bluuebunny/crossref_metadata_2025 huggingface dataset:
Management of uni- or bilateral retinoblastoma with radiologic optic nerve invasion at diagnosis.
Authors: Choucair Marie-Louise , Brisse Herve , Freneaux Paul , Lumbroso Livia , Chevrier Marion , Doz Francois P. , Aerts Isabelle
Published: September 2018

10551

Background: To evaluate treatment and outcome of patients with uni- or bilateral retinoblastoma (RB) with radiologic optic nerve invasion (RONI) at diagnosis. Methods: Retrospective clinical, radiological and histological review of patients with uni- or bilateral RB with RONI at diagnosis treated in the Institut Curie. Results: Between 1997 and 2014, 936 patients with RB were treated in the Institut Curie. Eleven patients had detectable RONI confirmed by Computed Tomography and/or Magnetic Resonance Imaging. RB was unilateral in 10/11 patients, bilateral in 1. Median age at diagnosis was 29 months (range 12-96). The patient with the bilateral RB had a unilateral RONI. Nine patients had ON enhancement and 3 had meningeal sheath enhancement. Nine received neoadjuvant chemotherapy (CT) and 2 had a primary enucleation. Partial response to neoadjuvant CT was obtained for all the patients. Enucleation was performed in 10/11 patients, by anterior approach in 3 patients, by anterior and subfrontal approach in 7 patients. Three patients had positive ON margin and among them, 2 were primary enucleated. All enucleated patients received adjuvant treatment (conventional CT: 10, High Dose CT: 7 and radiotherapy: 5). Three patients died of meningeal progression (2 during treatment and 1 during the first year after treatment). The patient with the bilateral RB was lost to follow up just after a meningeal progression during treatment. Seven are still alive (median follow up: 8 years, range : 1.5-17.5). Conclusions: Neoadjuvant CT has an important place in the management of unilateral RB with RONI at diagnosis. Pretreatment accurate staging by orbital and brain MRI is mandatory, as well as preoperative reassessment. Surgery should be performed by experienced ophthalmologists and if necessary neurosurgical team in order to obtain the best conditions for a tumor-free resection margin in patients with RONI.
Long-term growth and development in 268 bevacizumab (BEV)-treated and 135 control pediatric/adolescent patients (pts): An integrated analysis.
Authors: Müller Hermann L. , Merks Johannes H.M. , Geoerger Birgit , Grill Jacques , Hargrave Darren , Glade Bender Julia Lynne , Gururangan Sridharan , Navid Fariba , Johnston Michael , Bachir Jeanette , Hilton Magalie , Fürst-Recktenwald Sabine
Published: September 2018

10554

Background: BEV has an established safety profile in adults, but long-term data in children are limited. This analysis examined the effects of BEV on growth/development in pediatric/adolescent pts. Methods: Data (height, weight, body mass index [BMI], bone age data) were pooled (5 trials): NCT00643565 (Ph2/soft tissue sarcoma); NCT01390948 (Ph2/high-grade glioma); NCT00085111 (Ph1/refractory solid tumors); NCT00667342 (Ph2/osteosarcoma); NCT00381797 (Ph2/glioma, medulloblastoma, ependymoma). Pts (<18 yrs old) received ≥1 dose of BEV + chemotherapy (CT) (n=268) or CT alone (n=135). Analyses were exploratory/descriptive. Reference growth data: WHO (<2 yrs); Centres for Disease Control (≥2 yrs). Results: Across the trials, mean number of BEV administrations per pt ranged 5.6–19.9 (dose 5–15mg/kg every 2/3 weeks). Median follow-up time, months (range): BEV+CT, 37.9 (2.4–64.2); CT, 22.9 (2.8–69.2). At baseline, median height, weight, and BMI were close to that of the reference population (mean standard deviation scores [SDS] close to 0). Over 60 months, a slight decline was observed in the mean SDS for height and weight in both arms in this cohort with different tumors/treatments (Table), but remained within normal range of healthy children. Trends were similar for BMI. No delay in growth velocity or bone age in BEV-treated pts vs CT only was observed up to 3 yrs, regardless of age/gender. A subgroup analysis of pts in the growth hormone-dependent development phase was consistent with the overall results. Conclusions: In this analysis, BEV inclusion in the treatment regimen did not have a negative impact on pediatric growth/development beyond that of CT alone. [Table: see text]
Human papillomavirus (HPV)-associated malignancies as subsequent malignant neoplasms (SMN) in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Henderson Tara O. , Nathan Paul C. , Whitton John , Leisenring Wendy M. , Neglia Joseph Philip , Fowler Brynn , Arnold Michael A. , Howell Rebecca M. , Robison Leslie L. , Armstrong Gregory T. , Alexander Kenneth
Published: September 2018

10566

Background: It is not known whether childhood cancer survivors (CCS) develop human papillomavirus (HPV)-associated malignancies more frequently than the general population. Methods: We assessed the cumulative incidence of SMN in sites typically associated with HPV (HPV-SMN) and evaluated standardized incidence ratios (SIR) and absolute excess risks (AER) using age-, sex- and calendar-year specific rates from the Surveillance, Epidemiology and End Results (SEER) program. Multivariate Cox regression models identified associations between key risk factors and HPV-SMN development. Results: Among 27,620 CCS, 36 developed an HPV-SMN at a median age of 27 years (range: 8-42) and a median of 15 years (range: 5-29) after their primary cancer. The 30-year cumulative incidence of an HPV-SMN was 0.20% (95% confidence interval [CI]: 0.13%-0.28%). HPV-SMN locations included oral cavity/pharynx (N = 26, 72%), rectum (N = 4, 11%), cervix/uteri (N = 3, 8%), and vulva (N = 3, 8%). The incidence of HPV-SMN was almost 3-fold higher among CCS than the general population (SIR = 2.8, 95% CI 2.0-4.1) with an AER of 6.0/100,000 person-years. Rates were elevated in those exposed (SIR = 3.3, CI 2.1-5.2) and not exposed to radiotherapy (RT; SIR = 2.6, CI 1.4-4.8). Risk of oral cavity/pharynx SMN was elevated in both those exposed (SIR = 7.3, CI 3.9-13.6) and not exposed (SIR = 4.2, CI 2.2-8.1) to head or neck RT, whereas, risk in GU locations was elevated in those exposed (SIR = 4.1, CI 1.9-9.2) but not in those not exposed to pelvic RT (SIR = 0.8, CI 0.3-2.1). Male sex (HR = 2.9, CI 1.3-6.1), exposure to head/neck/pelvic RT (HR = 2.6, CI 1.2-6.1), and platinum chemotherapy (HR = 6.1, CI: 2.6-13.9) increased the risk. Among 15 deceased HPV-SMN cases, 10 (67%) died of their HPV-SMN. Conclusions: While the overall incidence is low, CCS are at increased risk of developing malignancies in locations commonly associated with HPV infection in the general population. Further research examining the role of HPV in the etiology of these SMNs is warranted. As HPV-SMNs are potentially preventable, promotion of HPV vaccination efforts should be considered in this population.
Second malignant neoplasms in a nationwide population-based cohort of childhood cancer survivors in Taiwan.
Authors: Yu Chu-Ling , Tonorezos Emily S. , Huang Chiung-Yu , Chiu Brian C-H , Chiang Chun-Ju , Ch'ang Hui-Ju , Liu Yen-Lin , Miser James S. , Chiou Hung-Yi , Yen Yun
Published: September 2018

