bluuebunny/crossref_metadata_2025 huggingface dataset:
Scalp-sparing radiation with concurrent temozolomide and tumor treating fields (SPARE) for patients with newly diagnosed glioblastoma.
Authors: Miller Ryan C , Song Andrew Jehyun , Ali Ayesha , Bar-Ad Voichita C , Martinez Nina Leyson , Glass Jon , Alnahhas Iyad , Andrews David W. , Judy Kevin , Evans James J , Farrell Christopher , Werner-Wasik Maria , Chervoneva Inna , Ly Michele , Palmer Joshua David , Liu Haisong , Shi Wenyin
Published: June 2021

2056

Background: Standard of care for patients with newly diagnosed glioblastoma includes concurrent chemoradiation and maintenance temozolomide with Tumor Treating Fields (TTFields). Preclinical studies suggest TTFields and radiation treatment have synergistic effects. We report our clinical trial evaluating safety and tolerability of scalp-sparing radiation with concurrent temozolomide and TTFields. Methods: This is a single arm pilot study. Adult patients (age ≥ 18 years) with newly diagnosed glioblastoma and a KPS of ≥ 60 were eligible. All patients received concurrent scalp-sparing radiation (60 Gy in 30 fractions) with temozolomide (75 mg/m2 daily) and TTFields (200 kHz). Maintenance therapy included temozolomide and continuation of TTFields. Radiation treatment was delivered through TTFields arrays. The primary endpoint was safety and toxicity of TTFields concurrent with chemoradiation in patients with newly diagnosed glioblastoma. Results: A total of 30 patients were enrolled in the trial. Twenty were male and ten were female, with a median age of 58 years (range 19 to 77 years). Median KPS was 90 (range 70 to 100). Median follow-up was 8.9 months (range 1.6 to 21.4 months). Twenty (66.7%) patients had unmethylated MGMT promotor status and ten (33.3%) patients had methylated promoter status. Median time from surgery to radiation was 34 days (26 to 49 days). Scalp dose constraints were achieved for all patients, with the mean dose having a median value of 8.3 Gy (range 4.3 to 14.8 Gy), the D20cc median was 26.1 Gy (range 17.7 to 42.8 Gy), and the D30cc median was 23.5 Gy (range 14.8 to 35.4 Gy). Skin adverse events (AEs; erythema, dermatitis, irritation, folliculitis) were noted in 83.3% of patients, however, these were limited to Grade 1 or 2 events, which resolved spontaneously or with topical medications. No patient had radiation treatment interruption due to skin AEs. Other Grade 1 events included pruritus (33.3%), fatigue (30%), nausea (13.3%), headache (10%), dizziness (6.7%), and cognitive impairment (3.3%). Other Grade 2 events included headache (3.3%). Nineteen patients (63.3%) had progression, with a median PFS of 7.6 months (range 1.6 to 12.7 months). Overall survival was not reached. Conclusions: Concurrent TTFields (200 kHz) with scalp-sparing chemoradiation is a safe and feasible treatment option with limited toxicity. Future randomized prospective trials are warranted to define therapeutic advantages of concurrent TTFields with chemoradiation. Clinical trial information: NCT03477110.
A single-arm phase Ib study of autologous cytokine-induced killer (CIK) cell immunotherapy in combination with sintilimab plus chemotherapy in patients with advanced non-small cell lung cancer (NSCLC)-CCICC-002.
Authors: Ren Xiubao , Zhou Li
Published: June 2021

2531

Background: Immune checkpoint inhibitors plus chemotherapy had showed benefits for advanced non–small-cell lung cancer (NSCLC) patients without targetable mutations. Autologous cytokine-induced killer (CIK) cells can restore the antitumor immunity to improve patient outcome. Combining CIK cells with anti-PD-1 mAb plus chemotherapy may strengthen the results in patients with advanced NSCLC. Methods: This is a single-center, open-label, phase 1b trial of combination CIK cells with sintilimab (anti-PD-1 mAb) plus chemotherapy in stage IIIB-IV NSCLC patients. Systemic therapy naïve patients received platinum-based doublet chemotherapy, sintilimab, and CIK cells every 3 weeks for 4 cycles，then sintilimab, and CIK cells for maintenance therapy until disease progression or unacceptable toxicity. Results: From May 2019 to Jan 2021, 34 patients (19 squamous， 15 non-squamous NCSLC)aged 46-73 years (median age 64 years) were enrolled. Among 32 evaluable patients, the ORR was 81.3% (73.7% in squamous and 92.3% in non-squamous NSCLC)and DCR was 100%. Among the 25 PR assessed by RECIST, CMR was demonstrated in 5 (23.1%) by PET-CT. Among 3 patients with brain metastases, 2 patients achieve intracranial CR, and 1 was PR. With a median follow-up of 7.5 months, the median DOR was not reached (range 0.5m-NA), and the median PFS and OS were not mature. Grade 3 or more TRAEs included pneumonia (n = 3); thrombocytopenia, leukopenia (n = 2 each); anemia, dysphagia, cardiomyopathy, rash (n = 1 each). Biomarkers and subgroups which correlated with efficacy and AEs are being analyzed included TMB, PDL1 expression, distribution of TILs, cytokines and so on. Conclusions: CIK cells therapy in combination with sintilimab plus chemotherapy were well tolerated and showed encouraging efficacy. Further studies are warranted to confirm these preliminary results. Research Sponsor: Tianjin Medical University Cancer Institute and Hospital. Clinical trial information: NCT03987867. [Table: see text]
GS-3583, a novel FLT3 agonist Fc fusion protein, to expand conventional dendritic cells in healthy volunteers.
Authors: Rajakumaraswamy Nishanthan , Dauki Anees , Kuhne Michelle R. , Trowe Torsten , He Jing , Clarke Christopher , Carr Brian , Worth Angela , Vashishtha Anshu , Schwabe Christian , Othman Ahmed A.
Published: June 2021

