bluuebunny/crossref_metadata_2025 huggingface dataset:
Germline testing in community oncology patients with somatic BRCA1/2 mutations.
Authors: Principe Kate , Nichols Trisha , Patel Gayle , Bunnell Ann , Fisher Camille , Lord Katharine , Carlisle Steven , Torres Vanessa , Wilfong Lalan S. , Kodali Dhatri
Published: June 2021

1523

Background: The primary purpose of tumor mutation profiling (TMP) is to molecularly characterize tumors to identify targeted treatments and improve outcomes, but it may also uncover germline mutations with implications for patients and families. In September 2016, the National Comprehensive Cancer Network (NCCN) added “BRCA1/2 mutation detected by TMP” as a criterion for germline BRCA1/2 testing. This study aims to assess rates of germline testing, with and without genetic consultations, for individuals with a somatic BRCA1/2 finding in community oncology centers. Methods: Retrospective data was abstracted from an internal database of results from four TMP laboratories. Individuals with a somatic BRCA1/2 pathogenic/likely pathogenic (P/LP) variant reported from January 1, 2017 to December 31, 2019 were included. Clinical data was obtained from electronic medical records. The project was approved by the Texas Oncology Privacy Board. Results: 221 patients had a P/LP somatic BRCA1/2 result on TMP, 138 of which were BRCA1/2 spectrum tumors (breast, ovary, pancreas, prostate). 144/221 patients (65.2%) had BRCA1/2 germline testing. 133/221 (60.2%) met NCCN guidelines for germline BRCA1/2 testing independent of their somatic results; they were statistically more likely to undergo germline testing than patients who did not otherwise meet germline BRCA1/2 testing criteria (p=2.3e-16) (Table). 70/144 (48.6%) had a germline P/LP BRCA1/2 mutation identified. At locations with genetic providers versus those without, there was a significant difference in rates of genetic consultation (p=0.02) but not in the rate of germline testing (p=0.3). This indicates patients were more likely to receive pre- and post-test counseling at clinics offering in-house genetic consultations. Conclusions: Most individuals who had a P/LP somatic BRCA1/2 mutation identified on TMP underwent germline genetic testing. As 60.2% of our cohort qualified independently for germline testing, somatic BRCA1/2results may not have been the driving force behind germline testing. However, individuals who had a non- BRCA1/2-spectrum tumor were significantly less likely to have the recommended confirmatory germline testing. Quality improvement initiatives can focus on improving rates of counseling and germline testing for patients with somatic BRCA1/2 mutations, regardless of tumor type.[Table: see text]
Use of deep learning frameworks to detect super-responder and super-survivor stage IV squamous non-small-cell lung cancer (NSCLC) patients treated with a gemcitabine and cisplatin combination.
Authors: Galmarini Carlos Maria , Lucius Maximiliano
Published: June 2021