10569

Background: Childhood cancer survivors have excess risk of second malignant neoplasms, but data are limited in Asian populations. We established a nationwide retrospective cohort of childhood cancer survivors in Taiwan to study the risk of second malignant neoplasms in the population. Methods: Children and adolescents diagnosed with cancer before age 21 years between 1990 and 2011 were identified from the Taiwan Cancer Registry, the national cancer registry in Taiwan. One-year survivors of childhood cancer were ascertained through data linkage with the national death registry. Survivors were followed up through December 2012. Standardized incidence ratios (SIRs), absolute excess risks (AERs), and cumulative incidence of second malignant neoplasms were calculated. Results: A total of 186 second malignant neoplasms occurred among 15,263 1-year survivors of childhood cancer after a mean follow-up time of 8.0 years (SIR = 5.4, 95% confidence interval [CI] = 4.6-6.2; AER = 12.4 per 10,000 person-years). The most common types of second malignant neoplasms were gastrointestinal cancers (n = 37), leukemia (n = 28), endocrine cancers (n = 18), and brain cancer (n = 17). Cancers in the liver (n = 11, including 9 hepatocellular carcinoma) and colorectum (n = 16) accounted for 73% of second gastrointestinal malignant neoplasms in this population. The cumulative incidence of second malignant neoplasms at 10 and 20 years from follow-up was 1.0% (95% CI = 0.8-1.2%) and 3.0% (95% CI = 2.3-3.6%), respectively. Conclusions: Childhood cancer survivors in Taiwan experience excess risk of second malignant neoplasms, in particular gastrointestinal cancers, compared with the general population.
Accuracy of self-reported smoking status in adult survivors of childhood cancer: A report from St. Jude Lifetime Cohort study.
Authors: Huang I-Chan , Klosky James L. , Young Chelsea , Murphy Sharon , Srivastava Deo Kumar , Hudson Melissa M. , Robison Leslie L.
Published: September 2018

10570

Background: Although clinicians often evaluate smoking behavior in cancer survivors via self-report, the validity of this approach is unknown. We validated self-reported smoking status by serum cotinine data in clinically assessed adult survivors of childhood cancer and identified factors contributing to misclassification. Methods: The study sample consists of 287 randomly selected adult survivors of childhood cancers participating in the St. Jude Lifetime Cohort Study and undergoing a risk-based clinical assessment in a survivorship clinic. Self-reported smoking status was classified as never (N = 105), past (N = 111), and current (N = 71) smokers. Age, sex, and race/ethnicity were balanced among the three groups (p’s > 0.05). Blood samples were obtained and serum cotinine levels were quantified by liquid chromatography tandem mass spectrometry. Misclassification was determined by the discrepancies between self-reported smoking status and race/ethnicity-specific serum cotinine thresholds (Benowitz et al. Am J Epidemiol 2009). Multiple logistic regression model was used to identify factors related to misclassification. Results: Of the 287 survivors (mean age = 34 years [range = 19-61]; mean time from diagnosis = 24 years [range = 11-46]), 55.4% were male and 84.0% non-Hispanic white. Cotinine levels consistent with recent active smoking were present in 39.4% compared to 24.7% who self-reported as being a current smoker (X2= 14.1; p = 0.0002). Rates of misclassification were 36.9%, 8.4%, and 6.7% in survivors who reported themselves as past, current, and never smokers, respectively. Among self-reported past smokers, 18-30 years of age at survey, male, and current marijuana use increased the risk of misclassification: RR = 3.0 (95%CI = 1.2-7.6), 2.5 (95%CI = 1.1-5.4) and 3.2 (95%CI = 1.1-9.3), respectively. Conclusions: Within a clinical setting, reliance on self-report of smoking status by survivors results in a high misclassification rate. For research, serum cotinine levels should be utilized to assign smoking status. For clinical care and health promotion, clinicians need to be aware of the high rate of misclassification when relying upon self-reported smoking status.
Pharmacogenetics revisits bevacizumab in breast cancer patients: An ancillary analysis of the UCBG trial COMET—A French multicentric prospective study from R&D UNICANCER.
Authors: Milano Gerard A. , Pierga Jean-Yves , Gal Jocelyn , Llorca Laurence , Dubot Coraline , Romieu Gilles , Desmoulins Isabelle , Brain Etienne , Goncalves Anthony , Ferrero Jean-Marc , Cottu Paul H. , Debled Marc , Tredan Olivier , Chamorey Emmanuel , Merlano Marco Carlo , Lemonnier Jérôme , Etienne-Grimaldi Marie-Christine
Published: September 2018

