bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase Ib study of RG7112 with doxorubicin (D) in advanced soft tissue sarcoma (ASTS).
Authors: Chawla Sant P. , Blay Jean-Yves , Italiano Antoine , Gutierrez Martin , Le Cesne Axel , Gomez-Roca Carlos Alberto , Gouw Launce G. , von Mehren Margaret , Wagner Andrew , Maki Robert G. , Higgins Brian , Middleton Steven , Nichols Gwen L. , Geho David , Blotner Steven , Zhi Jianguo , Chen Lin Chi 
Published: March 2020

10514 Background: Preclinical data demonstrate p53-dependent MIC-1 activation by both D and the MDM2 inhibitor RG7112. This study evaluated the tolerability of combining D with RG7112 in ASTS patients (pts) and pharmacokinetic (PK) and pharmacodynamic (PD) parameters of the combination. Methods: A phase 1b 3+3 dose escalation study was designed. Pts with ASTS in whom D was considered appropriate were eligible. D was administered IV at either 50 mg/m2 or 60 mg/m2on day 1 with RG7112 administered orally 500 or 1000 mg QD for 3 or 5 days (d1-3 or d1-5) in 28-d treatment cycles. Safety, PK and PD, including serum MIC-1 (an indicator of p53 activation), were assessed. Results: As of January 15, 2013, enrollment was complete with 23 pts with ASTS accrued; safety data for cycle 1 was available for preliminary review in 20 pts. Growth factor support was mandated following the first dosing group (D 60 mg/m2and RG7112 500 mg x 5d) due to febrile neutropenia or grade 4 neutropenia. Of the 20 pts for which cycle 1 safety data is available, 13 pts reported neutropenia (12 grade 3/4); 5 reported grade 3/4 febrile neutropenia (3 following mandatory GCSF prophylaxis); 12 pts developed thrombocytopenia (9 grade 3/4). PK parameters of the combination therapy are similar to single agent values and did not demonstrate evidence of drug-drug interactions. Serum MIC-1 rapidly increased to levels greater than for either agent alone. Best response to date is stable disease in 8/16 pts who have had interim evaluations. Conclusions: Combination therapy with D and RG7112 resulted in a high rate of grade 3/4 neutropenia (60%) or thrombocytopenia (45%). PK analysis does not suggest this is due to changes in the metabolism of either drug. This combination demonstrates apparent potentiation of p53 activation demonstrated by increased MIC-1 levels greater than additive effects of the single agents. Biomarker analyses, safety, PK, and MIC-1 data will be presented. Clinical trial information: NCT01605526. [Table: see text]
Gastrointestinal stromal tumor associated with neurofibromatosis type I.
Authors: Nishida Toshirou , Takahashi Tsuyoshi , Kaneda Mari , Ako Maiko , Omori Takeshi , Masuzawa Toru , Serada Satoshi , Naka Tetsuji , Tsujimoto Masahiko , Hirota Seiichi 
Published: March 2020

10539 Background: Most gastrointestinal stromal tumors (GIST) have either KIT or PDGFRA mutations. Neurofibromatosis type 1 pts caused by mutations in the NF1 gene have increased risk of GIST development, which may have no mutation in both genes. In this study, we analyzed clinical and pathological features of NF-1 associated GISTs. Methods: Study 1: We have screened 95 adults NF1 pts (age 31-66, 35 male and 60 female) by enhanced MDCT between 2003 and 2012. Study 2: We collected 1,184 sporadic GISTs from community hospitals in Japan between 2001 and 2010 retrospectively, and found 24 primary NF1-GISTs (1.7% of sporadic) and 2 recurrent NF1-GISTs, of whom clinicopathological features were analyzed. Results: Study1: By MDCT screening, we have found histologically confirmed 6 GISTs (4 males and 2 female; 6/1,000 NF1-persons/year) in the small intestine. Median age of NF1-GIST was 45, and five pts had multiple tumors, ICC hyperplasia in the normal intestine and no mutation in the KIT and PDGFRA genes. Study 2: Median age of 26 NF1-GIST (12 male and 14 female) was 58. 25 GISTs were located in the small bowel and one in the stomach. 17 pts had multiple GISTs and 9 pts single lesion. Pathologically, KIT was positive for all NF1-GISTs. 24 pts had spindle cell tumors and 2 had mixed or epithelioid. No mutation was found in the KIT and PDGFRA genes of 11 pts examined. Median values of mitosis (0/50HPF) and Ki67 (0.5%) were lower than those of sporadic GIST (3/50HPF and 2.5%). With media follow-up of 3.6 years, 8 pts had recurrences and 4 pts died of the disease. By western blotting, KIT was faintly phosphorylated but its downstream kinases including MEK, p44/22, AKT, mTOR, p38 and STAT3, were activated. Six pts received imatinib and had no response and, subsequently, 5 pts received sunitinib with 4 PD and 1 short-term SD. Conclusions: NF1-associated GIST is a rare entity of GIST and has distinctive features from conventional sporadic GISTs. KIT-targeted TKI appeared to be ineffective to recurrent and advanced NF1-GISTs.
Preclinical studies with neratinib in triple-negative breast cancer.
Authors: Mullooly Maeve , O'Brien Neil A. , Conklin Dylan , Finn Richard S. , Slamon Dennis J. , Crown John , O'Donovan Norma , McGowan Patricia M. , Duffy Michael J. 
Published: March 2020

