bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Identification of Non–Small Cell Lung Cancer Sensitive to Systemic Cancer Therapies Using Radiomics
Authors: Dercle Laurent , Fronheiser Matthew , Lu Lin , Du Shuyan , Hayes Wendy , Leung David K. , Roy Amit , Wilkerson Julia , Guo Pingzhen , Fojo Antonio T. , Schwartz Lawrence H. , Zhao Binsheng
Published: April 2023

AbstractPurpose:
Using standard-of-care CT images obtained from patients with a diagnosis of non–small cell lung cancer (NSCLC), we defined radiomics signatures predicting the sensitivity of tumors to nivolumab, docetaxel, and gefitinib.
Experimental Design:
Data were collected prospectively and analyzed retrospectively across multicenter clinical trials [nivolumab, n = 92, CheckMate017 (NCT01642004), CheckMate063 (NCT01721759); docetaxel, n = 50, CheckMate017; gefitinib, n = 46, (NCT00588445)]. Patients were randomized to training or validation cohorts using either a 4:1 ratio (nivolumab: 72T:20V) or a 2:1 ratio (docetaxel: 32T:18V; gefitinib: 31T:15V) to ensure an adequate sample size in the validation set. Radiomics signatures were derived from quantitative analysis of early tumor changes from baseline to first on-treatment assessment. For each patient, 1,160 radiomics features were extracted from the largest measurable lung lesion. Tumors were classified as treatment sensitive or insensitive; reference standard was median progression-free survival (NCT01642004, NCT01721759) or surgery (NCT00588445). Machine learning was implemented to select up to four features to develop a radiomics signature in the training datasets and applied to each patient in the validation datasets to classify treatment sensitivity.
Results:
The radiomics signatures predicted treatment sensitivity in the validation dataset of each study group with AUC (95 confidence interval): nivolumab, 0.77 (0.55–1.00); docetaxel, 0.67 (0.37–0.96); and gefitinib, 0.82 (0.53–0.97). Using serial radiographic measurements, the magnitude of exponential increase in signature features deciphering tumor volume, invasion of tumor boundaries, or tumor spatial heterogeneity was associated with shorter overall survival.
Conclusions:
Radiomics signatures predicted tumor sensitivity to treatment in patients with NSCLC, offering an approach that could enhance clinical decision-making to continue systemic therapies and forecast overall survival.
Data from Spatial Analysis and Clinical Significance of HLA Class-I and Class-II Subunit Expression in Non–Small Cell Lung Cancer
Authors: Datar Ila J. , Hauc Sacha C. , Desai Shruti , Gianino Nicole , Henick Brian , Liu Yuting , Syrigos Kostas , Rimm David L. , Kavathas Paula , Ferrone Soldano , Schalper Kurt A.
Published: April 2023

AbstractPurpose:
To analyze the distribution, associated immune contexture, and clinical significance of human leukocyte antigen (HLA) class-I and HLA class-II subunits in non–small cell lung cancer (NSCLC).
Experimental Design:
Using spatially resolved and quantitative multiplexed immunofluorescence we studied the tumor/stromal tissue distribution, cancer cell–specific defects, and clinicopathologic/survival associations of β2 microglobulin (β2M), HLA-A, and HLA-B,-C heavy chains, as well as HLA class-II β chain in >700 immunotherapy-naïve NSCLCs from four independent cohorts. Genomic analysis of HLA genes in NSCLC was performed using two publicly available cohorts.
Results:
Cancer cell–specific downregulation of HLA markers was identified in 30.4% of cases. β2M was downregulated in 9.8% (70/714), HLA-A in 9% (65/722), HLA-B,-C in 12.1% (87/719), and HLA class-II in 17.7% (127/717) of evaluable samples. Concurrent downregulation of β2M, HLA-B,-C, and HLA class-II was commonly identified. Deleterious mutations in HLA genes were detected in <5% of lung malignancies. Tumors with cancer cell–specific β2M downregulation displayed reduced T cells and increased natural killer (NK)–cell infiltration. Samples with cancer cell HLA-A downregulation displayed modest increase in CD8+ T cells and NK-cell infiltration. Samples with cancer cell–selective HLA-B,-C or HLA class-II downregulation displayed reduced T cells and NK-cell infiltration. There was limited association of the markers with clinicopathologic variables and KRAS/EGFR mutations. Cancer cell–selective downregulation of the HLA subunits was associated with shorter overall survival.
Conclusions:
Our results reveal frequent and differential defects in HLA class-I and HLA class-II protein subunit expression in immunotherapy-naïve NSCLCs associated with distinct tumor microenvironment composition and patient survival.
Data from EGFL7 Antagonizes NOTCH Signaling and Represents a Novel Therapeutic Target in Acute Myeloid Leukemia
Authors: Bill Marius , Pathmanathan Aparna , Karunasiri Malith , Shen Changxian , Burke Matthew H. , Ranganathan Parvathi , Papaioannou Dimitrios , Zitzer Nina C. , Snyder Katiri , LaRocco Allison , Walker Allison E. , Brannan Zachary J. , Nalin Ansel P. , Freud Aharon G. , Dikov Mikhail M. , Zhang Xiaoli , Bloomfield Clara D. , Garzon Ramiro , Dorrance Adrienne M.
Published: April 2023

