bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of automated TIL quantification in early-stage melanoma on accuracy of standard T staging using AJCC guidelines.
Authors: Moore Michael , Friesner Isabel D , Rizk Emanuelle M. , Trager Megan , Celebi Julide T. , Rich Jeani , Chikeka Ijeuru , Kurc Tahsin , Wang Jing , Rohr Bethany , Robinson Eric , Geskin Larisa J. , Horst Basil , Gardner Kevin , Niedt George , Messina Jane , Ferringer Tammy , Saltz Joel H. , Vanguri Rami , Saenger Yvonne M. 
Published: May 2020

10076 Background: Patients diagnosed with early stage melanoma are at risk of recurrence and death. Adjuvant therapy decreases risk but incurs toxicity and expense. While tumor-infiltrating lymphocytes (TILs) improve prognosis, studies have shown conflicting results due, at least in part, to inter-observer variability. Thus, TILs are not included in standard American Joint Committee on Cancer (AJCC) staging. Here, we quantitatively analyze TILs in hematoxylin and eosin (H&E) melanoma images using two machine learning algorithms. Methods: H&E images were evaluated by two methods for patients with resectable stage I-III melanoma from Columbia (N = 81) and validated using samples from Geisinger and Moffitt (N = 128). For both methods, H&E images were manually annotated using open source software, QuPath, to specify tumor regions. For Method A, images were divided into patches and, for each patch, a probability was generated to detect lymphocytes. Patches above a set threshold were considered to be “TIL positive”. Ratio of TIL positive patches to total patches was assessed for every image. For Method B, a classifier was manually trained in QuPath and then applied on each image to determine the ratio of the areas of all immune cells to all tumor cells as previously published. Cutoff values to define high and low risk groups were established based on a test set and then validated in an independent cohort. Results: Both methods distinguished patients with visceral recurrence from those without for the Columbia training set (Method A p = .0015, Method B p = .043). Using Method A, Kaplan-Meier curve at the selected cutoff also correlated significantly with disease specific survival (DSS) for Columbia (p = .022) and was validated in the Geisinger/Moffitt (p = .046) cohort. Cox analysis using Method A showed that TIL status predicted DSS in the validation set (p = .047) and added significantly to depth and ulceration (HR = 3.43, CI: 1.047-11.257, p = .042). Conclusions: Both open source machine learning algorithms find significantly higher TILs in patients who do not develop metastasis. Notably, Method A may add to standard predictors, such as depth and ulceration. These results demonstrate the promise of computational algorithms to enhance visual grading, and suggest that digital TIL evaluation may add to current AJCC staging. [Table: see text]
Pooled ctDNA analysis of the MONALEESA (ML) phase III advanced breast cancer (ABC) trials.
Authors: Andre Fabrice , Su Fei , Solovieff Nadia , Arteaga Carlos L. , Hortobagyi Gabriel N. , Chia Stephen K. L. , Neven Patrick , Bardia Aditya , Tripathy Debu , Lu Yen-Shen , Wang Yingbo , Rodriguez-Lorenc Karen , Taran Tetiana , Babbar Naveen , Slamon Dennis J. 
