bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi-center phase 1 safety and efficacy study of nivolumab in renal transplant patients with metastatic malignancy.
Authors: Zalcberg John Raymond , Boyer Michael J. , Taylor Anne Elizabeth , Tan Thean Hsiang , Hockley Bronwyn , Carroll Rob 
Published: June 2021

2567 Background: Organ Transplant Recipients (OTR) are generally excluded from trials of immune checkpoint inhibitors (ICI) due to the reported risk of allograft rejection. A recent systematic review of published case series includes only 65 cases. Transplant organ rejection rates of 41% are reported with cancer response rates of 39%. The majority of OTR treated with ICI have had reduction/cessation of immunosuppression (IS) prior to ICI. Isolated IS reduction is associated with organ rejection and therefore either IS manipulation alone and/or ICI could induce organ rejection episodes. Methods: Renal OTR with incurable cancer, for whom ICI would normally be used in the general population (without an organ transplant), were eligible if creatinine < 180 umol/l, no donor specific HLA antibodies and ECOG < 2. Treatment was with nivolumab (3mg/kg q 14 days for 5 doses, then 480 mg q 28 days), without manipulation of IS and pre-ICI-exposure alloimmune risk assessment. Treatment continued till progression, patient refusal, or graft rejection. Primary endpoint was rate of irretrievable renal graft rejection. Results: 15 patients (9 male:6 female; median age 66.6 years) were enrolled and treated with a median (range) 3(1-42) infusions and with median (range) follow-up of 128 (11-784) days. Tumour types included:1 melanoma; 2 renal tract; 1 hepatocellular carcinoma; 1 Merkel cell; 1 adenocarcinoma lung; 1 MSI high colorectal, 8 squamous cell carcinoma (SCC) head and neck. 2 patients experienced rejection; one at day 28 (2 infusions); one at day 36 (3 infusions). Both had SCC and have had a CR. One is on haemodialysis and alive at 2 years the other a creatinine 450 umol/l. Both rejections treated with steroid, plasma-exchange and anti-thymocyte-globulin (ATG). 1 patient (metastatic bladder cancer) experienced graft loss (at 300 days) due to ureteric-stent bleed and BK-nephritis indirectly related to nivolumab- this patient died of progressive disease at 65 days after nivolumab cessation. Median (range) progression free disease (PD) with ≥ 2 infusions was 300 (68-784+) days. There were 5 CR (1 MSI high colorectal, 4 SCC) median duration of response 13 months and 2 PR (1 SCC 1 bladder)- 1 without PD. Conclusions: In this interim analysis, rejection rates in OTR with incurable cancers treated with ICI was 2/15 (13%) when IS is maintained and there is pre exposure alloimmune assessment. The combined CR and PR rate was 7/15 (47%). Clinical trial information: 12617000741381.
The Tim3-galectin-9 interactions in the tumor microenvironment of nasopharyngeal cancer.
Authors: Kwong Dora Lai Wan , Kam Ngar-Woon , Tse Wai Chun , Lok Sing Hei , Tsao George , Lee Victor Ho-Fun 
Published: June 2021

2629 Background: The complex cell interactions within the tumor microenvironment (TME) have become a crucial point in cancer research. Yet, the cell interactions might not only depend on the frequency of immune cells, but also on the inter-individual distances as cells might interact via soluble factors and/or cell-cell contact. Accordingly, the mapping of TME has recently gained importance. The aim of this study is to investigate the alternations between galectin-9 (G9) and its natural immunosuppressive receptor, T cell immunoglobulin and mucin domain 3 (Tim3) in nasopharyngeal cancer (NPC). Methods: Using multiplexed quantitative immunofluorescence, we measured the levels of G9 and Tim3 in 95 NPC patients cancerous and 8 normal specimens in tissue microarray format. Cell densities and cell-to-cell distances were quantified. The interaction between G9-expressing tumor cell lines and T cells were also studied. Results: G9-expressing tumor cells were detected in all NPC cases and were significantly higher than normal tissue. Elevated G9 was associated with shorter overall survival (OS: 89% vs 70.5% at 7 years, p: 0.019). Incremental percentages of Tim3+ cells were shown in top 10% cases strongly positive for G9-expressing tumor cells. The number of Tim3+ cells was calculated at 15µm intervals from the nearest G9-expressing tumor cells, of which a significant difference of Tim3+ cells was observed at the 0-15µm distance from G9-expressing cell in cancerous compared to normal tissues. Epithelial short distances were associated with a unfavourable prognosis. Observed short distance were hypothesized to represent Tim3+ cells actively interacting with G9-expressing tumor cells. Accordingly, In vitro cocultured of G9-ovexpressing NPC cell lines induced Tim3 expression on T cells which suppressed the T-cell mediate cytotoxicity on tumor cells. Conclusions: Our findings indicate a specific preexisting profile of Tim3+ and G9-expressing tumor cells and demonstrated that Tim3+ cells were mainly found intratumorally within 15µm of a NPC cell. The relevance of Tim3+ and G9+ distances reflect a potential marker of their functional interaction. Our results could have important implications for clinical therapeutic strategies. Since high G9 expression have poorer OS, they would deserve a different therapeutic strategy.[Table: see text]
Detection of prognostic cancer-specific circular RNA in plasma.