1054 Background: Currently, one of the most urgent problems in breast cancer therapeutics is the validation of targeted therapy for triple-negative breast cancer (TNBC). Neratinib is an irreversible small molecule inhibitor that targets the kinase activity of EGFR, HER2 and HER4. As one of these targets, EGFR, is expressed at high levels in a subset of TNBC, we hypothesised that neratinib is a potential treatment for at least some patients with TNBC. Methods: The antiproliferative effects of neratinib were investigated in a panel of 35 breast cancer cells lines including 9 luminal, 12 HER2-positive and 14 triple-negative (TN). Baseline levels of total HER proteins were determined using flow cytometry. Results: IC50 values for neratinib across the panel of breast cancer cell lines ranged from < 0.001 - 1.9 µM. HER2-positive cell lines were significantly more sensitive to neratinib than HER2-negative cells (p = 0.008, Student’s t-test). For the 14 TN cell lines, IC50 values ranged from 0.03 – 1.9 µM. TN cell lines defined as basal-type A were significantly more sensitive to neratinib than those designated basal-type B (p = 0.02, Student’s t-test). Treatment with neratinib resulted in a reduction in HER-family signalling as detected by decreased Akt and ERK phosphorylation. Consistent with the finding that basal type A TN cells were more sensitive to neratinib than type B, significantly higher levels of EGFR expression were found in the A subtype compared to the B subtype (p = 0.02, Student’s t-test). To determine a possible predictive marker of response for neratinib, levels of all 4 HER proteins were related to response in the basal A subgroup. Baseline levels of HER3 expression were found to correlate significantly with response to neratinib (p = 0.02, r = -0.875, n = 7, Spearman), i.e., cell lines with the highest levels of HER3 expression had the lowest IC50values within this cohort. Conclusions: Our results suggest that neratinib is a potential novel therapeutic option for patients with basal A type triple negative breast cancer. HER3 may act as a predictive marker of response for this subgroup of patients. Acknowledgements: The authors thank SFI for funding MTCI (SRC award, 08/SRC/B1410 to MTCI) and an SFI Short Term Travel Fellowship to MM, for funding this work.
Genome study of PDGFRA D842V mutant GIST using next generation sequencing approach.
Authors: Pantaleo Maria A. , Astolfi Annalisa , Urbini Milena , Indio Valentina , Nannini Margherita , Saponara Maristella , Lolli Cristian , Pallotti Maria Caterina , Mandrioli Anna , Gatto Lidia , Biasco Guido 
Published: March 2020

