bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical activity of camizestrant, a next-generation SERD, versus fulvestrant in patients with a detectable ESR1 mutation: Exploratory analysis of the SERENA-2 phase 2 trial.
Authors: Oliveira Mafalda , Pominchuk Denys , Hamilton Erika P. , Kulyaba Yaroslav , Melkadze Tamar , Neven Patrick , Nemsadze Gia , Andabekov Timur , Semegen Yuriy , Hotko Yevhen , Zamagni Claudio , Vladimirov Vladimir , Bennett Maxine , Ciardullo Carmela , Klinowska Teresa , Lindemann Justin P O , McEwen Robert , Morrow Christopher J. , Arkania Ekaterine 
Published: June 2023

1066 Background: Camizestrant, a next-generation oral selective estrogen receptor antagonist and degrader (ngSERD), was compared at two dose levels to fulvestrant 500 mg (F) in post-menopausal women with advanced ER+, HER2˗ breast cancer with disease recurrence or progression after ≤1 endocrine therapy in the advanced setting in the Phase 2 randomized SERENA-2 study (NCT04214288). Camizestrant demonstrated statistically significant and clinically meaningful benefit vs F in progression-free survival (PFS) in the overall study population (Oliveira M et al. SABCS 2022 Annual Meeting. Abstract GS3-02.). Methods: Baseline circulating tumour DNA was collected at screening and/or Cycle 1 Day 1 and analysed by next-generation sequencing. A post hoc exploratory analysis compared investigator assessed PFS with camizestrant (data from 75 and 150 mg combined) vs F in patients with detectable baseline ESR1 (the gene that encodes ERα) hotspot mutations ( ESR1m). Patients were divided into subgroups based on whether 1 or >1 ESR1m variants were detected, the specific ESR1m, and whether mutations were detected in BRCA1/2 or the MAPK pathway. The most prevalent mutations are presented. A Cox proportional hazards model was used to compare PFS. Results: 48/147 (32.7%) patients treated with camizestrant and 35/73 (47.9%) treated with F had a detectable ESR1m in at least 1 baseline sample. ESR1m were detected in 6/9 (67%) patients with a BRCA1/2 mutation and 5/26 (19%) with a MAPK pathway alteration; however, the numbers were too small to analyse efficacy in these subgroups. Conclusions: Camizestrant showed improved outcome vs F in patients with a detectable ESR1m at baseline and in the subgroups tested. The greatest median PFS improvement was seen in patients where a single ESR1m variant was detected, suggesting that early intervention upon detection of an ESR1m may provide the maximum patient benefit for camizestrant, a hypothesis that is being tested in the SERENA-6 clinical trial (NCT04964934). Clinical trial information: NCT04214288 . [Table: see text]
Phase 1/2 dose expansion study evaluating first-in-class eIF4A inhibitor zotatifin in patients with ER+ metastatic breast cancer.
Authors: Rosen Ezra , Sharma Manish , Berz David , Caswell-Jin Jennifer Lee , Spira Alexander I. , Fulgar Georgina A. , Densel Mark , Rana Nawaid , Sperry Samuel , Warner Douglas , Meric-Bernstam Funda ,   ASCO Authors' Group
Published: June 2023

1080 Background: Zotatifin (eFT226) is a first-in-class, potent and sequence selective inhibitor of RNA helicase eIF4A that promotes a stable mRNA:eIF4A:drug ternary complex at specific polypurine motifs within the 5’-UTR, preventing translation of select transcripts. In preclinical models zotatifin treatment simultaneously down-regulated translation of numerous oncogenes including CDK4, ERα, ERBB2, KRAS, and CCND1. Methods: Following a 3+3 dose escalation portion of the protocol (Part 1), Part 2 is a Simon’s two-stage design of cohorts of up to 18 patients (pts) with ER+ metastatic breast cancer enrolled at the recommended phase 2 dose of zotatifin (0.07 mg/kg IV two weeks on/one week off) in combination with fulvestrant (ful) (ECBF: Expansion, Combination, Breast, Ful) or in combination with ful and abemaciclib (abema) (ECBF+A: Expansion, Combination, Breast, Ful + Abema). Key eligibility criteria included at least one line of therapy for advanced/metastatic disease, progression on hormone therapy, and in addition, the ECBF cohort required prior CDK 4/6 inhibitor (CDKI). Primary endpoint was objective response rate (ORR) per RECIST v1.1. Additional endpoints included safety, other efficacy analyses, and for Parts 1 and 2, characterization of pharmacodynamic (PD) markers and pharmacokinetics. Results: As