AbstractPurpose:
EGF-like domain 7 (EGFL7) is a secreted protein and recently has been shown to play an important role in acute myeloid leukemia (AML); however, the underlying mechanism by which EGFL7 promotes leukemogenesis is largely unknown.
Experimental Design:
Using an antibody interaction array, we measured the ability of EGFL7 to bind directly approximately 400 proteins expressed by primary AML blasts. Primary patient samples were stimulated in vitro with recombinant EGFL7 (rEGFL7) or anti-EGFL7 blocking antibody to assess alterations in downstream signaling and the ability to effect blast differentiation and survival. We treated three independent AML models with anti-EGFL7 or IgG1 control to determine whether anti-EGFL7 could prolong survival in vivo.
Results:
We found EGFL7 significantly binds several signaling proteins important for normal and malignant hematopoiesis including NOTCH. Stimulation of AML blasts with rEGFL7 reduced NOTCH intracellular domain and NOTCH target gene expression while treatment with an anti-EGFL7 blocking antibody resulted in reactivation of NOTCH signaling, increased differentiation, and apoptosis. Competitive ligand-binding assays showed rEGFL7 inhibits DELTA-like (DLL) 4-mediated NOTCH activation while anti-EGFL7 combined with DLL4 significantly increased NOTCH activation and induced apoptosis. Using three different AML mouse models, we demonstrated that in vivo treatment with anti-EGFL7 alone results in increased survival.
Conclusions:
Our data demonstrate that EGFL7 contributes to NOTCH silencing in AML by antagonizing canonical NOTCH ligand binding. Reactivation of NOTCH signaling in vivo using anti-EGFL7 results in prolonged survival of leukemic mice, supporting the use of EGFL7 as a novel therapeutic target in AML.
Data from The Use of Serial Circulating Tumor DNA to Detect Resistance Alterations in Progressive Metastatic Breast Cancer
Authors: Jacob Saya , Davis Andrew A. , Gerratana Lorenzo , Velimirovic Marko , Shah Ami N. , Wehbe Firas , Katam Neelima , Zhang Qiang , Flaum Lisa , Siziopikou Kalliopi P. , Platanias Leonidas C. , Gradishar William J. , Behdad Amir , Bardia Aditya , Cristofanilli Massimo
Published: April 2023

AbstractPurpose:
Circulating tumor DNA (ctDNA) is a promising tool for noninvasive longitudinal monitoring of genomic alterations. We analyzed serial ctDNA to characterize genomic evolution in progressive metastatic breast cancer.
Experimental Design:
This was a retrospective cohort between 2015 and 2019 obtained under an Institutional Review Board–approved protocol at Northwestern University (Chicago, IL). ctDNA samples were analyzed with Guardant360 next-generation sequencing (NGS) assay. A total of 86 patients had at least two serial ctDNA collections with the second drawn at first post-NGS progression (PN1) by imaging and clinical assessment. A total of 27 participants had ctDNA drawn at second post-NGS clinical progression (PN2). We analyzed alterations, mutant allele frequency (MAF), number of alterations (NOA), and sites of disease on imaging in close proximity to ctDNA evaluation. Matched pairs' variations in MAF, NOA, and alterations at progression were tested through Wilcoxon test. We identified an independent control cohort at Massachusetts General Hospital (Boston, MA) of 63 patients with serial ctDNA sampling and no evidence of progression.
Results:
We identified 44 hormone receptor–positive, 20 HER2+, and 22 triple-negative breast cancer cases. The significant alterations observed between baseline and PN1 were TP53 (P < 0.0075), PIK3CA (P < 0.0126), AR (P < 0.0126), FGFR1 (P < 0.0455), and ESR1 (P < 0.0143). Paired analyses revealed increased MAF and NOA from baseline to PN1 (P = 0.0026, and P < 0.0001, respectively). When compared with controls without progression, patients with ctDNA collection at times of progression were associated with increased MAF and NOA (P = 0.0042 and P < 0.0001, respectively).
Conclusions:
Serial ctDNA testing identified resistance alterations and increased NOA and MAF were associated with disease progression. Prospective longitudinal ctDNA evaluation could potentially monitor tumor genomic evolution.
Data from Predicting Therapeutic Antibody Delivery into Human Head and Neck Cancers
Authors: Lu Guolan , Fakurnejad Shayan , Martin Brock A. , van den Berg Nynke S. , van Keulen Stan , Nishio Naoki , Zhu Ashley J. , Chirita Stefania U. , Zhou Quan , Gao Rebecca W. , Kong Christina S. , Fischbein Nancy , Penta Mrudula , Colevas Alexander D. , Rosenthal Eben L.
Published: April 2023

AbstractPurpose:
The efficacy of antibody-based therapeutics depends on successful drug delivery into solid tumors; therefore, there is a clinical need to measure intratumoral antibody distribution. This study aims to develop and validate an imaging and computation platform to directly quantify and predict antibody delivery into human head and neck cancers in a clinical study.
Experimental Design:
Twenty-four patients received systemic infusion of a near-infrared fluorescence-labeled therapeutic antibody followed by surgical tumor resection. A computational platform was developed to quantify the extent of heterogeneity of intratumoral antibody distribution. Both univariate and multivariate regression analyses were used to select the most predictive tumor biological factors for antibody delivery. Quantitative image features from the pretreatment MRI were extracted and correlated with fluorescence imaging of antibody delivery.
Results:
This study not only confirmed heterogeneous intratumoral antibody distribution in-line with many preclinical reports, but also quantified the extent of interpatient, intertumor, and intratumor heterogeneity of antibody delivery. This study demonstrated the strong predictive value of tumor size for intratumoral antibody accumulation and its significant impact on antibody distribution in both primary tumor and lymph node metastasis. Furthermore, this study established the feasibility of using contrast-enhanced MRI to predict antibody delivery.
Conclusions:
This study provides a clinically translatable platform to measure antibody delivery into solid tumors and yields valuable insight into clinically relevant antibody tumor penetration, with implications in the selection of patients amenable to antibody therapy and the design of more effective dosing strategies.
Data from An Immune-Related Gene Prognostic Index for Head and Neck Squamous Cell Carcinoma
Authors: Chen Yue , Li Zhi-Yong , Zhou Guan-Qun , Sun Ying
Published: April 2023

