bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Examining Stripes on a Herd of Zebras: Impact of Genomic Matching for Ultrarare Sarcomas in Phase 1 Clinical Trials (SAMBA 102)
Authors: Moyers Justin T. , Pestana Roberto Carmagnani , Roszik Jason , Hong David S. , Naing Aung , Fu Siqing , Piha-Paul Sarina , Yap Timothy A. , Karp Daniel , Rodon Jordi , Livingston Andy , Zarzour Maria Alejandra , Ravi Vinod , Patel Shreyaskumar , Benjamin Robert S. , Ludwig Joseph , Herzog Cynthia , Ratan Ravin , Somaiah Neeta , Conley Anthony , Gorlick Richard , Meric-Bernstam Funda , Subbiah Vivek
Published: April 2023

AbstractPurpose:
Recently, the Connective Tissue Oncology Society published consensus guidelines for recognizing ultrarare sarcomas (URS), defined as sarcomas with an incidence ≤1 per 1,000,000. We assessed the outcomes of 56 patients with soft tissue, and 21 with bone sarcomas, enrolled in Phase 1 trials.
Experimental Design:
In this Sarcoma-Matched Biomarker Analysis (SAMBA-102 study), we reviewed records from patients on Phase 1 trials at the University of Texas MD Anderson Cancer Center between January 2013 and June 2021.
Results:
Among 587 sarcomas, 106 (18.1%) were classified as URS. Fifty (47%) were male, and the median age was 44.3 years (range, 19–82). The most common subtypes were alveolar soft part sarcoma (ASPS), chordoma, dedifferentiated chondrosarcoma, and sclerosing epithelioid fibrosarcoma. Compared with common sarcomas, median OS was similar 16.1 months [95% confidence interval (CI), 13.6–17.5] versus 16.1 (95% CI, 8.2–24.0) in URS (P = 0.359). Objective response to treatment was higher in URS 13.2% (n = 14/106) compared with common sarcomas 6.9% (n = 33/481; P = 0.029). Median OS for those treated on matched trials was 27.3 months (95% CI, 1.9–52.7) compared with 13.4 months (95% CI, 6.3–20.6) for those not treated on matched trials (P = 0.291). Eight of 33 (24%) molecularly matched treatments resulted in an objective response, whereas 6 of 73 unmatched treatments (8.2%) resulted in an objective response (P = 0.024). Clinical benefit rate was 36.4% (12/33) in matched trials versus 26.0% (19/73) in unmatched trials (P = 0.279).
Conclusions:
The results demonstrate the benefit of genomic selection in Phase 1 trials to help identify molecular subsets likely to benefit from targeted therapy.
Data from Plasma CD27, a Surrogate of the Intratumoral CD27–CD70 Interaction, Correlates with Immunotherapy Resistance in Renal Cell Carcinoma
Authors: Benhamouda Nadine , Sam Ikuan , Epaillard Nicolas , Gey Alain , Phan Letuan , Pham Hang Phuong , Gruel Nadège , Saldmann Antonin , Pineau Joséphine , Hasan Milena , Quiniou Valentin , Nevoret Camille , Verkarre Virginie , Libri Valentina , Mella Sebastien , Granier Clémence , Broudin Chloe , Ravel Patrice , De Guillebon Eléonore , Mauge Laetitia , Helley Dominique , Jabla Bernd , Chaput Nathalie , Albiges Laurence , Katsahian Sandrine , Adam Julien , Mejean Arnaud , Adotevi Olivier , Vano Yann A. , Oudard Stéphane , Tartour Eric
Published: April 2023

AbstractPurpose:
CD70 is a costimulatory molecule known to activate CD27-expressing T cells. CD27–CD70 interaction leads to the release of soluble CD27 (sCD27). Clear-cell renal cell carcinoma (ccRCC) expresses the highest levels of CD70 among all solid tumors; however, the clinical consequences of CD70 expression remain unclear.
Experimental Design:
Tumor tissue from 25 patients with ccRCC was assessed for the expression of CD27 and CD70 in situ using multiplex immunofluorescence. CD27+ T-cell phenotypes in tumors were analyzed by flow cytometry and their gene expression profile were analyzed by single-cell RNA sequencing then confirmed with public data. Baseline sCD27 was measured in 81 patients with renal cell carcinoma (RCC) treated with immunotherapy (35 for training cohort and 46 for validation cohort).
Results:
In the tumor microenvironment, CD27+ T cells interacted with CD70-expressing tumor cells. Compared with CD27− T cells, CD27+ T cells exhibited an apoptotic and dysfunctional signature. In patients with RCC, the intratumoral CD27–CD70 interaction was significantly correlated with the plasma sCD27 concentration. High sCD27 levels predicted poor overall survival in patients with RCC treated with anti–programmed cell death protein 1 in both the training and validation cohorts but not in patients treated with antiangiogenic therapy.
Conclusions:
In conclusion, we demonstrated that sCD27, a surrogate marker of T-cell dysfunction, is a predictive biomarker of resistance to immunotherapy in RCC. Given the frequent expression of CD70 and CD27 in solid tumors, our findings may be extended to other tumors.
Data from De-escalated Neoadjuvant Chemotherapy in Early Triple-Negative Breast Cancer (TNBC): Impact of Molecular Markers and Final Survival Analysis of the WSG-ADAPT-TN Trial
Authors: Gluz Oleg , Nitz Ulrike , Kolberg-Liedtke Cornelia , Prat Aleix , Christgen Matthias , Kuemmel Sherko , Mohammadian Mohammad Parsa , Gebauer Daniel , Kates Ronald , Paré Laia , Grischke Eva-Maria , Forstbauer Helmut , Braun Michael , Warm Mathias , Hackmann John , Uleer Christoph , Aktas Bahriye , Schumacher Claudia , Wuerstlein Rachel , Graeser Monika , Pelz Enrico , Jóźwiak Katarzyna , zu Eulenburg Christine , Kreipe Hans Heinrich , Harbeck Nadia
Published: April 2023

