bluuebunny/crossref_metadata_2025 huggingface dataset:
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]
Metabolomic differences in young-onset versus average-onset colorectal adenocarcinoma.
Authors: Jayakrishnan Thejus , Farha Nicole , Mariam Arshiya , Rotroff Daniel Miller , Aucejo Federico , Barot Shimoli V , Conces Madison , Nair Kanika G. , Krishnamurthi Smitha S. , Schmit Stephanie , Liska David , Khorana Alok A. , Kamath Suneel Deepak
Published: June 2023

3510

Background: Novel deleterious effects of environmental exposures may play a role in the rising incidence of young-onset colorectal cancer (yoCRC). We used metabolomics to assess differences between yoCRC and average-onset CRC (aoCRC), in comparison to healthy controls, which may provide insight into the pathogenesis and suggest any exposure risks. Methods: Patients with stage I-IV CRC and healthy controls were identified from prospective biobanks and categorized based on age < 50 years (yoCRC or young controls) or age > 60 years (aoCRC or older controls). Plasma metabolites were profiled using GC-TOF mass spectrometry. Differential abundance of metabolites was investigated using unadjusted and adjusted logistic regression. Metabolic pathway analysis was performed using Metaboanalyst 5.0. All p-values were adjusted for multiple testing (false-discovery rate, FDR p < 0.20 considered significant). Results: The study population comprised 170 CRC patients (66 yoCRC and 104 aoCRC) and 49 healthy controls (34 young and 15 old). Association analyses revealed four differentially abundant metabolites: citrate (FDR p = 0.04), cholesterol (0.14), and two unidentified metabolites (UM). Metabolic pathways significantly altered in yoCRC vs. aoCRC included: carbohydrate metabolism (citrate cycle, FDR p = 0.04), carbohydrate biosynthesis (glyoxylate and dicarboxylate metabolism, FDR p = 0.004), amino-acid metabolism (alanine, aspartate, and glutamate metabolism, FDR p = 0.01, arginine biosynthesis, FDR p = 0.02, and amino-acid t-RNA biosynthesis, FDR p = 0.03). There were no significant metabolomic differences between young and old controls. Significant associations on survival analysis included: adipic acid with aoCRC (HR = 3.1, 95% CI = , 1.7-5.6, FDR p = 0.13, unadjusted analysis) suggesting worse survival with higher levels and 4-hydroxyhippuric acid with the whole cohort (HR = 0.4, 95% CI = 0.3-0.7, FDR p = 0.05, adjusted analyses) indicating better survival with higher levels. Conclusions: We identified significant differences in the citrate cycle - a core pathway of cellular metabolism associated with colorectal cancer. Metabolomic differences in pathways of carcinogenic significance (aspartate) and environmental exposures (arginine and dietary red meat) were also noted, suggesting potential relationships with younger age of CRC onset. [Table: see text]
Adjuvant systemic chemotherapy with or without hepatic arterial infusion of floxuridine in patients following colorectal cancer liver metastases resection (HARVEST): A prospective, randomized controlled trial.
Authors: Li Yu-hong , Wang De-Shen , Gu Yang-Kui , Wen Lei , Ren Chao , Wu Xiao-Jun , Yuan Yun-Fei , Li Bin-Kui , Zheng Yun , Ding Pei-Rong , Wang Zhi-Qiang , Pan Zhi-Zhong , Chen Gong , Li Li-Ren , Lu Zhen-Hai , Tan Qiong , Wan De-Sen , Xu Rui-Hua
Published: June 2023

