bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Integrative Profiling of T790M-Negative EGFR-Mutated NSCLC Reveals Pervasive Lineage Transition and Therapeutic Opportunities
Authors: Chua Khi Pin , Teng Yvonne H.F. , Tan Aaron C. , Takano Angela , Alvarez Jacob J.S. , Nahar Rahul , Rohatgi Neha , Lai Gillianne G.Y. , Aung Zaw Win , Yeong Joe P.S. , Lim Kiat Hon , Naeini Marjan Mojtabavi , Kassam Irfahan , Jain Amit , Tan Wan Ling , Gogna Apoorva , Too Chow Wei , Kanesvaran Ravindran , Ng Quan Sing , Ang Mei Kim , Rajasekaran Tanujaa , Anantham Devanand , Phua Ghee Chee , Tan Bien Soo , Lee Yin Yeng , Wang Lanying , Teo Audrey S.M. , Khng Alexis Jiaying , Lim Ming Jie , Suteja Lisda , Toh Chee Keong , Lim Wan-Teck , Iyer N. Gopalakrishna , Tam Wai Leong , Tan Eng-Huat , Zhai Weiwei , Hillmer Axel M. , Skanderup Anders J. , Tan Daniel S.W.
Published: April 2023

AbstractPurpose:
Despite the established role of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutated NSCLC, drug resistance inevitably ensues, with a paucity of treatment options especially in EGFRT790M-negative resistance.
Experimental Design:
We performed whole-exome and transcriptome analysis of 59 patients with first- and second-generation EGFR TKI-resistant metastatic EGFR-mutated NSCLC to characterize and compare molecular alterations mediating resistance in T790M-positive (T790M+) and -negative (T790M−) disease.
Results:
Transcriptomic analysis revealed ubiquitous loss of adenocarcinoma lineage gene expression in T790M− tumors, orthogonally validated using multiplex IHC. There was enrichment of genomic features such as TP53 alterations, 3q chromosomal amplifications, whole-genome doubling and nonaging mutational signatures in T790M− tumors. Almost half of resistant tumors were further classified as immunehot, with clinical outcomes conditional on immune cell-infiltration state and T790M status. Finally, using a Bayesian statistical approach, we explored how T790M− and T790M+ disease might be predicted using comprehensive genomic and transcriptomic profiles of treatment-naïve patients.
Conclusions:
Our results illustrate the interplay between genetic alterations, cell lineage plasticity, and immune microenvironment in shaping divergent TKI resistance and outcome trajectories in EGFR-mutated NSCLC. Genomic and transcriptomic profiling may facilitate the design of bespoke therapeutic approaches tailored to a tumor's adaptive potential.
Data from Molecular Subtyping Combined with Biological Pathway Analyses to Study Regorafenib Response in Clinically Relevant Mouse Models of Colorectal Cancer
Authors: Lafferty Adam , O'Farrell Alice C. , Migliardi Giorgia , Khemka Niraj , Lindner Andreas U. , Sassi Francesco , Zanella Eugenia R. , Salvucci Manuela , Vanderheyden Evy , Modave Elodie , Boeckx Bram , Halang Luise , Betge Johannes , Ebert Matthias P.A. , Dicker Patrick , Argilés Guillem , Tabernero Josep , Dienstmann Rodrigo , Medico Enzo , Lambrechts Diether , Bertotti Andrea , Isella Claudio , Trusolino Livio , Prehn Jochen H.M. , Byrne Annette T.
Published: April 2023

AbstractPurpose:
Regorafenib (REG) is approved for the treatment of metastatic colorectal cancer, but has modest survival benefit and associated toxicities. Robust predictive/early response biomarkers to aid patient stratification are outstanding. We have exploited biological pathway analyses in a patient-derived xenograft (PDX) trial to study REG response mechanisms and elucidate putative biomarkers.
Experimental Design:
Molecularly subtyped PDXs were annotated for REG response. Subtyping was based on gene expression (CMS, consensus molecular subtype) and copy-number alteration (CNA). Baseline tumor vascularization, apoptosis, and proliferation signatures were studied to identify predictive biomarkers within subtypes. Phospho-proteomic analysis was used to identify novel classifiers. Supervised RNA sequencing analysis was performed on PDXs that progressed, or did not progress, following REG treatment.
Results:
Improved REG response was observed in CMS4, although intra-subtype response was variable. Tumor vascularity did not correlate with outcome. In CMS4 tumors, reduced proliferation and higher sensitivity to apoptosis at baseline correlated with response. Reverse phase protein array (RPPA) analysis revealed 4 phospho-proteomic clusters, one of which was enriched with non-progressor models. A classification decision tree trained on RPPA- and CMS-based assignments discriminated non-progressors from progressors with 92% overall accuracy (97% sensitivity, 67% specificity). Supervised RNA sequencing revealed that higher basal EPHA2 expression is associated with REG resistance.
Conclusions:
Subtype classification systems represent canonical “termini a quo” (starting points) to support REG biomarker identification, and provide a platform to identify resistance mechanisms and novel contexts of vulnerability. Incorporating functional characterization of biological systems may optimize the biomarker identification process for multitargeted kinase inhibitors.
Data from Diagnostic Performance of 18F-DCFPyL-PET/CT in Men with Biochemically Recurrent Prostate Cancer: Results from the CONDOR Phase III, Multicenter Study
Authors: Morris Michael J. , Rowe Steven P. , Gorin Michael A. , Saperstein Lawrence , Pouliot Frédéric , Josephson David , Wong Jeffrey Y.C. , Pantel Austin R. , Cho Steve Y. , Gage Kenneth L. , Piert Morand , Iagaru Andrei , Pollard Janet H. , Wong Vivien , Jensen Jessica , Lin Tess , Stambler Nancy , Carroll Peter R. , Siegel Barry A.
Published: April 2023