AbstractPurpose:
Although optimal treatment in early triple-negative breast cancer (TNBC) remains unclear, de-escalated chemotherapy appears to be an option in selected patients within this aggressive subtype. Previous studies have identified several pro-immune factors as prognostic markers in TNBC, but their predictive impact regarding different chemotherapy strategies is still controversial.
Experimental Design:
ADAPT-TN is a randomized neoadjuvant multicenter phase II trial in early patients with TNBC (n = 336) who were randomized to 12 weeks of nab-paclitaxel 125 mg/m2 + gemcitabine or carboplatin d 1,8 q3w. Omission of further (neo-) adjuvant chemotherapy was allowed only in patients with pathological complete response [pCR, primary endpoint (ypT0/is, ypN0)]. Secondary invasive/distant disease-free and overall survival (i/dDFS, OS) and translational research objectives included quantification of a predictive impact of markers regarding selection for chemotherapy de-escalation, measured by gene expression of 119 genes (including PAM50 subtype) by nCounter platform and stromal tumor-infiltrating lymphocytes (sTIL).
Results:
After 60 months of median follow-up, 12-week-pCR was favorably associated (HR, 0.24; P = 0.001) with 5y-iDFS of 90.6% versus 62.8%. No survival advantage of carboplatin use was observed, despite a higher pCR rate [HR, 1.04; 95% confidence interval (CI), 0.68–1.59]. Additional anthracycline-containing chemotherapy was not associated with a significant iDFS advantage in pCR patients (HR, 1.29; 95% CI, 0.41–4.02). Beyond pCR rate, nodal status and high sTILs were independently associated with better iDFS, dDFS, and OS by multivariable analysis.
Conclusions:
Short de-escalated neoadjuvant taxane/platinum-based combination therapy appears to be a promising strategy in early TNBC for using pCR rate as an early decision point for further therapy (de-) escalation together with node-negative status and high sTILs.

See related commentary by Sharma, p. 4840
Data from Membranous NECTIN-4 Expression Frequently Decreases during Metastatic Spread of Urothelial Carcinoma and Is Associated with Enfortumab Vedotin Resistance
Authors: Klümper Niklas , Ralser Damian J. , Ellinger Jörg , Roghmann Florian , Albrecht Julia , Below Eduard , Alajati Abdullah , Sikic Danijel , Breyer Johannes , Bolenz Christian , Zengerling Friedemann , Erben Philipp , Schwamborn Kristina , Wirtz Ralph M. , Horn Thomas , Nagy Dora , Toma Marieta , Kristiansen Glen , Büttner Thomas , Hahn Oliver , Grünwald Viktor , Darr Christopher , Erne Eva , Rausch Steffen , Bedke Jens , Schlack Katrin , Abbas Mahmoud , Zschäbitz Stefanie , Schwab Constantin , Mustea Alexander , Adam Patrick , Manseck Andreas , Wullich Bernd , Ritter Manuel , Hartmann Arndt , Gschwend Jürgen , Weichert Wilko , Erlmeier Franziska , Hölzel Michael , Eckstein Markus
Published: April 2023

AbstractPurpose:
The antibody–drug conjugate enfortumab vedotin (EV) releases a cytotoxic agent into tumor cells via binding to the membrane receptor NECTIN-4. EV was recently approved for patients with metastatic urothelial carcinoma (mUC) without prior assessment of the tumor receptor status as ubiquitous NECTIN-4 expression is assumed. Our objective was to determine the prevalence of membranous NECTIN-4 protein expression in primary tumors (PRIM) and patient-matched distant metastases (MET).
Experimental Design:
Membranous NECTIN-4 protein expression was measured (H-score) by IHC in PRIM and corresponding MET (N = 137) and in a multicenter EV-treated cohort (N = 47). Progression-free survival (PFS) after initiation of EV treatment was assessed for the NECTIN-4–negative/weak (H-score 0–99) versus moderate/strong (H-score 100–300) subgroup. The specificity of the NECTIN-4 IHC staining protocol was validated by establishing CRISPR-Cas9–induced polyclonal NECTIN-4 knockouts.
Results:
In our cohort, membranous NECTIN-4 expression significantly decreased during metastatic spread (Wilcoxon matched pairs P < 0.001; median H-score = 40; interquartile range, 0–140), with 39.4% of MET lacking membranous NECTIN-4 expression. In our multicenter EV cohort, absence or weak membranous NECTIN-4 expression (34.0% of the cohort) was associated with a significantly shortened PFS on EV (log-rank P < 0.001).
Conclusions:
Membranous NECTIN-4 expression is frequently decreased or absent in mUC tissue. Of note, the clinical benefit of EV strongly depends on membranous NECTIN-4 expression. Thus, our results are of highest clinical relevance and argue for a critical reconsideration of the current practice and suggest that the NECTIN-4 receptor status should be determined (ideally in a metastatic/progressive lesion) before initiation of EV.
Data from Obesity Is Associated with Altered Tumor Metabolism in Metastatic Melanoma
Authors: Hahn Andrew W. , Menk Ashley V. , Rivadeneira Dayana B. , Augustin Ryan C. , Xu Mingchu , Li Jun , Wu Xiaogang , Mishra Aditya K. , Gide Tuba N. , Quek Camelia , Zang Yan , Spencer Christine N. , Menzies Alexander M. , Daniel Carrie R. , Hudgens Courtney W. , Nowicki Theodore , Haydu Lauren E. , Khan M.A. Wadud , Gopalakrishnan Vancheswaran , Burton Elizabeth M. , Malke Jared , Simon Julie M. , Bernatchez Chantale , Putluri Nagireddy , Woodman Scott E. , Vashisht Gopal Y.N. , Guerrieri Renato , Fischer Grant M. , Wang Jian , Wani Khalida M. , Thompson John F. , Lee Jeffrey E. , Hwu Patrick , Ajami Nadim , Gershenwald Jeffrey E. , Long Georgina V. , Scolyer Richard A. , Tetzlaff Michael T. , Lazar Alexander J. , Schadendorf Dirk , Wargo Jennifer A. , Kirkwood John M. , DeBerardinis Ralph J. , Liang Han , Futreal Andrew , Zhang Jianhua , Wilmott James S. , Peng Weiyi , Davies Michael A. , Delgoffe Greg M. , Najjar Yana G. , McQuade Jennifer L.
Published: April 2023