2559

Background: Conventional dendritic cells subtype 1 (cDC1) play a vital role in the priming and expansion of tumor specific CD8+ T cells and their recruitment to tumor microenvironment (TME). However, cDC1s are often underrepresented in the TME. Systemic administration of Fms-like tyrosine kinase 3 ligand (FLT3L), a hematopoietic growth factor that binds to FLT3 on myeloid and lymphoid progenitor cells, leads to expansion of cDC1s in the periphery which can then be recruited into the TME. We hypothesize that FLT3 pathway stimulation using GS-3583, a FLT3 agonist Fc fusion protein, has the potential to promote T cell mediated anti-tumor activity. Methods: This was a first-in-human placebo-controlled study of GS-3583 in healthy volunteers to evaluate the safety, PK, and PD of escalating single doses (ranging from 75μg to 2000μg) of GS-3583. The study was blinded to the subjects and the investigator. Each dose cohort enrolled 8-12 healthy subjects who received GS-3583 or placebo as single IV infusion at 3:1 ratio. Subjects were observed in the phase 1 unit for 15 days and then for 12 weeks as outpatients. As part of the PD evaluation, we investigated the changes in the number of cDC1s and cDC subtype 2 (cDC2) cells. Results: As of 8th Feb 2021, selected safety, PK and PD data from the first 3 cohorts were available. GS-3583 was well tolerated and all subjects had been discharged. To date, there have been no serious or grade 3 or higher adverse events. Preliminary PK analysis suggested dose-dependent increase in GS-3583 exposure (AUC and Cmax). Preliminary PD analysis shows that administration of GS-3583 resulted in dose-dependent increases in cDC1/cDC2 cells that peaked at day 5 or day 8 and returned to baseline within three weeks of drug administration. Conclusions: GS-3583 was safe and well tolerated and induced dose dependent expansion of dendritic cells in the periphery. In patients with cancer, this increase in dendritic cells can be utilized to enhance anti-tumor responses to immuno-oncology therapies.[Table: see text]
Pembrolizumab in microsatellite instability high (MSI-H)/mismatch repair deficient (dMMR) cancers: Updated analysis from phase 2 KEYNOTE-158 study.
Authors: Maio Michele , Ascierto Paolo Antonio , Manzyuk Ludmila , Motola-Kuba Daniel , Penel Nicolas , Cassier Philippe A. , Bariani Giovanni , De Jesus-Acosta Ana , Doi Toshihiko , Longo Federico , Miller Wilson H. , Oh Do-Youn , Gottfried Maya , Wang Ruixue , Jin Fan , Norwood Kevin Glen , Marabelle Aurelien
Published: June 2021

2565

Background: Approval of pembrolizumab for the treatment of unresectable or metastatic MSI-H/dMMR solid tumors that have progressed on prior therapy was supported by data from KEYNOTE-158 (NCT02628067). At the data cutoff of Dec 6, 2018, the ORR was 34.3% among 233 patients (pts) with MSI-H/dMMR solid tumors enrolled in all cohorts of KEYNOTE-158, 77.6% had duration of response (DOR) ≥24 mo, median PFS was 4.1 mo, and median OS was 23.5 mo. We present results from 351 pts enrolled in KEYNOTE-158 cohort K at the data cutoff of Oct 5, 2020. Methods: Cohort K of this phase 2, open-label study enrolled adults with any previously treated advanced noncolorectal MSI-H solid tumor, measurable disease per RECIST v1.1, and ECOG PS of 0–1. MSI-H/dMMR status was assessed locally from a tumor tissue sample and defined as ≥1 of 4 MMR proteins absent by immunohistochemistry or as ≥2 allelic loci size shifts of 5 microsatellite markers by PCR. Pts received pembrolizumab 200 mg Q3W for up to 35 cycles or until PD, unacceptable toxicity, investigator decision, or withdrawal of consent. The primary endpoint was ORR per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints were DOR and PFS per RECIST v1.1 by BICR, OS, and safety. Efficacy was assessed in all pts who received ≥1 dose of treatment with ≥6 mo follow-up; safety was assessed in all treated pts. Results: 351 pts were enrolled in KEYNOTE-158 cohort K across multiple tumor types, including endometrial (22.5%), gastric (14.5%), small intestine (7.4%), ovarian (7.1%), cholangiocarcinoma (6.3%), and pancreatic (6.3%). 41.0% had 1 prior line of therapy; 55.6% had ≥2 prior lines. Median time from first dose to database cutoff (Oct 5, 2020) was 37.5 (range, 0.2–55.6) mo; 16.0% were continuing treatment. The ORR among the 321 eligble pts was 30.8% (CR, 27; PR, 72); median DOR was 47.5 mo (Table). Treatment-related AEs occurred in 64.7% of pts (grade 3–5, 12.0%), led to discontinuation in 6.6%, and led to death in 3 pts (myocarditis, pneumonia, and Guillain-Barre syndrome). Immune-mediated AEs and infusion reactions occurred in 20.2% of pts (grade 3–4, 4.3%) and led to death in 2 pts with no other contributing factors (myocarditis [AE start, day 26; death, day 33] and Guillain-Barre syndrome [AE start, day 22; death, day 41]). Conclusions: Pembrolizumab demonstrated a high ORR (30.8%), durable clinical benefit, and a manageable safety profile in this heavily pretreated advanced MSI-H/dMMR noncolorectal pan-tumor population. Clinical trial information: NCT02628067. [Table: see text]
Phase I dose escalation of KD033, a PDL1-IL15 bispecific molecule, in advanced solid tumors.
Authors: Luke Jason J. , Olszanski Anthony J. , Puzanov Igor , Lu Dan , Hackett Adrian , Martomo Stella , Patel Jeegar , Schueller Olivier , Mora Alessandro , Schlitt Miranda , Li Linghui
Published: June 2021

