bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterizing telomerase reverse transcriptase (TERT) promoter mutations (mut) across sex, race, and cancer types.
Authors: El Zarif Talal , Machaalani Marc , Nawfal Rashad , Xie Wanling , Choueiri Toni K. , Pomerantz Mark 
Published: June 2023

3122 Background: TERT promoter mut. have been evaluated as a predictive biomarker for patients (pts) receiving immune checkpoint inhibitors. Understanding the prevalence of TERT promoter mut. by sex, race, and cancer type is essential for optimizing its use. Methods: Pts who underwent next-generation sequencing at Dana-Farber Cancer Institute and Memorial Sloan Kettering Cancer Center were identified from the AACR Genomics Evidence Neoplasia Information Exchange (GENIE) registry v11.0. Self-reported race and sex data were extracted for ten cancer types with the highest prevalence of TERT promoter mut. The strength of associations with TERT promoter mut. was quantified by Odds ratios (ORs) and two-sided Fisher’s exact tests, along with FDR-adjusted q-values using the Benjamini-Hochberg method. Results: We identified 31,925 pts – 87.6% (27,970) self-identified as White, 7.1% (2,273) Asian, and 5.3% (1,682) Black. TERT promoter mut. were present in 17% (5,470) tumors, including 56% (1,346/2,411) bladder cancers, 43% (966/2,243) melanomas, 41% (395/959) thyroid cancers, and 23% (183/782) head and neck cancers (HNC). TERT promoter mut. were significantly higher in males vs. females in melanoma, cancer of unknown primary (CUP), hepatobiliary (HPB), and thyroid cancers. In contrast, males harbored fewer mut. vs. females with HNC. Interestingly, TERT promoter mut. varied by race. Mut. frequency was significantly higher in White pts with melanoma (44%, n=964/2176) compared to Asian and Black pts (2.9%, n= 2/67) (OR=25.8; 95% CI = 6.9 - 217, p<0.0001). Asian males with HNC (37%, n= 22/60) were enriched for TERT promoter mut. vs. White males (19%, n= 93/489) (OR = 2.5; 95% CI = 1.4 - 4.4; q=0.03). Within HNC tumors, oral cavity (OC) tumors (44.3%, n= 85/192) were associated with higher TERT promoter mut. vs. other HNC subtypes (16.6%, n= 98/590) (OR = 4.4; 95% CI = 3.03 - 6.26; p<0.0001). Asian pts with OC (70%, n=14/20) harbored more mut. vs. White pts with OC (41.4%, n=70/169) (OR = 3.3; 95% CI = 1.2 - 9; p<0.05). Conclusions: Our study demonstrates differences in the distribution of TERT promoter mut. by sex, race, and cancer type. Considering these variations is crucial for future clinical trial design and biomarker studies. [Table: see text]
Predictive biomarker for cisplatin in prospective phase 2 of liposomal cisplatin in metastatic breast cancer.
Authors: Nielsen Dorte , Jakobsen Erik , Langkjer Sven Tyge , Danoe Hella , Balslev Eva , Knoop Ann , Kümler Iben , Buhl Ida Kappel , Knudsen Steen , Hansen Anker , Winkel Madsen Mogens , Buhl Ulla Hald , Meland Nils , Smerud Knut , Jensen Peter Buhl , Lassen Ulrik Niels 
Published: June 2023

3130 Background: Heavily pretreated late-stage breast cancer patients of any subtype represent a huge treatment challenge. Cisplatin may work in selected patients but is often disqualified because of toxicity. LiPlaCis is a liposomal formulation of cisplatin in development utilizing the sPLA2-triggered targeted release of cisplatin. The prediction of cisplatin efficacy with a 205 mRNA profile has previously been demonstrated in a retrospective study in two NSCLC cancer patient cohorts receiving adjuvant cisplatin1. Methods: The dose-escalation part of a phase 1/2 study, of 20 patients with a variety of locally advanced or metastatic solid tumors, suggested a phase 2 dose of LiPlaCis to be 75mg on day 1 and 8 q 3 wks. In this phase 2 part, the cisplatin drug response predictor (DRP) was used to select metastatic breast cancer (mBC) patients with response likelihood scores from FFPE diagnostic or later biopsies. Patients were treated until progression or unacceptable toxicity. Halfway through phase 2 part, the dosing was changed to a per body surface schedule (40 mg/m2) after a fatal event with the flat dosing (in effect 51 mg/m2 for this patient). Among the 52 patients included in the phase 2 part, we here report data