AbstractPurpose:
Overweight/obese (OW/OB) patients with metastatic melanoma unexpectedly have improved outcomes with immune checkpoint inhibitors (ICI) and BRAF-targeted therapies. The mechanism(s) underlying this association remain unclear, thus we assessed the integrated molecular, metabolic, and immune profile of tumors, as well as gut microbiome features, for associations with patient body mass index (BMI).
Experimental Design:
Associations between BMI [normal (NL < 25) or OW/OB (BMI ≥ 25)] and tumor or microbiome characteristics were examined in specimens from 782 patients with metastatic melanoma across 7 cohorts. DNA associations were evaluated in The Cancer Genome Atlas cohort. RNA sequencing from 4 cohorts (n = 357) was batch corrected and gene set enrichment analysis (GSEA) by BMI category was performed. Metabolic profiling was conducted in a subset of patients (x = 36) by LC/MS, and in flow-sorted melanoma tumor cells (x = 37) and patient-derived melanoma cell lines (x = 17) using the Seahorse XF assay. Gut microbiome features were examined in an independent cohort (n = 371).
Results:
DNA mutations and copy number variations were not associated with BMI. GSEA demonstrated that tumors from OW/OB patients were metabolically quiescent, with downregulation of oxidative phosphorylation and multiple other metabolic pathways. Direct metabolite analysis and functional metabolic profiling confirmed decreased central carbon metabolism in OW/OB metastatic melanoma tumors and patient-derived cell lines. The overall structure, diversity, and taxonomy of the fecal microbiome did not differ by BMI.
Conclusions:
These findings suggest that the host metabolic phenotype influences melanoma metabolism and provide insight into the improved outcomes observed in OW/OB patients with metastatic melanoma treated with ICIs and targeted therapies.

See related commentary by Smalley, p. 5
Data from Acetylated HOXB13 Regulated Super Enhancer Genes Define Therapeutic Vulnerabilities of Castration-Resistant Prostate Cancer
Authors: Nguyen Duy T. , Yang Wei , Renganathan Arun , Weimholt Cody , Angappulige Duminduni H. , Nguyen Thanh , Sprung Robert W. , Andriole Gerald L. , Kim Eric H. , Mahajan Nupam P. , Mahajan Kiran
Published: April 2023

AbstractPurpose:
Androgen receptor (AR) antagonism is exacerbated by HOXB13 in castration-resistant prostate cancers (CRPC). However, it is unclear when and how HOXB13 primes CRPCs for AR antagonism. By mass-spectrometry analysis of CRPC extract, we uncovered a novel lysine 13 (K13) acetylation in HOXB13 mediated by CBP/p300. To determine whether acetylated K13-HOXB13 is a clinical biomarker of CRPC development, we characterized its role in prostate cancer biology.
Experimental Design:
We identified tumor-specific acK13-HOXB13 signal enriched super enhancer (SE)-regulated targets. We analyzed the effect of loss of HOXB13K13-acetylation on chromatin binding, SE proximal target gene expression, self-renewal, enzalutamide sensitivity, and CRPC tumor growth by employing isogenic parental and HOXB13K13A mutants. Finally, using primary human prostate organoids, we evaluated whether inhibiting an acK13-HOXB13 target, ACK1, with a selective inhibitor (R)-9b is superior to AR antagonists in inhibiting CRPC growth.
Results:
acK13-HOXB13 promotes increased expression of lineage (AR, HOXB13), prostate cancer diagnostic (FOLH1), CRPC-promoting (ACK1), and angiogenesis (VEGFA, Angiopoietins) genes early in prostate cancer development by establishing tumor-specific SEs. acK13-HOXB13 recruitment to key SE-regulated targets is insensitive to enzalutamide. ACK1 expression is significantly reduced in the loss of function HOXB13K13A mutant CRPCs. Consequently, HOXB13K13A mutants display reduced self-renewal, increased sensitivity to enzalutamide, and impaired xenograft tumor growth. Primary human prostate tumor organoids expressing HOXB13 are significantly resistant to AR antagonists but sensitive to (R)-9b.
Conclusions:
In summary, acetylated HOXB13 is a biomarker of clinically significant prostate cancer. Importantly, PSMA-targeting agents and (R)-9b could be new therapeutic modalities to target HOXB13–ACK1 axis regulated prostate cancers.
Data from Multifunctional mRNA-Based CAR T Cells Display Promising Antitumor Activity Against Glioblastoma
Authors: Meister Hanna , Look Thomas , Roth Patrick , Pascolo Steve , Sahin Ugur , Lee Sohyon , Hale Benjamin D. , Snijder Berend , Regli Luca , Ravi Vidhya M. , Heiland Dieter Henrik , Sentman Charles L. , Weller Michael , Weiss Tobias
Published: April 2023

AbstractPurpose:
Most chimeric antigen receptor (CAR) T-cell strategies against glioblastoma have demonstrated only modest therapeutic activity and are based on persistent gene modification strategies that have limited transgene capacity, long manufacturing processes, and the risk for uncontrollable off-tumor toxicities. mRNA-based T-cell modifications are an emerging safe, rapid, and cost-effective alternative to overcome these challenges, but are underexplored against glioblastoma.
Experimental Design:
We generated mouse and human mRNA-based multifunctional T cells coexpressing a multitargeting CAR based on the natural killer group 2D (NKG2D) receptor and the proinflammatory cytokines IL12 and IFNα2 and assessed their antiglioma activity in vitro and in vivo.
Results:
Compared with T cells that either expressed the CAR or cytokines alone, multifunctional CAR T cells demonstrated increased antiglioma activity in vitro and in vivo in three orthotopic immunocompetent mouse glioma models without signs of toxicity. Mechanistically, the coexpression of IL12 and IFNα2 in addition to the CAR promoted a proinflammatory tumor microenvironment and reduced T-cell exhaustion as demonstrated by ex vivo immune phenotyping, cytokine profiling, and RNA sequencing. The translational potential was demonstrated by image-based single-cell analyses of mRNA-modified T cells in patient glioblastoma samples with a complex cellular microenvironment. This revealed strong antiglioma activity of human mRNA-based multifunctional NKG2D CAR T cells coexpressing IL12 and IFNα2 whereas T cells that expressed either the CAR or cytokines alone did not demonstrate comparable antiglioma activity.
Conclusions:
These data provide a robust rationale for future clinical studies with mRNA-based multifunctional CAR T cells to treat malignant brain tumors.
Data from An Ex Vivo Organotypic Culture Platform for Functional Interrogation of Human Appendiceal Cancer Reveals a Prominent and Heterogenous Immunological Landscape
Authors: Weitz Jonathan , Hurtado de Mendoza Tatiana , Tiriac Herve , Lee James , Sun Siming , Garg Bharti , Patel Jay , Li Kevin , Baumgartner Joel , Kelly Kaitlin J. , Veerapong Jula , Hosseini Mojgan , Chen Yuan , Lowy Andrew M.
Published: April 2023