Authors: Brown Jason , Shah Palak , Vo Josh , Tsodikov Alex , Kleyman Lena , Cao Xuhong , Chinnaiyan Arul 
Published: June 2021

3032 Background: Earlier detection of cancer could lead to improved outcomes. Non-invasive biomarkers are integral for early detection, and protein and DNA-based assays have been previously described for this purpose. Evaluation of highly expressed circulating RNA would improve upon existing methods by allowing for quantitation, however RNA expression in plasma is low. Circular RNA (circRNA) is formed by alternative backsplicing and provide resistance to exoribonclease-mediated degradation. Therefore, circRNA is more stable in plasma and could potentially be more easily detected non-invasively. Here, we report results from a novel assay that identifies and quantitates expression of circRNA in cancer plasma. Methods: Cancer-specific circRNA targets were identified by analyzing differential expression and abundance based on capture RNA sequencing in tissues. CircRNA-specific probes were designed and validated by stable expression with RNAse R incubation. Expression of selected circRNA isoforms were measured using a quantitative PCR-based assay. For breast cancer specimens, plasma was collected from a cohort of 36 patients and 12 normal female controls without known cancer diagnosis. Expression was determined by normalizing signal to two averaged universally expressed circRNAs. Differential expression for each target was determined for cancer vs. normal and stratified based on ER and HER2 positivity as well as stage. Results: Normalized expression of seven proposed breast cancer-specific circRNA targets was determined for all patients in the cohort. All targets demonstrated resistance to RNAse R-mediated degradation in breast cancer cell lines. In the breast cancer cohort, CircTRPS1 expression was higher in cancer plasma than normal, trending toward significance. Expression of circTRPS1 was significantly more common in ER-negative than ER-positive breast cancer (p = 0.02). CircPDHX expression was elevated in normal plasma compared to cancer and relatively higher in ER-positive than ER-negative cancer (p = 0.05). Median expression in plasma was elevated in cancer specimens compared to normal for CircVAV3, circDNAH14, and circCDYL. CircERBB2 expression was also relatively higher in HER2-positive cancer when compared to other targets. Higher expression significantly positively correlated with metastatic disease for circERBB2 (p = 0.01) and circCDYL (p = 0.005) and negatively correlated with metastasis for circWDR78 (p = 0.02). Conclusions: CircRNA are promising biomarkers for early non-invasive detection of cancer. We identified seven circRNA biomarkers in breast cancer plasma which correlated with clinical characteristics. Three circRNAs were significantly prognostic for metastatic breast cancer. Identification of additional cancer-specific targets and multiplexing markers is underway. This assay is generalizable to other cancers, and similar studies in prostate and bladder cancer are in progress.
Incidence of ERBB gene fusions (EGFR, ERBB2, ERBB4) across tumor types.
Authors: Schubert Laura , Elliott Andrew , Doebele Robert Charles , Lou Emil , Borghaei Hossein , Demeure Michael J. , Kurzrock Razelle , Le Anh T. , Reuss Joshua E. , Ou Sai-Hong Ignatius , Braxton David R. , Thomas Christian A. , Darabi Sourat , Korn Wolfgang Michael , El-Deiry Wafik S. , Liu Stephen V. 