from the 37 patients with mBC platinum naïve, with DRP scores 34-100%, and with RECIST-defined response outcomes. Within this subgroup, we conducted a post hoc analysis of possible DRP cut-off values that could identify patients with a clinically meaningful response to treatment. Results: mBC patients had received a median of 7 previous treatment lines. A DRP score ≥80% (DRP80+) discriminated well between responders and non-responders to liposomal cisplatin. All 4 partial remissions in the study were in the DRP80+ group, and other key efficacy endpoints were in favor of the DRP80+ vs the lower scores (DRP80-). LiPlaCis was generally well tolerated, with a mean of 4.4 treatment cycles administered per patient. Only 1 SAE (pyelonephritis) was reported and considered related to treatment. One patient died whilst on treatment, but due to disease progression. From a total of 164 treatment cycles, 18 of the patients reported 1 grade 4 and 41 grade 3 AEs considered possibly related to treatment. Conclusions: LiPlaCis shows efficacy in heavily pretreated mBC patients, especially when using the DRP method as a companion diagnostic. Further, this is the first clinical study to prospectively validate DRP as a method to identify responders to chemotherapy cisplatin. 1) Buhl et al PLOS One doi: 10.1371/journal.pone0194609. Clinical trial information: NCT01861496 . [Table: see text]
NRG1 fusions in solid tumors.
Authors: Gupta Brinda , Wu Sharon , Ou Sai-Hong Ignatius , Darabi Sourat , Mileham Kathryn Finch , Gandhi Nishant , Weinberg Benjamin Adam , Nagasaka Misako , Borghaei Hossein , Ma Patrick C. , Farrell Alex Patrick , Sledge George W. , Vanderwalde Ari M. , El-Deiry Wafik S. , Liu Stephen V. 
Published: June 2023

3132 Background: NRG1 fusions are rare but actionable genomic drivers that occur across a growing number of tumor types. NRG1 has an EGF-like domain that serves as a ligand for ErbB (HER3) receptors, thereby inducing heterodimerization, usually with HER2, and subsequent activation of relevant downstream signaling pathways. Agents targeting the HER2/HER3 pathway have shown early clinical promise in NRG1 fusion-positive cancers: currently zenocutuzumab has FDA Fast Track Designation for tumors harboring NRG1-fusions. Here, we update the incidence and characterization of NRG1 fusions across tumor types. Methods: Samples were submitted for clinical molecular profiling at Caris Life Sciences via Caris MI Tumor Seek (Phoenix, AZ). Gene fusion detection was performed on mRNA isolated from a formalin-fixed paraffin-embedded tumor sample using the Illumina NovaSeq platform (Illumina, Inc., San Diego, CA) and Agilent SureSelect Human All Exon V7 bait panel (Agilent Technologies, Santa Clara, CA). All NRG1 fusions with ≥ 3 junction reads were identified for manual review and for characterization of fusion class, intact functional domains, domain prediction, breakpoints, frame retention and co-occurring alterations by next-generation sequencing. Results: In an analysis of 169,273 tumor specimens, 261 unique tumors with an NRG1 fusion were identified for an overall incidence of 0.154% across tumors. NRG1 fusions were most frequently detected in NSCLC, breast cancer, ovarian cancer, pancreatic ductal adenocarcinoma, colorectal cancer, cholangiocarcinoma, prostate cancer, bladder and urothelial cancers, esophagogastric cancers and less commonly, prostate cancer, soft tissue sarcoma, anal cancer, salivary gland cancers, head and neck cancer, small intestine cancer, small cell lung cancer, endometrial cancer, thyroid cancer, neuroendocrine cancer, high grade glioma, and melanoma. The highest incidence was in breast cancer (0.301%), followed by cholangiocarcinoma (0.263%), NSCLC (0.232%), carcinoma of unknown primary (0.215%), pancreatic ductal adenocarcinoma (0.190%), ovarian cancer (0.174%), bladder cancer (0.148%), esophageal cancer (0.145%) and vulvar cancers (0.145%). There were 153 unique NRG1 fusion partners. The most common fusion partner was CD74 (12.37%), followed by SLC3A2 (8.13%), ATP1B1 (4.59%), and RBPMS (4.24%). Conclusions: NRG1 fusions are rare but actionable genomic events with significant heterogeneity of tumor type and fusion partner.