10540 Background: Mutations of the receptors KIT and PDGFRA in GIST are the oncogenetic events of disease as well as the targets of molecular therapies. Within the PDGFRA mutations, the D842V mutation in exon 18 confers in vitro and in vivo resistance to imatinib. Next generation sequencing techniques may completely dissect all the possible somatic mutations and genomic rearrangements in order to identify novel therapeutic targets in this patients population. Methods: Five patients with gastric GIST were analyased (3 M, 2 F; mean age 65,5 years, range 51-77). The tumor dimension ranged between 3 and 15 cm, MI < 2 and 8 /50 HPF. No metastases were present in all cases. The KIT and PDGFRA anlysis showed a D842V mutation in exon 18 of PDGFRA in all cases. Whole transcriptome sequencing was performed with Illumina HiScanSQ platform with a paired-end strategy (75x2). After performing quality controls, the short reads were mapped with Tophat-Botie pipeline against the human reference genome (HG19). The variations, such as Single nucleotide variants (SNVs) and InDels, were called by SNVMix2 (a software suited for SNVs discovery in tumor samples) implementing an accurate filtering procedures developed in our laboratory. Two predictors of mutations effect at protein level (SNPs&GO and Provean) were employed in order to prioritize the emerging variation. Results: An average of 206 coding non-synonymous variants were highlighted in the five GIST samples, of which ~ 30% were predicted as deleterious with at least one predictor. In addition to PDGFRA D842V mutation, in all five patients were found mutations on different receptor tyrosine kinases, such as FGFR4 and DDR2. Moreover three out of five patients harboured mutations on members of the MDR/TAP subfamily that are involved in multidrug resistance, in particular on ABCB1, ABCB4 and on ABCB6 genes. Other mutations were found on the hedgehog and MAPK signaling pathway and on SNF/SWI chromatin remodeling complex. Conclusions: New molecular events have been identified in PDGFRA D842V mutant GIST. These data should be validated in larger series and the role of these mutations as therapeutic targets should be further investigated.
Long-term responders and survivors on pazopanib for soft tissue sarcomas (STS): Subanalysis of two European Organisation for Research and Treatment of Cancer (EORTC) clinical trials 62043 and 62072.
Authors: Kasper Bernd , Litière Saskia , Marreaud Sandrine , Sleijfer Stefan , Verweij Jaap , Bauer Sebastian , Kerst Jan M. , Van Der Graaf Winette T.A. 
Published: March 2020

10553 Background: Pazopanib has recently received approval in US, EU & Japan for use in certain STS subtypes. We conducted a retrospective analysis on pooled data from two EORTC clinical trials on pazopanib in STS in order to characterize long term responders and survivors. Methods: Patients selected for analysis were treated with pazopanib in phase II study 62043 (n = 142) and phase III study 62072 (PALETTE) (n = 246). Combined median progression-free survival (PFS) was 4.0 months; median overall survival (OS) was 11.3 months. 34 % of patients had a PFS ≥ 6 months (n = 133) and were defined as long term responders; 33 % of patients survived ≥ 18 months (n = 128), defined as long term survivors. Following patient characteristics were studied: gender, age, performance status, tumor localization, histology, grading, treatment exposure and dose modifications, severity of adverse events and post protocol therapy. Results: Clinical cut-off dates for this analysis resulted in a pooled database with a median follow-up of 2.3 years. Patient characteristics were compared between four subgroups based on short / long term PFS and OS, respectively. 79 patients were both long term responders and long term survivors. The descriptive analysis confirmed the importance of known prognostic factors such as age, performance status and grading, but did not add additional characteristics translating into long term response or survival. We identified 12 patients remaining on pazopanib for more than two years: 9 aged younger than 55 years, 9 females, four with smooth muscle tumors and nine with low or intermediate grade tumors at initial diagnosis. Only two of those patients achieved a partial response; the remaining 10 experienced stable disease as best overall response. Median time on pazopanib in these patients was 2.4 years with the longest duration of 3.7 years. Four patients were still on pazopanib at the end of the studies with a median PFS of 2.3 years and a median OS of 2.8 years. Conclusions: 34 % and 33 % of STS patients given pazopanib in these studies have a long PFS and / or OS respectively. 3.1 % of patients demonstrate a clinical benefit even beyond 2 years.
Guidelines for the definitions of time-to-event endpoints in randomized clinical trials: Results of the DATECAN Project for Sarcomas and GISTs.
Authors: Bellera Carine A. , Ouali Monia , Penel Nicolas , Bonvalot Sylvie , Casali Paolo Giovanni , Delannes Martine , Nielsen Ole Steen , Mathoulin-Pelissier Simone ,   DATECAN Group
Published: March 2020

