bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Comprehensive Molecular Analysis of Inflammatory Myofibroblastic Tumors Reveals Diverse Genomic Landscape and Potential Predictive Markers for Response to Crizotinib
Authors: Lee Che-Jui , Schöffski Patrick , Modave Elodie , van Wezel Tom , Boeckx Bram , Sufliarsky Jozef , Gelderblom Hans , Blay Jean-Yves , Debiec-Rychter Maria , Sciot Raf , Bovée Judith V.M.G. , Lambrechts Diether , Wozniak Agnieszka
Published: April 2023

AbstractPurpose:
The European Organization for Research and Treatment of Cancer (EORTC) clinical phase II trial 90101 “CREATE” showed high antitumor activity of crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK)/ROS1, in patients with advanced inflammatory myofibroblastic tumor (IMFT). However, recent findings suggested that other molecular targets in addition to ALK/ROS1 might also contribute to the sensitivity of this kinase inhibitor. We therefore performed an in-depth molecular characterization of archival IMFT tissue, collected from patients enrolled in this trial, with the aim to identify other molecular alterations that could play a role in the response to crizotinib.
Experimental Design:
Twenty-four archival IMFT samples were used for histopathological assessment and DNA/RNA evaluation to identify gene fusions, copy-number alterations (CNA), and mutations in the tumor tissue. Results were correlated with clinical parameters to assess a potential association between molecular findings and clinical outcomes.
Results:
We found 12 ALK fusions with 11 different partners in ALK-positive IMFT cases by Archer analysis whereas we did not identify any ROS1-rearranged tumor. One ALK-negative patient responding to crizotinib was found to have an ETV6–NTRK fusion in the tumor specimen. The CNA profile and mutational landscape of IMFT revealed extensive molecular heterogeneity. Loss of chromosome 19 (25% of cases) and PIK3CA mutations (9% of cases) were associated with shorter progression-free survival in patients receiving crizotinib.
Conclusions:
We identified multiple genetic alterations in archival IMFT material and provide further insight into the molecular profile of this ultra-rare, heterogeneous malignancy, which may potentially translate into novel treatment approaches for this orphan disease.
Data from Genetic Polymorphisms and Correlation with Treatment-Induced Cardiotoxicity and Prognosis in Patients with Breast Cancer
Authors: Peddi Parvin F. , Fasching Peter A. , Liu Duan , Quinaux Emmanuel , Robert Nicholas J. , Valero Vicente , Crown John , Falkson Carla , Brufsky Adam , Cunningham Julie M. , Weinshilboum Richard M. , Pienkowski Tadeusz , Eiermann Wolfgang , Martín Miguel , Bee Valerie , Wang Xiaoyan , Wang Liewei , Yang Eric , Slamon Dennis J. , Hurvitz Sara A.
Published: April 2023

AbstractPurpose:
Cardiac toxicity is a serious potential complication of HER2-directed therapies and anthracyclines. HER2 codon 655 and SLC28A3 gene polymorphisms have been reported to be associated with cardiac toxicity from anti-HER2 and anthracycline therapy, respectively. Association of the polymorphism at HER2 codon 655 with prognosis has also been reported.
Experimental Design:
Whole blood samples from patients treated on a randomized adjuvant breast cancer trial (BCIRG-006) that compared chemotherapy with or without trastuzumab plus either anthracycline or nonanthracycline chemotherapy were tested for genetic polymorphisms in HER2 codon 655 and SLC28A3. Genotypes were correlated with cardiac function and disease-free survival (DFS) outcomes.
Results:
Of 3,222 patients enrolled in BCIRG-006, 662 patient samples were successfully genotyped for the rs1136201 allele in HER2 (codon 655): 424 (64%) were AA, 30 (4.5%) were GG, and 208 (31%) were AG genotype. In addition, 665 patient samples were successfully genotyped for the rs7853758 allele in the SLC28A3 gene: 19 (3%) were AA, 475 (71%) were GG, and 171 (26%) were AG genotype. Follow-up time was 10 years. No correlation between DFS, cardiac event rate, or mean left ventricular ejection fraction (LVEF) and rs1136201 genotype was seen in the trastuzumab-treated or non–trastuzumab-treated patients. Moreover, mean LVEF and cardiac event rates were similar in all rs7853758 genotype groups treated with anthracycline-based therapy.
Conclusions:
In the largest study to date to evaluate whether two polymorphisms are associated with DFS and/or cardiac toxicity in HER2-positive breast cancer treated with trastuzumab and/or anthracyclines, we observed no correlation.
Data from Follicular Lymphoma–associated BTK Mutations are Inactivating Resulting in Augmented AKT Activation
Authors: Hu Nan , Wang Fangyang , Sun Tianyu , Xu Zhengfan , Zhang Jing , Bernard Denzil , Xu Shilin , Wang Shaomeng , Kaminski Mark , Devata Suma , Phillips Tycel , Malek Sami N.
Published: April 2023

AbstractPurpose:
On the basis of the recent discovery of mutations in Bruton tyrosine kinase (BTK) in follicular lymphoma, we studied their functional properties.
Experimental Design:
We identified novel somatic BTK mutations in 7% of a combined total of 139 follicular lymphoma and 11 transformed follicular lymphoma cases, none of which had received prior treatment with B-cell receptor (BCR) targeted drugs. We reconstituted wild-type (WT) and mutant BTK into various engineered lymphoma cell lines. We measured BCR-induced signal transduction events in engineered cell lines and primary human follicular lymphoma B cells.
Results:
We uncovered that all BTK mutants destabilized the BTK protein and some created BTK kinase-dead mutants. The phospholipase C gamma 2 (PLCγ2) is a substrate of BTK but the BTK mutants did not alter PLCγ2 phosphorylation. Instead, we discovered that BTK mutants induced an exaggerated AKT phosphorylation phenotype in anti-Ig-treated recombinant lymphoma cell lines. The short hairpin RNA–mediated knockdown of BTK expression in primary human nonmalignant lymph node–derived B cells resulted in strong anti-Ig-induced AKT activation, as did the degradation of BTK protein in cell lines using ibrutinib-based proteolysis targeting chimera. Finally, through analyses of primary human follicular lymphoma B cells carrying WT or mutant BTK, we detected elevated AKT phosphorylation following surface Ig crosslinking in all follicular lymphoma B cells, including all BTK-mutant follicular lymphoma. The augmented AKT phosphorylation following BCR crosslinking could be abrogated by pretreatment with a PI3Kδ inhibitor.
Conclusions:
Altogether, our data uncover novel unexpected properties of follicular lymphoma–associated BTK mutations with direct implications for targeted therapy development in follicular lymphoma.

