bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from MGMT Promoter Methylation Cutoff with Safety Margin for Selecting Glioblastoma Patients into Trials Omitting Temozolomide: A Pooled Analysis of Four Clinical Trials
Authors: Hegi Monika E. , Genbrugge Els , Gorlia Thierry , Stupp Roger , Gilbert Mark R. , Chinot Olivier L. , Nabors L. Burt , Jones Greg , Van Criekinge Wim , Straub Josef , Weller Michael
Published: April 2023

AbstractPurpose:
The methylation status of the O6-methylguanine DNA methyltransferase (MGMT) gene promoter is predictive for benefit from temozolomide in glioblastoma (GBM). A clinically optimized cutoff was sought allowing patient selection for therapy without temozolomide, while avoiding to withhold it from patients who may potentially benefit.

Experimental Design: Quantitative MGMT methylation-specific PCR data were obtained for newly diagnosed patients with GBM screened or treated with standard radiotherapy and temozolomide in four randomized trials. The pooled dataset was randomly split into a training and test dataset. The unsupervised cutoff was obtained at a 50% probability to be (un)methylated. ROC analysis identified an optimal cutoff supervised by overall survival (OS).
Results:
For 4,041 patients valid MGMT results were obtained, whereof 1,725 were randomized. The unsupervised cutoff in the training dataset was 1.27 (log2[1,000 × (MGMT+1)/ACTB]), separating unmethylated and methylated patients. The optimal supervised cutoff for unmethylated patients was −0.28 (AUC = 0.61), classifying “truly unmethylated” (≤−0.28) and “gray zone” patients (>−0.28, ≤1.27), the latter comprising approximately 10% of cases. In contrast, for patients with MGMT methylation (>1.27) more methylation was not related to better outcome. Both methylated and gray zone patients performed significantly better for OS than truly unmethylated patients [HR = 0.35, 95% confidence interval (CI), 0.27–0.45, P < 0.0001; HR = 0.58, 95% CI, 0.43–0.78, P < 0.001], validated in the test dataset. The MGMT assay was highly reproducible upon retesting of 218 paired samples (R2 = 0.94).
Conclusions:
Low MGMT methylation (gray zone) may confer some sensitivity to temozolomide treatment, hence the lower safety margin should be considered for selecting patients with unmethylated GBM into trials omitting temozolomide.
Data from Impact of Autologous Transplantation in Patients with Multiple Myeloma with t(11;14): A Propensity-Score Matched Analysis
Authors: Saini Neeraj , Ma Junsheng , Milton Denái R. , Patel Romil , Varma Ankur , Bashir Qaiser , Delgado Ruby , Mukherjee Akash , Rondon Gabriela , Popat Uday R. , Hosing Chitra M. , Nieto Yago , Kebriaei Partow , Alousi Amin M. , Ahmed Sairah , Tang Guilin , Mehta Rohtesh , Srour Samer , Khouri Issa F. , Iyer Swaminathan , Weber Donna M. , Thomas Sheeba K. , Lee Hans C. , Manasanch Elisabet E. , Patel Krina K. , Orlowski Robert Z. , Champlin Richard E. , Qazilbash Muzaffar H.
Published: April 2023

AbstractPurpose:
Patients with multiple myeloma with t(11;14) have been considered to have standard-risk disease. However, several recent reports have shown contradictory results. We identified 95 patients with multiple myeloma with t(11;14) on FISH studies, who underwent upfront autologous hematopoietic stem cell transplant (auto-HCT) at our center. We compared their outcome with a group of standard-risk patients with multiple myeloma who had diploid cytogenetics by both conventional cytogenetics (CC) and FISH (n = 287).
Experimental Design:
To reduce the bias between the groups, we performed a 1:1 propensity score matching technique for analysis. A total of 160 patients, 80 in each group, were identified. Patients in the 2 groups were matched for age, International staging system stage at diagnosis, serum creatinine at presentation, disease status at auto-HCT, type of preparative regimens, dose of melphalan used for conditioning, and induction and maintenance regimens.
Results:
Patients in t(11;14) group had a post auto-HCT overall response rate (ORR) of 97.5% (78/80), compared with 100% (80/80) in the standard-risk control group (P = 0.50). Complete response rate in the t(11;14) group was 35% (28/80), compared with 45% (36/80) in the standard-risk control group (P = 0.26). The 4-year PFS rates were 40.8% (95% CI, 29.6%–56.1%) and 51.1% (95% CI, 39.4%–66.3%) in the t(11;14) and standard-risk control groups, respectively (P = 0.14). The 4-year OS rates were 74.9% (95% CI, 63.3%–88.7%) and 88.3% (95% CI, 80.4%–97.0%) in the t(11;14) and standard-risk control groups, respectively (P = 0.17). Also, patients with t(11;14) with concurrent cytogenetics had significantly poor PFS and OS compared with a propensity matched standard-risk control group.
Conclusions:
Our study confirms that t(11;14) multiple myeloma undergoing upfront autologous transplantation had similar outcomes as patients with multiple myeloma with normal cytogenetic and FISH studies. Existence of additional genomic aberrations by CC or FISH was associated with a worse outcome.
Data from ImmunoPET, [64Cu]Cu-DOTA-Anti-CD33 PET-CT, Imaging of an AML Xenograft Model
Authors: Srideshikan Sargur Madabushi , Brooks Jamison , Zuro Darren , Kumar Bijender , Sanchez James , Echavarria Parra Liliana , Orellana Marvin , Vishwasrao Paresh , Nair Indu , Chea Junie , Poku Kofi , Bowles Nicole , Miller Aaron , Ebner Todd , Molnar Justin , Rosenthal Joseph , Vallera Daniel A. , Wong Jeffrey Y.C. , Stein Anthony S. , Colcher David , Shively John E. , Yazaki Paul J. , Hui Susanta K.
Published: April 2023