Published: May 2020

1009 Background: Biomarker analyses have been presented separately for each Phase III ML trial, which tested efficacy and safety of ribociclib (RIB) with different endocrine therapy (ET) combination partners as first- or second-line treatment for hormone receptor–positive, HER2-negative (HR+/HER2−) ABC. Here, using the largest pooled biomarker dataset of a CDK4/6 inhibitor in ABC to date, we identify potential biomarkers of response or resistance to RIB across ML trials. Methods: Baseline ctDNA from 1503 patients (pts) enrolled in ML-2, 3, and 7 was assessed using next-generation sequencing with a targeted panel of 557 genes. Genes with an alteration frequency ≥2% and in ≥15 pts per treatment arm were included (83 genes). Genetic alteration was defined as presence of a mutation, short insertion/deletion, or copy number alteration. Cox proportional hazard model of progression-free survival (PFS) was fit with gene-by-treatment interaction. Genes with interaction P< 0.10 and genes of interest were investigated. Results: Pts with alterations in FRS2 and PRKCA (treatment interaction P< 0.05) as well as MDM2, ERBB2, AKT1, and BRCA1/2 ( P> 0.05 but considered actionable) had a trend for increased PFS benefit of RIB vs PBO (Table). Pts with alterations in CHD4, BCL11B, ATM, or CDKN2A/2B/2C derived little to no added PFS benefit with RIB vs PBO ( P interaction < 0.10; hazard ratio [HR] > 0.80). Data on genes implicated in the literature as potential mechanisms of resistance to ET and/or CDK4/6 inhibition ( ESR1, PTEN, FAT1, RB1, and NF1) will be presented. Conclusions: Results of this pooled analysis of the ML-2, 3, and 7 trials, the largest biomarker analysis of any CDK4/6 inhibitor in ABC, revealed several potential biomarkers of response ( FRS2, MDM2, PRKCA, ERBB2, AKT1, and BRCA1/2) or resistance ( CHD4, BCL11B, ATM, or CDKN2A/2B/2C) to RIB. Clinical trial information: NCT01958021; NCT02422615; NCT02278120 . [Table: see text]
A phase Ib/II study of eribulin (ERI) plus pembrolizumab (PEMBRO) in metastatic triple-negative breast cancer (mTNBC) (ENHANCE 1).
Authors: Tolaney Sara M. , Kalinsky Kevin , Kaklamani Virginia G. , D'Adamo David R. , Aktan Gursel , Tsai Michaela L. , O'Regan Ruth , Kaufman Peter A. , Wilks Sharon , Andreopoulou Eleni , Patt Debra A. , Yuan Yuan , Wang Grace , Xing Dongyuan , Kleynerman Ella , Karantza Vassiliki , Diab Sami 
Published: May 2020

1015 Background: As monotherapies, both ERI (a chemotherapeutic microtubule inhibitor) and PEMBRO (a programmed death [PD]-1 blocking immunotherapy) have shown promising antitumor activity in mTNBC. Emerging data suggest that the addition of immunotherapy to traditional chemotherapy holds promise for mTNBC. This open-label, single-arm, phase 1b/2 study evaluated the safety and efficacy of ERI + PEMBRO in mTNBC. Methods: Patients (pts) with mTNBC and ≤2 prior systemic anticancer therapies for metastatic disease were enrolled and stratified by prior number of therapy (Stratum 1, 0; Stratum 2, 1–2). Pts received IV ERI 1.4 mg/m2 on day (d)1 and d8 and IV PEMBRO 200 mg on d1 of a 21-d cycle. The primary objectives were safety and objective response rate (ORR per RECIST 1.1 by independent imaging review). Assessments also included efficacy outcomes by PD ligand-1 (PD-L1) expression status; PD-L1+ was defined as a combined positive score ≥1 using the PD-L1 IHC 22C3 pharmDx. Results: As of data cutoff (July 31, 2019), 167 pts (Stratum 1, n=66; Stratum 2, n=101) were enrolled and treated. No dose-limiting toxicities were observed. The most common treatment-emergent adverse events were fatigue (66%), nausea (57%), peripheral sensory neuropathy (41%), alopecia (40%), and constipation (37%). No deaths were considered treatment related. The overall ORR was 23.4% (95% CI: 17.2–30.5). Efficacy outcomes by PD-L1 status (PD-L1+, n=74; PD-L1-, n=75) and stratum are presented (table). Conclusions: ERI + PEMBRO has activity in pts with mTNBC. There was a trend toward more robust activity for the combination among patients with PD-L1+ tumors compared to PD-L1- tumors in the first-line setting (Stratum 1); whereas, in the later-line setting (Stratum 2) similar survival outcomes were observed among the PD-L1+ and PD-L1- pts. ERI + PEMBRO shows promise for mTNBC with efficacy that appears greater than historical reports of either agent alone. Clinical trial information: NCT02513472 . [Table: see text]
Comparison of StemPrintER, a novel biology-based genomic predictor of distant recurrence in breast cancer, with Oncotype DX in the TransATAC cohort.
