bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Curation of the Pancreatic Ductal Adenocarcinoma Subset of the Cancer Genome Atlas Is Essential for Accurate Conclusions about Survival-Related Molecular Mechanisms
Authors: Peran Ivana , Madhavan Subha , Byers Stephen W. , McCoy Matthew D.
Published: April 2023

Abstract
Purpose: Publicly available databases, for example, The Cancer Genome Atlas (TCGA), containing clinical and molecular data from many patients are useful in validating the contribution of particular genes to disease mechanisms and in forming novel hypotheses relating to clinical outcomes.

Experimental Design: The impact of key drivers of cancer progression can be assessed by segregating a patient cohort by certain molecular features and constructing survival plots using the associated clinical data. However, conclusions drawn from this straightforward analysis are highly dependent on the quality and source of tissue samples, as demonstrated through the pancreatic ductal adenocarcinoma (PDAC) subset of TCGA.

Results: Analyses of the PDAC-TCGA database, which contains mainly resectable cancer samples from patients in stage IIB, reveal a difference from widely known historic median and 5-year survival rates of PDAC. A similar discrepancy was observed in lung, stomach, and liver cancer subsets of TCGA. The whole transcriptome expression patterns of PDAC-TCGA revealed a cluster of samples derived from neuroendocrine tumors, which have a distinctive biology and better disease prognosis than PDAC. Furthermore, PDAC-TCGA contains numerous pseudo-normal samples, as well as those that arose from tumors not classified as PDAC.

Conclusions: Inclusion of misclassified samples in the bioinformatic analyses distorts the association of molecular biomarkers with clinical outcomes, altering multiple published conclusions used to support and motivate experimental research. Hence, the stringent scrutiny of type and origin of samples included in the bioinformatic analyses by researchers, databases, and web-tool developers is of crucial importance for generating accurate conclusions. Clin Cancer Res; 24(16); 3813–9. ©2018 AACR.
Data from A Phase II Trial of the Aurora Kinase A Inhibitor Alisertib for Patients with Castration-resistant and Neuroendocrine Prostate Cancer: Efficacy and Biomarkers
Authors: Beltran Himisha , Oromendia Clara , Danila Daniel C. , Montgomery Bruce , Hoimes Christopher , Szmulewitz Russell Z. , Vaishampayan Ulka , Armstrong Andrew J. , Stein Mark , Pinski Jacek , Mosquera Juan M. , Sailer Verena , Bareja Rohan , Romanel Alessandro , Gumpeni Naveen , Sboner Andrea , Dardenne Etienne , Puca Loredana , Prandi Davide , Rubin Mark A. , Scher Howard I. , Rickman David S. , Demichelis Francesca , Nanus David M. , Ballman Karla V. , Tagawa Scott T.
Published: April 2023

AbstractPurpose:
Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that may develop de novo or as a mechanism of treatment resistance. N-myc is capable of driving NEPC progression. Alisertib inhibits the interaction between N-myc and its stabilizing factor Aurora-A, inhibiting N-myc signaling, and suppressing tumor growth.
Patients and Methods:
Sixty men were treated with alisertib 50 mg twice daily for 7 days every 21 days. Eligibility included metastatic prostate cancer and at least one: small-cell neuroendocrine morphology; ≥50% neuroendocrine marker expression; new liver metastases without PSA progression; or elevated serum neuroendocrine markers. The primary endpoint was 6-month radiographic progression-free survival (rPFS). Pretreatment biopsies were evaluated by whole exome and RNA-seq and patient-derived organoids were developed.
Results:
Median PSA was 1.13 ng/mL (0.01–514.2), number of prior therapies was 3, and 68% had visceral metastases. Genomic alterations involved RB1 (55%), TP53 (46%), PTEN (29%), BRCA2 (29%), and AR (27%), and there was a range of androgen receptor signaling and NEPC marker expression. Six-month rPFS was 13.4% and median overall survival was 9.5 months (7.3–13). Exceptional responders were identified, including complete resolution of liver metastases and prolonged stable disease, with tumors suggestive of N-myc and Aurora-A overactivity. Patient organoids exhibited concordant responses to alisertib and allowed for the dynamic testing of Aurora–N-myc complex disruption.
Conclusions:
Although the study did not meet its primary endpoint, a subset of patients with advanced prostate cancer and molecular features supporting Aurora-A and N-myc activation achieved significant clinical benefit from single-agent alisertib.
Data from Radiological Patterns of Drug-induced Interstitial Lung Disease (DILD) in Early-phase Oncology Clinical Trials
Authors: Terbuch Angelika , Tiu Crescens , Candilejo Irene Moreno , Scaranti Mariana , Curcean Andra , Bar Dan , Estevez Timon Miriam , Ameratunga Malaka , Ang Joo Ern , Ratoff Jonathan , Minchom Anna R. , Banerji Udai , de Bono Johann S. , Tunariu Nina , Lopez Juanita S.
Published: April 2023

AbstractPurpose:
Drug-induced interstitial lung disease (DILD) is a rare, but potentially fatal toxicity. Clinical and radiological features of DILD in the early experimental setting are poorly described.
Patients and Methods:
A total of 2,499 consecutive patients with advanced cancer on phase I clinical trials were included. DILD was identified by a dedicated radiologist and investigators, categorized per internationally recognized radiological patterns, and graded per Common Terminology Criteria for Adverse Events (CTCAE) and the Royal Marsden Hospital (RMH) DILD score. Clinical and radiological features of DILD were analyzed.
Results:
Sixty patients overall (2.4%) developed DILD. Median time to onset of DILD was 63 days (range, 14–336 days). A total of 45% of patients who developed DILD were clinically asymptomatic. Incidence was highest in patients receiving drug conjugates (7.4%), followed by inhibitors of the PI3K/AKT/mTOR pathway (3.9%). The most common pattern seen was hypersensitivity pneumonitis (33.3%), followed by nonspecific interstitial pneumonia (30%), and cryptogenic organizing pneumonia (26.7%). A higher DILD score [OR, 1.47, 95% confidence interval (CI), 1.19–1.81; P < 0.001] and the pattern of DILD (OR, 5.83 for acute interstitial pneumonia; 95% CI, 0.38–90.26; P = 0.002) were significantly associated with a higher CTCAE grading. The only predictive factor for an improvement in DILD was an interruption of treatment (OR, 0.05; 95% CI, 0.01–0.35; P = 0.01).
Conclusions:
DILD in early-phase clinical trials is a toxicity of variable onset, with diverse clinical and radiological findings. Radiological findings precede clinical symptoms. The extent of the affected lung parenchyma, scored by the RMH DILD score, correlates with clinical presentation. Most events are low grade, and improve with treatment interruption, which should be considered early.
Data from Undifferentiated Sarcomas in Children Harbor Clinically Relevant Oncogenic Fusions and Gene Copy-Number Alterations: A Report from the Children's Oncology Group
Authors: Laetsch Theodore W. , Roy Angshumoy , Xu Lin , Black Jennifer O. , Coffin Cheryl M. , Chi Yueh-Yun , Tian Jing , Spunt Sheri L. , Hawkins Douglas S. , Bridge Julia A. , Parsons D. Williams , Skapek Stephen X.
Published: April 2023