1548

Background: Synthetic fingerprints integrate clinical data within computational models allowing the identification of particular clinical subpopulations at a given moment. We here describe a deep learning strategy to detect super-responder and super-survivor patients with squamous NSCLC by setting up synthetic fingerprints and using unsupervised deep learning frameworks (UDLF). Methods: Through www.projectdatasphere.org, we accessed the control arm clinical data (N = 548) of the randomised phase III SQUIRE trial (NCT00981058). This trial included patients with stage IV squamous NSCLC who had not received previous chemotherapy. These patients were treated with gemcitabine 1,250 mg/m2 (IV, 30-min infusion, d1/d8) and cisplatin 75 mg/m2 (IV, 120 min infusion, d1) on a 3-week cycle for a maximum of six cycles. Synthetic fingerprints resulted of the integration of 180 features collected during the first 3 cycles including demographics, medical history, physical exam, concomitant medication, histopathology, PK parameters, adverse events and common labs. These fingerprints were used as input for the UDLF. The resultant clusters were correlated with overall-response rate (ORR) and overall survival (OS). Results: After missing data removal and feature standardization, 192 patients were eligible for the study. The UDLF was able to generate two different clusters: P0 (n = 107) and P1 (n = 84). ORR was higher in the P1 than in the P0 cluster (mean 41.6% [95% CI 31.7-52.3] vs. 28.0% [95% CI 20.4-37.2]; p = 0.04). OS was significantly longer in the P1 than in the P0 cluster (median 13.2 months vs. 9.7 months; hazard ratio 1.56 [95% CI 1.12-2.17; p = 0.008]). Feature contribution analysis showed that P1 had more patients and more events of grade III/IV neutropenia. In contrast, P0 had more patients and more events of grade III/IV nausea and vomiting. Other major differences were observed on vital signs (SBP, DBP, HR, RR, Temp), concomitant medication (osmotically-active laxatives, dexamethasone, furosemide, granisetron and ondansetron) and in hematological (RBC, HGB, HCT, MCV, WBC, neutrophils, monocytes, lymphocytes) and biochemistry (albumin, globulins, ALP, LDH, creatinine, BUN, urea, sodium, magnesium and phosphate) tests. Conclusions: Our findings show that synthetic fingerprints and subsequent deep learning analysis can be of use to identify patients with clinical characteristics associated with high-response rate and long-term survival.
Automated imaging-based stratification of early-stage lung cancer patients prior to receiving surgical resection using deep learning applied to CTs.
Authors: Torres Felipe Soares , Akbar Shazia , Raman Srinivas , Yasufuku Kazuhiro , Baldauf-Lenschen Felix , Leighl Natasha B.
Published: June 2021

1552

Background: Computed tomography (CT) imaging is an important tool to guide further investigation and treatment in patients with lung cancer. For patients with early stage lung cancer, surgery remains an optimal treatment option. Artificial intelligence applied to pretreatment CTs may have the ability to quantify mortality risk and stratify patients for more individualized diagnostic, treatment and monitoring decisions. Methods: A fully automated, end-to-end model was designed to localize the 36cm x 36cm x 36cm space centered on the lungs and learn deep prognostic features using a 3-dimensional convolutional neural network (3DCNN) to predict 5-year mortality risk. The 3DCNN was trained and validated in a 5-fold cross-validation using 2,924 CTs of 1,689 lung cancer patients from 6 public datasets made available in The Cancer Imaging Archive. We evaluated 3DCNN’s ability to stratify stage I & II patients who received surgery into mortality risk quintiles using the Cox proportional hazards model. Results: 260 of the 1,689 lung cancer patients in the withheld validation dataset were diagnosed as stage I or II, received a surgical resection within 6 months of their pretreatment CT and had known 5-year disease and survival outcomes. Based on the 3DCNN’s predicted mortality risk, patients in the highest risk quintile had a 14.2-fold (95% CI 4.3-46.8, p < 0.001) increase in 5-year mortality hazard compared to patients in the lowest risk quintile. Conclusions: Deep learning applied to pretreatment CTs provides personalised prognostic insights for early stage lung cancer patients who received surgery and has the potential to inform treatment and monitoring decisions.[Table: see text]
Nodule net: A prospective safety net program to reduce loss to follow-up and increase early detection of lung cancer.
Authors: Singh Harpreet , Jani Chinmay , Rupal Arashdeep , Tewari Arti , Walker Alexander , Casasola Marcel , Khoory Joseph , Ranker Lynsie , Koster Megan , Thomson Carey
Published: June 2021

