assessed in preclinical mouse models of pediatric osteosarcoma and malignant rhabdoid tumor.

Results: In vitro olaratumab treatment of osteosarcoma and rhabdoid tumor cell lines reduced proliferation and inhibited invasion driven by individual platelet-derived growth factors (PDGFs) or serum. Furthermore, olaratumab delayed primary tumor growth in mouse models of pediatric osteosarcoma and malignant rhabdoid tumor, and this activity was enhanced by combination with either doxorubicin or cisplatin.

Conclusions: Overall, these data indicate that olaratumab, alone and in combination with standard of care, blocks the growth of some preclinical PDGFRα-expressing pediatric bone and soft tissue tumor models. Clin Cancer Res; 24(4); 847–57. ©2017 AACR.
Data from Risk Assessment after Neoadjuvant Chemotherapy in Luminal Breast Cancer Using a Clinicomolecular Predictor
Authors: Loibl Sibylle , Weber Karsten , Huober Jens , Krappmann Kristin , Marmé Frederik , Schem Christian , Engels Knut , Pfitzner Berit Maria , Kümmel Sherko , Furlanetto Jenny , Hartmann Arndt , Darb-Esfahani Silvia , Müller Volkmar , Staebler Annette , von Minckwitz Gunter , Kronenwett Ralf , Denkert Carsten
Published: April 2023

Abstract
Purpose: This study aimed to evaluate a modified EPclin test (mEPclin), a combination of EndoPredict (EP) score, post-neoadjuvant pathologic tumor size and nodal status, for predicting the risk of distance recurrence after neoadjuvant chemotherapy (NACT) in patients with residual estrogen receptor (ER)–positive/HER2-negative breast cancer. We also compared the prognostic power of the mEPclin with that of the CPS-EG score.

Experimental Design: A total of 428 formalin-fixed, paraffin-embedded tumor samples from GeparTrio and GeparQuattro studies were evaluated for mRNA expression of eight cancer-related and three reference genes. The mEPclin score was computed using a modified algorithm and predefined cut-off values were used to classify each patient at low or high risk. Primary endpoint was disease-free survival (DFS).

Results: A higher continuous mEPclin score was significantly associated with increased risk of relapse [HR, 2.16; 95% confidence interval (CI), 1.86–2.51; P < 0.001] and death (HR, 2.28; 95% CI, 1.90–2.75; P < 0.001). Similarly, patients classified at high risk by dichotomous mEPclin showed significantly poorer DFS and overall survival compared with those at low risk. In contrast with CPS-EG, the mEPclin remained significantly prognostic for DFS in multivariate analysis (HR, 2.13; 95% CI, 1.73–2.63; P < 0.001). Combining CPS-EG and other clinicopathological variables with mEPclin yielded a significant improvement of the prognostic power for DFS versus without mEPclin (c-indices: 0.748 vs. 0.660; P < 0.001).

Conclusions: The mEPclin score independently predicted the risk of distance recurrence and provided additional prognostic information to the CPS-EG score to assess more accurately the prognosis after NACT in the luminal non-pCR patient population. Therefore, this approach can be used to select patients for additional post-neoadjuvant therapies. Clin Cancer Res; 24(14); 3358–65. ©2018 AACR.
Data from Concurrent Alterations in EGFR-Mutant Lung Cancers Associated with Resistance to EGFR Kinase Inhibitors and Characterization of MTOR as a Mediator of Resistance
Authors: Yu Helena A. , Suzawa Ken , Jordan Emmet , Zehir Ahmet , Ni Ai , Kim Ryan , Kris Mark G. , Hellmann Matthew D. , Li Bob T. , Somwar Romel , Solit David B. , Berger Michael F. , Arcila Maria , Riely Gregory J. , Ladanyi Marc
Published: April 2023

Abstract
Purpose: To identify molecular factors that determine duration of response to EGFR tyrosine kinase inhibitors and to identify novel mechanisms of drug resistance, we molecularly profiled EGFR-mutant tumors prior to treatment and after progression on EGFR TKI using targeted next-generation sequencing.

Experimental Design: Targeted next-generation sequencing was performed on 374 consecutive patients with metastatic EGFR-mutant lung cancer. Clinical data were collected and correlated with somatic mutation data. Erlotinib resistance due to acquired MTOR mutation was functionally evaluated by in vivo and in vitro studies.

Results: In 200 EGFR-mutant pretreatment samples, the most frequent concurrent alterations were mutations in TP53, PIK3CA, CTNNB1, and RB1 and focal amplifications in EGFR, TTF1, MDM2, CDK4, and FOXA1. Shorter time to progression on EGFR TKI was associated with amplification of ERBB2 (HR = 2.4, P = 0.015) or MET (HR = 3.7, P = 0.019), or mutation in TP53 (HR = 1.7, P = 0.006). In the 136 posttreatment samples, we identified known mechanisms of acquired resistance: EGFR T790M (51%), MET (7%), and ERBB2 amplifications (5%). In the 38 paired samples, novel acquired alterations representing putative resistance mechanisms included BRAF fusion, FGFR3 fusion, YES1 amplification, KEAP1 loss, and an MTOR E2419K mutation. Functional studies confirmed the contribution of the latter to reduced sensitivity to EGFR TKI in vitro and in vivo.