Abstract
Purpose: A comprehensive analysis of the genomics of undifferentiated sarcomas (UDS) is lacking. We analyzed copy-number alterations and fusion status in patients with UDS prospectively treated on Children's Oncology Group protocol ARST0332.

Experimental Design: Copy-number alterations were assessed by OncoScan FFPE Express on 32 UDS. Whole-exome and transcriptome libraries from eight tumors with sufficient archived material were sequenced on HiSeq (2 × 100 bp). Targeted RNA-sequencing using Archer chemistry was performed on two additional cases.

Results: Five-year overall survival for patients with UDS was 83% (95% CI, 69%–97%) with risk-adapted therapy (surgery, chemotherapy, and radiotherapy). Both focal and arm-level copy-number alterations were common including gain of 1q (8/32, 25%) and loss of 1p (7/32, 22%), both of which occurred more often in clinically defined high-risk tumors. Tumors with both loss of 1p and gain of 1q carried an especially poor prognosis with a 5-year event-free survival of 20%. GISTIC analysis identified recurrent amplification of FGF1 on 5q31.3 (q = 0.03) and loss of CDKN2A and CDKN2B on 9p21.3 (q = 0.07). Known oncogenic fusions were identified in eight of 10 cases analyzed by next-generation sequencing.

Conclusions: Pediatric UDS generally has a good outcome with risk-adapted therapy. A high-risk subset of patients whose tumors have copy-number loss of 1p and gain of 1q was identified with only 20% survival. Oncogenic fusions are common in UDS, and next-generation sequencing should be considered for children with UDS to refine the diagnosis and identify potentially targetable drivers. Clin Cancer Res; 24(16); 3888–97. ©2018 AACR.
Data from A Phase I/II Study of Neoadjuvant Cisplatin, Docetaxel, and Nintedanib for Resectable Non–Small Cell Lung Cancer
Authors: Cascone Tina , Sepesi Boris , Lin Heather Y. , Kalhor Neda , Parra Edwin R. , Jiang Mei , Godoy Myrna C.B. , Zhang Jianjun , Fossella Frank V. , Tsao Anne S. , Lam Vincent K. , Lu Charles , Mott Frank E. , Simon George R. , Antonoff Mara B. , Mehran Reza J. , Rice David C. , Behrens Carmen , Weissferdt Annikka , Moran Cesar , Vaporciyan Ara A. , Lee J. Jack , Swisher Stephen G. , Gibbons Don L. , Wistuba Ignacio I. , William William N. , Heymach John V.
Published: April 2023

AbstractPurpose:
Nintedanib enhances the activity of chemotherapy in metastatic non–small cell lung cancer (NSCLC). In this phase I/II study, we assessed safety and efficacy of nintedanib plus neoadjuvant chemotherapy, using major pathologic response (MPR) as primary endpoint.
Patients and Methods:
Eligible patients had stage IB (≥4 cm)–IIIA resectable NSCLC. A safety run-in phase was followed by an expansion phase with nintedanib 200 mg orally twice a day (28 days), followed by three cycles of cisplatin (75 mg/m2), docetaxel (75 mg/m2) every 21 days plus nintedanib, followed by surgery. With 33 planned patients, the study had 90% power to detect an MPR increase from 15% to 35%.
Results:
Twenty-one patients (stages I/II/III, N = 1/8/12) were treated. One of 15 patients treated with nintedanib 200 mg achieved MPR [7%, 95% confidence interval (CI), 0.2%–32%]. Best ORR in 20 evaluable patients was 30% (6/20, 95% CI, 12%–54%). Twelve-month recurrence-free survival and overall survival were 66% (95% CI, 47%–93%) and 91% (95% CI, 79%–100%), respectively. Most frequent treatment-related grade 3–4 toxicities were transaminitis and electrolyte abnormalities. On the basis of an interim analysis the study was discontinued for futility. Higher levels of CD3+ and cytotoxic CD3+CD8+ T cells were found in treated tumors of patients who were alive than in those who died (652.8 vs. 213.4 cells/mm2, P = 0.048; 142.3 vs. 35.6 cells/mm2, P = 0.018).
Conclusions:
Although tolerated, neoadjuvant nintedanib plus chemotherapy did not increase MPR rate compared with chemotherapy historical controls. Additional studies of the combination in this setting are not recommended. Posttreatment levels of tumor-infiltrating T cells were associated with patient survival. Use of MPR facilitates the rapid evaluation of neoadjuvant therapies.