AbstractPurpose:
Current FDA-approved imaging modalities are inadequate for localizing prostate cancer biochemical recurrence (BCR). 18F-DCFPyL is a highly selective, small-molecule prostate-specific membrane antigen–targeted PET radiotracer. CONDOR was a prospective study designed to determine the performance of 18F-DCFPyL-PET/CT in patients with BCR and uninformative standard imaging.
Experimental Design:
Men with rising PSA ≥0.2 ng/mL after prostatectomy or ≥2 ng/mL above nadir after radiotherapy were eligible. The primary endpoint was correct localization rate (CLR), defined as positive predictive value with an additional requirement of anatomic lesion colocalization between 18F-DCFPyL-PET/CT and a composite standard of truth (SOT). The SOT consisted of, in descending priority (i) histopathology, (ii) subsequent correlative imaging findings, or (iii) post-radiation PSA response. The trial was considered a success if the lower bound of the 95% confidence interval (CI) for CLR exceeded 20% for two of three 18F-DCFPyL-PET/CT readers. Secondary endpoints included change in intended management and safety.
Results:
A total of 208 men with a median baseline PSA of 0.8 ng/mL (range: 0.2–98.4 ng/mL) underwent 18F-DCFPyL-PET/CT. The CLR was 84.8%–87.0% (lower bound of 95% CI: 77.8–80.4). A total of 63.9% of evaluable patients had a change in intended management after 18F-DCFPyL-PET/CT. The disease detection rate was 59% to 66% (at least one lesion detected per patient by 18F-DCFPyL-PET/CT by central readers).
Conclusions:
Performance of 18F-DCFPyL-PET/CT achieved the study’s primary endpoint, demonstrating disease localization in the setting of negative standard imaging and providing clinically meaningful and actionable information. These data further support the utility of 18F-DCFPyL-PET/CT to localize disease in men with recurrent prostate cancer.

See related commentary by True and Chen, p. 3512
Data from Independent Validation of the PAM50-Based Chemo-Endocrine Score (CES) in Hormone Receptor–Positive HER2-Positive Breast Cancer Treated with Neoadjuvant Anti–HER2-Based Therapy
Authors: Pascual Tomás , Fernandez-Martinez Aranzazu , Tanioka Maki , Dieci M. Vittoria , Pernas Sonia , Gavila Joaquin , Guarneri Valentina , Cortes Javier , Villagrasa Patricia , Chic Núria , Vidal Maria , Adamo Barbara , Muñoz Montserrat , Griguolo Gaia , Llombart Antonio , Conte Pierfranco , Oliveira Mafalda , Conte Benedetta , Paré Laia , Galvan Patricia , Carey Lisa A. , Perou Charles M. , Prat Aleix
Published: April 2023

AbstractPurpose:
We do not yet have validated biomarkers to predict response and outcome within hormone receptor–positive/HER2-positive (HR+/HER2+) breast cancer. The PAM50-based chemo-endocrine score (CES) predicts chemo-endocrine sensitivity in hormone receptor–positive/HER2-negative (HR+/HER2−) breast cancer. Here, we evaluate the relationship of CES with response and survival in HR+/HER2+ breast cancer.
Experimental Design:
Intrinsic subtype and clinicopathologic data were obtained from seven studies in which patients were treated with HER2-targeted therapy either with endocrine therapy (ET) or with chemotherapy (CTX). CES was evaluated as a continuous variable and categorically from low to high scores [CES-C (chemo-sensitive), CES-U (uncertain), and CES-E (endocrine-sensitive)]. We first analyzed each dataset individually, and then all combined. Multivariable analyses were used to test CES association with pathologic complete response (pCR) and disease-free survival (DFS).
Results:
A total of 457 patients were included (112 with ET and 345 with CTX). In the combined cohort, CES-C, CES-U, and CES-E were identified in 60%, 23%, and 17% of the patients, respectively. High CES (i.e., CES-E) was associated with a lower probability of achieving pCR independently of clinical characteristics, therapy, intrinsic subtype, and study (adjusted OR = 0.42; P = 0.016). A total of 295 patients were analyzed for DFS with a median follow-up of 66 months. High CES was also associated with better DFS (adjusted HR, 0.174; P = 0.003) independently of pCR, clinical characteristics and intrinsic subtype. In patients with residual disease, the adjusted DFS HR of CES was 0.160 (P = 0.012).
Conclusions:
In HER2+/HR+ breast cancer, CES is useful for predicting chemo-endocrine sensitivity and provides additional prognostication beyond intrinsic subtype and clinicopathologic characteristics.
Data from Activation of the IFN Signaling Pathway is Associated with Resistance to CDK4/6 Inhibitors and Immune Checkpoint Activation in ER-Positive Breast Cancer
Authors: De Angelis Carmine , Fu Xiaoyong , Cataldo Maria Letizia , Nardone Agostina , Pereira Resel , Veeraraghavan Jamunarani , Nanda Sarmistha , Qin Lanfang , Sethunath Vidyalakshmi , Wang Tao , Hilsenbeck Susan G. , Benelli Matteo , Migliaccio Ilenia , Guarducci Cristina , Malorni Luca , Litchfield Lacey M. , Liu Jiangang , Donaldson Joshua , Selenica Pier , Brown David N. , Weigelt Britta , Reis-Filho Jorge S. , Park Ben H. , Hurvitz Sara A. , Slamon Dennis J. , Rimawi Mothaffar F. , Jansen Valerie M. , Jeselsohn Rinath , Osborne C. Kent , Schiff Rachel
Published: April 2023

AbstractPurpose:
Cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (CDK4/6i) are highly effective against estrogen receptor–positive (ER+)/HER2− breast cancer; however, intrinsic and acquired resistance is common. Elucidating the molecular features of sensitivity and resistance to CDK4/6i may lead to identification of predictive biomarkers and novel therapeutic targets, paving the way toward improving patient outcomes.
Experimental Design:
Parental breast cancer cells and their endocrine-resistant derivatives (EndoR) were used. Derivatives with acquired resistance to palbociclib (PalboR) were generated from parental and estrogen deprivation–resistant MCF7 and T47D cells. Transcriptomic and proteomic analyses were performed in palbociclib-sensitive and PalboR lines. Gene expression data from CDK4/6i neoadjuvant trials and publicly available datasets were interrogated for correlations of gene signatures and patient outcomes.
Results:
Parental and EndoR breast cancer lines showed varying degrees of sensitivity to palbociclib. Transcriptomic analysis of these cell lines identified an association between high IFN signaling and reduced CDK4/6i sensitivity; thus an “IFN-related palbociclib-resistance Signature” (IRPS) was derived. In two neoadjuvant trials of CDK4/6i plus endocrine therapy, IRPS and other IFN-related signatures were highly enriched in patients with tumors exhibiting intrinsic resistance to CDK4/6i. PalboR derivatives displayed dramatic activation of IFN/STAT1 signaling compared with their short-term treated or untreated counterparts. In primary ER+/HER2− tumors, the IRPS score was significantly higher in lumB than lumA subtype and correlated with increased gene expression of immune checkpoints, endocrine resistance, and poor prognosis.
Conclusions:
Aberrant IFN signaling is associated with intrinsic resistance to CDK4/6i. Experimentally, acquired resistance to palbociclib is associated with activation of the IFN pathway, warranting additional studies to clarify its involvement in resistance to CDK4/6i.
Data from Adjuvant Low-dose Statin Use after Radical Prostatectomy: The PRO-STAT Randomized Clinical Trial
Authors: Jeong In Gab , Lim Bumjin , Yun Sung-Cheol , Lim Ju Hyun , Hong Jun Hyuk , Kim Choung-Soo
Published: April 2023