Published: June 2021

3091 Background: Gene fusions often represent critical therapeutic targets across cancer subtypes. Fusions within the ErbB family of receptor tyrosine kinases, including EGFR, ERBB2 ( HER2) and ERBB4 ( HER4), have been previously described and represent potentially actionable alterations. Here, we report the relative incidence and functional characterization of these rare genomic events. Methods: Tumor samples (n = 64,354; representing > 40 tumors types) submitted to Caris Life Sciences (Phoenix, AZ) were molecularly profiled by next-generation sequencing of DNA (NextSeq, 592-gene panel; or NovaSeq, whole exome) and RNA (whole transcriptome). Gene fusion partners, in/out-of-frame status, retention of ERBB kinase domain, and topology of fusion breakpoints were characterized for each ERBB fusion transcript detected. Fusion prevalence was further examined in public data sets (TCGA, MSK-IMPACT and AACR GENIE). Results: From the Caris database, a total of 64 EGFR fusion isoforms were detected in 59 tumors (incidence 0.09%); 83% were in-frame and 91% retained the EGFR kinase domain. 206 ERBB2 fusion isoforms were detected in 114 tumors (0.18%); 37% were in-frame and 34% retained the ERBB2 kinase domain. 131 ERBB4 fusion isoforms were detected in 108 tumors (0.17%); 62% were in-frame and 51% retained the kinase domain. All fusions were detected at low incidence across all tumor types. EGFR fusions were most common in high grade glioma (1.7%, n = 35), largely driven by recurrent EGFR-SEPT14 fusions (n = 20). ERBB2 fusions were most common in esophageal/gastroesophageal junction carcinoma (1.1%, n = 20), with recurrent fusion to PGAP3 observed in multiple tumor types (n = 37). ERBB4 fusions were most common in ovarian (0.7%, n = 40) and bladder (0.7%, n = 15) cancers, which often resulted from recurrent fusion with IKZF2 (n = 36). EGFR and ERBB2 fusions were generated predominantly (44-48%) from inversion events, while ERBB4 fusions arose more frequently and at similar rates (27-32%) from deletions, duplications, or translocations. Mining of public data sets corroborated the prevalence of ERBB gene fusions: the frequency of EGFR fusions was 0.63%, ERBB2 was 0.14% and ERBB4 was 0.04%. TP53 mutations frequently co-occurred with ERBB2 and ERBB4 fusions ( > 60% average across public data sets), with higher co-mutation rates ( > 70%) observed for samples in the Caris database. Conclusions: ERBB gene fusions are detectable at low frequency in various tumor types and may represent a unique genomic subset of cancer. Identification of novel ERBB gene fusions warrants further investigation to determine the potential pathogenicity and actionability of these fusions.
Optimal dose selection in oncology biologics development: Need for a paradigm shift.
Authors: Mittapalli Rajendar K , Liao Kai Hsin , Williams Jason , Palaparthy Rameshraja , Yin Donghua 
Published: June 2021

3093 Background: In oncology, the recommended phase 2 dose (RP2D) is typically selected from the first-in-patient (FIP) dose escalation and then carried forward to late stage trials. The RP2D is often informed by limited data from a relatively small number of patients. Further dose optimization in late stage trials is rare as these trials often evaluate only one dose/dosing regimen. Traditionally oncology development relied on establishing an MTD with the expectation this dose would ultimately provide an optimal benefit/risk profile. However, for biologics there are clear examples suggesting a need to reconsider this approach to dose selection during drug development. The present review attempts to evaluate the dose selection approaches for approved oncology biologics to identify opportunities for improved dose optimization of future oncology drugs. Methods: The dose selection steps for oncology biologics approved by the USFDA from 2010 to 2020 were reviewed. The primary focus of the review was RP2D selection based on early clinical data, doses tested in pivotal trials, exposure-response and dose justification for the proposed dose, and post-marketing requirements (PMR) or post-marketing commitments (PMC) related to dose optimization. Results: The dose selection process for a total of 22 biologics was analyzed. Among these, 17 (77%) did not identify MTD during the FIP trial, and 6 (27%) tested more than one dose in the registration trials. In the initial approval, 2 (10%) had PMR or PMC for further dose optimization. For majority of the biologics the dose justification was based on 1) receptor occupancy 2) biomarker response 3) early clinical activity and 4) target efficacious concentration based on xenograft data. The majority of biologics had shown a shallow exposure-response relationship in safety or efficacy end points which partly can be attributed to the common practice of testing single dose level in the registrational trial. The dose recommended in the FDA label appears to be highly correlated to the RP2D determined in FIP studies. Conclusions: Oncology biologics have heavily relied on pharmacodynamic, early signs of efficacy, and safety data from the limited number of patients in the FIP dose escalation to identify the dose for pivotal trials. In most cases, there have been no dose ranging or optimization based on the final therapeutic outcome. While integration of relevant biomarker, PK, and PD data for optimal dose selection is an important aspect, there is a need to change the paradigm to consider more robust dose optimization, especially in early stage development. Dose ranging assessments incorporating therapeutically relevant endpoints and adequate sample size should be considered, ideally prior to pivotal trials.