See related commentary by Blakely and McCoach, p. 3499
Data from Tumor Subtype Determines Therapeutic Response to Chimeric Polypeptide Nanoparticle–based Chemotherapy in Pten-deleted Mouse Models of Sarcoma
Authors: Dodd Rebecca D. , Scherer Amanda , Huang Wesley , McGivney Gavin R. , Gutierrez Wade R. , Laverty Emily A. , Ashcraft Kathleen A. , Stephens Victoria R. , Yousefpour Parisa , Saha Soumen , Knepper-Adrian Vickie , Floyd Warren , Chen Mark , Ma Yan , Mastria Eric M. , Cardona Diana M. , Eward William C. , Chilkoti Ashutosh , Kirsch David G.
Published: April 2023

AbstractPurpose:
Nanoparticle-encapsulated drug formulations can improve responses to conventional chemotherapy by increasing drug retention within the tumor and by promoting a more effective antitumor immune response than free drug. New drug delivery modalities are needed in sarcomas because they are often chemoresistant cancers, but the rarity of sarcomas and the complexity of diverse subtypes makes it challenging to investigate novel drug formulations.
Experimental Design:
New drug formulations can be tested in animal models of sarcomas where the therapeutic response of different formulations can be compared using mice with identical tumor-initiating mutations. Here, using Cre/loxP and CRISPR/Cas9 techniques, we generated two distinct mouse models of Pten-deleted soft-tissue sarcoma: malignant peripheral nerve sheath tumor (MPNST) and undifferentiated pleomorphic sarcoma (UPS). We used these models to test the efficacy of chimeric polypeptide doxorubicin (CP-Dox), a nanoscale micelle formulation, in comparison with free doxorubicin.
Results:
The CP-Dox formulation was superior to free doxorubicin in MPNST models. However, in UPS tumors, CP-Dox did not improve survival in comparison with free doxorubicin. While CP-Dox treatment resulted in elevated intratumoral doxorubicin concentrations in MPNSTs, this increase was absent in UPS tumors. In addition, elevation of CD8+ T cells was observed exclusively in CP-Dox–treated MPNSTs, although these cells were not required for full efficacy of the CP nanoparticle–based chemotherapy.
Conclusions:
These results have important implications for treating sarcomas with nanoparticle-encapsulated chemotherapy by highlighting the tumor subtype–dependent nature of therapeutic response.
Data from Integrated Analysis of RNA and DNA from the Phase III Trial CALGB 40601 Identifies Predictors of Response to Trastuzumab-Based Neoadjuvant Chemotherapy in HER2-Positive Breast Cancer
Authors: Tanioka Maki , Fan Cheng , Parker Joel S. , Hoadley Katherine A. , Hu Zhiyuan , Li Yan , Hyslop Terry M. , Pitcher Brandelyn N. , Soloway Matthew G. , Spears Patricia A. , Henry Lynn N. , Tolaney Sara , Dang Chau T. , Krop Ian E. , Harris Lyndsay N. , Berry Donald A. , Mardis Elaine R. , Winer Eric P. , Hudis Clifford A. , Carey Lisa A. , Perou Charles M.
Published: April 2023

Abstract
Purpose: Response to a complex trastuzumab-based regimen is affected by multiple features of the tumor and its microenvironment. Developing a predictive algorithm is key to optimizing HER2-targeting therapy.

Experimental Design: We analyzed 137 pretreatment tumors with mRNA-seq and DNA exome sequencing from CALGB 40601, a neoadjuvant phase III trial of paclitaxel plus trastuzumab with or without lapatinib in stage II to III HER2-positive breast cancer. We adopted an Elastic Net regularized regression approach that controls for covarying features within high-dimensional data. First, we applied 517 known gene expression signatures to develop an Elastic Net model to predict pCR, which we validated on 143 samples from four independent trials. Next, we performed integrative analyses incorporating clinicopathologic information with somatic mutation status, DNA copy number alterations (CNA), and gene signatures.

Results: The Elastic Net model using only gene signatures predicted pCR in the validation sets (AUC = 0.76). Integrative analyses showed that models containing gene signatures, clinical features, and DNA information were better pCR predictors than models containing a single data type. Frequently selected variables from the multiplatform models included amplifications of chromosome 6p, TP53 mutation, HER2-enriched subtype, and immune signatures. Variables predicting resistance included Luminal/ER+ features.

Conclusions: Models using RNA only, as well as integrated RNA and DNA models, can predict pCR with improved accuracy over clinical variables. Somatic DNA alterations (mutation, CNAs), tumor molecular subtype (HER2E, Luminal), and the microenvironment (immune cells) were independent predictors of response to trastuzumab and paclitaxel-based regimens. This highlights the complexity of predicting response in HER2-positive breast cancer. Clin Cancer Res; 24(21); 5292–304. ©2018 AACR.
Data from 21-Gene Recurrence Score Assay Predicts Benefit of Post-Mastectomy Radiotherapy in T1-2 N1 Breast Cancer
Authors: Goodman Chelain R. , Seagle Brandon-Luke L. , Kocherginsky Masha , Donnelly Eric D. , Shahabi Shohreh , Strauss Jonathan B.
Published: April 2023

Abstract
Purpose: Post-mastectomy radiotherapy (PMRT) yields improvements in both locoregional control and overall survival (OS) for women with T1-2 N1 breast cancer. The value of PMRT in this population has been questioned given advances in systemic therapy. The 21-gene recurrence score (RS) assay was evaluated as a predictor of OS among women with T1-2 N1 breast cancer who received or did not receive PMRT.

Experimental Design: An observational cohort study was performed on women with T1-2 N1 estrogen receptor–positive breast cancer from the National Cancer Database (NCDB) and, as a validation cohort, from the surveillance, epidemiology, and end results (SEER) registry who underwent mastectomy and were evaluated for RS. Multivariable parametric accelerated failure time models were used to estimate associations of RS and PMRT with OS using propensity score-adjusted matched cohorts.

Results: In both the NCDB (N = 7,332) and SEER (N = 3,087) cohorts, there was a significant interaction of RS and PMRT with OS (P = 0.009 and P = 0.03, respectively). PMRT was associated with longer OS in women with a low RS [NCDB: time ratio (TR) = 1.70; 95% CI (confidence interval), 1.30–2.22; P < 0.001; SEER: TR = 1.85; 95% CI, 1.33–2.57; P < 0.001], but not in women with an intermediate RS (NCDB: TR = 0.89; 95% CI, 0.69–1.14; P = 0.35; SEER: TR = 0.84; 95% CI, 0.62–1.14; P = 0.26), or a high RS (NCDB: TR = 1.10; 95% CI, 0.91–1.34; P = 0.33; SEER: TR = 0.79; 95% CI, 0.50–1.23; P = 0.28).

