bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Development and Validation of Machine Learning–based Model for the Prediction of Malignancy in Multiple Pulmonary Nodules: Analysis from Multicentric Cohorts
Authors: Chen Kezhong , Nie Yuntao , Park Samina , Zhang Kai , Zhang Yangming , Liu Yuan , Hui Bengang , Zhou Lixin , Wang Xun , Qi Qingyi , Li Hao , Kang Guannan , Huang Yuqing , Chen Yingtai , Liu Jiabao , Cui Jian , Li Mingru , Park In Kyu , Kang Chang Hyun , Shen Haifeng , Yang Yingshun , Guan Tian , Zhang Yaxiao , Yang Fan , Kim Young Tae , Wang Jun
Published: April 2023

AbstractPurpose:
Nodule evaluation is challenging and critical to diagnose multiple pulmonary nodules (MPNs). We aimed to develop and validate a machine learning–based model to estimate the malignant probability of MPNs to guide decision-making.
Experimental Design:
A boosted ensemble algorithm (XGBoost) was used to predict malignancy using the clinicoradiologic variables of 1,739 nodules from 520 patients with MPNs at a Chinese center. The model (PKU-M model) was trained using 10-fold cross-validation in which hyperparameters were selected and fine-tuned. The model was validated and compared with solitary pulmonary nodule (SPN) models, clinicians, and a computer-aided diagnosis (CADx) system in an independent transnational cohort and a prospective multicentric cohort.
Results:
The PKU-M model showed excellent discrimination [area under the curve; AUC (95% confidence interval (95% CI)), 0.909 (0.854–0.946)] and calibration (Brier score, 0.122) in the development cohort. External validation (583 nodules) revealed that the AUC of the PKU-M model was 0.890 (0.859–0.916), higher than those of the Brock model [0.806 (0.771–0.838)], PKU model [0.780 (0.743–0.817)], Mayo model [0.739 (0.697–0.776)], and VA model [0.682 (0.640–0.722)]. Prospective comparison (200 nodules) showed that the AUC of the PKU-M model [0.871 (0.815–0.915)] was higher than that of surgeons [0.790 (0.711–0.852), 0.741 (0.662–0.804), and 0.727 (0.650–0.788)], radiologist [0.748 (0.671–0.814)], and the CADx system [0.757 (0.682–0.818)]. Furthermore, the model outperformed the clinicians with an increase of 14.3% in sensitivity and 7.8% in specificity.
Conclusions:
After its development using machine learning algorithms, validation using transnational multicentric cohorts, and prospective comparison with clinicians and the CADx system, this novel prediction model for MPNs presented solid performance as a convenient reference to help decision-making.
Data from Therapy-Related Transcriptional Subtypes in Matched Primary and Recurrent Head and Neck Cancer
Authors: Weber Peter , Künstner Axel , Hess Julia , Unger Kristian , Marschner Sebastian , Idel Christian , Ribbat-Idel Julika , Baumeister Philipp , Gires Olivier , Walz Christoph , Rietzler Sibylle , Valeanu Laura , Herkommer Timm , Kreutzer Lisa , Klymenko Olena , Drexler Guido , Kirchner Thomas , Maihöfer Cornelius , Ganswindt Ute , Walch Axel , Sterr Michael , Lickert Heiko , Canis Martin , Rades Dirk , Perner Sven , Berriel Diaz Mauricio , Herzig Stefan , Lauber Kirsten , Wollenberg Barbara , Busch Hauke , Belka Claus , Zitzelsberger Horst
Published: April 2023

AbstractPurpose:
The genetic relatedness between primary and recurrent head and neck squamous cell carcinomas (HNSCC) reflects the extent of heterogeneity and therapy-driven selection of tumor subpopulations. Yet, current treatment of recurrent HNSCC ignores the molecular characteristics of therapy-resistant tumor populations.
Experimental Design:
From 150 tumors, 74 primary HNSCCs were RNA sequenced and 38 matched primary/recurrent tumor pairs were both whole-exome and RNA sequenced. Transcriptome analysis determined the predominant classical (CL), basal (BA), and inflamed-mesenchymal (IMS) transcriptional subtypes according to an established classification. Genomic alterations and clonal compositions of tumors were evaluated from whole-exome data.
Results:
Although CL and IMS subtypes were more common in primary HNSCC with low recurrence rates, the BA subtype was more prevalent and stable in recurrent tumors. The BA subtype was associated with a transcriptional signature of partial epithelial-to-mesenchymal transition (p-EMT) and early recurrence. In 44% of matched cases, the dominant subtype changed from primary to recurrent tumors, preferably from IMS to BA or CL. Expression analysis of prognostic gene sets identified upregulation of hypoxia, p-emt, and radiotherapy resistance signatures and downregulation of tumor inflammation in recurrences compared with index tumors. A relevant subset of primary/recurrent tumor pairs presented no evidence for a common clonal origin.
Conclusions:
Our study showed a high degree of genetic and transcriptional heterogeneity between primary/recurrent tumors, suggesting therapy-related selection of a transcriptional subtype with characteristics unfavorable for therapy. We conclude that therapy decisions should be based on genetic and transcriptional characteristics of recurrences rather than primary tumors to enable optimally tailored treatment strategies.
Data from Phase Ib/II Study of Cetuximab plus Pembrolizumab in Patients with Advanced RAS Wild-Type Colorectal Cancer
Authors: Fountzilas Christos , Bajor David L. , Mukherjee Sarbajit , Saltzman Joel , Witkiewicz Agnieszka K. , Maguire Orla , Minderman Hans , Nambiar Ram , Rosenheck Hanna R. , Knudsen Erik S. , Muhitch Jason B. , Abrams Scott I. , Wang Chong , Hutson Alan D. , Attwood Kristopher , Hicks Karen A. , Jurcevic Jennifer A. , Kalinski Pawel , Iyer Renuka , Boland Patrick M.
Published: April 2023