AbstractPurpose:
Acute myeloid leukemia (AML) is a highly aggressive form of leukemia, which results in poor survival outcomes. Currently, diagnosis and prognosis are based on invasive single-point bone marrow biopsies (iliac crest). There is currently no AML-specific noninvasive imaging method to detect disease, including in extramedullary organs, representing an unmet clinical need. About 85% to 90% of human myeloid leukemia cells express CD33 cell surface receptors, highlighting CD33 as an ideal candidate for AML immunoPET.
Experimental Design:
We evaluated whether [64Cu]Cu-DOTA-anti-CD33 murine mAb can be used for immunoPET imaging of AML in a preclinical model. MicroCT was adjusted to detect spatial/anatomical details of PET activity. For translational purposes, a humanized anti-CD33 antibody was produced; we confirmed its ability to detect disease and its distribution. We reconfirmed/validated CD33 antibody-specific targeting with an antibody–drug conjugate (ADC) and radioimmunotherapy (RIT).
Results:
[64Cu]Cu-DOTA-anti-CD33–based PET-CT imaging detected CD33+ AML in mice with high sensitivity (95.65%) and specificity (100%). The CD33+ PET activity was significantly higher in specific skeletal niches [femur (P < 0.00001), tibia (P = 0.0001), humerus (P = 0.0014), and lumber spine (P < 0.00001)] in AML-bearing mice (over nonleukemic control mice). Interestingly, the hybrid PET-CT imaging showed high disease activity in the epiphysis/metaphysis of the femur, indicating regional spatial heterogeneity. Anti-CD33 therapy using newly developed humanized anti-CD33 mAb as an ADC (P = 0.02) and [225Ac]Ac-anti-CD33-RIT (P < 0.00001) significantly reduced disease burden over that of respective controls.
Conclusions:
We have successfully developed a novel anti-CD33 immunoPET-CT–based noninvasive modality for AML and its spatial distribution, indicating a preferential skeletal niche.
Data from Tumor Lysis, Adverse Events, and Dose Adjustments in 297 Venetoclax-Treated CLL Patients in Routine Clinical Practice
Authors: Roeker Lindsey E. , Fox Christopher P. , Eyre Toby A. , Brander Danielle M. , Allan John N. , Schuster Stephen J. , Nabhan Chadi , Hill Brian T. , Shah Nirav N. , Lansigan Frederick , Yazdy Maryam , Cheson Bruce D. , Lamanna Nicole , Singavi Arun K. , Coombs Catherine C. , Barr Paul M. , Skarbnik Alan P. , Shadman Mazyar , Ujjani Chaitra S. , Tuncer Hande H. , Winter Allison M. , Rhodes Joanna , Dorsey Colleen , Morse Hannah , Kabel Charlene , Pagel John M. , Williams Annalynn M. , Jacobs Ryan , Goy Andre , Muralikrishnan Sivraj , Pearson Laurie , Sitlinger Andrea , Bailey Neil , Schuh Anna , Kirkwood Amy A. , Mato Anthony R.
Published: April 2023

AbstractPurpose:
Clinical trials of venetoclax reported negligible rates of clinical tumor lysis syndrome (TLS) in patients with chronic lymphocytic leukemia (CLL) when using an extended dose escalation schedule. We aimed to understand TLS prophylaxis, rates of select adverse events (AE), and impact of dosing modifications in routine clinical practice.
Experimental Design:
This retrospective cohort study included 297 CLL venetoclax-treated patients outside of clinical trials in academic and community centers. Demographics, baseline disease characteristics, venetoclax dosing, TLS risk and prophylaxis, and AEs were collected.
Results:
The group was 69% male, 96% had relapsed/refractory CLL, 45% had deletion chromosome 17p, 84% had unmutated IGHV, 80% received venetoclax monotherapy, and median age was 67. TLS risk was categorized as low (40%), intermediate (32%), or high (28%), and 62% had imaging prior to venetoclax initiation. Clinical TLS occurred in 2.7% of patients and laboratory TLS occurred in 5.7%. Pre-venetoclax TLS risk group and creatinine clearance independently predict TLS development in multivariable analysis. Grade 3/4 AEs included neutropenia (39.6%), thrombocytopenia (29.2%), infection (25%), neutropenic fever (7.9%), and diarrhea (6.9%). Twenty-two patients (7.4%) discontinued venetoclax due to an AE. Progression-free survival was similar regardless of number of dose interruptions, length of dose interruption, and stable venetoclax dose.
Conclusions:
These data provide insights into current use of venetoclax in clinical practice, including TLS rates observed in clinical practice. We identified opportunities for improved adherence to TLS risk stratification and prophylaxis, which may improve safety.
Data from Pleiotropic Impact of DNA-PK in Cancer and Implications for Therapeutic Strategies
Authors: Dylgjeri Emanuela , McNair Christopher , Goodwin Jonathan F. , Raymon Heather K. , McCue Peter A. , Shafi Ayesha A. , Leiby Benjamin E. , de Leeuw Renée , Kothari Vishal , McCann Jennifer J. , Mandigo Amy C. , Chand Saswati N. , Schiewer Matthew J. , Brand Lucas J. , Vasilevskaya Irina , Gordon Nicolas , Laufer Talya S. , Gomella Leonard G. , Lallas Costas D. , Trabulsi Edouard J. , Feng Felix Y. , Filvaroff Ellen H. , Hege Kristin , Rathkopf Dana , Knudsen Karen E.
Published: April 2023

AbstractPurpose:
DNA-dependent protein kinase catalytic subunit (DNA-PK) is a pleiotropic kinase involved in DNA repair and transcriptional regulation. DNA-PK is deregulated in selected cancer types and is strongly associated with poor outcome. The underlying mechanisms by which DNA-PK promotes aggressive tumor phenotypes are not well understood. Here, unbiased molecular investigation in clinically relevant tumor models reveals novel functions of DNA-PK in cancer.