2568

Background: IL-2 and IL-15 signal through the shared IL-2/15 βγ receptor, but unlike IL-2, IL-15 does not expand regulatory T cells (Tregs), does not mediate activation-induced cell death and may have an improved therapeutic index. KD033 is a fusion antibody combining a fully human, high affinity anti-human Programmed Death Ligand 1 (PD-L1) IgG1 antibody with the human IL-15 receptor alpha (IL15Rα) sushi domain and human IL-15 (IL-15). KD033 (or its mouse cross reactive surrogate molecule, srKD033) has been extensively characterized in multiple in vitro and in vivo nonclinical studies. The fusion of anti-PD-L1 antibody to IL-15 significantly increases the maximal-tolerated dose (MTD) of srKD033 in mice compared to free IL-15. In addition, srKD033 has exhibited increased efficacy in rejecting tumors in mice as compared to the combination of its individual components, anti-PD-L1 antibody and IL-15. Methods: This is a phase 1, open-label, multiple ascending dose, multi-center clinical trial being conducted in patients with metastatic or locally advanced solid tumors (NCT04242147). The primary objective is to determine the safety and tolerability and the MTD of KD033. Secondary objectives include characterization of PK and immunogenicity, evaluation of CD8 T and NK cell activation and assessment of best overall response and duration of response. KD033 is administered by IV infusion over 30 minutes every 14 days. Accelerated intra-patient dose escalation across the initial three dose levels, followed by 3+3 escalation thereafter, is investigating dose ranges from 3 µg/kg to 600 µg/kg. Efficacy evaluation is planned in an expansion cohort of patients with PD-1/L1 refractory tumors. Results: A total of 7 patients have received treatment. Three patients were dosed in Cohort 1 and four patients were dosed in Cohort 2. Through two dose escalation cohorts (3 µg/kg – 25 µg/kg), no dose-limiting toxicities have been reported. Grade 1-2 treatment-related toxicities, when observed, resolved within 24 hours with supportive management. 6 patients are evaluable for treatment response with one patient (adenoid cystic carcinoma) in the first cohort having stable disease for more than 6 months. Conclusions: KD033 has been well tolerated early in dose escalation with on-mechanism pharmacodynamics consistent with IL-15 agonism. Clinical trial information: NCT04242147.
IFN-α, IFN-γ, IL-2 combined with TNF-α for predicting efficacy of PD-1 inhibitors combination therapy in patients with solid cancers.
Authors: Xing Penghui , Zhang Jinyan , Liu Rongfeng , Wang Junyan , Ma Ming , Wang Lixing , Jiao Wenjing , Shao Junguo , Wang Yuxiang , He Hongtao , Shan Baoen , Shi Jian
Published: June 2021

2584

Background: PD-1 inhibitors have transformed the treatment landscape for patients (pts) with many advanced malignancies. Combination therapy with PD-1 inhibitors for cancer is a trend. However, Biomarkers for the efficacy of combination therapy remains unknown. In order for the benefited population to be screened out, biomarkers need to be established. we will conduct the following study, to explore the IFN-α, IFN-γ, IL-2 combined with TNF-α for predicting efficacy of PD-1 inhibitors combination therapy. Methods: Using postoperative without lesions as control group (n=7). Pts with lesions as the experimental group (n=66). 27 of 66 pts received chemoradiotherapy (group A), 39 of 66 pts received PD-1 inhibitors combined with therapy (group B). IFN-α, IFN-γ, IL-2, TNF-α in peripheral blood of all pts were measured using flow cytometry. Results: 1) There was significant difference in proportion above normal concentrations (ANCs) of IFN-α between two groups (57.1% vs 43.5%, P<0.05), but there was no significant difference in IFN-γ, IL-2 and TNF-α between two groups (IFN-γ 57.1% vs 52.2%, IL-2 14.3% vs 5.8%, TNF-α 42.9% vs 43.5%, P>0.05). 2) The normal ratios of IFN-α, IFN-γ and TNF-α in group B was significantly higher than that in group A (IFN-α 64.1% vs 51.9%, IFN-γ 59% vs 37%, TNF-α 69.2% vs 44.4%, P<0.05). The proportion ANCs of IFN-α, IFN-γ, and TNF-α were lower in group A (IFN-α 35.9% vs 63%, P>0.05; IFN-γ 41% vs 63%, P<0.05; TNF-α 30.8% vs 55.6%, P<0.05). However, the proportion ANCs of IL-2 detection was lower (7.4% vs 5.1%). 3) In group B, 21 of 39 pts were evaluable. ORR was 52.4% (11/21) and DCR was 85.7% (18/21). The proportion ANCs of IFN-α, IFN-γ and TNF-α in the pts with PR was higher than that with SD (IFN-α 37.5% vs 28.6%, IFN-γ 37.5% vs 28.6%, TNF-α 50% vs 38.8%, P<0.05). 4) We found that the coincidence rate of IFN-α+ IFN-γ and IFN-α+ IFN-γ+TNF-α was higher in group B (Table). Conclusions: Our results suggest that the proportion ANCs of IFN-α, IFN-γ, and TNF-α in the pts with lesions were lower than that without lesions, it may be the decrease of immune function with lesions. There was positive correlation between proportion ANCs of IFN-α, IFN-γ and TNF-α and efficacy in these pts. IL-2 was not used as a routine detection indicator. The coincidence rate of IFN-α, IFN-γ combined with TNF-α was higher, it may help predict the outcome of PD-1 inhibitors combination therapy in pts with solid cancers, and helpful to screen the benefit population. Further study is needed.[Table: see text]
A pan-cancer analysis of MUC family genes as potential biomarkers for immune checkpoint therapy.
Authors: Li Yang , Duan Qianqian , Tan Yuan
Published: June 2021

