bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from MTL-CEBPA, a Small Activating RNA Therapeutic Upregulating C/EBP-α, in Patients with Advanced Liver Cancer: A First-in-Human, Multicenter, Open-Label, Phase I Trial
Authors: Sarker Debashis , Plummer Ruth , Meyer Tim , Sodergren Mikael H. , Basu Bristi , Chee Cheng Ean , Huang Kai-Wen , Palmer Daniel H. , Ma Yuk Ting , Evans T.R. Jeff , Spalding Duncan R.C. , Pai Madhava , Sharma Rohini , Pinato David J. , Spicer James , Hunter Sarah , Kwatra Vineet , Nicholls Joanna P. , Collin David , Nutbrown Robert , Glenny Helen , Fairbairn Sonia , Reebye Vikash , Voutila Jon , Dorman Stephanie , Andrikakou Pinelopi , Lloyd Peter , Felstead Steve , Vasara Jenni , Habib Robert , Wood Chris , Saetrom Pal , Huber Hans E. , Blakey David C. , Rossi John J. , Habib Nagy
Published: April 2023

AbstractPurpose:
Transcription factor C/EBP-α (CCAAT/enhancer-binding protein alpha) acts as a master regulator of hepatic and myeloid functions and multiple oncogenic processes. MTL-CEBPA is a first-in-class small activating RNA oligonucleotide drug that upregulates C/EBP-α.
Patients and Methods:
We conducted a phase I, open-label, dose-escalation trial of MTL-CEBPA in adults with advanced hepatocellular carcinoma (HCC) with cirrhosis, or resulting from nonalcoholic steatohepatitis or with liver metastases. Patients received intravenous MTL-CEBPA once a week for 3 weeks followed by a rest period of 1 week per treatment cycle in the dose-escalation phase (3+3 design).
Results:
Thirty-eight participants have been treated across six dose levels (28–160 mg/m2) and three dosing schedules. Thirty-four patients were evaluable for safety endpoints at 28 days. MTL-CEBPA treatment–related adverse events were not associated with dose, and no maximum dose was reached across the three schedules evaluated. Grade 3 treatment-related adverse events occurred in nine (24%) patients. In 24 patients with HCC evaluable for efficacy, an objective tumor response was achieved in one patient [4%; partial response (PR) for over 2 years] and stable disease (SD) in 12 (50%). After discontinuation of MTL-CEBPA, seven patients were treated with tyrosine kinase inhibitors (TKIs); three patients had a complete response with one further PR and two with SD.
Conclusions:
MTL-CEBPA is the first saRNA in clinical trials and demonstrates an acceptable safety profile and potential synergistic efficacy with TKIs in HCC. These encouraging phase I data validate targeting of C/EBP-α and have prompted MTL-CEBPA + sorafenib combination studies in HCC.
Data from Clinical and Genome-Wide Analysis of Multiple Severe Cisplatin-Induced Neurotoxicities in Adult-Onset Cancer Survivors
Authors: Trendowski Matthew R. , Wheeler Heather E. , El-Charif Omar , Feldman Darren R. , Hamilton Robert J. , Vaughn David J. , Fung Chunkit , Kollmannsberger Christian , Einhorn Lawrence H. , Travis Lois B. , Dolan M. Eileen
Published: April 2023

AbstractPurpose:
Cisplatin is a first-line chemotherapeutic for many cancers, but causes neurotoxicity including hearing loss, tinnitus, and peripheral sensory neuropathy. However, no study has comprehensively characterized risk factors for developing multiple (>1) severe neurotoxicities.
Experimental Design:
The relationship between multiple severe neurotoxicities and age, cumulative cisplatin dose, medical history, and lifestyle/behavioral factors was evaluated in 300 cisplatin-treated testicular cancer survivors using logistic regression. Case–control genome-wide association study (GWAS; cases, n = 104 and controls, n = 196) was also performed.
Results:
Age at clinical examination (P = 6.4 × 10−16) and cumulative cisplatin dose (P = 5.4 × 10−4) were positively associated with multiple severe neurotoxicity risk, as were high serum platinum levels (P = 0.02), tobacco use (ever smoker, P = 0.001 and current smoker, P = 0.002), and hypertension (P = 0.01) after adjustment for age and cumulative cisplatin dose. Individuals with multiple severe neurotoxicities were more likely to experience dizziness/vertigo (P = 0.01), Raynaud phenomenon (P = 3.7 × 10−9), and symptoms consistent with peripheral motor neuropathy (P = 4.3 × 10−14) after age and dose adjustment. These patients also reported poorer overall health (P = 2.7 × 10−5) and a greater use of psychotropic medications (P = 0.06). GWAS identified no genome-wide significant SNPs. Gene-based association analysis identified RGS17 (P = 3.9 × 10−5) and FAM20C (P = 5.5 × 10−5) as near genome-wide significant. Decreased FAM20C expression was associated with increased cisplatin sensitivity in tumor cell lines.
Conclusions:
Certain survivors are more susceptible to cisplatin-induced neurotoxicity, markedly increasing likelihood of developing numerous neuro-otological symptoms that affect quality of life. Genome-wide analysis identified genetic variation in FAM20C as a potentially important risk factor.
Data from Integrative Analysis of Pleomorphic Dermal Sarcomas Reveals Fibroblastic Differentiation and Susceptibility to Immunotherapy
Authors: Klein Sebastian , Quaas Alexander , Noh Ka-Won , Cartolano Maria , Abedpour Nima , Mauch Cornelia , Quantius Jennifer , Reinhardt Hans Christian , Buettner Reinhard , Peifer Martin , Helbig Doris
Published: April 2023