1079

Background: Bevacizumab (Beva) is no longer unanimously recommended in the management of breast cancer (BC). Given the absence of faithful predictors of Beva treatment outcome, we made the hypothesis that constitutional gene polymorphisms could play a role in this context. We report the pharmacogenetic ancillary study of the prospective COMET trial conducted in advanced BC patients (pts) receiving first-line Beva associated with paclitaxel. Methods: Relevant targeted gene polymorphisms were analyzed (blood) in 203 prospective pts (mean age 55.3, median follow-up 24 months). VEGFA at positions -2578C > A (rs699947), -1498T > C (rs833061), -634G > C (rs2010963), and 936C > T (rs3025039) were analyzed by PCR-RFLP. VEGFR1 319A > C (rs9582036), VEGFR2 at positions 604C > T (rs2071559), 1192C > T (rs2305948), 1416T > A (rs1870377), IL8 251T > A (rs4073), CYP2C8 139C > T (rs1572080), 399T > C (rs10509681) and ABCB1 at positions 1199 C > TA (rs2229109), 2677G > TAC (rs2032582) were analyzed by Mass-Array Agena. ABCB1 1236C > T (rs1128503) and 3435T > C (rs1045642) were analyzed by pyrosequencing. All fitted HWE. Results: Median progression-free survival (PFS) was 10.8 months. VEGFR1 319A allele was associated with longer PFS (p = 0.03). The VEGFA-1498T allele was significantly associated with both longer overall survival (OS) (p = 0.005) and PFS (p = 0.065). The VEGFA -2578C allele was associated with greater OS (p = 0.002) and PFS (p = 0.071). These two VEGFA polymorphisms were in linkage disequilibrium (p < 0.0001). Multivariate Cox analysis showed that VEGFA -2578 (p = 0.001) and VEGFR2 1416 (p = 0.025) were significant predictors of OS: the score of favorable alleles (VEGFA -2575C and VEGFR2 1416T) was highly associated with OS (p = 0.0003), with median survival at 24 months being 30% for score 0 (95%CI 15-61), 65% for score 1 (95%CI 55-75) and 90% for score 2 (95%CI 67-90). Conclusions: Application of an easy-to-perform low-cost genotyping test may identify strong predictors of Beva outcome in metastatic BC pts. In the current era of precision medicine, a pharmacogenetic-based personalized Beva therapy deserves to be prospectively validated in BC pts. Clinical trial information: 2012-A00244-39.
A phase II, multicenter, randomized trial of eribulin plus gemcitabine (EG) vs. paclitaxel plus gemcitabine (PG) in patients with HER2-negative metastatic breast cancer (MBC) as first-line chemotherapy (KCSG BR13-11, NCT02263495).
Authors: Jung Kyung Hae , Park Yeon Hee , Im Seock-Ah , Sohn Joohyuk , Lee Keun-Seok , Chae Yee Soo , Lee Ki Hyeong , Kim Jee Hyun , Im Young-Hyuck , Kim Ji-Yeon , Kim Tae-Yong , Lee Kyung-Hun , Kim Sung-Bae , Ahn Jin-Hee , Kim Gun Min , Park In Hae , Lee Soo Jung , Han Hye Sook , Kim Se Hyun
Published: September 2018

1082

Background: PG chemotherapy is one of the preferred chemotherapeutic regimens for patients with MBC. Eribulin mesylate is a non-taxane inhibitor of microtubule dynamics of the halichondrin class. A recent pooled analysis with eribulin showed improved overall survival (OS) in various patient subgroups. Furthermore, eribulin may have rational benefit compared with paclitaxel in terms of neurotoxicity. Methods: This study was a prospective randomized phase 2, open-label, two-arm, multi-center study comparing EG with PG chemotherapy for patients with HER-2 negative MBC as first-line treatment. Histologically confirmed breast cancer patients, at least 19 years of age, with no prior history of chemotherapy for MBC with evaluable lesions were included. Prior hormonal therapy as a treatment of Hormone Receptor (HR)-positive MBC was allowed. This design was hypothesized that EG chemotherapy would not be inferior to PG chemotherapy. The primary endpoint was Progression-Free Survival (PFS). Estimated 6 mo. PFS rate for each arm was 70%. The secondary endpoints were: Time to Treatment Failure (TTF); OS; neuropathic scale; toxicity; clinical benefit rate. Results: A total of 118 patients (median age: 50, 24-66) were enrolled between 2015 and 2016, and were randomly assigned to PG (n = 59) or EG (n = 59) chemotherapy. Mean number of metastatic sites was 3 (1-8). Six month PFS rates for both arms were 72% for EG and 73% for PG arm (p = 0.457). PFS in PG arm tends to be longer than in EG group (median PFS 12.6 for PG vs. 9.6 months for EG) without statistical significance. In addition, there was no significant difference in OS between the two groups (not reached vs. 21.2 months, p = 0.223). The median numbers of chemotherapy cycles of both groups were 8 for EG and 10 for PG (range 2-32). CBRs were 44% for EG and 45% for PG arm. Major toxicities were neutropenia and neurotoxicity. Grade II or more neurotoxicity was more common in PG than in EG group (40% vs.25%). Conclusions: EG chemotherapy showed similar clinical benefit with PG chemotherapy in terms of PFS but, more favorable neurotoxicity than PG chemotherapy. Clinical trial information: NCT02263495.
Association between insulin-like growth factor-1 receptor (IGF1R) expression in circulating tumor cells (CTCs) and prognosis in patients with metastatic breast cancer (MBC).
Authors: Gennari Alessandra , Zamarchi Rita , Amadori Dino , De Censi Andrea , Nanni Oriana , Bologna Alessandra , Cavanna Luigi , Gianni Lorenzo , Scaltriti Laura , Rossi Elisabetta , Facchinetti Antonella , Corradengo Davide , Foca Flavia , Bruzzi Paolo
Published: September 2018