Novel LTK fusions based on NGS sequencing data in Chinese patients with solid tumors.
Authors: Chen Hui , Yuan Shaohua , Shi Xiaoliang , Pang Fei 
Published: June 2023

3144 Background: Leukocyte receptor tyrosine kinase ( LTK) gene has the same kinase domain (PTKc_ALK_LTK) as ALK, and could functionally response to ALK inhibitors such as lorlatinib. Previous study reported that CLIP1-LTK fusion was a novel oncogenic driver mutation in lung cancer (occur in 0.4% of non-small cell lung cancer), which was sensitive to the ALK tyrosine kinase inhibitor lorlatinib. So far, LTK fusion has been rarely reported. Methods: A total of 11 Chinese solid tumor patients were reviewed, including 6 cases of LTK positive rearrangements in DNA and 5 cases of LTK positive fusion in RNA. FFPE samples were collected for NGS-based 450 cancer gene panel detection in both DNA and RNA level, and matched blood samples were used as normal control to filter out germline mutations. LTK fusions were analyzed by OrigiFus algorithm. Results: We found 6 patients with LTK rearrangements by DNA-based NGS detection, including lung adenocarcinoma, colorectal cancer, stomach cancer, spindle cell sarcoma of small intestine, adenocarcinoma of the pancreas, and cancer of unknown primary, and 5 soft tissue sarcoma patients with RPAP1 E25- LTK E2 fusions by RNA-based NGS detection. We analyzed the patterns of partner genes and breakpoints of the 6 LTK rearrangements. The partner genes included NUSAP1 (n=2), NDUFAF1 (n=1), LOC105370802 (n=1), EHD4 (n=1), and AGBL1 (n=1). All these partner genes were located on the same chromosome as LTK, rather than CLIP1, which was identified as a translocation. The breakpoints on LTK included exon20 (n=2), intron1 (n=2), exon6 (n=1), and exon10 (n=1). Five of the 6 fusions consisted of a complete PTKc_ALK_LTK domain. Among the 6 LTK rearrangements, LTK E20- NUSAP1 E2 was predicted as a fusion. Interestingly, this clinical real-world sample also harbored a classic NTRK1 fusion, LMNA E2- NTRK1 E11. The other NUSAP1- LTK was predicted to have a transcript of 3’-3’, but one of the breakpoints was observed at LTK exon6, which could be located at the kinase domain, so the possibility of eventual fusion cannot be excluded. The two NUSAP1-LTK fusions were found in a stomach tumor and a soft tissue sarcoma, respectively. One non-small-cell lung cancer (NSCLC) patient had a breakpoint detected on LTK exon10, which is the same as the exon of CLIP1- LTK reported. Conclusions: This study revealed novel LTK fusions/rearrangements and their cancer distribution in Chinese patients with solid tumors. We gave the details of these fusions/rearrangements which enrich our understanding of the LTK fusion. Although the small number of cases, our analysis promoted the attention on LTK and its potential value of drug research and clinical treatment in pan-cancer.
Reporting and impact of subsequent cycle toxicities in oncology phase I clinical trials.
Authors: Rami Avina , DuBois Steven G. , Campbell Kevin M. 