Authors: Pece Salvatore , Sestak Ivana , Montani Francesca , Tillhon Micol , Freddi Stefano , Maisonneuve Patrick , Colleoni Marco , Veronesi Paolo , Disalvatore Davide , Viale Giuseppe , Buus Richard , Cuzick Jack M. , Dowsett Mitchell , Di Fiore Pier Paolo 
Published: May 2020

1020 Background: Accurate prediction of distant metastasis (DM) in early stage ER+/HER2- breast cancer (BC) patients is vital to avoid over/under-treatment with adjuvant chemotherapy (CT). The OncotypeDX Recurrence Score (RS) is a widely used tool to assist clinical decision-making for CT. The StemPrintER Risk Score (SPRS) is an alternative genomic predictor based on the biology of cancer stem cells that predicts recurrence risk in ER+/HER2- BCs (Pece S. et al., EBioMedicine 2019). Here, we analyze the prognostic value of SPRS in the TransATAC cohort of post-menopausal ER+/HER2- BC patients, and compare the prognostic information provided by SPRS and RS for 10-year risk of DM. Methods: The likelihood χ2 (LRχ2) and Kaplan-Meier survival analyses were used to assess prognostic information provided by SPRS, RS and the clinical treatment score (CTS) in 818 TransATAC patients treated with anastrozole or tamoxifen for 5 years. Comparative analyses were made for DM risk over the 10-year follow-up, as well as in the early (0-5 years) or late (5-10 years) interval, according to nodal status. Results: Used as a continuous variable, SPRS was an independent predictor of DM in years 0-10 among all patients when adjusted for clinical parameters as expressed by the CTS [HR=1.43 (1.18-1.73), P<0.0001], as well as in node-negative [HR=1.51 (1.17-1.94), P=0.001] but not node-positive (N1-3) patients [HR=1.29 (0.95-1.75), P=0.11]. A predefined SPRS cut-off was used to stratify patients into low vs. high risk groups [LOW: N=454, 10-year DM rate=5.8%; HIGH: N=364, 10-year DM rate=21.9%; HRHIGH vs. LOW=2.96 (1.85-4.73); P<0.0001]. SPRS outperformed RS in providing prognostic information for 10-year DM risk (SPRS: HR=1.79, P<0.0001, LRχ2=33.4; RS: HR=1.52, P<0.0001, LRχ2=22.1), with even greater differences in late DM prediction in N0 patients. SPRS also provided more prognostic information than RS to CTS (ΔLRχ2: SPRS+CTS vs. CTS= 14.9; RS+CTS vs. CTS= 9.7). Conclusions: In ER+/HER2- TransATAC BC patients, SPRS was highly prognostic for DM and was superior to RS in providing additional prognostic information to conventional clinicopathological parameters.
The contribution of clinical subtype to survival differences among patients with de novo and recurrent metastatic breast cancer (dMBC).
Authors: File Danielle Marie , Pascual Tomas , Deal Allison Mary , Wheless Amy , Dees Elizabeth Claire , Carey Lisa A. 
Published: May 2020

1030 Background: Patients with de novo metastatic breast cancer (dMBC) have superior median overall survival (mOS) compared to recurrent metastatic breast cancer (rMBC). Whether patient characteristics, prior treatment, tumor stage and innate biological differences contribute to this observation is unknown. Methods: Clinical and pathological data from patients diagnosed with MBC from 2011 to 2017 at the University of North Carolina (UNC) was obtained from the prospective UNC Metastatic Breast Cancer Clinical Database (223 dMBC, 607 rMBC). Only patients with known survival status were included. Subtype was determined by hormone receptor (HR) and HER2 staining of the primary tumor. Pathologic staging results were used when available, otherwise clinical staging was used. Patient and tumor characteristics were compared using chi-square testing, and survival outcomes by Cox proportional hazards modeling. Results: 26.9% of patients with MBC presented with dMBC, with significant variation in the ratio of dMBC to rMBC across subtypes. In particular, there were more cases of HER2+ dMBC than rMBC (26.9% vs 14.0%) and fewer cases of triple negative dMBC (20.6% vs 35.3%)(p-value < 0.001). Nearly half of all cases of HR-/HER2+ MBC were de novo (48.2%). dMBC was significantly associated with older age (p = 0.002), lower grade (p = 0.027), higher T and N stage (p < 0.001) and African American race (30% vs 22%, p = 0.022). There was no significant difference in proportion of patients with visceral metastatic disease or in number of metastatic sites at diagnosis. Median follow up was 39 months in both cohorts. mOS was 12 months greater in dMBC than rMBC (34m vs 22m, p < 0.001). These differences were significant across all subtypes except HR+/HER2+. The difference in mOS between dMBC and rMBC was greatest in the HR-/HER2+ subgroup (45m vs 15m, p = 0.006). In multivariable analysis, dMBC remained associated with improved survival (adjusted hazard ratio 0.59, p < 0.001) independent of variables including age, race, subtype, grade and number of metastatic sites at diagnosis. Conclusions: Patients with dMBC have significantly better prognosis than those with rMBC. This improved outcome is in part due to subtype variation, with more triple negative and fewer HER2+ tumors in rMBC, however these differences largely remained when stratified by subtype. In multivariable analysis, de novo presentation of MBC remained an independently significant contributor to longer survival. Further investigation should focus on biologic differences between dMBC and rMBC.