Experimental Design: DNA-PK function was modulated using both genetic and pharmacologic methods in a series of in vitro models, in vivo xenografts, and patient-derived explants (PDE), and the impact on the downstream signaling and cellular cancer phenotypes was discerned. Data obtained were used to develop novel strategies for combinatorial targeting of DNA-PK and hormone signaling pathways.
Results:
Key findings reveal that (i) DNA-PK regulates tumor cell proliferation; (ii) pharmacologic targeting of DNA-PK suppresses tumor growth both in vitro, in vivo, and ex vivo; (iii) DNA-PK transcriptionally regulates the known DNA-PK–mediated functions as well as novel cancer-related pathways that promote tumor growth; (iv) dual targeting of DNA-PK/TOR kinase (TORK) transcriptionally upregulates androgen signaling, which can be mitigated using the androgen receptor (AR) antagonist enzalutamide; (v) cotargeting AR and DNA-PK/TORK leads to the expansion of antitumor effects, uncovering the modulation of novel, highly relevant protumorigenic cancer pathways; and (viii) cotargeting DNA-PK/TORK and AR has cooperative growth inhibitory effects in vitro and in vivo.
Conclusions:
These findings uncovered novel DNA-PK transcriptional regulatory functions and led to the development of a combinatorial therapeutic strategy for patients with advanced prostate cancer, currently being tested in the clinical setting.
Data from Functional and Mechanistic Interrogation of BET Bromodomain Degraders for the Treatment of Metastatic Castration-resistant Prostate Cancer
Authors: Kregel Steven , Malik Rohit , Asangani Irfan A. , Wilder-Romans Kari , Rajendiran Thekkelnaycke , Xiao Lanbo , Vo Josh N. , Soni Tanu , Cieslik Marcin , Fernadez-Salas Ester , Zhou Bing , Cao Xuhong , Speers Corey , Wang Shaomeng , Chinnaiyan Arul M.
Published: April 2023

AbstractPurpose:
The bromodomain and extraterminal (BET)-containing proteins (BRD2/3/4) are essential epigenetic coregulators for prostate cancer growth. BRD inhibitors have shown promise for treatment of metastatic castration-resistant prostate cancer (mCRPC), and have been shown to function even in the context of resistance to next-generation AR-targeted therapies such as enzalutamide and abiraterone. Their clinical translation, however, has been limited by off-target effects, toxicity, and rapid resistance.
Experimental Design:
We have developed a series of molecules that target BET bromodomain proteins through their proteasomal degradation, improving efficacy and specificity of standard inhibitors. We tested their efficacy by utilizing prostate cancer cell lines and patient-derived xenografts, as well as several techniques including RNA-sequencing, mass spectroscopic proteomics, and lipidomics.
Results:
BET degraders function in vitro and in vivo to suppress prostate cancer growth. These drugs preferentially affect AR-positive prostate cancer cells (22Rv1, LNCaP, VCaP) over AR-negative cells (PC3 and DU145), and proteomic and genomic mechanistic studies confirm disruption of oncogenic AR and MYC signaling at lower concentrations than BET inhibitors. We also identified increases in polyunsaturated fatty acids (PUFA) and thioredoxin-interacting protein (TXNIP) as potential pharmacodynamics biomarkers for targeting BET proteins.
Conclusions:
Compounds inducing the pharmacologic degradation of BET proteins effectively target the major oncogenic drivers of prostate cancer, and ultimately present a potential advance in the treatment of mCRPC. In particular, our compound dBET-3, is most suited for further clinical development.
Data from A Phase I and Pharmacokinetic Study of Oral Dabrafenib in Children and Adolescent Patients with Recurrent or Refractory BRAF V600 Mutation–Positive Solid Tumors
Authors: Kieran Mark W. , Geoerger Birgit , Dunkel Ira J. , Broniscer Alberto , Hargrave Darren , Hingorani Pooja , Aerts Isabelle , Bertozzi Anne-Isabelle , Cohen Kenneth J. , Hummel Trent R. , Shen Violet , Bouffet Eric , Pratilas Christine A. , Pearson Andrew D.J. , Tseng Lillian , Nebot Noelia , Green Steven , Russo Mark W. , Whitlock James A.
Published: April 2023

AbstractPurpose:
The 2-part, phase I/IIa, open-label study (NCT01677741) sought to determine the safety, tolerability, pharmacokinetics, and preliminary activity of dabrafenib in pediatric patients with advanced BRAF V600–mutated cancers.
Patients and Methods:
This phase I dose-finding part treated patients ages 1 to <18 years with BRAF V600 mutation–positive tumors with oral dabrafenib 3 to 5.25 mg/kg/day to determine the RP2D based on safety and drug exposure target.
Results:
Between May 2013 and November 2014, 27 patients [12 male; median age, 9 years (range, 1–17 years)] with BRAF V600–mutant solid tumors recurrent/refractory to treatment (low- or high-grade glioma, Langerhans cell histiocytosis, neuroblastoma, or thyroid cancer) were enrolled. The median treatment duration was 75.6 weeks (range, 5.6–148.7 weeks), with 63% treated for >52 weeks and 52% undergoing treatment at data cutoff date. The most common grade 3/4 adverse events suspected to be related to study drug were maculopapular rash and arthralgia (2 patients each). No dose-limiting toxicities were observed. Pharmacokinetic analyses showed a dose-dependent increase in AUC0–12 and achievement of adult exposure levels at the recommended phase II doses of 5.25 mg/kg/day (age <12 years) and 4.5 mg/kg/day (age ≥12 years) divided into 2 equal doses daily, not exceeding 300 mg daily.
Conclusions:
In this first clinical trial in pediatric patients with pretreated BRAF V600–mutant tumors, dabrafenib was well tolerated while achieving target exposure levels; the average treatment duration was >1 year with many patients still on treatment. The phase II component is also closed and will be reported separately.
Data from Triple Therapy with MerTK and PD1 Inhibition Plus Radiotherapy Promotes Abscopal Antitumor Immune Responses
Authors: Caetano Mauricio S. , Younes Ahmed I. , Barsoumian Hampartsoum B. , Quigley Michael , Menon Hari , Gao Chan , Spires Thomas , Reilly Timothy P. , Cadena Alexandra P. , Cushman Taylor R. , Schoenhals Jonathan E. , Li Ailin , Nguyen Quynh-Nhu , Cortez Maria Angelica , Welsh James W.
Published: April 2023