2598

Background: Mucin (MUC) is a family of high-molecular weight glycoproteins and increased mucin production occurs in many malignant tumors. Recent studies have found relationship between mutations of some MUC family genes and efficacy of immunotherapy. Here, we explored the associations of MUC family genes (MUC2, MUC3A, MUC4, MUC5B, MUC6, MUC12, MUC16, MUC17, MUC19) mutation with ICI response based on multidimensional data from multiple solid tumors. Methods: 15 solid tumor types of TCGA genomic data for 6138 patients was used to evaluate tumor mutational burden (TMB) differences between MUC family genes mutation group and wildtype group. TMB was calculated as the total count of nonsynonymous mutations in coding sequence. Neoantigens of 3039 samples across 11 solid tumor types were obtained from The Cancer Immunome Atlas. A pan-cancer immunotherapy cohort (Broad/Dana-Farber, Nat Genet 2018, N = 249) was used to explore the relationship between mutations of MUC family genes and its efficacy of immunotherapy. Results: The most common mutated MUC genes (frequency > 5%) were MUC16 (25.3%), MUC17 (10.8%), MUC5B (10.5%), MUC4 (8.6%), and MUC2 (5.1%). The data between MUC mutation group and wild type group showed a significant difference (P < 0.01) in TMB. Median TMB across fifteen tumors in MUC mutation group and wild type group is 7.04 mutations per Mb and 2.07 mutations per Mb, separately. The TNB between two group is also showed a significant difference (P < 0.01). Median TNB across nine types tumor in MUC mutation group and wild type group is 121.5 neoantigens and 34.0 neoantigens, separately. A multivariable analysis across the pan-cancer cohort using Cox proportional-hazards regression demonstrated that KMT2C mutation was associated with better OS (hazard ratio, 0.66; 95%CI, 0.45-0.99; P = 0.042), adjusting for sex and cancer type. Conclusions: The results indicated that MUC family genes mutation was associated with a higher TMB and TNB. Analysis of immunotherapy cohort data showed MUC family was associated with better OS. These findings indicate that these genes mutation may serve as a predictive biomarker for ICI in solid tumor patients.
Pan-cancer analysis of CD274 (PD-L1) mutations in 314,631 patient samples and subset correlation with PD-L1 protein expression.
Authors: Huang Richard S.P. , Decker Brennan , Murugesan Karthikeyan , Hiemenz Matthew , Mata Douglas A. , Li Gerald , Creeden James , Ramkissoon Shakti H. , Ross Jeffrey S.
Published: June 2021

2605

Background: The effects of non-amplification short variant (SV) mutations in CD274 (PD-L1) on PD-L1 protein expression and immune checkpoint inhibitor (ICPI) therapy are unknown. Here, we present a retrospective analysis of CD274 mutations detected by comprehensive genomic profiling (CGP) and correlate these results with tumor-cell PD-L1 immunohistochemistry (IHC)-based expression assessment to better understand the relationship between mutations and protein expression of PD-L1. Methods: FoundationOne CGP was performed on hybridization-captured, adaptor ligation-based libraries using DNA and/or RNA extracted from 314,631 tumor samples that were sequenced for up to 406 cancer related genes and select gene rearrangements. PD-L1 IHC was performed on a subset of cases (n = 213) using the DAKO 22C3 PD-L1 IHC assay and scored with the tumor proportion score (TPS). Results: Overall, the prevalence of CD274 SV mutations was low (0.3%, 1,081/314,631) with 577 unique variants. The most common CD274 SV mutations were R260H (n = 51), R260C (n = 18), R125Q (n = 12), C272fs*13 (n = 11), R86W (n = 10), and R113H (n = 10). The prevalence of CD274 mutations varied depending on tumor type with diffuse large B-cell lymphoma (1.9%, 19/997), cutaneous squamous cell carcinoma (1.6%, 14/868), endometrial adenocarcinoma (1.0%, 36/3740), unknown primary melanoma (0.9%, 33/3679), and cutaneous melanoma (0.8%, 32/3874) having the highest frequency of mutations. Ultraviolet exposure was likely a mechanism for CD274 SV mutations in cutaneous tumors with high frequencies of ultraviolet mutational signatures (cutaneous squamous cell carcinoma [84.6%, 11/13], cutaneous melanoma [93.8%, 30/32], and unknown primary melanoma [100%, 32/32]), and microsatellite instability (MSI) was likely a mechanism for development of CD274 mutations in non-serous endometrial adenocarcinoma. Of the R260H cases concurrently tested with PD-L1 IHC, most (81.8%, 9/11) had no PD-L1 expression, which contrasts to the five E237K cases where most (80%, 4/5) had PD-L1 expression. This difference in protein expression of these two mutations was significantly different (p = 0.036). It was notable that nearly all samples (88.9%, 16/18) with a clonal truncating variant (nonsense or frame shift indel) and PD-L1 testing showed a PD-L1 TPS score ≤1, whereas three of four samples with sub-clonal truncating variants had TPS scores ≥5. Conclusions: We defined the landscape of CD274 mutations in a large cohort of tumor types that can be used as a reference for examining CD274 mutations as potential resistance biomarkers for ICPI. Furthermore, we presented novel data on the correlation of CD274 mutations and PD-L1 protein expression, providing important new information on the potential functionality of these mutations and can serve as a basis for future research.
A dual target sequencing solution to assess genomic and epigenomic alterations in cell-free DNA with no sample splitting.
Authors: Zhao Grace Q. , Bao Yun , Wang Heng , Hu Wanping , Coller John , Lin Shengrong
Published: June 2021