AbstractPurpose:
Epithelial neoplasms of the appendix are difficult to study preclinically given their low incidence, frequent mucinous histology, and absence of a comparable organ in mice for disease modeling. Although surgery is an effective treatment for localized disease, metastatic disease has a poor prognosis as existing therapeutics borrowed from colorectal cancer have limited efficacy. Recent studies reveal that appendiceal cancer has a genomic landscape distinct from colorectal cancer and thus preclinical models to study this disease are a significant unmet need.
Experimental Design:
We adopted an ex vivo slice model that permits the study of cellular interactions within the tumor microenvironment. Mucinous carcinomatosis peritonei specimens obtained at surgical resection were cutoff using a vibratome to make 150-μm slices cultured in media.
Results:
Slice cultures were viable and maintained their cellular composition regarding the proportion of epithelial, immune cells, and fibroblasts over 7 days. Within donor specimens, we identified a prominent and diverse immune landscape and calcium imaging confirmed that immune cells were functional for 7 days. Given the diverse immune landscape, we treated slices with TAK981, an inhibitor of SUMOylation with known immunomodulatory functions, in early-phase clinical trials. In 5 of 6 donor samples, TAK981-treated slices cultures had reduced viability, and regulatory T cells (Treg). These data were consistent with TAK981 activity in purified Tregs using an in vitro murine model.
Conclusions:
This study demonstrates an approach to study appendiceal cancer therapeutics and pathobiology in a preclinical setting. These methods may be broadly applicable to the study of other malignancies.
Data from Effective Tumor Debulking with Ibrutinib Before Initiation of Venetoclax: Results from the CAPTIVATE Minimal Residual Disease and Fixed-Duration Cohorts
Authors: Barr Paul M. , Tedeschi Alessandra , Wierda William G. , Allan John N. , Ghia Paolo , Vallisa Daniele , Jacobs Ryan , O'Brien Susan , Grigg Andrew P. , Walker Patricia , Zhou Cathy , Ninomoto Joi , Krigsfeld Gabriel , Tam Constantine S.
Published: April 2023

AbstractPurpose:
The phase II CAPTIVATE study investigated first-line treatment with ibrutinib plus venetoclax for chronic lymphocytic leukemia in two cohorts: minimal residual disease (MRD)-guided randomized treatment discontinuation (MRD cohort) and fixed duration (FD cohort). We report tumor debulking and tumor lysis syndrome (TLS) risk category reduction with three cycles of single-agent ibrutinib lead-in before initiation of venetoclax using pooled data from the MRD and FD cohorts.
Patients and Methods:
In both cohorts, patients initially received three cycles of ibrutinib 420 mg/day then 12 cycles of ibrutinib plus venetoclax (5-week ramp-up to 400 mg/day).
Results:
In the total population (N = 323), the following decreases from baseline to after ibrutinib lead-in were observed: percentage of patients with a lymph node diameter ≥5 cm decreased from 31% to 4%, with absolute lymphocyte count ≥25 × 109/L from 76% to 65%, with high tumor burden category for TLS risk from 23% to 2%, and with an indication for hospitalization (high TLS risk, or medium TLS risk and creatinine clearance <80 mL/minute) from 43% to 18%. Laboratory TLS per Howard criteria occurred in one patient; no clinical TLS was observed.
Conclusions:
Three cycles of ibrutinib lead-in before venetoclax initiation provides effective tumor debulking, decreases the TLS risk category and reduces the need for hospitalization for intensive monitoring for TLS.
Data from High-Dimensional and Spatial Analysis Reveals Immune Landscape–Dependent Progression in Cutaneous Squamous Cell Carcinoma
Authors: Ferguson Angela L. , Sharman Ashleigh R. , Allen Ruth O. , Ye Thomas , Lee Jenny H. , Low Tsu-Hui H. , Ch'ng Sydney , Palme Carsten E. , Ashford Bruce , Ranson Marie , Clark Jonathan R. , Patrick Ellis , Gupta Ruta , Palendira Umaimainthan
Published: April 2023

AbstractPurpose:
The tumor immune microenvironment impacts the biological behavior of the tumor, but its effect on clinical outcomes in head and neck cutaneous squamous cell carcinomas (HNcSCC) is largely unknown.
Experimental Design:
We compared the immune milieu of high-risk HNcSCC that never progressed to metastasis with those that metastasized using multiparameter imaging mass cytometry. The cohort included both immunosuppressed patients (IS) and patients with an absence of clinical immune-suppression (ACIS). Spatial analyses were used to identify cellular interactions that were associated with tumor behavior.
Results:
Nonprogressing primary HNcSCC were characterized by higher CD8+ and CD4+ T-cell responses, including numerically increased regulatory T cells. In contrast, primary lesions from HNcSCC patients who progressed were largely devoid of T cells with lower numbers of innate immune cells and increased expression of checkpoint receptors and in the metastatic lesions were characterized by an accumulation of B cells. Spatial analysis reveals multiple cellular interactions associated with nonprogressing primary tumors that were distinct in primary tumors of disease-progressing patients. Cellular regional analysis of the tumor microenvironment also shows squamous cell–enriched tumor regions associated with primary nonprogressing tumors.
Conclusions:
Effective responses from both CD8+ and CD4+ T cells in the tumor microenvironment are essential for immune control of primary HNcSCC. Our findings indicate that the early events that shape the immune responses in primary tumors dictate progression and disease outcomes in HNcSCC.
Data from Human Metastatic Cholangiocarcinoma Patient-Derived Xenografts and Tumoroids for Preclinical Drug Evaluation
Authors: Serra-Camprubí Queralt , Verdaguer Helena , Oliveros Winona , Lupión-Garcia Núria , Llop-Guevara Alba , Molina Cristina , Vila-Casadesús Maria , Turpin Anthony , Neuzillet Cindy , Frigola Joan , Querol Jessica , Yáñez-Bartolomé Mariana , Castet Florian , Fabregat-Franco Carles , Escudero-Iriarte Carmen , Escorihuela Marta , Arenas Enrique J. , Bernadó-Morales Cristina , Haro Noemí , Giles Francis J. , Pozo Óscar J. , Miquel Josep M. , Nuciforo Paolo G. , Vivancos Ana , Melé Marta , Serra Violeta , Arribas Joaquín , Tabernero Josep , Peiró Sandra , Macarulla Teresa , Tian Tian V.
Published: April 2023

