bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel methods to assess cell-free circulating tumor DNA in acute lymphoblastic leukemia.
Authors: Haney Meghan G , Sampathi Shilpa , Chernyavskaya Yelena , Moore Henry , Badgett Tom C. , Blackburn Jessica S 
Published: June 2021

10034 Background: Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, with a relatively high relapse rate, which is associated with poor prognosis. Currently, minimal residual disease (MRD) at the end of induction and consolidation therapy is the best predictor of patient relapse, however obtaining bone marrow aspirate is invasive and not always accurate. Another major concern in ALL is the presence of central nervous system (CNS) disease, which is often present long before clinical diagnosis can be made by flow cytometry. To circumvent these clinical challenges, we developed a new assay quantifying cell-free, circulating tumor (cfDNA) as a biomarker of disease progression, which can be correlated with MRD status as a predictor of relapse. cfDNA is frequently used to monitor progression of solid tumors, but pediatric leukemias lack common mutations that can be used to distinguish leukemic cfDNA from normal cfDNA. Methods: We examined two possible methods for using ctDNA as a biomarker: leukemia cell clonality and DNA methylation profiling. We developed a novel workflow for identifying VDJ rearrangements in leukemia cells and tracking their presence in cfDNA. We collected bone marrow, blood, and CSF samples from newly diagnosed patients, and cfDNA was isolated from blood and CSF samples throughout treatment. Invivoscribe Lymphotrack PCR assays combined with MinION (Oxford Nanopore Technologies) sequencing were used to identify the VDJ sequence of the immunoglobulin (B-ALL) or T-cell receptor (T-ALL) rearrangements of leukemic clones in genomic DNA. The MinION assay relies on patient-specific sequencing. We are also in the process of developing a universal assay that utilizes recurrent methylation changes in ALL to identify leukemic cfDNA in patient samples. Results: The MinION workflow was used to follow leukemic cfDNA throughout the course of treatment, and accurately identified MRD and CNS disease in patients. This workflow performed equivalent or better at detecting leukemic clones compared to MiSeq and droplet digital polymerase chain reaction (ddPCR), and is faster and less expensive than traditional Illumina sequencing. Methylation analysis of 865 ALL and 79 healthy samples yielded 55 regions and 19 specific methylation sites that were uniquely present in ALL samples. We are validating these sites by ddPCR to establish a panel of biomarkers to track ALL over time via cfDNA. Conclusions: The end goal of our study is provide a more sensitive and less invasive method for tracking MRD and CNS disease than current approaches. Results will ultimately be correlated with patient response to therapy, the presence of relapse or CNS disease, and overall outcomes determined by standard clinical diagnostic procedures.
Discovery and validation of a cross-platform 21-gene prognostic signature in neuroblastoma.
Authors: Gupta Mehul , Kannappan Sunand Nageswaran , Narendran Aru , Bose Pinaki 
Published: June 2021

10035 Background: Neuroblastoma (NB) is the most common extracranial solid tumor in children. Despite the development of risk stratification tools to improve prognostication, prediction of patient survival outcomes in NB remains poor. In this study we used an unbiased machine-learning algorithm to develop and validate a transcriptomic signature capable of predicting 5-year overall (OS) and event-free survival (EFS) in these patients. Methods: The TARGET-Neuroblastoma dataset (n = 243) was used as the training set. Two independent NB cohorts, E-MTAB-179 (n = 478) and GSE85047 (n = 266) were used as validation sets. Elastic net regression was employed to identify transcripts associated with EFS. Association of the developed signature with EFS and OS was evaluated using univariate Cox proportional hazards (CoxPH), Kaplan-Meier, and 5-year receiver-operator characteristic curves in validation cohorts. Further, the independent prognostic value of the signature was assessed using multivariate CoxPH models with relevant clinicopathologic variables including age, INSS stage, and N-Myc amplification status in both validation sets. Finally, a nomogram was developed to integrate the signature with prognostic clinicopathologic variables to evaluate their combined efficacy for prediction of 5-year EFS and OS. Results: We identified a 21-gene signature that demonstrates significant association with EFS and OS in both E-MTAB-178 and GSE49710 validation cohorts. Moreover, the signature is independent of clinicopathological variables and can be effectively incorporated into a risk model, improving the prognostic performance. Several genes within the signature have been previously implicated in NB, including ECEL1, HOXC9 and ARAF1. Conclusions: To the best of our knowledge, we are the first to use an unbiased machine learning approach to generate a transcriptomic gene signature for neuroblastoma prognosis externally validated in multiple cohorts across platforms. This 21-gene transcriptomic signature significantly associated with EFS and OS in this disease. Combining this signature with current prognostic clinicopathologic variables will improve risk stratification of affected patients and may inform effective clinical decision-making.[Table: see text]
Standardization of fertility preservation discussion amongst pediatric oncology and bone marrow transplant patients.