AbstractPurpose:
We evaluated the antitumor efficacy of cetuximab in combination with pembrolizumab in patients with RAS wild-type (RASwt), metastatic colorectal adenocarcinoma (mCRC).
Patients and Methods:
In this phase Ib/II study, cetuximab was combined with pembrolizumab in patients with RASwt mCRC with ≥ one prior line of therapy for advanced disease. We analyzed baseline on-treatment tumor tissues for changes in the tumor microenvironment (TME), using flow cytometry and multispectral immunofluorescence.
Results:
Forty-four patients were evaluable for efficacy. The study was negative for the primary efficacy endpoint [overall response rate: 2.6%, 6-month progression-free survival (PFS): 31%; P = 0.52]. Median PFS was 4.1 months [95% confidence interval (CI): 3.9–5.5 months]. No increase in adverse effects was identified. We observed favorable immunomodulation with 47% increase in the number of intratumoral CTLs posttreatment (P = 0.035). These changes were more pronounced in patients with tumor shrinkage (P = 0.05). The TME was characterized by high numbers of TIM3+ and CTLA4+ cells; there were few activated OX40+ cells. PD-L1 expression was higher in pretreatment tumor cells from metastatic sites versus primary tumor samples (P < 0.05). Higher numbers of PD-L1+ tumor cells at baseline were associated with tumor shrinkage (P = 0.04). Analysis of immune populations in the blood demonstrated decreases in PD-1+ memory effector cells (P = 0.04) and granulocytic myeloid-derived suppressor cells (P = 0.03), with simultaneous increases in CD4+/CTLA4+ cells (P = 0.01).
Conclusions:
The combination of cetuximab and pembrolizumab is inactive in patients with RASwt mCRC, despite its partial local immunologic efficacy. Further development of immuno-oncology combinations with enhanced efficacy and/or targeting additional or alternative immune checkpoints merits investigation.
Data from An Open-label, Multicenter, Single-arm, Phase II Study of Fluzoparib in Patients with Germline BRCA1/2 Mutation and Platinum-sensitive Recurrent Ovarian Cancer
Authors: Li Ning , Bu Hualei , Liu Jihong , Zhu Jianqing , Zhou Qi , Wang Li , Yin Rutie , Wu Xiaohua , Yao Shuzhong , Gu Kangsheng , Zhang Hui , Li Guiling , Pan Hongming , Wu Qiang , An Ruifang , Yang Xinfeng , Zhu Yaping , Wan Xiaoping , Duan Wei , Xiong Jianping , Guo Hongyan , Lou Ge , Wang Jing , Hu Wenjing , Zhang Xin , Meng Yuanguang , Zhang Ben , Wang Yuting , Wang Quanren , Wu Lingying
Published: April 2023

AbstractPurpose:
Fluzoparib (PARP inhibitor) showed promising antitumor activity for advanced ovarian cancer in a phase I study. This study aimed to assess the efficacy and safety of fluzoparib in patients with germline BRCA1/2-mutated recurrent ovarian cancer.
Patients and Methods:
This open-label, multicenter, single-arm, phase II study enrolled patients with platinum-sensitive recurrent ovarian cancer and germline BRCA1/2 mutation who had previously received two to four lines of platinum-based chemotherapy. Fluzoparib 150 mg was administered orally twice daily. The primary endpoint was independent review committee (IRC)-assessed objective response rate per RECIST v1.1.
Results:
A total of 113 patients were enrolled and received at least one dose of fluzoparib. As of data cutoff on March 21, 2020, the median follow-up period was 15.9 months (interquartile range, 13.5–18.5). The IRC- and investigator-assessed objective response rates were 69.9% [95% confidence interval (CI), 60.6–78.2] and 70.8% (95% CI, 61.5–79.0), respectively. The objective response rates were similar across all prespecified subgroups. The median IRC- and investigator-assessed progression-free survival was 12.0 months (95% CI, 9.3–13.9) and 10.3 months (95% CI, 9.2–12.0), respectively. The 12-month survival rate was 93.7% (95% CI, 87.2–96.9). Grade ≥3 adverse events occurred in 63.7% (72/113) of the patients, with the most common one being anemia/decreased hemoglobin. Adverse events that led to treatment interruption, dose reduction, and discontinuation occurred in 39.8%, 34.5%, and 0.9% of patients, respectively. One treatment-related death occurred.
Conclusions:
Fluzoparib demonstrated promising antitumor activity and acceptable safety profile in germline BRCA1/2-mutated, platinum-sensitive relapsed ovarian cancer. Thus, fluzoparib might be a novel treatment option for this population.
Data from Transcriptomic Profiling Identifies a Risk Stratification Signature for Predicting Peritoneal Recurrence and Micrometastasis in Gastric Cancer
Authors: Lee In-Seob , Lee Heonyi , Hur Hoon , Kanda Mitsuro , Yook Jeong-Hwan , Kim Byung-Sik , Woo Yanghee , Kodera Yasuhiro , Kim Kwangsoo , Goel Ajay
Published: April 2023