AbstractPurpose:
Statin use is reportedly associated with the risk of prostate cancer, outcomes after treatment, and prostate cancer-specific mortality. We sought to determine the efficacy of adjuvant atorvastatin in prostate cancer after radical prostatectomy.
Patients and Methods:
In this randomized, double-blind trial, we assigned patients with pathologic high-risk prostate cancer to receive either low-dose atorvastatin (20 mg/day, n = 183) or placebo (n = 181) for 1 year after radical prostatectomy. The primary endpoint was the 1-year biochemical recurrence rate. The secondary endpoints included the 5-year biochemical recurrence-free survival and changes in lipid, testosterone, and sex hormone binding globulin levels.
Results:
From October 2012 through January 2019, a total of 364 patients underwent randomization. Among 59 total primary end points, 30 (16.4%) and 29 (16.0%) occurred in the atorvastatin and placebo groups, respectively. Atorvastatin did not significantly reduce the primary endpoint of 1-year biochemical recurrence [HR, 0.96; 95% confidence interval (CI), 0.58–1.60]. During a median follow-up of 24 months, 131 patients experienced biochemical recurrence (68 in the atorvastatin group and 63 in the placebo group), representing Kaplan–Meier estimated event rates of 24.0% and 25.4% in the atorvastatin and placebo groups, respectively, at 24 months (HR, 1.00; 95% CI, 0.71–1.41). We observed no significant between-group differences in the testosterone and sex hormone binding globulin levels.
Conclusions:
Among patients with high-risk pathologic features after radical prostatectomy for prostate cancer, 1-year adjuvant use of atorvastatin was not associated with a lower risk of disease recurrence compared with that for placebo. (ClinicalTrials.gov number, NCT01759836).

See related commentary by Murtola and Siltari, p. 4947
Data from Fecal Microbiota Transplantation from Overweight or Obese Donors in Cachectic Patients with Advanced Gastroesophageal Cancer: A Randomized, Double-blind, Placebo-Controlled, Phase II Study
Authors: de Clercq Nicolien C. , van den Ende Tom , Prodan Andrei , Hemke Robert , Davids Mark , Pedersen Helle K. , Nielsen Henrik B. , Groen A.K. , de Vos Willem M. , van Laarhoven Hanneke W.M. , Nieuwdorp Max
Published: April 2023

AbstractPurpose:
Cachexia is a multifactorial syndrome, associated with poor survival in patients with cancer, and is influenced by the gut microbiota. We investigated the effects of fecal microbiota transplantation (FMT) on cachexia and treatment response in patients with advanced gastroesophageal cancer.
Experimental Design:
In a double-blind randomized placebo-controlled trial performed in the Amsterdam University Medical Center, we assigned 24 cachectic patients with metastatic HER2-negative gastroesophageal cancer to either allogenic FMT (healthy obese donor) or autologous FMT, prior to palliative chemotherapy (capecitabine and oxaliplatin). Primary objective was to assess the effect of allogenic FMT on satiety. Secondary outcomes were other features of cachexia, along with disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and toxicity. Finally, exploratory analyses were performed on the effect of FMT on gut microbiota composition (metagenomic sequencing) and metabolites (untargeted metabolomics).
Results:
Allogenic FMT did not improve any of the cachexia outcomes. Patients in the allogenic group (n = 12) had a higher DCR at 12 weeks (P = 0.035) compared with the autologous group (n = 12), longer median OS of 365 versus 227 days [HR = 0.38; 95% confidence interval (CI), 0.14–1.05; P = 0.057] and PFS of 204 versus 93 days (HR = 0.50; 95% CI, 0.21–1.20; P = 0.092). Patients in the allogenic group showed a significant shift in fecal microbiota composition after FMT (P = 0.010) indicating proper engraftment of the donor microbiota.
Conclusions:
FMT from a healthy obese donor prior to first-line chemotherapy did not affect cachexia, but may have improved response and survival in patients with metastatic gastroesophageal cancer. These results provide a rational for larger FMT trials.
Data from Inhibition of Hedgehog Signaling Alters Fibroblast Composition in Pancreatic Cancer
Authors: Steele Nina G. , Biffi Giulia , Kemp Samantha B. , Zhang Yaqing , Drouillard Donovan , Syu LiJyun , Hao Yuan , Oni Tobiloba E. , Brosnan Erin , Elyada Ela , Doshi Abhishek , Hansma Christa , Espinoza Carlos , Abbas Ahmed , The Stephanie , Irizarry-Negron Valerie , Halbrook Christopher J. , Franks Nicole E. , Hoffman Megan T. , Brown Kristee , Carpenter Eileen S. , Nwosu Zeribe C. , Johnson Craig , Lima Fatima , Anderson Michelle A. , Park Youngkyu , Crawford Howard C. , Lyssiotis Costas A. , Frankel Timothy L. , Rao Arvind , Bednar Filip , Dlugosz Andrzej A. , Preall Jonathan B. , Tuveson David A. , Allen Benjamin L. , Pasca di Magliano Marina
Published: April 2023