Conclusions: Longer survival associated with PMRT was limited to women with a low RS. PMRT may confer the greatest OS benefit for patients at the lowest risk of distant recurrence. These results caution against omission of PMRT among women with low RS. Clin Cancer Res; 24(16); 3878–87. ©2018 AACR.
Data from The Immune Microenvironment and Neoantigen Landscape of Aggressive Salivary Gland Carcinomas Differ by Subtype
Authors: Linxweiler Maximilian , Kuo Fengshen , Katabi Nora , Lee Mark , Nadeem Zaineb , Dalin Martin G. , Makarov Vladimir , Chowell Diego , Dogan Snjezana , Ganly Ian , Hakimi A. Ari , Wong Richard J. , Riaz Nadeem , Ho Alan L. , Chan Timothy A. , Morris Luc G.T.
Published: April 2023

AbstractPurpose:
Salivary gland carcinomas (SGC) are rare, aggressive cancers with high rates of recurrence and distant metastasis. These factors, and a lack of active systemic therapies, contribute to poor clinical outcome. Response rates with immune checkpoint blockade have been low, although clinical data remain sparse. To improve the efficacy of therapies, a more comprehensive understanding of relevant molecular alterations and immunologic processes is needed.
Experimental Design:
To characterize the immune microenvironment and neoantigen landscape of SGCs, we performed RNA sequencing (RNA-seq) in 76 tumors representing the three most lethal histologies: adenoid cystic carcinoma (ACC), myoepithelial carcinoma (MECA), and salivary duct carcinoma (SDC). We analyzed transcriptomic profiles, tumor-infiltrating immune cell populations, and measures of T-cell activation/dysfunction. In 37 cases also undergoing exome sequencing, we analyzed somatic mutations and neoantigens.
Results:
SDCs exhibited high levels of immune infiltration, with corresponding higher levels of T-cell dysfunction, and higher mutational load. In contrast, ACCs were characterized by an immune-excluded microenvironment, the presence of M2-polarized macrophages and myeloid-derived suppressor cells, and very low mutational load. MECAs were more heterogeneous, with both immune-low and immune-high phenotypes represented. Across all SGCs, levels of immune infiltration were associated with mutation- and fusion-derived neoantigens, and with aggressive clinical behavior.
Conclusions:
These findings provide new insights into the immune microenvironment and neoantigen landscape of SGCs, showing that mechanisms of immune escape appear to differ by histology. These data nominate potential immunologic vulnerabilities and may help guide the next steps of investigation in precision immunotherapy for these difficult-to-treat cancers.
Data from Cancer-Stimulated CAFs Enhance Monocyte Differentiation and Protumoral TAM Activation via IL6 and GM-CSF Secretion
Authors: Cho Haaglim , Seo Youngha , Loke Kin Man , Kim Seon-Wook , Oh Seong-Min , Kim Jun-Hyeong , Soh Jihee , Kim Hyoen Sik , Lee Hyunju , Kim Jin , Min Jung-Joon , Jung Da-Woon , Williams Darren Reece
Published: April 2023

Abstract
Purpose: M2-type TAMs are increasingly implicated as a crucial factor promoting metastasis. Numerous cell types dictate monocyte differentiation into M2 TAMs via a complex network of cytokine-based communication. Elucidating critical pathways in this network can provide new targets for inhibiting metastasis. In this study, we focused on cancer cells, CAFs, and monocytes as a major node in this network.

Experimental Design: Monocyte cocultures with cancer-stimulated CAFs were used to investigate differentiation into M2-like TAMs. Cytokine array analyses were employed to discover the CAF-derived regulators of differentiation. These regulators were validated in primary CAFs and bone marrow-derived monocytes. Orthotopic, syngeneic colon carcinoma models using cotransplanted CAFs were established to observe effects on tumor growth and metastasis. To confirm a correlation with clinical evidence, meta-analyses were employed using the Oncomine database.

Results: Our coculture studies identify IL6 and GM-CSF as the pivotal signals released from cancer cell–activated CAFs that cooperate to induce monocyte differentiation into M2-like TAMs. In orthotopic, syngeneic colon carcinoma mouse models, cotransplanted CAFs elevated IL6 and GM-CSF levels, TAM infiltration, and metastasis. These pathologic effects were dramatically reversed by joint IL6 and GM-CSF blockade. A positive correlation between GM-CSF and IL6 expression and disease course was observed by meta-analyses of the clinical data.

Conclusions: Our studies indicate a significant reappraisal of the role of IL6 and GM-CSF in metastasis and implicate CAFs as the “henchmen” for cancer cells in producing an immunosuppressive tumor ecological niche. Dual targeting of GM-CSF and IL6 is a promising new approach for inhibiting metastasis. Clin Cancer Res; 24(21); 5407–21. ©2018 AACR.
Data from Analysis of Mucosal Melanoma Whole-Genome Landscapes Reveals Clinically Relevant Genomic Aberrations
Authors: Zhou Rong , Shi Chaoji , Tao Wenjie , Li Jiang , Wu Jing , Han Yong , Yang Guizhu , Gu Ziyue , Xu Shengming , Wang Yujue , Wang Lizhen , Wang Yanan , Zhou Guoyu , Zhang Chenping , Zhang Zhiyuan , Sun Shuyang
Published: April 2023

AbstractPurpose:
Unlike advances in the genomics-driven precision treatment of cutaneous melanomas, the current poor understanding of the molecular basis of mucosal melanomas (MM) has hindered such progress for MM patients. Thus, we sought to characterize the genomic landscape of MM to identify genomic alterations with prognostic and/or therapeutic implications.
Experimental Design:
Whole-genome sequencing (WGS) was performed on 65 MM samples, including 63 paired tumor blood samples and 2 matched lymph node metastases, with a further droplet digital PCR–based validation study of an independent MM cohort (n = 80). Guided by these molecular insights, the FDA-approved CDK4/6 inhibitor palbociclib was tested in an MM patient-derived xenograft (PDX) trial.
Results:
Besides the identification of well-recognized driver mutations of BRAF (3.1%), RAS family (6.2%), NF1 (7.8%), and KIT (23.1%) in MMs, our study also found that (i) mutations and amplifications in the transmembrane nucleoporin gene POM121 (30.8%) defined a patient subgroup with higher tumor proliferation rates; (ii) enrichment of structural variations between chromosomes 5 and 12 defined a patient subgroup with significantly worse clinical outcomes; (iii) over 50% of the MM patients harbored recurrent focal amplification of several oncogenes (CDK4, MDM2, and AGAP2) at 12q13-15, and this co-occurred significantly with amplification of TERT at 5p15, which was verified in the validation cohort; (iv) the PDX trial demonstrated robust antitumor effects of palbociclib in MMs harboring CDK4 amplification.
Conclusions:
Our largest-to-date cohort WGS analysis of MMs defines the genomic landscape of this deadly cancer at unprecedented resolution and identifies genomic aberrations that could facilitate the delivery of precision cancer treatments.