AbstractPurpose:
To construct an immune-related gene prognostic index (IRGPI) for head and neck squamous cell carcinoma (HNSCC) and clarify the molecular and immune characteristics and the benefit of immune checkpoint inhibitor (ICI) therapy in IRGPI-defined subgroups of HNSCC.
Experimental Design:
On the basis of The Cancer Genome Atlas HNSCC immune dataset (n = 546), 22 immune-related hub genes were identified by weighted gene coexpression network analysis. Three genes were identified to construct an IRGPI by using the Cox regression method and validated with the Gene Expression Omnibus (GEO) dataset (n = 270). Afterward, the molecular and immune characteristics and the benefit of ICI therapy in IRGPI-defined subgroups were analyzed.
Results:
The IRGPI was constructed on the basis of SFRP4, CPXM1, and COL5A1 genes. IRGPI-high patients had a better overall survival than IRGPI-low patients, consistent with the results in the GEO cohort. The comprehensive results showed that a high IRGPI score was correlated with DNA repair–related pathways; low TP53 mutation rate; high infiltration of CD8 T cells, CD4 T cells, and M1 macrophages; active immunity and less aggressive phenotypes; and more benefit from ICI therapy. In contrast, a low IRGPI score was associated with cancer and metastasis-related pathways; high TP53 and PIK3CA mutation rate; high infiltration of B cells, M0 macrophages, and M2 macrophages; suppressive immunity and more aggressive phenotypes; and less benefit from ICI therapy.
Conclusions:
IRGPI is a promising biomarker to distinguish the prognosis, the molecular and immune characteristics, and the immune benefit from ICI therapy in HNSCC.
Data from Breast Cancer Index Predicts Extended Endocrine Benefit to Individualize Selection of Patients with HR+ Early-stage Breast Cancer for 10 Years of Endocrine Therapy
Authors: Noordhoek Iris , Treuner Kai , Putter Hein , Zhang Yi , Wong Jenna , Meershoek-Klein Kranenbarg Elma , Duijm-de Carpentier Marjolijn , van de Velde Cornelis J.H. , Schnabel Catherine A. , Liefers Gerrit-Jan
Published: April 2023

AbstractPurpose:
Individualized selection of patients with early-stage hormone receptor–positive (HR+) breast cancer for extended endocrine therapy (EET) is required to balance modest gains in outcome with toxicities of prolonged use. This study examined the Breast Cancer Index [BCI; HOXB13/IL17BR ratio (H/I)] as a predictive biomarker of EET benefit in patients from the Investigation on the Duration of Extended Adjuvant Letrozole trial.
Experimental Design:
BCI was tested in primary tumor specimens from 908 patients randomized to receive 2.5 versus 5 years of extended letrozole. The primary endpoint was recurrence-free interval. Cox models and likelihood ratios tested the interaction between EET and BCI (H/I).
Results:
BCI (H/I)-high significantly predicted benefit from extended letrozole in the overall cohort [HR 0.42; 95% confidence interval (CI), 0.21–0.84; P = 0.011] and any aromatase inhibitor subset [HR 0.34; 95% CI, 0.16–0.73; P = 0.004), whereas BCI (H/I)-low patients did not derive significant benefit (HR 0.95; 95% CI, 0.58–1.56; P = 0.84 and HR 0.90; 95% CI, 0.53–1.55; P = 0.71, respectively) treatment to biomarker interaction was significant (P = 0.045, P = 0.025, respectively). BCI identified approximately 50% of patients with clinically high-risk disease that did not benefit, and with clinically low-risk disease that derived significant benefit, from an additional 2.5 years of EET.
Conclusions:
BCI (H/I) predicted preferential benefit from 5 versus 2.5 years of EET and identified patients with improved outcomes from completing 10 years of adjuvant endocrine therapy. Findings expand the clinical utility of BCI (H/I) to a broader range of patients and beyond prognostic risk factors as a predictive endocrine response biomarker for early-stage HR+ breast cancer.
Data from A Phase Ib Study of Alpelisib or Buparlisib Combined with Tamoxifen Plus Goserelin in Premenopausal Women with HR-Positive HER2-Negative Advanced Breast Cancer
Authors: Lu Yen-Shen , Lee Keun Seok , Chao Tsu-Yi , Tseng Ling-Ming , Chitapanarux Imjai , Chen Shin-Cheh , Liu Chien-Ting , Sohn Joohyuk , Kim Jee Hyun , Chang Yuan-Ching , Yang Youngsen , Shotelersuk Kanjana , Jung Kyung Hae , Valenti Roberta , Slader Cassandra , Gao Melissa , Park Yeon Hee
Published: April 2023

AbstractPurpose:
This study reports the MTD, recommended phase 2 dose (RP2D), and preliminary efficacy of alpelisib or buparlisib used in combination with tamoxifen plus goserelin in premenopausal patients with hormone receptor–positive (HR+), HER2-negative (HER2−) advanced breast cancer (ABC).
Patients and Methods:
This study enrolled premenopausal women with HR+, HER2− ABC. Patients received tamoxifen (20 mg once daily) and goserelin acetate (3.6 mg every 28 days) with either alpelisib (350 mg once daily; n = 16) or buparlisib (100 mg once daily; n = 13) in 28-day cycles until MTD was observed.
Results:
The criteria for MTD were not met for both alpelisib and buparlisib. The RP2D of alpelisib and buparlisib in combination with tamoxifen and goserelin were 350 mg and 100 mg, respectively. Both combinations met protocol-specified criteria for tolerability. The most common grade 3/4 treatment-emergent adverse events (TEAE) were hypokalemia (12.5%), hyperglycemia (6.3%), and rash (6.3%) for alpelisib and alanine aminotransferase increase (30.8%), aspartate aminotransferase increase (23.1%), and anxiety (15.4%) for buparlisib. TEAEs led to treatment discontinuation in 18.8% and 53.8% of alpelisib- and buparlisib-treated patients, respectively. Progression-free survival was 25.2 months in the alpelisib group and 20.6 months in the buparlisib group.
Conclusions:
The RP2Ds of alpelisib and buparlisib were 350 mg and 100 mg, respectively. No unexpected safety findings were reported. Although an early-phase study, data suggest that alpelisib plus endocrine therapy may be a potentially efficacious treatment that warrants further evaluation for premenopausal patients with HR+, HER2− ABC.