Authors: Dargan Chandni , Mc Dermott Sarah , Chesbro Shelby , Fulbright Joy M. 
Published: June 2021

10051 Background: As treatment for pediatric malignancies improves long term survival, physicians are shifting focus to late effects of therapy such as infertility. Currently, options for fertility preservation include cryopreservation of mature oocytes, sperm, and gonadal tissue, although barriers remain present. Within our division, we lacked a standard approach to discussing fertility preservation options. Methods: Records from 474 pediatric patients with new oncologic diagnoses at CMH from 2014-2020 were retrospectively reviewed. We evaluated the frequency that reproductive health discussions were documented in pubertal males and females requiring chemotherapy or radiation treatment. We implemented a standard fertility preservation note and patient handouts, then surveyed our department to identify diagnoses that place patients at risk for infertility and barriers to formalized fertility consultations. We then provided educational sessions to address these barriers with pre- and post-evaluation to measure efficacy. Our longitudinal assessment, encompassing multiple points of intervention, was compared to results from previous chart review (2010-2013). Results: Of 474 patients diagnosed between 2014-2020, 175 (90 females, 85 males) warranted a fertility discussion per inclusion criteria. 61 (67.8%) females received a fertility discussion and of those 8 (8.9%) completed oocyte or gonadal tissue preservation, all between 2017-2020. 52 (61.2%) males received a fertility discussion and 20 (23.5%) completed sperm cryopreservation, with even distribution pattern between 2014-2020. Following implementation of an electronic fertility consult process and standardized fertility preservation documentation, there was an increase in documented fertility discussions from 30% in 2014 to 63.6% in 2020. Internal department survey responses identified a lack of comfort with knowing fertility preservation options available and diagnoses that should prompt this conversation. Education sessions with pre- and post-provider assessment demonstrated more comfort discussing fertility preservation (average score increase from 3.44 to 4.33) and knowledge regarding diagnoses at higher risk of infertility (average score increase from 3.67 to 4.33). Conclusions: Integration of a standardized fertility preservation process and addressing barriers identified within our division have led to a 33.6% increase in fertility discussions over the last 6 years. While the data shows a promising increase in oocyte and ovarian tissue preservation, sperm banking completion rates remained unchanged. Further steps include incorporation of an automated fertility consultation order into electronic chemotherapy orders, hospital-wide identification of other high-risk patient populations, and continued education of patient, families, and the health care team.
Favorable prognostic factors of oligometastatic breast cancer: A subset analysis of OLIGO-BC1.