Conclusions: EGFR-mutant lung cancers harbor a spectrum of concurrent alterations that have prognostic and predictive significance. By utilizing paired samples, we identified several novel acquired alterations that may be relevant in mediating resistance, including an activating mutation in MTOR further validated functionally. Clin Cancer Res; 24(13); 3108–18. ©2018 AACR.
Data from Integrated Analysis of Multiple Biomarkers from Circulating Tumor Cells Enabled by Exclusion-Based Analyte Isolation
Authors: Sperger Jamie M. , Strotman Lindsay N. , Welsh Allison , Casavant Benjamin P. , Chalmers Zachery , Horn Sacha , Heninger Erika , Thiede Stephanie M. , Tokar Jacob , Gibbs Benjamin K. , Guckenberger David J. , Carmichael Lakeesha , Dehm Scott M. , Stephens Philip J. , Beebe David J. , Berry Scott M. , Lang Joshua M.
Published: April 2023

Abstract
Purpose: There is a critical clinical need for new predictive and pharmacodynamic biomarkers that evaluate pathway activity in patients treated with targeted therapies. A microscale platform known as VERSA (versatile exclusion-based rare sample analysis) was developed to integrate readouts across protein, mRNA, and DNA in circulating tumor cells (CTC) for a comprehensive analysis of the androgen receptor (AR) signaling pathway.

Experimental Design: Utilizing exclusion-based sample preparation principles, a handheld chip was developed to perform CTC capture, enumeration, quantification, and subcellular localization of proteins and extraction of mRNA and DNA. This technology was validated across integrated endpoints in cell lines and a cohort of patients with castrate-resistant prostate cancer (CRPC) treated with AR-targeted therapies and chemotherapies.

Results: The VERSA was validated in cell lines to analyze AR protein expression, nuclear localization, and gene expression targets. When applied to a cohort of patients, radiographic progression was predicted by the presence of multiple AR splice variants and activity in the canonical AR signaling pathway. AR protein expression and nuclear localization identified phenotypic heterogeneity. Next-generation sequencing with the FoundationOne panel detected copy number changes and point mutations. Longitudinal analysis of CTCs identified acquisition of multiple AR variants during targeted treatments and chemotherapy.

Conclusions: Complex mechanisms of resistance to AR-targeted therapies, across RNA, DNA, and protein endpoints, exist in patients with CRPC and can be quantified in CTCs. Interrogation of the AR signaling pathway revealed distinct patterns relevant to tumor progression and can serve as pharmacodynamic biomarkers for targeted therapies. Clin Cancer Res; 23(3); 746–56. ©2016 AACR.
Data from Immunotherapy with a HER2-Targeting Listeria Induces HER2-Specific Immunity and Demonstrates Potential Therapeutic Effects in a Phase I Trial in Canine Osteosarcoma
Authors: Mason Nicola J. , Gnanandarajah Josephine S. , Engiles Julie B. , Gray Falon , Laughlin Danielle , Gaurnier-Hausser Anita , Wallecha Anu , Huebner Margie , Paterson Yvonne
Published: April 2023

Abstract
Purpose: Recombinant Listeria vaccines induce tumor-specific T-cell responses that eliminate established tumors and prevent metastatic disease in murine cancer models. We used dogs with HER2/neu+ appendicular osteosarcoma, a well-recognized spontaneous model for pediatric osteosarcoma, to determine whether a highly attenuated, recombinant Listeria monocytogenes expressing a chimeric human HER2/neu fusion protein (ADXS31-164) could safely induce HER2/neu-specific immunity and prevent metastatic disease.

Experimental Design: Eighteen dogs that underwent limb amputation or salvage surgery and adjuvant chemotherapy were enrolled in a phase I dose escalation clinical trial and received either 2 × 108, 5 × 108, 1 × 109, or 3.3 × 109 CFU of ADXS31-164 intravenously every 3 weeks for 3 administrations.

Results: Only low-grade, transient toxicities were observed. ADXS31-164 broke peripheral tolerance and induced antigen-specific IFNγ responses against the intracellular domain of HER2/neu in 15 of 18 dogs within 6 months of treatment. Furthermore, ADXS31-164 reduced the incidence of metastatic disease and significantly increased duration of survival time and 1-, 2-, and 3-year survival rates when compared with a historical control group with HER2/neu+ appendicular osteosarcoma treated with amputation and chemotherapy alone.