AbstractPurpose:
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease characterized by an extensive fibroinflammatory stroma, which includes abundant cancer-associated fibroblast (CAF) populations. PDAC CAFs are heterogeneous, but the nature of this heterogeneity is incompletely understood. The Hedgehog pathway functions in PDAC in a paracrine manner, with ligands secreted by cancer cells signaling to stromal cells in the microenvironment. Previous reports investigating the role of Hedgehog signaling in PDAC have been contradictory, with Hedgehog signaling alternately proposed to promote or restrict tumor growth. In light of the newly discovered CAF heterogeneity, we investigated how Hedgehog pathway inhibition reprograms the PDAC microenvironment.
Experimental Design:
We used a combination of pharmacologic inhibition, gain- and loss-of-function genetic experiments, cytometry by time-of-flight, and single-cell RNA sequencing to study the roles of Hedgehog signaling in PDAC.
Results:
We found that Hedgehog signaling is uniquely activated in fibroblasts and differentially elevated in myofibroblastic CAFs (myCAF) compared with inflammatory CAFs (iCAF). Sonic Hedgehog overexpression promotes tumor growth, while Hedgehog pathway inhibition with the smoothened antagonist, LDE225, impairs tumor growth. Furthermore, Hedgehog pathway inhibition reduces myCAF numbers and increases iCAF numbers, which correlates with a decrease in cytotoxic T cells and an expansion in regulatory T cells, consistent with increased immunosuppression.
Conclusions:
Hedgehog pathway inhibition alters fibroblast composition and immune infiltration in the pancreatic cancer microenvironment.
Data from Genome-Wide miRNA Expression Profiling of Molecular Subgroups of Peripheral T-cell Lymphoma
Authors: Lone Waseem , Bouska Alyssa , Sharma Sunandini , Amador Catalina , Saumyaranjan Mallick , Herek Tyler A. , Heavican Tayla B. , Yu Jiayu , Lim Soon Thye , Ong Choon Kiat , Slack Graham W. , Savage Kerry J. , Rosenwald Andreas , Ott German , Cook James R. , Feldman Andrew L. , Rimsza Lisa M. , McKeithan Timothy W. , Greiner Timothy C. , Weisenburger Dennis D. , Melle Federica , Motta Giovanna , Pileri Stefano , Vose Julie M. , Chan Wing C. , Iqbal Javeed
Published: April 2023

AbstractPurpose:
Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non–Hodgkin lymphomas with aggressive clinical behavior. We performed comprehensive miRNA profiling in PTCLs and corresponding normal CD4+ Th1/2 and TFH-like polarized subsets to elucidate the role of miRNAs in T-cell lymphomagenesis.
Experimental Design:
We used nCounter (NanoString Inc) for miRNA profiling and validated using Taqman qRT-PCR (Applied Biosystems, Inc). Normal CD4+ T cells were polarized into effector Th subsets using signature cytokines, and miRNA significance was revealed using functional experiments.
Results:
Effector Th subsets showed distinct miRNA expression with corresponding transcription factor expression (e.g., BCL6/miR-19b, -106, -30d, -26b, in IL21-polarized; GATA3/miR-155, miR-337 in Th2-polarized; and TBX21/miR-181a, -331-3p in Th1-polarized cells). Integration of miRNA signatures suggested activation of TCR and PI3K signaling in IL21-polarized cells, ERK signaling in Th1-polarized cells, and AKT–mTOR signaling in Th2-polarized cells, validated at protein level. In neoplastic counterparts, distinctive miRNAs were identified and confirmed in an independent cohort. Integrative miRNA–mRNA analysis identified a decrease in target transcript abundance leading to deregulation of sphingolipid and Wnt signaling and epigenetic dysregulation in angioimmunoblastic T-cell lymphoma (AITL), while ERK, MAPK, and cell cycle were identified in PTCL subsets, and decreased target transcript abundance was validated in an independent cohort. Elevated expression of miRNAs (miR-126-3p, miR-145-5p) in AITL was associated with poor clinical outcome. In silico and experimental validation suggest two targets (miR-126→ SIPR2 and miR-145 → ROCK1) resulting in reduced RhoA-GTPase activity and T–B-cell interaction.
Conclusions:
Unique miRNAs and deregulated oncogenic pathways are associated with PTCL subtypes. Upregulated miRNA-126-3p and miR-145-5p expression regulate RhoA-GTPase and inhibit T-cell migration, crucial for AITL pathobiology.
Data from Attenuation of SRC Kinase Activity Augments PARP Inhibitor–mediated Synthetic Lethality in BRCA2-altered Prostate Tumors
Authors: Chakraborty Goutam , Patail Nabeela Khan , Hirani Rahim , Nandakumar Subhiksha , Mazzu Ying Z. , Yoshikawa Yuki , Atiq Mohammad , Jehane Lina E. , Stopsack Konrad H. , Lee Gwo-Shu Mary , Abida Wassim , Morris Michael J. , Mucci Lorelei A. , Danila Daniel , Kantoff Philip W.
Published: April 2023

AbstractPurpose:
Alterations in DNA damage repair (DDR) pathway genes occur in 20%–25% of men with metastatic castration-resistant prostate cancer (mCRPC). Although PARP inhibitors (PARPis) have been shown to benefit men with mCRPC harboring DDR defects due to mutations in BRCA1/2 and ATM, additional treatments are necessary because the effects are not durable.
Experimental Design:
We performed transcriptomic analysis of publicly available mCRPC cases, comparing BRCA2 null with BRCA2 wild-type. We generated BRCA2-null prostate cancer cells using CRISPR/Cas9 and treated these cells with PARPis and SRC inhibitors. We also assessed the antiproliferative effects of combination treatment in 3D prostate cancer organoids.
Results:
We observed significant enrichment of the SRC signaling pathway in BRCA2-altered mCRPC. BRCA2-null prostate cancer cell lines had increased SRC phosphorylation and higher sensitivity to SRC inhibitors (e.g., dasatinib, bosutinib, and saracatinib) relative to wild-type cells. Combination treatment with PARPis and SRC inhibitors was antiproliferative and had a synergistic effect in BRCA2-null prostate cancer cells, mCRPC organoids, and Trp53/Rb1-null prostate cancer cells. Inhibition of SRC signaling by dasatinib augmented DNA damage in BRCA2-null prostate cancer cells. Moreover, SRC knockdown increased PARPi sensitivity in BRCA2-null prostate cancer cells.
Conclusions:
This work suggests that SRC activation may be a potential mechanism of PARPi resistance and that treatment with SRC inhibitors may overcome this resistance. Our preclinical study demonstrates that combining PARPis and SRC inhibitors may be a promising therapeutic strategy for patients with BRCA2-null mCRPC.
Data from Changes in Diffuse Optical Tomography Images During Early Stages of Neoadjuvant Chemotherapy Correlate with Tumor Response in Different Breast Cancer Subtypes
Authors: Altoe Mirella L. , Kalinsky Kevin , Marone Alessandro , Kim Hyun K. , Guo Hua , Hibshoosh Hanina , Tejada Mariella , Crew Katherine D. , Accordino Melissa K. , Trivedi Meghna S. , Hershman Dawn L. , Hielscher Andreas H.
Published: April 2023