3043

Background: Assessing the genomic and epigenomic changes on plasma cell-free DNA (cfDNA) using next-generation sequencing (NGS) has become increasingly important for cancer detection and treatment selection guidance. However, two major hurdles of existing targeted NGS methods make them impractical for the clinical setting. First, there is no comprehensive, end to end, kit solution available for targeted methylation sequencing (TMS), let alone one that analyzes both mutation and methylation information in one assay. Second, the low yield of cfDNA from clinical blood samples presents a major challenge for conducting multi-omic analysis. Thus, an assay that is capable of both genomic and epigenomic analysis would be advantageous for clinical research and future diagnostic assays. Methods: Here, we report the performance of Point-n-SeqTM dual analysis, a kit solution that can provide in-depth DNA analysis with highly flexible and customizable focused panels to enable both genomic and epigenomic analysis without sample splitting. With custom panels of tens to thousands of markers designed with > 99% first-pass success rate, we conducted both performance validation and multi-center, multi-operator, reproducibility studies. Using spike-in titration of cancer cell-line gDNA with known mutation and methylation profiles, Point-n-Seq assay achieved a reliable detection level down to 0.003% of tumor DNA with a linear relationship between the measured and expected fractions. Benchmarked with conventional targeted sequencing and methylation sequencing, Point-n-Seq solution also demonstrated improved performance, speed and shortened hands-on time. Results: In a pilot clinical study, a colorectal cancer (CRC) TMS panel covering 560 methylation markers and a mutation panel with > 350 hotspot mutations in 22 genes were used in the dual assay. Using 1ml of plasma from late-stage CRC patients, cancer-specific methylation signals were detected in all samples tested, and oncogenic mutations. In an early-stage cohort (33 stage I/II CRC patient ), comparison of the analysis between tumor-informed, personalized-mutation panels (̃100 private SNVs) for each patient and the tumor-independent CRC methylation panels were conducted. The initial results showed that tumor-independent TMS assay achieved a comparable detection compared to the personalized tumor-informed approach. Moreover, cfDNA size information (fragmentome) is also integrated into the analysis of the same Point-n-Seq workflow to improve the assay sensitivity. Conclusions: Point-n-Seq dual analysis is poised to advance both research and clinical applications of early cancer detection, minimal residual disease (MRD), and monitoring.
Modeling cell-free DNA fragment size densities for non-invasive detection of cancer.
Authors: Carey Jacob , Chesnick Bryan , Butler Denise , Rongione Michael , Parmigiani Giovanni , Velculescu Victor E. , Dracopoli Nicholas C , Scharpf Robert B.
Published: June 2021

3058

Background: Circulating cell-free DNA (cfDNA) is largely nucleosomal in origin with typical fragment lengths of 167 base-pairs reflecting the length of DNA wrapped around-the histone and H1 linker. Given the nucleosomal origin of cfDNA, we have previously used low coverage whole genome sequencing to evaluate DNA fragmentation profiles to sensitively and specifically detect tumor-derived DNA with altered fragment lengths or coverage. Methods: Here we evaluate the use of Bayesian finite mixtures to model the fragment length distribution and demonstrate how the parameters from these models can be useful to distinguish between individuals with and without cancer. We examined the number of cfDNA fragments by size ranging from 100-220bp and approximated the mixture component location, scale, and weight using Markov Chain Monte Carlo. The performance of the method was determined using a ten-fold, ten repeat cross-validation of Gradient Boosted Machine model using 1) our previously described genome-wide fragmentation profile approach, 2) the parameters from the mixture model and 3) a combination of approaches 1) and 2) as features. Results: In this study of 215 cancer patients and 208 cancer-free individuals, we observed cross-validated AUCs of 1) 0.94, 2) 0.95, and 3) 0.97 among the three approaches. Conclusions: Our findings indicate that parsimonious mixture models may improve detection of cancer in conjunction with fragmentation profile analyses across the genome.
Survival and organ preservation according to clinical response after total neoadjuvant therapy in locally advanced rectal cancer patients: A secondary analysis from the organ preservation in rectal adenocarcinoma (OPRA) trial.
Authors: Thompson Hannah , Kim Jin Ki , Yuval Jonathan B. , Verheij Floris , Patil Sujata , Gollub Marc J , Wu Abraham Jing-Ching , Lee Meghan , Hezel Aram F , Marcet Jorge , Cataldo Peter , Polite Blase N. , Herzig Daniel , Liska David , Oommen Samuel , Friel Charles , Ternent Charles A. , Coveler Andrew L. , Hunt Steven R. , Garcia-Aguilar Julio
Published: June 2021

3509

Background: Clinical response following neoadjuvant therapy is paramount to identifying locally advanced rectal cancer (LARC) patients suitable for Watch and Wait (WW). A 3-tier schema was devised to stratify clinical response. Patients with a complete clinical response (cCR) are considered for WW, while those with an incomplete clinical response (iCR) are recommended for total mesorectal excision (TME). A near complete response (nCR) tier captures patients with significant, but not complete, response to be considered for WW. This schema’s efficacy has yet to be validated. We investigated survival and organ preservation (OP) rates based on this 3-tier clinical response assessment in patients with LARC who underwent total neoadjuvant therapy (TNT) in a prospective, multi-center clinical trial. Methods: Patients with MRI stage II and III rectal adenocarcinoma were randomized to either induction chemotherapy (FOLFOX or CAPEOX) followed by chemoradiation or chemoradiation followed by consolidation chemotherapy (FOLFOX or CAPEOX). At 8+/-4 weeks following TNT, response on digital rectal and endoscopic examinations was evaluated by the 3-tier schema. The date of this restaging clinical response assessment was used as time zero. The endpoints of rate of OP, disease-free survival (DFS), TME-free DFS, and overall survival (OS) were evaluated using the Kaplan-Meier method with differences analyzed by the log-rank test. Results: Clinical response assessments were available for 294 patients. The median time to assessment after neoadjuvant therapy was 7.9 weeks. Based on the 3-tier schema, 124 patients were categorized as cCR, 113 as nCR, and 57 as iCR. Baseline age, sex, average distance from the anal verge, clinical T classification, and clinical N classification were similar between the response groups. The table shows the 3-year rates of OP, DFS, TME-free DFS, and OS. The median follow-up was 2.36 years. Of the patients with a nCR, the 3-year TME rate was 48% compared with 21% in the cCR group. Conclusions: The 3-tier clinical response assessment has prognostic implications for OP and DFS in patients with LARC who underwent TNT. In patients with a nCR, more than half achieved OP at 3 years. This information should be utilized to counsel patients regarding their expected outcomes. Clinical trial information: NCT02008656. [Table: see text]
Molecular correlates of clinical benefit in previously treated patients (pts) with BRAF V600E-mutant metastatic colorectal cancer (mCRC) from the BEACON study.
Authors: Kopetz Scott , Murphy Danielle A. , Pu Jie , Ciardiello Fortunato , Desai Jayesh , Grothey Axel , Van Cutsem Eric , Wasan Harpreet Singh , Yaeger Rona , Yoshino Takayuki , Donahue Amber C , Golden Adele , Gollerkeri Ashwin , Zhu Zhou , Tabernero Josep
Published: June 2021