Published: June 2023

3149 Background: In recent years, the landscape of clinical trial development has evolved to include immunotherapy and targeted therapies, which have different lengths of administration and toxicity profiles compared to standard chemotherapy. As treatments have evolved, the classic assumptions of toxicity associated with cytotoxic agents may be less relevant, requiring new strategies for design of trials intended to inform dosing strategies for agents that may be administered beyond a set number of defined cycles. We aimed to describe the overall incidence of dose-limiting toxicities (DLTs) during and after cycle 1, the frequency of reporting subsequent cycle toxicities, and the impact of post-cycle 1 DLTs on conclusions drawn from oncology phase I clinical trials. Methods: We conducted a systematic review of subsequent cycle toxicities in oncology phase I clinical trials published in the Journal of Clinical Oncology from 2000 to 2020. Only trials that included more than one cycle of therapy were included. Data elements captured included: year of publication, study design, trial sponsor type, intervention type, number of anti-cancer therapies involved, primary diagnosis, incidence and type of cycle 1 DLT, incidence of dose modification in cycle 1, incidence and type of post-cycle 1 DLTs, incidence of dose modification in post-cycle 1, presence of a recommended phase 2 dose (RP2D) and impact of subsequent cycle toxicity on RP2D. Results: From 2000 to 2020, we identified 489 full-text articles reporting on therapeutic phase I clinical trials. Of these, 421 (86%) reported data regarding cycle 1 DLTs and 170 (35%) reported cycle 1 dose modifications. The overall median cycle 1 DLT rate was 8.89%. Only 47 (9.6%) publications reported whether or not there were post-cycle 1 DLTs and only 92 (19%) reported whether or not there were dose modifications beyond cycle 1. The overall median post-cycle 1 DLT rate among trials that reported post-cycle 1 data was 14.8%. A RP2D was reported in 76% (371 of 489) trials. Among these 371 studies, 89% did not report whether post-cycle 1 toxicities impacted the RP2D. Independent predictors of reporting toxicity data beyond cycle 1 included year of publication, investigational agent type, novelty, disease type, trial size, and sponsor. Conclusions: Reporting of subsequent cycle DLTs and dose modification is uncommon in oncology phase I clinical trial publications. As newer oncology treatments trend towards longer duration of treatment, there will be an increased need to understand toxicities occurring post-cycle 1. Guidelines for reporting of phase I clinical trials should expand to include toxicity data beyond the first cycle.
FOLFOXIRI plus bevacizumab and atezolizumab as upfront treatment of unresectable metastatic colorectal cancer (mCRC): Updated and overall survival results of the phase II randomized AtezoTRIBE study.
Authors: Antoniotti Carlotta , Rossini Daniele , Pietrantonio Filippo , Salvatore Lisa , Marmorino Federica , Ambrosini Margherita , Lonardi Sara , Bensi Maria , Moretto Roberto , Tamberi Stefano , Toma Ilaria , Passardi Alessandro , De Grandis Maria Caterina , Conca Veronica , Palermo Federica , Cappetta Alessandro , Catteau Aurelie , Boni Luca , Galon Jérôme , Cremolini Chiara 
Published: June 2023

3500 Background: AtezoTRIBE (NCT03721653) is a phase II randomized trial in which unresectable mCRC pts were randomized 1:2 to 1st-line FOLFOXIRI/bev [arm A] or FOLFOXIRI/bev/atezo [arm B]. Adding atezo to FOLFOXIRI/bev was safe and improved PFS (primary endpoint), with a modest benefit also among pts with pMMR tumors. Subgroup analyses suggest that TMB and Immunoscore IC (IS IC) -an IHC biomarker measuring CD8 and PD-L1 cell densities and their proximity- may identify pts with pMMR tumors deriving benefit from adding atezo to FOLFOXIRI/bev. Methods: The study had 85% power to detect a HR for PFS (time from randomization to 1st PD or death [PD1]) of .66 in favor of arm B with 1-sided α error of .10. Secondary endpoints included PFS2 (time from randomization to PD on any treatment given after PD1 or death [PD2]), 2nd PFS (time from PD1 to PD2), and OS. MMR, TMB, IS IC were correlated to clinical outcome. Results: 218 pts (arm A/B:73/145) were enrolled. Main pts’ characteristics were right-sided 44%/45%, RAS mut 71%/74%, BRAF mut 14%/8%, dMMR 7%/6%, high TMB 10%/12%, high IS IC 32%/32%. At