AbstractPurpose:
This study's primary objective was to evaluate the changes in optically derived parameters acquired with a diffuse optical tomography breast imaging system (DOTBIS) in the tumor volume of patients with breast carcinoma receiving neoadjuvant chemotherapy (NAC).
Experimental Design:
In this analysis of 105 patients with stage II–III breast cancer, normalized mean values of total hemoglobin (ctTH{b_N}$), oxyhemoglobin (ct{O_2}H{b_N}$), deoxy-hemoglobin concentration (ctHH{b_N}$), water, and oxygen saturation (St{O_2}_N$) percentages were collected at different timepoints during NAC and compared with baseline measurements. This report compared changes in these optical biomarkers measured in patients who did not achieve a pathologic complete response (non-pCR) and those with a pCR. Differences regarding molecular subtypes were included for hormone receptor–positive and HER2-negative, HER2-positive, and triple-negative breast cancer.
Results:
At baseline, ctHH{b_N}$ was higher for pCR tumors (3.97 ± 2.29) compared with non-pCR tumors (3.00 ± 1.72; P = 0.031). At the earliest imaging point after starting therapy, the mean change of ctHH{b_N}$ compared with baseline ({\Delta _{TP1}}ctHH{b_N}$) was statistically significantly higher in non-pCR (1.23 ± 0.67) than in those with a pCR (0.87 ± 0.61; P < 0.0005), and significantly correlated to residual cancer burden classification (r = 0.448; P < 0.0005). {\Delta _{TP1}}ctHH{b_N}$ combined with HER2 status was proposed as a two-predictor logistic model, with AUC = 0.891; P < 0.0005; and 95% confidence interval, 0.812–0.969.
Conclusions:
This study demonstrates that DOTBIS measured features change over time according to tumor pCR status and may predict early in the NAC treatment course whether a patient is responding to NAC.
Data from Differences in Prostate Cancer Genomes by Self-reported Race: Contributions of Genetic Ancestry, Modifiable Cancer Risk Factors, and Clinical Factors
Authors: Stopsack Konrad H. , Nandakumar Subhiksha , Arora Kanika , Nguyen Bastien , Vasselman Samantha E. , Nweji Barbara , McBride Sean M. , Morris Michael J. , Rathkopf Dana E. , Slovin Susan F. , Danila Daniel C. , Autio Karen A. , Scher Howard I. , Mucci Lorelei A. , Solit David B. , Gönen Mithat , Chen Yu , Berger Michael F. , Schultz Nikolaus , Abida Wassim , Kantoff Philip W.
Published: April 2023

AbstractPurpose:
Black men die from prostate cancer twice as often as White men, a disparity likely due to inherited genetics, modifiable cancer risk factors, and healthcare access. It is incompletely understood how and why tumor genomes differ by self-reported race and genetic ancestry.
Experimental Design:
Among 2,069 men with prostate cancer (1,841 self-reported White, 63 Asian, 165 Black) with access to clinical-grade sequencing at the same cancer center, prevalence of tumor and germline alterations was assessed in cancer driver genes reported to have different alteration prevalence by race.
Results:
Clinical characteristics such as prostate-specific antigen and age at diagnosis as well as cancer stage at sample procurement differed by self-reported race. However, most genomic differences persisted when adjusting for clinical characteristics. Tumors from Black men harbored fewer PTEN mutations and more AR alterations than those from White men. Tumors from Asian men had more FOXA1 mutations and more ZFHX3 alterations than White men. Despite fewer TP53 mutations, tumors from Black men had more aneuploidy, particularly chromosome arm 8q gains, an adverse prognostic factor. Genetic ancestry was associated with similar tumor alterations as self-reported race, but also with modifiable cancer risk factors. Community-level average income was associated with chr8q gains after adjusting for race and ancestry.
Conclusions:
Tumor genomics differed by race even after accounting for clinical characteristics. Equalizing access to care may not fully eliminate such differences. Therapies for alterations more common in racial minorities are needed. Tumor genomic differences should not be assumed to be entirely due to germline genetics.
Data from Spatially Distinct Reprogramming of the Tumor Microenvironment Based On Tumor Invasion in Diffuse-Type Gastric Cancers
Authors: Jeong Hye Young , Ham In-Hye , Lee Sung Hak , Ryu Daeun , Son Sang-Yong , Han Sang-Uk , Kim Tae-Min , Hur Hoon
Published: April 2023

AbstractPurpose:
Histologic features of diffuse-type gastric cancer indicate that the tumor microenvironment (TME) may substantially impact tumor invasiveness. However, cellular components and molecular features associated with cancer invasiveness in the TME of diffuse-type gastric cancers are poorly understood.
Experimental Design:
We performed single-cell RNA-sequencing (scRNA-seq) using tissue samples from superficial and deep invasive layers of cancerous and paired normal tissues freshly harvested from five patients with diffuse-type gastric cancer. The scRNA-seq results were validated by immunohistochemistry (IHC) and duplex in situ hybridization (ISH) in formalin-fixed paraffin-embedded tissues.
Results:
Seven major cell types were identified. Fibroblasts, endothelial cells, and myeloid cells were categorized as being enriched in the deep layers. Cell type–specific clustering further revealed that the superficial-to-deep layer transition is associated with enrichment in inflammatory endothelial cells and fibroblasts with upregulated CCL2 transcripts. IHC and duplex ISH revealed the distribution of the major cell types and CCL2-expressing endothelial cells and fibroblasts, indicating tumor invasion. Elevation of CCL2 levels along the superficial-to-deep layer axis revealed the immunosuppressive immune cell subtypes that may contribute to tumor cell aggressiveness in the deep invasive layers of diffuse-type gastric cancer. The analyses of public datasets revealed the high-level coexpression of stromal cell–specific genes and that CCL2 correlated with poor survival outcomes in patients with gastric cancer.
Conclusions:
This study reveals the spatial reprogramming of the TME that may underlie invasive tumor potential in diffuse-type gastric cancer. This TME profiling across tumor layers suggests new targets, such as CCL2, that can modify the TME to inhibit tumor progression in diffuse-type gastric cancer.