AbstractPurpose:
Radiotherapy (RT) traditionally has been used for local tumor control in the treatment of cancer. The recent discovery that radiotherapy can have anticancer effects on the immune system has led to recognition of its ability to sensitize the tumor microenvironment to immunotherapy. However, radiation can also prompt adverse immunosuppressive effects that block aspects of systemic response at other tumor sites. Our hypothesis was that inhibition of the MER proto-oncogene tyrosine kinase (MerTK) in combination with anti-programmed cell death-1 (α-PD1) checkpoint blockade will enhance immune-mediated responses to radiotherapy.
Experimental Design:
We tested the efficacy of this triple therapy (Radiation + α-PD1 + α-MerTK mAbs) in 129Sv/Ev mice with bilateral lung adenocarcinoma xenografts. Primary tumors were treated with stereotactic radiotherapy (36 Gy in 3 12-Gy fractions), and tumors were monitored for response.
Results:
The triple therapy significantly delayed abscopal tumor growth, improved survival rates, and reduced numbers of lung metastases. We further found that the triple therapy increased the activated CD8+ and NK cells populations measured by granzyme B expression with upregulation of CD8+CD103+ tissue-resident memory cells (TRM) within the abscopal tumor microenvironment relative to radiation only.
Conclusions:
The addition of α-PD1 + α-MerTK mAbs to radiotherapy could alter the cell death to be more immunogenic and generate adaptive immune response via increasing the retention of TRM cells in the tumor islets of the abscopal tumors which was proven to play a major role in survival of non-small cell lung cancer patients.
Data from Central Nervous System Metastasis in Patients with HER2-Positive Metastatic Breast Cancer: Patient Characteristics, Treatment, and Survival from SystHERs
Authors: Hurvitz Sara A. , O'Shaughnessy Joyce , Mason Ginny , Yardley Denise A. , Jahanzeb Mohammad , Brufsky Adam , Rugo Hope S. , Swain Sandra M. , Kaufman Peter A. , Tripathy Debu , Chu Laura , Li Haocheng , Antao Vincent , Cobleigh Melody
Published: April 2023

AbstractPurpose:
Patients with HER2-positive metastatic breast cancer (MBC) with central nervous system (CNS) metastasis have a poor prognosis. We report treatments and outcomes in patients with HER2-positive MBC and CNS metastasis from the Systemic Therapies for HER2-positive Metastatic Breast Cancer Study (SystHERs).
Experimental Design:
SystHERs (NCT01615068) was a prospective, U.S.-based, observational registry of patients with newly diagnosed HER2-positive MBC. Study endpoints included treatment patterns, clinical outcomes, and patient-reported outcomes (PRO).
Results:
Among 977 eligible patients enrolled (2012–2016), CNS metastasis was observed in 87 (8.9%) at initial MBC diagnosis and 212 (21.7%) after diagnosis, and was not observed in 678 (69.4%) patients. White and younger patients, and those with recurrent MBC and hormone receptor–negative disease, had higher risk of CNS metastasis. Patients with CNS metastasis at diagnosis received first-line lapatinib more commonly (23.0% vs. 2.5%), and trastuzumab less commonly (70.1% vs. 92.8%), than patients without CNS metastasis at diagnosis. Risk of death was higher with CNS metastasis observed at or after diagnosis [median overall survival (OS) 30.2 and 38.3 months from MBC diagnosis, respectively] versus no CNS metastasis [median OS not estimable: HR 2.86; 95% confidence interval (CI), 2.05–4.00 and HR 1.94; 95% CI, 1.52–2.49]. Patients with versus without CNS metastasis at diagnosis had lower quality of life at enrollment.
Conclusions:
Despite advances in HER2-targeted treatments, patients with CNS metastasis continue to have a poor prognosis and impaired quality of life. Observation of CNS metastasis appears to influence HER2-targeted treatment choice.
Data from Predicting the 1p/19q Codeletion Status of Presumed Low-Grade Glioma with an Externally Validated Machine Learning Algorithm
Authors: van der Voort Sebastian R. , Incekara Fatih , Wijnenga Maarten M.J. , Kapas Georgios , Gardeniers Mayke , Schouten Joost W. , Starmans Martijn P.A. , Nandoe Tewarie Rishie , Lycklama Geert J. , French Pim J. , Dubbink Hendrikus J. , van den Bent Martin J. , Vincent Arnaud J.P.E. , Niessen Wiro J. , Klein Stefan , Smits Marion
Published: April 2023

AbstractPurpose:
Patients with 1p/19q codeleted low-grade glioma (LGG) have longer overall survival and better treatment response than patients with 1p/19q intact tumors. Therefore, it is relevant to know the 1p/19q status. To investigate whether the 1p/19q status can be assessed prior to tumor resection, we developed a machine learning algorithm to predict the 1p/19q status of presumed LGG based on preoperative MRI.
Experimental Design:
Preoperative brain MR images from 284 patients who had undergone biopsy or resection of presumed LGG were used to train a support vector machine algorithm. The algorithm was trained on the basis of features extracted from post-contrast T1-weighted and T2-weighted MR images and on patients' age and sex. The performance of the algorithm compared with tissue diagnosis was assessed on an external validation dataset of MR images from 129 patients with LGG from The Cancer Imaging Archive (TCIA). Four clinical experts also predicted the 1p/19q status of the TCIA MR images.
Results:
The algorithm achieved an AUC of 0.72 in the external validation dataset. The algorithm had a higher predictive performance than the average of the neurosurgeons (AUC 0.52) but lower than that of the neuroradiologists (AUC of 0.81). There was a wide variability between clinical experts (AUC 0.45–0.83).
Conclusions:
Our results suggest that our algorithm can noninvasively predict the 1p/19q status of presumed LGG with a performance that on average outperformed the oncological neurosurgeons. Evaluation on an independent dataset indicates that our algorithm is robust and generalizable.
Data from Vaccine-Induced Memory CD8+ T Cells Provide Clinical Benefit in HER2 Expressing Breast Cancer: A Mouse to Human Translational Study
Authors: Crosby Erika J. , Gwin William , Blackwell Kimberly , Marcom Paul K. , Chang Serena , Maecker Holden T. , Broadwater Gloria , Hyslop Terry , Kim Sungjin , Rogatko Andre , Lubkov Veronica , Snyder Joshua C. , Osada Takuya , Hobeika Amy C. , Morse Michael A. , Lyerly H. Kim , Hartman Zachary C.
Published: April 2023