10570 Background: With the necessity of reducing randomized clinical trial (RCT) duration, cost and number of patients, surrogate endpoints of overall survival (OS) are increasingly being used as replacement for OS in cancer RCTs. However, most of these endpoints currently lack of standardized definition enabling a comparison of RCT results. Some recommendations have been proposed for specific cancer sites but they do not rely on a formal consensus methodology. The objective of the Definition for the Assessment of Time-to-event Endpoints in Cancer trials (DATECAN) project is to provide guidelines to standardize definitions of time-to-event endpoints in RCTs for different cancer sites. We present results for sarcomas and GISTs. Methods: We relied on the modified Delphi consensus method, a validated formalized consensus process for the development of practice guidelines. International experts with various backgrounds and expertise were involved. First, the coordinating committee, a group of statisticians and epidemiologists involved in the design and conduct of RCTs, led a comprehensive literature review to identify time-to-event endpoints and events of interest. The steering committee, which included additional medical experts, validated the list and prepared the questionnaire sent for rating to an independent expert committee. Results: The consensus process is finalized. It involved 2 rounds of scoring (28 experts) and 1 in-person meeting (in parallel to ASCO'12). Each expert had to rate on a 1-9 scale if s/he agreed or not for including events (e.g. death related to primitive cancer) in the definition of time-to-event endpoints (e.g. progression-free survival). 16 events were rated for inclusion or not in the definitions of 14 time-to-event endpoints. Consensus was reached for 73% of the events after the 2 rounds of scoring. Consensus was finalized at the in-person meeting for the remaining events. Conclusions: The DATECAN guidelines should help standardizing definitions of commonly used endpoints. This process should (i) facilitate the comparison of RCTs and (ii) improve the quality of future RCTs by providing better estimation of sample size and treatment effect.
Metronomic continuous oral cyclophosphamide as second and further line in soft-tissue sarcomas (STS) of the adult.
Authors: Comandone Alessandro , Boglione Antonella , Giubellino Elena , Bergnolo Paola , Gino Giancarlo , Brach del Prever Elena Maria , Turbiglio Marco , Piana Raimondo , Pochettino Paolo , Linari Alessandra , Dal Canton Orietta , Chiado Cutin Simona , Garetto Ferdinando , Oliva Cristiano , Ottaviani Davide , Pazienza Paola 
Published: March 2020

10572 Background: In STS third line treatment is poorly defined. However many patients (pts), after aggressive therapy as first and second line progress in their disease ask to be treated. Oral cyclophosphamide (CPM) was already used in breast cancer, prostate cancer and in elderly pts with STS with favourable results. Aim of our study was to define the feasibility, tolerability and activity of oral CPM as third line and further line chemotherapy Methods: 45 pts (19 M; 26 F) with advanced or metastatic STS heavily pretreated were included. Oral CPM was given daily at total dose of 50 mg/day without interruption excepted for toxicity or progressive disease Results: Median age was 60 (32-81), histological subtypes were: leiomyosarcoma 12, liposarcoma 10, condrosarcoma 5, sinovialsarcoma 4, sarcoma NOS 4, other 10. Primary sites were: extremities 21, retroperitoneum 19, trunk 5. 41 pts were metastatic, 4 locally advanced. 41 pts were pretreated with chemotheraphy (15 were in II line, 17 in III line, 7 in IV line, 2 in V line). Median PS (ECOG) was 2 . Median duration of theraphy was 4 months (1-38). Progression free survival (PFS) ranged from 0 to 42+ months (median 4 months). Treatment was well tolerated, we registred only one episode of leucopenia G2 and one of asthenia G2. No complete responses were seen. Only 3 minimal responses and 18 stable disease were seen. Conclusions: Oral CPM showed a mild activity and good tolerability in advanced soft tissue and metastatic STS. It could be an appropriate solution as second line and further therapy and in unfit or elderly pts.
Serum protein acidic and rich in cysteine (SPARC) as a prognostic marker in soft tissue sarcoma.
Authors: Morgan Sherif S. , Nagle Raymond B. , Cranmer Lee D. 
Published: March 2020

10581 Background: SPARC is a matricellular secreted glycoprotein that performs several functions, including modulating cellular adhesion and proliferation. It has been implicated in tumorigenesis and identified as an adverse prognostic factor in a number of cancers. The specific mechanisms involved have yet to be identified. Agents targeting SPARC-expressing tumors, such as nanoparticle albumin-bound-paclitaxel (NAB-P), have been developed. Soft tissue sarcomas (STS) represent a heterogeneous group of tumors with inadequate systemic therapies. Our objective was to explore the pattern of SPARC expression and its prognostic significance in STS. Methods: Formalin-fixed paraffin-embedded tissue sections were stained by immunohistochemistry using a mouse monoclonal antibody for SPARC (Abnova). Staining intensity was scored blindly. Patient survival was determined from patients’ medical records. Kaplan-Meier and log-rank analyses were used to compare survival by SPARC expression level. Results: 27 tissue specimens of various STS subtypes were investigated (Table). Elevated SPARC expression was observed in 56% of specimens, but did not correlate with underlying histology. Overall survival segregated into 2 groups based on SPARC levels. Patients who expressed low-to-moderate levels of SPARC exhibited median survival of 22.1 months, while the median survival of patients with moderate-to-high expression levels was 4.4 months (log rank; p=0.0016). Conclusions: A significant proportion of STS specimens exhibit elevated SPARC expression. Elevated SPARC does not correlate with underlying histology, although analysis of a greater number of specimens might reveal subtypes with more frequently elevated expression. Overall survival segregates strongly by degree of SPARC expression, with elevated expression being adverse. Our results suggest that analysis in STS of agents targeting SPARC, such as NAB-P, should be stratified by extent of SPARC expression. [Table: see text]
Evaluating surgery and first-line imatinib (ima) treatment patterns for patients with gastrointestinal stromal tumors (GIST).
Authors: Eaddy Michael , Seal Brian S. , Green Mark R. , Stafkey-Mailey Dana 
Published: March 2020