See related commentary by Huang and Brekken, p. 6284
Data from Long-Acting Recombinant Human Interleukin-7, NT-I7, Increases Cytotoxic CD8 T Cells and Enhances Survival in Mouse Glioma Models
Authors: Campian Jian L. , Ghosh Subhajit , Kapoor Vaishali , Yan Ran , Thotala Sukrutha , Jash Arijita , Hu Tong , Mahadevan Anita , Rifai Kasem , Page Logan , Lee Byung Ha , Ferrando-Martinez Sara , Wolfarth Alexandra A. , Yang Se Hwan , Hallahan Dennis , Chheda Milan G. , Thotala Dinesh
Published: April 2023

AbstractPurpose:
Patients with glioblastoma (GBM) are treated with radiotherapy (RT) and temozolomide (TMZ). These treatments may cause prolonged systemic lymphopenia, which itself is associated with poor outcomes. NT-I7 is a long-acting IL7 that expands CD4 and CD8 T-cell numbers in humans and mice. We tested whether NT-I7 prevents systemic lymphopenia and improves survival in mouse models of GBM.
Experimental Design:
C57BL/6 mice bearing intracranial tumors (GL261 or CT2A) were treated with RT (1.8 Gy/day × 5 days), TMZ (33 mg/kg/day × 5 days), and/or NT-I7 (10 mg/kg on the final day of RT). We followed the mice for survival while serially analyzing levels of circulating T lymphocytes. We assessed regulatory T cells (Treg) and cytotoxic T lymphocytes in the tumor microenvironment, cervical lymph nodes, spleen, and thymus, and hematopoietic stem and progenitor cells in the bone marrow.
Results:
GBM tumor–bearing mice treated with RT+NT-I7 increased T lymphocytes in the lymph nodes, thymus, and spleen, enhanced IFNγ production, and decreased Tregs in the tumor which was associated with a significant increase in survival. NT-I7 also enhanced central memory and effector memory CD8 T cells in lymphoid organs and tumor. Depleting CD8 T cells abrogated the effects of NT-I7. Furthermore, NT-I7 treatment decreased progenitor cells in the bone marrow.
Conclusions:
In orthotopic glioma-bearing mice, NT-I7 mitigates RT-related lymphopenia, increases cytotoxic CD8 T lymphocytes systemically and in the tumor, and improves survival. A phase I/II trial to evaluate NT-I7 in patients with high-grade gliomas is ongoing (NCT03687957).
Data from Single-Cell Profiling Reveals Metabolic Reprogramming as a Resistance Mechanism in BRAF-Mutated Multiple Myeloma
Authors: Waldschmidt Johannes M. , Kloeber Jake A. , Anand Praveen , Frede Julia , Kokkalis Antonis , Dimitrova Valeriya , Potdar Sayalee , Nair Monica S. , Vijaykumar Tushara , Im Nam Gyu , Guillaumet-Adkins Amy , Chopra Nitish , Stuart Hannah , Budano Lillian , Sotudeh Noori , Guo Guangwu , Grassberger Clemens , Yee Andrew J. , Laubach Jacob P. , Richardson Paul G. , Anderson Kenneth C. , Raje Noopur S. , Knoechel Birgit , Lohr Jens G.
Published: April 2023

AbstractPurpose:
Although remarkably effective in some patients, precision medicine typically induces only transient responses despite initial absence of resistance-conferring mutations. Using BRAF-mutated myeloma as a model for resistance to precision medicine we investigated if BRAF-mutated cancer cells have the ability to ensure their survival by rapidly adapting to BRAF inhibitor treatment.
Experimental Design:
Full-length single-cell RNA (scRNA) sequencing (scRNA-seq) was conducted on 3 patients with BRAF-mutated myeloma and 1 healthy donor. We sequenced 1,495 cells before, after 1 week, and at clinical relapse to BRAF/MEK inhibitor treatment. We developed an in vitro model of dabrafenib resistance using genetically homogeneous single-cell clones from two cell lines with established BRAF mutations (U266, DP6). Transcriptional and epigenetic adaptation in resistant cells were defined by RNA-seq and H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq). Mitochondrial metabolism was characterized by metabolic flux analysis.
Results:
Profiling by scRNA-seq revealed rapid cellular state changes in response to BRAF/MEK inhibition in patients with myeloma and cell lines. Transcriptional adaptation preceded detectable outgrowth of genetically discernible drug-resistant clones and was associated with widespread enhancer remodeling. As a dominant vulnerability, dependency on oxidative phosphorylation (OxPhos) was induced. In treated individuals, OxPhos was activated at the time of relapse and showed inverse correlation to MAPK activation. Metabolic flux analysis confirmed OxPhos as a preferential energetic resource of drug-persistent myeloma cells.
Conclusions:
This study demonstrates that cancer cells have the ability to rapidly adapt to precision treatments through transcriptional state changes, epigenetic adaptation, and metabolic rewiring, thus facilitating the development of refractory disease while simultaneously exposing novel vulnerabilities.
Data from Safety and Antitumor Activity of α-PD-L1 Antibody as Monotherapy or in Combination with α-TIM-3 Antibody in Patients with Microsatellite Instability–High/Mismatch Repair–Deficient Tumors
Authors: Hollebecque Antoine , Chung Hyun C. , de Miguel Maria J. , Italiano Antoine , Machiels Jean-Pascal , Lin Chia-Chi , Dhani Neesha C. , Peeters Marc , Moreno Victor , Su Wu-Chou , Chow Kay Hoong , Galvao Violeta R. , Carlsen Michelle , Yu Danni , Szpurka Anna M. , Zhao Yumin , Schmidt Shelly L. , Gandhi Leena , Xu Xiaojian , Bang Yung-Jue
Published: April 2023