AbstractPurpose:
Immune-based therapy for metastatic breast cancer has had limited success, particularly in molecular subtypes with low somatic mutations rates. Strategies to augment T-cell infiltration of tumors include vaccines targeting established oncogenic drivers such as the genomic amplification of HER2. We constructed a vaccine based on a novel alphaviral vector encoding a portion of HER2 (VRP-HER2).
Patients and Methods:
In preclinical studies, mice were immunized with VRP-HER2 before or after implantation of hHER2+ tumor cells and HER2-specific immune responses and antitumor function were evaluated. We tested VRP-HER2 in a phase I clinical trial where subjects with advanced HER2-overexpressing malignancies in cohort 1 received VRP-HER2 every 2 weeks for a total of 3 doses. In cohort 2, subjects received the same schedule concurrently with a HER2-targeted therapy.
Results:
Vaccination in preclinical models with VRP-HER2 induced HER2-specific T cells and antibodies while inhibiting tumor growth. VRP-HER2 was well tolerated in patients and vaccination induced HER2-specific T cells and antibodies. Although a phase I study, there was 1 partial response and 2 patients with continued stable disease. Median OS was 50.2 months in cohort 1 (n = 4) and 32.7 months in cohort 2 (n = 18). Perforin expression by memory CD8 T cells post-vaccination significantly correlated with improved PFS.
Conclusions:
VRP-HER2 increased HER2-specific memory CD8 T cells and had antitumor effects in preclinical and clinical studies. The expansion of HER2-specific memory CD8 T cells in vaccinated patients was significantly correlated with increased PFS. Subsequent studies will seek to enhance T-cell activity by combining with anti-PD-1.
Data from Clinical Validity of HPV Circulating Tumor DNA in Advanced Anal Carcinoma: An Ancillary Study to the Epitopes-HPV02 Trial
Authors: Bernard-Tessier Alice , Jeannot Emmanuelle , Guenat David , Debernardi Alice , Michel Marc , Proudhon Charlotte , Vincent-Salomon Anne , Bièche Ivan , Pierga Jean-Yves , Buecher Bruno , Meurisse Aurélia , François Éric , Cohen Romain , Jary Marine , Vendrely Véronique , Samalin Emmanuelle , El Hajbi Farid , Baba-Hamed Nabil , Borg Christophe , Bidard François-Clément , Kim Stefano
Published: April 2023

AbstractPurpose:
Human papillomavirus (HPV) is found in 90% of squamous cell carcinomas of the anal canal (SCCA). We investigated the clinical validity of HPV circulating tumor DNA (ctDNA) detection in patients enrolled in the Epitopes-HPV02 trial that demonstrated the efficacy of docetaxel, cisplatin, and 5-FU as first-line chemotherapy in advanced SCCA.
Experimental Design:
According to the protocol, serum samples were collected before chemotherapy and on completion of chemotherapy. HPV16 ctDNA was quantified by droplet digital PCR (ddPCR) and correlated with prospectively registered patient characteristics and outcomes. A landmark was set at the time of chemotherapy completion for postchemotherapy progression-free survival (PFS) analyses.
Results:
Among 57 patients with HPV16-related advanced SCCA, HPV ctDNA was detected in 91.1% (95% confidence interval, 81.1–96.2) of baseline samples. Baseline HPV ctDNA levels were not associated with any patient characteristics; baseline ctDNA level below the cutoff obtained by AUC (area under the curve) was associated with a longer PFS (HR = 2.1; P = 0.04). Among the 36 patients who completed 5 months of chemotherapy, residual HPV ctDNA was detected after chemotherapy in 38.9% of patients. Residual HPV ctDNA detected at chemotherapy completion was associated with shorter postchemotherapy PFS (median PFS 3.4 months vs. not reached; HR = 5.5; P < 0.001) and a reduction of 1-year overall survival rate (OR = 7.0; P = 0.02).
Conclusions:
This prospective study in advanced SCCA demonstrated a significant prognostic impact of HPV ctDNA level before first-line chemotherapy and HPV ctDNA negativity after chemotherapy completion. With a limited cost and short turnaround, this assay is a promising tool to optimize the therapeutic management of SCCA.

See related commentary by Morris, p. 2030
Data from Advances in HER2-Targeted Therapy: Novel Agents and Opportunities Beyond Breast and Gastric Cancer
Authors: Meric-Bernstam Funda , Johnson Amber M. , Dumbrava Ecaterina E. Ileana , Raghav Kanwal , Balaji Kavitha , Bhatt Michelle , Murthy Rashmi K. , Rodon Jordi , Piha-Paul Sarina A.
Published: April 2023

Abstract
The introduction of HER2-targeted therapy for breast and gastric patients with ERBB2 (HER2) amplification/overexpression has led to dramatic improvements in oncologic outcomes. In the past 20 years, five HER2-targeted therapies have been FDA approved, with four approved in the past 8 years. HER2-targeted therapy similarly was found to improve outcomes in HER2-positive gastric cancer. Over the past decade, with the introduction of next-generation sequencing into clinical practice, our understanding of HER2 biology has dramatically improved. We have recognized that HER2 amplification is not limited to breast and gastric cancer but is also found in a variety of tumor types such as colon cancer, bladder cancer, and biliary cancer. Furthermore, HER2-targeted therapy has signal of activity in several tumor types. In addition to HER2 amplification and overexpression, there is also increased recognition of activating HER2 mutations and their potential therapeutic relevance. Furthermore, there is a rapidly growing number of new therapeutics targeting HER2 including small-molecule inhibitors, antibody–drug conjugates, and bispecific antibodies. Taken together, an increasing number of patients are likely to benefit from approved and emerging HER2-targeted therapies.
Data from The Interleukin 22 Pathway Interacts with Mutant KRAS to Promote Poor Prognosis in Colon Cancer
Authors: McCuaig Sarah , Barras David , Mann Elizabeth H. , Friedrich Matthias , Bullers Samuel J. , Janney Alina , Garner Lucy C. , Domingo Enric , Koelzer Viktor Hendrik , Delorenzi Mauro , Tejpar Sabine , Maughan Timothy S. , West Nathaniel R. , Powrie Fiona
Published: April 2023