AbstractPurpose:
Pleomorphic dermal sarcoma (PDS) is a rare malignant cutaneous tumor with an unknown cell of origin. Locally defined tumors can be treated by curative excisions, whereas advanced stages of the disease are difficult to treat, using standard regimens.
Experimental Design:
We performed whole-exome sequencing on a cohort of 28 individuals and corresponding transcriptomic analysis on 21 patients, as well as quantitative IHC image analysis on 27 patients.
Results:
PDS exhibits a universally high mutational load (42.7 mutations/mega base) with an inflamed, immunogenic tumor microenvironment. Three cases of PDS showed response to immune checkpoint blockade. Local mutation rate variation together with mRNA expression data demonstrate that PDS form a distinct entity, with PDGFRB as a lineage marker. In addition, we found that PDS is of mesenchymal, fibroblastic differentiation.
Conclusions:
PDS is of fibroblastic differentiation and exhibits a strong susceptibility to immunotherapy, including a high mutational burden and an inflamed tumor microenvironment.
Data from Nectin-2 Expression on Malignant Plasma Cells Is Associated with Better Response to TIGIT Blockade in Multiple Myeloma
Authors: Lozano Ester , Mena Mari-Pau , Díaz Tania , Martin-Antonio Beatriz , León Sheila , Rodríguez-Lobato Luis-Gerardo , Oliver-Caldés Aina , Cibeira Maria Teresa , Bladé Joan , Prat Aleix , Rosiñol Laura , Fernández de Larrea Carlos
Published: April 2023

AbstractPurpose:
T-cell immunoreceptor with Ig and ITIM domain (TIGIT) blockade could represent an alternative therapeutic option to release the immune response in patients with multiple myeloma. Here we analyzed the expression of TIGIT and its ligands poliovirus receptor (PVR) and nectin-2 in the bone marrow (BM) of patients with monoclonal gammopathies and the efficacy of TIGIT blockade activating antimyeloma immunity.
Experimental Design:
Expression levels of TIGIT and its ligands were characterized by flow cytometry and ELISA. TIGIT blockade was analyzed in in vitro functional assays with peripheral T cells. BM cells were studied with NanoString technology, real-time PCR, and ex vivo patient BM cell models.
Results:
TIGIT and its ligands are highly expressed in the BM of patients with multiple myeloma, suggesting that may play a role in restraining immune activation. TIGIT blockade depleted FoxP3+ Tregs while increasing proliferation of IFNγ-producing CD4+ T cells from patients with multiple myeloma. PVR ligation inhibited CD8+ T-cell signaling and cell proliferation which could be overcome with anti-TIGIT mAb. However, BM cells showed a remarkable heterogeneity in immune signature. Accordingly, functional ex vivo BM assays revealed that only some patients respond to checkpoint blockade. Thus, response to TIGIT blockade correlated with low frequency of TIGIT+ cells and high nectin-2 expression on malignant plasma cells.
Conclusions:
TIGIT blockade efficiently reinvigorated peripheral T cells from patients with multiple myeloma. However, in the BM, the efficacy of blocking anti-TIGIT mAb to achieve tumor cell death may depend on the expression of TIGIT and nectin-2, becoming potential predictive biomarkers for identifying patients who may benefit from TIGIT blockade.
Data from Epithelial-to-Mesenchymal Transition is a Cause of Both Intrinsic and Acquired Resistance to KRAS G12C Inhibitor in KRAS G12C–Mutant Non–Small Cell Lung Cancer
Authors: Adachi Yuta , Ito Kentaro , Hayashi Yuko , Kimura Ryo , Tan Tuan Zea , Yamaguchi Rui , Ebi Hiromichi
Published: April 2023

AbstractPurpose:
KRAS is among the most commonly mutated oncogene in cancer including non–small cell lung cancer (NSCLC). In early clinical trials, inhibitors targeting G12C-mutant KRAS have achieved responses in some patients with NSCLC. Possible intrinsic and acquired resistance mechanisms to KRAS G12C inhibitors are not fully elucidated and will likely become important to identify.
Experimental Design:
To identify potential resistance mechanisms, we defined the sensitivity of a panel of KRAS G12C–mutant lung cancer cell lines to a KRAS G12C inhibitor, AMG510. Gene set enrichment analyses were performed to identify pathways related to the sensitivity, which was further confirmed biochemically. In addition, we created two cell lines that acquired resistance to AMG510 and the underlying resistance mechanisms were analyzed.
Results:
KRAS expression and activation were associated with sensitivity to KRAS G12C inhibitor. Induction of epithelial-to-mesenchymal transition (EMT) led to both intrinsic and acquired resistance to KRAS G12C inhibition. In these EMT-induced cells, PI3K remained activated in the presence of KRAS G12C inhibitor and was dominantly regulated by the IGFR–IRS1 pathway. We found SHP2 plays a minimal role in the activation of the PI3K pathway in contrast to its critical role in the activation of the MAPK pathway. The combination of KRAS G12C inhibitor, PI3K inhibitor, and SHP2 inhibitor resulted in tumor regressions in mouse models of acquired resistance to AMG510.
Conclusions:
Our findings suggest that EMT is a cause of both intrinsic and acquired resistance by activating the PI3K pathway in the presence of KRAS G12C inhibitor.
Data from B Cells Improve Overall Survival in HPV-Associated Squamous Cell Carcinomas and Are Activated by Radiation and PD-1 Blockade
Authors: Kim Sangwoo S. , Shen Sarek , Miyauchi Sayuri , Sanders P. Dominick , Franiak-Pietryga Ida , Mell Loren , Gutkind J. Silvio , Cohen Ezra E.W. , Califano Joseph A. , Sharabi Andrew B.
Published: April 2023