AbstractPurpose:
Immune checkpoint inhibitors show high response rates and durable clinical benefit in microsatellite instability–high/mismatch repair–deficient (MSI-H/dMMR) tumors. However, 50%–60% do not respond to single-agent anti–programmed death-1/programmed death ligand 1 (PD-1/PD-L1) antibodies, and approximately 50% of responders relapse within 6–12 months. This phase Ib trial evaluated safety and antitumor activity of anti–PD-L1 antibody LY3300054 monotherapy or in combination with anti–TIM-3 antibody LY3321367 in patients with MSI-H/dMMR advanced solid tumors.
Patients and Methods:
Eligible patients ≥18 years without prior anti–PD-1/PD-L1 therapy received LY3300054 monotherapy (N = 40) or combination (N = 20); patients with PD-1/PD-L1 inhibitor–resistant/refractory tumors received the combination (N = 22). LY3300054 (700 mg) and anti–TIM-3 antibody (cycles 1–2: 1,200 mg, cycle 3 onward: 600 mg) were administered intravenously every 2 weeks. Primary endpoints were safety and tolerability.
Results:
Eighty-two patients were enrolled. Most had colorectal (n = 39, 47.6%) or endometrial (n = 14, 17.1%) tumors. More than 70% of patients in the PD-1/PD-L1 inhibitor–resistant/refractory combination cohort had received ≥3 treatment lines. Treatment-related adverse events (TRAE) occurred in 22 patients (55.0%) receiving monotherapy, 13 (65.0%) in the PD-1/PD-L1 inhibitor–naïve combination cohort, and 6 (27.3%) in the PD-1/PD-L1 inhibitor–resistant/refractory combination cohort. A total of 2 patients (5.0%) receiving monotherapy and 3 (7.1%) receiving the combination experienced grade ≥3 TRAEs. Objective responses occurred in 13 patients (32.5%) with monotherapy, 9 (45.0%) in the PD-1/PD-L1 inhibitor–naïve combination cohort, and 1 patient (4.5%) in the PD-1/PD-L1 inhibitor–resistant/refractory combination cohort.
Conclusions:
LY3300054 monotherapy and combined LY3300054/anti–TIM-3 had manageable safety profiles. Both regimens showed promising clinical activity against PD-1/PD-L1 inhibitor–naïve MSI-H/dMMR tumors. The combination had limited clinical benefit in patients with PD-1/PD-L1 inhibitor–resistant/refractory MSI-H/dMMR tumors.
Data from Phase I Study of Taminadenant (PBF509/NIR178), an Adenosine 2A Receptor Antagonist, with or without Spartalizumab (PDR001), in Patients with Advanced Non–Small Cell Lung Cancer
Authors: Chiappori Alberto A. , Creelan Ben , Tanvetyanon Tawee , Gray Jhanelle E. , Haura Eric B. , Thapa Ram , Barlow Margaret L. , Chen Zhihua , Chen Dung Tsa , Beg Amer A. , Boyle Theresa A. , Castro Julio , Morgan Liza , Morris Erick , Aregay Mehreteab , Hurtado Felipe K. , Manenti Luigi , Antonia Scott
Published: April 2023

AbstractPurpose:
The adenosine 2A receptor (A2AR) mediates the immunosuppressive effects of adenosine in the tumor microenvironment and is highly expressed in non–small cell lung cancer (NSCLC). Taminadenant (PBF509/NIR178) is an A2AR antagonist able to reactivate the antitumor immune response.
Patients and Methods:
In this phase I/Ib, dose-escalation/expansion study, patients with advanced/metastatic NSCLC and ≥1 prior therapy received taminadenant (80–640 mg, orally, twice a day) with or without spartalizumab (anti–programmed cell death-1, 400 mg, i.v., every 4 weeks). Primary endpoints were safety, tolerability, and feasibility of the combination.
Results:
During dose escalation, 25 patients each received taminadenant alone or with spartalizumab; 19 (76.0%) and 9 (36.0%) had received prior immunotherapy, respectively. Dose-limiting toxicities (all Grade 3) with taminadenant alone were alanine/aspartate aminotransferase increase and nausea [n = 1 (4.0%) each; 640 mg], and in the combination group were pneumonitis [n = 2 (8.0%); 160 and 240 mg] and fatigue and alanine/aspartate aminotransferase increase [n = 1 (4.0%) each; 320 mg]; pneumonitis cases responded to steroids rapidly and successfully. Complete and partial responses were observed in one patient each in the single-agent and combination groups; both were immunotherapy naïve. In the single-agent and combination groups, 7 and 14 patients experienced stable disease; 7 and 6 patients were immunotherapy pretreated, respectively.
Conclusions:
Taminadenant, with and without spartalizumab, was well tolerated in patients with advanced NSCLC. The maximum tolerated dose of taminadenant alone was 480 mg twice a day, and 240 mg twice a day plus spartalizumab. Efficacy was neither a primary or secondary endpoint; however, some clinical benefit was noted regardless of prior immunotherapy or programmed cell death ligand-1 status.
Data from Association of Neutrophil-to-Lymphocyte Ratio with Efficacy of First-Line Avelumab plus Axitinib vs. Sunitinib in Patients with Advanced Renal Cell Carcinoma Enrolled in the Phase 3 JAVELIN Renal 101 Trial
Authors: Bilen Mehmet A. , Rini Brian I. , Voss Martin H. , Larkin James , Haanen John B.A.G. , Albiges Laurence , Pagliaro Lance C. , Voog Eric G. , Lam Elaine T. , Kislov Nikolay , McGregor Bradley A. , Lalani Aly-Khan A. , Huang Bo , di Pietro Alessandra , Krulewicz Stan , Robbins Paul B. , Choueiri Toni K.
Published: April 2023