1564

Background: Inadequate follow-up of suspicious lung nodules can result in a delay in diagnosis and potential progression to advanced staged lung cancer. A multidisciplinary lung nodule program entitled "Nodule Net" was implemented in 2017 to provide a safety net, increase the rate of follow-up, streamline management. The program consisted of a multidisciplinary team with EMR notification by the radiologist to a centralized nurse navigator for inclusion in a follow-up database, outreach with reminders to the primary care provider if follow-up was not completed, and referral for management where appropriate. In this study, we sought to evaluate program effectiveness in tracking and rate of follow-up imaging of suspicious pulmonary nodules. Methods: 2,398 chest CT scans were reviewed between January and May 2018 for the presence of a lung nodule that required follow-up. Nodules known to be inflammatory or associated with a metastatic malignancy were excluded. Baseline demographics, medical history, primary care affiliation, type of imaging scan, nodule characteristics, and presence and specifics of follow-up recommendations were collected. For reports that did not include a follow-up recommendation, Fleischner’s recommendations were applied or an independent pulmonologist’s review was completed. The rate of follow-up imaging was recorded and compared with historical rates prior to Nodule Net implementation. Prevalence ratios were generated for each comparison. Results: 1,367 (57%) reported lung nodules. Recommendations for follow-up imaging were recorded in 632 (46.2%), and 523 (82.8%) of these were reported to the program navigator. The rate of follow-up completion of those referred to the program was significantly higher [408 (78%)] than standard of care prior to program implementation [442/1202 (36.8%), (2.90, 95% CI: 2.65-3.18)]. Out of 408 patients who completed follow-up, nodule net outreach was required in 116 (28.4%). Of these 116, malignancy was identified in 4/116 (3.4%). Increased nodule size requiring referral was identified in 17 (14.7%). Out of 109 who were not transmitted to the program navigator and not present in the database, 57 (52.3%) had completed the recommended follow-up compared with 78% among those referred (1.49, 95% CI:1.23-1.79). Conclusions: Management of lung nodules is a complex process with poor follow-up completion reported in prior studies (29%-33%). Implementation of a multidisciplinary lung nodule care program for tracking lung nodules led to a significant increase in completion of recommended follow-up imaging. Developing a comprehensive lung nodule management program using software and navigation may further enhance detection, reduce human errors, augment the necessary follow-up for suspicious lung nodules, and ultimately the prevalence of advanced stage lung cancer.
Serial plasma and CSF cell-free tumor DNA (cf-tDNA) tracking in diffuse midline glioma patients undergoing treatment with ONC201.
Authors: Cantor Evan , Wierzbicki Kyle , Tarapore Rohinton , Thomas Chase , Cartaxo Rodrigo , Yadav Viveka Nand , Ravindran Ramya , Bruzek Amy , Franson Andrea , Mody Rajen , Garton Hugh , Odia Yazmin , Kline Cassie , Vitanza Nicholas A , Khatua Soumen , Mueller Sabine , Allen Joshua E. , Gardner Sharon L. , Koschmann Carl Johannes
Published: June 2021

2012

Background: Diffuse midline glioma (DMG) with the H3K27M mutation is a lethal childhood brain cancer, with patients rarely surviving 2 years from diagnosis. There are few available means of monitoring the disease beyond serial MRI scans, making clinical decision making slow, difficult, and often reactive. Methods: We conducted a multi-site phase 1 trial of the imipridone ONC201 for children with H3K27M-mutant glioma (NCT03416530). Patients enrolled on Arm D of the trial (n=24) underwent serial lumbar puncture (baseline, 2 and 6 months) for cell-free tumor DNA (cf-tDNA) analysis at time of MRI. Additionally, patients on all arms of the trial at the University of Michigan underwent serial plasma collection. CSF collection was feasible in this cohort, with no procedural complications. We collected a total of 96 plasma samples and 53 CSF samples from 29 patients, including those with H3F3A (H3.3) (n=13), HIST13HB (H3.1) (n= 4), and unknown H3 status/not biopsied (n=12) [range of 0-8 CSF samples and 0-10 plasma samples]. We performed digital droplet polymerase chain reaction (ddPCR) analysis and/or amplicon-based electronic sequencing (Oxford Nanopore) of cf-tDNA samples and compared variant allele fraction (VAF) to radiographic change (maximal 2D tumor area on MRI). Results: Preliminary analysis of samples (n=58) demonstrates a correlation between changes in tumor size and H3K27M cf-tDNA VAF, when removing samples with concurrent bevacizumab. Analysis of remaining CSF and plasma samples is ongoing, including analysis of novel biomarkers of response. In multiple cases, early reduction in CSF cf-tDNA predicts long-term clinical response (>1 year) to ONC201 and does not increase in cases of later-defined pseudo-progression (radiation necrosis). For example, a now 9-year old patient with thalamic H3K27M-mutant DMG underwent treatment with ONC201 after initial radiation and developed an increase in tumor size at 4 months post-radiation (124% baseline) of unclear etiology at the time. Meanwhile, her ddPCR declined from baseline 6.76% VAF to <1%, which has persisted, with now near complete response (85% tumor reduction) at 30 months on treatment from diagnosis. Conclusions: In summary, we present the feasibility and utility of serial CSF/plasma monitoring of a promising experimental therapy for DMG.
SER-ONCOVID: Seroconversion in solid-tumor cancer patients after COVID-19 diagnosis.
Authors: Pous Anna , Felip Eudald , Etxaniz Olatz , Hernandez Gonzalez Ainhoa , España Sofia , Romeo Margarita , Pinato David James , Esteve Anna , Mesia Ricard
Published: June 2021