3516

Background: Several retrospective studies have previously demonstrated that a combination of adjuvant systemic chemotherapy and hepatic arterial infusion (HAI) could benefit patients following colorectal cancer liver metastases (CRLM) resection. This prospective clinical study aimed to determine whether adding HAI to adjuvant systemic chemotherapy could reduce the risk of recurrence following CRLM resection. Methods: The HARVEST study is an investigator-initiated, prospective, randomized controlled trial investigating the efficacy and safety of adjuvant intravenous chemotherapy with or without HAI floxuridine (FUDR) in CRLM patients that underwent liver metastasectomy. Patients in the systemic chemotherapy plus HAIC arm (HAI group) received systemic FOLFOX (q2w) plus HAI (FUDR, d1-14, q4w) for up to 6 months, while the systemic chemotherapy group without HAI (non-HAI group) received intravenous FOLFOX only. The primary study endpoint is the relapse-free survival in the modified intention-to-treat (mITT) population. Blood samples at different time points were also collected and circulating tumor DNA (ctDNA) was tested for NPY and SEPT9 methylation. Results: The study was prematurely terminated due to FUDR production halt in China. Ninety-two patients were randomized and seventy-seven patients (38 in the HAI group and 39 in the non-HAI group) were eventually included in our mITT analysis. After a median follow-up of 35.8 months, there were 22 (57.9%) and 25 (64.1%) recurrences in the HAI and non-HAI groups, respectively. The median relapse-free survival was 20.0 months in the HAI group and 11.7 months in the non-HAI group (p = 0.14; HR 0.65; 95% confidence interval [CI] 0.37 to 1.16). No significant difference was found in terms of overall survival between the two groups (p = 0.461). Our subgroup analysis revealed that patients with multiple liver metastases (p < 0.01) and RAS/BRAF mutation (p < 0.01) could benefit from adjuvant HAI treatment. Based on ctDNA status, patients with positive postoperative ctDNA methylation benefited from adjuvant HAI treatment (p < 0.01), while those with negative postoperative ctDNA methylation status (p = 0.95) did not. Chemotherapy-related adverse events were comparable between the two groups. Conclusions: Adjuvant chemotherapy intensification using HAI did not significantly reduce recurrence following CRLM resection. However, patients with multiple liver metastases, RAS/BRAF mutation and those with positive postoperative ctDNA might benefit from adjuvant HAI treatment. Clinical trial information: NCT03500874 .
Sustained organ preservation in patients with rectal cancer treated with total neoadjuvant therapy: Long-term results of the OPRA trial.
Authors: Verheij Floris S , Omer Dana Mohamed Rashid , Williams Hannah , Buckley James T , Lin Sabrina T , Qin Li-Xuan , Thompson Hannah M , Yuval Jonathan B , Gollub Marc J , Wu Abraham Jing-Ching , Saltz Leonard B. , Garcia-Aguilar Julio ,   on behalf of the OPRA Consortium
Published: June 2023

3520

Background: The preliminary results of the OPRA trial demonstrated that a substantial number of patients with locally advanced rectal cancer treated with total neoadjuvant therapy (TNT) could achieve organ preservation. Although most tumor regrowths seem to occur within the first 3 years, longer follow-up is needed to assess the ongoing risk of regrowth. Here, we report the long-term organ preservation rate and oncologic outcomes of the OPRA trial. Methods: A prospective, multi-institutional phase II trial, in which patients with stage II or III rectal cancer were randomized to receive either induction chemotherapy followed by chemoradiation (INCT-CRT) or chemoradiation followed by consolidation chemotherapy (CRT-CNCT). Patients underwent reassessment for treatment response 8-12 weeks after TNT. Patients who achieved a complete or near-complete response after finishing TNT were offered a watch and wait approach (WW). Those with incomplete response were recommended total mesorectal excision (TME). We report 5-year disease-free survival (DFS), organ preservation (defined as TME-free survival), local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS) and overall survival (OS) for each treatment group. We also compared DFS between patients who underwent upfront TME after restaging and patients who underwent TME after tumor regrowth. All analyses followed the intention-to-treat principle and groups were compared using the log-rank test. Results: Of the 324 patients randomized, 158 were assigned to the INCT-CRT group and 166 to the CRT-CNCT group. Median follow-up was 56 months; 85 DFS events were observed. The rates of 3- and 5-year DFS, TME-free survival, LRFS, DMFS and OS are listed in the Table. In total, 80 of the 225 (36%) patients who started WW developed a regrowth; 94% occurred within 2 years and 99% occurred within 3 years. The rate of TME-free survival at 5 years was significantly higher for CRT-CNCT (54%) than in INCT-CRT (39%). 5-year DFS was similar for patients who underwent TME after restaging (61%) compared to patients who underwent TME after regrowth (62%, p = 0.86). Conclusions: In patients with rectal cancer treated with TNT and WW, the majority of tumor regrowths occur in the first 2 years, and regrowth after 3 years is vanishingly rare. Salvage TME for tumor regrowth during WW appears to offer similar outcome to immediate TME after incomplete response to TNT. Distant metastases remain the most frequent cause of treatment failure, with similar rates in the two treatment groups. Clinical trial information: NCT02008656 . [Table: see text]
Association of positive ctDNA-based minimal residual disease assays during surveillance and undiagnosed concomitant radiographic recurrences in colorectal cancer (CRC): Results from the MD Anderson INTERCEPT program.
Authors: Dasari Arvind , Bent Alisha Heather , Alfaro-Munoz Kristin , Huey Ryan W , Johnson Benny , Lee Michael Sangmin , Morelli Maria Pia , Morris Van K. , Overman Michael J. , Parseghian Christine Megerdichian , Raghav Kanwal Pratap Singh , Shen John , Willis Jason , Newhook Timothy E. , Uppal Abhineet , You Y. Nancy , Konishi Tsuyoshi , Chang George J. , Kopetz Scott , Wolff Robert A. ,   MD Anderson INTERCEPT
Published: June 2023