AbstractPurpose:
To characterize the role of B cells on human papilloma virus (HPV)-associated cancer patient outcomes and determine the effects of radiation and PD-1 blockade on B-cell populations.
Experimental Design:
Tumor RNA-sequencing data from over 800 patients with head and neck squamous cell carcinoma (HNSCC) and cervical cancer, including a prospective validation cohort, was analyzed to study the impact of B-cell gene expression on overall survival (OS). A novel murine model of HPV+ HNSCC was used to study the effects of PD-1 blockade and radiotherapy on B-cell activation, differentiation, and clonality including analysis by single-cell RNA-sequencing and B-cell receptor (BCR)-sequencing. Human protein microarray was then used to quantify B-cell–mediated IgG and IgM antibodies to over 16,000 proteins in the serum of patients treated on a clinical trial with PD-1 blockade.
Results:
RNA-sequencing identified CD19 and IGJ as novel B-cell prognostic biomarkers for 3-year OS (HR, 0.545; P < 0.001). PD-1 blockade and radiotherapy enhance development of memory B cells, plasma cells, and antigen-specific B cells. BCR-sequencing found that radiotherapy enhances B-cell clonality, decreases CDR3 length, and induces B-cell somatic hypermutation. Single-cell RNA-sequencing identified dramatic increases in B-cell germinal center formation after PD-1 blockade and radiotherapy. Human proteome array revealed enhanced IgG and IgM antibody responses in patients who derived clinical benefit but not those with progressive disease after treatment with PD-1 blockade.
Conclusions:
These findings establish a key role for B cells in patient outcomes and responses to PD-1 blockade in HPV-associated squamous cell carcinomas and demonstrate the need for additional diagnostics and therapeutics targeting B cells.
Data from Association of NOS3 and ANGPT2 Gene Polymorphisms with Survival in Patients with Hepatocellular Carcinoma Receiving Sorafenib: Results of the Multicenter Prospective INNOVATE Study
Authors: Casadei-Gardini Andrea , Marisi Giorgia , Dadduzio Vincenzo , Gramantieri Laura , Faloppi Luca , Ulivi Paola , Foschi Francesco Giuseppe , Tamburini Emiliano , Vivaldi Caterina , Rizzato Mario Domenico , Ielasi Luca , Canale Matteo , Conti Fabio , Rudnas Britt , Fornaro Lorenzo , Silvestris Nicola , Silletta Marianna , Cardellino Giovanni Gerardo , Lonardi Sara , Fornari Francesca , Orsi Giulia , Rovesti Giulia , Zagonel Vittorina , Cascinu Stefano , Scartozzi Mario
Published: April 2023

AbstractPurpose:
After 10 years of clinical practice and research studies, there are still no validated prognostic or predictive factors of response to sorafenib for hepatocellular carcinoma (HCC). On the basis of the results of our two retrospective studies, we designed the multicenter INNOVATE study with the aim to validate the role of nitric oxide synthase 3 (NOS3) and ANGPT2 polymorphisms in patients with HCC treated with sorafenib [NCT02786342].
Patients and Methods:
This prospective multicenter study was conducted at 10 centers in Italy. All eligible patients received a continuous oral treatment with 400 mg of sorafenib twice daily. Genotyping analysis was performed for NOS3 (rs2070744) and ANGPT2 SNPs (rs55633437). The primary outcome was progression-free survival (PFS), whereas secondary outcomes included overall survival (OS) and disease-control rate.
Results:
A total of 165 patients were enrolled between March 2016 and June 2018. NOS3 rs2070744 CC/CT genotypes were significantly associated with a higher median PFS (5.9 months vs. 2.4 months; HR = 0.43; P = 0.0007) and OS (15.7 months vs. 8.6 months; HR = 0.38; P < 0.0001) compared with TT genotype. There was no statistically significant association between ANGPT2 rs55633437 TT/GT genotypes and PFS (2.4 months vs. 5.7 months; HR = 1.93; P = 0.0833) and OS (15.1 months vs. 13.0 months; HR = 2.68; P = 0.55) when compared with the other genotype. Following adjustment for clinical covariates, multivariate analysis confirmed NOS3 as an independent prognostic factor for PFS (HR = 0.50; P = 0.0128) and OS (HR = 0.29; P = 0.0041).
Conclusions:
The INNOVATE study met the primary endpoint, confirming that patients with advanced HCC with NOS3 rs2070744 CC/CT genotypes had a better prognosis with respect to TT genotype patients.
Data from Serum IL6 as a Prognostic Biomarker and IL6R as a Therapeutic Target in Biliary Tract Cancers
Authors: Høgdall Dan , O'Rourke Colm J. , Dehlendorff Christian , Larsen Ole F. , Jensen Lars H. , Johansen Astrid Z. , Dang Hien , Factor Valentina M. , Grunnet Mie , Mau-Sørensen Morten , Oliveira Douglas V.N.P. , Linnemann Dorte , Boisen Mogens K. , Wang Xin W. , Johansen Julia S. , Andersen Jesper B.
Published: April 2023

AbstractPurpose:
Biliary tract cancer (BTC) is a heterogeneous group of rare gastrointestinal malignancies with dismal prognosis often associated with inflammation. We assessed the prognostic value of IL6 and YKL-40 compared with CA19-9 before and during palliative chemotherapy. We also investigated in mice whether IL6R inhibition in combination with gemcitabine could prolong chemosensitivity.
Experimental Design:
A total of 452 Danish participants with advanced (locally advanced and metastatic) BTC were included from six clinical trials (February 2004 to March 2017). Serum CA19-9, IL6, and YKL-40 were measured before and during palliative treatment. Associations between candidate biomarkers and progression-free survival (PFS) and overall survival (OS) were analyzed by univariate and multivariate Cox regression. Effects of inhibiting IL6R and YKL-40 were assessed in vitro, and of IL6R inhibition in vivo.
Results:
High pretreatment levels of CA19-9, IL6, and YKL-40, and increasing levels during treatment, were associated with short PFS and OS in patients with advanced BTC. IL6 provided independent prognostic information, independent of tumor location and in patients with normal serum CA19-9. ROC analyses showed that IL6 and YKL-40 were predictive of very short OS (OS < 6 months), whereas CA19-9 was best to predict OS > 1.5 years. Treatment with anti-IL6R and gemcitabine significantly diminished tumor growth when compared with gemcitabine monotherapy in an in vivo transplant model of BTC.
Conclusions:
Serum IL6 and YKL-40 are potential new prognostic biomarkers in BTC. IL6 provides independent prognostic information and may be superior to CA19-9 in certain contexts. Moreover, anti-IL6R should be considered as a new treatment option to sustain gemcitabine response in patients with BTC.
Data from Arginine Depletion Therapy with ADI-PEG20 Limits Tumor Growth in Argininosuccinate Synthase–Deficient Ovarian Cancer, Including Small-Cell Carcinoma of the Ovary, Hypercalcemic Type
Authors: Ji Jennifer X. , Cochrane Dawn R. , Tessier-Cloutier Basile , Chen Shary Yutin , Ho Germain , Pathak Khyatiben V. , Alcazar Isabel N. , Farnell David , Leung Samuel , Cheng Angela , Chow Christine , Colborne Shane , Negri Gian Luca , Kommoss Friedrich , Karnezis Anthony , Morin Gregg B. , McAlpine Jessica N. , Gilks C. Blake , Weissman Bernard E. , Trent Jeffrey M. , Hoang Lynn , Pirrotte Patrick , Wang Yemin , Huntsman David G.
Published: April 2023