AbstractPurpose:
To evaluate the association between neutrophil-to-lymphocyte ratio (NLR) and efficacy of avelumab plus axitinib or sunitinib.
Experimental Design:
Adult patients with untreated advanced renal cell carcinoma (RCC) with a clear-cell component, ≥1 measurable lesions, Eastern Cooperative Oncology Group performance status of 0 or 1, fresh or archival tumor specimen, and adequate renal, cardiac, and hepatic function were included. Retrospective analyses of the association between baseline NLR and progression-free survival (PFS) and overall survival (OS) in the avelumab plus axitinib or sunitinib arms were performed using the first interim analysis of the phase 3 JAVELIN Renal 101 trial (NCT02684006). Multivariate Cox regression analyses of PFS and OS were conducted. Translational data were assessed to elucidate the underlying biology associated with differences in NLR.
Results:
Patients with below-median NLR had longer observed PFS with avelumab plus axitinib [stratified HR, 0.85; 95% confidence interval (CI), 0.634–1.153] or sunitinib (HR, 0.56; 95% CI, 0.415–0.745). In the avelumab plus axitinib or sunitinib arms, respectively, median PFS was 13.8 and 11.2 months in patients with below-median NLR, and 13.3 and 5.6 months in patients with median-or-higher NLR. Below-median NLR was also associated with longer observed OS in the avelumab plus axitinib (HR, 0.51; 95% CI, 0.300–0.871) and sunitinib arms (HR, 0.30; 95% CI, 0.174–0.511). Tumor analyses showed an association between NLR and key biological characteristics, suggesting a role of NLR in underlying mechanisms influencing clinical outcome.
Conclusions:
Current data support NLR as a prognostic biomarker in patients with advanced RCC receiving avelumab plus axitinib or sunitinib.
Data from Mitochondrial Inhibitor Atovaquone Increases Tumor Oxygenation and Inhibits Hypoxic Gene Expression in Patients with Non–Small Cell Lung Cancer
Authors: Skwarski Michael , McGowan Daniel R. , Belcher Elizabeth , Di Chiara Francesco , Stavroulias Dionisios , McCole Mark , Derham Jennifer L. , Chu Kwun-Ye , Teoh Eugene , Chauhan Jagat , O’Reilly Dawn , Harris Benjamin H.L. , Macklin Philip S. , Bull Joshua A. , Green Marcus , Rodriguez-Berriguete Gonzalo , Prevo Remko , Folkes Lisa K. , Campo Leticia , Ferencz Petra , Croal Paula L. , Flight Helen , Qi Cathy , Holmes Jane , O’Connor James P.B. , Gleeson Fergus V. , McKenna W. Gillies , Harris Adrian L. , Bulte Daniel , Buffa Francesca M. , Macpherson Ruth E. , Higgins Geoff S.
Published: April 2023

AbstractPurpose:
Tumor hypoxia fuels an aggressive tumor phenotype and confers resistance to anticancer treatments. We conducted a clinical trial to determine whether the antimalarial drug atovaquone, a known mitochondrial inhibitor, reduces hypoxia in non–small cell lung cancer (NSCLC).
Patients and Methods:
Patients with NSCLC scheduled for surgery were recruited sequentially into two cohorts: cohort 1 received oral atovaquone at the standard clinical dose of 750 mg twice daily, while cohort 2 did not. Primary imaging endpoint was change in tumor hypoxic volume (HV) measured by hypoxia PET-CT. Intercohort comparison of hypoxia gene expression signatures using RNA sequencing from resected tumors was performed.
Results:
Thirty patients were evaluable for hypoxia PET-CT analysis, 15 per cohort. Median treatment duration was 12 days. Eleven (73.3%) atovaquone-treated patients had meaningful HV reduction, with median change −28% [95% confidence interval (CI), −58.2 to −4.4]. In contrast, median change in untreated patients was +15.5% (95% CI, −6.5 to 35.5). Linear regression estimated the expected mean HV was 55% (95% CI, 24%–74%) lower in cohort 1 compared with cohort 2 (P = 0.004), adjusting for cohort, tumor volume, and baseline HV. A key pharmacodynamics endpoint was reduction in hypoxia-regulated genes, which were significantly downregulated in atovaquone-treated tumors. Data from multiple additional measures of tumor hypoxia and perfusion are presented. No atovaquone-related adverse events were reported.
Conclusions:
This is the first clinical evidence that targeting tumor mitochondrial metabolism can reduce hypoxia and produce relevant antitumor effects at the mRNA level. Repurposing atovaquone for this purpose may improve treatment outcomes for NSCLC.
Data from Treatment-free Survival after Immune Checkpoint Inhibitor Therapy versus Targeted Therapy for Advanced Renal Cell Carcinoma: 42-Month Results of the CheckMate 214 Trial
Authors: Regan Meredith M. , Jegede Opeyemi A. , Mantia Charlene M. , Powles Thomas , Werner Lillian , Motzer Robert J. , Tannir Nizar M. , Lee Chung-Han , Tomita Yoshihiko , Voss Martin H. , Plimack Elizabeth R. , Choueiri Toni K. , Rini Brian I. , Hammers Hans J. , Escudier Bernard , Albiges Laurence , Huo Stephen , Del Tejo Viviana , Stwalley Brian , Atkins Michael B. , McDermott David F.
Published: April 2023

AbstractPurpose:
Patients discontinuing immuno-oncology regimens may experience periods of disease control without need for ongoing anticancer therapy, but toxicity may persist. We describe treatment-free survival (TFS), with and without toxicity.
Patients and Methods:
Data were analyzed from the randomized phase III CheckMate 214 trial of nivolumab plus ipilimumab (n = 550) versus sunitinib (n = 546) for treatment-naïve, advanced renal cell carcinoma (aRCC). TFS was estimated by the 42-month restricted mean times defined by the area between Kaplan–Meier curves for two time-to-event endpoints defined from randomization: time to protocol therapy cessation and time to subsequent systemic therapy initiation or death. TFS was subdivided as TFS with and without toxicity by counting days with ≥1 grade ≥3 treatment-related adverse event (TRAE).
Results:
At 42 months since randomization, 52% of nivolumab plus ipilimumab and 39% of sunitinib intermediate/poor-risk patients were alive; 18% and 5% surviving treatment-free, respectively. Among favorable-risk patients, 70% and 73% of nivolumab plus ipilimumab and sunitinib patients were alive; 20% and 9% treatment-free. Over the 42-month period, mean TFS was over twice as long after nivolumab plus ipilimumab than sunitinib for intermediate/poor-risk (6.9 vs. 3.1 months) and three times as long for favorable-risk patients (11.0 vs. 3.7 months). Mean TFS with grade ≥3 TRAEs was a small proportion of time for both treatments (0.6 vs. 0.3 months after nivolumab plus ipilimumab vs. sunitinib for intermediate/poor-risk, and 0.9 vs. 0.3 months for favorable-risk patients).
Conclusions:
Patients initiating first-line nivolumab plus ipilimumab for aRCC spent more survival time treatment-free without toxicity versus those on sunitinib, regardless of risk group.