AbstractPurpose:
Gastric cancer peritoneal carcinomatosis is fatal. Delay in detection of peritoneal metastases contributes to high mortality, highlighting the need to develop biomarkers that can help identify patients at high risk for peritoneal recurrence or metastasis.
Experimental Design:
We performed a systematic discovery and validation for the identification of peritoneal recurrence prediction and peritoneal metastasis detection biomarkers by analyzing expression profiling datasets from 249 patients with gastric cancer, followed by analysis of 426 patients from three cohorts for clinical validation.
Results:
Genome-wide expression profiling identified a 12-gene panel for robust prediction of peritoneal recurrence in patients with gastric cancer (AUC = 0.95), which was successfully validated in a second dataset (AUC = 0.86). Examination of 216 specimens from a training cohort allowed us to establish a six gene–based risk-prediction model [AUC = 0.72; 95% confidence interval (CI): 0.66–0.78], which was subsequently validated in an independent cohort of 111 patients with gastric cancer (AUC = 0.76; 95% CI: 0.67–0.83). In both cohorts, combining tumor morphology and depth of invasion further improved the predictive accuracy of the prediction model (AUC = 0.84). Thereafter, we evaluated the performance of the identical six-gene panel for its ability to detect peritoneal metastasis by analyzing 210 gastric cancer specimens (prior 111 patients plus additional 99 cases), which discriminated patients with and without peritoneal metastasis (AUC = 0.72). Finally, our biomarker panel was also remarkably effective for identifying peritoneal micrometastasis (AUC = 0.72), and its diagnostic accuracy was significantly enhanced when depth of invasion was included in the model (AUC = 0.85).
Conclusions:
Our novel transcriptomic signature for risk stratification and identification of high-risk patients with peritoneal carcinomatosis might serve as an important clinical decision making in patients with gastric cancer.
Data from Differential Survival and Therapy Benefit of Patients with Breast Cancer Are Characterized by Distinct Epithelial and Immune Cell Microenvironments
Authors: Kester Lennart , Seinstra Danielle , van Rossum Annelot G.J. , Vennin Claire , Hoogstraat Marlous , van der Velden Daphne , Opdam Mark , van Werkhoven Erik , Hahn Kerstin , Nederlof Iris , Lips Ester H. , Mandjes Ingrid A.M. , van Leeuwen-Stok A. Elise , Canisius Sander , van Tinteren Harm , Imholz Alex L.T. , Portielje Johanneke E.A. , Bos Monique E.M.M. , Bakker Sandra D. , Rutgers Emiel J. , Horlings Hugo M. , Wesseling Jelle , Voest Emile E. , Wessels Lodewyk F.A. , Kok Marleen , Oosterkamp Hendrika M. , van Oudenaarden Alexander , Linn Sabine C. , van Rheenen Jacco
Published: April 2023

AbstractPurpose:
Extensive work in preclinical models has shown that microenvironmental cells influence many aspects of cancer cell behavior, including metastatic potential and their sensitivity to therapeutics. In the human setting, this behavior is mainly correlated with the presence of immune cells. Here, in addition to T cells, B cells, macrophages, and mast cells, we identified the relevance of nonimmune cell types for breast cancer survival and therapy benefit, including fibroblasts, myoepithelial cells, muscle cells, endothelial cells, and seven distinct epithelial cell types.
Experimental Design:
Using single-cell sequencing data, we generated reference profiles for all these cell types. We used these reference profiles in deconvolution algorithms to optimally detangle the cellular composition of more than 3,500 primary breast tumors of patients that were enrolled in the SCAN-B and MATADOR clinical trials, and for which bulk mRNA sequencing data were available.
Results:
This large data set enables us to identify and subsequently validate the cellular composition of microenvironments that distinguish differential survival and treatment benefit for different treatment regimens in patients with primary breast cancer. In addition to immune cells, we have identified that survival and therapy benefit are characterized by various contributions of distinct epithelial cell types.
Conclusions:
From our study, we conclude that differential survival and therapy benefit of patients with breast cancer are characterized by distinct microenvironments that include specific populations of immune and epithelial cells.
Data from Therapeutic Targeting of LIF Overcomes Macrophage-mediated Immunosuppression of the Local Tumor Microenvironment
Authors: Hallett Robin M. , Bonfill-Teixidor Ester , Iurlaro Raffaella , Arias Alexandra , Raman Swetha , Bayliss Peter , Egorova Olga , Neva-Alejo Almudena , McGray AJ Robert , Lau Esther , Bosch Alexandre , Beilschmidt Melissa , Maetzel Dorothea , Fransson Johan , Huber-Ruano Isabel , Anido Judit , Julien Jean-Philippe , Giblin Patricia , Seoane Joan
Published: April 2023

AbstractPurpose:
Leukemia inhibitory factor (LIF) is a multifunctional cytokine with numerous reported roles in cancer and is thought to drive tumor development and progression. Characterization of LIF and clinical-stage LIF inhibitors would increase our understanding of LIF as a therapeutic target.
Experimental Design:
We first tested the association of LIF expression with transcript signatures representing multiple processes regulating tumor development and progression. Next, we developed MSC-1, a high-affinity therapeutic antibody that potently inhibits LIF signaling and tested it in immune competent animal models of cancer.
Results:
LIF was associated with signatures of tumor-associated macrophages (TAM) across 7,769 tumor samples spanning 22 solid tumor indications. In human tumors, LIF receptor was highly expressed within the macrophage compartment and LIF treatment drove macrophages to acquire immunosuppressive capacity. MSC-1 potently inhibited LIF signaling by binding an epitope that overlaps with the gp130 receptor binding site on LIF. MSC-1 showed monotherapy efficacy in vivo and drove TAMs to acquire antitumor and proinflammatory function in syngeneic colon cancer mouse models. Combining MSC-1 with anti-PD1 leads to strong antitumor response and a long-term tumor-free survival in a significant proportion of treated mice.
Conclusions:
Overall, our findings highlight LIF as a therapeutic target for cancer immunotherapy.
Data from Whole-body PET Imaging of T-cell Response to Glioblastoma
Authors: Nobashi Tomomi W. , Mayer Aaron T. , Xiao Zunyu , Chan Carmel T. , Chaney Aisling M. , James Michelle L. , Gambhir Sanjiv S.
Published: April 2023