See related commentary by Afaghani and Taylor, p. 2123
Data from Trilaciclib Prior to Chemotherapy in Patients with Metastatic Triple-Negative Breast Cancer: Final Efficacy and Subgroup Analysis from a Randomized Phase II Study
Authors: Tan Antoinette R. , Wright Gail S. , Thummala Anu R. , Danso Michael A. , Popovic Lazar , Pluard Timothy J. , Han Hyo S. , Vojnović Željko , Vasev Nikola , Ma Ling , Richards Donald A. , Wilks Sharon T. , Milenković Dušan , Xiao Jie , Sorrentino Jessica , Horton Janet , O'Shaughnessy Joyce
Published: April 2023

AbstractPurpose:
We report final antitumor efficacy results from a phase II study of trilaciclib, an intravenous cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, administered prior to gemcitabine plus carboplatin (GCb) in patients with metastatic triple-negative breast cancer (NCT02978716).
Patients and Methods:
Patients were randomized (1:1:1) to group 1 [GCb (days 1, 8); n = 34], group 2 [trilaciclib prior to GCb (days 1, 8); n = 33], or group 3 [trilaciclib (days 1, 8) and trilaciclib prior to GCb (days 2, 9); n = 35]. Subgroup analyses were performed according to CDK4/6 dependence, level of programmed death-ligand 1 (PD-L1) expression, and RNA-based immune signatures using proportional hazards regression. T-cell receptor (TCR) β CDR3 regions were amplified and sequenced to identify, quantify, and compare the abundance of each unique TCRβ CDR3 at baseline and on treatment.
Results:
Median overall survival (OS) was 12.6 months in group 1, not reached in group 2 (HR = 0.31; P = 0.0016), 17.8 months in group 3 (HR = 0.40; P = 0.0004), and 19.8 months in groups 2 and 3 combined (HR = 0.37; P < 0.0001). Efficacy outcomes were comparable regardless of cancer CDK4/6 dependence status and immune signatures. Administering trilaciclib prior to GCb prolonged OS irrespective of PD-L1 status but had greater benefit in the PD-L1–positive population. T-cell activation was enhanced in patients receiving trilaciclib.
Conclusions:
Administering trilaciclib prior to GCb enhanced antitumor efficacy, with significant improvements in OS. Efficacy outcomes in immunologic subgroups and enhancements in T-cell activation suggest these improvements may be mediated via immunologic mechanisms.
Data from Phase II, Randomized Study of Spartalizumab (PDR001), an Anti–PD-1 Antibody, versus Chemotherapy in Patients with Recurrent/Metastatic Nasopharyngeal Cancer
Authors: Even Caroline , Wang Hung-Ming , Li Shau-Hsuan , Ngan Roger K-C , Dechaphunkul Arunee , Zhang Li , Yen Chia-Jui , Chan Po Chung , Chakrabandhu Somvilai , Ma Brigette B.Y. , Tanasanvimon Suebpong , Lee Victor H.F. , Lou Pei-Jen , Li Zujun , Spira Alexander I. , Sukari Ammar , Guigay Joël , McCune Steven , Gonzalez-Maffe Juan , Szpakowski Sebastian , Yao Yao , Liang Hongzi , Mataraza Jennifer , Séchaud Romain , Manenti Luigi , Lim Darren W-T.
Published: April 2023

AbstractPurpose:
No standard treatment exists for platinum-refractory, recurrent/metastatic nasopharyngeal cancer (NPC). This phase II study (NCT02605967) evaluated progression-free survival (PFS) of spartalizumab, an antiprogrammed cell death protein-1 (PD-1) monoclonal antibody, versus chemotherapy, in NPC.
Patients and Methods:
Patients with nonkeratinizing recurrent/metastatic NPC who progressed on/after platinum-based chemotherapy were enrolled. Spartalizumab was dosed 400 mg once every 4 weeks, and chemotherapy was received per investigator's choice.
Results:
Patients were randomized to receive either spartalizumab (82 patients) or chemotherapy (40 patients). The most common spartalizumab treatment-related adverse events were fatigue (10.3%) and pruritus (9.3%). Median PFS in the spartalizumab arm was 1.9 months versus 6.6 months in the chemotherapy arm (P = 0.915). The overall response rate in the spartalizumab arm was 17.1% versus 35.0% in the chemotherapy arm. Median duration of response was 10.2 versus 5.7 months in the spartalizumab versus chemotherapy arms, respectively. Median overall survival was 25.2 and 15.5 months in the spartalizumab and chemotherapy arms, respectively. Tumor RNA sequencing showed a correlation between response to spartalizumab and IFNγ, LAG-3, and TIM-3 gene expression.
Conclusions:
Spartalizumab demonstrated a safety profile consistent with other anti–PD-1 antibodies. The primary endpoint of median PFS was not met; however, median overall survival and median duration of response were longer with spartalizumab compared with chemotherapy.
Data from Phase II Study of Ponatinib in Advanced Gastrointestinal Stromal Tumors: Efficacy, Safety, and Impact of Liquid Biopsy and Other Biomarkers
Authors: George Suzanne , von Mehren Margaret , Fletcher Jonathan A. , Sun Jichao , Zhang Sen , Pritchard Justin R. , Hodgson John Graeme , Kerstein David , Rivera Victor M. , Haluska Frank G. , Heinrich Michael C.
Published: April 2023