See related commentary by Clark et al., p. 371
Data from Capecitabine and Temozolomide versus FOLFIRI in RAS-Mutated, MGMT-Methylated Metastatic Colorectal Cancer
Authors: Pietrantonio Filippo , Lobefaro Riccardo , Antista Maria , Lonardi Sara , Raimondi Alessandra , Morano Federica , Mosconi Stefania , Rimassa Lorenza , Murgioni Sabina , Sartore-Bianchi Andrea , Tomasello Gianluca , Longarini Raffaella , Farina Gabriella , Petrelli Fausto , Gori Stefania , Randon Giovanni , Corallo Salvatore , Pagani Filippo , Guarini Vincenzo , Palermo Federica , Martinetti Antonia , Macagno Marco , Barault Ludovic , Perrone Federica , Tamborini Elena , Milione Massimo , Di Nicolantonio Federica , Di Maio Massimo , Fucà Giovanni , Di Bartolomeo Maria , de Braud Filippo
Published: April 2023

AbstractPurpose:
To determine whether second-line therapy with capecitabine and temozolomide was superior to irinotecan, leucovorin, and fluorouracil (FOLFIRI) in patients with RAS-mutated, methyl-guanine methyltransferase (MGMT)-methylated metastatic colorectal cancer (mCRC).
Patients and Methods:
In this randomized, phase II trial, we enrolled patients with RAS-mutated, MGMT-methylated mCRC after failure of oxaliplatin-based regimen. Patients with centrally confirmed MGMT methylation were stratified by first-line progression-free survival (PFS) and prior bevacizumab and randomized to either capecitabine plus temozolomide (arm A, CAPTEM) or FOLFIRI (arm B). The primary endpoint was PFS analyzed on intention-to-treat basis, with 90% power and one-sided significance level of 0.05 to detect an increase of median time from 2 months in arm B to 4 months in arm A.
Results:
Between November 2014 and May 2019, 86 patients were randomly assigned to arm A (n = 43) or arm B (n = 43). After a median follow-up of 30.5 months (interquartile range, 12.2–36.3), 79 disease progression or death events occurred. Superiority of arm A was not demonstrated (one-sided P = 0.223). Progression-free survival and overall survival were 3.5 (2.0–5.0) and 9.5 (8.2–25.8) in arm A versus 3.5 (2.3–6.1) and 10.6 (8.5–20.8) in arm B [HR = 1.19 (0.82–1.72) and HR = 0.97 (0.58–1.61)], respectively. Grade ≥3 treatment-related adverse events had higher incidence in arm B versus A (47.6% vs 16.3%), and quality of life was significantly worse in arm B. Patients with positive MGMT expression by IHC did not benefit from CAPTEM.
Conclusions:
Temozolomide-based therapy warrants further investigation in molecularly hyperselected subgroups.
Data from Clinical Impact of Presurgery Circulating Tumor DNA after Total Neoadjuvant Treatment in Locally Advanced Rectal Cancer: A Biomarker Study from the GEMCAD 1402 Trial
Authors: Vidal Joana , Casadevall David , Bellosillo Beatriz , Pericay Carles , Garcia-Carbonero Rocio , Losa Ferran , Layos Laia , Alonso Vicente , Capdevila Jaume , Gallego Javier , Vera Ruth , Salud Antonieta , Martin-Richard Marta , Nogué Miguel , Cillán Elena , Maurel Joan , Faull Iris , Raymond Victoria , Fernández-Martos Carlos , Montagut Clara
Published: April 2023

AbstractPurpose:
Total neoadjuvant treatment (TNT) is a valid strategy for patients with high-risk locally advanced rectal cancer (LARC). Biomarkers of response to TNT are an unmet clinical need. We aimed to determine the value of circulating tumor DNA (ctDNA) to predict tumor response, recurrence, and survival in patients with LARC treated with TNT.
Experimental Design:
The GEMCAD 1402 was a phase II randomized, multicentric clinical trial that randomized 180 patients with LARC to modified schedule of fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) +/− aflibercept, followed by chemoradiation and surgery. Plasma samples were collected at baseline and after TNT within 48 hours before surgery (presurgery). An ultrasensitive assay that integrates genomic and epigenomic cancer signatures was used to assess ctDNA status. ctDNA results were correlated with variables of local tumor response in the surgery sample, local/systemic recurrence, and survival.
Results:
A total of 144 paired plasma samples from 72 patients were included. ctDNA was detectable in 83% of patients at baseline and in 15% following TNT (presurgery). No association was found between ctDNA status and pathologic response. Detectable presurgery ctDNA was significantly associated with systemic recurrence, shorter disease-free survival (HR, 4; P = 0.033), and shorter overall survival (HR, 23; P < 0.0001).
Conclusions:
In patients with LARC treated with TNT, presurgery ctDNA detected minimal metastatic disease identifying patients at high risk of distant recurrence and death. This study sets the basis for prospective clinical trials that use liquid biopsy to personalize the therapeutic approach following TNT.
Data from Development and Validation of a Novel Nomogram for Individualized Prediction of Survival in Cancer of Unknown Primary
Authors: Raghav Kanwal , Hwang Hyunsoo , Jácome Alexandre A. , Bhang Eric , Willett Anneleis , Huey Ryan W. , Dhillon Nishat P. , Modha Jignesh , Smaglo Brandon , Matamoros Aurelio , Estrella Jeannelyn S. , Jao Justin , Overman Michael J. , Wang Xuemei , Greco F. Anthony , Loree Jonathan M. , Varadhachary Gauri R.
Published: April 2023