AbstractPurpose:
Many rare ovarian cancer subtypes, such as small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT), have poor prognosis due to their aggressive nature and resistance to standard platinum- and taxane-based chemotherapy. The development of effective therapeutics has been hindered by the rarity of such tumors. We sought to identify targetable vulnerabilities in rare ovarian cancer subtypes.
Experimental Design:
We compared the global proteomic landscape of six cases each of endometrioid ovarian cancer (ENOC), clear cell ovarian cancer (CCOC), and SCCOHT to the most common subtype, high-grade serous ovarian cancer (HGSC), to identify potential therapeutic targets. IHC of tissue microarrays was used as validation of arginosuccinate synthase (ASS1) deficiency. The efficacy of arginine-depriving therapeutic ADI-PEG20 was assessed in vitro using cell lines and patient-derived xenograft mouse models representing SCCOHT.
Results:
Global proteomic analysis identified low ASS1 expression in ENOC, CCOC, and SCCOHT compared with HGSC. Low ASS1 levels were validated through IHC in large patient cohorts. The lowest levels of ASS1 were observed in SCCOHT, where ASS1 was absent in 12 of 31 cases, and expressed in less than 5% of the tumor cells in 9 of 31 cases. ASS1-deficient ovarian cancer cells were sensitive to ADI-PEG20 treatment regardless of subtype in vitro. Furthermore, in two cell line mouse xenograft models and one patient-derived mouse xenograft model of SCCOHT, once-a-week treatment with ADI-PEG20 (30 mg/kg and 15 mg/kg) inhibited tumor growth in vivo.
Conclusions:
Preclinical in vitro and in vivo studies identified ADI-PEG20 as a potential therapy for patients with rare ovarian cancers, including SCCOHT.
Data from Phase I Study of Trifluridine/Tipiracil Plus Irinotecan and Bevacizumab in Advanced Gastrointestinal Tumors
Authors: Varghese Anna M. , Cardin Dana B. , Hersch Jonathan , Benson Al B. , Hochster Howard S. , Makris Lukas , Hamada Kensuke , Berlin Jordan D. , Saltz Leonard B.
Published: April 2023

AbstractPurpose:
This two-part phase Ib trial determined the maximum tolerated dose (MTD) of the combination of trifluridine/tipiracil (FTD/TPI) and irinotecan in patients with advanced gastrointestinal tumors, and evaluated the safety, pharmacokinetics, and antitumor activity of the FTD/TPI, irinotecan, and bevacizumab triplet combination in previously treated metastatic colorectal cancer (mCRC).
Patients and Methods:
Dose escalation (3+3 design) in advanced gastrointestinal tumors was followed by expansion in mCRC. During dose escalation, patients received FTD/TPI (20–35 mg/m2 twice daily; days 1–5 of a 14-day cycle) and irinotecan (120–180 mg/m2; day 1). During expansion, the MTD of FTD/TPI and irinotecan plus bevacizumab (5 mg/kg; day 1) was administered.
Results:
Fifty patients (26 across six dose-escalation cohorts and 24 in the expansion phase) were enrolled. Two dose-limiting toxicities (fatigue and neutropenia) were observed in the dose-escalation phase, and MTD was defined as FTD/TPI 25 mg/m2 twice daily plus irinotecan 180 mg/m2. In the expansion phase, 83% (20/24) experienced any-cause grade ≥3 adverse events (AEs) with the triplet combination, most frequently neutropenia (42%), leukopenia (25%), and diarrhea (12%). AEs of any-cause led to dosing interruptions, modifications, and discontinuations in 29%, 17%, and 4% of patients, respectively. No treatment-related deaths occurred. Three patients (12%) experienced partial responses and 16 (67%) patients had stable disease lasting >4 months. The median progression-free survival was 7.9 months (95% confidence interval, 5.1–13.4 months).
Conclusions:
Tolerability and activity observed in this phase I trial support further investigation of the FTD/TPI–irinotecan–bevacizumab combination in previously treated mCRC.
Data from The DNA Cytosine Deaminase APOBEC3B is a Molecular Determinant of Platinum Responsiveness in Clear Cell Ovarian Cancer
Authors: Serebrenik Artur A. , Argyris Prokopios P. , Jarvis Matthew C. , Brown William L. , Bazzaro Martina , Vogel Rachel I. , Erickson Britt K. , Lee Sun-Hee , Goergen Krista M. , Maurer Matthew J. , Heinzen Ethan P. , Oberg Ann L. , Huang Yajue , Hou Xiaonan , Weroha S. John , Kaufmann Scott H. , Harris Reuben S.
Published: April 2023