AbstractPurpose:
The purpose of this study is to evaluate ponatinib for advanced gastrointestinal stromal tumors (GIST).
Patients and Methods:
This single-arm phase II trial enrolled patients with metastatic and/or unresectable GIST with failure of prior tyrosine kinase inhibitor (TKI) treatment into two cohorts based on presence or absence of KIT exon 11 (ex11) primary mutations. Patients initially received ponatinib 45 mg once daily. Following a temporary clinical hold in October 2013, dose reductions were implemented to reduce risk of arterial occlusive events (AOE). Primary endpoint was 16-week clinical benefit rate (CBR) in KIT ex11–positive cohort. KIT mutations in circulating tumor DNA (ctDNA) were assessed.
Results:
Forty-five patients enrolled (30 KIT ex11–positive and 15 KIT ex11–negative); median follow-up was 14.7 and 13.6 months, respectively, as of August 1, 2016. Sixteen-week CBR was 36% (KIT ex11–positive; primary endpoint) and 20% (KIT ex11–negative). ctDNA analyses (n = 37) demonstrated strong concordance of primary KIT mutations between plasma and tumor. At least two secondary mutations were detected in 35% of patients overall and 54% of KIT ex11–positive patients. Changes from baseline in mutated ctDNA levels were consistent with clinical activity. Ponatinib was ineffective in patients with KIT exon 9 primary mutations. Resistance was associated with emergence of V654A. AOEs and venous thromboembolic events occurred in three and two patients, respectively. Six patients died; two deaths (pneumonia and pulmonary embolism) were considered possibly ponatinib-related.
Conclusions:
Ponatinib demonstrated activity in advanced GIST, particularly in KIT ex11–positive disease. ctDNA analysis confirmed heterogeneous resistance mutations in TKI-pretreated advanced GIST. Safety was consistent with previous studies.
Data from A Randomized Trial of Combined PD-L1 and CTLA-4 Inhibition with Targeted Low-Dose or Hypofractionated Radiation for Patients with Metastatic Colorectal Cancer
Authors: Monjazeb Arta M. , Giobbie-Hurder Anita , Lako Ana , Thrash Emily M. , Brennick Ryan C. , Kao Katrina Z. , Manuszak Claire , Gentzler Ryan D. , Tesfaye Anteneh , Jabbour Salma K. , Alese Olatunji B. , Rahma Osama E. , Cleary James M. , Sharon Elad , Mamon Harvey J. , Cho May , Streicher Howard , Chen Helen X. , Ahmed Mansoor M. , Mariño-Enríquez Adrian , Kim-Schulze Seunghee , Gnjatic Sacha , Maverakis Emanual , Marusina Alina I. , Merleev Alexander A. , Severgnini Mariano , Pfaff Kathleen L. , Lindsay James , Weirather Jason L. , Ranasinghe Srinika , Spektor Alexander , Rodig Scott J. , Hodi F. Stephen , Schoenfeld Jonathan D.
Published: April 2023

AbstractPurpose:
Prospective human data are lacking regarding safety, efficacy, and immunologic impacts of different radiation doses administered with combined PD-L1/CTLA-4 blockade.
Patients and Methods:
We performed a multicenter phase II study randomly assigning patients with metastatic microsatellite stable colorectal cancer to repeated low-dose fractionated radiation (LDFRT) or hypofractionated radiation (HFRT) with PD-L1/CTLA-4 inhibition. The primary endpoint was response outside the radiation field. Correlative samples were analyzed using multiplex immunofluorescence (IF), IHC, RNA/T-cell receptor (TCR) sequencing, cytometry by time-of-flight (CyTOF), and Olink.
Results:
Eighteen patients were evaluable for response. Median lines of prior therapy were four (range, 1–7). Sixteen patients demonstrated toxicity potentially related to treatment (84%), and 8 patients had grade 3–4 toxicity (42%). Best response was stable disease in 1 patient with out-of-field tumor shrinkage. Median overall survival was 3.8 months (90% confidence interval, 2.3–5.7 months). Correlative IF and RNA sequencing (RNA-seq) revealed increased infiltration of CD8+ and CD8+/PD-1+/Ki-67+ T cells in the radiation field after HFRT. LDFRT increased foci of micronuclei/primary nuclear rupture in two subjects. CyTOF and RNA-seq demonstrated significant declines in multiple circulating immune populations, particularly in patients receiving HFRT. TCR sequencing revealed treatment-associated changes in T-cell repertoire in the tumor and peripheral blood.
Conclusions:
We demonstrate the feasibility and safety of adding LDFRT and HFRT to PD-L1/CTLA-4 blockade. Although the best response of stable disease does not support the use of concurrent PD-L1/CTLA-4 inhibition with HFRT or LDFRT in this population, biomarkers provide support that both LDFRT and HFRT impact the local immune microenvironment and systemic immunogenicity that can help guide future studies.
Data from Development and Multiple Validation of the Protein Multi-marker Panel for Diagnosis of Pancreatic Cancer
Authors: Kim Yoseop , Yeo Injoon , Huh Iksoo , Kim Jaenyeon , Han Dohyun , Jang Jin-Young , Kim Youngsoo
Published: April 2023