See related commentary by Shoushtari, p. 3473
Data from Low-Dose Metformin Reprograms the Tumor Immune Microenvironment in Human Esophageal Cancer: Results of a Phase II Clinical Trial
Authors: Wang Shuhong , Lin Yusheng , Xiong Xiao , Wang Lu , Guo Yi , Chen Yuping , Chen Shaobin , Wang Geng , Lin Peng , Chen Hongcai , Yeung Sai-Ching Jim , Bremer Edwin , Zhang Hao
Published: April 2023

AbstractPurpose:
The tumor immune microenvironment (TIME) has an important impact on response to cancer immunotherapy using immune checkpoint inhibitors. Specifically, an “infiltrated-excluded”/“cold” TIME is predictive of poor response. The antidiabetic agent metformin may influence anticancer immunity in esophageal squamous cell carcinoma (ESCC).
Experimental Design:
We analyzed matched pre- and posttreatment ESCC specimens in a phase II clinical trial of low-dose metformin treatment (250 mg/day) to evaluate direct anti-ESCC activity and TIME reprogramming. Follow-up correlative studies using a carcinogen-induced ESCC mouse model were performed with short-term (1 week) or long-term (12 weeks) low-dose metformin (50 mg/kg/day) treatment.
Results:
In the clinical trial, low-dose metformin did not affect proliferation or apoptosis in ESCC tumors as assayed by Ki67 and cleaved caspase-3 immunostaining. However, metformin reprogrammed the TIME toward “infiltrated-inflamed” and increased the numbers of infiltrated CD8+ cytotoxic T lymphocyte and CD20+ B lymphocyte. Further, an increase in tumor-suppressive (CD11c+) and a decrease in tumor-promoting (CD163+) macrophages were observed. Metformin augmented macrophage-mediated phagocytosis of ESCC cells in vitro. In the ESCC mouse model, short-term metformin treatment reprogrammed the TIME in a similar fashion to humans, whereas long-term treatment further shifted the TIME toward an active state (e.g., reduction in CD4+ FoxP3+ regulatory T cells) and inhibited ESCC growth. In both humans and mice, metformin triggered AMPK activation and STAT3 inactivation, and altered the production of effector cytokines (i.e., TNFα, IFNγ, and IL10) in the immune cells.
Conclusions:
Low-dose metformin reprograms the TIME to an activated status and may be a suitable immune response modifier for further investigation in patients with ESCC.
Data from Identification of Deleterious NOTCH Mutation as Novel Predictor to Efficacious Immunotherapy in NSCLC
Authors: Zhang Kai , Hong Xiaohua , Song Zhengbo , Xu Yu , Li Chengcheng , Wang Guoqiang , Zhang Yuzi , Zhao Xiaochen , Zhao Zhengyi , Zhao Jing , Huang Mengli , Huang Depei , Qi Chuang , Gao Chan , Cai Shangli , Gu Feifei , Hu Yue , Xu Chunwei , Wang Wenxian , Lou Zhenkun , Zhang Yong , Liu Li
Published: April 2023

AbstractPurpose:
NOTCH signaling is associated with tumorigenesis, mutagenesis, and immune tolerance in non–small cell lung cancer (NSCLC), indicating its association with the clinical benefit of immune checkpoint inhibitors (ICI). We hypothesized that NOTCH mutation in NSCLC might be a robust predictor of immunotherapeutic efficacy.
Experimental Design:
Multiple-dimensional data including genomic, transcriptomic, and clinical data from cohorts of NSCLC internal and public cohorts involving immunotherapeutic patients were analyzed. Polymorphism Phenotyping v2 (PolyPhen-2) system was performed to determine deleterious NOTCH mutation (del-NOTCHmut). Further investigation on molecular mechanism was performed in The Cancer Genome Atlas (TCGA) data via CIBERSORT and gene set enrichment analysis.
Results:
Our 3DMed cohort (n = 58) and other four cohorts (Rizvi, POPLAR/OAK, Van Allen, and MSKCC; n = 1,499) uncovered marked correlation between NOTCH1/2/3 mutation and better ICI outcomes in EGFR/ALKWT population, including objective response rate (2.20-fold, P = 0.001), progression-free survival [HR, 0.61; 95% confidence interval (CI), 0.46–0.81; P = 0.001], and overall survival (HR, 0.56; 95% CI, 0.32–0.96; P = 0.035). Del-NOTCHmut exhibited better predictive function than non-deleterious NOTCH mutation, potentially via greater transcription of genes related to DNA damage response and immune activation. Del-NOTCHmut was not linked with prognosis in TCGA cohorts and chemotherapeutic response, but was independently associated with immunotherapeutic benefit, delineating the predictive, but not prognostic, utility of del-NOTCHmut.
Conclusions:
This work distinguishes del-NOTCHmut as a potential predictor to favorable ICI response in NSCLC, highlighting the importance of genomic profiling in immunotherapy. More importantly, our results unravel a possibility of personalized combination immunotherapy as adding NOTCH inhibitor to ICI regimen in NSCLC, for the optimization of ICI treatment in clinical practice.
Data from A First-in-Human Study of Novel Cereblon Modulator Avadomide (CC-122) in Advanced Malignancies
Authors: Rasco Drew W. , Papadopoulos Kyriakos P. , Pourdehnad Michael , Gandhi Anita K. , Hagner Patrick R. , Li Yan , Wei Xin , Chopra Rajesh , Hege Kristen , DiMartino Jorge , Shih Kent
Published: April 2023

