bluuebunny/crossref_metadata_2025_split huggingface dataset:
Treatment patterns and clinical outcomes among patients (pts) with HER2+ advanced breast cancer (ABC) and germline BRCA1/2 mutation(s) (gBRCA1/2mut): Results from a US real-world study.
Authors: Obeid Elias , Parikh Rohan , Esterberg Elizabeth , Arondekar Bhakti , Hitchens Abigail , Arruda Lillian Shahied , Niyazov Alexander 
Published: May 2020

e13076 Background: g BRCA1/2mut ABC represents ~5% of all breast cancer (BC) including pts with HER2+ BC. While HER2-targeted therapy remains an effective tx for those pts, limited information is available on the use and effectiveness of PARP inhibitors (PARPi) for pts with HER2+ g BRCA1/2mut ABC. Recently, NCCN updated its guidelines (v1.2020) to support the use of PARPi in pts with g BRCA1/2mut metastatic BC regardless of subtype. In order to establish a baseline reference point, we assessed real-world tx patterns and clinical outcomes among pts with g BRCA1/2mut HER2+. Methods: Oncologists retrospectively reviewed charts (July-Oct 2019) of randomly selected pts ≥18 y, with g BRCA1/2mut HER2+ABC who received ≥1 cytotoxic chemotherapy (CT) regimen(s) for ABC between Jan 2013-April 2018. Descriptive analysis was performed for 1st line ABC tx patterns. Clinical outcomes (1st line ABC PFS rates) were estimated using the Kaplan-Meier method. PARPi clinical outcomes data was immature given its recent launch. Additional analyses evaluating outcomes in pts receiving PARPi are planned. Results: Of the 225 pts with g BRCA1/2mut ABC included in the study, 48 (21%) female pts had HER2+ disease. Of the g BRCA1/2mut HER2+ pts, 77% were white with a median age of 58 y. Clinical characteristics: 42% HR+/HER2+, 56% HR-/HER2+, 2% had unknown HR/HER2+ ABC. Txs in the 1st line setting for HR+/HER2+ ABC pts (n = 20) included: CT (75%), CT + HER2-targeted therapy (25%) (Table). First-line txs used for HR-/HER2+ ABC pts (n = 27) included: CT + HER2-targeted therapy (78%), CT (15%), other (7%) (Table). 12-month PFS for 1st line HR+/HER2+ pts was 73% and for HR-/HER2+ pts was 69% (Table). Later line tx patterns will be presented. Conclusions: In this analysis of pts with g BRCA1/2mut HR+/HER2+, unexpectedly low rates of HER2-targeted therapy were observed. As expected, high rates of HER2-targeted therapy with CT were observed among g BRCA1/2mut HR-/HER2+ pts. Clinical outcome findings demonstrate the need for more efficacious tx options. Studies assessing clinical outcomes among g BRCA1/2mut HER2+ ABC pts receiving PARPi +/- HER2-targeted tx are warranted. This is a limited sample size; additional data collection including median PFS is ongoing. [Table: see text]
A phase Ib/II study of eribulin with cyclophosphamide (EC) in patients (pts) with advanced breast cancer (ABC).
Authors: Gumusay Ozge , Renslo Jonathan R. , Wabl Chiara A. , Chien Amy Jo , Melisko Michelle E. , Majure Melanie Catherine , Rahmaputri Siti D. , Moasser Mark , Park John , Rugo Hope S. 