AbstractPurpose:
To develop and validate a protein-based, multi-marker panel that provides superior pancreatic ductal adenocarcinoma (PDAC) detection abilities with sufficient diagnostic performance.
Experimental Design:
A total of 959 plasma samples from patients at multiple medical centers were used. To construct an optimal, diagnostic, multi-marker panel, we applied data preprocessing procedure to biomarker candidates. The multi-marker panel was developed using a training set comprised of 261 PDAC cases and 290 controls. Subsequent evaluations were performed in a validation set comprised of 65 PDAC cases and 72 controls. Further validation was performed in an independent set comprised of 75 PDAC cases and 47 controls.
Results:
A multi-marker panel containing 14 proteins was developed. The multi-marker panel achieved AUCs of 0.977 and 0.953 for the training set and validation set, respectively. In an independent validation set, the multi-marker panel yielded an AUC of 0.928. The diagnostic performance of the multi-marker panel showed significant improvements compared with carbohydrate antigen (CA) 19-9 alone (training set AUC = 0.977 vs. 0.872, P < 0.001; validation set AUC = 0.953 vs. 0.832, P < 0.01; independent validation set AUC = 0.928 vs. 0.771, P < 0.001). When the multi-marker panel and CA 19-9 were combined, the diagnostic performance of the combined panel was improved for all sets.
Conclusions:
This multi-marker panel and the combined panel showed statistically significant improvements in diagnostic performance compared with CA 19-9 alone and has the potential to complement CA 19-9 as a diagnostic marker in clinical practice.
Data from The Effect of Corticosteroids on Prostate Cancer Outcome Following Treatment with Enzalutamide: A Multivariate Analysis of the Phase III AFFIRM Trial
Authors: Zhao Jimmy L. , Fizazi Karim , Saad Fred , Chi Kim N. , Taplin Mary-Ellen , Sternberg Cora N. , Armstrong Andrew J. , de Bono Johann S. , Duggan William T. , Scher Howard I.
Published: April 2023

AbstractPurpose:
The clinical impact of concurrent corticosteroid use (CCU) on enzalutamide-treated patients with metastatic castration-resistant prostate cancer (mCRPC) is unknown. We investigated the association of CCU with overall survival (OS), radiographic progression-free survival (rPFS), and time to prostate-specific antigen progression (TTPP) in post-chemotherapy, enzalutamide-treated patients with mCRPC.
Patients and Methods:
Post hoc analysis of AFFIRM (NCT00974311) with patients (n = 1,199) randomized 2:1 to enzalutamide 160 mg/day or placebo. Treatment group, CCU, and known prognostic factors were evaluated for impact on OS, rPFS, and TTPP using a multivariate Cox proportional hazards model. CCU was defined as “baseline” (use started at baseline) or “on-study” (baseline plus use that was started during the trial).
Results:
Enzalutamide significantly improved OS, rPFS, and TTPP independent of baseline CCU but was associated with inferior clinical outcomes when compared with no baseline CCU, including a shorter OS [10.8 months vs. not reached (NR); HR for use vs. no use, 2.13; 95% confidence interval (CI), 1.79–2.54], rPFS (5.2 months vs. 8.0 months; HR, 1.49; 95% CI, 1.29–1.72], and TTPP (4.6 months vs. 5.7 months; HR, 1.50; 95% CI, 1.25–1.81). These findings held in a multivariate analysis adjusting for baseline prognostic factors wherein baseline CCU was independently associated with decreased OS (HR, 1.71; 95% CI, 1.43–2.04; P < 0.0001) and rPFS (HR, 1.28; 95% CI, 1.11–1.48; P = 0.0007).
Conclusions:
Patients with mCRPC benefited from enzalutamide treatment independent of CCU, but CCU was associated with worse baseline prognostic factors and outcomes.
Data from Emergence of Enzalutamide Resistance in Prostate Cancer is Associated with BCL-2 and IKKB Dependencies
Authors: Liang Yi , Jeganathan Sujeeve , Marastoni Stefano , Sharp Adam , Figueiredo Ines , Marcellus Richard , Mawson Amanda , Shalev Zvi , Pesic Aleksandra , Sweet Joan , Guo Haiyang , Uehling David , Gurel Bora , Neeb Antje , He Housheng Hansen , Montgomery Bruce , Koritzinsky Marianne , Oakes Samantha , de Bono Johann S. , Gleave Martin , Zoubeidi Amina , Wouters Bradly G. , Joshua Anthony M.
Published: April 2023

AbstractPurpose:
Although enzalutamide (ENZ) has been widely used to treat de novo or castration-resistant metastatic prostate cancer, resistance develops and disease progression is ultimately inevitable. There are currently no approved targeted drugs to specifically delay or overcome ENZ resistance.
Experimental Design:
We selected several ENZ-resistant cell lines that replicated clinical characteristics of the majority of patients with ENZ-resistant disease. A high-throughput pharmacologic screen was utilized to identify compounds with greater cytotoxic effect for ENZ-resistant cell lines, compared with parental ENZ-sensitive cells. We validated the potential hits in vitro and in vivo, and used knockdown and overexpression assays to study the dependencies in ENZ-resistant prostate cancer.
Results:
ABT199 (BCL-2 inhibitor) and IMD0354 (IKKB inhibitor) were identified as potent and selective inhibitors of cell viability in ENZ-resistant cell lines in vitro and in vivo which were further validated using loss-of-function assays of BCL-2 and IKKB. Notably, we observed that overexpression of BCL-2 and IKKB in ENZ-sensitive cell lines was sufficient for the emergence of ENZ resistance. In addition, we confirmed that BCL-2 or IKKB inhibitors suppressed the development of ENZ resistance in xenografts. However, validation of both BCL-2 and IKKB in matched castration-sensitive/resistant clinical samples showed that, concurrent with the development of ENZ/abiraterone resistance in patients, only the protein levels of IKKB were increased.
Conclusions:
Our findings identify BCL-2 and IKKB dependencies in clinically relevant ENZ-resistant prostate cancer cells in vitro and in vivo, but indicate that IKKB upregulation appears to have greater relevance to the progression of human castrate-resistant prostate cancer.
Data from Immune Activity and Response Differences of Oncolytic Viral Therapy in Recurrent Glioblastoma: Gene Expression Analyses of a Phase IB Study
Authors: Miller Katherine E. , Cassady Kevin A. , Roth Justin C. , Clements Jennifer , Schieffer Kathleen M. , Leraas Kristen , Miller Anthony R. , Prasad Nripesh , Leavenworth Jianmei W. , Aban Inmaculada B. , Whitley Richard J. , Gillespie G. Yancey , Mardis Elaine R. , Markert James M.
Published: April 2023