AbstractPurpose:
Clear cell ovarian carcinoma (CCOC) is an aggressive disease that often demonstrates resistance to standard chemotherapies. Approximately 25% of patients with CCOC show a strong APOBEC mutation signature. Here, we determine which APOBEC3 enzymes are expressed in CCOC, establish clinical correlates, and identify a new biomarker for detection and intervention.
Experimental Designs:
APOBEC3 expression was analyzed by IHC and qRT-PCR in a pilot set of CCOC specimens (n = 9 tumors). The IHC analysis of APOBEC3B was extended to a larger cohort to identify clinical correlates (n = 48). Dose-response experiments with platinum-based drugs in CCOC cell lines and carboplatin treatment of patient-derived xenografts (PDXs) were done to address mechanistic linkages.
Results:
One DNA deaminase, APOBEC3B, is overexpressed in a formidable subset of CCOC tumors and is low or absent in normal ovarian and fallopian tube epithelial tissues. High APOBEC3B expression associates with improved progression-free survival (P = 0.026) and moderately with overall survival (P = 0.057). Cell-based studies link APOBEC3B activity and subsequent uracil processing to sensitivity to cisplatin and carboplatin. PDX studies extend this mechanistic relationship to CCOC tissues.
Conclusions:
These studies demonstrate that APOBEC3B is overexpressed in a subset of CCOC and, contrary to initial expectations, associated with improved (not worse) clinical outcomes. A likely molecular explanation is that APOBEC3B-induced DNA damage sensitizes cells to additional genotoxic stress by cisplatin. Thus, APOBEC3B is a molecular determinant and a candidate predictive biomarker of the therapeutic response to platinum-based chemotherapy. These findings may have broader translational relevance, as APOBEC3B is overexpressed in many different cancer types.
Data from Adjuvant Sirolimus Does Not Improve Outcome in Pet Dogs Receiving Standard-of-Care Therapy for Appendicular Osteosarcoma: A Prospective, Randomized Trial of 324 Dogs
Authors: LeBlanc Amy K. , Mazcko Christina N. , Cherukuri Aswini , Berger Erika P. , Kisseberth William C. , Brown Megan E. , Lana Susan E. , Weishaar Kristen , Flesner Brian K. , Bryan Jeffrey N. , Vail David M. , Burton Jenna H. , Willcox Jennifer L. , Mutsaers Anthony J. , Woods J. Paul , Northrup Nicole C. , Saba Corey , Curran Kaitlin M. , Leeper Haley , Wilson-Robles Heather , Wustefeld-Janssens Brandan G. , Lindley Stephanie , Smith Annette N. , Dervisis Nikolaos , Klahn Shawna , Higginbotham Mary Lynn , Wouda Raelene M. , Krick Erika , Mahoney Jennifer A. , London Cheryl A. , Barber Lisa G. , Balkman Cheryl E. , McCleary-Wheeler Angela L. , Suter Steven E. , Martin Olya , Borgatti Antonella , Burgess Kristine , Childress Michael O. , Fidel Janean L. , Allstadt Sara D. , Gustafson Daniel L. , Selmic Laura E. , Khanna Chand , Fan Timothy M.
Published: April 2023

AbstractPurpose:
The mTOR pathway has been identified as a key nutrient signaling hub that participates in metastatic progression of high-grade osteosarcoma. Inhibition of mTOR signaling is biologically achievable with sirolimus, and might slow the outgrowth of distant metastases. In this study, pet dogs with appendicular osteosarcoma were leveraged as high-value biologic models for pediatric osteosarcoma, to assess mTOR inhibition as a therapeutic strategy for attenuating metastatic disease progression.
Patients and Methods:
A total of 324 pet dogs diagnosed with treatment-naïve appendicular osteosarcoma were randomized into a two-arm, multicenter, parallel superiority trial whereby dogs received amputation of the affected limb, followed by adjuvant carboplatin chemotherapy ± oral sirolimus therapy. The primary outcome measure was disease-free interval (DFI), as assessed by serial physical and radiologic detection of emergent macroscopic metastases; secondary outcomes included overall 1- and 2-year survival rates, and sirolimus pharmacokinetic variables and their correlative relationship to adverse events and clinical outcomes.
Results:
There was no significant difference in the median DFI or overall survival between the two arms of this trial; the median DFI and survival for standard-of-care (SOC; defined as amputation and carboplatin therapy) dogs was 180 days [95% confidence interval (CI), 144–237] and 282 days (95% CI, 224–383) and for SOC + sirolimus dogs, it was 204 days (95% CI, 157–217) and 280 days (95% CI, 252–332), respectively.
Conclusions:
In a population of pet dogs nongenomically segmented for predicted mTOR inhibition response, sequentially administered adjuvant sirolimus, although well tolerated when added to a backbone of therapy, did not extend DFI or survival in dogs with appendicular osteosarcoma.
Data from Randomized Phase II Trial of Anthracycline-free and Anthracycline-containing Neoadjuvant Carboplatin Chemotherapy Regimens in Stage I–III Triple-negative Breast Cancer (NeoSTOP)
Authors: Sharma Priyanka , Kimler Bruce F. , O'Dea Anne , Nye Lauren , Wang Yen Y. , Yoder Rachel , Staley Joshua M. , Prochaska Lindsey , Wagner Jamie , Amin Amanda L. , Larson Kelsey , Balanoff Christa , Elia Manana , Crane Gregory , Madhusudhana Sheshadri , Hoffmann Marc , Sheehan Maureen , Rodriguez Roberto , Finke Karissa , Shah Rajvi , Satelli Deepti , Shrestha Anuj , Beck Larry , McKittrick Richard , Pluenneke Robert , Raja Vinay , Beeki Venkatadri , Corum Larry , Heldstab Jaimie , LaFaver Stephanie , Prager Micki , Phadnis Milind , Mudaranthakam Dinesh Pal , Jensen Roy A. , Godwin Andrew K. , Salgado Roberto , Mehta Kathan , Khan Qamar
Published: April 2023