3513

Background: Encorafenib + binimetinib + cetuximab (enco/bini/cetux; triplet) and enco + cetux (doublet) regimens improved overall survival and objective response rate vs standard of care in pts with previously treated BRAF V600E-mutant mCRC in the randomized phase 3 BEACON study. To identify molecular correlates of clinical outcome, we performed molecular profiling in tumors from pts in the study. Methods: Baseline tumor samples were retrospectively analyzed by whole-exome sequencing (WES) and whole transcriptome sequencing (WTS) using ImmunoID NeXT (Personalis, Menlo Park, CA, USA). BRAF-mutant (BM) and consensus molecular subtypes (CMS) were determined using published classifiers. Pathway activities were evaluated with gene set variation analysis. Objective tumor response was evaluated according to each subtype. Additional association and interaction analyses between molecular features and clinical outcomes by treatments are ongoing and will be presented. Results: Baseline tumor samples were analyzed by WES and/or WTS from 527 of 665 (79.2%) randomized pts. The biomarker analyses set is representative of the total pt population and had similar clinical outcomes. Of the 460 pts analyzed by WTS (165/224 [73.7%] in the triplet arm, 146/220 [66.4%] in the doublet arm, and 149/221 [67.4%] in the control arm), 84.6% were classified as either CMS1 (n = 225) or CMS4 (n = 164). The proportion of pts classified as BM1 was 32.2% (n = 148) and the majority (84.5%) of these were CMS4, whereas many of those classified as BM2 (67.8%, n = 312) were CMS1 (64.7%). In the BM1 and CMS4 tumors, expression of inflammatory response and epithelial mesenchymal transition genes were elevated, and expression of cell cycle genes was reduced. The response rate in pts with CMS4 and/or BM1 tumors was higher in the triplet arm (CMS4: 33.3% [95% CI: 21.7–46.7]; BM1: 33.3% [95% CI: 21.4–47.1]) compared with the doublet arm (CMS4: 19.2% [95% CI: 9.6–32.5]; BM1: 14.9% [95% CI: 6.2–28.3]). Conclusions: Molecular characteristics and biological properties observed in BRAF V600E-mutant mCRC suggest that a subset of pts with specific molecular features may derive greater clinical benefit from triplet than doublet therapy. Additionally, these findings support the utility of gaining further understanding of the biological landscape in BRAF-mutant mCRC to enable potential hypotheses for pt selection to improve clinical outcome in future studies. Clinical trial information: NCT02928224.
Multi-omics analysis to reveal the role of gut microbiome–associated serum metabolites in the detection of colorectal cancer and adenoma.
Authors: Chen Feng , Dai Xudong , Cui Wei
Published: June 2021

3539

Background: Gut microbiome and their metabolites have been revealed to be associated with the initiation and progression of colorectal cancer (CRC), and gut microbiome produced or associated metabolites could enter the circulation system. Methods: Integrated analysis of untargeted serum metabolomics by liquid chromatography–mass spectrometry (LS-MS) and metagenome sequencing of fecal samples derived from matched individuals were used to profile serum metabolites that are both significantly affected by CRC and co-related with the gut microbiome. Targeted LC-MS was further used to test the ability of these metabolites for discriminating CRC and adenoma from healthy individuals. Results: More than 300 gut microbiome–associated serum metabolites with significantly altered abundance in both colorectal carcinoma (CRC) and adenoma patients have been identified. A panel of eight gut microbiome–associated serum metabolites (GMSM panel) was established and accurately discriminated CRC and adenoma from normal population. The GMSM panel–based CRC and colorectal adenoma prediction model yielded an area under the curve (AUC) of 0.94 (95% confidence interval: 0.90–0.99) and AUC of 0.91 (sensitivity 82%, specificity 91%) in the training and validation set respectively. This GMSM model shows significantly superior performance to the clinical marker carcinoembryonic antigen (CEA) (AUC 0.72), and more importantly, it suggests promising diagnostic potential in detecting adenoma (AUC = 0.81) and early-stage CRC (AUC = 0.91). Conclusions: Our results indicate that gut microbiome reprogramming in CRC patients is associated with the alterations of the serum metabolome, and these gut microbiome–associated serum metabolites has potential application for the detection of earlier CRC and adenoma.
Genome-wide analysis indicating cancer associated fibroblast (CAF) impacts on colorectal cancer (CRC) prognosis via immunosuppression.
Authors: Chen Yu-feng , Wu Xiaojian , Gao Feng
Published: June 2021