2544

Background: Cancer patients (pts) represent a high-risk population for severe COVID-19. Cancer-associated immunosuppression may hinder in the development of anti-SARS-CoV-2 antibodies. Methods: Data regarding baseline characteristics, COVID-19 and anti-SARS-Cov2 IgG were collected from cancer pts (solid tumors) who tested positive for COVID-19 (PCR+) between March and April 2020 at Catalan Institute of Oncology. We prospectively assessed anti-SARS-Cov2 IgG seroprevalence at 3 and 9 months post infection and explored clinico-pathologic factors associated with IgG positivity. We explored the impact of potential factors influencing antibody production at >9 months. Results: Of 49 pts registered between 10th March-26th April 2020, 21 died <3 months after the infection and 5 pts refused to participate, leaving 23 eligible pts for IgG testing. With respect to those not tested, IgG tested cohort was younger (median age: 64.0 vs 72.9 years, p = 0.001) and presented oncologic remission in 68.2% of cases (vs 34.6%, p = 0.043) at COVID-19 diagnosis. Median time from PCR+ to first and second IgG determination was 3.2 months (Interquartile range [IQR]: 2.9-4.1) and 9.5 months (IQR: 8.8-9.8), respectively. Out of 23 pts, 15 had both determinations and 8 had only one (3 in the first time point, 5 in the second one). We identified 16/18 pts IgG+ (88.9%) at 3 months and 17/20 pts IgG+ (85%) at 9 months. One IgG+ pt became IgG- at the second determination, one was IgG- at both timepoints, and one had an inconclusive result at the first but negative at the second timepoint. Key characteristics of patients by IgG result 9 months after COVID-19 diagnosis are shown in the table. Conclusions: We describe a high seroprevalence of anti-SARS-CoV-2 IgG at 3 and 9 months after COVID-19 diagnosis in solid tumour patients, irrespective of anti-cancer therapy exposure. Pts who were IgG+ at 9 months were older, and more likely to have required oxygen during prior COVID-19 in comparison to IgG- pts suggesting that infection severity may promote durable immunity. Frequency of early stage cancers was higher among IgG+ pts, suggesting less cancer-related immunosupression. Older (>70 years) and advanced cancer pts were under-represented in this series, warranting confirmation of these preliminary results in a larger cohort.[Table: see text]
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]
The role of HPSE in BRAF V600E-mutant colorectal cancer.
Authors: Liu Mengling , Xu Xiaojing , Peng Ke , Hou Pengcong , Liu Qing , Yu Yiyi , Liu Tianshu
Published: June 2021