AbstractPurpose:
Prognostic uncertainty is a major challenge for cancer of unknown primary (CUP). Current models limit a meaningful patient-provider dialogue. We aimed to establish a nomogram for predicting overall survival (OS) in CUP based on robust clinicopathologic prognostic factors.
Experimental Design:
We evaluated 521 patients with CUP at MD Anderson Cancer Center (MDACC; Houston, TX; 2012–2016). Baseline variables were analyzed using Cox regression and nomogram developed using significant predictors. Predictive accuracy and discriminatory performance were assessed by calibration curves, concordance probability estimate (CPE ± SE), and concordance statistic (C-index). The model was subjected to bootstrapping and multi-institutional external validations using two independent CUP cohorts: V1 [MDACC (2017), N = 103] and V2 (BC Cancer, Vancouver, Canada and Sarah Cannon Cancer Center/Tennessee Oncology, Nashville, TN; N = 302).
Results:
Baseline characteristics of entire cohort (N = 926) included: median age (63 years), women (51%), Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1 (64%), adenocarcinomas (52%), ≥3 sites of metastases (30%), and median follow-up duration and OS of 40.1 and 14.7 months, respectively. Five independent prognostic factors were identified: gender, ECOG PS, histology, number of metastatic sites, and neutrophil-lymphocyte ratio. The resulting model predicted OS with CPE of 0.69 [SE: ± 0.01; C-index: 0.71 (95% confidence interval: 0.68–0.74)] outperforming Culine/Seve prognostic models (CPE: 0.59 ± 0.01). CPE for external validation cohorts V1 and V2 were 0.67 (± 0.02) and 0.70 (± 0.01), respectively. Calibration curves for 1-year OS showed strong agreement between nomogram prediction and actual observations in all cohorts.
Conclusions:
Our user-friendly CUP nomogram integrating commonly available baseline factors provides robust personalized prognostication which can aid clinical decision making and selection/stratification for clinical trials.
Data from Sulindac, a Nonselective NSAID, Reduces Breast Density in Postmenopausal Women with Breast Cancer Treated with Aromatase Inhibitors
Authors: Thompson Patricia A. , Huang Chuan , Yang Jie , Wertheim Betsy C. , Roe Denise , Zhang Xiaoyue , Ding Jie , Chalasani Pavani , Preece Christina , Martinez Jessica , Chow H.-H. Sherry , Stopeck Alison T.
Published: April 2023

AbstractPurpose:
To evaluate the effect of sulindac, a nonselective anti-inflammatory drug (NSAID), for activity to reduce breast density (BD), a risk factor for breast cancer.
Experimental Design:
An open-label phase II study was conducted to test the effect of 12 months' daily sulindac at 150 mg twice daily on change in percent BD in postmenopausal hormone receptor–positive breast cancer patients on aromatase inhibitor (AI) therapy. Change in percent BD in the contralateral, unaffected breast was measured by noncontrast magnetic resonance imaging (MRI) and reported as change in MRI percent BD (MRPD). A nonrandomized patient population on AI therapy (observation group) with comparable baseline BD was also followed for 12 months. Changes in tissue collagen after 6 months of sulindac treatment were explored using second-harmonic generated microscopy in a subset of women in the sulindac group who agreed to repeat breast biopsy.
Results:
In 43 women who completed 1 year of sulindac (86% of those accrued), relative MRPD significantly decreased by 9.8% [95% confidence interval (CI), −14.6 to −4.7] at 12 months, an absolute decrease of −1.4% (95% CI, −2.5 to −0.3). A significant decrease in mean breast tissue collagen fiber straightness (P = 0.032), an investigational biomarker of tissue inflammation, was also observed. MRPD (relative or absolute) did not change in the AI-only observation group (N = 40).
Conclusions:
This is the first study to indicate that the NSAID sulindac may reduce BD. Additional studies are needed to verify these findings and determine if prostaglandin E2 inhibition by NSAIDs is important for BD or collagen modulation.
Data from A Pan-Histone Deacetylase Inhibitor Enhances the Antitumor Activity of B7-H3–Specific CAR T Cells in Solid Tumors
Authors: Lei Xinyuan , Ou Zhanpeng , Yang Zhaohui , Zhong Jianglong , Zhu Yanliang , Tian Jing , Wu Jiannan , Deng Heran , Lin Xinyu , Peng Yu , Li Bowen , He Lile , Tu Zhiming , Chen Weixiong , Li Qunxing , Liu Niu , Zhang Hanqing , Wang Zhangsong , Fang Zezhen , Yamada Teppei , Lv Xiaobin , Tian Tian , Pan Guokai , Wu Fan , Xiao Liping , Zhang Lizao , Cai Tingting , Wang Xinhui , Tannous Bakhos A. , Li Jinsong , Kontos Filippos , Ferrone Soldano , Fan Song
Published: April 2023

AbstractPurpose:
The limited efficacy of chimeric antigen receptor (CAR) T-cell therapies with solid malignancies prompted us to test whether epigenetic therapy could enhance the antitumor activity of B7-H3.CAR T cells with several solid cancer types.
Experimental Design:
We evaluated B7-H3 expression in many human solid cancer and normal tissue samples. The efficacy of the combinatorial therapy with B7-H3.CAR T cells and the deacetylase inhibitor SAHA with several solid cancer types and the potential underlying mechanisms were characterized with in vitro and ex vivo experiments.
Results:
B7-H3 is expressed in most of the human solid tumor samples tested, but exhibits a restricted expression in normal tissues. B7-H3.CAR T cells selectively killed B7-H3 expressing human cancer cell lines in vitro. A low dose of SAHA upregulated B7-H3 expression in several types of solid cancer cells at the transcriptional level and B7-H3.CAR expression on human transgenic T-cell membrane. In contrast, the expression of immunosuppressive molecules, such as CTLA-4 and TET2, by T cells was downregulated upon SAHA treatment. A low dose of SAHA significantly enhanced the antitumor activity of B7-H3.CAR T cells with solid cancers in vitro and ex vivo, including orthotopic patient-derived xenograft and metastatic models treated with autologous CAR T-cell infusions.
Conclusions:
Our results show that our novel strategy which combines SAHA and B7-H3.CAR T cells enhances their therapeutic efficacy with solid cancers and justify its translation to a clinical setting.
Data from First-in-Human Study of the Biodistribution and Pharmacokinetics of 89Zr-CX-072, a Novel Immunopet Tracer Based on an Anti–PD-L1 Probody
Authors: Kist de Ruijter Laura , Hooiveld-Noeken Jahlisa S. , Giesen Danique , Lub-de Hooge Marjolijn N. , Kok Iris C. , Brouwers Adrienne H. , Elias Sjoerd G. , Nguyen Margaret T.L. , Lu Hong , Gietema Jourik A. , Jalving Mathilde , de Groot Derk J.A. , Vasiljeva Olga , de Vries Elisabeth G.E.
Published: April 2023