of a data cut-off of Jan 31, 2023, 18 pts were enrolled in each cohort. Median prior metastatic lines of therapy were 3 and 7 in ECBF+A and ECBF, respectively. In 16 evaluable pts in ECBF+A cohort, there were two confirmed partial responses (PR), two additional PRs awaiting confirmatory scans, and 8 pts with best overall response (OR) of stable disease (SD). All pts with PR/unconfirmed PR received prior CDKI and ful, including one pt with disease progression on combination abema and ful as the last therapy prior to enrollment. In 18 evaluable pts in ECBF, there was one confirmed PR and six SD as best OR. There were no dose-limiting toxicities or grade (Gr) 5 adverse events (AEs) in either cohort. In ECBF+A the most common AEs (all Gr 1/2) were diarrhea (44%) and nausea (31%) and 21% of pts had Gr 3/4 AEs. The most common AEs in ECBF (all Gr 1/2) were nausea (39%) and constipation (27%), and 28% of pts had Gr 3/4 AEs. Blood-based PD markers and ctDNA in Part 1 showed dose-dependent evidence of target engagement and anti-tumor activity. Conclusions: In dose expansion cohorts of heavily pre-treated metastatic breast cancer pts, eIF4A inhibitor zotatifin showed evidence of anti-tumor activity in combination with fulvestrant and abemaciclib and had a favorable safety profile consisting of primarily grade 1/2 adverse events. Clinical trial information: NCT04092673 .
Discovery of CDK4/6 bifunctional degraders for ER+/HER2- breast cancer.
Authors: Majeski Hannah , Okano Akinori , Pasis Angela , Carlson Casey , Shakya Arvind , Huang Shenlin , Chourasia Aparajita Hoskote , Fung Leah M. , Liu Qiao 
Published: June 2023

1083 Background: CDK4/6 inhibitors (CDK4/6i) such as palbociclib and ribociclib are used to treat ER+/HER2- breast cancer, but patients can develop resistance via many mechanisms, several of which converge on the upregulation of CDK6. This has been shown to limit the effectiveness of CDK4/6i in ER+ breast cancer with up to 20% patients exhibiting innate resistance and up to 70% patients developing acquired resistance after 3 years on therapy (Scheidemann, 2021, doi:10.3390/ijms222212292). Methods: To address this limitation, we utilized our PRODEGY platform of Cereblon (CRBN) binders to synthesize CRBN mediated CDK4/6 bifunctional degraders to potently inhibit tumor growth for treatment of naïve ER+/HER2- breast cancer and CDK4/6i resistant tumors. Results: Target degradation by immunoblot analysis of the triple negative breast cancer (TNBC) cell line, MDA-MB-231, treated with our CDK4/6 bifunctional degraders for 6 hours showed up to 85% degradation of CDK4 and CDK6 with DC50s of 1-100nM. CDK4/6 phosphorylates the protein RB which releases the transcription factor E2F, inducing the expression of genes which promote cell cycle progression. Analysis of RB phosphorylation by in-cell western upon 24 hours of CDK4/6 degrader treatment showed phospho-RB IC50s at <30nM. Cell cycle analysis by staining with propidium iodide after 24 hours of treatment with CDK4/6 degraders induced G0/G1 cell cycle arrest at concentrations as low as 10nM. We used a 2D colony formation assay (CFA) as a readout for inhibition of proliferation by cell cycle arrest. Our CDK4/6 degraders showed potent inhibition of cell proliferation with CFA IC50s of <100nM in TNBC cell lines and <25nM in ER+ cell lines, including MCF7, T47D and ZR751 compared to CDK4/6i which ranged from 200nM to 500nM in MCF7 cells. We demonstrated that our CDK4/6 bifunctional degraders were significantly more potent in vitro than the CDK4/6i ribociclib and palbociclib, and the increased activity was due to CRBN mediated target degradation. Our CDK4/6 bifunctional degraders display excellent pharmacokinetic properties in mice with half-lives between 2-10 hours, oral bioavailability between 50-96%. MCF7 xenograft results with our proof-of-concept CDK4/6 degrader showed dose-dependent tumor growth inhibition and greater potency compared to the clinical CDK4/6i ribociclib. We saw tumor regression with our degrader at higher doses which we did not see at any dose of CDK4/6i. Conclusions: Our CDK4/6 bifunctional degraders display excellent single agent activity in vitro and in vivo particularly in comparison to clinically approved CDK4/6i, indicating that using a degrader approach to targeting this pathway may be more effective than current inhibitor therapies.