AbstractPurpose:
Previously, clinical trials of experimental virotherapy for recurrent glioblastoma multiforme (GBM) demonstrated that inoculation with a conditionally replication–competent Δγ134.5 oncolytic herpes simplex virus (oHSV), G207, was safe. Following the initial safety study, a phase Ib trial enrolled 6 adult patients diagnosed with GBM recurrence from which tumor tissue was banked for future studies.
Patients and Methods:
Here, we analyzed tumor RNA sequencing (RNA-seq) data obtained from pre- and posttreatment (collected 2 or 5 days after G207 injection) biopsies from the phase Ib study patients.
Results:
Using a Spearman rank-order correlation analysis, we identified approximately 500 genes whose expression pattern correlated with survival duration. Many of these genes were enriched for the intrinsic IFN-mediated antiviral and adaptive immune functional responses, including immune cell chemotaxis and antigen presentation to T-cells. Furthermore, we show that the expression of several T-cell–related genes was highest in the patient with the longest survival after G207 inoculation.
Conclusions:
Our data support that the oHSV-induced type I IFN production and the subsequent recruitment of an adaptive immune response differed between enrolled patients and showed association with survival duration in patients with recurrent malignant glioma after treatment with an early generation oHSV.
Data from Predictive Biomarkers of Overall Survival in Patients with Metastatic Renal Cell Carcinoma Treated with IFNα ± Bevacizumab: Results from CALGB 90206 (Alliance)
Authors: Nixon Andrew B. , Halabi Susan , Liu Yingmiao , Starr Mark D. , Brady John C. , Shterev Ivo , Luo Bin , Hurwitz Herbert I. , Febbo Phillip G. , Rini Brian I. , Beltran Himisha , Small Eric J. , Morris Michael J. , George Daniel J.
Published: April 2023

AbstractPurpose:
CALGB 90206 was a phase III trial of 732 patients with metastatic renal cell carcinoma (mRCC) comparing bevacizumab plus IFNα (BEV + IFN) with IFNα alone (IFN). No difference in overall survival (OS) was observed. Baseline samples were analyzed to identify predictive biomarkers for survival benefit.
Patients and Methods:
A total of 32 biomarkers were assessed in 498 consenting patients randomly assigned into training (n = 279) and testing (n = 219) sets. The proportional hazards model was used to test for treatment arm and biomarker interactions of OS. The estimated coefficients from the training set were used to compute a risk score for each patient and to classify patients by risk in the testing set. The resulting model was assessed for predictive accuracy using the time-dependent area under the ROC curve (tAUROC).
Results:
A statistically significant three-way interaction between IL6, hepatocyte growth factor (HGF), and bevacizumab treatment was observed in the training set and confirmed in the testing set (P < 0.0001). The model based on IL6, HGF, and bevacizumab treatment was predictive of OS (P < 0.001), with the high- and low-risk groups having a median OS of 10.2 [95% confidence interval (CI), 8.0–13.8] and 34.3 (95% CI, 28.5–40.5) months, respectively. The average tAUROC for the final model of OS based on 100 randomly split testing sets was 0.78 (first, third quartiles = 0.77, 0.79).
Conclusions:
IL6 and HGF are potential predictive biomarkers of OS benefit from BEV + IFN in patients with mRCC. The model based on key biological and clinical factors demonstrated predictive efficacy for OS. These markers warrant further validation in future anti-VEGF and immunotherapy in mRCC trials.

See related commentaries by Mishkin and Kohn, p. 2722 and George and Bertagnolli, p. 2725
Data from Pamiparib Monotherapy for Patients with Germline BRCA1/2-Mutated Ovarian Cancer Previously Treated with at Least Two Lines of Chemotherapy: A Multicenter, Open-Label, Phase II Study
Authors: Wu Xiaohua , Zhu Jianqing , Wang Jing , Lin Zhongqiu , Yin Rutie , Sun Wei , Zhou Qi , Zhang Songling , Wang Danbo , Shi Hong , Gao Yunong , Huang Yi , Li Guiling , Wang Xiuli , Cheng Ying , Lou Ge , Gao Qinglei , Wang Li , Du Xiuping , Pan Mei , Mu Xiyan , Li Li , Li Miao , Mu Song , Kong Beihua
Published: April 2023

AbstractPurpose:
Phase I results of this phase I/II study showed that pamiparib 60 mg twice a day had antitumor activity and an acceptable safety profile in Chinese patients with advanced cancer, including epithelial ovarian cancer.
Patients and Methods:
This open-label phase II study was conducted in China and enrolled adult (≥18 years) patients with platinum-sensitive ovarian cancer (PSOC; disease progression occurring ≥6 months after last platinum treatment) or platinum-resistant ovarian cancer (PROC; disease progression occurring <6 months after last platinum treatment). Eligible patients had known or suspected deleterious germline BRCA mutation (gBRCAmut) and had previously received ≥2 lines of therapy. Pamiparib 60 mg orally twice a day was administered until disease progression, toxicity, or patient withdrawal. The primary endpoint was objective response rate (ORR) assessed by independent review committee (IRC) per RECIST version 1.1.
Results:
In the total patient population (N = 113; PSOC, n = 90; PROC, n = 23), median age was 54 years (range, 34–79) and 25.6% of patients received ≥4 prior systemic chemotherapy lines. Median study follow-up was 12.2 months (range, 0.2–21.5). Eighty-two patients with PSOC and 19 patients with PROC were evaluable for efficacy. In patients with PSOC, 8 achieved a complete response (CR) and 45 achieved a partial response (PR); ORR was 64.6% [95% confidence interval (CI), 53.3–74.9]. In patients with PROC, 6 achieved a PR; ORR was 31.6% (95% CI, 12.6–56.6). Frequently reported grade ≥3 adverse events were hematologic toxicities, including anemia and decreased neutrophil count.
Conclusions:
Pamiparib 60 mg twice a day showed antitumor activity with durable responses in patients with PSOC or PROC with gBRCAmut, and had a manageable safety profile.
Data from Clinicopathologic and Genomic Analysis of TP53-Mutated Endometrial Carcinomas
Authors: Momeni-Boroujeni Amir , Dahoud Wissam , Vanderbilt Chad M. , Chiang Sarah , Murali Rajmohan , Rios-Doria Eric V. , Alektiar Kaled M. , Aghajanian Carol , Abu-Rustum Nadeem R. , Ladanyi Marc , Ellenson Lora H. , Weigelt Britta , Soslow Robert A.
Published: April 2023