3543

Background: Cancer associated fibroblast (CAF) in tumor microenvironment is associated with poor prognosis and chemo-resistance in multiple solid tumors, however, there is lack of universal measure of CAF in colorectal cancer (CRC). The aim of this study was to assess fibroblast-signature for predicting outcome and analyze relevant mechanism. Methods: A dataset including 316 CRC patients without adjuvant chemotherapy was used as the discovery cohort for the identification of prognostic fibroblast-related genes (FRGs). A total of 1,352 CRC patients were then divided into one training cohort (n = 461) and two validation cohorts (n = 338, n = 553, respectively) for the construction of fibroblast-related gene signature (FRGS) and the verification of its prognostic value in stage II/III CRC patients. Functional annotation and analysis were performed to reveal the relevant mechanism. Results: A 11-gene signature was derived, which was prognostic for stage II/III CRC patients in two validation cohort (Validation-1 cohort: HR = 1.90, 95%CI = 1.16-3.12, P< 0.01; Validation-2 cohort: HR = 1.95, 95%CI = 1.39-2.73, P< 0.001). High CAF risk was correlated with worse prognosis in CRC patients without adjuvant chemotherapy (HR = 3.63, 95%CI = 2.24-5.88, P< 0.001), but not in patients who received adjuvant chemotherapy ( P= 0.154). Similar trends were found in Validation-1 cohort. After integrated with clinical characteristics, FRGS was confirmed as an independent prognostic factor after adjusted for TNM stage of tumor in multivariate analysis (Training cohort: HR = 3.19, 95%CI = 1.88-5.41, P< 0.001; Validation-1 cohort: HR = 5.00, 95%CI = 1.58-15.85, P= 0.007; Validation-2 cohort: HR = 2.99, 95%CI = 1.44-6.21, P= 0.003). Furthermore, enrichment analysis found that anti-tumor immune response was suppressed in the high CAF risk group. Conclusions: The 11-gene FRGS had independent prognostic value for CRC patients, as well as in prediction of benefit from chemotherapy. CAF in tumor microenvironment might impact on the prognosis of CRC patients via inhibiting immune response.
Repeat sequential oxaliplatin-based chemotherapy (FLOX) and nivolumab versus FLOX alone as first-line treatment of microsatellite-stable (MSS) metastatic colorectal cancer (mCRC): Initial results from the randomized METIMMOX study.
Authors: Ree Anne Hansen , Hamre Hanne , Kersten Christian , Hofsli Eva , Guren Marianne Grønlie , Sorbye Halfdan , Johansen Christin , Negård Anne , Flatmark Kjersti , Meltzer Sebastian
Published: June 2021

3556

Background: Immune checkpoint blockade (ICB) has revolutionized patient outcome for the small mCRC subgroup with highly immunogenic disease. The majority of mCRC cases, however, are MSS without innate ICB susceptibility. In our ongoing METIMMOX study, we hypothesize that MSS mCRC can be transformed into an immunogenic condition by short-course oxaliplatin-based therapy (FLOX), enabling patients with unresectable, previously untreated metastases to obtain durable disease control when adding ICB therapy. Here we present the protocol-planned interim analysis. Methods: Eligibility criteria include infradiaphragmatic metastasis and C-reactive protein < 60 mg/L. At analysis 15 January 2021, 54 patients stratified according to primary tumor sidedness and mutational status and evaluable for the primary end point (progression-free survival; PFS) had been randomly assigned to a standard-of-care schedule of 8 FLOX cycles Q2W (control arm) or repeat sequential 2 FLOX cycles and 2 nivolumab cycles (240 mg Q2W) to a total of 8 cycles (experimental arm), for both arms before treatment break until disease progression and reintroduction of a new treatment sequence. Radiologic response assessment is every 8 weeks. Safety, tolerability, objective response rate, and duration of response are among secondary end points. Results: At median follow-up of 6.4 (range, 0.5-20) months, patients were well balanced between the treatment arms with regard to the predefined strata and single-organ or multiple-organ metastases. Median PFS for the entire groups of control and experimental arm patients was 5.6 (range, 0.5-15; n = 26) and 6.6 (range, 0.5-20; n = 28) months, respectively. The number of FLOX-related CTCAE grade 3 or higher adverse events, including 2 deaths after initial FLOX administration, was comparable in the two arms. Twelve immune-related grade 3-4 adverse events (no new safety signals) were recorded. In the experimental arm, 4 (16%) patients, all RAS/BRAF-mutant cases, had experienced complete response and 9 (32%) patients had ongoing objective response at 8 months. The control arm cases had 0 with complete response and 6 (23%) with ongoing objective response at 8 months, 1 of whom had proceeded to curative-intent liver surgery. Conclusions: MSS mCRC patients may hold the opportunity of ICB responsiveness evoked by short-course oxaliplatin-based chemotherapy. The search for predictive biomarkers of ICB responsiveness is ongoing in the specifically designed METIMMOX correlative study program. Clinical trial information: NCT03388190.
Differential impact of different TP53 gain-of-function mutations on overall survival of patients with metastatic colorectal cancer: Results from a large integrated healthcare system.
Authors: Pan Minggui , Jiang Chen , Tse Pamela , Chung Elaine , Solorzano Aleyda , Hu Wenwei , Truong Thach-Giao , Arora Amit , Sundaresan Tilak Kumar , Suga Jennifer Marie Marie , Habel Laurel A. , Thomas Sachdev P.
Published: June 2021

3585

Background: TP53 mutation is present in approximately 50% of metastatic colorectal cancer (CRC). The spectrum of the TP53 mutations is extremely broad including approximately 80% missense mutations. Several missense mutations have been found to possess gain-of-function (GOF) properties in cell line and animal studies, however, confirmation of the concept of GOF in human malignancies is still lacking. Methods: We investigated the impact of TP53 GOF mutations in patients with metastatic CRC using the NGS data within Kaiser Permanente Northern California (KPNC), a large integrated healthcare system. Results: From November 2017 to January 2021, genomic profiling by StrataNGS was performed on 8658 patients, with 1056 patients being metastatic CRC, among whom 740 patients harbored a TP53 mutation (TP53mut) and 316 patients had wild-type TP53 (TP53wt). Ras (KRAS and NRAS) and BRAF mutation appropriately discriminated the overall survival (OS) of patient populations with either TP53wt or TP53mut, confirming the validity of our dataset. We identified seven GOF TP53 mutations (R175H, R248W, R248Q, R249S, R273H, R273L, R282W) in these CRC patients. We show that different GOF mutation differentially impacts the OS. Patients whose CRC harbored TP53mut R248W, R249S, and R282W (poor prognostic TP53mut, N = 47) had significantly worse OS versus patients whose CRC harbored TP53mut R248Q, R175H, R273H and R273L (N = 160, median OS 29.4 vs 44.2 months, HR 0.47, p = 0.007). The OS of the poor prognostic TP53mut patients was also significantly inferior compared to patients whose CRC harbored all other TP53 mutations (N = 1099, median OS 50.1 months, HR 0.55, p = 0.01) or TP53wt (N = 316, median OS 47,5 months, HR 0.54, p = 0.01). The demographics and the percent of Ras, BRAF, and PI3KCA mutations were similar except that the patients with the poor prognostic TP53mut had significantly higher percent of Ras mutation compared to the rest of the GOF TP53mut patients (p = 0.035). When compared to R248Q alone, R248W confers worse OS (median OS 36.3 vs 63.2 months, p = 0.05). Conclusions: Our data suggest that different TP53 GOF mutations are associated with very different clinical outcomes. Additional studies identifying specific TP53 GOF mutations that impact outcomes may provide further insight for drug development and clinical trial design.
Real-world survival outcomes associated with completion of adjuvant chemotherapy for stage III colon cancer.
Authors: Boyle Jemma Megan , Kuryba Angela , Cowling Thomas E , van der Meulen Jan , Fearnhead Nicola S , Walker Kate , Braun Michael , Aggarwal Ajay
Published: June 2021