1086

Background: CTCs are strongly associated with prognosis in MBC. In a recent metanalysis on 1944 patients, a CTC count > 5/7.5 ml was associated with a 2-fold increased risk of progression and death. Little evidence is available on the prognostic role of phenotypic CTC assessment, however. In this study, nested in a randomized clinical trial of Ist line chemotherapy ± metformin, we evaluated the prognostic role of IGF1R expression in CTCs, given its potential growth promoting effect. Methods: CTCs were isolated from blood samples of enrolled patients; an automated sample preparation and analysis system (CellSearch) was customized for detecting IGF1R positive CTCs. The prognostic role of total CTCs, IGF1R positive (+ve) and negative (-ve) CTCs was assessed by fitting different PFS and OS multivariate Cox’s models.Results: CTC evaluation at baseline was performed in 72 of 126 patients, of whom 30 (42%) had CTCs ≥5/7,5ml and 41 (57%) had at least one IGF1R+ve CTC. In univariate analysis the prognostic role of total CTCs was confirmed: PFS ( < 5 vs ≥5) HR = 1.69, 95%CI 1.01-2.69, p 0.042 and OS HR = 2.80, 95%CI 1.47-5.30, p 0.002).However, when total CTCs were split in IGF1R+ve and IGF1R–ve, a striking difference was seen in the prognostic effect of these cell types.While no association was detected between an increasing number of IGF1R+ve CTCs and PFS or OS (p = 0.56 and p = 0.99), the number of IGF1R-ve CTCs ( < 4 vs ≥4) was strongly associated with an increased risk of progression and death: HR 1.93 (95%CI 1.15-3.23, p 0.013) and 3.65 (95%CI 1.88-7.09, p 0.001). In multivariate analysis, adjusted for metformin, the prognostic role of the number of IGF1R-ve CTCs was confirmed, while no residual prognostic role of total CTCs or number of IGF1R+ve cells was found (p = 0.55 and p = 0.64 for PFS; p = 0.86 in both cases for OS). Conclusions: In our study, the loss of IGF1R expression in CTCs exhibited a significant adverse prognostic effect, whereas no significant effect of total CTCs and IGF1R+ve CTCs was observed. This finding supports the biological characterization of CTCs as a critical step for further definition of their prognostic significance.
Retinoblastoma (Rb) protein expression in triple-negative breast cancer.
Authors: Patel Jaymin M , Torous Vanda , Hacker Michele R , Nalven Tessa , Garber Judy Ellen , Alexander Brian Michael , Lee Larissa Janeen , Collins Laura C. , Schnitt Stuart J. , Tung Nadine M.
Published: September 2018

1097

Background: Expression of Rb, the protein product of the RB tumor suppressor gene, is required for cyclin D kinase (CDK) 4/6 inhibition in luminal breast cancers. Triple negative breast cancers (TNBC) frequently exhibit Rb loss and are thus believed to be poor candidates for CDK4/6 inhibition. However, the features associated with Rb loss in TNBC are poorly-defined. We aimed to assess whether TNBC that express the androgen receptor (AR) and resemble a more luminal subtype retain Rb more often than other TNBC. Methods: To assess the frequency and correlates of Rb expression in TNBC, we stained tissue microarrays (TMAs) containing 180 Stage I-III TNBC, 71 with germline BRCA1 mutations ( BRCA1+) and 109 without BRCA1 mutation (sporadic), using a mouse monoclonal antibody to human Rb (clone G3-245, BD Biosciences). Assessment of tumor size, histologic type, grade, lymphovascular invasion and lymph node status were assessed on histologic review. The TMAs, containing three 0.6mm cores/tumor, had been previously stained for AR, CK5/6, CK14 and EGFR. Log-binomial regression was used to calculate risk ratios (RR). Results: Fifty percent of TNBC were Rb-positive (Rb+; ≥10% nuclei staining) of which 84.4% had > 50% nuclei staining. Among TNBC that were Rb-negative, 76.6% had < 1% nuclei staining for Rb. AR expression (≥10% nuclei staining) was more common in Rb+ than Rb-negative TNBC (16.7% vs 4.5%; p = 0.01). In addition, Rb expression was significantly more common among sporadic than BRCA1+ TNBC (59.6% vs 35.2%, p = 0.001). Compared with Rb-negative TNBC, Rb+ tumors were associated with older age (mean 48.7 vs 45.7 years; p = 0.06) and lower histologic grade (grade 1 or 2: 9.2% vs 2.2%; p = 0.05). No other clinical or pathologic features were significantly associated with Rb status. In a multivariable model, both AR expression (RR, 1.65; 95% CI, 1.31-2.08) and lack of BRCA1 mutation (RR, 1.63; 95% CI, 1.17-2.29) significantly predicted for Rb expression among TNBC. Conclusions: Sporadic TNBC is significantly more likely to be Rb+ than BRCA1+ TNBC. Among TNBC, AR expression significantly predicts for Rb expression. These results suggest clinically relevant biomarkers that may predict for Rb expression and potential targeted therapies in TNBC.
Genetic landscape of soft-tissue sarcomas: Moving toward personalized medicine.
Authors: Italiano Antoine , Khalifa Emmanuel , Laizet Yec'han , Toulmonde Maud , Cousin Sophie , Lucchesi Carlo
Published: September 2018

11002

Background: Patients with advanced soft-tissue sarcomas have a very poor outcome with a median overall survival of less than 18 months. Identification of molecular abnormalities for which targeted therapies are available or can be developed is critical for improving their outcomes. Methods: We have analyzed the mutational and copy number profiles of patients with sarcoma sequenced through the AACR Project GENIE Consortium in order to identify the proportion of cases bearing actionable mutation. Results: 587 patients (pts) were included in the study (295 males). 331 pts (56%) had complex genomics sarcomas, 144 (25%) translocation-related sarcomas and 112 (19%) others sarcomas (inactivating mutation, simple amplicon). The five most frequent histology were: Leiomyosarcoma (n = 112; 19.1%); Undifferentiated Pleomorphic Sarcomas (n = 74, 12.6%), dedifferentiated liposarcoma (n = 55, 9.4 %), angiosarcoma (n = 43, 7.3%), synovial sarcoma (n = 38, 6.5%). 430 pts (73%) had at least one mutation. The ten most frequently mutated genes were: TP53 (34.7%); ATRX (9.1%), RB1 (8.4%), KMT2D (5.8%), NF1 (5.3%), ATM (5.1%), PI3KCA (4.9%), ERBB4 (4.2%), PTEN (4%), and ARID1A (3.7%). 504 patients (85.9%) presented at least one copy number alteration. The 5 five most frequently amplified genes were: MDM2 (20%), CDK4 (16.7%), GLI1, MAP2KA, and TERT (3.2% for each gene), and the most frequently deleted were RB1 (12.7%), CDKN2A (10.3%), CDKN2B (9.7%), TP53(9.5%), PTEN (8.5). 92.5% of pts had at least one targetable mutation, copy number alteration and/or fusion gene ( Leiomyosarcoma n = 100/17%, UPS n = 74/12%, dedifferentiated diposarcoma n = 54/9%, angiosarcoma n = 41/7%, synovial Sarcoma n = 36/6%), with incidences reported that will be reported in details at the meeting. Conclusions: This is the first large report of genomic landscape including mutation and copy number profiling through NGS of soft-tissue sarcomas. Our results indicate a significant proportion of actionable mutations and represent a rationale for the MULTISARC study: the first study implementing Exome Seq and RNA Seq for clinical decision making in patients with advanced STS. The design of this study supported by the French government and launched in 09/2017 will be presented at the meeting.
Multi-institutional European single-arm phase II trial of pazopanib in advanced malignant/dedifferentiated solitary fibrous tumors (SFT): A collaborative Spanish (GEIS), Italian (ISG), and French (FSG) sarcoma groups study.
Authors: Martin Broto Javier , Stacchiotti Silvia , Lopez-Pousa Antonio , Redondo Andres , Bernabeu Daniel , Casali Paolo Giovanni , Italiano Antoine , Grignani Giovanni , Dumont Sarah , Garcia del Muro Xavier , Gutierrez Antonio , Martinez Trufero Javier , Palmerini Emanuela , Hindi Nadia , de Alava Enrique , Collini Paola , Ranchère-Vince Dominique , Blay Jean-Yves , Cruz Josefina
Published: September 2018