Olaparib (O) + ceralasertib (C) in patients (pts) with metastatic triple-negative breast cancer (mTNBC): Translational analysis of the VIOLETTE trial.
Authors: Lukashchuk Natalia , Punie Kevin , Nowecki Zbigniew , Im Seock-Ah , Armstrong Anne C. , Jacot William , Kim Jee Hyun , Webster Marc A. , Balmaña Judith , Delaloge Suzette , Casson Ed , Loembe Bienvenu , Dean Emma , Armenia Joshua , Tutt Andrew NJ 
Published: June 2023

1087 Background: O is a PARP inhibitor approved in a number of tumor types and for use in pts with germline (g) mutations in BRCA ( BRCAm) HER2-negative metastatic breast cancer. C is an inhibitor of DDR kinase ATR. Analysis of VIOLETTE (NCT03330847) in pts with mTNBC showed no improvement in PFS with a combination of C and O vs. O, whether in the context of pathogenic BRCAm, non-BRCA HRR pathway mutations (HRRm), or homologous recombination repair (HRR) wildtype (HRRwt) tumors. We report an exploratory translational analysis of predictive genomic biomarkers of response to O ± C beyond g BRCAm. Methods: Pts received O (300 mg twice daily) ± C (160 mg daily; days 1–7; 28-day cycles) as a second- or third-line treatment option. Pts were prospectively stratified into molecular strata based on pathogenic/likely pathogenic alterations in BRCA1/2 ( BRCAm; n=83) or in ≥1 of 13 selected non- BRCA HRR genes (HRRm; n=40) or HRRwt (n=103) using FoundationOneCDx (F1CDx) sequencing assay of archival tumor sample. Advanced genomic analysis included genome-wide loss of heterozygosity (a marker of HRR deficiency [HRD] with a 16% cut-off to define HRD+ [≥16%] vs HRD− [<16%]), zygosity, and predicted g/somatic (s) status of BRCA and HRR alterations based on a validated computational FMI algorithm. Efficacy was evaluated by blinded independent central review of PFS, RECIST response, and best percentage change from baseline in target lesion size. Results: Out of evaluable pts for origin of BRCAm (n=42), 81% (n=34) were of germline, and 19% (n=8) were of somatic origin. Of pts evaluable for zygosity (n=48), most BRCA alterations were biallelic (90%; n=43), and of pts evaluable for HRD status (n=47), most were HRD+ (94%; n=44). Of HRRwt pts evaluable for HRD status (n=79), 57% were HRD+ (n=45). Responses by biomarker are shown. Responses in BRCAm pts were seen in all subgroups (zygosity, HRD, or g/s origin of mutation), including s BRCAm (ORR: n=3/4 on O; n=2/4 on O+C). Responses were also seen in patients with heterozygous BRCA alteration (n=3/5) by genomic result and in BRCAm/HRD− pts (n=3/3) across both arms. Pts with select HRR genes ( BARD1, RAD51C/D, ATM, CDK12) also achieved responses on O or O+C. Conclusions: Responses to O were seen in pts with both g BRCAm and s BRCAm. Beyond BRCAm, the efficacy of O was observed in pts with alterations in select HRR genes, such as BARD1 or RAD51C/D; further clinical investigation is required. Small sample size and HRD analysis performed on archival tumor samples should be considered limitations. Clinical trial information: NCT03330847 . [Table: see text]
Olaparib (O) in advanced triple negative breast cancer (aTNBC) patients (pts) with BRCA1/2 promoter methylation: GEICAM/2015-06 study (COMETA-Breast).