Conclusions: These findings demonstrate that ADXS31-164 administered in the setting of minimal residual disease can induce HER2/neu-specific immunity and may reduce the incidence of metastatic disease and prolong overall survival in a clinically relevant, spontaneous, large animal model of cancer. These findings, therefore, have important translational relevance for children with osteosarcoma and adults with other HER2/neu+ cancers. Clin Cancer Res; 22(17); 4380–90. ©2016 AACR.
Data from Nitric Oxide Production by Myeloid-Derived Suppressor Cells Plays a Role in Impairing Fc Receptor–Mediated Natural Killer Cell Function
Authors: Stiff Andrew , Trikha Prashant , Mundy-Bosse Bethany , McMichael Elizabeth , Mace Thomas A. , Benner Brooke , Kendra Kari , Campbell Amanda , Gautam Shalini , Abood David , Landi Ian , Hsu Vincent , Duggan Megan , Wesolowski Robert , Old Matthew , Howard John Harrison , Yu Lianbo , Stasik Nancy , Olencki Thomas , Muthusamy Natarajan , Tridandapani Susheela , Byrd John C. , Caligiuri Michael , Carson William E.
Published: April 2023

Abstract
Purpose: mAbs are used to treat solid and hematologic malignancies and work in part through Fc receptors (FcRs) on natural killer cells (NK). However, FcR-mediated functions of NK cells from patients with cancer are significantly impaired. Identifying the mechanisms of this dysfunction and impaired response to mAb therapy could lead to combination therapies and enhance mAb therapy.

Experimental Design: Cocultures of autologous NK cells and MDSC from patients with cancer were used to study the effect of myeloid-derived suppressor cells (MDSCs) on NK-cell FcR-mediated functions including antibody-dependent cellular cytotoxicity, cytokine production, and signal transduction in vitro. Mouse breast cancer models were utilized to study the effect of MDSCs on antibody therapy in vivo and test the efficacy of combination therapies including a mAb and an MDSC-targeting agent.

Results: MDSCs from patients with cancer were found to significantly inhibit NK-cell FcR-mediated functions including antibody-dependent cellular cytotoxicity, cytokine production, and signal transduction in a contact-independent manner. In addition, adoptive transfer of MDSCs abolished the efficacy of mAb therapy in a mouse model of pancreatic cancer. Inhibition of iNOS restored NK-cell functions and signal transduction. Finally, nonspecific elimination of MDSCs or inhibition of iNOS in vivo significantly improved the efficacy of mAb therapy in a mouse model of breast cancer.

Conclusions: MDSCs antagonize NK-cell FcR-mediated function and signal transduction leading to impaired response to mAb therapy in part through nitric oxide production. Thus, elimination of MDSCs or inhibition of nitric oxide production offers a strategy to improve mAb therapy. Clin Cancer Res; 24(8); 1891–904. ©2018 AACR.
Data from Intratumoral HPV16-Specific T Cells Constitute a Type I–Oriented Tumor Microenvironment to Improve Survival in HPV16-Driven Oropharyngeal Cancer
Authors: Welters Marij J.P. , Ma Wenbo , Santegoets Saskia J.A.M. , Goedemans Renske , Ehsan Ilina , Jordanova Ekaterina S. , van Ham Vanessa J. , van Unen Vincent , Koning Frits , van Egmond Sylvia I. , Charoentong Pornpimol , Trajanoski Zlatko , van der Velden Lilly-Ann , van der Burg Sjoerd H.
Published: April 2023

Abstract
Purpose: Human papillomavirus (HPV)–associated oropharyngeal squamous cell cancer (OPSCC) has a much better prognosis than HPV-negative OPSCC, and this is linked to dense tumor immune infiltration. As the viral antigens may trigger potent immunity, we studied the relationship between the presence of intratumoral HPV-specific T-cell responses, the immune contexture in the tumor microenvironment, and clinical outcome.

Experimental Design: To this purpose, an in-depth analysis of tumor-infiltrating immune cells in a prospective cohort of 97 patients with HPV16-positive and HPV16-negative OPSCC was performed using functional T-cell assays, mass cytometry (CyTOF), flow cytometry, and fluorescent immunostaining of tumor tissues. Key findings were validated in a cohort of 75 patients with HPV16-positive OPSCC present in the publicly available The Cancer Genome Atlas database.

Results: In 64% of the HPV16-positive tumors, type I HPV16-specific T cells were present. Their presence was not only strongly related to a better overall survival, a smaller tumor size, and less lymph node metastases but also to a type I–oriented tumor microenvironment, including high numbers of activated CD161+ T cells, CD103+ tissue-resident T cells, dendritic cells (DC), and DC-like macrophages.

Conclusions: The viral antigens trigger a tumor-specific T-cell response that shapes a favorable immune contexture for the response to standard therapy. Hence, reinforcement of HPV16-specific T-cell reactivity is expected to boost this process. Clin Cancer Res; 24(3); 634–47. ©2017 AACR.

See related commentary by Laban and Hoffmann, p. 505