AbstractPurpose:
Copy number–high endometrial carcinomas were described by The Cancer Genome Atlas as high-grade endometrioid and serous cancers showing frequent copy-number alterations (CNA), low mutational burden (i.e., non-hypermutant), near-universal TP53 mutation, and unfavorable clinical outcomes. We sought to investigate and compare the clinicopathologic and molecular characteristics of non-hypermutant TP53-altered endometrial carcinomas of four histologic types.
Experimental Design:
TP53-mutated endometrial carcinomas, defined as TP53-mutant tumors lacking microsatellite instability or pathogenic POLE mutations, were identified (n = 238) in a cohort of 1,239 endometrial carcinomas subjected to clinical massively parallel sequencing of 410–468 cancer-related genes. Somatic mutations and CNAs (n = 238), and clinicopathologic features were determined (n = 185, initial treatment planning at our institution).
Results:
TP53-mutated endometrial carcinomas encompassed uterine serous (n = 102, 55.1%), high-grade endometrial carcinoma with ambiguous features/not otherwise specified (EC-NOS; n = 44, 23.8%), endometrioid carcinomas of all tumor grades (n = 28, 15.1%), and clear cell carcinomas (n = 11, 5.9%). PTEN mutations were significantly more frequent in endometrioid carcinomas, SPOP mutations in clear cell carcinomas, and CCNE1 amplification in serous carcinomas/EC-NOS; however, none of these genomic alterations were exclusive to any given histologic type. ERBB2 amplification was present at similar frequencies across TP53-mutated histologic types (7.7%–18.6%). Although overall survival was similar across histologic types, serous carcinomas presented more frequently at stage IV, had more persistent and/or recurrent disease, and reduced disease-free survival.
Conclusions:
TP53-mutated endometrial carcinomas display clinical and molecular similarities across histologic subtypes. Our data provide evidence to suggest performance of ERBB2 assessment in all TP53-mutated endometrial carcinomas. Given the distinct clinical features of serous carcinomas, histologic classification continues to be relevant.
Data from Cell Type–specific Adaptive Signaling Responses to KRASG12C Inhibition
Authors: Solanki Hitendra S. , Welsh Eric A. , Fang Bin , Izumi Victoria , Darville Lancia , Stone Brandon , Franzese Ryan , Chavan Sandip , Kinose Fumi , Imbody Denis , Koomen John M. , Rix Uwe , Haura Eric B.
Published: April 2023

AbstractPurpose:
Covalent inhibitors of KRASG12C specifically target tumors driven by this form of mutant KRAS, yet early studies show that bypass signaling drives adaptive resistance. Although several combination strategies have been shown to improve efficacy of KRASG12C inhibitors (KRASi), underlying mechanisms and predictive strategies for patient enrichment are less clear.
Experimental Design:
We performed mass spectrometry–based phosphoproteomics analysis in KRASG12C cell lines after short-term treatment with ARS-1620. To understand signaling diversity and cell type–specific markers, we compared proteome and phosphoproteomes of KRASG12C cells. Gene expression patterns of KRASG12C cell lines and lung tumor tissues were examined.
Results:
Our analysis suggests cell type–specific perturbation to ERBB2/3 signaling compensates for repressed ERK and AKT signaling following ARS-1620 treatment in epithelial cell type, and this subtype was also more responsive to coinhibition of SHP2 and SOS1. Conversely, both high basal and feedback activation of FGFR or AXL signaling were identified in mesenchymal cells. Inhibition of FGFR signaling suppressed feedback activation of ERK and mTOR, while AXL inhibition suppressed PI3K pathway. In both cell lines and human lung cancer tissues with KRASG12C, we observed high basal ERBB2/3 associated with epithelial gene signatures, while higher basal FGFR1 and AXL were observed in cells/tumors with mesenchymal gene signatures.
Conclusions:
Our phosphoproteomic study identified cell type–adaptive responses to KRASi. Markers and targets associated with ERBB2/3 signaling in epithelial subtype and with FGFR1/AXL signaling in mesenchymal subtype should be considered in patient enrichment schemes with KRASi.
Data from ImmunoPET of Ovarian and Pancreatic Cancer with AR9.6, a Novel MUC16-Targeted Therapeutic Antibody
Authors: Sharma Sai Kiran , Mack Kyeara N. , Piersigilli Alessandra , Pourat Jacob , Edwards Kimberly J. , Keinänen Outi , Jiao Maria S. , Zhao Huiyong , White Brandy , Brooks Cory L. , de Stanchina Elisa , Madiyalakan Madi R. , Hollingsworth Michael A. , Radhakrishnan Prakash , Lewis Jason S. , Zeglis Brian M.
Published: April 2023