Authors: Wang Kun , Bi XiWen , Liu Guangyu , Ueno Takayuki , Takao Shintaro , Sim Sung Hoon , Im Young-Hyuck , Im Seock-Ah , Ahn Sung Gwe , Lee Jeong Eon , Park Yeon Hee , Futamura Manabu , Toi Masakazu , Fujiwara Yasuhiro , Saito-Oba Mari , Kitagawa Yuko , Nishiyama Masahiko , Imoto Shigeru 
Published: June 2021

1026 Background: The Federation of Asian Clinical Oncology (FACO) conducted an international retrospective cohort study of oligometastatic breast cancer (BC) (OLIGO-BC1) (UMIN No.000030047). At ASCO2020, we demonstrated that locoregional and systemic therapy prolonged overall survival (OS) for patients with oligometastatic BC, especially for cases with some type of systemic therapy, younger age, ECOG performance status 0, stage I BC, non-triple negative subtype, fewer metastatic sites, local recurrence and longer disease-free interval from a multivariate analysis (#1025). Although BC is heterogeneous and a retrospective dataset has many kinds of bias, we attempted a subset analysis based on intrinsic subtype and several prognostic factors. Methods: Oligometastatic BC patients diagnosed from 2007 to 2012 were registered from CSCO, KSMO and JSCO. OS period was measured from the diagnosis of oligometastases to the latest follow-up. ER, PgR and HER2 status were determined by immunohistochemistry and/or in situ hybridization. A hazard ratio (HR) of OS was calculated by using a univariate analysis. Results: In 1200 eligible cases, one oligometastatic site was found in 578 cases, two in 289, three in 154, four in 102 and five in 77. Bone metastases were recorded in 301 cases, visceral metastases in 387, locoregional recurrence in 25, local recurrence in 83 and multiple metastatic sites in 404. Luminal subtype was recorded in 526 cases (44%), luminal-HER2 in 189 (16%), HER2 in 154 (13%), triple-negative in 166 (14%) and others in 165 (13%). In any subtype, locoregional and systemic therapy and ECOG performance status 0 were beneficial for OS. Stage I BC, one oligometastatic site and longer disease-free interval were also related to favorable prognosis in luminal and HER2 subtype. However, triple-negative subtype had no survival advantage with these 3 factors. On the other hand, pathological negative or micrometastatic lymph nodes at primary BC and one oligometastatic site of lymph node, lung, liver and bone were favorable prognostic factors. In addition, cases treated locally with surgical resection and conventional radiation therapy were expected to prolong OS. Discussions: Locoregional therapy for oligometastatic BC may be considered in luminal and HER2 subtype with some conditions. As reported in ASCO2020, triple-negative BC should be managed with systemic therapy. Conclusions: Oligometastatic BC is diagnosed by chance, but some cases seem to survive with multidisciplinary treatment. It is worthwhile to consider locoregional therapy in oligometastatic BC after evaluating favorable prognostic factors.
Characterization of long-term responders following treatment with talazoparib (TALA) or physician’s choice of chemotherapy (PCT) in the phase 3 embraca trial.
Authors: Ettl Johannes , Rugo Hope S. , Hurvitz Sara A. , Martin Miguel , Roche Henri , Lee Kyung-Hun , Goodwin Annabel , Usari Tiziana , Lanzalone Silvana , Guenzel Carolin , Blum Joanne Lorraine , Litton Jennifer Keating 
Published: June 2021

1029 Background: In the EMBRACA trial (NCT01945775), the poly(ADP-ribose) polymerase inhibitor (PARPi) TALA significantly improved progression-free survival (PFS) versus PCT in patients (pts) with germline BRCA1/2-mutated HER2-negative locally advanced/metastatic breast cancer (BC) (8.6 vs 5.6 months [mo]; hazard ratio [HR, 95% CI] 0.54 [0.41-0.71]; P < 0.0001). Predictive markers for response to PARPi, other than germline BRCA1/2 mutational status, are largely unknown. A previous analysis investigated biomarkers associated with long and short responders in EMBRACA. Here, we report the clinical characteristics of long and short responders. Methods: Pts were randomized 2:1 to TALA or PCT. In this retrospective analysis, pts in the intent-to-treat (ITT) population were mapped into two groups based on response: LONG (pts in TALA arm with overall survival [OS] ≥30 mo and duration of treatment ≥24 mo; pts in PCT arm with OS ≥30 mo); SHORT (pts in either arm with a PFS event [progressive disease by Independent Radiological Facility or death] ≤12 wks). Data cutoff date was Sept 30, 2019. Results: Of 431 pts randomized, 412 pts were treated (286 received TALA; 126 received PCT). In the ITT population, 37 pts receiving TALA and 34 pts receiving PCT were identified as LONG responders; 40 pts receiving TALA and 32 pts receiving PCT were SHORT responders. The Table shows a summary of pt characteristics for LONG and SHORT responders. More pts with HR+ BC and no prior CT for ABC were associated with LONG response; more pts with TNBC and ≥2 prior CT regimens or platinum were associated with SHORT response (Table). Median treatment duration for LONG responders (n = 37, TALA; n = 31, PCT) was 33.5 (24.0-61.4) mo for TALA and 7.6 (1.1-36.3) mo for PCT; 51.4% receiving TALA and 91.2% receiving PCT had subsequent therapy. In SHORT responders, median treatment duration was 2.0 (0.1-5.5) mo (TALA) and 1.4 (0.2-5.6) mo (PCT); 67.5% and 68.8% received subsequent therapy following TALA or PCT, respectively. Conclusions: In this clinical characterization of responders from the EMBRACA study, a higher number of LONG responders had HR+ BC and received no prior CT for ABC. A greater proportion of SHORT responders had TNBC and received ≥2 prior CT regimens or platinum. Further investigation is warranted in a larger number of pts. Clinical trial information: NCT01945775 .[Table: see text]
Cyclin-dependent kinase 4/6 (CDK4/6) inhibitor SHR6390 combined with pyrotinib and letrozole in patients with human epidermal growth factor receptor 2-positive (HER2+), hormone receptor positive (HR+) metastatic breast cancer (MBC): Phase Ib study results.