AbstractPurpose:
Addition of carboplatin (Cb) to anthracycline chemotherapy improves pathologic complete response (pCR), and carboplatin plus taxane regimens also yield encouraging pCR rates in triple-negative breast cancer (TNBC). Aim of the NeoSTOP multisite randomized phase II trial was to assess efficacy of anthracycline-free and anthracycline-containing neoadjuvant carboplatin regimens.
Patients and Methods:
Patients aged ≥18 years with stage I–III TNBC were randomized (1:1) to receive either paclitaxel (P) weekly × 12 plus carboplatin AUC6 every 21 days × 4 followed by doxorubicin/cyclophosphamide (AC) every 14 days × 4 (CbP → AC, arm A), or carboplatin AUC6 + docetaxel (D) every 21 days × 6 (CbD, arm B). Stromal tumor-infiltrating lymphocytes (sTIL) were assessed. Primary endpoint was pCR in breast and axilla. Other endpoints included residual cancer burden (RCB), toxicity, cost, and event-free (EFS) and overall survival (OS).
Results:
One hundred patients were randomized; arm A (n = 48) or arm B (n = 52). pCR was 54% [95% confidence interval (CI), 40%–69%] in arm A and 54% (95% CI, 40%–68%) in arm B. RCB 0+I rate was 67% in both arms. Median sTIL density was numerically higher in those with pCR compared with those with residual disease (20% vs. 5%; P = 0.25). At median follow-up of 38 months, EFS and OS were similar in the two arms. Grade 3/4 adverse events were more common in arm A compared with arm B, with the most notable differences in neutropenia (60% vs. 8%; P < 0.001) and febrile neutropenia (19% vs. 0%; P < 0.001). There was one treatment-related death (arm A) due to acute leukemia. Mean treatment cost was lower for arm B compared with arm A (P = 0.02).
Conclusions:
The two-drug CbD regimen yielded pCR, RCB 0+I, and survival rates similar to the four-drug regimen of CbP → AC, but with a more favorable toxicity profile and lower treatment-associated cost.
Data from TBCRC 032 IB/II Multicenter Study: Molecular Insights to AR Antagonist and PI3K Inhibitor Efficacy in Patients with AR+ Metastatic Triple-Negative Breast Cancer
Authors: Lehmann Brian D. , Abramson Vandana G. , Sanders Melinda E. , Mayer Erica L. , Haddad Tufia C. , Nanda Rita , Van Poznak Catherine , Storniolo Anna Maria , Nangia Julie R. , Gonzalez-Ericsson Paula I. , Sanchez Violeta , Johnson Kimberly N. , Abramson Richard G. , Chen Sheau-Chiann , Shyr Yu , Arteaga Carlos L. , Wolff Antonio C. , Pietenpol Jennifer A.
Published: April 2023

AbstractPurpose:
Preclinical data demonstrating androgen receptor (AR)–positive (AR+) triple-negative breast cancer (TNBC) cells are sensitive to AR antagonists, and PI3K inhibition catalyzed an investigator-initiated, multi-institutional phase Ib/II study TBCRC032. The trial investigated the safety and efficacy of the AR-antagonist enzalutamide alone or in combination with the PI3K inhibitor taselisib in patients with metastatic AR+ (≥10%) breast cancer.
Patients and Methods:
Phase Ib patients [estrogen receptor positive (ER+) or TNBC] with AR+ breast cancer received 160 mg enzalutamide in combination with taselisib to determine dose-limiting toxicities and the maximum tolerated dose (MTD). Phase II TNBC patients were randomized to receive either enzalutamide alone or in combination with 4 mg taselisib until disease progression. Primary endpoint was clinical benefit rate (CBR) at 16 weeks.
Results:
The combination was tolerated, and the MTD was not reached. The adverse events were hyperglycemia and skin rash. Overall, CBR for evaluable patients receiving the combination was 35.7%, and median progression-free survival (PFS) was 3.4 months. Luminal AR (LAR) TNBC subtype patients trended toward better response compared with non-LAR (75.0% vs. 12.5%, P = 0.06), and increased PFS (4.6 vs. 2.0 months, P = 0.082). Genomic analyses revealed subtype-specific treatment response, and novel FGFR2 fusions and AR splice variants.
Conclusions:
The combination of enzalutamide and taselisib increased CBR in TNBC patients with AR+ tumors. Correlative analyses suggest AR protein expression alone is insufficient for identifying patients with AR-dependent tumors and knowledge of tumor LAR subtype and AR splice variants may identify patients more or less likely to benefit from AR antagonists.
Data from Tarloxotinib Is a Hypoxia-Activated Pan-HER Kinase Inhibitor Active Against a Broad Range of HER-Family Oncogenes
Authors: Estrada-Bernal Adriana , Le Anh T. , Doak Andrea E. , Tirunagaru Vijaya G. , Silva Shevan , Bull Matthew R. , Smaill Jeff B. , Patterson Adam V. , Kim Chul , Liu Stephen V. , Doebele Robert C.
Published: April 2023

AbstractPurpose:
Approved therapies for EGFR exon 20, ERBB2 mutations, and NRG1 fusions are currently lacking for non–small cell lung cancer and other cancers. Tarloxotinib is a prodrug that harnesses tumor hypoxia to generate high levels of a potent, covalent pan-HER tyrosine kinase inhibitor, tarloxotinib-effector (tarloxotinib-E), within the tumor microenvironment. This tumor-selective delivery mechanism was designed to minimize the dose-limiting toxicities that are characteristic of systemic inhibition of wild-type EGFR.
Experimental Design:
Novel and existing patient-derived cell lines and xenografts harboring EGFR exon 20 insertion mutations, ERBB2 mutations and amplification, and NRG1 fusions were tested in vitro and in vivo with tarloxotinib to determine its impact on cancer cell proliferation, apoptosis, and cell signaling.
Results:
Tarloxotinib-E inhibited cell signaling and proliferation in patient-derived cancer models in vitro by directly inhibiting phosphorylation and activation of EGFR, HER2, and HER2/HER3 heterodimers. In vivo, tarloxotinib induced tumor regression or growth inhibition in multiple murine xenograft models. Pharmacokinetic analysis confirmed markedly higher levels of tarloxotinib-E in tumor tissue than plasma or skin. Finally, a patient with lung adenocarcinoma harboring an ERBB2 exon 20 p.A775_G776insYVMA mutation demonstrated a dramatic clinical response to tarloxotinib.
Conclusions:
Experimental data with tarloxotinib validate the novel mechanism of action of a hypoxia-activated prodrug in cancer models by concentrating active drug in the tumor versus normal tissue, and this activity can translate into clinical activity in patients.
Data from Discrimination of Breast Cancer from Healthy Breast Tissue Using a Three-component Diffusion-weighted MRI Model
Authors: Andreassen Maren M. Sjaastad , Rodríguez-Soto Ana E. , Conlin Christopher C. , Vidić Igor , Seibert Tyler M. , Wallace Anne M. , Zare Somaye , Kuperman Joshua , Abudu Boya , Ahn Grace S. , Hahn Michael , Jerome Neil P. , Østlie Agnes , Bathen Tone F. , Ojeda-Fournier Haydee , Goa Pål Erik , Rakow-Penner Rebecca , Dale Anders M.
Published: April 2023