11003

Background: SFT is a rare soft tissue tumor. In advanced SFT chemotherapy has only limited activity. With the rationale of a rich vascular network & VEGF (tumor cells and endothelium) and VEGFR1/2 (endothelial cells) expression in SFT, we designed an international, single-arm phase II trial to test pazopanib (P) in advanced SFT. Clinical and preclinical evidence suggesting that antiangiogenics was less effective in more aggressive compared with less aggressive SFT (Stacchiotti et al), led us to conduct the trial on two different cohorts: typical and malignant (M)/dedifferentiated (DD) SFT. Here we present the outcome of the latter cohort. Methods: Most relevant inclusion criteria were: unresectable or metastatic, M/DD SFT confirmed by central pathologic review with evidence of STAT6 (IHC and /or FISH or RT-PCR), ≥ 18 years, ECOG 0-2, progressive and measurable disease. Main endpoint was response rate (RR) according Choi criteria. Central radiological assessment was mandatory. P was administered at 800 mg/d continuously until progression or toxicity. Results: From June 2014 to November 2016, 34 patients (pts) were enrolled with a median age of 61 y (23-87). Median tumor size and mitosis at diagnosis were 77 mm and 8x10 HPF. Most relevant grade 3-4 toxicity were neutropenia (9%) and hypertension (12%). At the time of the present analysis, 31 pts are evaluable for response. RR according to Choi and RECIST were: PR 16 (52%), SD 7 (22%), PD 8 (26%) and PR 1 (3%), SD 19 (61%), PD 11 (35%) respectively. With a median follow-up of 15 months, the median PFS was 5.53 months (4.24-6.82), while 72% survived at 18 months. Size > 5 cm, mitosis > 8 and DD subtype showed significantly worse PFS. The 18-month OS was 90% for those with SD and PR and 25% for PD according to Choi (p < 0.001), while 94% for SD and PR and 45% for PD according RECIST (p = 0.002). In multivariate analysis, only Choi was an independent prognostic factor for OS with PD showing a HR of 11.9 (2.3-63.1), p = 0.003 for the risk of death. Conclusions: Pazopanib showed activity in malignant SFT. Choi criteria exhibited a more accurate assessment of response than RECIST. Clinical trial information: NCT02066285.
Activity of cediranib in alveolar soft part sarcoma (ASPS) confirmed by CASPS (cediranib in ASPS), an international, randomised phase II trial (C2130/A12118).
Authors: Judson Ian Robert , Morden James P , Leahy Michael Gordon , Bhadri Vivek , Campbell-Hewson Quentin , Cubedo Ricardo , Dangoor Adam , Hennig Ivo M. , Joubert Warren Lance , Kernaghan Sarah , Lopez-Pousa Antonio , Seddon Beatrice M. , Snowdon Claire , Tatersall Martin , Toms Christy , Martinez-Trufero Javier , Bliss Judith ,   On Behalf of the CASPS Trial Management Group and Investigators
Published: September 2018

11004

Background: ASPS is a rare disease (0.5-1% of soft tissue sarcomas) mainly affecting young people. It is unresponsive to conventional chemotherapy. Cediranib (C), an inhibitor of vascular endothelial growth factor receptors and other receptor tyrosine kinases, has shown significant activity in ASPS in single arm phase II trials. CASPS (NCT01337401) was designed to permit discrimination between the impact of cediranib and the often intrinsically indolent nature of the disease. Methods: CASPS compared C (30mg od) with placebo (P) in a 2:1 double blind randomisation in patients (pts) age ≥16 years with metastatic ASPS progressive in the previous 6 months. Pts were unblinded at week 24, or at progression if sooner, when those on P started C. The primary endpoint of percentage change in the sum of target marker lesions (TMLsum) between baseline and week 24 (or progression if sooner) was compared between groups by Mann-Whitney test. Secondary endpoints were progression-free survival (PFS), week 24 response rate and best response (RECIST v1.1), safety/tolerability and overall survival (OS). One-sided p-values and two-sided 90% confidence intervals are reported. Results: 48 pts were recruited between 07/2011 and 07/2016 from 12 centres (UK, Australia & Spain). 52% of pts were female, median age was 31. Most common grade ≥3 adverse events on C were hypertension (23%), diarrhoea (14%) and fatigue (9%). In the evaluable population (N = 44) median change in TMLsum on C was minus 8.3% (IQR minus 26.2% to +5.9%); versus P: +13.4% (IQR minus 0.6% to +21.3%), p = 0.0013. Best response by week 24 was partial response for 6/28 (21%) C pts compared with 0/16 on P (p = 0.053) and stable disease for an additional 19/28 (68%) on C and 12/16 (75%) on P. The PFS HR (C versus P) was 0.54 (90% CI 0.30-0.97, p = 0.041), median PFS: 10.8 mths on C versus 3.7 mths on P, OS at 12 mths was C: 96%; P: 64.3%. Conclusions: CASPS, the largest randomised trial to date in this disease, confirms the activity of C in ASPS, showing a significant reduction in tumour burden and improvement in PFS. Tumour tissue and serial blood samples will subsequently be investigated to identify potential predictive and prognostic biomarkers. Clinical trial information: NCT01337401.
Failure rate of standard rescue with leucovorin for high-dose methotrexate (HDMTX) in osteosarcoma.
Authors: Eriksson Mikael , Rychlowska-Pruszynska Magdalena , Csóka Mónika , Hall Kirsten Sundby , Karlén Jonas , Kvistgaard Louise , Lisjö Pia , Ganlöv Karin
Published: September 2018