Pre-therapeutic dihydropyridimidine dehydrogenase (DPD) deficiency screening: Impact on fluoropyrimidine dose reduction at the second chemotherapy cycle and on early severe toxicity.
Authors: De Metz Côme , Hennart Benjamin , Le Deley Marie-Cecile , Cren Pierre-Yves , Desauw Christophe , Bourgeois Vincent , Laestadius Fredrik , Rad Emilia , Lebellec Loic , Penel Nicolas , Carnot Aurelien 
Published: June 2021

3096 Background: DPD deficiency screening before fluoropyrimidine is a matter of debate. To avoid lethal toxicity, French authorities impose DPD screening before fluoropyrimidine-based chemotherapy by dosing uracilemia since April 2019. Methods: We have included all consecutive adult patients receiving 5-fluorouracil (5-FU) or capecitabin from April 2019 to January 2020 in 6 cancer centers. During the study period, different methods for screening had been applied: DPYD complete sequencing, phenotype (uracilemia and/or dihydrouracilemia/uracilemia ratio - UH2/U -) or both. All sceening tests were conducted in the same laboratory. Association between the method of DPD screening and fluoropyrimidine dose reduction at second chemotherapy cycle or on severe ≥grade 3 early toxicity (between first and second cycle) was evaluated using multivariate logistic regression. Concordance between genotype and phenotype for DPD deficiency was explored using Cohen Kappa test. Results: We included 597 patients, the median age was 63 (range, 55-77). The most prevalent cancers were digestive (68.3%), head and neck (19.4%) and breast (9.2%). 12.3% of patients received capecitabine and 87.3% received polychemotherapy. DPD deficiency screening was done for most of patients (n=519, 86.9%). DPD screening method consisted in full sequencing of DPYP (n=41; 7.9%), phenotype analysis (n=44, 8.5%) or both (n=424, 83.6%). We did not identify any complete DPD deficiency. Uracilemia was dosed for 467 patients, the median was 6.5 ng/mL and for 21 patients (4.5%) uracilemia was > 16 ng/mL and/or UH2/U <6, suggesting DPD deficiency. Severe early toxicities were observed for 82 patients (14%), with two patients presenting grade 5 toxicity. Overall DPD screening and method of DPD screening were not associated with fluoropyrimidine dose reduction at second cycle or early severe toxicity. In multivariate analysis, the only predictor for fluoropyrimidine reduction at second cycle (n = 125 patients) was polychemotherapy (OR=2.8; p=0.012). Kappa between uracilemia and UH2/U was 0.23 (poor concordance). Kappa between DPYP sequencing and uracilemia or UH2/U was 0.09 (very poor concordance). Conclusions: No DPD deficiency screening method was associated with dose adaptation at second cycle or early severe toxicity. The optimal strategy for DPD screening requires further clinical evaluation.
Landscape of KRASG12C, associated genomic alterations, and interrelation with immuno-oncology (IO) biomarkers.
Authors: Salem Mohamed E. , El-Refai Sherif , Sha Wei , Grothey Axel , Puccini Alberto , George Thomas J. , Hwang Jimmy J. , Musselwhite Laura W. , King David , Kadakia Kunal C. , Raghavan Derek , Van Cutsem Eric , Tabernero Josep , Tie Jeanne 
Published: June 2021

3127 Background: Sotorasib has shown promising activity in cancer patients (pts) specifically harboring the KRASG12C mutation. Response rates vary significantly by tumor type, suggesting KRASG12C pathogenesis may be cancer-type-dependent. Methods: We retrospectively analyzed de-identified records of 79,004 pts with various cancer types that underwent Tempus xT and xF next generation sequencing assays. Fisher’s exact test was used to analyze the association between cancer subtypes and KRAS variants. Logistic regression was used to study co-mutations between KRASG12C and other oncogenes, as well as the association between KRAS variants and IO biomarkers. False discovery rate-adjusted P-value (FDR P) was used for multiple testing. Results: In total, 13,578 (17.4%) tumors harbored KRAS mutations, of which 1,632 were G12C; 750 KRAS wild-type (WT) tumors gained KRAS mutation on follow-up testing, with 79 harboring G12C. The most frequent KRAS variants across all cancers were G12D, G12V, G12C, and G13D (see Table). The distribution of KRAS variants significantly varied by cancer type, with G12C