Authors: Zhang Jian , Meng Yanchun , Wang Biyun , Wang Leiping , Cao Jun , Tao Zhonghua , Li Ting , Yao Wenqing , Hu Xichun 
Published: June 2021

1035 Background: The combining of HER2 targeted therapy and endocrine therapy (ET) has been demonstrated to be a reasonable therapeutic approach and recommended for highly selected patients (pts) with HR+/HER2+ MBC. CDK4/6 inhibitors could sensitize HER2 targeted therapies in multiple patient-derived xenograft models and delay tumor recurrence in a transgenic model of HER2+ breast cancer. The aim of this phase Ib/II study was to investigate the safety and efficacy of adding a CDK 4/6 inhibitor to the combination. Primary phase Ib results were reported. Methods: Patients with HR+/HER2+ MBC who were eligible for first- or second-line treatment were enrolled, and orally received letrozole, pyrotinib, and a novel CDK4/6 inhibitor SHR6390. In the “3+3” dose-exploring phase, letrozole was given at a fixed dose of 2.5mg/d. Pyrotinib and SHR6390 were initially given at a dose of 400mg/d and 125 mg/d respectively (Level I). If the initial dose level could be tolerated, subsequent pts were assigned to the higher level (Level H) with pyrotinib 400 mg/d and SHR6390 150mg/d; otherwise, simultaneously to Level L1 with pyrotinib 400 mg/d, and SHR6390 100 mg/d, or Level L2 with pyrotinib 320mg/d, and SHR6390 125 mg/d. Primary endpoints of phase Ib included dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety and efficacy. Results: As of 4 Jan 2021, a total of 15 pts (Level I 5 pts, Level L1 6 pts, and Level L2 4 pts) were enrolled in phase Ib and received the study treatment. 6 of them had received systemic therapies in the advanced stage, and 10 of them had been previously treated with trastuzumab. The most frequent grade 3/4 adverse events included neutrophil count decreased (n = 6), white blood cell count decreased (n = 4), stomatitis (n = 4) and diarrhea (n = 3). 3 pts (2 in Level I, and 1 in Level L1) had experienced DLTs, all of which were grade 3 stomatitis. Of the 15 pts evaluable for response, 7 pts（46.7%） had achieved confirmed partial responses (1 in Level I, 3 in Level L1, and 3 in Level L2) and 7 pts (46.7%) had stable disease. Based on DLTs and clinical efficacy, pyrotinib 320mg/d, SHR6390 125mg/d, and letrozole 2.5mg/d was declared as RP2D. Conclusions: Data from phase Ib showed the triplet combination of pyrotinib, letrozole, and SHR6390 had an acceptable safety profile and encouraging preliminary efficacy, potentially offering a chemotherapy sparing treatment option for patients with HR+/HER2+ MBC. Enrollment on phase II is ongoing. Clinical trial information: NCT03772353 .
Phase I study of LZM005, a HER2 antibody, as monotherapy or in combination with trastuzumab and docetaxel in patients with HER2-positive metastatic breast cancer.