11028

Background: HDMTX followed by leucovorin rescue is well established as part of MAP chemotherapy for osteosarcoma. However, leucovorin rescue is not always effective as rescue, resulting in delays to subsequent courses of chemotherapy. Methods: This retrospective observational study involved patients ≥2 years of age with osteosarcoma treated with MAP during 2009 - 2014. Data was extracted from medical records from five clinics in Poland, Hungary, Norway and Sweden. The study objective was to determine to what extent patients treated with MAP encountered treatment delays due to MTX-related toxicity or delayed MTX elimination. Results: All patients fulfilling the inclusion criteria were included. Of 116 patients (ages 5-39 with a mean of 14 years; 59% males), 97% completed their first MAP cycle while only 48% completed six treatment cycles. The analysis of the primary endpoint included 114 evaluable patients. At least one treatment delay due to MTX toxicity or delayed MTX elimination was reported for 89 patients (78%) and only six patients (5%) completed the entire MAP treatment according to plan. Delay in subsequent treatment was observed following 183 of 369 evaluated MAP cycles (50%). About three quarters of the delays were found to be due to MTX-related toxicity while only a small number were related to delayed MTX elimination. The treatment related issues most commonly registered were increased liver enzymes, hematological disturbances, increased bilirubin and mucositis. Conclusions: We found at least one treatment delay due to MTX toxicity or delayed MTX elimination in 78% of all MAP-treated patients and that 50% of the administered MAP cycles resulted in a delay in subsequent treatment, mostly due to MTX toxicity. Only six patients (5%) completed the entire MAP treatment according to plan. The retrospective methodology with broad inclusion criteria implies that the results can be extrapolated to the entire target population. Thus, there appears to be an unmet need for a more effective HDMTX rescue that could reduce MTX toxicity and be expected to enable more patients to maintain planned MAP treatment intensity and duration, thereby improving the overall efficacy of the MAP regimen.
Long-term survival (over 10 years) of inoperable/metastatic GISTs: A retrospective series of 141 patients (pts) of the french sarcoma group (FSG).
Authors: Duffaud Florence , Auclin Edouard , Italiano Antoine , Mancini Julien , Bertucci Francois , Penel Nicolas , Pracht Marc , Vogin Guillaume , Collard Olivier , Bompas Emmanuelle , Landi Bruno , Valentin Thibaud , Chaigneau Loic , Toulmonde Maud , Adenis Antoine , Ray-Coquard Isabelle Laure , Rios Maria , Salas S Bastien , Le Cesne Axel , Blay Jean-Yves ,   French Sarcoma Group
Published: September 2018

11041

Background: A subset of metastatic GIST exhibit very long-term survival after imatinib (IM) introduction. The aim of this study was to analyse the clinico-biological characteristics of GIST pts alive > 10 years (yrs) after diagnosis (dx) of metastases (mets) and identify possible factors associated with long-term survival. Methods: Pts were identified from 2 sarcoma databases; NetSarc and ConticaGIST. Clinical data prospectively registered in the databases were supplemented with retrospective review of medical records. Results: We identified 141 pts (75 men, 66 women) with median age 54 (17-84) yrs and median ECOG 0 (0-2). Primary tumors (T) were all CD117+, and mainly gastric or intestinal (64 & 45 pts), with median size 10 (2-40) cm, CD34+ (82 pts), mitoses/50 HPF ≤ 5 (n = 36), or > 5 (n = 81). Genotype was documented in 82 (58%) pts with 73 (89%) KIT mutations (in exons 11,9 and 12 of 69, 3, and 1 pts respectively) and 9 WT KIT. 129 (91%) T were resected, 124 upfront, 5 post IM, with R0/R1/R2 resections in 61, 11, and 10 pts. Mets were mainly hepatic or peritoneal (78 & 51 respectively). 1st line TKI was given to 139 pts: 130 received IM; 88 (63%) within a clinical trial (CT), 41 (29%) had mets resection. Second, 3d and 4th line TKI were given to 81, 51 and 37 pts respectively, comprising 27, 7 and 10 from CT. Median number of TKIs was 2 (0-7), but 60 (44%) pts received only 1st line with no GIST progression within or after 10 yrs. 2 pts never received TKI but had mets resection. After median FU of 14.3 yrs (10-34.5), 104 remain alive, 37 died. Mean and Median OS from initial dx are 24 yrs (CI95% 21.6-27) and 20,8 yrs. Median PFS on TKIs are 127, 29, 21 and 22 mos on 1st, 2d, 3d and 4th line of TKI. In univariate analysis no factor is significantly associated with OS, but T size (≤ 10 vs > 10 cm) and oligometastatic disease (≤5 vs > 5 mets) are borderline significant (p = 0.056 and 0.07), and good PS (ECOG ≤ 1) at 2dline TKI initiation is associated with better PFS (p = 0.03). Conclusions: This large series of long-term ( > 10 yrs) survivors of metastatic GIST shows a high proportion of mets resection and a longer duration of PFS for TKI at any line. In this selected population, no prognostic factor is associated with long OS.
Post-cross-over activity of regorafenib (RE) in soft tissue sarcoma: Analysis from the REGOSARC trial.
Authors: Kotecki Nuria , Brodowicz Thomas , Le Cesne Axel , Le Deley Marie-Cecile , Wallet Jennifer , Italiano Antoine , Blay Jean-Yves , Bertucci Francois , Chevreau Christine , Piperno-Neumann Sophie , Bompas Emmanuelle , Salas S Bastien , Perrin Christophe , Delcambre Corinne , Lieg-Atzwanger Bernadette , Toulmonde Maud , Ray-Coquard Isabelle Laure , Thery Julien , Mir Olivier , Penel Nicolas
Published: September 2018