3522

Background: Observational cohorts have shown that detection of circulating tumor DNA (ctDNA)-defined minimal residual disease (MRD) following curative intent therapy has very high specificity and positive predictive value for future radiographic recurrence with a lead time of over 9 months. However, such data have not incorporated rigorous clinical evaluation for concomitant recurrence, nor have they established the clinical utility of MRD monitoring after completion of curative intent therapy. Methods: Pts with stages II-IV CRC (6/1/19 - 12/31/22, data cutoff) treated with curative intent at MD Anderson Cancer Center were evaluated with a tumor-informed MRD assay (Signatera, Natera), as part of the institutional INTERCEPT program that aims to integrate MRD-based testing into CRC clinical care. Surveillance visits including scans and tumor markers were performed per established guidelines. ctDNA was recommended post-operatively and q3m with each surveillance visit. Pts and providers were informed of the results and subsequent clinical courses including additional radiologic testing for ctDNA+ MRD tests were tracked. Results: 1259 pts were included in the INTERCEPT program (median 57y, [21-93]; 55% male; stage% I-III/IV 69/31; colon/rectum% 61/39), with 1049 pts tested after curative intent surgery. Of these, 159/1049 pts (15%) had ctDNA+; distribution of pts, % (+ve/total) from time of such surgery in m was: 0 - 3 (54.6/43.8); 3-6 (21.3/30); 6-12 (24/33.2). Of the pts with ctDNA+ after surgery, 49 pts (32%) were ctDNA+ prior to or during adjuvant therapy and 86 (57%) during surveillance. Of the 86 pts who were ctDNA+ during surveillance, imaging revealed concomitant new metastases in 46 (53%); i.e. only 40 (47%) were true MRD+. A total of 191 imaging studies were done (range 1-4) within 90d of the initial ctDNA+ including 99 as routine surveillance concurrent with ctDNA testing and 92 as additional follow up based on results. Of 40 pts with true MRD, majority (27 pts, 67.5%) were enrolled onto ongoing MRD trials ( https://crcmrd.com/ ). Conclusions: Our experience provides support for the feasibility of incorporation of MRD testing as part of routine surveillance. ctDNA+ results trigger a high rate of reflex imaging and, as a result, 53% of ctDNA+ patients have concomitant new radiographic findings. While clinical trials are feasible in true MRD+ pts, eligibility criteria for these trials need to be carefully specified about adequate radiographic evaluation.
Pathological analysis of tumor microenvironmental features using deep learning to predict survival of colon carcinomas.
Authors: Sinicrope Frank A. , Nelson Garth D. , Saberzadeh Ardestani Bahar , Yan Dongyao , Shanmugam Kandavel , Alberts Steven R , Shi Qian , Pai Rish , Segovia Diana I
Published: June 2023