AbstractPurpose:
Immunotherapy is a promising approach for many oncological malignancies, including glioblastoma, however, there are currently no available tools or biomarkers to accurately assess whole-body immune responses in patients with glioblastoma treated with immunotherapy. Here, the utility of OX40, a costimulatory molecule mainly expressed on activated effector T cells known to play an important role in eliminating cancer cells, was evaluated as a PET imaging biomarker to quantify and track response to immunotherapy.
Experimental Design:
A subcutaneous vaccination approach of CpG oligodeoxynucleotide, OX40 mAb, and tumor lysate at a remote site in a murine orthotopic glioma model was developed to induce activation of T cells distantly while monitoring their distribution in stimulated lymphoid organs with respect to observed therapeutic effects. To detect OX40-positive T cells, we utilized our in-house–developed 89Zr-DFO-OX40 mAb and in vivo PET/CT imaging.
Results:
ImmunoPET with 89Zr-DFO-OX40 mAb revealed strong OX40-positive responses with high specificity, not only in the nearest lymph node from vaccinated area (mean, 20.8%ID/cc) but also in the spleen (16.7%ID/cc) and the tumor draining lymph node (11.4%ID/cc). When the tumor was small (<106 p/sec/cm2/sr in bioluminescence imaging), a high number of responders and percentage shrinkage in tumor signal was indicated after only a single cycle of vaccination.
Conclusions:
The results highlight the promise of clinically translating cancer vaccination as a potential glioma therapy, as well as the benefits of monitoring efficacy of these treatments using immunoPET imaging of T-cell activation.
Data from Immune-related Gene Expression Predicts Response to Neoadjuvant Chemotherapy but not Additional Benefit from PD-L1 Inhibition in Women with Early Triple-negative Breast Cancer
Authors: Sinn Bruno V. , Loibl Sibylle , Hanusch Claus A. , Zahm Dirk-Michael , Sinn Hans-Peter , Untch Michael , Weber Karsten , Karn Thomas , Becker Clemens , Marmé Frederik , Schmitt Wolfgang D. , Müller Volkmar , Schem Christian , Treue Denise , Stickeler Elmar , Klauschen Frederik , Burchardi Nicole , Furlanetto Jenny , van Mackelenbergh Marion , Fasching Peter A. , Schneeweiss Andreas , Denkert Carsten
Published: April 2023

AbstractPurpose:
We evaluated mRNA signatures to predict response to neoadjuvant PD-L1 inhibition in combination with chemotherapy in early triple-negative breast cancer.
Experimental Design:
Targeted mRNA sequencing of 2,559 transcripts was performed in formalin-fixed, paraffin-embedded samples from 162 patients of the GeparNuevo trial. We focused on validation of four predefined gene signatures and differential gene expression analyses for new predictive markers.
Results:
Two signatures [GeparSixto signature (G6-Sig) and IFN signature (IFN-Sig)] were predictive for treatment response in a multivariate model including treatment arm [G6-Sig: OR, 1.558; 95% confidence interval (CI), 1.130–2.182; P = 0.008 and IFN-Sig: OR, 1.695; 95% CI, 1.234–2.376; P = 0.002), while the CYT metric predicted pathologic complete response (pCR) in the durvalumab arm, and the proliferation-associated gene signature in the placebo arm. Expression of PD-L1 mRNA was associated with better response in both arms, indicating that increased levels of PD-L1 are a general predictor of neoadjuvant therapy response. In an exploratory analysis, we identified seven genes that were higher expressed in responders in the durvalumab arm, but not the placebo arm: HLA-A, HLA-B, TAP1, GBP1, CXCL10, STAT1, and CD38. These genes were associated with cellular antigen processing and presentation and IFN signaling.
Conclusions:
Immune-associated signatures are associated with pCR after chemotherapy, but might be of limited use for the prediction of response to additional immune checkpoint blockade. Gene expressions related to antigen presentation and IFN signaling might be interesting candidates for further evaluation.
Data from AMC-070: Lenalidomide Is Safe and Effective in HIV-Associated Kaposi Sarcoma
Authors: Reid Erin G. , Shimabukuro Kelly , Moore Page , Ambinder Richard F. , Bui Jack D. , Han Semi , Martínez-Maza Otoniel , Dittmer Dirk P. , Aboulafia David , Chiao Elizabeth Yu , Maurer Toby , Baiocchi Robert , Mitsuyasu Ronald , Wachsman William
Published: April 2023

AbstractPurpose:
Kaposi sarcoma (KS), an endothelial cell tumor associated with KS herpesvirus (KSHV), remains among the most common malignancies occurring with HIV infection (HIV-KS). As an oral anti-inflammatory, antiangiogenic, and immunomodulatory agent, lenalidomide is potentially an attractive alternative to standard chemotherapy for KS.
Experimental Design:
The primary objectives of this phase I/II trial were to determine the maximum tolerated dose (MTD) and response rates for lenalidomide in HIV-KS. Secondary objectives included correlating response with natural killer (NK) and T-cell subsets, plasma cytokines, viral copy number, and KSHV gene expression in biopsies. Four dose levels of oral lenalidomide taken 21 consecutive days of 28-day cycles were evaluated in adults with HIV-KS on antiretroviral therapy with controlled viremia.
Results:
Fifteen and 23 participants enrolled in phases I and II, respectively, 76% of whom had received prior KS therapy. The MTD was not reached, declaring 25 mg as the recommended phase II dose (RP2D). The most frequent adverse events were neutropenia, fatigue, leukopenia, and diarrhea. Of the 25 evaluable participants receiving RP2D, 60% responded. Correlative studies performed in a subset of participants demonstrated a significant increase in proportions of blood T cells with T-regulatory phenotype, and plasma cytokines trended toward a less inflammatory pattern. Clinical response was associated with loss of KSHV transcription.
Conclusions:
Lenalidomide is active in HIV-KS. The most common adverse events were manageable. With 60% of participants receiving RP2D obtaining a partial response and <10% discontinuing due to adverse events, the response and tolerability to lenalidomide support its use in HIV-KS.

See related commentary by Henry and Maki, p. 2485
Data from Translocon-associated Protein Subunit SSR3 Determines and Predicts Susceptibility to Paclitaxel in Breast Cancer and Glioblastoma
Authors: Dmello Crismita , Sonabend Aarón , Arrieta Victor A. , Zhang Daniel Y. , Kanojia Deepak , Chen Li , Gould Andrew , Zhang Jiangshan , Kang Seong Jae , Winter Jan , Horbinski Craig , Amidei Christina , Győrffy Balázs , Cordero Alex , Chang Catalina Lee , Castro Brandyn , Hsu Patrick , Ahmed Atique U. , Lesniak Maciej S. , Stupp Roger , Sonabend Adam M.
Published: April 2023