AbstractPurpose:
Avadomide is a novel, small-molecule therapeutic agent that modulates cereblon E3 ligase activity and exhibits potent antitumor and immunomodulatory activities. This first-in-human phase I study (NCT01421524) evaluated the safety and clinical activity of avadomide in patients with advanced solid tumors, non-Hodgkin lymphoma (NHL), and multiple myeloma.
Patients and Methods:
Thirty-four patients were treated with avadomide in 7 dose-escalation cohorts using a 3 + 3 design (0.5–3.5 mg, 28-day continuous dosing cycles). The primary objectives were to determine the dose-limiting toxicity (DLT), nontolerated dose (NTD), maximum tolerated dose (MTD), recommended phase II dose, and pharmacokinetics of avadomide. The secondary objective was to determine preliminary avadomide efficacy. Exploratory objectives included evaluation of pharmacodynamic effects of avadomide.
Results:
DLTs were reported in 2 patients, and grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 14 patients (41%). The most common TEAEs (≥15%) were fatigue, neutropenia, and diarrhea. The NTD and MTD were 3.5 and 3.0 mg, respectively. Of 5 patients with NHL, 1 achieved a complete response, and 2 had partial responses. Although no objective responses were observed in patients with solid tumors, 5 of 6 patients with brain cancer experienced nonprogression of ≥6 months. A dose-dependent relationship between Aiolos degradation in peripheral B and T cells occurred within 5 hours of the first dose of avadomide administered, starting at 0.5 mg.
Conclusions:
Avadomide monotherapy demonstrated acceptable safety and favorable pharmacokinetics in patients with solid tumors, NHL, and multiple myeloma. In addition, 3 objective responses were observed in NHL.
Data from Phase I Immunotherapy Trial with Two Chimeric HER-2 B-Cell Peptide Vaccines Emulsified in Montanide ISA 720VG and Nor-MDP Adjuvant in Patients with Advanced Solid Tumors
Authors: Bekaii-Saab Tanios , Wesolowski Robert , Ahn Daniel H. , Wu Christina , Mortazavi Amir , Lustberg Maryam , Ramaswamy Bhuvaneswari , Fowler Jeffrey , Wei Lai , Overholser Jay , Kaumaya Pravin T.P.
Published: April 2023

AbstractPurpose:
This first-in-human phase I study (NCT 01417546) evaluated the safety profile, optimal immunologic/biological dose (OID/OBD), and immunogenicity of the combination of two peptide B-cell epitope vaccines engineered to represent the trastuzumab- and pertuzumab-binding sites. Although trastuzumab and pertuzumab have been approved for clinical use, patients often develop resistance to these therapies. We have advanced a new paradigm in immunotherapy that focuses on humoral responses based on conformational B-cell epitope vaccines.
Patients and Methods:
The vaccine is comprised of two chimeric HER-2 B-cell peptide vaccines incorporating a “promiscuous T-cell epitope.” Patients were immunized with the vaccine constructs emulsified with nor-muramyl-dipeptide adjuvant in a water-in-oil Montanide ISA 720VG vehicle. Eligible patients with metastatic and/or recurrent solid tumors received three inoculations every 3 weeks.
Results:
Forty-nine patients with a median of 4 prior lines of chemotherapy received at least 1 vaccination. Twenty-eight patients completed the 3 vaccination regimens. Six patients received 1 six-month boost after the regimen, and one patient received 7 six-month boosts. No serious adverse reactions or dose-limiting toxicities were observed. The vaccine was well tolerated with dose level 2 as the recommended phase II dose. The most common related toxicity in all patients was injection-site reactions (24%). Two patients had a partial response, 14 had stable disease, and 19 had progressive disease.
Conclusions:
The study vaccine is safe, exhibits antitumor activity, and shows preliminary indication that peptide vaccination may avoid therapeutic resistance and offer a promising alternative to monoclonal antibody therapies.
Data from Age Correlates with Response to Anti-PD1, Reflecting Age-Related Differences in Intratumoral Effector and Regulatory T-Cell Populations
Authors: Kugel Curtis H. , Douglass Stephen M. , Webster Marie R. , Kaur Amanpreet , Liu Qin , Yin Xiangfan , Weiss Sarah A. , Darvishian Farbod , Al-Rohil Rami N. , Ndoye Abibatou , Behera Reeti , Alicea Gretchen M. , Ecker Brett L. , Fane Mitchell , Allegrezza Michael J. , Svoronos Nikolaos , Kumar Vinit , Wang Daniel Y. , Somasundaram Rajasekharan , Hu-Lieskovan Siwen , Ozgun Alpaslan , Herlyn Meenhard , Conejo-Garcia Jose R. , Gabrilovich Dmitry , Stone Erica L. , Nowicki Theodore S. , Sosman Jeffrey , Rai Rajat , Carlino Matteo S. , Long Georgina V. , Marais Richard , Ribas Antoni , Eroglu Zeynep , Davies Michael A. , Schilling Bastian , Schadendorf Dirk , Xu Wei , Amaravadi Ravi K. , Menzies Alexander M. , McQuade Jennifer L. , Johnson Douglas B. , Osman Iman , Weeraratna Ashani T.
Published: April 2023

Abstract
Purpose: We have shown that the aged microenvironment increases melanoma metastasis, and decreases response to targeted therapy, and here we queried response to anti-PD1.

Experimental Design: We analyzed the relationship between age, response to anti-PD1, and prior therapy in 538 patients. We used mouse models of melanoma, to analyze the intratumoral immune microenvironment in young versus aged mice and confirmed our findings in human melanoma biopsies.

Results: Patients over the age of 60 responded more efficiently to anti-PD-1, and likelihood of response to anti-PD-1 increased with age, even when we controlled for prior MAPKi therapy. Placing genetically identical tumors in aged mice (52 weeks) significantly increased their response to anti-PD1 as compared with the same tumors in young mice (8 weeks). These data suggest that this increased response in aged patients occurs even in the absence of a more complex mutational landscape. Next, we found that young mice had a significantly higher population of regulatory T cells (Tregs), skewing the CD8+:Treg ratio. FOXP3 staining of human melanoma biopsies revealed similar increases in Tregs in young patients. Depletion of Tregs using anti-CD25 increased the response to anti-PD1 in young mice.