a median follow-up of 37.0 mos, 175 (80%, arm A/B: 64/111) PD1, 150 (69%, arm A/B: 53/97) PD2, and 118 (54%, arm A/B: 43/75) OS events were collected. Out of 175 pts with a PD1 event, 135 (77%, arm A/B:50/85) received a subsequent treatment; among them, 121 pts (arm A/B: 43/78) had a PD2 event. PFS, PFS2, 2nd PFS and OS results in the intention-to-treat (ITT) population and the pMMR group are listed in the Table. In the ITT population, significant interactions between treatment and MMR status (Pint .011), TMB (Pint .008), and IS IC (Pint .037) were reported in terms of PFS. Only IS IC was associated with a differential OS benefit (Pint .065), with pts bearing IS IC-high tumors deriving benefit from adding atezo (HR 0.43, 95%CI 0.19-1.00), differently than those with IS IC-low tumors (HR 1.09, 95%CI 0.65-1.83). In the pMMR group, significant interactions between treatment and TMB and IS IC were reported in terms of PFS (Pint .016 and .051, respectively) and OS (Pint .043 and .063, respectively). Pts bearing IS IC-high tumors derived higher OS benefit from adding atezo (HR 0.44, 95%CI 0.19-1.03), than those with IS IC-low tumors (HR 1.15, 95% CI 0.67-1.97). Conclusions: Pts with IS IC-high and/or TMB high pMMR mCRC seem to derive a survival benefit from adding atezo to FOLFOXIRI/bev as upfront treatment. These findings deserve confirmation in a properly designed phase III trial. Clinical trial information: NCT03721653 . [Table: see text]
Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-overexpressing/amplified (HER2+) metastatic colorectal cancer (mCRC): Primary results from the multicenter, randomized, phase 2 DESTINY-CRC02 study.
Authors: Raghav Kanwal Pratap Singh , Siena Salvatore , Takashima Atsuo , Kato Takeshi , Van Den Eynde Marc , Di Bartolomeo Maria , Komatsu Yoshito , Kawakami Hisato , Peeters Marc , Andre Thierry , Lonardi Sara , Yamaguchi Kensei , Tie Jeanne , Gravalos Castro Cristina , Strickler John H , Barrios Daniel , Yan Qi , Kamio Takahiro , Kobayashi Kojiro , Yoshino Takayuki 
Published: June 2023

3501 Background: T-DXd (6.4 mg/kg, every 3 weeks [Q3W]) demonstrated antitumor activity in pts with HER2+ mCRC in DESTINY-CRC01 (Siena et al. Lancet Oncol. 2021). We present primary results of DESTINY-CRC02 (NCT04744831), which assessed the efficacy and safety of T-DXd (5.4 and 6.4 mg/kg) in pts with HER2+ mCRC. Methods: This was a multicenter phase 2 study. Eligible pts had centrally confirmed HER2+ (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+) mCRC. Pts with RAS wild-type (wt) or mutant (m) mCRC were eligible. Pts had received prior standard therapy, unless contraindicated; prior anti-HER2 therapy was allowed. In stage 1, 80 pts were randomized 1:1 to 5.4 (n = 40) or 6.4 (n = 40) mg/kg T-DXd Q3W. In stage 2, an additional 42 pts received 5.4 mg/kg T-DXd. Primary endpoint was confirmed objective response rate (cORR) by blinded independent central review (BICR). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Results: At data cutoff (Nov 1, 2022), most pts in the 5.4 and 6.4 mg/kg T-DXd arms had HER2 IHC 3+ (78.0% and 85.0%), RAS wt tumors (82.9% and 85.0%), and a median of 3 and 4 prior lines of therapy, respectively. cORR was 37.8% (95% CI, 27.3-49.2%) in the 5.4 mg/kg arm and 27.5% (95% CI, 14.6-43.9%) in the 6.4 mg/kg arm (all partial responses in both arms). Key efficacy data are shown in the Table: Grade ≥3 treatment-emergent adverse events (AEs) were observed in 41/83 pts (49.4%) and 23/39 pts (59.0%) in the 5.4 and 6.4 mg/kg T-DXd arms, respectively. Serious AEs were observed in 20/83 pts (24.1%) and 12/39 pts (30.8%) in the 5.4 and 6.4 mg/kg arms, respectively. Independently adjudicated drug-related interstitial lung disease occurred in 7/83 pts (8.4%) with 5.4 mg/kg T-DXd and 5/39 pts (12.8%) with 6.4 mg/kg T-DXd, and most events were grade 1/2 (1 grade 5 in the 6.4 mg/kg arm). Conclusions: T-DXd showed promising antitumor activity in pts with HER2+ mCRC at both 5.4 and 6.4 mg/kg doses. Antitumor efficacy was observed irrespective of RAS mutation status at 5.4 mg/kg T-DXd, and in those with prior anti-HER2 therapy. Overall, safety was consistent with the known safety profile of T-DXd and favored the 5.4 mg/kg dose. Clinical trial information: NCT04744831 . [Table: see text]
Efficacy of panitumumab in patients with left-sided disease, MSS/MSI-L, and RAS/BRAF WT: A biomarker study of the phase III PARADIGM trial.