AbstractPurpose:
Advances in our understanding of the contribution of aberrant glycosylation to the pro-oncogenic signaling and metastasis of tumor cells have reinvigorated the development of mucin-targeted therapies. Here, we validate the tumor-targeting ability of a novel monoclonal antibody (mAb), AR9.6, that binds MUC16 and abrogates downstream oncogenic signaling to confer a therapeutic response.
Experimental Design:
The in vitro and ex vivo validation of the binding of AR9.6 to MUC16 was achieved via flow cytometry, radioligand binding assay (RBA), and immunohistochemistry (IHC). The in vivo MUC16 targeting of AR9.6 was validated by creating a 89Zr-labeled radioimmunoconjugate of the mAb and utilizing immunoPET and ex vivo biodistribution studies in xenograft models of human ovarian and pancreatic cancer.
Results:
Flow cytometry, RBA, and IHC revealed that AR9.6 binds to ovarian and pancreatic cancer cells in an MUC16-dependent manner. The in vivo radiopharmacologic profile of 89Zr-labeled AR9.6 in mice bearing ovarian and pancreatic cancer xenografts confirmed the MUC16-dependent tumor targeting by the radioimmunoconjugate. Radioactivity uptake was also observed in the distant lymph nodes (LNs) of mice bearing xenografts with high levels of MUC16 expression (i.e., OVCAR3 and Capan-2). IHC analyses of these PET-positive LNs highlighted the presence of shed antigen as well as necrotic, phagocytized, and actively infiltrating neoplastic cells. The humanization of AR9.6 did not compromise its ability to target MUC16-expressing tumors.
Conclusions:
The unique therapeutic mechanism of AR9.6 combined with its excellent in vivo tumor targeting makes it a highly promising theranostic agent. huAR9.6 is poised for clinical translation to impact the management of metastatic ovarian and pancreatic cancers.
Data from cfTrack: A Method of Exome-Wide Mutation Analysis of Cell-free DNA to Simultaneously Monitor the Full Spectrum of Cancer Treatment Outcomes Including MRD, Recurrence, and Evolution
Authors: Li Shuo , Zeng Weihua , Ni Xiaohui , Zhou Yonggang , Stackpole Mary L. , Noor Zorawar S. , Yuan Zuyang , Neal Adam , Memarzadeh Sanaz , Garon Edward B. , Dubinett Steven M. , Li Wenyuan , Zhou Xianghong Jasmine
Published: April 2023

AbstractPurpose:
Cell-free DNA (cfDNA) offers a noninvasive approach to monitor cancer. Here we develop a method using whole-exome sequencing (WES) of cfDNA for simultaneously monitoring the full spectrum of cancer treatment outcomes, including minimal residual disease (MRD), recurrence, evolution, and second primary cancers.
Experimental Design:
Three simulation datasets were generated from 26 patients with cancer to benchmark the detection performance of MRD/recurrence and second primary cancers. For further validation, cfDNA samples (n = 76) from patients with cancer (n = 35) with six different cancer types were used for performance validation during various treatments.
Results:
We present a cfDNA-based cancer monitoring method, named cfTrack. Taking advantage of the broad genome coverage of WES data, cfTrack can sensitively detect MRD and cancer recurrence by integrating signals across known clonal tumor mutations of a patient. In addition, cfTrack detects tumor evolution and second primary cancers by de novo identifying emerging tumor mutations. A series of machine learning and statistical denoising techniques are applied to enhance the detection power. On the simulation data, cfTrack achieved an average AUC of 99% on the validation dataset and 100% on the independent dataset in detecting recurrence in samples with tumor fractions ≥0.05%. In addition, cfTrack yielded an average AUC of 88% in detecting second primary cancers in samples with tumor fractions ≥0.2%. On real data, cfTrack accurately monitors tumor evolution during treatment, which cannot be accomplished by previous methods.
Conclusions:
Our results demonstrated that cfTrack can sensitively and specifically monitor the full spectrum of cancer treatment outcomes using exome-wide mutation analysis of cfDNA.
Data from Phase Ib Dose Expansion and Translational Analyses of Olaparib in Combination with Capivasertib in Recurrent Endometrial, Triple-Negative Breast, and Ovarian Cancer
Authors: Westin Shannon N. , Labrie Marilyne , Litton Jennifer K. , Blucher Aurora , Fang Yong , Vellano Christopher P. , Marszalek Joseph R. , Feng Ningping , Ma XiaoYan , Creason Allison , Fellman Bryan , Yuan Ying , Lee Sanghoon , Kim Tae-Beom , Liu Jinsong , Chelariu-Raicu Anca , Chen Tsun Hsuan , Kabil Nashwa , Soliman Pamela T. , Frumovitz Michael , Schmeler Katheleen M. , Jazaeri Amir , Lu Karen H. , Murthy Rashmi , Meyer Larissa A. , Sun Charlotte C. , Sood Anil K. , Coleman Robert L. , Mills Gordon B.
Published: April 2023

AbstractPurpose:
On the basis of strong preclinical rationale, we sought to confirm recommended phase II dose (RP2D) for olaparib, a PARP inhibitor, combined with the AKT inhibitor capivasertib and assess molecular markers of response and resistance.
Patients and Methods:
We performed a safety lead-in followed by expansion in endometrial, triple-negative breast, ovarian, fallopian tube, or peritoneal cancer. Olaparib 300 mg orally twice daily and capivasertib orally twice daily on a 4-day on 3-day off schedule was evaluated. Two dose levels (DL) of capivasertib were planned: 400 mg (DL1) and 320 mg (DL-1). Patients underwent biopsies at baseline and 28 days.
Results:
A total of 38 patients were enrolled. Seven (18%) had germline BRCA1/2 mutations. The first 2 patients on DL1 experienced dose-limiting toxicities (DLT) of diarrhea and vomiting. No DLTs were observed on DL-1 (n = 6); therefore, DL1 was reexplored (n = 6) with no DLTs, confirming DL1 as RP2D. Most common treatment-related grade 3/4 adverse events were anemia (23.7%) and leukopenia (10.5%). Of 32 evaluable subjects, 6 (19%) had partial response (PR); PR rate was 44.4% in endometrial cancer. Seven (22%) additional patients had stable disease greater than 4 months. Tumor analysis demonstrated strong correlations between response and immune activity, cell-cycle alterations, and DNA damage response. Therapy resistance was associated with receptor tyrosine kinase and RAS-MAPK pathway activity, metabolism, and epigenetics.
Conclusions:
The combination of olaparib and capivasertib is associated to no serious adverse events and demonstrates durable activity in ovarian, endometrial, and breast cancers, with promising responses in endometrial cancer. Importantly, tumor samples acquired pre- and on-therapy can help predict patient benefit.
Data from Deuterium Metabolic Imaging Reports on TERT Expression and Early Response to Therapy in Cancer
Authors: Batsios Georgios , Taglang Céline , Tran Meryssa , Stevers Nicholas , Barger Carter , Gillespie Anne Marie , Ronen Sabrina M. , Costello Joseph F. , Viswanath Pavithra
Published: April 2023