10590 Background: In 2002, ima was FDA approved for advanced metastatic GIST, followed in 2008 with an indication for adjuvant therapy. Real-world data on changing patterns of ima therapy, including adjuvant management, is sparse. This study evaluated changes in treatment patterns, resection rates, and corresponding costs of care among patients receiving first-line (1LT) ima for GIST over an 8-yr period, with a breakpoint around time of initial reporting of phase III adjuvant therapy data showing survival benefit. Methods: The study was conducted Jan 1, 2003–Dec 31, 2010 utilizing pharmacy/medical claims data from a large health plan. Patients with a GIST-related ICD9 code who also received ima were eligible, and excluded if they received any chemotherapy prior to date of first diagnosis or ima. All were designated into 1 of 3 cohorts: metastatic disease at first recognition (MP), non-metastatic non-surgical (NS) patients, and non-metastatic patients undergoing a GIST-related surgical procedure before ima (SP). Patients were followed from diagnosis to end of study period or loss of continuous eligibility. Results: Patient assignment across the disease extent and surgery/no surgery cohorts by the phase III reporting event is shown in the Table. A change in distribution of primary disease presentation and/or management across two time intervals is suggested by marked decrease in percentage of MP (54.9%→36.1%) and greater than doubling of SP patients presumably receiving adjuvant therapy following initial resection attempt. In the study population, 18.8% of patients who initiated 1LT with ima went on to 2LT (73.7% sunitinib); 5.9% receive 3LT (44.4% nilotinib and 38.9% sorafenib); <1% receive 4LT (66.7% sorafenib). In general, 1LT was more costly than subsequent therapies. Across all lines of care, oral TKI drug acquisition cost was the dominant determinant of total cost of care. Conclusions: A change in distribution of primary disease presentation and/or management across the two time intervals is suggested. In each cohort, overall cost of care was largely a function of TKI acquisition cost. [Table: see text]
Triple-negative breast cancer survival in women age 75 and older.
Authors: Malmgren Judith April , Kaplan Henry G. , Atwood Mary K. 
Published: March 2020

1060 Background: Triple-negative breast cancer (TNBC) is associated with a high recurrence rate and poor prognosis, despite high initial response to chemotherapy. It is not known if TNBC patients 75 years older, an age group less likely to be treated with adjuvant chemotherapy, have the same mortality risk as younger women. Methods: We conducted a prospective cohort study of all women presenting with primary TNBC, age 21-89, stage I-III from 1998-2009 identified and tracked by our registry (n=529). Clinical characteristics were chart abstracted at diagnosis and follow up. The Kaplan-Meier method and log rank test were used for disease specific survival (DSS) and overall survival (OS) by age. Results: Mean follow up was 6.6 years, range 1.98-13.41 years. Distribution by age was 92% <75 years (n = 485) and 8% 75+ years (n = 44). The two age groups did not differ by histologic or nuclear grade, stage, or radiation therapy receipt (age 75+ by stage: I = 46%, II = 34%, III 21%, age <75: I = 37%, II = 46%, III = 17% [not significant]). Patients 75 and older were less likely to be treated with adjuvant chemotherapy (32% vs. 91%, Pearson chi square test = 119.32, p <.001). 5 year DSS was not significantly different for patients age <75 years compared to patients age 75+ years (85% vs. 84%). However, 5 year OS was significantly worse for 75 year and older patients (65%) compared to <75 year old patients (83%) (log rank test = 13.97, p < .001). Conclusions: In our institutional cohort, triple-negative breast cancer in older women had similar prognostic indicators (stage and histologic grade) compared to younger women and older women had equivalent disease specific survival in spite of substantially less chemotherapy treatment. At 5 years post diagnosis, women 75 years and older were 18% more likely to die of causes other than breast cancer.