Addition of endocrine therapy to dual anti-HER2 targeted therapy in initial treatment of HER2+/HR+ metastatic breast cancer.
Authors: Loft Matthew , Lok Sheau Wen , De Boer Richard H. , Malik Laeeq , Greenberg Sally , Yeo Belinda , Anton Angelyn , Nott Louise M. , Richardson Gary Edward , Collins Ian M. , Torres Javier , Barnett Frances Sarah , Devitt Bianca Alix , Gibbs Peter , Gately Lucy 
Published: May 2020

1038 Background: The combination of dual anti-HER2 targeted therapy and chemotherapy is the current first line standard of care for HER2+ metastatic breast cancer. Endocrine therapy (ET) is the backbone of treatment in hormone receptor positive (HR+) disease, but the role of the addition of endocrine therapy following chemotherapy in HER2+/HR+ disease remains unclear as pivotal first line clinical trials excluded endocrine therapy use. Methods: Data from a multi-site community cohort of consecutive HER2+ metastatic breast cancer patients diagnosed between 1 January 2012 and 31 August 2019 was examined. Patients were treated at clinician discretion. The subset of patients eligible for this analysis were those that were HR+ and had received first line dual anti-HER2 targeted therapy. Results: Of 132 eligible patients included in the analysis, 78 (59.1%) received endocrine therapy and 54 (40.9%) did not. Median follow up was 25.9 months. There were no significant differences between the two groups based on age, performance status, previous therapy or de novo disease (Table), however, patients with bone metastases were more likely to receive ET in conjunction with first line dual anti-HER2 therapy (71% vs 52%, p= .043). The addition of ET was associated with improved progression free (HR 2.1, 95% CI 1.2-3.5, p = 0.007) and overall survival (HR 2.7, 95% CI 1.2-5.5, p = 0.007) in multivariate analysis. No increase in serious adverse events was noted although endocrine therapy related toxicities were not specifically collected. Conclusions: In this real-world series, the addition of ET to first line dual anti-HER2 therapy in HER2+/HR+ metastatic breast cancer was associated with improved progression free and overall survival. Further research is required to validate these findings and examine the role of CDK4/6 inhibitors in this disease, but may provide reassurance to clinicians considering ET in this clinical context. [Table: see text]
Preliminary safety, efficacy and pharmacokinetics (PK) results of KN026, a HER2 bispecific antibody in patients (pts) with HER2-positive metastatic breast cancer.