3527

Background: Advances in deep learning may improve the ability to evaluate and quantify pathological features in solid tumors to improve prediction of patient disease-free survival (DFS). We used an artificial intelligence (AI) algorithm to quantify morphological features in the tumor microenvironment of stage III colon cancers. Methods: We analyzed digitized stage III colon carcinomas (N = 402; 382 met QC) from participants in a phase III trial of FOLFOX-based adjuvant chemotherapy that included all available tumors with dMMR and a randomly selected cohort of pMMR tumors (median follow-up 60 months) [NCCTG N0147; Alliance for Clinical Trials in Oncology]. Fifteen morphological features were extracted using the QuantCRC algorithm that segments images into carcinoma (low-grade, high-grade, signet ring cell), stroma (immature, mature, and inflammatory), mucin, tumor/stroma ratio, tumor budding/poorly differentiated clusters (TB/PDC), necrosis, smooth muscle, fat, and tumor-infiltrating lymphocytes (TILs) and tumor area (mucin, epithelium and TB/PDC). Analysis of AI-derived features with clinical variables, molecular alterations ( BRAF/KRAS), and DFS were examined using Kaplan-Meier methodology and multivariable Cox regression. Results: Among the 15 AI-derived morphological features, the following differed significantly between dMMR (n = 191) and pMMR (n = 189) whereby dMMR tumors had lower mature stroma, but higher inflammatory stroma and tumor, higher tumor grade and increased mucin, TB/PDCs, signet ring cells, and TILs (all p< 0.05). Among dMMR tumors, multivariable analysis revealed that tumor area [mucin, epithelium and TB/PDC] (HR adj 0.45, 95%CI (0.24, 0.84), p:0.01, [Q2/3 vs Q1]) and N stage were the only significant and independent prognostic variables. Among pMMR tumors, multivariable analysis identified that tumor budding/poorly differentiated clusters (TB/PDCs) (HR adj 0.20, 95%CI (0.06, 0.61), p:0.01, [Q1 vs Q4]) was the strongest prognostic variable and the only morphological feature that was significantly associated with DFS along with age, N stage and T stage. Conclusions: Using AI, we can extract and quantify distinct morphological features in tumor sections that differ between dMMR and pMMR and multivariately, can significantly and robustly enhance prognostication within each MMR group. Among pMMR tumors, tumor budding/poorly differentiated clusters was the strongest predictor of DFS. Support: NIH U10CA180821, U10CA180882, U24CA196171, R01 CA210509 (to FAS). Study NCCTG N0147 received funds from Sanofi https://acknowledgments.alliancefound.org . ClinicalTrials.gov Identifier: NCT00079274 Key words Artificial Intelligence; Tumor Microenvironment; Colonic Neoplasms; Disease-free survival.
HER2 testing in the MOUNTAINEER trial: Analysis of treatment response based on central HER2 assessment using IHC/ISH and NGS.
Authors: Strickler John H , Cercek Andrea , Ng Kimmie , Siena Salvatore , Andre Thierry , Van Cutsem Eric , Wu Christina , Paulson Andrew Scott , Hubbard Joleen M. , Coveler Andrew L. , Fountzilas Christos , Kardosh Adel , Kasi Pashtoon Murtaza , Lenz Heinz-Josef , Ciombor Kristen Keon , Elez Elena , Stecher Michael , Cronin Pauline , Bieda Mark , Bekaii-Saab Tanios S.
Published: June 2023

3528

Background: Tucatinib (TUC) is a highly selective HER2-directed TKI approved by the FDA in combination w/trastuzumab (Tras) for treatment (tx) of pts w/ RAS wild-type HER2+ unresectable or metastatic colorectal cancer (mCRC) that has progressed following tx w/ fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. There are currently no established best practices for HER2 testing/interpretation in mCRC. Here we present results of central HER2 testing across multiple platforms and response to tx for MOUNTAINEER pts treated w/ TUC + Tras based on central HER2 status. Methods: MOUNTAINEER (NCT03043313) enrolled pts w/ local HER2+ mCRC using ≥1 method: IHC, ISH, and/or NGS testing; retrospective central assessment of HER2 status was performed on multiple platforms. Pts in cohorts A+B were treated w/ TUC + Tras; pts in cohort C were treated w/ TUC monotherapy. Confirmed objective response rates (cORRs) using RECIST v1.1 per BICR, DOR, and PFS were calculated for pts treated w/ TUC + Tras based on each central testing method. Results: 114 pts were enrolled in cohorts A (n = 45), B (n = 39), and C (n = 30) w/ HER2+ tumors per ≥1 local testing method. Of samples submitted for central testing for Cohorts A and B, 70 per IHC/FISH, 50 per tissue NGS, and 71 per blood NGS had evaluable results. In all cohorts, there was 81.0% (95% CI, 68.6-90.1) agreement between blood and tissue NGS, 92.6% (95% CI, 83.7-97.6) between IHC/FISH and tissue NGS, and 79.5% (95% CI, 69.2-87.6) between IHC/FISH and blood NGS. In cohorts A and B, pts w/ HER2+ tumors by central IHC/ISH had a mDOR of 16.4 months (95% CI: 10.6-25.5) and mPFS of 10.1 months (95% CI: 4.2-15.2). cORR was 41.1% to 47.7% for the 3 assays. Detailed HER2 results are presented in the Table. Conclusions: Percent agreement of HER2 status was highest w/ tissue-based platforms. Detection of HER2 amplification by ctNDA NGS is useful; however, pts w/o HER2 amplification should be confirmed w/ a tissue-based assay. HER2 status by all 3 platforms predicted tx response to TUC + Tras. cORR in IHC2+/ISH+ was numerically lower but remained clinically relevant. These data support use of the above methods to identify HER2+ mCRC patients that may benefit from TUC + Tras. Clinical trial information: NCT03043313 . [Table: see text]
Chemotherapeutic sensitivity in colorectal cancer expressing low RNA of wild type homologous recombination genes.
Authors: Walden Daniel , Deshmukh Sachin , Batalini Felipe , Zheng-Lin Binbin , Wu Sharon , Xiu Joanne , Caughey Bennett Adam , Strickler John H , Korn Wolfgang Michael , Lou Emil , Ahn Daniel H. , Wu Christina , Goel Sanjay , Shields Anthony F. , Bekaii-Saab Tanios S.
Published: June 2023