Authors: Yamazaki Kentaro , Muro Kei , Watanabe Jun , Shitara Kohei , Ohori Hisatsugu , Shiozawa Manabu , Yasui Hirofumi , Oki Eiji , Sato Takeo , Naito Takeshi , Komatsu Yoshito , Kato Takeshi , Soeda Junpei , Yamamoto Kouji , Yamashita Riu , Akagi Kiwamu , Ochiai Atsushi , Uetake Hiroyuki , Tsuchihara Katsuya , Yoshino Takayuki 
Published: June 2023

3508 Background: The PARADIGM trial (NCT02394795) showed longer median overall survival (OS) with first-line mFOLFOX6 plus panitumumab (PAN) vs bevacizumab (BEV) in patients (pts) with RAS wild type (WT) and left-sided metastatic colorectal cancer (mCRC; 37.9 vs 34.3 months, respectively; hazard ratio [HR], 0.82; P=0.031) and similar OS in right-sided pts (HR 1.09; Yoshino T, et al. ASCO 2022 LBA1). Based on current guideline recommendations regarding clinically relevant biomarkers, here we report clinical outcomes in left-sided mCRC pts with microsatellite stable or microsatellite instability low (MSS/MSI-L) and RAS (KRAS/NRAS)/ BRAF (V600E) WT from PARADIGM. Methods: Baseline plasma circulating tumor DNA (ctDNA; >10 ng/mL and >10 nM DNA) from pts enrolled in the biomarker study (NCT02394834) was assessed using a custom panel (PlasmaSELECT-R 91, PGDx). The efficacy (OS, progression-free survival [PFS], response rate [RR], and curative resection rate [R0]) of PAN plus mFOLFOX6 compared with BEV plus mFOLFOX6 according to RAS, BRAF (V600E), and MSI status and primary tumor location was evaluated. Results: Among 802 pts in the full analysis set, 733 (91%) had evaluable pretreatment samples for ctDNA analysis. Of these pts, 53 (7.2%) and 78 (10.6%) pts had RAS and BRAF ( V600E) mutations, respectively, and 20 (2.7%) pts had MSI high (MSI-H) status. In left-sided mCRC pts with MSS/MSI-L and RAS/ BRAF WT, OS tended to be longer with PAN vs BEV (40.6 [95% CI, 36.3-44.4] vs 34.8 [95% CI, 31.3-41.2] months, respectively; HR, 0.79 [95% CI, 0.64–0.97]). Although PFS was comparable between PAN (13.6 months [95% CI, 12.6–15.3]) and BEV (12.6 months [95% CI, 11.3–14.1]; HR, 0.95 [95% CI, 0.77–1.17]), RR and R0 resection rates were higher with PAN (RR: 83.2% [95% CI, 78.0–87.6]; R0: 18.8% [95% CI: 14.2–24.1]) compared with BEV (RR: 66.4% [95% CI, 60.0–72.3]; R0: 10.0% [95% CI: 6.5–14.5]). OS was similar or inferior to PAN vs BEV regardless of the primary sidedness in pts with MSI-H or RAS/ BRAF mutations (Table). Conclusions: These results support PAN + mFOLFOX6 as a first-line therapy for left-sided pts with MSS/MSI-L and RAS/ BRAF WT. Clinical trial information: NCT02394795 . [Table: see text]