Published: May 2020

e13079 Background: Eribulin is an effective microtubule inhibitor for the treatment of ABC. Based on encouraging efficacy with docetaxel/cyclophosphamide, we hypothesized that eribulin combined with cyclophosphamide (EC) would be effective with tolerable toxicity. The aim of the study was to determine the maximum tolerated dose (MTD) of EC, followed by a dose expansion study to estimate the clinical benefit rate (CBR) of EC in pts with ABC. Methods: Study eligibility included pts with histologically confirmed ABC with any number of prior lines of therapy. Pts were treated using a dose escalation strategy with cohort expansion once MTD was determined. Dose level 0 (DL0): E 1.1 mg/m2 on days 1 and 8, C 600 mg/m2 on day 1 of a 21-day cycle. DL1: E 1.4 mg/m2 on days 1 and 8, C 600 mg/m2 on day 1 of a 21-day cycle. Phase II expanded enrollment at DL1. The primary objective of the phase II study was CBR [(complete response (CR), partial response (PR), and stable disease (SD)]. Secondary objectives were response rate (RR), duration of response (DOR), time to progression (TTP), and safety. Using a 2-stage design, responses in 3 of the first 22 pts allowed continued enrollment to a planned 40. Results: No dose limiting toxicities (DLT) were identified in phase Ib (n = 6). 3 pts were treated at DL0 and 3 at DL1, the MTD. 44 pts with ABC were enrolled at the MTD and are included in the analysis. 31 pts had HR+/HER2- disease, 12 pts had triple negative disease (TNBC), 1 pt had HR+/HER2+ disease. Median age was 56 yrs, prior treatment (rx) for ABC included a median of 1 line of hormone rx (range 0-6) and 2 lines of prior chemorx (range 0-7). CBR was 79.5% (35/44; 7 PR, 28 SD) and median PFS 16.4 wks (95%CI:13.8-21.1 wks). Longer PFS was observed in those with HR+ disease vs TNBC (18.1 vs 10.8 wks; P = 0.067). Adverse events (AE) of any grade included fatigue (68.2%, n = 30), neutropenia (ntp) (59.1%, n = 26), nausea (56.8%, n = 25), constipation (50%, n = 22), peripheral neuropathy (47.7%, n = 21), dyspnea (40.9%, n = 18), headache (36.4%, n = 16), and anorexia (36.4%, n = 16). The most common grade 3/4 AE ntp (47.7%, n = 21); 3 pts had febrile ntp. Dose reductions due to ntp were required to 500 mg/m2 C (n = 17) and to 1.1 mg/m2 in eribulin (n = 12). Conclusions: EC in heavily pretreated ABC resulted in an encouraging CBR of 79.5% and PFS of 16.4 wks, comparing favorably to single agent E (PFS 14.8 wks). Dose reduction and delays were due primarily to ntp. EC is an effective combination therapy with manageable toxicity in ABC. Clinical trial information: NCT01554371 .
Expression of CD44 and CD133 markers in regional metastases from breast cancer.
Authors: Sagakyants Aleksandr B. , Ulianova Elena P. , Zlatnik Elena Yu. , Novikova Inna A. , Shulgina Oksana G. , Karnaukhov Nikolay S. , Kuznetsova Marina A. , Petriashvili Inna R. , Gaysultanova Yakha S. , Vladimirova Liubov Yu , Shatova Iuliana S. , Vashchenko Larisa N. , Lisutin Aleksandr E. , Kit Oleg I. 
Published: May 2020

e13087 Background: High incidence and mortality of breast cancer (BC) require a constant search for the most informative and effective methods of diagnosis and treatment evaluation. The purpose of the study was to analyze phenotypic characteristics of cancer stem cells in tumor tissues and regional metastases of breast cancer (BC). Methods: The study included 20 BC patients with regional metastases (lymph nodes) aged 32-74 years, mean age 56.1±3.3 years. IHC analysis was performed on sections from paraffin blocks of tumors using monoclonal mouse antibodies to CD44 (156-3C11 Thermo Scientific) at a dilution of 1:2500 and polyclonal rabbit antibodies to CD133 (Cloud-Clone Corp.) at a dilution of 1:700 using the Thermo Scientific automated stainer. Membrane staining and staining intensity were evaluated: 0, 1+ weak, 2+ moderate, 3+ strong staining. CD44 expression was considered positive when staining was detected in more than 10% (cut-off) tumor cells. CD133 expression was considered positive when staining was detected in more than 5% (cut-off) of the tumor. Results: CD44 + expression was detected in 80% of breast tumor tissues (16 samples), while in 20% this marker was not determined. The average CD44 expression was 27.2±13.9%. The expression of CD44 in regional metastases (RM) from BC was 35% (from 0 to 30%), on average 17.0±6.8%. When distributed according to the χ2 criterion in the tumor and RM, an association between factorial and resultant signs was statistically significant (8.286, at p < 0.004). CD133+ expression in tumor tissues was detected in 80%, with an average expression level of 56.0±14.6%, with a predominance of positive cytoplasmic staining in 60%. Determination of this marker in BC RM gave a positive result in 15% (3 samples), with expression fluctuations from 0 to 60%, the average level was 33.0±15.4%. When distributed according to the χ2 criterion in the tumor and RM, an association between factorial and resultant signs was statistically significant (16.942, at p < 0.001). Conclusions: Determination of tumor cells with the stem phenotype directly in the tissue of primary BC tumors and in tissues of regional metastases demonstrated that the percentage of CD44+ and CD133+ cells in the primary BC tumor was higher.
Enzymatic tissue disintegration leads to the loss of immunophenotype of breast cancer stem cells.