3596

Background: The optimal duration of adjuvant combination chemotherapy administered to patients with stage III colon cancer is debated. Our study assessed the effect of completed chemotherapy cycles on 3-year colon cancer-specific mortality, as well as the effect of dose reduction and early discontinuation of oxaliplatin in patients with 100% completion, within a real-world population. Methods: 4,147 patients undergoing major resection between 01 June 2014 and 30 April 2017 with pathological stage III colon cancer in the English National Health Service were identified. Chemotherapy data were obtained from linked administrative hospital records and a national chemotherapy dataset. Patients were stratified according to completion of < 50% ( < 6 FOLFOX cycles or < 4 CAPOX cycles), 50-92% (6-11 FOLFOX cycles or 4-7 CAPOX cycles) or 100% of cycles (12 FOLFOX cycles or 8 CAPOX cycles). Competing-risk regression analysis for 3-year colon cancer-specific death was performed with adjustment for patient, tumour and hospital-level characteristics to estimate subdistribution hazard ratios (sHR) as a measure of relative risk. Results: Patients included within our study were less fit and had increased rates of high-risk disease (T4 and/or N2 pathological staging) compared to the IDEA study. For FOLFOX, the 3-year cumulative incidence of colon cancer-specific death in patients completing 100% of cycles was 15.1% (95% CI, 12.8% to 17.6%), 18.2% (95% CI, 15.3% to 21.3%) for 50-92% of cycles and 26.4% (95% CI, 20.6% to 32.5%) for < 50% of cycles. For CAPOX, this was 12.0% (95% CI, 10.2% to 14.0%) for 100% completion of cycles, 18.2% (95% CI, 15.6% to 21.0%) for 50-92% of cycles, and 19.8% (95% CI, 15.8% to 24.1%) for < 50% cycles. Compared to 100% completion of FOLFOX cycles, colon cancer-specific death was higher in patients recorded as completing < 50% (sHR 2.17; 95% CI, 1.56 to 3.03; P = < 0.001) and 50-92% of FOLFOX cycles (sHR 1.40; 95% CI, 1.09 to 1.78; P = 0.007). Compared to 100% completion of CAPOX cycles, colon cancer-specific death was higher in patients recorded as completing < 50% (sHR 2.02; 95% CI 1.53 to 2.67; P< 0.001) and 50-92% of CAPOX cycles (sHR 1.63; 95% CI 1.27 to 2.10; P< 0.001). Dose reduction and early discontinuation of oxaliplatin did not have a statistically significant effect on mortality. Conclusions: Patients within the real world setting were more likely to have poor prognostic factors. Those who completed adjuvant chemotherapy for stage III colon cancer had improved survival rates regardless of dose reduction or early discontinuation of oxaliplatin.
Phase I study of transarterial chemoembolization of lung metastases.
Authors: Boas Franz Edward , Kemeny Nancy E. , Sofocleous Constantinos T. , Yeh Randy , Thompson Vanessa R , Hsu Meier , Moskowitz Chaya S. , Ziv Etay , Yarmohammadi Hooman , Bendet Achiude , Solomon Stephen Barnett
Published: June 2021

3602

Background: Lung chemoembolization (via the bronchial or pulmonary artery) is a new treatment option for unresectable and unablatable lung metastases. Methods: 10 patients with unresectable and unablatable lung, endobronchial, or mediastinal metastases, who failed systemic chemotherapy, were enrolled in this single center, single arm, phase I trial. Pulmonary and bronchial angiography was performed in all patients, to determine the blood supply to the lung metastases. Based on the angiographic findings, bronchial or pulmonary artery chemoembolization was performed, using a lipiodol / mitomycin emulsion, followed by spherical particles. Technical success, safety, efficacy, and pharmacokinetics were evaluated. Wilcoxon signed-rank test was used to compare change in size of treated versus untreated tumors. Results: On angiography, all patients had lung metastases that were hypervascular compared to normal lung. 90% of patients had lung metastases supplied by the bronchial artery, and 10% were supplied by the pulmonary artery. Technical success rate of intra-tumoral drug delivery was 100% (95% CI: 76-100%). There were no severe adverse events, and all patients met criteria for discharge 4 hours post procedure. Response rate of treated lesions was 10% by RECIST and 40% by PERCIST. Treated tumors were mostly stable to decreased in size after chemoembolization (median change in size: 0%; IQR: -11% to 2%; mean: -4%), and untreated tumors were mostly increased in size (median change in size: 10%; IQR: 0% to 17%; mean 9%; p= 0.02). Intra-tumoral lipiodol retention at 4-6 weeks was correlated with decreased tumor size and metabolic activity. Pharmacokinetics showed that 45% of the mitomycin dose underwent burst release in 2 minutes, and 55% of the dose was retained intratumorally with a half-life > 5 hours. Initial tumor-to-plasma ratio of mitomycin concentration was 380. Half-life of intratumoral lipiodol retention was 16 days. In vitro experiments showed 50% emulsion separation in 6.2 days, and 50% drug release in 7.1 hours. Conclusions: Lung chemoembolization can safely treat lung, mediastinal, and endobronchial metastases, with minimal systemic toxicity. High intratumoral drug concentrations after chemoembolization can overcome chemoresistance. Clinical trial information: NCT04200417.