Conclusions: While there are obvious limitations to our study, including our inability to conduct a meta-analysis due to a lack of available data, and our inability to control for mutational burden, there is a remarkable consistency in these data from over 500 patients across 8 different institutes worldwide. These results stress the importance of considering age as a factor for immunotherapy response. Clin Cancer Res; 24(21); 5347–56. ©2018 AACR.

See related commentary by Pawelec, p. 5193
Data from The MD Anderson Prostate Cancer Patient-derived Xenograft Series (MDA PCa PDX) Captures the Molecular Landscape of Prostate Cancer and Facilitates Marker-driven Therapy Development
Authors: Palanisamy Nallasivam , Yang Jun , Shepherd Peter D.A. , Li-Ning-Tapia Elsa M. , Labanca Estefania , Manyam Ganiraju C. , Ravoori Murali K. , Kundra Vikas , Araujo John C. , Efstathiou Eleni , Pisters Louis L. , Wan Xinhai , Wang Xuemei , Vazquez Elba S. , Aparicio Ana M. , Carskadon Shannon L. , Tomlins Scott A. , Kunju Lakshmi P. , Chinnaiyan Arul M. , Broom Bradley M. , Logothetis Christopher J. , Troncoso Patricia , Navone Nora M.
Published: April 2023

AbstractPurpose:
Advances in prostate cancer lag behind other tumor types partly due to the paucity of models reflecting key milestones in prostate cancer progression. Therefore, we develop clinically relevant prostate cancer models.
Experimental Design:
Since 1996, we have generated clinically annotated patient-derived xenografts (PDXs; the MDA PCa PDX series) linked to specific phenotypes reflecting all aspects of clinical prostate cancer.
Results:
We studied two cell line–derived xenografts and the first 80 PDXs derived from 47 human prostate cancer donors. Of these, 47 PDXs derived from 22 donors are working models and can be expanded either as cell lines (MDA PCa 2a and 2b) or PDXs. The histopathologic, genomic, and molecular characteristics (androgen receptor, ERG, and PTEN loss) maintain fidelity with the human tumor and correlate with published findings. PDX growth response to mouse castration and targeted therapy illustrate their clinical utility. Comparative genomic hybridization and sequencing show significant differences in oncogenic pathways in pairs of PDXs derived from different areas of the same tumor. We also identified a recurrent focal deletion in an area that includes the speckle-type POZ protein-like (SPOPL) gene in PDXs derived from seven human donors of 28 studied (25%). SPOPL is a SPOP paralog, and SPOP mutations define a molecular subclass of prostate cancer. SPOPLdeletions are found in 7% of The Cancer Genome Atlas prostate cancers, which suggests that our cohort is a reliable platform for targeted drug development.
Conclusions:
The MDA PCa PDX series is a dynamic resource that captures the molecular landscape of prostate cancers progressing under novel treatments and enables optimization of prostate cancer–specific, marker-driven therapy.
Data from Local Phototherapy Synergizes with Immunoadjuvant for Treatment of Pancreatic Cancer through Induced Immunogenic Tumor Vaccine
Authors: Zhou Feifan , Yang Jingxuan , Zhang Yuqing , Liu Mingyang , Lang Mark L. , Li Min , Chen Wei R.
Published: April 2023

Abstract
Purpose: To develop a synergistic combination therapy for advanced pancreatic cancer, using local phototherapy and immunotherapy, and to determine the efficacy and mechanism of the novel combination therapy using a highly metastatic pancreatic tumor model in mice.

Experimental Design: Mice bearing Panc02-H7 pancreatic tumors (both subcutaneous and orthotopic) were treated with noninvasive or interventional photothermal therapy, followed by local application of an immunoadjuvant. Tumor growth and animal survival were assessed. Immune cell populations within spleen and tumors were evaluated by FACS and IHC, and cytokine levels were determined by ELISA.

Results: Up to 75% of mice bearing subcutaneous tumors treated with combination therapy had complete tumor regression. Local photothermal therapy exposed/released damage-associated molecular patterns, which initiated an immunogenic tumor cell death, resulting in infiltration of antigen-presenting cells and Th1 immunity. Concomitant application of immunoadjuvant amplified Th1 immunity, especially the tumor-specific cytotoxic T lymphocyte response, with increased quantity and quality of T cells. Combination therapy also induced tumor-specific immune memory, as demonstrated by resistance to tumor rechallenge and production of memory T cells. For the treatment of orthotopic tumor, the combination therapy significantly reduced the primary tumors and metastases, and prolonged the animal survival time.

Conclusions: This study indicated that combination of local phototherapy and immunotherapy induced a systemic immunity against established tumors and metastases in an aggressive, preclinical pancreatic tumor model, leading to a potential clinical method for patients with advanced pancreatic cancer. Clin Cancer Res; 24(21); 5335–46. ©2018 AACR.
Data from Combined CDK4/6 and Pan-mTOR Inhibition Is Synergistic Against Intrahepatic Cholangiocarcinoma
Authors: Song Xinhua , Liu Xianqiong , Wang Haichuan , Wang Jingxiao , Qiao Yu , Cigliano Antonio , Utpatel Kirsten , Ribback Silvia , Pilo Maria G. , Serra Marina , Gordan John D. , Che Li , Zhang Shanshan , Cossu Antonio , Porcu Alberto , Pascale Rosa M. , Dombrowski Frank , Hu Hongbo , Calvisi Diego F. , Evert Matthias , Chen Xin
Published: April 2023

AbstractPurpose:
Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer type, lacking effective therapies and associated with a dismal prognosis. Palbociclib is a selective CDK4/6 inhibitor, which has been shown to suppress cell proliferation in many experimental cancer models. Recently, we demonstrated that pan-mTOR inhibitors, such as MLN0128, effectively induce apoptosis, although have limited efficacy in restraining proliferation of ICC cells. Here, we tested the hypothesis that palbociclib, due to its antproliferative properties in many cancer types, might synergize with MLN0128 to impair ICC growth.
Experimental Design:
Human ICC cell lines and the AKT/YapS127A ICC mouse model were used to test the therapeutic efficacy of palbociclib and MLN0128, either alone or in combination.
Results:
Administration of palbociclib suppressed in vitro ICC cell growth by inhibiting cell-cycle progression. Concomitant administration of palbociclib and MLN0128 led to a pronounced, synergistic growth constraint of ICC cell lines. Furthermore, while treatment with palbociclib or MLN0128 alone resulted in tumor growth reduction in AKT/YapS127A mice, a remarkable tumor regression was achieved when the two drugs were administered simultaneously. Mechanistically, palbociclib was found to potentiate MLN0128 mTOR inhibition activity, whereas MLN0128 prevented the upregulation of cyclin D1 induced by palbociclib treatment.
Conclusions:
Our study indicates the synergistic activity of palbociclib and MLN0128 in inhibiting ICC cell proliferation. Thus, combination of CDK4/6 and mTOR inhibitors might represent a novel, promising, and effective therapeutic approach against human ICC.