Authors: Sagakyants Aleksandr B. , Sitkovskaya Anastasia O. , Shamova Tatiana V. , Filippova Svetlana Yu. , Bondarenko Elena S. , Zlatnik Elena Yu. , Novikova Inna A. , Vashchenko Larisa N. , Kechedzhieva Emma E. , Ausheva Tatiana V. , Andreyko Elena A. , Saforyan Natalya S. , Dashkova Irina R. , Shatova Iuliana S. , Vladimirova Liubov Yu , Lisutin Aleksandr E. , Kit Oleg I. 
Published: May 2020

e13089 Background: Cancer stem cells (CSC) are a population in the complex hierarchy of tumor tissue responsible for growth, metastasis and resistance to chemotherapy and radiotherapy. The purpose of the study was to reveal the effect of the enzymatic disintegration of breast cancer (BC) tissue on the CSC immunophenotype. Methods: BC tumor samples obtained during surgery were placed for 2 hours in a sterile Hanks’ solution immediately after collection. Samples were fragmented to 1 mm in diameter, the fragments were evenly distributed into 4 Petri dishes with (6 cm diameter) and placed in DMEM medium (Gibco, USA) without collagenase and with the addition of collagenase (Biolot, Russia) to a final concentration of 150, 300 and 450 units/ml. Samples were cultured for 48 hours at 37°C and 5.5% CO2. On day 2, the samples incubated in collagenase were grinded by passing through tips of decreasing diameter; the reference sample was grinded in the Medimachine system (BD, USA). The effect of enzymatic tissue disintegration on the preservation of BC SC immunophenotype (CD24low/-CD44+) was evaluated using the BD FacsCanto II flow cytometer (BD, USA) and PE Mouse Anti-Human CD24 (clone ML5; BD, USA) and FITC Mouse Anti-Human CD44 (clone G44-26; BD, USA) antibodies. Results: The total number of isolated cells increased almost exponentially with increasing collagenase concentration. The trypan blue test showed that cell viability did not change significantly with an increase in collagenase concentration and was approximately 50%, being an order of magnitude higher compared to mechanical dissociation (4%). However, 48 h incubation in a collagenase solution led decreased the number of CD44+ cells in proportion to the enzyme concentration by 3 to 10 times in comparison with the control. Similarly, inhibition of CD24 expression was observed compared with the control, inevitably leading to a decreased purity of the isolated subpopulation with the CD24low/-CD44+ phenotype. Conclusions: Despite an increase in the yield of viable cells, prolonged incubation in a collagenase solution leads to a loss of the immunophenotype of BC SC.
Identification of a stemness-related gene panel associated with BET inhibition in triple negative breast cancer.
Authors: Nuncia Cantarero Miriam , Serrano-Oviedo Leticia , Nieto Jiménez Cristina , Tébar García David , Burgos Lozano Miguel , Morcillo García Sara , Perez Peña Javier , Corrales-Sanchez Veronica , Gyorffy Balazs , Ocana Alberto , Galan-Moya Eva María 
Published: May 2020

e13098 Background: Triple negative breast cancers (TNBCs) are enriched in cells bearing stem-like features, i.e., cancer stem cells (CSCs), which underlie cancer progression. Thus, targeting stemness may be an interesting treatment approach. The epigenetic machinery is crucial for maintaining the stemness phenotype. Bromodomain and extra-terminal domain (BET) epigenetic reader family members are emerging as novel targets for cancer therapy, and have already shown preclinical effects in breast cancer. Here, we aimed to evaluate the effect of the BET inhibitor JQ1 on stemness in TNBC. Methods: Transcriptomic, functional annotation and qRT-PCR studies were performed on JQ1-exposed TNBC cells in culture. The results obtained were confirmed in spheroids and spheroid-derived tumours. In addition, limiting dilution, secondary and tertiary tumour sphere formation, matrigel invasion, immunofluorescence and flow cytometry assays were performed to evaluate the effect of JQ1 on CSC features. For clinical outcome analyses, the online tool Kaplan-Meier Plotter and an integrated response database were used. Results: We found that JQ1 modified the expression of stemness-related genes in two TNBC-derived cell lines, MDA-MB-231 and BT549. Among these changes, the CD44/CD24 ratio and ALDH1A1 expression level, i.e., both classical stemness markers, were found to be decreased by JQ1. Using a validated spheroid model to mimic the intrinsic characteristics of CSCs, we found that JQ1 decreased surface CD44 expression, inhibited self-renewal and invasion, and induced cell cycle arrest in G0/G1, thereby altering the stemness phenotype. We also found associations between four of the identified stemness genes, GJA1 , CD24, EPCAM and SOX9, and a worse TNBC patient outcome. The expression of another two of the stemness-related genes was found to be decreased by JQ1, ABCG2 and RUNX2, and predicted a low response to chemotherapy in TNBC patients, which supports a role for RUNX2 as a potential predictive marker for chemotherapy response in TNBC. Conclusions: We identified a stemness-related gene panel associated with JQ1 and describe how this inhibitor modifies the stemness landscape in TNBC. Therefore, we propose a novel role for JQ1 as a stemness-targeting drug. Loss of the stem cell phenotype via JQ1 treatment could lead to less aggressive and more chemo-sensitive tumours, reflecting a better patient prognosis. Thus, the identified gene panel may be of interest for the clinical management of patients with aggressive TNBC.