AbstractPurpose:
The cytokine IL22 promotes tumor progression in murine models of colorectal cancer. However, the clinical significance of IL22 in human colorectal cancer remains unclear. We sought to determine whether the IL22 pathway is associated with prognosis in human colorectal cancer, and to identify mechanisms by which IL22 can influence disease progression.
Experimental Design:
Transcriptomic data from stage II/III colon cancers in independent discovery (GSE39582 population-based cohort, N = 566) and verification (PETACC3 clinical trial, N = 752) datasets were used to investigate the association between IL22 receptor expression (encoded by the genes IL22RA1 and IL10RB), tumor mutation status, and clinical outcome using Cox proportional hazard models. Functional interactions between IL22 and mutant KRAS were elucidated using human colorectal cancer cell lines and primary tumor organoids.
Results:
Transcriptomic analysis revealed a poor-prognosis subset of tumors characterized by high expression of IL22RA1, the alpha subunit of the heterodimeric IL22 receptor, and KRAS mutation [relapse-free survival (RFS): HR = 2.93, P = 0.0006; overall survival (OS): HR = 2.45, P = 0.0023]. KRAS mutations showed a similar interaction with IL10RB and conferred the worst prognosis in tumors with high expression of both IL22RA1 and IL10RB (RFS: HR = 3.81, P = 0.0036; OS: HR = 3.90, P = 0.0050). Analysis of human colorectal cancer cell lines and primary tumor organoids, including an isogenic cell line pair that differed only in KRAS mutation status, showed that IL22 and mutant KRAS cooperatively enhance cancer cell proliferation, in part through augmentation of the Myc pathway.
Conclusions:
Interactions between KRAS and IL22 signaling may underlie a previously unrecognized subset of clinically aggressive colorectal cancer that could benefit from therapeutic modulation of the IL22 pathway.
Data from BRCA1 Promoter Methylation Is Linked to Defective Homologous Recombination Repair and Elevated miR-155 to Disrupt Myeloid Differentiation in Myeloid Malignancies
Authors: Poh Weijie , Dilley Robert L. , Moliterno Alison R. , Maciejewski Jaroslaw P. , Pratz Keith W. , McDevitt Michael A. , Herman James G.
Published: April 2023

AbstractPurpose:
Defective homologous recombination (HR) has been reported in multiple myeloid disorders, suggesting a shared dysregulated pathway in these diverse malignancies. Because targeting HR-defective cancers with PARP inhibition (PARPi) has yielded clinical benefit, improved understanding of HR defects is needed to implement this treatment modality.
Experimental Design:
We used an ex vivo irradiation-based assay to evaluate HR repair, HR gene promoter methylation, and mRNA expression in primary myeloid neoplastic cells. In vitro BRCA1 gene silencing was achieved to determine the consequences on HR repair, sensitivity to PARPi, and expression of miR-155, an oncogenic miRNA.
Results:
Impaired HR repair was frequently detected in myeloid neoplasm samples (9/21, 43%) and was linked to promoter methylation-mediated transcriptional repression of BRCA1, which was not observed for other members of the HR pathway (BRCA2, ATM, ATR, FANC-A). In vitro BRCA1 knockdown increased sensitivity to PARP inhibition, and BRCA1 expression is inversely correlated with miR-155 expression, a finding reproduced in vitro with BRCA1 knockdown. Increased miR-155 was associated with PU.1 and SHIP1 repression, known myeloid differentiation factors that are frequently downregulated during leukemic transformation.
Conclusions:
This study demonstrates frequent defective HR, associated with BRCA1 epigenetic silencing, in a broad range of myeloid neoplasms. The increased prevalence of BRCA1 promoter methylation, resulting in repressed BRCA1, may have an additional role in leukemogenesis by increasing miR-155 expression, which then inhibits transcription factors associated with normal myeloid differentiation. Further study of HR defects may facilitate the identification of HR-defective myeloid neoplasms sensitive to PARPi.
Data from BET Inhibition as a Rational Therapeutic Strategy for Invasive Lobular Breast Cancer
Authors: Walsh Louise , Haley Kathryn E. , Moran Bruce , Mooney Brian , Tarrant Finbarr , Madden Stephen F. , Di Grande Alessandra , Fan Yue , Das Sudipto , Rueda Oscar M. , Dowling Catríona M. , Varešlija Damir , Chin Suet-Feung , Linn Sabine , Young Leonie S. , Jirström Karin , Crown John P. , Bernards Rene , Caldas Carlos , Gallagher William M. , O'Connor Darran P. , Ní Chonghaile Tríona
Published: April 2023