AbstractPurpose:
Telomere maintenance is a hallmark of cancer. Most tumors maintain telomere length via reactivation of telomerase reverse transcriptase (TERT) expression. Identifying clinically translatable imaging biomarkers of TERT can enable noninvasive assessment of tumor proliferation and response to therapy.
Experimental Design:
We used RNAi, doxycycline-inducible expression systems, and pharmacologic inhibitors to mechanistically delineate the association between TERT and metabolism in preclinical patient-derived tumor models. Deuterium magnetic resonance spectroscopy (2H-MRS), which is a novel, translational metabolic imaging modality, was used for imaging TERT in cells and tumor-bearing mice in vivo.
Results:
Our results indicate that TERT expression is associated with elevated NADH in multiple cancers, including glioblastoma, oligodendroglioma, melanoma, neuroblastoma, and hepatocellular carcinoma. Mechanistically, TERT acts via the metabolic regulator FOXO1 to upregulate nicotinamide phosphoribosyl transferase, which is the key enzyme for NAD+ biosynthesis, and the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase, which converts NAD+ to NADH. Because NADH is essential for pyruvate flux to lactate, we show that 2H-MRS–based assessment of lactate production from [U-2H]-pyruvate reports on TERT expression in preclinical tumor models in vivo, including at clinical field strength (3T). Importantly, [U-2H]-pyruvate reports on early response to therapy in mice bearing orthotopic patient-derived gliomas at early timepoints before radiographic alterations can be visualized by MRI.
Conclusions:
Elevated NADH is a metabolic consequence of TERT expression in cancer. Importantly, [U-2H]-pyruvate reports on early response to therapy, prior to anatomic alterations, thereby providing clinicians with a novel tool for assessment of tumor burden and treatment response in cancer.
Data from Assessing CSF ctDNA to Improve Diagnostic Accuracy and Therapeutic Monitoring in Breast Cancer Leptomeningeal Metastasis
Authors: Fitzpatrick Amanda , Iravani Marjan , Mills Adam , Childs Lucy , Alaguthurai Thanussuyah , Clifford Angela , Garcia-Murillas Isaac , Van Laere Steven , Dirix Luc , Harries Mark , Okines Alicia , Turner Nicholas C. , Haider Syed , Tutt Andrew N.J. , Isacke Clare M.
Published: April 2023

AbstractPurpose:
Cerebrospinal fluid (CSF) cytology is the gold standard diagnostic test for breast cancer leptomeningeal metastasis (BCLM), but has impaired sensitivity, often necessitating repeated lumbar puncture to confirm or refute diagnosis. Further, there is no quantitative response tool to assess response or progression during BCLM treatment.
Experimental Design:
Facing the challenge of working with small-volume samples and the lack of common recurrent mutations in breast cancers, cell-free DNA was extracted from the CSF and plasma of patients undergoing investigation for BCLM (n = 30). ctDNA fraction was assessed by ultra-low-pass whole genome sequencing (ulpWGS), which does not require prior tumor sequencing.
Results:
In this proof-of-concept study, ctDNA was detected (fraction ≥0.10) in the CSF of all 24 patients with BCLM+ (median ctDNA fraction, 0.57), regardless of negative cytology or borderline MRI imaging, whereas CSF ctDNA was not detected in the six patients with BCLM− (median ctDNA fraction 0.03, P < 0.0001). Plasma ctDNA was only detected in patients with extracranial disease progression or who had previously received whole brain radiotherapy. ctDNA fraction was highly concordant with mutant allele fraction measured by tumor mutation-specific ddPCR assays (r = 0.852; P < 0.0001). During intrathecal treatment, serial monitoring (n = 12 patients) showed that suppression of CSF ctDNA fraction was associated with longer BCLM survival (P = 0.034), and rising ctDNA fraction was detectable up to 12 weeks before clinical progression.
Conclusions:
Measuring ctDNA fraction by ulpWGS is a quantitative marker demonstrating potential for timely and accurate BCLM diagnosis and therapy response monitoring, with the ultimate aim to improve management of this poor-prognosis patient group.
Data from First Clinical Results of Fluorescence Lifetime-enhanced Tumor Imaging Using Receptor-targeted Fluorescent Probes
Authors: Pal Rahul , Hom Marisa E. , van den Berg Nynke S. , Lwin Thinzar M. , Lee Yu-Jin , Prilutskiy Andrey , Faquin William , Yang Eric , Saladi Srinivas V. , Varvares Mark A. , Rosenthal Eben L. , Kumar Anand T.N.
Published: April 2023

AbstractPurpose:
Fluorescence molecular imaging, using cancer-targeted near infrared (NIR) fluorescent probes, offers the promise of accurate tumor delineation during surgeries and the detection of cancer specific molecular expression in vivo. However, nonspecific probe accumulation in normal tissue results in poor tumor fluorescence contrast, precluding widespread clinical adoption of novel imaging agents. Here we present the first clinical evidence that fluorescence lifetime (FLT) imaging can provide tumor specificity at the cellular level in patients systemically injected with panitumumab-IRDye800CW, an EGFR-targeted NIR fluorescent probe.
Experimental Design:
We performed wide-field and microscopic FLT imaging of resection specimens from patients injected with panitumumab-IRDye800CW under an FDA directed clinical trial.
Results:
We show that the FLT within EGFR-overexpressing cancer cells is significantly longer than the FLT of normal tissue, providing high sensitivity (>98%) and specificity (>98%) for tumor versus normal tissue classification, despite the presence of significant nonspecific probe accumulation. We further show microscopic evidence that the mean tissue FLT is spatially correlated (r > 0.85) with tumor-specific EGFR expression in tissue and is consistent across multiple patients. These tumor cell-specific FLT changes can be detected through thick biological tissue, allowing highly specific tumor detection and noninvasive monitoring of tumor EFGR expression in vivo.
Conclusions:
Our data indicate that FLT imaging is a promising approach for enhancing tumor contrast using an antibody-targeted NIR probe with a proven safety profile in humans, suggesting a strong potential for clinical applications in image guided surgery, cancer diagnostics, and staging.