12-month uptake of PD-L1 testing and atezolizumab (atezo) + nab-paclitaxel (nab-pac) treatment in metastatic triple-negative breast cancer (mTNBC) following accelerated FDA-approval in the United States.
Authors: Emens Leisha A. , Craggs Christopher , Debiasi Marcio , Kent Matthew , Luhn Patricia , Hamilton Erika Paige 
Published: May 2020

e13103 Background: In March 2019, atezo + nab-pac received accelerated FDA-approval for the treatment (tx) of patients (pts) with unresectable locally advanced or metastatic TNBC who express PD-L1 in immune cells (IC), based on the results from the randomized IMpassion130 clinical trial. A companion diagnostic, the Ventana SP142 PD-L1 assay, was concurrently approved. This real-world data analysis describes the uptake of both PD-L1 testing and therapy with atezo + nab-pac from the time of approval. Methods: This is a retrospective study using the Flatiron Health electronic health record (EHR) derived de-identified database, representing > 2.4 million US cancer pts from > 280 cancer clinics. Pts diagnosed with mTNBC starting any line of systemic therapy between March 9, 2019 and December 31, 2019 (to be updated in April 2020 for 12-months follow-up) were included. Two cohorts were examined: pts receiving either atezo-based tx, or tx without atezo. Demographics were described in the pt group overall and by line of therapy (LOT). Steroid tx at baseline was classified as any order/administration of a steroid within the first three administrations of a systemic therapy in a given LOT. Any record of a PD-L1 test was reported. Results: 228 pts diagnosed with mTNBC were included; 65 pts (28%) received any atezo combination, the majority in combination with nab-pac: 57% (n = 37) in first-line (1L), 25% (n = 16) in second-line (2L), and 18% (n = 12) in third-line or later (3L+). Median age at metastatic diagnosis (mDx) for atezo-treated pts was: 1L, 65 y (IQR: 49, 72); 2L, 56 y (IQR: 48, 64); 3L+, 52 y (IQR: 42, 60). Median age at mDx for non-atezo-treated patients was: 1L, 63 y (IQR: 53, 74); 2L, 59 y (IQR: 51, 65); 3L+, 61 y (IQR: 53, 71). Of 228 pts, 158 (69%) had any PD-L1 test recorded. Among atezo-treated pts, 62 (95%) had a documented PD-L1 test; of those 40 (62%) were tested using the SP142 assay. Overall, 205 tests were recorded: SP142, n = 96 (46.8%); unknown/not documented, n = 44 (21.5%); 22C3, n = 36 (17.6%); lab-developed test, n = 26 (12.7%); SP263, n = 2 (1.0%); and 28-8, n = 1, (0.5%). 37 (57%) atezo-treated pts received a steroid at baseline. Conclusions: Atezo tx and testing with SP142 is being implemented following accelerated FDA-approval. A considerable proportion of pts received steroids at baseline and had nab-pac as chemotherapy backbone in clinical practice. Clinical outcomes of atezo-treated pts in the real-world setting remain to be further explored pending longer pt follow-up times.
Genomic landscape of FGF/FGFR pathway alternations across 12,372 pan-cancer patients.