See related commentary by Malumbres, p. 6
Data from The Novel Bromodomain and Extraterminal Domain Inhibitor INCB054329 Induces Vulnerabilities in Myeloma Cells That Inform Rational Combination Strategies
Authors: Stubbs Matthew C. , Burn Timothy C. , Sparks Richard , Maduskuie Thomas , Diamond Sharon , Rupar Mark , Wen Xiaoming , Volgina Alla , Zolotarjova Nina , Waeltz Paul , Favata Margaret , Jalluri Ravi , Liu Huiqing , Liu Xuesong Mike , Li Jun , Collins Robert , Falahatpisheh Nikoo , Polam Padmaja , DiMatteo Darlise , Feldman Patricia , Dostalik Valerie , Thekkat Pramod , Gardiner Christine , He Xin , Li Yanlong , Covington Maryanne , Wynn Richard , Ruggeri Bruce , Yeleswaram Swamy , Xue Chu-Biao , Yao Wenqing , Combs Andrew P. , Huber Reid , Hollis Gregory , Scherle Peggy , Liu Phillip C.C.
Published: April 2023

AbstractPurpose:
Bromodomain and extraterminal domain (BET) proteins regulate the expression of many cancer-associated genes and pathways; BET inhibitors have demonstrated activity in diverse models of hematologic and solid tumors. We report the preclinical characterization of INCB054329, a structurally distinct BET inhibitor that has been investigated in phase I clinical trials.
Experimental Design:
We used multiple myeloma models to investigate vulnerabilities created by INCB054329 treatment that could inform rational combinations.
Results:
In addition to c-MYC, INCB054329 decreased expression of oncogenes FGFR3 and NSD2/MMSET/WHSC1, which are deregulated in t(4;14)-rearranged cell lines. The profound suppression of FGFR3 sensitized the t(4;14)-positive cell line OPM-2 to combined treatment with a fibroblast growth factor receptor inhibitor in vivo. In addition, we show that BET inhibition across multiple myeloma cell lines resulted in suppressed interleukin (IL)-6 Janus kinase–signal transducers and activators of transcription (JAK–STAT) signaling. INCB054329 displaced binding of BRD4 to the promoter of IL6 receptor (IL6R) leading to reduced levels of IL6R and diminished signaling through STAT3. Combination with JAK inhibitors (ruxolitinib or itacitinib) further reduced JAK–STAT signaling and synergized to inhibit myeloma cell growth in vitro and in vivo. This combination potentiated tumor growth inhibition in vivo, even in the MM1.S model of myeloma that is not intrinsically sensitive to JAK inhibition alone.
Conclusions:
Preclinical data reveal insights into vulnerabilities created in myeloma cells by BET protein inhibition and potential strategies that can be leveraged in clinical studies to enhance the activity of INCB054329.
Data from TERT Promoter Mutation Detection in Cell-Free Tumor-Derived DNA in Patients with IDH Wild-Type Glioblastomas: A Pilot Prospective Study
Authors: Juratli Tareq A. , Stasik Sebastian , Zolal Amir , Schuster Caroline , Richter Sven , Daubner Dirk , Juratli Mazen A. , Thowe Rachel , Hennig Silke , Makina Meriem , Meinhardt Matthias , Lautenschlaeger Tim , Schackert Gabriele , Krex Dietmar , Thiede Christian
Published: April 2023

Abstract
Purpose: We conducted a pilot study to assess the feasibility and the potential implications of detecting TERT promoter (TERTp)–mutant cell-free tumor-derived DNA (tDNA) in the cerebrospinal fluid (CSF) and plasma of glioblastoma patients.

Experimental Design: Matched CSF and plasma samples were collected in 60 patients with glial tumors. The CSF collection was obtained during surgery, before any surgical manipulation of the tumor. The extracted tDNA and corresponding tumor DNA samples were analyzed for TERTp and isocitrate dehydrogenase (IDH) hotspot mutations. In addition, the variant allele frequency (VAF) of TERTp mutation in the CSF-tDNA was correlated with tumor features and patients’ outcome.

Results: Thirty-eight patients had TERTp-mutant/IDH wild-type glioblastomas. The matched TERTp mutation in the CSF-tDNA was successfully detected with 100% specificity (95% CI, 87.6–100%) and 92.1% sensitivity (95% CI, 78.6–98.3%) (n = 35/38). In contrast, the sensitivity in the plasma-tDNA was far lower [n = 3/38, 7.9% (95% CI, 1.6–21.4%)]. We concordantly observed a longer overall survival of patients with low VAF in the CSF-tDNA when compared with patients with high VAF, irrespective of using the lower quartile VAF [11.45%; 14.0 mo. (95% confidence interval, CI, 10.3–17.6) vs. 8.6 mo. (95% CI, 4.1–13.2), P = 0.035], the lower third VAF [13%; 15.4 mo. (95% CI, 11.6–19.2) vs. 8.3 mo. (95% CI, 2.3–14.4), P = 0.008], or the median VAF [20.3%; 14.0 mo. (95% CI, 9.2–18.7) vs. 8.6 mo. (95% CI, 7.5–9.8), P = 0.062] to dichotomize the patients.

Conclusions: This pilot study highlights the value of CSF-tDNA for an accurate and reliable detection of TERTp mutations. Furthermore, our findings suggest that high TERTp mutation VAF levels in the CSF-tDNA may represent a suitable predictor of poor survival in glioblastoma patients. Further studies are needed to complement the findings of our exploratory analysis. Clin Cancer Res; 24(21); 5282–91. ©2018 AACR.