Authors: De La Haba Juan , Anton Antonio , Quiroga Vanesa , Guerrero Angel , Andrés Raquel , Mele Mireia , Gonzalez- Santiago Santiago , Perez-Fidalgo Jose Alejandro , Ramon y Cajal Teresa , Escudero Maria Jose , Bezares Susana , Caballero Rosalia , Rojo Federico 
Published: June 2023

1093 Background: Epigenetic silencing by aberrant BRCA1/2 promoters’ methylation ( BRCA-meth) can be responsible for a dysfunctional BRCA protein. BRCA-meth occurs in 15-57% of TNBC pts. BRCA-meth breast cancer (BC) display pathologic features and genetic profiles like germline BRCA1/2-mutated (g BRCA1/2m) carriers. O is a PARP inhibitor approved for treating g BRCAm HER2-negative advanced BC (aBC) pts. These are the results of a phase II study assessing the O efficacy in aTNBC pts with BRCA1/2-meth (NCT03205761). Methods: We included aTNBC pretreated pts (≥1 line) with centrally confirmed somatic BRCA1/2-meth (in most recent lesion(s) available) and no g BRCA1/2m. O 300mg b.i.d. was administered. BRCA1/2 CpG island was considered methylated if value was ≥25%. Overall response rate (ORR) (complete response [CR] + partial response [PR]) according to RECIST 1.1) was the primary objective. Thirty-one evaluable pts were required based on an optimal 2-stage Simon’s design (α error=0.05, 1-β error=80%), estimating an ORR increase of 24%, with a null hypothesis of 30%. Whole exome/transcriptome and 105-genes NGS assays (Tempus xE & xF) were performed on pretreatment tumor and sequential ctDNA of a long-term responder. Results: Eleven pts received ≥1 cycle of O (ITT population). Median age was 51 years (37-64), and 8 pts were postmenopausal. All M0 pts at diagnosis had neo-/adjuvant chemotherapy (CT). Median O exposure duration was 8 (1-88) weeks and relative dose-intensity was 97% (76-100), with any dose modifications in 6 pts. ORR was 9% (1 PR/11; 95% CI, 0.2-41). Clinical benefit rate (CR + PR + stable disease of any duration) was 36% (4/11; 95% CI, 11-69). Most pts (n=9) discontinued O due to BC progression. Median PFS was 2 months (95% CI, 1-4), and median OS was 9 months (95% CI, 1-14). One pt with confirmed PR was on O for >20 months. AEs were reported in 3 pts in line with O safety profile. No AE led to O discontinuation and no SAEs were reported. The statistical assumptions for the 1st Simon’s model stage were not met (≥ 4/12 pts with CR or PR), so the recruitment did not proceed onto the 2nd stage. Preliminary NGS analysis on the long-term responder identified alterations on tumor (TP53, BCL11A, MYC) and on-treatment ctDNA (PMS2). Conclusions: In this proof-of-concept study, O did not show clinically nor statistically significant antitumor activity in pretreated aTNBC pts with BRCA1/2-meth . Clinical trial information: NCT03205761 . [Table: see text]
Efficacy of oral selective estrogen receptor degraders (SERD)s in the treatment of estrogen receptor positive (ER+), HER2-negative metastatic breast cancer (MBC): A stratified analysis of the ESR1 wild type (wt) and mutant (mt) subgroups.
Authors: Zhao Joseph J , Wong Zhun Hong Nicky , Yap Dominic Wei Ting , Ong Rebecca Jia Min , Sundar Raghav , Lim Joline Si Jing , Dawood Shaheenah S. 