Authors: Yin Yongmei , Zuo Wei , Yan He , Zhao Zhengyi , Zhang Yuzi , Zhao Jing , Cui Longgang , Wang Guoqiang , Cai Shangli , Bai Yuezong , Li Wei , Wu Hao 
Published: May 2020

e13503 Background: The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling pathway is involved in diverse biological processes and plays a crucial role in carcinogenesis. FGFR targeted therapies have shown great promise in the treatment of a multitude of malignancies. This study aimed to assess the alternations of FGF/FGFR pathway and explore the potential relationships between the genetic alternations in a pan-cancer setting. Methods: Next-generation sequencing was conducted with formalin-fixed, paraffin-embedded tumor specimens from 12,372 Chinese cancer patients with over 21 tumor types, including lung cancer (n = 3557), liver cancer (n = 1433), colorectal cancer (n = 1310), biliary tract cancer (n = 960), gastric cancer (n = 758), etc. Somatic mutations including single nucleotide variations (SNVs), amplifications, and fusions were analyzed, and microsatellite instability status was also assayed. Results: Of all patients, the frequency of genomic alterations in FGF/FGFR pathway (FGF3/4/6/10/14/19/23 and FGFR1-4) ranged from 54.1% (86/159) in esophagus cancer, 40.7% (112/275) in bladder/urinary tract cancer, 28.4% (73/257) in head and neck cancer to 5.3% (5/95) in prostate cancer and 4.0% (22/548) in kidney cancer. Amongst all, the highest mutational prevalence fell in FGFR SNV (5.13%) and FGF amplification (5.08%), followed by FGF SNV (3.90%), FGFR amplification (2.89%), FGFR fusion (0.88%), and FGF fusion (0.06%). Partial co-occurrence was observed between alternations of FGFR1 and 11q13 (FGF3/4/19) and between FGF6 and FGF23. On the other side, alternations of FGFR1, FGFR2, FGFR3, and FGFR4 were found to be mutually exclusive ( p< 0.001). In addition, microsatellite instability was found to be positively correlated with FGF/FGFR pathway mutation ( p< 0.001), while was negatively correlated with pathway amplifications ( p= 0.002). Conclusions: Our study investigated the molecular landscape of FGF/FGFR pathway alternations and the interplay between co-occurrence and mutual exclusivity between pathway genes in a large pan-cancer cohort. FGF/FGFR pathway mutations occurs in a variety of solid tumors, indicating that these patients may benefit from FGFR inhibitors.
Identification of paclitaxel resistance through a new statistical approach based on a random forest of perfect trees classifcation.
Authors: Nguyen Jean-Michel , Juin Philippe , Antonioli Daniel , Moreau-Gaudry Alexandre , Campone Mario , Jézéquel Pascal 
Published: May 2020

e13513 Background: Predictors of paclitaxel sensitivity in breast cancer published ten years ago, are still pending. The authors showed that paclitaxel pathological complete response (pCR) was in one hand, encountered in aggressive breast tumor with immune response and in another hand, paclitaxel resistance in less aggressive tumor. We have developed a new analysis paradigm, mixing neurons into nodes of trees classification and news class of statistical information based on free-error trees classification. We proposed to reanalyze the Bauer et al’s dataset using this novel approach. Methods: GES22513 dataset including 14 duplicated observations and 54675 anonymized probes was analyzed. A random forest of one million trees whose nodes were composed of neurons including 15 probes, was developped. We selected probes for which a free-error classification was obtained and ranked them according to the inverse of the probability of being a confounding factor and to the inverse of the probability of interacting with another probe. We compared the sets of probes which were necessary to obtain an error-free classification between those associated with a decrease and those associated with an increase of the probability of pCR. Results: Our 15 best ranked predictors were free-error classification for all observations. This includes gene expression of TLCD2, BRCC3, CHI3L2 and PROX1. Their over-expressions were associated with an increase in the probability of pCR, and gene expression of APH1B, ARFGEF1, ARID2, BPGM, CAMK2N1, CCNY, PARM1, PHKA1, PSMD9, SUDS3 (two probes) whose over-expressions are associated with a decrease in the probability of pCR. Ten out of these probes were concordant with Bauer et al’s conclusion. Four probes ( BPGM, PHKA1, CCNY and ARFGEF1) are in contradiction with it. The limited biological information were available for TLCD2. The statistical analysis also showed that TLCD2, BBRCC3, CHI3L2 and PROX1 were altogether positively modulated by eight genes/probes ( CKS1B, ADIG, NCR3, RIN3, NIPAL1, 234422_at, DCLRE1C, SLC17A4). At the opposite, the modulation of genes associated with a decrease in the probability of pCR, was rather heterogeneous and involves many more genes. Conclusions: This preliminary work shows that our statistical approach allows a perfect classification of tumors with and without pCR. Also, it proves that the selected probes/genes are respectively associated with aggressiveness/basal and less aggressiveness/luminal phenotypes. These results need to be validated on an independent cohort.