AbstractPurpose:
Paclitaxel (PTX) is one of the most potent and commonly used chemotherapies for breast and pancreatic cancer. Several ongoing clinical trials are investigating means of enhancing delivery of PTX across the blood–brain barrier for glioblastomas. Despite the widespread use of PTX for breast cancer, and the initiative to repurpose this drug for gliomas, there are no predictive biomarkers to inform which patients will likely benefit from this therapy.
Experimental Design:
To identify predictive biomarkers for susceptibility to PTX, we performed a genome-wide CRISPR knockout (KO) screen using human glioma cells. The genes whose KO was most enriched in the CRISPR screen underwent further selection based on their correlation with survival in the breast cancer patient cohorts treated with PTX and not in patients treated with other chemotherapies, a finding that was validated on a second independent patient cohort using progression-free survival.
Results:
Combination of CRISPR screen results with outcomes from patients with taxane-treated breast cancer led to the discovery of endoplasmic reticulum (ER) protein SSR3 as a putative predictive biomarker for PTX. SSR3 protein levels showed positive correlation with susceptibility to PTX in breast cancer cells, glioma cells, and in multiple intracranial glioma xenografts models. KO of SSR3 turned the cells resistant to PTX while its overexpression sensitized the cells to PTX. Mechanistically, SSR3 confers susceptibility to PTX through regulation of phosphorylation of ER stress sensor IRE1α.
Conclusions:
Our hypothesis generating study showed SSR3 as a putative biomarker for susceptibility to PTX, warranting its prospective clinical validation.
Data from Genome-wide Copy-number Alterations in Circulating Tumor DNA as a Novel Biomarker for Patients with High-grade Serous Ovarian Cancer
Authors: Paracchini Lara , Beltrame Luca , Grassi Tommaso , Inglesi Alessia , Fruscio Robert , Landoni Fabio , Ippolito Davide , Delle Marchette Martina , Paderno Mariachiara , Adorni Marco , Jaconi Marta , Romualdi Chiara , D'Incalci Maurizio , Siravegna Giulia , Marchini Sergio
Published: April 2023

AbstractPurpose:
High-grade serous epithelial ovarian cancer (HGS-EOC) is defined by high levels of somatic copy-number alterations (SCNA) with marked spatial and temporal tumor heterogeneity. Biomarkers serving to monitor drug response and detect disease recurrence are lacking, a fact which reflects an unmet clinical need.
Experimental Design:
A total of 185 plasma samples and 109 matched tumor biopsies were collected from 46 patients with HGS-EOC, and analyzed by shallow whole-genome sequencing (sWGS). The percentage of tumor fraction (TF) in the plasma was used to study the biological features of the disease at the time of diagnosis (T0) and correlated with patients' survival. Longitudinal analysis of TF was correlated with CA-125 levels and radiological images to monitor disease recurrence.
Results:
Gain in the clonal regions, 3q26.2 and 8q24.3, was observed in the 87.8% and 78.05% of plasma samples, suggesting that plasma sWGS mirrors solid biopsies. At T0, multivariate analysis revealed that plasma TF levels were an independent prognostic marker of relapse (P < 0.022). After platinum (Pt)-based treatment, circulating tumor DNA (ctDNA) analysis showed a change in the heterogeneous pattern of genomic amplification, including an increased frequency of amplification, compared with before Pt-based treatment in the 19p31.11 and 19q13.42 regions. TF in serially collected ctDNA samples outperformed CA-125 in anticipating clinical and radiological progression by 240 days (range, 37–491).
Conclusions:
Our results support the notion that sWGS is an inexpensive and useful tool for the genomic analysis of ctDNA in patients with HGS-EOC to monitor disease evolution and to anticipate relapse better than serum CA-125, the routinely used clinical biomarker.

See related commentary by Dhani, p. 2372
Data from Therapeutic Targeting of Nemo-like Kinase in Primary and Acquired Endocrine-resistant Breast Cancer
Authors: Wang Xian , Veeraraghavan Jamunarani , Liu Chia-Chia , Cao Xixi , Qin Lanfang , Kim Jin-Ah , Tan Ying , Loo Suet Kee , Hu Yiheng , Lin Ling , Lee Sanghoon , Shea Martin J. , Mitchell Tamika , Li Shunqiang , Ellis Matthew J. , Hilsenbeck Susan G. , Schiff Rachel , Wang Xiao-Song
Published: April 2023

AbstractPurpose:
Endocrine resistance remains a major clinical challenge in estrogen receptor (ER)–positive breast cancer. Despite the encouraging results from clinical trials for the drugs targeting known survival signaling, relapse is still inevitable. There is an unmet need to discover new drug targets in the unknown escape pathways. Here, we report Nemo-like kinase (NLK) as a new actionable kinase target that endows previously uncharacterized survival signaling in endocrine-resistant breast cancer.
Experimental Design:
The effects of NLK inhibition on the viability of endocrine-resistant breast cancer cell lines were examined by MTS assay. The effect of VX-702 on NLK activity was verified by kinase assay. The modulation of ER and its coactivator, SRC-3, by NLK was examined by immunoprecipitation, kinase assay, luciferase assay, and RNA sequencing. The therapeutic effects of VX-702 and everolimus were tested on cell line- and patient-derived xenograft (PDX) tumor models.
Results:
NLK overexpression endows reduced endocrine responsiveness and is associated with worse outcome of patients treated with tamoxifen. Mechanistically, NLK may function, at least in part, via enhancing the phosphorylation of ERα and its key coactivator, SRC-3, to modulate ERα transcriptional activity. Through interrogation of a kinase profiling database, we uncovered and verified a highly selective dual p38/NLK inhibitor, VX-702. Coadministration of VX-702 with the mTOR inhibitor, everolimus, demonstrated a significant therapeutic effect in cell line-derived xenograft and PDX tumor models of acquired or de novo endocrine resistance.
Conclusions:
Together, this study reveals the potential of therapeutic modulation of NLK for the management of the endocrine-resistant breast cancers with active NLK signaling.
Data from Determinants of Response to Talazoparib in Patients with HER2-Negative, Germline BRCA1/2-Mutated Breast Cancer
Authors: Blum Joanne L. , Laird A. Douglas , Litton Jennifer K. , Rugo Hope S. , Ettl Johannes , Hurvitz Sara A. , Martin Miguel , Roché Henri H. , Lee Kyung-Hun , Goodwin Annabel , Chen Ying , Lanzalone Silvana , Chelliserry Jijumon , Czibere Akos , Hopkins Julia F. , Albacker Lee A. , Mina Lida A.
Published: April 2023