AbstractPurpose:
CX-072, a PD-L1–targeting Probody therapeutic, is engineered to be activated by tumor proteases that remove a masking peptide. To study effects on biodistribution and pharmacokinetics, we performed 89Zr-CX-072 positron emission tomography (PET) imaging.
Experimental Design:
Patients received ∼1 mg, 37 MBq 89Zr-CX-072 plus 0, 4, or 9 mg unlabeled CX-072 and PET scans at days 2, 4, and 7. After that, treatment comprised 10 mg/kg CX-072 q2 weeks (n = 7) + 3 mg/kg ipilimumab q3w 4× (n = 1). Normal organ tracer uptake was expressed as standardized uptake value (SUV)mean and tumor uptake as SUVmax. PD-L1 expression was measured immunohistochemically in archival tumor tissue.
Results:
Three of the eight patients included received 10-mg protein dose resulting in a blood pool mean SUVmean ± SD of 4.27 ± 0.45 on day 4, indicating sufficient available tracer. Tumor uptake was highest at day 7, with a geometric mean SUVmax 5.89 (n = 113) and present in all patients. The median follow-up was 12 weeks (4–76+). One patient experienced stable disease and two patients a partial response. PD-L1 tumor expression was 90% in one patient and ≤1% in the other patients. Mean SUVmean ± SD day 4 at 10 mg in the spleen was 8.56 ± 1.04, bone marrow 2.21 ± 0.46, and liver 4.97 ± 0.97. Four patients out of seven showed uptake in normal lymph nodes and Waldeyer's ring. The tracer was intact in the serum or plasma.
Conclusions:
89Zr-CX-072 showed tumor uptake, even in lesions with ≤1% PD-L1 expression, and modest uptake in normal lymphoid organs, with no unexpected uptake in other healthy tissues.
Data from STK11/LKB1 Mutations in NSCLC Are Associated with KEAP1/NRF2-Dependent Radiotherapy Resistance Targetable by Glutaminase Inhibition
Authors: Sitthideatphaiboon Piyada , Galan-Cobo Ana , Negrao Marcelo V. , Qu Xiao , Poteete Alissa , Zhang Fahao , Liu Diane D. , Lewis Whitney E. , Kemp Haley N. , Lewis Jeff , Rinsurongkawong Waree , Giri Uma , Lee J. Jack , Zhang Jianjun , Roth Jack A. , Swisher Stephen , Heymach John V.
Published: April 2023

AbstractPurpose:
Radiotherapy with or without chemotherapy is a mainstay of treatment for locally advanced non–small cell lung cancer (NSCLC), but no predictive markers are currently available to select patients who will benefit from these therapies. In this study, we investigated the association between alterations in STK11/LKB1, the second most common tumor suppressor in NSCLC, and response to radiotherapy as well as potential therapeutic approaches to improve outcomes.
Experimental Design:
We conducted a retrospective analysis of 194 patients with stage I–III NSCLC, including 164 stage III patients bearing mutant or wild-type STK11/LKB1 treated with radiotherapy, and assessed locoregional recurrence (LRR), distant metastasis rates, disease-free survival (DFS), and overall survival (OS), and we investigated the causal role of LKB1 in mediating radiotherapy resistance using isogenic pairs of NSCLC cell lines with LKB1 loss or gain.
Results:
In stage III patients, with 4 years median follow-up, STK11/LKB1 mutations were associated with higher LRR (P = 0.0108), and shorter DFS (HR 2.530, P = 0.0029) and OS (HR 2.198, P = 0.0263). LKB1 loss promoted relative resistance to radiotherapy, which was dependent on the KEAP1/NRF2 pathway for redox homeostasis. Suppression of the KEAP1/NRF2 pathway via KEAP1 expression, or pharmacologic blockade of glutaminase (GLS) 1 sensitized LKB1-deficient tumors to radiotherapy.
Conclusions:
These data provide evidence that LKB1 loss is associated with LRR and poor clinical outcomes in patients with NSCLC treated with radiotherapy and that targeting the KEAP1/NRF2 pathway or GLS inhibition are potential approaches to radiosensitize LKB1-deficient tumors.
Data from Multiomic Analysis Reveals Comprehensive Tumor Heterogeneity and Distinct Immune Subtypes in Multifocal Intrahepatic Cholangiocarcinoma
Authors: Chen Shuling , Xie Yubin , Cai Yuhong , Hu Huanjing , He Minghui , Liu Lijuan , Liao Changyi , Wang Yuanqi , Wang Jianping , Ren Xiaoxue , Zeng Qianwen , Peng Hong , Shen Shunli , Li Shaoqiang , Li Dongming , Lai Jiaming , Peng Baogang , Ren Jian , Kuang Ming , Peng Sui
Published: April 2023

AbstractPurpose:
Targeted therapy and immunotherapy are transforming the treatment approach for intrahepatic cholangiocarcinoma (ICC). However, little is known about the intertumor heterogeneity (ITH) of multifocal ICC and its impacts on patient response to these treatments. We aimed to characterize the immunogenomic and epigenomic heterogeneity of multifocal ICC to guide treatment decision making.
Experimental Design:
We obtained 66 tumor samples from 16 patients with multifocal ICC and characterized the tumor and immune heterogeneity using whole-exome sequencing, bulk and single-cell RNA sequencing, methylation microarray, and multiplex immunostaining. Patients were divided into high- or low-ITH groups according to the median ITH index. Two independent cohorts were used to validate findings. Responses to anti-PD-1 therapy were assessed.
Results:
Multifocal ICC presented considerable intertumor genomic, transcriptional, and epigenomic heterogeneity within a patient in high ITH group. The immune profile among multiple tumors within a patient was relatively less heterogeneous in high- or low-ITH group, and consistent responses of multiple tumors to anti-PD-1 immunotherapy were observed. Unsupervised clustering of immune markers identified one low and one high immune subtype, with higher immune cell infiltration, closer tumor–immune cell interactions, and upregulated IFN-signature expression in high-immune subtype. Determining expression levels of CD8B and ICOS facilitated this immune classification and prediction of patient prognosis. Finally, promoter DNA methylation contributed to different immune profiles of two subtypes by regulating immune-gene expression.
Conclusions:
There is comprehensive heterogeneity in the genome, transcriptome, and epigenome of multifocal ICC. On the basis of the less heterogeneous immune profile of ICC, we suggest an immune classification that stratifies patients' prognosis and may support personalized immunotherapy.
Data from Immunization with a Plasmid DNA Vaccine Encoding the N-Terminus of Insulin-like Growth Factor Binding Protein-2 in Advanced Ovarian Cancer Leads to High-level Type I Immune Responses
Authors: Cecil Denise L. , Liao John B. , Dang Yushe , Coveler Andrew L. , Kask Angela , Yang Yi , Childs Jennifer S. , Higgins Doreen M. , Disis Mary L.
Published: April 2023