Authors: Ji Dongmei , Zhang Jian , Shen Weina , Du Yiqun , Xu June , Yang Jing , Luo Xin , Kong Paul , Yang Fei , Hu Xi-Chun 
Published: May 2020

1041 Background: KN026 is a novel bispecific antibody that simultaneously binds to two distinct HER2 epitopes, the same domains as trastuzumab (ECD4) and pertuzumab (ECD2). It blocks ligand-dependent and independent tumor growth and enhances HER2 receptor internalization. In preclinical studies, KN026 showed activity in trastuzumab plus pertuzumab resistant tumor cell lines. This first-in-human study evaluated the safety/tolerability, pharmacokinetics (PK), and preliminary efficacy of KN026 monotherapy. Methods: This dose-escalation and expansion study enrolled Chinese patients (pts) with metastatic breast cancer who have failed prior anti-HER2 therapy. All pts intravenously received KN026 monotherapy at ascending dose of 5 mg/kg (QW), 10 mg/kg (QW), 20 mg/kg (Q2W) or 30 mg/kg (Q3W). Dose limiting toxicity (DLT) evaluation period was 28 days for QW and Q2W, and 21 days for Q3W. Efficacy evaluation was performed by RECIST 1.1 every 6 weeks and safety assessment according to CTCAE v 4.03. Results: As of the Jan, 22, 2020, 63 pts [median age: 54 years (31~69)] enrolled and 62 pts were included in the efficacy analysis. 41 pts remained on treatment and 22 pts discontinued treatment due to disease progression (n = 21) and adverse events (n = 1). The median treatment duration was 12 weeks (range: 4~62 weeks). Median prior lines of therapies are 3 (range: 1~15), and median prior lines of HER2 target therapies are 2 (range: 1~12). No DLTs were observed. Treatment-related AEs (TRAEs) occurred in 49 pts and 4 pts experienced 4 grade 3 TRAE (hypertension, infusion related reaction, transaminases increased and ventricular arrhythmia). The common (≥ 10%) TRAE were pyrexia (23.8%), diarrhea (19.0%), aspartate aminotransferase increased (15.9%), neutrophil count decreased (11.1%) and white blood cell count decreased (11.1%). The objective response rate at recommended Phase 2 dose levels (n = 56) was 32.1% (95% CI 20.3, 46.0) and disease control rate 76.8% (95% CI 63.6, 87.0). Pharmacokinetic analysis showed exposure (Cmax and AUC0-t) of KN026 increased by dose. The recommended Phase 2 dose (RP2D) were 20 mg/kg Q2W and 30 mg/kg Q3W. Conclusions: KN026 is well tolerated and has demonstrated encouraging anti-tumor activity in HER2-positive breast cancer patients who have failed standard anti-HER2 therapies. The recommended Phase 2 dose (RP2D) of KN026 were 20 mg/kg Q2W and 30 mg/kg Q3W. Phase II trials in various HER2-positive and HER2-low/intermediate solid tumors are currently ongoing. Clinical trial information: NCT03619681 .
Final analysis of phase I study of ceritinib in pediatric patients with malignancies harboring activated anaplastic lymphoma kinase (ALK).
Authors: Schulte Johannes H , Moreno Lucas , Ziegler David Simon , Marshall Lynley V. , Zwaan C. Michel , Irwin Meredith , Casanova Michela , Sabado Constantino , Wulff Beate , Stegert Mario , Wang Luojun , Hurtado Felipe K. , Branle Fabrice , Fischer Matthias , Geoerger Birgit 
Published: May 2020

10505 Background: Activation of anaplastic lymphoma kinase has been detected in several pediatric malignancies, including anaplastic large-cell lymphoma (ALCL), inflammatory myofibroblastic tumor (IMT), neuroblastoma and others. Preliminary findings from this phase 1, multicenter, dose-escalation study (NCT01742286) indicated a Maximum Tolerated Dose (MTD)/Recommended Dose for Expansion (RDE) of the potent oral ALK inhibitor ceritinib to be 510 mg/m2 (fasted) and 500 mg/m2 (fed) in pediatric patients (pts). Here, we report final safety, pharmacokinetics (PK) and efficacy results. Methods: Children aged ≥1 to <18 years with advanced, mostly pretreated, ALK-aberrant malignancies were enrolled in this study. Dose escalation was conducted to determine the MTD/RDE of ceritinib (primary objective), in both fasted and fed states, following which pts entered an expansion phase to evaluate safety, tolerability, and efficacy at the MTD/RDE. Secondary objectives were evaluation of safety, PK, and efficacy (overall response rate [ORR], duration of response [DOR] and progression-free survival [PFS]). Results: A total of 83 pts (median age, 8 years) with ALK-aberrant