11052

Background: Based on the placebo (PBO) controlled phase 2 trial (Mir, Lancet Oncol 2016), RE has shown to be an active drug in patients (pts) with leiomyosarcoma (LMS), synovial sarcoma (SS) and other non-adipocytic sarcoma (OTH), but not in liposarcoma. Pts initially allocated to PBO were allowed to cross-over to RE after progression. We here report the activity of RE after cross-over. Methods: From July 2013 to Dec 2014, 138 pts were enrolled in the non-adipocytic sarcoma cohorts (LMS, SS & OTH). After update in Dec 2016, median follow-up was 32 mo (vs 17 mo in the initial publication). Benefit of RE vs PBO in terms of progression-free survival (PFS) and overall survival (OS) from randomization was estimated by hazard ratio (HR) in Cox models. In the PBO arm, intra-patient benefit of RE after cross-over was evaluated by the growth modulation index (GMI), where PFS1=PFS with PBO before cross-over, and PFS2=PFS with RE after cross-over. The impact of timing of RE allocation (delayed after cross-over, vs early at study entry) was evaluated by comparing PFS after cross-over in PBO arm to PFS after randomization in RE arm. Results: As detailed in the table, major PFS benefit of RE vs PBO allocated by randomization was confirmed with long follow-up (HR=0.50 [95%CI 0.35-0.71] p<.0001). However, this translates into a smaller and non-significant OS benefit (HR=0.78 [0.54-1.12] p=.18). This finding may partially be explained by the fact that 55 of the 68 pts who progressed in the PBO arm (81%) could receive RE after progression and benefit from RE: 56% of them had a GMI greater than 1.3. Delayed start of RE was associated with a non-significantly shorter PFS compared to earlier treatment (HR=1.21, [0.84-1.73] p=.30). Conclusions: Efficacy of RE vs PBO is confirmed with longer follow-up in non-adipocytic sarcoma. PFS of pts receiving RE after cross-over is not significantly shorter than that of pts initially randomized to receive RE. Clinical trial information: NCT01900743. [Table: see text]
SYNFRIZZ: A first-in-human (FIH) study of a radiolabeled monoclonal antibody (Mab) targeting frizzled homolog 10 (FZD10) in patients (pts) with advanced synovial sarcomas (SyS).
Authors: Cassier Philippe Alexandre , Giraudet Anne Laure , Iwao-Fukukawa Chicaco , Garin Gwenaelle , Badel Jean-Noel , Kryza David , Chabaud Sylvie , Cropet Claire , Sarrut David , Gilles-Afchain Laurence , Halty Adrien , Italiano Antoine , Penel Nicolas , Mori Masaharu , Tsunoda Takuya , Katagiri Toyomasa , Nakamura Yusuke , Baconnier Simon J , Pérol David , Blay Jean-Yves
Published: September 2018

11054

Background: Advanced SyS are rare tumors with limited curative options. FZD10 is highly expressed in SyS but not in normal adult tissue. OTSA101 is a MAb targeting FZD10, labelled with a radioisotope. Methods: We conducted a phase I, FIH study including adult pts with advanced, refractory SyS. In part 1, pts received OTSA101 labelled with In111 used as radiotracer to assess biodistribution and tumor uptake. In part 2, pts with significant tumor uptake were randomized to receive OTSA101 labelled with 370MBq of Y90 (Arm A) or 1110MBq Y90 (Arm B). Primary endpoints were occurrence of unacceptable biodistribution /lack of tumor uptake in part 1 and occurrence of related adverse events (AEs) Grade ≥ 3 during the first 8 weeks following injection of Y90OTSA101 in part 2. Responses were assessed per RECIST 1.1. Results: From January 2012 to June 2015, 20 pts (10 females, median age 43, range 21-67) with advanced SyS were enrolled. Ten pts (50%) had sufficient tumor uptake to proceed to part 2 and 8 were randomized (Arm A: 3 and Arm B: 5). Two pts were not randomized due to worsening PS. During part 2, the most common Grade ≥ 3 AEs were haematological, including reversible lymphopenia, thrombocytopenia and neutropenia, and were more common in Arm B. One pt with SD after 12 weeks received a 2nd injection of 90Y-OTSA101, but experienced fatal hemoptysis. No objective response was observed. Best response was SD in 5/8 pts lasting up to 21 weeks for 1 pt. Conclusions: This FIH shows that radioimmunotherapy targeting FZD10 is feasible and safe in SyS pts. Tumor uptake was heterogeneous but sufficient to select 50% of pts for 90Y-OTSA101 treatment. Due to limited sample size, further clinical investigations are needed to assess the therapeutic activity of 90Y-OTSA101 with a recommended dose of 1110MBq of 90Y. Clinical trial information: NCT01469975.
Outcome of 212 malignant phyllod tumor patients: A retrospective study from the French Sarcoma Group (GSF-GETO).
Authors: Neron Mathias , Sajous Christophe , Piperno Neumann Sophie , Chakiba Camille , Ducoulombier Agnes , Owen Clémentine , Salas S Bastien , Bertucci Francois , Saada-Bouzid Esma , Valentin Thibaud , Bay Jacques-Olivier , Bompas Emmanuelle , Isambert Nicolas , Maran-Gonzalez Aurélie , Llacer Carmen , Carrère Sebastien , Cupissol Didier , Thezenas Simon , Blay Jean-Yves , Firmin Nelly ,   French Sarcoma Group (GSF-GETO)
Published: September 2018