AbstractPurpose:
Cancer vaccines targeting nonmutated proteins elicit limited type I T-cell responses and can generate regulatory and type II T cells. Class II epitopes that selectively elicit type I or type II cytokines can be identified in nonmutated cancer-associated proteins. In mice, a T-helper I (Th1) selective insulin-like growth factor binding protein-2 (IGFBP-2) N-terminus vaccine generated high levels of IFNγ secreting T cells, no regulatory T cells, and significant antitumor activity. We conducted a phase I trial of T-helper 1 selective IGFBP-2 vaccination in patients with advanced ovarian cancer.
Patients and Methods:
Twenty-five patients were enrolled. The IGFBP-2 N-terminus plasmid-based vaccine was administered monthly for 3 months. Toxicity was graded by NCI criteria and antigen-specific T cells measured by IFNγ/IL10 ELISPOT. T-cell diversity and phenotype were assessed.
Results:
The vaccine was well tolerated, with 99% of adverse events graded 1 or 2, and generated high levels of IGFBP-2 IFNγ secreting T cells in 50% of patients. Both Tbet+ CD4 (P = 0.04) and CD8 (P = 0.007) T cells were significantly increased in immunized patients. There was no increase in GATA3+ CD4 or CD8, IGFBP-2 IL10 secreting T cells, or regulatory T cells. A significant increase in T-cell clonality occurred in immunized patients (P = 0.03, pre- vs. post-vaccine) and studies showed the majority of patients developed epitope spreading within IGFBP-2 and/or to other antigens. Vaccine nonresponders were more likely to have preexistent IGFBP-2 specific immunity and demonstrated defects in CD4 T cells, upregulation of PD-1, and downregulation of genes associated with T-cell activation, after immunization.
Conclusions:
IGFBP-2 N-terminus Th1 selective vaccination safely induces type I T cells without evidence of regulatory responses.
Data from Diminished Immune Surveillance during Histologic Progression of Intraductal Papillary Mucinous Neoplasms Offers a Therapeutic Opportunity for Cancer Interception
Authors: Hernandez Sharia , Parra Edwin Roger , Uraoka Naohiro , Tang Ximing , Shen Yu , Qiao Wei , Jiang Mei , Zhang Shanyu , Mino Barbara , Lu Wei , Pandurengan Renganayaki , Haymaker Cara , Affolter Kajsa , Scaife Courtney L. , Yip-Schneider Michele , Schmidt C. Max , Firpo Matthew A. , Mulvihill Sean J. , Koay Eugene J. , Wang Huamin , Wistuba Ignacio I. , Maitra Anirban , Solis Luisa M. , Sen Subrata
Published: April 2023

AbstractPurpose:
Intraductal papillary mucinous neoplasms (IPMN) are bona fide precursors to pancreatic ductal adenocarcinoma (PDAC). While genomic alterations during multistep IPMN progression have been well cataloged, the accompanying changes within the tumor immune microenvironment (TIME) have not been comprehensively studied. Herein, we investigated TIME-related alterations during IPMN progression, using multiplex immunofluorescence (mIF) coupled with high-resolution image analyses.
Experimental Design:
Two sets of formalin-fixed, paraffin-embedded tissue samples from surgically resected IPMNs were analyzed. The training set of 30 samples consisted of 11 low-grade IPMN (LG-IPMN), 17 high-grade IPMN (HG-IPMN), and 2 IPMN with PDAC, while a validation set of 93 samples comprised of 55 LG-IPMN and 38 HG-IPMN. The training set was analyzed with two panels of immuno-oncology–related biomarkers, while the validation set was analyzed with a subset of markers found significantly altered in the training set.
Results:
Cell types indicative of enhanced immune surveillance, including cytotoxic and memory T cells, and antigen-experienced T cells and B cells, were all found at higher densities within isolated LG-IPMNs compared with HG-IPMNs. Notably, the TIME of LG-IPMNs that had progressed at the time of surgical resection (progressor LGD) resembled that of the synchronous HG-IPMNs, underscoring that attenuated immune surveillance occurs even in LG-IPMNs destined for progression.
Conclusions:
Our findings provide a basis for interception of cystic neoplasia to PDAC, through maintenance of sustained immune surveillance using vaccines and other prevention approaches.
Data from Biomarkers of Response and Resistance to Palbociclib Plus Letrozole in Patients With ER+/HER2− Breast Cancer
Authors: Dowsett Mitch , Kilburn Lucy , Rimawi Mothaffar F. , Osborne C. Kent , Pogue-Geile Katherine , Liu Yuan , Jacobs Samuel A. , Finnigan Melanie , Puhalla Shannon , Dodson Andrew , Martins Vera , Cheang Maggie , Perry Sophie , Holcombe Chris , Turner Nick , Swift Claire , Bliss Judith M. , Johnston Stephen
Published: April 2023