3530

Background: BRAF mutations occur in about 10% of colorectal cancer (CRC), more than 90% of which are BRAF V600E mutation. Patients (pts) with BRAF V600E mutation present poor prognosis. Complex molecular biological mechanisms in this population have not been well annotated. HPSE plays a multifunctional role in cell proliferation, invasion and angiogenesis in cancer. Here we identified differentially expressed genes (DEGs) between pts with and without BRAF V600E mutation, and then focused on the function of HPSE, one of top DEGs, in BRAF V600E-mutant CRC. Methods: Clinical and transcriptional data of pts with CRC from The Cancer Genome Atlas (TCGA, n = 525) database and GSE39582 dataset (n = 510) were analyzed to explore the top overlapped DEGs between BRAF V600E mutant and wild-type pts. Records and tumor samples of 172 pts with BRAF V600E-mutant CRC diagnosed at Zhongshan Hospital Fudan University between 6/2015-12/2018 were collected. The HPSE protein expression status of tumor samples was evaluated by immunohistochemistry staining. Moderate or strong staining in > 25% of tumor cells was interpreted as HPSE positive. Overall survival (OS) was analyzed using Kaplan-Meier Curves with Log-rank test and multivariable Cox regression. Next, lentiviral shRNA-based silencing of HPSE was performed in two BRAF V600E-mutant CRC cell lines (HT-29, RKO). The effect of HPSE on tumor growth was investigated through colony formation assays, cell cycle assays and subcutaneous xenograft models. Results: The top overlapped genes of the DEGs list included HPSE, TFF2, AXIN2, MLH1, RNF43, EPM2AIP1. Among them, HPSE had significantly high expression in BRAF V600E-mutant group. Of 172 pts with BRAF V600E mutation, 83 were identified as HPSE positive and 89 were negative. Two groups were generally well balanced on age (p = 0.096), gender (p = 1.000), location (p = 0.658), stage (p = 0.249) and MMR status (p = 0.129). HPSE positive pts had a significantly worse OS in comparison to HPSE negative pts (p = 0.037, median OS not reached). The multivariate analysis showed that HPSE positive was independently associated with inferior OS [HR 1.97 (95%CI: 1.02 – 3.80), p = 0.044). Silencing HPSE gene impaired colony formation activity significantly and arrested more cells in G0/G1 phase of BRAF V600E-mutant CRC cell lines. Tumor growth was inhibited apparently in HPSE-silencing xenograft models. Conclusions: Pts with BRAF V600E-mutant CRC had a high HPSE expression level, while HPSE protein expression was an independent prognostic factor for this population. The silencing of HPSE expression in BRAF V600E-mutant CRC cell lines inhibited cell proliferation and tumor growth in vitro and in vivo. HPSE may contribute to the poor prognosis of BRAF V600E-mutant CRC and might be a promising therapeutic target for this subtype of CRC.
Investigating intra-tumor microbes, blood microbes, and CEA for development of non-invasive biomarkers in colorectal cancer.
Authors: Malalur Pannaga G. , Mo Xiaokui , Hoyd Rebecca , Hays John L. , Carbone David Paul , Spakowicz Daniel
Published: June 2021