AbstractPurpose:
Cholangiocarcinoma (CCA) is usually diagnosed at advanced stages, with limited therapeutic options. Preclinical models focused on unresectable metastatic CCA are necessary to develop rational treatments. Pathogenic mutations in IDH1/2, ARID1A/B, BAP1, and BRCA1/2 have been identified in 30%–50% of patients with CCA. Several types of tumor cells harboring these mutations exhibit homologous recombination deficiency (HRD) phenotype with enhanced sensitivity to PARP inhibitors (PARPi). However, PARPi treatment has not yet been tested for effectiveness in patient-derived models of advanced CCA.
Experimental Design:
We have established a collection of patient-derived xenografts from patients with unresectable metastatic CCA (CCA_PDX). The CCA_PDXs were characterized at both histopathologic and genomic levels. We optimized a protocol to generate CCA tumoroids from CCA_PDXs. We tested the effects of PARPis in both CCA tumoroids and CCA_PDXs. Finally, we used the RAD51 assay to evaluate the HRD status of CCA tissues.
Results:
This collection of CCA_PDXs recapitulates the histopathologic and molecular features of their original tumors. PARPi treatments inhibited the growth of CCA tumoroids and CCA_PDXs with pathogenic mutations of BRCA2, but not those with mutations of IDH1, ARID1A, or BAP1. In line with these findings, only CCA_PDX and CCA patient biopsy samples with mutations of BRCA2 showed RAD51 scores compatible with HRD.
Conclusions:
Our results suggest that patients with advanced CCA with pathogenic mutations of BRCA2, but not those with mutations of IDH1, ARID1A, or BAP1, are likely to benefit from PARPi therapy. This collection of CCA_PDXs provides new opportunities for evaluating drug response and prioritizing clinical trials.
Data from The Mutational Landscape of Cancer's Vulnerability to Ionizing Radiation
Authors: Gopal Priyanka , Yard Brian D. , Petty Aaron , Lal Jessica C. , Bera Titas K. , Hoang Trung Q. , Buhimschi Alexandru D. , Abazeed Mohamed E.
Published: April 2023

AbstractPurpose:
Large-scale sequencing efforts have established that cancer-associated genetic alterations are highly diverse, posing a challenge to the identification of variants that regulate complex phenotypes like radiation sensitivity. The impact of the vast majority of rare or common genetic variants on the sensitivity of cancers to radiotherapy remains largely unknown.
Experimental Design:
We developed a scalable gene editing and irradiation platform to assess the role of categories of variants in cells. Variants were prioritized on the basis of genotype–phenotype associations from a previously completed large-scale cancer cell line radiation profiling study. Altogether, 488 alleles (396 unique single-nucleotide variants) from 92 genes were generated and profiled in an immortalized lung cell line, BEAS-2B. We validated our results in other cell lines (TRT-HU1 and NCI-H520), in vivo via the use of both cell line and patient-derived murine xenografts, and in clinical cohorts.
Results:
We show that resistance to radiation is characterized by substantial inter- and intra-gene allelic variation. Some genes (e.g., KEAP1) demonstrated significant intragenic allelic variation in the magnitude of conferred resistance and other genes (e.g., CTNNB1) displayed both resistance and sensitivity in a protein domain-dependent manner. We combined results from our platform with gene expression and metabolite features and identified the upregulation of amino acid transporters that facilitate oxidative reductive capacity and cell-cycle deregulation as key regulators of radiation sensitivity.
Conclusions:
Our results reveal new insights into the genetic determinants of tumor sensitivity to radiotherapy and nominate a multitude of cancer mutations that are predicted to impact treatment efficacy.
Data from Preclinical Study of a Biparatopic METxMET Antibody–Drug Conjugate, REGN5093-M114, Overcomes MET-driven Acquired Resistance to EGFR TKIs in EGFR-mutant NSCLC
Authors: Oh Seung Yeon , Lee You Won , Lee Eun Ji , Kim Jae Hwan , Park YoungJoon , Heo Seong Gu , Yu Mi Ra , Hong Min Hee , DaSilva John , Daly Christopher , Cho Byoung Chul , Lim Sun Min , Yun Mi Ran
Published: April 2023

AbstractPurpose:
MET amplification is a frequent mechanism of resistance to EGFR tyrosine kinase inhibitors (TKI) in patients with EGFR-mutated non–small cell lung cancer (NSCLC), and combined treatment with EGFR TKIs and MET TKIs has been explored as a strategy to overcome resistance. However, durable response is invariably limited by the emergence of acquired resistance. Here, we investigated the preclinical activity of REGN5093-M114, a novel antibody–drug conjugate targeting MET in MET-driven patient-derived models.
Experimental Design:
Patient-derived organoids, patient-derived cells, or ATCC cell lines were used to investigate the in vitro/in vivo activity of REGN5093-M114.
Results:
REGN5093-M114 exhibited significant antitumor efficacy compared with MET TKI or unconjugated METxMET biparatopic antibody (REGN5093). Regardless of MET gene copy number, MET-overexpressed TKI-naïve EGFR-mutant NSCLC cells responded to REGN5093-M114 treatment. Cell surface MET expression had the most predictive power in determining the efficacy of REGN5093-M114. REGN5093-M114 potently reduced tumor growth of EGFR-mutant NSCLC with PTEN loss or MET Y1230C mutation after progression on prior osimertinib and savolitinib treatment.
Conclusions:
Altogether, REGN5093-M114 is a promising candidate to overcome the challenges facing functional MET pathway blockade.
Data from A Randomized Multi-institutional Phase II Trial of Everolimus as Adjuvant Therapy in Patients with Locally Advanced Squamous Cell Cancer of the Head and Neck
Authors: Nathan Cherie-Ann O. , Hayes D. Neil , Karrison Theodore , Harismendy Olivier , Flores José M. , Moore-Medlin Tara , Vokes Everett E. , Gutkind J. Silvio , Neupane Prakash , Mills Glenn , Sargi Zoukaa , Seiwert Tanguy , Grilley-Olson Juneko , Day Terry , Gillison Maura , Wade James L. , Feldman Lawrence , Jha Gautam , Kozloff Mark , O'Leary Miriam , Worden Francis P. , Cohen Ezra E.W.
Published: April 2023