3531

Background: Homologous recombination deficient (HRD) colorectal cancer (CRC) has improved overall survival (OS) when exposed to DNA damaging agents (DDA) oxaliplatin (OX) and irinotecan (IR). However, this OS benefit is only observed in HRD mutated CRC. Low expression of wild type (WT) BRCA1 RNA displays prolonged OS in ovarian cancer; this finding has not been investigated in CRC or outside BRCA. We investigate if low expression of WT HR genes is associated with prolonged OS in response to DDA. Methods: A total of 12,860 CRC patients tumor biopsies were analyzed by next-generation sequencing (592, NextSeq; WES, WTS NovaSeq). Patients with HRD mutations and MSI-H were excluded (N = 935). 11,925 patients were included in the analysis. A total of 11 core ( BARD1, BLM, BRCA1, BRCA2, BRIP1, MRE11, NBN, PALB2, RAD50, RAD51, RAD51B) and 7 related ( BAP1, WRN, DNMT3A, ERCC1, FANCA, FANCF, RECQL4) HR genes were analyzed. Samples were classified by RNA expression percentiles within the studied cohort. Real world OS was extracted from insurance claims and calculated using Kaplan-Meier estimates for molecularly defined cohorts from first of OX or IR to last contact. Results: OS benefit is seen in low RNA expression (bottom 10%) compared to high expression (top 10%) of all core WT HR genes except RAD51B, BARD1 and BRCA2 in response to IR. We observe a progressively longer OS with lower associated RNA expression in response to DDA. OS of nearly 7 years was observed in low expressing BRCA1 and RAD51 following IR exposure and 4.5-year OS benefit when compared to high expression of these genes. OS benefit in response to OX was less robust but significantly prolonged in BRCA1 and BRIP1 (Table). Patients harboring HRD mutations had similar OS to WT HR RNA low (bottom 10%) in response to OX (HR = 0.75; p = 0.1) and IR (HR = 0.82; p = 0.36). Conclusions: Here we report a novel subclass of CRC defined as patients with low RNA expressing WT HR genes that exhibit differential sensitivity to DDA. Significantly longer survival is noted in CRC with low expression BRCA1, RAD51 and BLM, while post-OX survival was significantly prolonged with low expression of BRCA1, BRIP1 and FANCA. Further characterization of sensitive HR genes will better predict DDA sensitivity and impact treatment sequencing. [Table: see text]
Circulating tumor DNA in plasma as an early predictor for pathological lymph node involvement and (neo-)adjuvant chemotherapy in patients with colon cancer.
Authors: Raunkilde Louise , Andersen Rikke Fredslund , Hansen Torben , Jensen Lars Henrik
Published: June 2023