Authors: Xue Cong , Yao Herui , Lin Ying , An Xin , Chen Meiting , Dong Yugang , Li Su , Shi Yanxia 
Published: June 2021

1042 Background: LZM005 is a novel anti-HER2 antibody that binds with elevated affinity to the domain II of HER2. This phase I study assessed the safety, tolerability, pharmacokinetics (PK) and activity of LZM005, as monotherapy or combined with trastuzumab and docetaxel in patients with HER2-positive metastatic breast cancer. Methods: The phase I trial included phase Ia and Ib. Phase Ia was the monotherapy dosage escalation design. LZM005 was administered intravenously with 5mg/kg, 10mg/kg, 15mg/kg and 20mg/kg. The endpoints were dose limited toxicity (DLT) and maximum-tolerated dose (MTD), safety, tolerability and PK analysis. In phase Ib, LZM005 was combined with trastuzumab and docetaxel with MTD. The endpoints included safety and tolerability, response, PK and biomarker analysis. Results: From Jan 2017 to Feb 2020, 35 patients received LZM005 (15 monotherapy, 20 combination). No DLT was observed from 5mg/kg to 20mg/kg. In phase Ib two arms were set: 420mg arm and 525mg arm. The pharmacokinetics of LZM005 were similar to pertuzumab (Table). Common adverse events included increased transaminases, diarrhea and anemia in monotherapy and combination therapy. The common AE in phase Ia trial included diarrhea (21.4%), anemia (14.3%), elevated transaminase (14.3%). The common AE in phase Ib trial included anemia (44.1%), diarrhea (41.2%), fatigue (26.5%), elevated transaminases (23.5%), nausea (20.6%), rash (17.6%) and asymptomatic urinary tract infection (11.7%). All adverse events were manageable. No treatment-related death occurred. The clinical benefit rate and objective response rate was respectively 42.90% (6/14) and 7.14% (1/14) with monotherapy, with combination cohort was 100% (8/8) and 62.5% (5/8) in trastuzumab-naive, 83.3% (11/12) and 41.7% (5/12) in trastuzumab-pretreated patients. The median progression free survival was 22.5 weeks. Conclusions: LZM005 was well tolerated and showed potent activity in patients with HER2-positive metastatic breast cancer. Further evaluation was warranted. Clinical trial information: CTR20191921 .[Table: see text]
Gene methylation and cytological atypia in random fine needle aspirates for assessment of breast cancer risk: 10-year follow up in average risk women.
Authors: Wrubel Erica , Fackler Mary Jo , Huang Peng , Pulliam Natalie , Montanari Amanda , Zalles Carola Maria , Sukumar Saraswati , Stearns Vered , Khan Seema Ahsan 
Published: June 2021

10520 Background: Alterations in DNA methylation occur early in tumorigenesis, and are a potential breast cancer risk biomarker. We previously reported a study where healthy volunteers underwent random fine needle aspiration (rFNA) of the breasts; cumulative methylation index of eight preselected tumor suppressor genes (CMI) was associated with the presence of cytological atypia in rFNA samples. We now report 10-year follow-up of this population, to evaluate whether increased CMI is associated with subsequent breast cancer development. Methods: 380 women, unselected by breast cancer risk, were enrolled. Demographics, breast cancer risk factors, lifetime Gail model risk estimates (Gail-LR), and %breast density were obtained at baseline. rFNA samples were assessed for cytopathology (Masood Score, MS) and CMI. Patients were contacted annually for 10 years to ascertain development of invasive or non-invasive breast cancer. In univariate analysis, log-rank test was used to compare breast cancer incidence rates between individuals with high and low baseline measures (separated by median). Area under the ROC curve was used to evaluate the cancer prediction accuracy. In multivariate analysis, the effect of CMI (after log-transformation to reduce skewness) was further studied using Cox regression model adjusting for confounding baseline variables. Results: 362 women participated in follow up. At a median follow up time of 9.5 years after rFNA sampling, 16 women developed invasive or non-invasive breast cancer. There were no significant differences between women who developed cancer and those that did not in regard to demographic factors, %breast density, MS, or Gail-LR. On univariate analysis, Gail-LR was higher in women who developed cancer (13.0 vs. 16.5, p=0.08). The largest hazard ratios were observed from high breast density (2.30, 95% CI 0.8, 6.6) and high CMI (2.26, 95% CI 0.8, 6.6, p=0.07). In breast cancer prediction, the AUC for CMI was 0.64 (95% CI 0.51, 0.77). In separate bivariable models that adjusted for age, Gail-LR, MS, and %breast density, the HR for log CMI was consistently above unity, with a p value consistently below 0.1, except for the model that included MS (see Table). Conclusions: Elevated CMI has potential as a robust predictor of future breast cancer occurrence in average risk women, even when adjusted for breast density or cytologic atypia. Our prior analysis established that CMI is not susceptible to variation with menstrual cycle phase and menopausal status. These features support its further evaluation in larger trials. Clinical trial information: NCT00896636 .[Table: see text]