AbstractPurpose:
Invasive lobular carcinoma (ILC) is a subtype of breast cancer accounting for 10% of breast tumors. The majority of patients are treated with endocrine therapy; however, endocrine resistance is common in estrogen receptor–positive breast cancer and new therapeutic strategies are needed. Bromodomain and extraterminal inhibitors (BETi) are effective in diverse types of breast cancer but they have not yet been assessed in ILC.
Experimental Design:
We assessed whether targeting the BET proteins with JQ1 could serve as an effective therapeutic strategy in ILC in both 2D and 3D models. We used dynamic BH3 profiling and RNA-sequencing (RNA-seq) to identify transcriptional reprograming enabling resistance to JQ1-induced apoptosis. As part of the RATHER study, we obtained copy-number alterations and RNA-seq on 61 ILC patient samples.
Results:
Certain ILC cell lines were sensitive to JQ1, while others were intrinsically resistant to JQ1-induced apoptosis. JQ1 treatment led to an enhanced dependence on antiapoptotic proteins and a transcriptional rewiring inducing fibroblast growth factor receptor 1 (FGFR1). This increase in FGFR1 was also evident in invasive ductal carcinoma (IDC) cell lines. The combination of JQ1 and FGFR1 inhibitors was highly effective at inhibiting growth in both 2D and 3D models of ILC and IDC. Interestingly, we found in the RATHER cohort of 61 ILC patients that 20% had FGFR1 amplification and we showed that high BRD3 mRNA expression was associated with poor survival specifically in ILC.
Conclusions:
We provide evidence that BETi either alone or in combination with FGFR1 inhibitors or BH3 mimetics may be a useful therapeutic strategy for recurrent ILC patients.
Data from Efficacy of Affibody-Based Ultrasound Molecular Imaging of Vascular B7-H3 for Breast Cancer Detection
Authors: Bam Rakesh , Lown Patrick S. , Stern Lawrence A. , Sharma Karina , Wilson Katheryne E. , Bean Gregory R. , Lutz Amelie M. , Paulmurugan Ramasamy , Hackel Benjamin J. , Dahl Jeremy , Abou-Elkacem Lotfi
Published: April 2023

AbstractPurpose:
Human B7-H3 (hB7-H3) is a promising molecular imaging target differentially expressed on the neovasculature of breast cancer and has been validated for preclinical ultrasound (US) imaging with anti–B7-H3-antibody-functionalized microbubbles (MB). However, smaller ligands such as affibodies (ABY) are more suitable for the design of clinical-grade targeted MB.
Experimental Design:
Binding of ABYB7-H3 was confirmed with soluble and cell-surface B7-H3 by flow cytometry. MB were functionalized with ABYB7-H3 or anti–B7-H3-antibody (AbB7-H3). Control and targeted MB were tested for binding to hB7-H3–expressing cells (MS1hB7-H3) under shear stress conditions. US imaging was performed with MBABY-B7-H3 in an orthotopic mouse model of human MDA-MB-231 coimplanted with MS1hB7-H3 or control MS1WT cells and a transgenic mouse model of breast cancer development.
Results:
ABYB7-H3 specifically binds to MS1hB7-H3 and murine-B7-H3–expressing monocytes. MBABY-B7-H3 (8.5 ± 1.4 MB/cell) and MBAb-B7-H3 (9.8 ± 1.3 MB/cell) showed significantly higher (P < 0.0001) binding to the MS1hB7-H3 cells compared with control MBNon-targeted (0.5 ± 0.1 MB/cell) under shear stress conditions. In vivo, MBABY-B7-H3 produced significantly higher (P < 0.04) imaging signal in orthotopic tumors coengrafted with MS1hB7-H3 (8.4 ± 3.3 a.u.) compared with tumors with MS1WT cells (1.4 ± 1.0 a.u.). In the transgenic mouse tumors, MBABY-B7-H3 (9.6 ± 2.0 a.u.) produced higher (P < 0.0002) imaging signal compared with MBNon-targeted (1.3 ± 0.3 a.u.), whereas MBABY-B7-H3 signal in normal mammary glands and tumors with B7-H3 blocking significantly reduced (P < 0.02) imaging signal.
Conclusions:
MBABY-B7-H3 enhances B7-H3 molecular signal in breast tumors, improving cancer detection, while offering the advantages of a small size ligand and easier production for clinical imaging.
Data from Validation of a Ductal Carcinoma In Situ Biomarker Profile for Risk of Recurrence after Breast-Conserving Surgery with and without Radiotherapy
Authors: Weinmann Sheila , Leo Michael C. , Francisco Melanie , Jenkins Charisma L. , Barry Todd , Leesman Glen , Linke Steven P. , Whitworth Pat W. , Patel Rakesh , Pellicane James , Wärnberg Fredrik , Bremer Troy
Published: April 2023

AbstractPurpose:
A major challenge in ductal carcinoma in situ (DCIS) treatment is selection of the most appropriate therapeutic approach for individual patients. We conducted an external prospective–retrospective clinical validation of a DCIS biologic risk signature, DCISionRT, in a population-based observational cohort of women diagnosed with DCIS and treated with breast-conserving surgery (BCS).
Experimental Design:
Participants were 455 health plan members of Kaiser Permanente Northwest diagnosed with DCIS and treated with BCS with or without radiotherapy from 1990 to 2007. The biologic signature combined seven protein tumor markers assessed in formalin-fixed, paraffin-embedded tumor tissue with four clinicopathologic factors to provide a DCISionRT test result, termed decision score (DS). Cox regression and Kaplan–Meier analysis were used to measure the association of the DS, continuous (linear) or categorical (DS ≤ 3 vs. DS > 3), and subsequent total ipsilateral breast events and invasive ipsilateral breast events at least 6 months after initial surgery.
Results:
In Cox regression, the continuous and categorical DS variables were positively associated with total and invasive breast event risk after adjustment for radiotherapy. In a subset analysis by treatment group, categorical Kaplan–Meier analyses showed at least 2-fold differences in 10-year risk of total breast events between the elevated-risk and low-risk DS categories.
Conclusions:
In this first external validation study of the DCISionRT test, the DS was prognostic for the risk of later breast events for women diagnosed with DCIS, following BCS.
Data from Development of 2 Bromodomain and Extraterminal Inhibitors With Distinct Pharmacokinetic and Pharmacodynamic Profiles for the Treatment of Advanced Malignancies
Authors: Falchook Gerald , Rosen Seth , LoRusso Patricia , Watts Justin , Gupta Shilpa , Coombs Catherine C. , Talpaz Moshe , Kurzrock Razelle , Mita Monica , Cassaday Ryan , Harb Wael , Peguero Julio , Smith David C. , Piha-Paul Sarina A. , Szmulewitz Russ , Noel Marcus S. , Yeleswaram Swamy , Liu Phillip , Switzky Julie , Zhou Gongfu , Zheng Fred , Mehta Amitkumar
Published: April 2023