3532

Background: Postoperative chemotherapy is standard for colon cancer patients with pathological lymph node involvement (pN+). If the presence of pN+ could be accurately predicted prior to surgery, the initiation of neoadjuvant chemotherapy could potentially reduce the presence of micrometastasis and enhance survival. The objective of this study was to assess the utility of preoperative methylated circulating tumor DNA (meth-ctDNA) as a predictive marker for pN+ and its clinical value as a marker for the initiation of neoadjuvant chemotherapy. Methods: The clinical data of 203 colon cancer patients (stage I-III) was collected from the Colorectal Cancer Database established at Danish Colorectal Cancer Center South, Vejle Hospital, Denmark. Patients were randomized into a discovery and a validation cohort. Plasma collected preoperatively was analyzed for three different meth-ctDNAs (Neuropeptide Y, Galactose-3-O-Sulfotransferase 3, and KN Motif and Ankyrin Repeat Domains 1) by droplet digital PCR (ddPCR). Results: Based on analysis of the discovery cohort, samples were considered positive if two or more of the three methylation markers had at least three positive droplets in the ddPCR analysis. 40% of patients in the discovery cohort and 46% of patients in the validation cohort were considered positive. When using meth-ctDNA as a diagnostic tool to predict pN+, the sensitivity and specificity in the discovery cohort were 42% and 61% respectively. In the validation cohort the values were 54% and 59%, respectively. AUC was < 60% in both cohorts. Meth-ctDNA was associated to clinical tumor (T)- and node (N)-category in both cohorts (p≤0.01). Four-year disease free survival (DFS) in patients with and without detectable meth-ctDNA was 60% and 90% in the discovery cohort (p = 0.01), and 62% and 78% in the validation cohort (p = 0.04). Meth-ctDNA remained the strongest prognostic factor of DFS in the multivariate analysis compared to clinical T- or N-category, gender and age (p = 0.065, HR 2.46, 95% CI 1.03-5.88), however not statistically significant. Four-year overall survival (OS) in patients with and without detectable meth-ctDNA was 75% and 95% in the discovery cohort (p = 0.006), and 78% and 91% in the validation cohort (p = 0.02). In the multivariate analysis, meth-ctDNA was the strongest prognostic factor of OS compared to clinical T- or N-category, gender and age (p = 0.016, HR 4.54, 95% CI 1.32-15.6). Conclusions: The preoperative measurement of meth-ctDNA was not found to be a clinically significant predictor of pN+ or a reliable indicator for the initiation of neoadjuvant chemotherapy. Nonetheless, the results showed that preoperative ctDNA is a powerful prognostic indicator, suggesting that randomized controlled trials should be conducted to determine the efficacy of neoadjuvant chemotherapy in colon cancer patients with preoperative detectable ctDNA.
Correlation of single-cell cytokine secretion with clinical outcome in patients (pts) with metastatic colorectal cancer (mCRC) treated with capecitabine (C), bevacizumab (B), ± atezolizumab (A).
Authors: Mettu Niharika B. , Waechter Blake , Zemla Tyler J. , Liu Yingmiao , Brady John C. , Lin Lynn , Gnjatic Sacha , Weinhold Kent J. , Bekaii-Saab Tanios S. , Ou Fang-Shu , Nixon Andrew B.
Published: June 2023

3533

Background: The BACCI trial (NCT02873195) randomized 133 mCRC pts to C+B+A (investigational) or C+B+placebo. Longer progression free survival (PFS) was observed in the investigational vs placebo arm. To investigate T-cell functional heterogeneity, we performed single-cell proteomic analyses on pts with either long or short PFS and evaluated T-cell function as a prognostic and predictive biomarker. Methods: Isolated CD8+ and CD4+ cells were analyzed at baseline and first restaging from pts with long ( > 6 mo, N = 14) or short ( < 2 mo, N = 13) PFS. Single-cell, functional proteomic analyses were conducted using the IsoLight system (Isoplexis), which assessed secretion of 32 cytokines from an average of 786 cells per sample. The cumulative readout was polyfunctional strength index (PSI), a composite score of frequency and magnitude of secreted cytokines. Cytokines are organized into effector (E), stimulatory, chemoattractive (CA), regulatory, and inflammatory (I) clusters. Differential expression analyses were done using Wilcoxon rank-sum tests. Potential predictive effects were assessed using logistic regressions with interaction between treatment and biomarkers. No multiple comparison control was done due to the exploratory nature of analyses. Results: Baseline CD8+ and CD4+ cells were stimulated ex vivo and single-cell cytokine analyses performed. Prognostic analyses indicated that CD8+ cells from pts with long PFS had ~3-fold higher PSI compared to pts with short PFS (p = 0.005). Further analysis identified that the E (p = 0.005) and CA clusters (p = 0.005) most impacted PSI, significant individual cytokines are listed in the table. Baseline CD8+ cell function was not predictive of outcome. Baseline CD4+ cell function was not prognostic or predictive of outcome. Analysis of CD8+ cells after treatment identified that changes in CA cluster was prognostic of long PFS (p = 0.024). Cytokine changes from CD4+ cells were not prognostic; however, early changes in the CD4+ CA cluster were predictive of outcome (p-int = 0.055). Similarly, early changes in the CD8+ I cluster were predictive of outcome (p-int = 0.073). Conclusions: These results reveal pts with long PFS had more functional CD8+ T-cells with a higher PSI than pts with short PFS. Predictive analyses suggested that early changes in the CD4+ CA and CD8+ I clusters were associated with benefit from immunotherapy. These preliminary results highlight the importance of single-cell functional proteomic analyses. [Table: see text]