AbstractPurpose:
PARP inhibitors (PARPi) have demonstrated efficacy in tumors with germline breast cancer susceptibility genes (gBRCA) 1 and 2 mutations, but further factors influencing response to PARPi are poorly understood.
Experimental Design:
Breast cancer tumor tissue from patients with gBRCA1/2 mutations from the phase III EMBRACA trial of the PARPi talazoparib versus chemotherapy was sequenced using FoundationOne CDx.
Results:
In the evaluable intent-to-treat population, 96.1% (296/308) had ≥1 tumor BRCA (tBRCA) mutation and there was strong concordance (95.3%) between tBRCA and gBRCA mutational status. Genetic/genomic characteristics including BRCA loss of heterozygosity (LOH; identified in 82.6% of evaluable patients), DNA damage response (DDR) gene mutational burden, and tumor homologous recombination deficiency [assessed by genomic LOH (gLOH)] demonstrated no association with talazoparib efficacy.
Conclusions:
Overall, BRCA LOH status, DDR gene mutational burden, and gLOH were not associated with talazoparib efficacy; however, these conclusions are qualified by population heterogeneity and low patient numbers in some subgroups. Further investigation in larger patient populations is warranted.
Data from Outcome and Immune Correlates of a Phase II Trial of High-Dose Interleukin-2 and Stereotactic Ablative Radiotherapy for Metastatic Renal Cell Carcinoma
Authors: Hannan Raquibul , Mohamad Osama , Diaz de Leon Alberto , Manna Subrata , Pop Laurentiu M. , Zhang Ze , Mannala Samantha , Christie Alana , Christley Scott , Monson Nancy , Ishihara Dan , Hsu Eric J. , Ahn Chul , Kapur Payal , Chen Mingyi , Arriaga Yull , Courtney Kevin , Cantarel Brandi , Wakeland Edward K. , Fu Yang-Xin , Pedrosa Ivan , Cowell Lindsay , Wang Tao , Margulis Vitaly , Choy Hak , Timmerman Robert D. , Brugarolas James
Published: April 2023

AbstractPurpose:
This phase II clinical trial evaluated whether the addition of stereotactic ablative radiotherapy (SAbR), which may promote tumor antigen presentation, improves the overall response rate (ORR) to high-dose IL2 (HD IL2) in metastatic renal cell carcinoma (mRCC).
Patients and Methods:
Patients with pathologic evidence of clear cell renal cell carcinoma (RCC) and radiographic evidence of metastasis were enrolled in this single-arm trial and were treated with SAbR, followed by HD IL2. ORR was assessed based on nonirradiated metastases. Secondary endpoints included overall survival (OS), progression-free survival (PFS), toxicity, and treatment-related tumor-specific immune response. Correlative studies involved whole-exome and transcriptome sequencing, T-cell receptor sequencing, cytokine analysis, and mass cytometry on patient samples.
Results:
Thirty ethnically diverse mRCC patients were enrolled. A median of two metastases were treated with SAbR. Among 25 patients evaluable by RECIST v1.1, ORR was 16% with 8% complete responses. Median OS was 37 months. Treatment-related adverse events (AE) included 22 grade ≥3 events that were not dissimilar from HD IL2 alone. There were no grade 5 AEs. A correlation was observed between SAbR to lung metastases and improved PFS (P = 0.0165). Clinical benefit correlated with frameshift mutational load, mast cell tumor infiltration, decreased circulating tumor-associated T-cell clones, and T-cell clonal expansion. Higher regulatory/CD8+ T-cell ratios at baseline in the tumor and periphery correlated with no clinical benefit.
Conclusions:
Adding SAbR did not improve the response rate to HD IL2 in patients with mRCC in this study. Tissue analyses suggest a possible correlation between frameshift mutation load as well as tumor immune infiltrates and clinical outcomes.
Data from Preclinical Characterization of a Next-Generation Brain Permeable, Paradox Breaker BRAF Inhibitor
Authors: Wichmann Jürgen , Rynn Caroline , Friess Thomas , Petrig-Schaffland Jeannine , Kornacker Martin , Handl Cornelia , Emmenegger Jasmin , Eckmann Jan , Herting Frank , Frances Nicolas , Hunziker Daniel , Krummenacher Daniela , Rüttinger Dominik , Ribeiro Alison , Bacac Marina , Brigo Alessandro , Hewings David S. , Dummer Reinhard , Levesque Mitchell P. , Schnetzler Gabriel , Martoglio Bruno , Bischoff James R. , Pettazzoni Piergiorgio
Published: April 2023

AbstractPurpose:
Disease progression in BRAF V600E/K positive melanomas to approved BRAF/MEK inhibitor therapies is associated with the development of resistance mediated by RAF dimer inducing mechanisms. Moreover, progressing disease after BRAFi/MEKi frequently involves brain metastasis. Here we present the development of a novel BRAF inhibitor (Compound Ia) designed to address the limitations of available BRAFi/MEKi.
Experimental Design:
The novel, brain penetrant, paradox breaker BRAFi is comprehensively characterized in vitro, ex vivo, and in several preclinical in vivo models of melanoma mimicking peripheral disease, brain metastatic disease, and acquired resistance to first-generation BRAFi.
Results:
Compound Ia manifested elevated potency and selectivity, which triggered cytotoxic activity restricted to BRAF-mutated models and did not induce RAF paradoxical activation. In comparison to approved BRAFi at clinical relevant doses, this novel agent showed a substantially improved activity in a number of diverse BRAF V600E models. In addition, as a single agent, it outperformed a currently approved BRAFi/MEKi combination in a model of acquired resistance to clinically available BRAFi. Compound Ia presents high central nervous system (CNS) penetration and triggered evident superiority over approved BRAFi in a macro-metastatic and in a disseminated micro-metastatic brain model. Potent inhibition of MAPK by Compound Ia was also demonstrated in patient-derived tumor samples.
Conclusions:
The novel BRAFi demonstrates preclinically the potential to outperform available targeted therapies for the treatment of BRAF-mutant tumors, thus supporting its clinical investigation.
Data from Inactivation of AMPK Leads to Attenuation of Antigen Presentation and Immune Evasion in Lung Adenocarcinoma
Authors: Gao Yajing , Päivinen Pekka , Tripathi Sushil , Domènech-Moreno Eva , Wong Iris P.L. , Vaahtomeri Kari , Nagaraj Ashwini S. , Talwelkar Sarang S. , Foretz Marc , Verschuren Emmy W. , Viollet Benoit , Yan Yan , Mäkelä Tomi P.
Published: April 2023