AbstractPurpose:
Investigate whether adjuvant everolimus, an mTOR inhibitor, improves progression-free survival (PFS) in advanced-stage head and neck squamous cell carcinoma (HNSCC) and provide outcomes related to correlative biological factors associated with disease control.
Patients and Methods:
This was a prospective, randomized, double-blind phase II trial of patients with advanced-stage HNSCC from 13 institutions who were confirmed disease-free post-definitive therapy and enrolled between December 2010 and March 2015. Patients received adjuvant everolimus or placebo daily (10 mg, oral) for a maximum of 1 year. p16 IHC as a surrogate marker for human papillomavirus infection and whole-exome sequencing were performed. Cox proportional hazard models estimated hazard rates. Log-rank tests evaluated differences in survival. The primary endpoint was PFS. Secondary endpoints and objectives included overall survival (OS) and toxicity assessment.
Results:
52 patients [median (range) age, 58 (37–76) years; 43 men (83%), 9 women (17%)] were randomized to placebo (n = 24) or everolimus (n = 28). PFS favored everolimus, but was not significant [log-rank P = 0.093; HR = 0.44; 95% confidence interval (CI), 0.17–1.17]. There was no difference in OS (P = 0.29; HR = 0.57; 95% CI, 0.20–16.2). Everolimus resulted in significant improvement in PFS for p16-negative patients (n = 31; P = 0.031; HR = 0.26; 95% CI, 0.07–0.97), although subgroup analysis showed no difference for p16-positive patients (n = 21; P = 0.93). Further, PFS was significantly higher in TP53-mutated (TP53mut) patients treated with everolimus compared with placebo (log-rank P = 0.027; HR = 0.24; 95% CI, 0.06–0.95). No treatment difference was seen in patients with TP53 wild-type tumors (P = 0.79).
Conclusions:
p16-negative and TP53mut patients may benefit from adjuvant treatment with everolimus.
Data from Palbociclib Rechallenge for Hormone Receptor–Positive/HER-Negative Advanced Breast Cancer: Findings from the Phase II BioPER Trial
Authors: Albanell Joan , Pérez-García José Manuel , Gil-Gil Miguel , Curigliano Giuseppe , Ruíz-Borrego Manuel , Comerma Laura , Gibert Joan , Bellet Meritxell , Bermejo Begoña , Calvo Lourdes , de la Haba Juan , Espinosa Enrique , Minisini Alessandro Marco , Quiroga Vanesa , Santaballa Bertran Ana , Mina Leonardo , Bellosillo Beatriz , Rojo Federico , Menéndez Silvia , Sampayo-Cordero Miguel , Popa Crina , Malfettone Andrea , Cortés Javier , Llombart-Cussac Antonio
Published: April 2023

AbstractPurpose:
To assess the efficacy and exploratory biomarkers of continuing palbociclib plus endocrine therapy (ET) beyond progression on prior palbociclib-based regimen in patients with hormone receptor–positive/HER2-negative (HR+/HER2−) advanced breast cancer (ABC).
Patients and Methods:
The multicenter, open-label, phase II BioPER trial included women who had experienced a progressive disease (PD) after having achieved clinical benefit on the immediately prior palbociclib plus ET regimen. Palbociclib (125 mg, 100 mg, or 75 mg daily orally for 3 weeks and 1 week off as per prior palbociclib-based regimen) plus ET of physician's choice were administered in 4-week cycles until PD or unacceptable toxicity. Coprimary endpoints were clinical benefit rate (CBR) and percentage of tumors with baseline loss of retinoblastoma (Rb) protein expression. Additional endpoints included safety and biomarker analysis.
Results:
Among 33 patients enrolled, CBR was 34.4% [95% confidence interval (CI), 18.6–53.2; P < 0.001] and 13.0% of tumors (95% CI, 5.2–27.5) showed loss of Rb protein expression, meeting both coprimary endpoints. Median progression-free survival was 2.6 months (95% CI, 1.8–6.7). No new safety signals were reported. A signature that included baseline mediators of therapeutic resistance to palbociclib and ET (low Rb score, high cyclin E1 score, ESR1 mutation) was independently associated with shorter median progression-free survival (HR, 22.0; 95% CI, 1.71–282.9; P = 0.018).
Conclusions:
Maintaining palbociclib after progression on prior palbociclib-based regimen seems to be a reasonable, investigational approach for selected patients. A composite biomarker signature predicts a subset of patients who may not derive a greater benefit from palbociclib rechallenge, warranting further validation in larger randomized controlled trials.
Data from Allogeneic CAR T Cells Targeting DLL3 Are Efficacious and Safe in Preclinical Models of Small Cell Lung Cancer
Authors: Zhang Yi , Tacheva-Grigorova Silvia K. , Sutton Janette , Melton Zea , Mak Yvonne S.L. , Lay Cecilia , Smith Bryan A. , Sai Tao , Van Blarcom Thomas , Sasu Barbra J. , Panowski Siler H.
Published: April 2023