3551

Background: The development of non-invasive biomarkers has the potential to revolutionize clinical care for colorectal cancer (CRC) patients. The presence of bacteria in CRC tumor biopsies has been shown to contribute to CRC development. In a previous study, our group showed some intra-tumor microbes in CRC tumor biopsies correlated with overall survival in CRC patients. However, the correlations between microbes in tumor vs blood, and between non-invasive serum marker carcinoembryonic antigen (CEA) and microbes are unknown. We hypothesize that tumor microbes will also be found in blood, and that CEA will correlate with certain microbes. Methods: We obtained RNA-seq data from CRC tumor biopsies from patients treated at The Ohio State University Comprehensive Cancer Center as part of the Oncology Research Information Exchange Network (ORIEN). Reads were aligned to human and exogenous genomes using TopHat2 and Kraken2/Bracken, respectively. RNA-seq from CRC tumor biopsies as well as peripheral blood at the Cancer Genome Atlas (TCGA) consortium were processed by the same method. Results: The analyzed ORIEN cohort included 93 CRC patients with an age range from 30-83 years, 60.2% male, 87.1% adenocarcinoma, and 47.3% with metastatic CRC. The TGCA cohort included 495 CRC patients with an age range from 31-90 years, 53.3% male, 85.1% adenocarcinoma, and 15.5% with metastatic CRC. Over fifteen exogenous phyla (including bacteria, viruses, fungi) were observed in both ORIEN and TCGA cohorts. Several of the samples were dominated by viral sequences while others by bacteria, suggesting considerable tumor microbiome heterogeneity. Evaluation of the fraction of microbes in tumor and blood showed that nearly all the microbes found in blood (97.6%) were also observable in tumor in the TCGA cohort. Microbial abundances of various taxa, including Fusobacterium, significantly correlated between blood and tumor. Several bacteria including members of the genera Bacillus and Staphylococcus were positively associated with tumor stage (metastatic vs non-metastatic), but microbial relative abundances were not correlated with the location of tumor in colon (right, left, transverse colon). Certain microbial species from the ORIEN cohort were found to positively correlate with CEA, (including from the genera Fusobacterium, Lactobacillus, Pseudomonas, Vibrio, Clostridium) and these associations remained when adjusted for alcohol and smoking by multivariate analysis. Conclusions: Nearly all the microbes found in blood were found in tumor and abundances of various taxa were significantly correlated, suggesting that blood-based cancer microbiome analysis has great potential. Serum CEA has a low diagnostic ability when used alone, but combining this with blood microbiome could improve diagnostic/prognostic utility as a non-invasive biomarker.
Patient-specific meta-analysis of 3 validation studies of the 12-gene colon cancer recurrence score assay for recurrence risk assessment after surgery with or without 5FU and oxaliplatin.
Authors: Yothers Greg , Venook Alan P. , Yamanaka Takeharu , Lin Yan , Crager Michael , Chao Calvin Y. , Baehner Frederick L , Yoshino Takayuki
Published: June 2021

3599

Background: The 12-gene Oncotype DX Colon Recurrence Score assay is a clinically validated genomic assay that evaluates recurrence risks in stage II and stage III colon cancer patients independent of clinical-pathologic features. Improved colon cancer care has reduced recurrence rates since the late 1990’s. Methods: Pre-specified patient-specific meta-analysis methods were used to estimate 1-, 3- and 5-year recurrence risk combining the 12-gene colon recurrence score (RS) validation studies CALGB 9581, NSABP C-07 and SUNRISE. Cox models had effects for RS result, number of nodes examined (<12 or ≥ 12), T-stage, MMR status, and stage (II, IIIAB or IIIC). Baseline cumulative hazard estimates used the latest two studies to reflect current medical practice. Estimates for surgery, surgery+5FU and surgery+5FU+oxaliplatin treatment were provided by integrating stage-specific 5FU hazard ratios from a meta-analysis of the QUASAR study (2007) and a pooled analysis of NSABP studies (Wilkinson 2010), and oxaliplatin treatment effect estimates from NSABP C-07. Recurrence risk with 5FU alone was not estimated for MMR-deficient patients due to expected lack of 5FU efficacy in these patients (Sargent 2010). Results: In the overall population of 2,179 patients, 55%, 32% and 13% were Stage II, IIIA/B and IIIC, 63% had ≥12 nodes examined, 90% were T3, and 88% were MMR proficient. Median RS result was 31 (IQR 23–39). RS result and each clinical-pathologic factor contributed independent prognostic information (meta-analysis Wald tests, all p<.001). Risk estimates are generally lower than previous RS report risk estimates. For patients with pathological stage II, T3, MMR-proficient tumors with ≥12 nodes examined, approximately 40% are expected to have 5-year recurrence risk ≤10% with surgery alone based on the distribution of RS results. The table shows example 5-year recurrence risk estimates for specific RS results and clinical-pathologic characteristics. Conclusions: The new recurrence risk estimates provide more patient-specific information reflecting more current medical practice than previous reports using RS result, allowing better, more individualized treatment decisions.[Table: see text]