AbstractPurpose:
To determine (i) the relationship between candidate biomarkers of the antiproliferative (Ki67) response to letrozole and palbociclib alone and combined in ER+/HER2− breast cancer; and (ii) the pharmacodynamic effect of the agents on the biomarkers.
Experimental Design:
307 postmenopausal women with ER+/HER2− primary breast cancer were randomly assigned to neoadjuvant treatment with letrozole for 14 weeks; letrozole for 2 weeks, then letrozole+palbociclib to 14 weeks; palbociclib for 2 weeks, then letrozole+palbociclib to 14 weeks; or letrozole+palbociclib for 14 weeks. Biopsies were taken at baseline, 2 and 14 weeks and surgery at varying times after stopping palbociclib. Immunohistochemical analyses were conducted for Ki67, c-PARP, ER, PgR, RB1, CCNE1, and CCND1.
Results:
Higher baselines ER and PgR were significantly associated with a greater chance of complete cell-cycle arrest (CCCA: Ki67 <2.7%) at 14 weeks and higher baseline Ki67, c-PARP, and CCNE1 with a lower chance. The interaction with treatment was significant only for c-PARP. CCND1 levels were decreased c.20% by letrozole at 2 and 14 weeks but showed a tendency to increase with palbociclib. CCNE1 levels fell 82% (median) in tumors showing CCCA but were unchanged in those with no CCCA. Only 2/9 tumors showed CCCA 3–9 days after stopping palbociclib. ESR1 mutations were found in 2/4 tumors for which surgery took place ≥6 months after starting treatment.
Conclusions:
High CCNE1 levels were confirmed as a biomarker of resistance to letrozole+palbociclib. Ki67 recovery within 3–9 days of discontinuing palbociclib indicates incomplete suppression of proliferation during the “off” week of its schedule.
Data from Transcriptomic Determinants of Response to Pembrolizumab Monotherapy across Solid Tumor Types
Authors: Cristescu Razvan , Nebozhyn Michael , Zhang Chunsheng , Albright Andrew , Kobie Julie , Huang Lingkang , Zhao Qing , Wang Anran , Ma Hua , Alexander Cao Z. , Morrissey Michael , Ribas Antoni , Grivas Petros , Cescon David W. , McClanahan Terrill K. , Snyder Alexandra , Ayers Mark , Lunceford Jared , Loboda Andrey
Published: April 2023

AbstractPurpose:
To explore relationships between biological gene expression signatures and pembrolizumab response.
Experimental Design:
RNA-sequencing data on baseline tumor tissue from 1,188 patients across seven tumor types treated with pembrolizumab monotherapy in nine clinical trials were used. A total of 11 prespecified gene expression signatures [18-gene T-cell–inflamed gene expression profile (TcellinfGEP), angiogenesis, hypoxia, glycolysis, proliferation, MYC, RAS, granulocytic myeloid-derived suppressor cell (gMDSC), monocytic myeloid-derived suppressor cell (mMDSC), stroma/epithelial-to-mesenchymal transition (EMT)/TGFβ, and WNT] were evaluated for their relationship to objective response rate (per RECIST, version 1.1). Logistic regression analysis of response for consensus signatures was adjusted for tumor type, Eastern Cooperative Oncology Group performance status, and TcellinfGEP, an approach equivalent to evaluating the association between response and the residuals of consensus signatures after detrending them for their relationship with the TcellinfGEP (previously identified as a determinant of pembrolizumab response) and tumor type. Testing of the 10 prespecified non-TcellinfGEP consensus signatures for negative association [except proliferation (hypothesized positive association)] with response was adjusted for multiplicity.
Results:
Covariance patterns of the 11 signatures (including TcellinfGEP) identified in Merck–Moffitt and The Cancer Genome Atlas datasets showed highly concordant coexpression patterns in the RNA-sequencing data from pembrolizumab trials. TcellinfGEP was positively associated with response; signatures for angiogenesis, mMDSC, and stroma/EMT/TGFβ were negatively associated with response to pembrolizumab monotherapy.
Conclusions:
These findings suggest that features beyond IFNγ-related T-cell inflammation may be relevant to anti–programmed death 1 monotherapy response and may define other axes of tumor biology as candidates for pembrolizumab combinations.

See related commentary by Cho et al., p. 1479
Data from Neoadjuvant Chemoimmunotherapy for the Treatment of Locally Advanced Head and Neck Squamous Cell Carcinoma: A Single-Arm Phase 2 Clinical Trial
Authors: Zhang Zhanjie , Wu Bian , Peng Gang , Xiao Guixiang , Huang Jing , Ding Qian , Yang Chengzhang , Xiong Xingao , Ma Hui , Shi Liangliang , Yang Jinsong , Hong Xiaohua , Wei Jielin , Qin You , Wan Chao , Zhong Yi , Zhou Yan , Zhao Xueyan , Leng Yangming , Zhang Tao , Wu Gang , Yao Min , Zhang Xiaomeng , Yang Kunyu
Published: April 2023

AbstractPurpose:
This study aimed to assess the antitumor activity and safety of neoadjuvant chemotherapy combined with PD-1 inhibitor camrelizumab in patients with locally advanced head and neck squamous cell carcinoma (HNSCC).
Patients and Methods:
In this single-center, single-arm, phase 2 trial, patients with resectable stage III–IVB HNSCC received chemotherapy [albumin-bound paclitaxel 260 mg/m2 (or docetaxel 75 mg/m2) plus cisplatin 75 mg/m2] and camrelizumab 200 mg on day 1 of each 21-day cycle for three cycles, followed by surgery, and adjuvant radiotherapy. Co-primary end points were pathological complete response (pCR) rate and safety.
Results:
Thirty patients were enrolled and completed the neoadjuvant therapy, with an objective response rate (ORR) of 96.7% (29/30). Twenty-seven patients underwent surgery without delay, with an R0 resection rate of 92.6% (25/27). The clinical to pathological downstaging rate was 100% (27/27). The pCR rate was 37.0% [95% confidence interval (CI), 19.4%–57.6%], and the major pathological response (MPR) rate was 74.1% (95% CI, 53.7%–88.9%). The median follow-up duration was 16.1 months (range, 8.3–28.5), and the disease-free survival rate at 12 months was 95.8% (95% CI, 73.9%–99.4%). Grade 3 neoadjuvant therapy–related adverse events included rash (1; 3.3%), pruritis (1; 3.3%), and thrombocytopenia (1; 3.3%), and no grade 4 or 5 treatment-related events occurred. The most common surgical complication was delayed wound healing (5; 18.5%).
Conclusions:
Neoadjuvant chemotherapy plus camrelizumab for locally advanced HNSCC showed high ORR, pCR, and MPR rates, with an acceptable safety profile. These data support further evaluation of neoadjuvant chemoimmunotherapy for the treatment of locally advanced HNSCC.