AbstractPurpose:
Mutations in STK11 (LKB1) occur in 17% of lung adenocarcinoma (LUAD) and drive a suppressive (cold) tumor immune microenvironment (TIME) and resistance to immunotherapy. The mechanisms underpinning the establishment and maintenance of a cold TIME in LKB1-mutant LUAD remain poorly understood. In this study, we investigated the role of the LKB1 substrate AMPK in immune evasion in human non—small cell lung cancer (NSCLC) and mouse models and explored the mechanisms involved.
Experimental Design:
We addressed the role of AMPK in immune evasion in NSCLC by correlating AMPK phosphorylation and immune-suppressive signatures and by deleting AMPKα1 (Prkaa1) and AMPKα2 (Prkaa2) in a KrasG12D-driven LUAD. Furthermore, we dissected the molecular mechanisms involved in immune evasion by comparing gene-expression signatures, AMPK activity, and immune infiltration in mouse and human LUAD and gain or loss-of-function experiments with LKB1- or AMPK-deficient cell lines.
Results:
Inactivation of both AMPKα1 and AMPKα2 together with Kras activation accelerated tumorigenesis and led to tumors with reduced infiltration of CD8+/CD4+ T cells and gene signatures associated with a suppressive TIME. These signatures recapitulate those in Lkb1-deleted murine LUAD and in LKB1-deficient human NSCLC. Interestingly, a similar signature is noted in human NSCLC with low AMPK activity. In mechanistic studies, we find that compromised LKB1 and AMPK activity leads to attenuated antigen presentation in both LUAD mouse models and human NSCLC.
Conclusions:
The results provide evidence that the immune evasion noted in LKB1-inactivated lung cancer is due to subsequent inactivation of AMPK and attenuation of antigen presentation.
Data from Phase I/IIa Trial of BMS-986148, an Anti-mesothelin Antibody–drug Conjugate, Alone or in Combination with Nivolumab in Patients with Advanced Solid Tumors
Authors: Rottey Sylvie , Clarke Jeffrey , Aung Kyaw , Machiels Jean-Pascal , Markman Ben , Heinhuis Kimberley M. , Millward Michael , Lolkema Martijn , Patel Sandip Pravin , de Souza Paul , Duca Matteo , Curigliano Giuseppe , Santoro Armando , Koyama Takafumi , Brown Michelle , Vezina Heather , He Chunsheng , Chu Quincy Siu-Chung
Published: April 2023

AbstractPurpose:
To assess the safety and tolerability of BMS-986148, a mesothelin-directed antibody–drug conjugate (ADC) ± nivolumab, in patients with selected tumors.
Patients and Methods:
In an international phase I/IIa study [NCT02341625 (CA008-002)], patients received BMS-986148 monotherapy (0.1–1.6 mg/kg intravenously (i.v.) every 3 weeks or 0.4 or 0.6 mg/kg i.v. once weekly; n = 96) or BMS-986148 0.8 mg/kg + nivolumab 360 mg i.v. every 3 weeks (n = 30). The primary endpoint was safety and tolerability.
Results:
In CA008-002, the most common (≥ 10%) treatment-related adverse events (TRAEs) included increased aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. Grade 3/4 TRAEs occurred in 42 patients (49%) receiving BMS-986148 every 3 weeks monotherapy, three (25%) receiving BMS-986148 once-weekly monotherapy, and 10 (33%) receiving BMS-986148 + nivolumab every 3 weeks. Overall, 17 of 126 patients (13%) discontinued because of a TRAE. The MTD of BMS-986148 was 1.2 mg/kg i.v. every 3 weeks. The safety profile of BMS-986148 + nivolumab was similar to that of BMS-986148 monotherapy (0.8 mg/kg). Active ADC exposures increased in a dose-proportional manner with both dosing regimens (every 3 weeks and once weekly). Preliminary clinical activity was observed with BMS-986148 ± nivolumab. No association between mesothelin expression and response was detected.
Conclusions:
BMS-986148 ± nivolumab demonstrated a clinically manageable safety profile and preliminary evidence of clinical activity, supporting additional studies combining directed cytotoxic therapies with checkpoint inhibitors as potential multimodal therapeutic strategies in patients with advanced solid tumors.
Data from Agrin Loss in Barrett's Esophagus-Related Neoplasia and Its Utility as a Diagnostic and Predictive Biomarker
Authors: Rickelt Steffen , Neyaz Azfar , Condon Charlene , Whittaker Charles A. , Zaidi Ali H. , Taylor Martin S. , Abbruzzese Genevieve , Mattia Anthony R. , Zukerberg Lawrence , Shroff Stuti G. , Yilmaz Omer H. , Yilmaz Osman , Wu Elizabeth Y. , Choi Won-Tak , Jobe Blair A. , Odze Robert D. , Patil Deepa T. , Deshpande Vikram , Hynes Richard O.
Published: April 2023