Published: June 2023

1096 Background: Oral SERDs are a novel drug class developed to counteract endocrine resistance due to ESR1 mutations. Several SERDs have emerged from phase 2 and 3 trials, and the FDA has most recently limited approval for Elacestrant to patients with ESR1mt tumours despite PFS benefit in the overall population. Questions remain on whether patients with ESR1wt tumours stand to benefit from SERDs. We conducted an IPD meta-analysis of the trials EMERALD, SERENA2, ACELERA and AMEERA3 to compare survival outcomes of SERDs in the 2nd or 3rd line setting against endocrine therapy (ET), using KMSubtraction to unveil HRs of unreported ESR1wt subgroups from AMEERA3 and EMERALD. Meta-analysis results were stratified by ESR1 status. Methods: RCTs investigating the efficacy of novel SERDs versus ET for ER+, HER2- MBC, and which reported the Kaplan Meier (KM) plots of progression free survival (PFS) were selected after a systematic search of Embase and PubMed from inception until January 21,2023. A graphical reconstructive algorithm was applied to estimate time-to-event outcomes from reported KM plots in all overall and reported subgroup cohorts, deriving IPD. A bipartite matching algorithm, KMSubtraction was used to subtract patients in the reported subgroup from the overall cohort, to derive survival data for unreported ESR1wt subgroups. An IPD meta-analysis was then performed, pooling data by ESR1 mutation. Results: A total of 1216 patients were included in this analysis. In the pooled analysis of the overall cohort, PFS benefit was observed with SERDs compared to treatment of physician's choice (TPC) (HR 0.787, 95%CI 0.683-0.908, p<0.001). In the ESR1mt subgroup SERDs demonstrated improved PFS (HR 0.557, 95%CI 0.440-0.705, p<0.001) compared with TPC. In the ESR1wt subgroup, SERDs demonstrated no significant PFS benefit (HR 0.948, 95%CI 0.790-1.137, p=0.565) when compared to TPC. KMSubtraction was implemented on AMEERA3 to reveal survival data in ESR1wt subgroup. Amcenestrant revealed no significant PFS difference in the ESR1wt population (HR 1.197, 95% CI 0.857-1.670, p=0.291) when compared to ET. Additionally, a separate analysis of EMERALD was performed using KMSubtraction to derive survival data of the ESR1wt subgroup comparing Elacestrant vs Fulvestrant. No significant PFS difference was observed between the 2 agents in the ESR1wt population (HR 0.832, 95% CI 0.587-1.178, p=0.299). Conclusions: Our results suggest that PFS benefit in the overall population is mainly driven by the ESR1mt subgroup. These findings are in line with the recent FDA approval of Elacestrant for patients with ESR1mt tumours. [Table: see text]
Phase II study of trifluridine/tipiracil (FTD/TPI) in HER2-negative metastatic breast cancers with or without prior exposure to fluoropyrimidines.
Authors: Lim Joline Si Jing , Ow Samuel Guan Wei , Wong Andrea , Lee Matilda , Chan Gloria HJ , Low Jia Li , Sundar Raghav , Choo Joan RE , Tai Bee Choo , Lee Soo-Chin 
Published: June 2023

1099 Background: Fluoropyrimidines are commonly used in the treatment of patients (pts) with metastatic breast cancers (MBC). FTD/TPI is an oral drug combination of trifluridine with tipiracil, a thymidine phosphorylase inhibitor preventing rapid degradation of trifluridine, thus allowing for increased exposure to active agent, and has showed activity in pts with colorectal and gastric cancers despite prior exposure to fluoropyrimidines. We investigate the role of FTD/TPI in MBC pts with (Cohort A) or without (Cohort B) prior exposure to fluoropyridines in a single arm phase II study. Methods: Pts were treated with FTD/TPI, and enrolled first into a lead-in dose confirmation phase, followed by two parallel cohorts based on prior exposure to fluoropyrimidines. Primary objectives for each cohort included determination of progression-free survivals (PFS), and secondary objectives included determination of objective response rates (ORR), safety and tolerability. Results: A total of 74 pts were recruited (42 for Cohort A, 32 for Cohort B), of whom 4 belonged to lead-in phase. Dosing was confirmed at FTD/TPI 35mg/m2 days 1-5 and 8-12 of 4-weekly cycles based on lead-in phase with no dose-limiting toxicities observed, and recruitment then proceeded in 2 parallel cohorts. All pts were evaluable for toxicity and survival analyses, and 72 were evaluable for ORR. Median age at enrolment was 62 years (range 32-85), with median of 4 (range 0-14) prior lines therapy in the metastatic setting, and 47% had de novo metastatic disease. Median PFS was 5.7 months (95% CI 3.8 to 8.3) and 9.4 months (95% CI 5.5 to 14.0) respectively in Cohorts A and B. Similar response rates were observed regardless of prior exposure to fluoropyrimidine, with ORR of 19.5% (95% CI 8.8 to 34.9) and 16.1% (95% CI 5.5 to 33.7) in Cohorts A and B, with 6-month clinical benefit rates of 56.1% (95% CI 39.7 to 71.5) and 61.3% (95% CI 42.2 to 78.2) respectively. Safety profile was consistent with known toxicities of FTD/TPI, with most common treatment-related adverse events of neutropenia, fatigue, nausea and anorexia. 64% of pts required dose modifications during study treatment, most commonly due to neutropenia, that could be overcome by dose reduction or prolongation from 4- to 5-weekly cycles. Only 1 pt required discontinuation due to toxicity from therapy. Conclusions: FTD/TPI showed promising anti-tumor activity with meaningful clinical benefit even among pts with prior exposure to fluoropyrimidines, and has a reasonable toxicity profile with appropriate dose modification. An oral chemotherapy option with good disease control provides an attractive treatment alternative to pts with MBC where quality of life is paramount, warranting further investigation in randomised studies. Clinical trial information: NCT04280536 .