AbstractPurpose:
Small cell lung cancer (SCLC) is an aggressive disease with limited treatment options. Delta-like ligand 3 (DLL3) is highly expressed on SCLC and several other types of neuroendocrine cancers, with limited normal tissue RNA expression in brain, pituitary, and testis, making it a promising CAR T-cell target for SCLC and other solid tumor indications.
Experimental Design:
A large panel of anti-DLL3 scFv-based CARs were characterized for both in vitro and in vivo activity. To understand the potential for pituitary and brain toxicity, subcutaneous or intracranial tumors expressing DLL3 were implanted in mice and treated with mouse cross-reactive DLL3 CAR T cells.
Results:
A subset of CARs demonstrated high sensitivity for targets with low DLL3 density and long-term killing potential in vitro. Infusion of DLL3 CAR T cells led to robust antitumor efficacy, including complete responses, in subcutaneous and systemic SCLC in vivo models. CAR T-cell infiltration into intermediate and posterior pituitary was detected, but no tissue damage in brain or pituitary was observed, and the hormone-secretion function of the pituitary was not ablated.
Conclusions:
In summary, the preclinical efficacy and safety data presented here support further evaluation of DLL3 CAR T cells as potential clinical candidates for the treatment of SCLC.
Data from Tumor Dynamic Model-Based Decision Support for Phase Ib/II Combination Studies: A Retrospective Assessment Based on Resampling of the Phase III Study IMpower150
Authors: Bruno René , Marchand Mathilde , Yoshida Kenta , Chan Phyllis , Li Haocheng , Zou Wei , Mercier Francois , Chanu Pascal , Wu Benjamin , Lee Anthony , Li Chunze , Jin Jin Y. , Maitland Michael L. , Reck Martin , Socinski Mark A.
Published: April 2023

AbstractPurpose:
Model-based tumor growth inhibition (TGI) metrics are increasingly incorporated into go/no-go decisions in early clinical studies. To apply this methodology to new investigational combinations requires independent evaluation of TGI metrics in recently completed Phase III trials of effective immunotherapy.
Patients and Methods:
Data were extracted from IMpower150, a positive, randomized, Phase III study of first-line therapy in 1,202 patients with non–small cell lung cancer. We resampled baseline characteristics and longitudinal sum of longest diameters of tumor lesions of patients from both arms, atezolizumab+ bevacizumab+chemotherapy (ABCP) versus BCP, to mimic Phase Ib/II studies of 15 to 40 patients/arm with 6 to 24 weeks follow-up. TGI metrics were estimated using a bi-exponential TGI model. Effect sizes were calculated as TGI metrics geometric mean ratio (GMR), objective response rate (ORR) difference (d), and progression-free survival (PFS), hazard ratio (HR) between arms. Correct and incorrect go decisions were evaluated as the probability to achieve desired effect sizes in ABCP versus BCP and BCP versus BCP, respectively, across 500 replicated subsamples for each design.
Results:
For 40 patients/24 weeks follow-up, correct go decisions based on probability tumor growth rate (KG) GMR <0.90, dORR >0.10, and PFS HR <0.70 were 83%, 69%, and 58% with incorrect go decision rates of 4%, 12%, and 11%, respectively. For other designs, the ranking did not change with TGI metrics consistently overperforming RECIST endpoints. The predicted overall survival (OS) HR was around 0.80 in most of the scenarios investigated.
Conclusions:
Model-based estimate of KG GMR is an exploratory endpoint that informs early clinical decisions for combination studies.
Data from Liquid Biopsy of Cerebrospinal Fluid Enables Selective Profiling of Glioma Molecular Subtypes at First Clinical Presentation
Authors: Orzan Francesca , De Bacco Francesca , Lazzarini Elisabetta , Crisafulli Giovanni , Gasparini Alessandra , Dipasquale Angelo , Barault Ludovic , Macagno Marco , Persico Pasquale , Pessina Federico , Bono Beatrice , Giordano Laura , Zeppa Pietro , Melcarne Antonio , Cassoni Paola , Garbossa Diego , Santoro Armando , Comoglio Paolo M. , Indraccolo Stefano , Simonelli Matteo , Boccaccio Carla
Published: April 2023

AbstractPurpose:
Current glioma diagnostic guidelines call for molecular profiling to stratify patients into prognostic and treatment subgroups. In case the tumor tissue is inaccessible, cerebrospinal fluid (CSF) has been proposed as a reliable tumor DNA source for liquid biopsy. We prospectively investigated the use of CSF for molecular characterization of newly diagnosed gliomas.
Experimental design:
We recruited two cohorts of newly diagnosed patients with glioma, one (n = 45) providing CSF collected in proximity of the tumor, the other (n = 39) CSF collected by lumbar puncture (LP). Both cohorts provided tumor tissues by surgery concomitant with CSF sampling. DNA samples retrieved from CSF and matched tumors were systematically characterized and compared by comprehensive (NGS, next-generation sequencing) or targeted (ddPCR, droplet digital PCR) methodologies. Conventional and molecular diagnosis outcomes were compared.
Results:
We report that tumor DNA is abundant in CSF close to the tumor, but scanty and mostly below NGS sensitivity threshold in CSF from LP. Indeed, tumor DNA is mostly released by cells invading liquoral spaces, generating a gradient that attenuates by departing from the tumor. Nevertheless, in >60% of LP CSF samples, tumor DNA is sufficient to assess a selected panel of genetic alterations (IDH and TERT promoter mutations, EGFR amplification, CDKN2A/B deletion: ITEC protocol) and MGMT methylation that, combined with imaging, enable tissue-agnostic identification of main glioma molecular subtypes.
Conclusions:
This study shows potentialities and limitations of CSF liquid biopsy in achieving molecular characterization of gliomas at first clinical presentation and proposes a protocol to maximize diagnostic information retrievable from CSF DNA.
Data from Functional Homologous Recombination Assay on FFPE Specimens of Advanced High-Grade Serous Ovarian Cancer Predicts Clinical Outcomes
Authors: Pikkusaari Sanna , Tumiati Manuela , Virtanen Anni , Oikkonen Jaana , Li Yilin , Perez-Villatoro Fernando , Muranen Taru , Salko Matilda , Huhtinen Kaisa , Kanerva Anna , Koskela Heidi , Tapper Johanna , Koivisto-Korander Riitta , Joutsiniemi Titta , Haltia Ulla-Maija , Lassus Heini , Hautaniemi Sampsa , Färkkilä Anniina , Hynninen Johanna , Hietanen Sakari , Carpén Olli , Kauppi Liisa
Published: April 2023