AbstractPurpose:
There is an unmet need for identifying novel biomarkers in Barrett's esophagus that could stratify patients with regards to neoplastic progression. We investigate the expression patterns of extracellular matrix (ECM) molecules in Barrett's esophagus and Barrett's esophagus–related neoplasia, and assess their value as biomarkers for the diagnosis of Barrett's esophagus–related neoplasia and to predict neoplastic progression.
Experimental Design:
Gene-expression analyses of ECM matrisome gene sets were performed using publicly available data on human Barrett's esophagus, Barrett's esophagus–related dysplasia, esophageal adenocarcinoma (ADCA) and normal esophagus. Immunohistochemical expression of basement membrane (BM) marker agrin (AGRN) and p53 was analyzed in biopsies of Barrett's esophagus–related neoplasia from 321 patients in three independent cohorts.
Results:
Differential gene-expression analysis revealed significant enrichment of ECM matrisome gene sets in dysplastic Barrett's esophagus and ADCA compared with controls. Loss of BM AGRN expression was observed in both Barrett's esophagus–related dysplasia and ADCA. The mean AGRN loss in Barrett's esophagus glands was significantly higher in Barrett's esophagus–related dysplasia and ADCA compared with non-dysplastic Barrett's esophagus (NDBE; P < 0.001; specificity = 82.2% and sensitivity = 96.4%). Loss of AGRN was significantly higher in NDBE samples from progressors compared with non-progressors (P < 0.001) and identified patients who progressed to advanced neoplasia with a specificity of 80.2% and sensitivity of 54.8%. Moreover, the combination of AGRN loss and abnormal p53 staining identified progression to Barrett's esophagus–related advanced neoplasia with a specificity and sensitivity of 86.5% and 58.7%.
Conclusions:
We highlight ECM changes during Barrett's esophagus progression to neoplasia. BM AGRN loss is a novel diagnostic biomarker that can identify patients with NDBE at increased risk of developing advanced neoplasia.
Data from Cholesterol-Lowering Intervention Decreases mTOR Complex 2 Signaling and Enhances Antitumor Immunity
Authors: Wang Yanping , You Sungyong , Su Shengchen , Yeon Austin , Lo Eric M. , Kim Sungjin , Mohler James L. , Freeman Michael R. , Kim Hyung L.
Published: April 2023

AbstractPurpose:
There is a need for strategies to prevent prostate cancer. Cholesterol-lowering interventions are employed widely and safely to reduce risk of cardiovascular disease and has been proposed for chemoprevention. Using preclinical models and a window-of-opportunity clinical trial, we describe an adaptive antitumor immunity resulting from cholesterol lowering.
Experimental Design:
Statins do not reliably lower serum cholesterol in mice. Therefore, oral ezetimibe was administered to mice to lower serum cholesterol to clinically relevant levels and evaluated the final adaptive immune response. T-lymphocytes-specific mTORC2 knockout mice were used to evaluate mTOR signaling and antitumor immunity. Pretreatment and posttreatment prostate tumors and lymphocytes were examined from a window-of-opportunity clinical trial where men with prostate cancer were treated with 2 to 6 weeks of aggressive cholesterol-lowering intervention prior to radical prostatectomy.
Results:
Mice treated with oral ezetimibe exhibited enhanced antitumor immunity against syngeneic cancers in a CD8+ lymphocyte-dependent manner, produced immunity that was transferrable through lymphocytes, and had enhanced central CD8+ T-cell memory. In mice and in patients undergoing prostatectomy, lowering serum cholesterol inhibited mTORC2 signaling in lymphocytes and increased infiltration of CD8+ lymphocytes into prostate tumors. T-lymphocyte-specific mTORC2 knockout mice demonstrated enhanced CD8+ lymphocyte function and antitumor capacity. In patients, cholesterol-lowering intervention prior to prostatectomy decreased the proliferation of normal prostate and low-grade adenocarcinomas.
Conclusions:
Lowering serum cholesterol decreased signaling through mTORC2 and enhanced antitumor CD8+ T-cell memory. We provide a rationale for large-scale clinical testing of cholesterol lowering strategies for prostate cancer chemoprevention.
Data from Plasma Protein Biomarkers in Advanced or Metastatic Colorectal Cancer Patients Receiving Chemotherapy With Bevacizumab or Cetuximab: Results from CALGB 80405 (Alliance)
Authors: Nixon Andrew B. , Sibley Alexander B. , Liu Yingmiao , Hatch Ace J. , Jiang Chen , Mulkey Flora , Starr Mark D. , Brady John C. , Niedzwiecki Donna , Venook Alan P. , Baez-Diaz Luis , Lenz Heinz-Josef , O'Neil Bert H. , Innocenti Federico , Meyerhardt Jeffrey A. , O'Reilly Eileen M. , Owzar Kouros , Hurwitz Herbert I.
Published: April 2023

AbstractPurpose:
CALGB 80405 compared the combination of first-line chemotherapy with cetuximab or bevacizumab in the treatment of advanced or metastatic colorectal cancer (mCRC). Although similar clinical outcomes were observed in the cetuximab-chemotherapy group and the bevacizumab-chemotherapy group, biomarkers could identify patients deriving more benefit from either biologic agent.
Patients and Methods:
In this exploratory analysis, the Angiome, a panel of 24 soluble protein biomarkers were measured in baseline plasma samples in CALGB 80405. Prognostic biomarkers were determined using univariate Cox proportional hazards models. Predictive biomarkers were identified using multivariable Cox regression models including interaction between biomarker level and treatment.
Results:
In the total population, high plasma levels of Ang-2, CD73, HGF, ICAM-1, IL6, OPN, TIMP-1, TSP-2, VCAM-1, and VEGF-R3 were identified as prognostic of worse progression-free survival (PFS) and overall survival (OS). PlGF was identified as predictive of lack of PFS benefit from bevacizumab [bevacizumab HR, 1.51; 95% confidence interval (CI), 1.10–2.06; cetuximab HR, 0.94; 95% CI, 0.71–1.25; Pinteraction = 0.0298] in the combined FOLFIRI/FOLFOX regimens. High levels of VEGF-D were predictive of lack of PFS benefit from bevacizumab in patients receiving FOLFOX regimen only (FOLFOX/bevacizumab HR, 1.70; 95% CI, 1.19–2.42; FOLFOX/cetuximab HR, 0.92; 95% CI, 0.68–1.24; Pinteraction = 0.0097).
Conclusions:
In this exploratory, hypothesis-generating analysis, the Angiome identified multiple prognostic biomarkers and two potential predictive biomarkers for patients with mCRC enrolled in CALGB 80405. PlGF and VEGF-D predicted lack of benefit from bevacizumab in a chemo-dependent manner.

See related commentaries by Mishkin and Kohn, p. 2722 and George and Bertagnolli, p. 2725