Differential burnout by race, sex, and sexual orientation in academic oncology.
Authors: Odei Bismarck , Velazquez Manana Ana I. , Pandya Sankalp , Dandar Valerie M , Suneja Gita , Chino Fumiko 
Published: June 2023

11000 Background: Burnout is a concern in medicine with negative effects on physician wellbeing, workforce retention, and patient outcomes. Research has shown that rising burnout can lead to medical errors, lower patient satisfaction, and decreased professional work effort. The presence of burnout in oncology is well documented, however it is unclear if burnout affects all groups equally in academic oncology. Methods: We obtained national faculty data from the Association of American Medical Colleges StandPoint Faculty Engagement Survey, conducted 2017-2020 (overall response rate 64%). Burnout was considered any response endorsing at least “one or more symptoms of burnout”. Self-reported workplace culture was assessed for key factors: collegiality, diversity, faculty wellness, and recruitment/retention of underrepresented in medicine (UiM) faculty. Faculty demographics included age, sex, race/ethnicity, sexual orientation (heterosexual, bisexual, lesbian/gay), rank, degree, and any department or institutional leadership role. Multivariate analysis (MVA) identified factors associated with faculty burnout. Results: A total of 724 academic oncologists were identified. Most were male (58%) and identified as heterosexual (95%). Race/ethnicity were mostly White (65%), with 29% Asian, 2% Black, and 3% Hispanic/Latino; 7% were considered UiM. Most (53%) were senior faculty; 37% had a leadership role. Overall, 22% reported burnout. Self-identified lesbian/gay/bisexual faculty had the highest rate of burnout (43% vs 21%, p = 0.0005) followed by female faculty (31% vs 16% men, p = < 0.0001). Asian faculty had the lowest burnout rates (12%) followed by White and Hispanic (both 26%), Black (33%), and multi-racial physicians (50%, p = 0.003 for comparisons). Pooled UiM had numerically higher burnout but this was not statistically significant (30% vs 22%, p = NS). On MVA, lesbian/gay/bisexual (OR = 3.56, 95%CI 1.55-8.18, p = 0.003) and female (OR = 2.32, 95%CI 1.51-3.56, p < 0.0001) faculty had increased odds of burnout. Most agreed that their institution cultivates collegiality (80%), diversity (73%), and faculty wellness (53%); men were more likely to endorse positive diversity (77% vs 68% women, p = 0.004). Most agreed their institution was successful in recruiting (63%) and retaining (58%) UiM faculty, however non-UiM were more likely to agree with this for recruitment (64% vs 46% UiM, p = 0.01) and retention (50% vs 42% UiM, p = 0.01). Conclusions: Nearly 1 in 4 oncologists report burnout with self-identified female and lesbian/gay/bisexual faculty at the highest risk. Additionally, in general, men and non-UiM faculty were more likely to feel their workplace culture was favorable. Urgent and tailored interventions at the institutional and departmental level will be critical to address both drivers of faculty burnout and the impact of burnout on attrition and career trajectory for marginalized and minoritized groups.