AbstractPurpose:
Deficiency in homologous recombination (HR) repair of DNA damage is characteristic of many high-grade serous ovarian cancers (HGSC). It is imperative to identify patients with homologous recombination–deficient (HRD) tumors as they are most likely to benefit from platinum-based chemotherapy and PARP inhibitors (PARPi). Existing methods measure historical, not necessarily current HRD and/or require high tumor cell content, which is not achievable for many patients. We set out to develop a clinically feasible assay for identifying functionally HRD tumors that can predict clinical outcomes.
Experimental Design:
We quantified RAD51, a key HR protein, in immunostained formalin-fixed, paraffin-embedded (FFPE) tumor samples obtained from chemotherapy-naïve and neoadjuvant chemotherapy (NACT)-treated HGSC patients. We defined cutoffs for functional HRD separately for these sample types, classified the patients accordingly as HRD or HR-proficient, and analyzed correlations with clinical outcomes. From the same specimens, genomics-based HRD estimates (HR gene mutations, genomic signatures, and genomic scars) were also determined, and compared with functional HR (fHR) status.
Results:
fHR status significantly predicted several clinical outcomes, including progression-free survival (PFS) and overall survival (OS), when determined from chemo-naïve (PFS, P < 0.0001; OS, P < 0.0001) as well as NACT-treated (PFS, P < 0.0001; OS, P = 0.0033) tumor specimens. The fHR test also identified as HRD those PARPi-at-recurrence–treated patients with longer OS (P = 0.0188).
Conclusions:
We developed an fHR assay performed on routine FFPE specimens, obtained from either chemo-naïve or NACT-treated HGSC patients, that can significantly predict real-world platinum-based chemotherapy and PARPi response.

See related commentary by Garg and Oza, p. 2957
Data from Event-Free Survival as a Surrogate for Overall Survival in Gastric and Gastroesophageal Junction Adenocarcinoma: A Meta-analysis in the Neoadjuvant ± Adjuvant Setting
Authors: Wainberg Zev A. , Xie Jipan , Valderrama Adriana , Yin Lei , Zhang Shujing , Shih Chie-Schin , Bhagia Pooja , Gu Qianqian , Shitara Kohei , Janjigian Yelena Y. , Tabernero Josep
Published: April 2023

AbstractPurpose:
This study assessed the trial-level association between event-free survival (EFS) and overall survival (OS) in gastric or gastroesophageal junction (GEJ) adenocarcinoma in the neoadjuvant ± adjuvant settings.
Experimental Design:
A systematic literature review was conducted to identify randomized controlled trials (RCT) that evaluated neoadjuvant therapies with or without adjuvant therapies for gastric or GEJ adenocarcinoma. A meta-analysis was performed using weighted linear regressions of the treatment effect of OS on the treatment effect of EFS. The coefficient of determination (R2) and associated 95% confidence interval (CI) were used to evaluate the association between treatment effects of EFS and OS. The threshold used for defining good trial-level surrogacy was a correlation coefficient (R) of 0.8 or R2 of 0.65, based on prior literature. Sensitivity analyses were performed to assess the robustness of the association with divergent study designs, including study population, inclusion of adjuvant therapy, and definitions of EFS and OS.
Results:
The main analysis included 16 comparisons from 15 RCTs. The log(HR) of EFS was a significant predictor of log(HR) of OS, with an estimated coefficient of 0.72 (P < 0.001) and R2 = 0.75 (95% CI, 0.49–0.95), indicating that EFS was a good surrogate outcome for OS. The results of the sensitivity analyses were consistent with the primary results, with R2 ranging from 0.76 to 0.89.
Conclusions:
This study suggests that EFS is a good surrogate for OS in gastric or GEJ adenocarcinoma in the neoadjuvant ± adjuvant setting.
Data from Survival Outcomes, Digital TILs, and On-treatment PET/CT During Neoadjuvant Therapy for HER2-positive Breast Cancer: Results from the Randomized PREDIX HER2 Trial
Authors: Matikas Alexios , Johansson Hemming , Grybäck Per , Bjöhle Judith , Acs Balazs , Boyaci Ceren , Lekberg Tobias , Fredholm Hanna , Elinder Ellinor , Margolin Sara , Isaksson-Friman Erika , Bosch Ana , Lindman Henrik , Adra Jamila , Andersson Anne , Agartz Susanne , Hellström Mats , Zerdes Ioannis , Hartman Johan , Bergh Jonas , Hatschek Thomas , Foukakis Theodoros
Published: April 2023

AbstractPurpose:
PREDIX HER2 is a randomized Phase II trial that compared neoadjuvant docetaxel, trastuzumab, and pertuzumab (THP) with trastuzumab emtansine (T-DM1) for HER2-positive breast cancer. Rates of pathologic complete response (pCR) did not differ between the two groups. Here, we present the survival outcomes from PREDIX HER2 and investigate metabolic response and tumor-infiltrating lymphocytes (TIL) as prognostic factors.
Patients and Methods:
In total, 202 patients with HER2-positive breast cancer were enrolled and 197 patients received six cycles of either THP or T-DM1. Secondary endpoints included event-free survival (EFS), recurrence-free survival (RFS), and overall survival (OS). Assessment with PET/CT was performed at baseline, after two and six treatment cycles. TILs were assessed manually at baseline biopsies, while image-based evaluation of TILs [digital TILs (DTIL)] was performed in digitized full-face sections.
Results:
After a median follow-up of 5.21 years, there was no difference between the two treatment groups in terms of EFS [HR = 1.26; 95% confidence interval (CI), 0.54–2.91], RFS (HR = 0.69; 95% CI, 0.24–1.93), or OS (HR = 0.52; 95% CI, 0.09–2.82). Higher SUVmax at cycle 2 (C2) predicted lower pCR (ORadj = 0.65; 95% CI, 0.48–0.87; P = 0.005) and worse EFS (HRadj = 1.27; 95% CI, 1.12–1.41; P < 0.001). Baseline TILs and DTILs provided additional prognostic information to clinical parameters and C2 SUVmax.
Conclusions:
Long-term outcomes following neoadjuvant T-DM1 were similar to neoadjuvant THP. SUVmax after two cycles of neoadjuvant therapy for HER2-positive breast cancer may be an independent predictor of both short- and long-term outcomes. Combined assessment with TILs may facilitate early selection of poor responders for alternative treatment strategies.