AbstractPurpose:
Diffusion-weighted MRI (DW-MRI) is a contrast-free modality that has demonstrated ability to discriminate between predefined benign and malignant breast lesions. However, how well DW-MRI discriminates cancer from all other breast tissue voxels in a clinical setting is unknown. Here we explore the voxelwise ability to distinguish cancer from healthy breast tissue using signal contributions from the newly developed three-component multi-b-value DW-MRI model.
Experimental Design:
Patients with pathology-proven breast cancer from two datasets (n = 81 and n = 25) underwent multi-b-value DW-MRI. The three-component signal contributions C1 and C2 and their product, C1C2, and signal fractions F1, F2, and F1F2 were compared with the image defined on maximum b-value (DWImax), conventional apparent diffusion coefficient (ADC), and apparent diffusion kurtosis (Kapp). The ability to discriminate between cancer and healthy breast tissue was assessed by the false-positive rate given a sensitivity of 80% (FPR80) and ROC AUC.
Results:
Mean FPR80 for both datasets was 0.016 [95% confidence interval (CI), 0.008–0.024] for C1C2, 0.136 (95% CI, 0.092–0.180) for C1, 0.068 (95% CI, 0.049–0.087) for C2, 0.462 (95% CI, 0.425–0.499) for F1F2, 0.832 (95% CI, 0.797–0.868) for F1, 0.176 (95% CI, 0.150–0.203) for F2, 0.159 (95% CI, 0.114–0.204) for DWImax, 0.731 (95% CI, 0.692–0.770) for ADC, and 0.684 (95% CI, 0.660–0.709) for Kapp. Mean ROC AUC for C1C2 was 0.984 (95% CI, 0.977–0.991).
Conclusions:
The C1C2 parameter of the three-component model yields a clinically useful discrimination between cancer and healthy breast tissue, superior to other DW-MRI methods and obliviating predefining lesions. This novel DW-MRI method may serve as noncontrast alternative to standard-of-care dynamic contrast-enhanced MRI.
Data from Inhibition of MDSC Trafficking with SX-682, a CXCR1/2 Inhibitor, Enhances NK-Cell Immunotherapy in Head and Neck Cancer Models
Authors: Greene Sarah , Robbins Yvette , Mydlarz Wojciech K. , Huynh Angel P. , Schmitt Nicole C. , Friedman Jay , Horn Lucas A. , Palena Claudia , Schlom Jeffrey , Maeda Dean Y. , Zebala John A. , Clavijo Paul E. , Allen Clint
Published: April 2023

AbstractPurpose:
Natural killer (NK)-cell–based immunotherapy may overcome obstacles to effective T-cell–based immunotherapy such as the presence of genomic alterations in IFN response genes and antigen presentation machinery. All immunotherapy approaches may be abrogated by the presence of an immunosuppressive tumor microenvironment present in many solid tumor types, including head and neck squamous cell carcinoma (HNSCC). Here, we studied the role of myeloid-derived suppressor cells (MDSC) in suppressing NK-cell function in HNSCC.
Experimental Design:
The ability of peripheral and tumor-infiltrating MDSC from mice bearing murine oral cancer 2 (MOC2) non-T-cell–inflamed tumors and from patients with HNSCC to suppress NK-cell function was studied with real-time impedance and ELISpot assays. The therapeutic efficacy of SX-682, a small-molecule inhibitor of CXCR1 and CXCR2, was assessed in combination with adoptively transferred NK cells.
Results:
Mice bearing MOC2 tumors pathologically accumulate peripheral CXCR2+ neutrophilic-MDSC (PMN-MDSC) that traffic into tumors and suppress NK-cell function through TGFβ and production of H2O2. Inhibition of MDSC trafficking with orally bioavailable SX-682 significantly abrogated tumor MDSC accumulation and enhanced the tumor infiltration, activation, and therapeutic efficacy of adoptively transferred murine NK cells. Patients with HNSCC harbor significant levels of circulating and tumor-infiltrating CXCR1/2+ CD15+ PMN-MDSC and CD14+ monocytic-MDSC. Tumor MDSC exhibited greater immunosuppression than those in circulation. HNSCC tumor MDSC immunosuppression was mediated by multiple, independent, cell-specific mechanisms including TGFβ and nitric oxide.
Conclusions:
The clinical study of CXCR1/2 inhibitors in combination with adoptively transferred NK cells is warranted.
Data from Safety and Immunogenicity of LY3415244, a Bispecific Antibody Against TIM-3 and PD-L1, in Patients With Advanced Solid Tumors
Authors: Hellmann Matthew D. , Bivi Nicoletta , Calderon Boris , Shimizu Toshio , Delafontaine Brant , Liu Zhuqing Tina , Szpurka Anna M. , Copeland Victoria , Hodi F. Stephen , Rottey Sylvie , Aftimos Philippe , Piao Yongzhe , Gandhi Leena , Galvao Violeta Regnier , Leow Ching Ching , Doi Toshihiko
Published: April 2023

AbstractPurpose:
Investigate the safety and efficacy of LY3415244, a TIM-3/PD-L1 bispecific antibody that blocks TIM-3 and PD-L1 in patients with advanced solid tumors.
Patients and Methods:
A phase I, multicenter, open-label study was conducted in patients with advanced solid tumors. Patients were dosed every 2 weeks intravenously with flat doses of LY3415244 escalating from 3 to 70 mg. The primary endpoints were safety, tolerability, and identification of the recommended phase II dose.
Results:
Between November 2018 and October 2019, 12 patients were enrolled into four cohorts and received at least one dose of LY3415244. Two patients (16.7%) developed clinically significant anaphylactic infusion-related reactions and all patients developed treatment-emergent antidrug antibodies (TE-ADA). ADA titers were sometimes very high and negatively impacted soluble TIM-3 target engagement in most patients. ADA epitope specificity was against both TIM-3 and PD-L1 arms of the bispecific antibody; most TE-ADAs initially targeted the TIM-3 arm after the first dose. Preexisting ADAs against LY3415244 were also detected in normal (unexposed) human serum samples. One patient with PD-1 refractory non–small cell lung cancer had a near partial response (−29.6%).
Conclusions:
This TIM-3 and PD-L1 bispecific format was associated with unexpected immunogenicity targeting both arms of the bispecific antibody, resulting in early study termination. Epitope specificity analysis revealed an initial response toward the TIM-3 arm and presence of preexisting ADAs to the bispecific molecule in the general population. This experience emphasizes the importance of thorough analyses for preexisting ADAs as part of immunogenicity risk assessment of novel antibodies.