and G12D being the most prevalent in non-small cell lung (NSCLC) and colorectal (CRC) cancers, respectively. G12C was most prevalent in NSCLC (9%), appendiceal cancer (3.9%), CRC (3.2%), tumors of unknown origin (1.6%), and pancreatic cancer (1.3%). Compared to non-G12C, G12C was more frequently identified in females (56% vs. 51%, FDR P = 0.0005), smokers/prior smokers (85% vs. 56%, FDR P < 0.0001), and pts > 60 years of age (73% vs. 63%, FDR P = 0.0006). While no G12C tumors exhibited BRAFV600E co-mutations, BRAFnon-V600E co-mutations were seen in 3.1% of pts. Significant differences were observed in genomic alterations co-occurring with G12C compared to non-G12C (e.g., STK11 (20.6% vs 6%), KEAP1 (15.4% vs 4.6%), SMAD4 (7.2% vs 19%), and PDGFRA (5.8% vs 3%); FDR P < 0.0001). However, G12C and oncogene co-mutations were not significantly different between NSCLC and CRC, except for KEAP1 (FDR_ P = 0.04). Compared to non-G12C and WT, G12C tumors were associated with TMB-High and PD-L1 over expression but were less likely to have MSI-H status (FDR P < 0.0001; Table). Conclusions: Our data suggest that KRAS variants significantly differ by cancer type. Tumors harboring KRASG12C were significantly associated with high TMB and PD-L1 overexpression. KRASG12C mutation appeared to be associated with smoking status. These results may guide future therapeutic strategies.[Table: see text]
CCTG CO.28 primary endpoint analysis: Neoadjuvant chemotherapy, excision and observation for early rectal cancer, the NEO trial.
Authors: Kennecke Hagen Fritz , Brown Carl J , Loree Jonathan M. , Moloo Husein , Jonker Derek J. , Raval Manoj , Musselman Reilly , Ma Grace , Caycedo-Marulanda Antonio , Simianu Val , Patel Sunil , Pitre Lacey D. , Helewa Ramzi , Gordon Vallerie Lynn , Neumann Katerina , Sherry Max , Tu Dongsheng , O'Callaghan Christopher J. 
Published: June 2021

3508 Background: CO.28 (NCT03259035) is a phase II study designed to determine if patients with cT1-T3a/bN0 rectal cancer can be treated with induction chemotherapy (FOLFOX/CAPOX) and organ-preserving surgery. Methods: Patients with MRI staged cT1-3a/bN0 tumors and no pathologic (p) high risk features received 6/4 cycles of FOLFOX/CAPOX, repeat sigmoidoscopy/pelvic MRI and subsequent Transanal Endoscopic Surgery (TES) in the absence of tumor progression. ypT0/T1N0 tumors were treated with observation while ypT2+ or ypN+ stage were recommended Total Mesorectal Excision (TME). The primary endpoint was protocol specified Organ Preservation Rate (psOPR = ypT0/T1N0, no p high risk features) and actual Organ Preservation Rate (aOPR = ypT0/T1N0 stage plus higher yp stage patients who declined TME surgery). The study would be considered negative with an psOPR of 50% or lower (H0) and as promising if it is 65% or higher (H1). Results: Between 08/2017 to 05/2020, 58 eligible patients were accrued in Canada and the United States, median age was 67 years, 71% male. All had well-moderately differentiated, non-mucinous rectal adenocarcinoma and median tumor height was 6 cm (range 0-18). Median follow-up was 15.4 months. Chemotherapy with FOLFOX (32) or CAPOX (26) was administered, 90% completed all planned cycles. A total of 56/58 (97%) proceeded to TES, while one patient was ineligible due to tumor progression (1.7%) and one declined. In the intention to treat analysis, the psOPR was 57% (95% CI 43-70%) while the aOPR was 79% (95% CI 67% to 89%) due to 13/23 declining recommended TME surgery. Of 10 patients who proceeded to recommended TME, a complete R0 TME was performed in 9/10, and no p residual carcinoma was found in 7/10. Crude loco-regional (LR) and distant recurrence rates were 3.5% (95% CI 0.4 to 12%) and 0%, respectively. A recurrence occurred in 1/13 patients who initially declined TME surgery. Conclusions: In select patients with early stage rectal cancer, three months of induction CAPOX/FOLFOX followed by TES resulted in a high OPR without the use of pelvic irradiation. The observed high rate of pathologic downstaging may point to high chemo-responsiveness in early rectal adenocarcinoma with no p high risk features. Further trials to evaluate this approach are justified and updated results will be presented. Clinical trial information: NCT03259035. [Table: see text]