malignancies were enrolled into dose-escalation (n = 40) and expansion (n = 43) study periods. Of these, 55 pts (neuroblastoma, n = 30; IMT, n = 10; ALCL, n = 8; others, n = 7) were treated with ceritinib at MTD/RDE (510 mg/m2 [fasted], n = 13; 500 mg/m2 [fed], n = 42). Systemic exposure of ceritinib between the two doses was comparable, so data were pooled for efficacy assessment. The ORRs (95% CI) were 75% (34.9-96.8) for pts with ALCL, 70% (34.8-93.3) for IMT and 20% (7.7-38.6) for neuroblastoma. The median DOR was 15 months (95% CI: 5.8, 22.2) for the 6/30 pts with neuroblastoma who had confirmed CR or PR treated at fasted/fed MTD/RDE. Median DOR was not reached for those with ALCL and IMT. Most common adverse events (AEs) (N = 83; all-grades, all-causality, ≥50% of pts): vomiting (86.7%), diarrhea (78.3%), increased ALT (65.1%), increased AST (59.0%), nausea (56.6%), and abdominal pain (50.6%). Grade 3/4 AEs were observed in 80.7% of pts (mostly transaminase elevations) and were manageable. Six pts (7.2%) were discontinued from ceritinib due to a grade 3/4 AE (mostly transaminase elevation). Conclusions: Substantial activity was observed with ceritinib at the RDE in pts with IMT, ALCL and heavily pretreated neuroblastoma. The toxicity profile of ceritinib in children was manageable and similar to that previously reported in adults. Clinical trial information: NCT01742286.
Phase II study of antidisialoganglioside antibody, dinutuximab, in combination with GM-CSF in patients with recurrent osteosarcoma (AOST1421): A report from the Children’s Oncology Group.
Authors: Hingorani Pooja , Krailo Mark D. , Buxton Allen , Hutson Paul R. , Davis Justin , Janeway Katherine A. , Gorlick Richard Greg , Isakoff Michael 
Published: May 2020

10508 Background: Treatment of patients with recurrent osteosarcoma (OS) is challenging and novel effective therapies are urgently needed. This study evaluated disease control rate (DCR) in patients with recurrent pulmonary OS, when treated with dinutuximab plus cytokine therapy as compared to a historical benchmark. The rationale for dinutuximab was the ubiquitous ( > 95%) GD2 positivity in OS tumors and cell lines. Methods: AOST1421 was a single-arm phase 2 study. Patients with recurrent pulmonary OS in complete surgical remission were eligible. Patients received five cycles of dinutuximab 70mg/m2/cycle with GM-CSF. Two different dinutuximab infusion schedules were used - 35mg/m2/day over 20 hours (2-day) and 17.5mg/m2/day over 10 hours (4-day) schedule. Primary end point was DCR, defined as proportion of patients event-free at 12 months from enrollment. Events were progressive disease or death within 12 months attributed to treatment or progression. The historical benchmark was AOST0221 with a 12-month DCR of 20% (95% CI 10-34%). Success was defined as ≥16/ 39 patients ( > 40%) event-free at 12 months from enrollment. Secondary objectives included toxicity evaluation and dinutuximab pharmacokinetics (PK). Results: Forty-one patients were enrolled from Nov 2015 - Jan 2018. Thirty nine were eligible and evaluable (age 7-26 yr; median 15 yr). Data current to December 31, 2019 was used for analysis. Accrual rate was higher than expected (22.1 vs. 19.2 patients/ yr.) despite a concurrently open competing study. One of 136 administered therapy cycles met criteria for unacceptable toxicity when one patient receiving the 2-day schedule died after cycle 2 due to an unknown cause, attributed as probably related to protocol therapy. The protocol was revised to allow only the 4-day schedule. Other ≥ Grade 3 toxicities occurring in > 10 % participants were expected dinutuximab toxicities such as pain, diarrhea, hypoxia and hypotension. Dinutuximab did not demonstrate sufficient evidence of efficacy as 27/ 39 patients experienced an event for a DCR of 30.7% (95% CI 17- 47%). PK studies are pending and will be reported. Conclusions: Dinutuximab toxicity in adolescent and young adult OS patients was similar to younger patients. While GD2 remains a relevant target in OS, combination of dinutuximab with GM-CSF did not meet the targeted successful DCR in patients with completely resected tumor. Other strategies for targeting GD2 or dinituximab combination therapy may still be warranted. Clinical trial information: NCT02484443.