See related commentary by de Spéville and Moreno, p. 2669
Data from Immune Infiltrate in the Primary Tumor Predicts Effect of Adjuvant Radiotherapy in Breast Cancer; Results from the Randomized SweBCG91RT Trial
Authors: Stenmark Tullberg Axel , Puttonen Henri A.J. , Sjöström Martin , Holmberg Erik , Chang S. Laura , Feng Felix Y. , Speers Corey , Pierce Lori J. , Lundstedt Dan , Killander Fredrika , Niméus Emma , Kovács Anikó , Karlsson Per
Published: April 2023

AbstractPurpose:
Tumor-infiltrating immune cells play a key role in tumor progression. The purpose of this study was to analyze whether the immune infiltrate predicts benefit from postoperative radiotherapy in a large randomized breast cancer radiotherapy trial.
Experimental Design:
In the SweBCG91RT trial, patients with stage I and II breast cancer were randomized to breast-conserving surgery (BCS) and postoperative radiotherapy or to BCS only and followed for a median time of 15.2 years. The primary tumor immune infiltrate was quantified through two independent methods: IHC and gene expression profiling. For IHC analyses, the absolute stromal area occupied by CD8+ T cells and FOXP3+ T cells, respectively, was used to define the immune infiltrate. For gene expression analyses, immune cells found to be prognostic in independent datasets were pooled into two groups consisting of antitumoral and protumoral immune cells, respectively.
Results:
An antitumoral immune response in the primary tumor was associated with a reduced risk of breast cancer recurrence and predicted less benefit from adjuvant radiotherapy. The interaction between radiotherapy and immune phenotype was significant for any recurrence in both the IHC and gene expression analyses (P = 0.039 and P = 0.035) and was also significant for ipsilateral breast tumor recurrence in the gene expression analyses (P = 0.025).
Conclusions:
Patients with an antitumoral immune infiltrate in the primary tumor have a reduced risk of any recurrence and may derive less benefit from adjuvant radiotherapy. These results may impact decisions regarding postoperative radiotherapy in early breast cancer.
Data from Interventional Radiology for Local Immunotherapy in Oncology
Authors: Tselikas Lambros , Champiat Stephane , Sheth Rahul A. , Yevich Steve , Ammari Samy , Deschamps Frederic , Farhane Siham , Roux Charles , Susini Sandrine , Mouraud Severine , Delpla Alexandre , Raoult Thibault , Robert Caroline , Massard Christophe , Barlesi Fabrice , Soria Jean-Charles , Marabelle Aurélien , de Baere Thierry
Published: April 2023

Abstract
Human intratumoral immunotherapy (HIT-IT) is under rapid development, with promising preliminary results and high expectations for current phase III trials. While outcomes remain paramount for patients and the referring oncologists, the technical aspects of drug injection are critical to the interventional radiologist to ensure optimal and reproducible outcomes. The technical considerations for HIT-IT affect the safety, efficacy, and further development of this treatment option. Image-guided access to the tumor allows the therapeutic index of a treatment to be enhanced by increasing the intratumoral drug concentration while minimizing its systemic exposure and associated on-target off-tumor adverse events. Direct access to the tumor also enables the acquisition of cancer tissue for sequential sampling to better understand the pharmacodynamics of the injected immunotherapy and its efficacy through correlation of immune responses, pathologic responses, and imaging tumor response. The aim of this article is to share the technical insights of HIT-IT, with particular consideration for patient selection, lesion assessment, image guidance, and technical injection options. In addition, the organization of a standard patient workflow is discussed, so as to optimize HIT-IT outcome and the patient experience.
Data from Predictive Biomarkers for Adjuvant Capecitabine Benefit in Early-Stage Triple-Negative Breast Cancer in the FinXX Clinical Trial
Authors: Asleh Karama , Brauer Heather Ann , Sullivan Amy , Lauttia Susanna , Lindman Henrik , Nielsen Torsten O. , Joensuu Heikki , Thompson E. Aubrey , Chumsri Saranya
Published: April 2023

AbstractPurpose:
Recent studies have demonstrated a benefit of adjuvant capecitabine in early breast cancer, particularly in patients with triple-negative breast cancer (TNBC). However, TNBC is heterogeneous and more precise predictive biomarkers are needed.
Experimental Design:
Tumor tissues collected from TNBC patients in the FinXX trial, randomized to adjuvant anthracycline–taxane–based chemotherapy with or without capecitabine, were analyzed using a 770-gene panel targeting multiple biological mechanisms and additional 30-custom genes related to capecitabine metabolism. Hypothesis-generating exploratory analyses were performed to assess biomarker expression in relation to treatment effect using the Cox regression model and interaction tests adjusted for multiplicity.
Results:
One hundred eleven TNBC samples were evaluable (57 without capecitabine and 54 with capecitabine). The median follow-up was 10.2 years. Multivariate analysis showed significant improvement in recurrence-free survival (RFS) favoring capecitabine in four biologically important genes and metagenes, including cytotoxic cells [hazard ratio (HR) = 0.38; 95% confidence intervals (CI), 0.16–0.86, P-interaction = 0.01], endothelial (HR = 0.67; 95% CI, 0.20–2.22, P-interaction = 0.02), mast cells (HR = 0.78; 95% CI, 0.49–1.27, P-interaction = 0.04), and PDL2 (HR = 0.31; 95% CI, 0.12–0.81, P-interaction = 0.03). Furthermore, we identified 38 single genes that were significantly associated with capecitabine benefit, and these were dominated by immune response pathway and enzymes involved in activating capecitabine to fluorouracil, including TYMP. However, these results were not significant when adjusted for multiple testing.
Conclusions:
Genes and metagenes related to antitumor immunity, immune response, and capecitabine activation could identify TNBC patients who are more likely to benefit from adjuvant capecitabine. Given the reduced power to observe significant findings when correcting for multiplicity, our findings provide the basis for future hypothesis-testing validation studies on larger clinical trials.