AbstractPurpose:
Bromodomain and extraterminal (BET) proteins are key epigenetic transcriptional regulators, inhibition of which may suppress oncogene expression. We report results from 2 independent first-in-human phase 1/2 dose–escalation and expansion, safety and tolerability studies of BET inhibitors INCB054329 (study INCB 54329-101; NCT02431260) and INCB057643 (study INCB 57643-101; NCT02711137).
Patients and Methods:
Patients (≥18 years) with advanced malignancies, ≥1 prior therapy, and adequate organ functions received oral INCB054329 (monotherapy) or INCB057643 (monotherapy or in combination with standard-of-care) in 21-day cycles (or 28-day cycles depending on standard-of-care combination). Primary endpoints were safety and tolerability.
Results:
Sixty-nine and 134 patients received INCB054329 and INCB057643, respectively. Study INCB 54329-101 has been completed; INCB 57643-101 is currently active, but not recruiting (no patients were receiving treatment as of January 8, 2019). Terminal elimination half-life was shorter for INCB054329 versus INCB057643 (mean [SD], 2.24 [2.03] vs. 11.1 [8.27] hours). INCB054329 demonstrated higher interpatient variability in oral clearance versus INCB057643 (CV%, 142% vs. 45.5%). Most common (>20%) any-grade treatment-related adverse events were similar for both drugs (INCB054329; INCB057643): nausea (35%; 30%), thrombocytopenia (33%; 32%), fatigue (29%; 30%), decreased appetite (26%; 22%). Two confirmed complete responses and 4 confirmed partial responses with INCB057643 were reported as best responses.
Conclusions:
INCB057643 exhibited a more favorable PK profile versus INCB054329; exposure-dependent thrombocytopenia was observed with both drugs which limited the target inhibition that could be safely maintained. Further efforts are required to identify patient populations that can benefit most, and an optimal dosing scheme to maximize therapeutic index.
Data from Elastography Can Map the Local Inverse Relationship between Shear Modulus and Drug Delivery within the Pancreatic Ductal Adenocarcinoma Microenvironment
Authors: Wang Hexuan , Mislati Reem , Ahmed Rifat , Vincent Phuong , Nwabunwanne Solumtochukwu F. , Gunn Jason R. , Pogue Brian W. , Doyley Marvin M.
Published: April 2023

AbstractPurpose:
High tissue pressure prevents chemotherapeutics from reaching the core of pancreatic tumors. Therefore, targeted therapies have been developed to reduce this pressure. While point probes have shown the effectiveness of these pressure-reducing therapies via single-location estimates, ultrasound elastography is now widely available as an imaging technique to provide real-time spatial maps of shear modulus (tissue stiffness). However, the relationship between shear modulus and the underlying tumor microenvironmental causes of high tissue pressure has not been investigated. In this work, elastography was used to investigate how shear modulus influences drug delivery in situ, and how it correlates with collagen density, hyaluronic acid content, and patent vessel density—features of the tumor microenvironment known to influence tissue pressure.
Experimental Design:
Intravenous injection of verteporfin, an approved human fluorescent drug, was used in two pancreatic cancer xenograft models [AsPC-1 (n = 25) and BxPC-3 (n = 25)].
Results:
Fluorescence intensity was higher in AsPC-1 tumors than in BxPC-3 tumors (P < 0.0001). Comparing drug uptake images and shear wave elastographic images with histologic images revealed that: (i) drug delivery and shear modulus were inversely related, (ii) shear modulus increased linearly with increasing collagen density, and (iii) shear modulus was marginally correlated with the local assessment of hyaluronic acid content.
Conclusions:
These results demonstrate that elastography could guide targeted therapy and/or identify patients with highly elevated tissue pressure.

See related commentary by Nia et al., p. 2024
Data from A Th1/IFNγ Gene Signature Is Prognostic in the Adjuvant Setting of Resectable High-Risk Melanoma but Not in Non–Small Cell Lung Cancer
Authors: Dizier Benjamin , Callegaro Andrea , Debois Muriel , Dreno Brigitte , Hersey Peter , Gogas Helen J. , Kirkwood John M. , Vansteenkiste Johan F. , Sequist Lecia V. , Atanackovic Djordje , Goeman Jelle , van Houwelingen Hans , Salceda Susana , Wang Fawn , Therasse Patrick , Debruyne Channa , Spiessens Bart , Brichard Vincent G. , Louahed Jamila , Ulloa-Montoya Fernando
Published: April 2023

AbstractPurpose:
Immune components of the tumor microenvironment (TME) have been associated with disease outcome. We prospectively evaluated the association of an immune-related gene signature (GS) with clinical outcome in melanoma and non–small cell lung cancer (NSCLC) tumor samples from two phase III studies.
Experimental Design:
The GS was prospectively validated using an adaptive signature design to optimize it for the sample type and technology used in phase III studies. One-third of the samples were used as “training set”; the remaining two thirds, constituting the “test set,” were used for the prospective validation of the GS.
Results:
In the melanoma training set, the expression level of eight Th1/IFNγ-related genes in tumor-positive lymph node tissue predicted the duration of disease-free survival (DFS) and overall survival (OS) in the placebo arm. This GS was prospectively and independently validated as prognostic in the test set. Building a multivariate Cox model in the test set placebo patients from clinical covariates and the GS score, an increased number of melanoma-involved lymph nodes and the GS were associated with DFS and OS. This GS was not associated with DFS in NSCLC, although expression of the Th1/IFNγ-related genes was associated with the presence of lymphocytes in tumor samples in both indications.
Conclusions:
These findings provide evidence that expression of Th1/IFNγ genes in the TME, as measured by this GS, is associated with clinical outcome in melanoma. This suggests that, using this GS, patients with stage IIIB/C melanoma can be classified into different risk groups.