11055

Background: The optimal management of malignant phyllod tumors (MPT) is poorly documented. Objective:To study the characteristics and outcome of MPT patients (pts). Methods: Retrospective study from the nation-wide French sarcoma network (NetSarc) from 2000 to 2016. Inclusion criteria was central pathological review of MPT. End-points were local recurrence-free survival (LRFS), metastasis-free survival (MFS), and overall survival (OS). Results: 212 pts, from 13 centers, were included. Median age was 52.8 years (range: 16.8 - 90.5). All localized MPT pts (96.7%) underwent surgery with 41.4% of mastectomy. The median size was 5.8 cm (range: 1.5 - 30). R1/R2 resection was achieved in 40.1% pts (26.9% 1-2 mm margin, 12.2% 3-7 mm, 20.3% ≥8 mm), with 44.8% of second surgery (SS) for a final mastectomy rate of 72.6%. Presurgical biopsy was performed in 86.3% and associated with R0 resection ( p=0.044) and better LRFS ( p=0.012). Median follow-up was 4.1 years (range 0-14.8) and revealed 34 (16.6%), 48 (22.9%), 44 (20.8%) events for LRFS, MFS and OS, respectively. The 2-year OS rate was 89%. Prognostic factors found in multivariate analysis are presented in Table 1. Wider margins (≥8mm) were not associated with better outcomes. Adjuvant radiotherapy and chemotherapy were performed in 43.6% and 13.3% respectively and associated with longer LRFS, not significant in multivariate analysis. Conclusions: Mastectomy is associated with better local control, but not with MFS and OS. Age, tumor necrosis and metastatic disease are associated with poor prognosis in MPT pts. Our study suggests that margins of 3 mm are necessary and sufficient for the surgical management of MPT and emphasizes the importance of SS to obtain clear margins. [Table: see text]
International single-arm phase II trial of pazopanib in advanced extraskeletal myxoid chondrosarcoma: A Collaborative Spanish (GEIS), Italian (ISG) and French (FSG) Sarcoma Groups study.
Authors: Stacchiotti Silvia , Ferrari Stefano , Redondo Andres , Palmerini Emanuela , Hindi Nadia , Vaz M. Angeles , Frezza Anna Maria , Gutierrez Antonio , Lopez-Pousa Antonio , Grignani Giovanni , Italiano Antoine , Dumont Sarah , Blay Jean-Yves , Penel Nicolas , Bernabeu Daniel , de Alava Enrique , Ranchère-Vince Dominique , Collini Paola , Cruz Josefina , Martin Broto Javier
Published: September 2018

11062

Background: Extraskeletal myxoid chondrosarcoma (EMC) is an exceedingly rare sarcoma, marked by a specific translocation involving the gene NR4A3 that can be rearranged with different partners. Preliminary retrospective data suggest that sunitinib is active, but no formal prospective studies are available. We report on a multicentric European prospective, investigator-driven, Phase 2 study on pazopanib (P) in NR4A3+ advanced EMC patients (pts), carried out by the Spanish, Italian and French Sarcoma groups. Methods: From June 2014 to November 2016, 24 advanced EMC pts entered this study (median age: 64 yrs - disease extent: metastatic 77%, locally advanced 23% - prior medical treatment: 18 (86%) naive; 2 (9%) 1 line, 1 (5%) > 1 line). Path diagnosis and NR4A3 rearrangement (FISH and/or real-time PCR analysis) were centrally confirmed. Pts received P 800 mg/day (relative dose intensity = 0,82%, 658 mg/day), until progression or toxicity. The primary study end-point was response rate as per RECIST 1.1. Secondary end-points were overall survival, progression-free survival (PFS), clinical benefit rate (CBR) (RECIST CR+PR+SD≥6mos). An exploratory evaluation of the correlation between the rearrangement subtype and the outcome is ongoing. Results: 20/24 pts were evaluable for response (1 early death; 3 too early). One patient (5%) had a partial response, 17 (75%) stable disease, 2 (10%) progression as their best RECIST responses. At the time of this analysis, 12 pts were still under treatment, while 12 interrupted P (10 progression, 1 toxicity, 1 other). At a 13-month median follow-up, the median PFS was 13 months (range 1.6-25.1), with 29% pts progression-free at 18 months and a 65% CBR. Median OS was not reached. Conclusions: This Phase 2 study is formally negative since the target of at least 3/21 RECIST responses was not reached. However, looking at PFS, P was associated with a prolonged disease stabilization in a significant proportion of pts. This suggests to further explore the use of P in EMC. Clinical trial information: NCT02066285.
Anthracycline, gemcitabine, and pazopanib in epithelioid sarcoma: Results of a retrospective multi-institutional case series.
Authors: Frezza Anna Maria , Asano Naofumi , Jones Robin , Ratan Ravin , Teterycz Pawel , Gelderblom Hans , Boye Kjetil , Brahmi Mehdi , Palmerini Emanuela , Hindi Nadia , Brunello Antonella , Desar Ingrid , Grignani Giovanni , Fedenko Alexander A. , Vincenzi Bruno , Papai Zsuzsanna , Kawai Akira , Lo Vullo Salvatore , Casali Paolo Giovanni , Stacchiotti Silvia
Published: September 2018

11065

Background: To report on a multi-institution retrospective study on the activity of anthracycline-based (Ab) and gemcitabine-based (Gb) regimens as well as pazopanib (P) in patients with advanced epithelioid sarcoma (ES) treated within 16 sarcoma reference centres in Europe, US and Japan. Methods: Patients with a histologically confirmed diagnosis of locally advanced/metastatic ES were selected. Classic and distal subtypes were defined based on morphology (WHO 2014). INI1 expression is under evaluation.Response was evaluated by RECIST.Progression-free survival (PFS) and overall survival (OS) were computed by Kaplan-Meier method. Results: Ninety ES patients were identified (Table 1). They were treated with Ab (72), Gb (30) and P (20); 25 pts received more than one treatment. The median follow-up for Ab, Gb and P groups was 32, 24 and 22 months, respectively. The response rate (RR) for Ab was 25% (95% CI 16%-37%), with a median PFS and OS of 6 and 17 months. The RR for Gb was 23% (95% CI 10% - 42%), with 1 complete response and a median PFS and OS of 5 and 20 months. In the P group, no objective responses were reported, and median PFS and OS were 3 and 9 months. A non-statistically significant trend towards a greater RR in proximal than classic subtype was seen in both Ab (27% vs 22%) and Gb (30% vs 13%) groups. Conclusions: This retrospective series, the largest currently available, confirms the activity of Ab and Gb in ES, with a similar RR and PFS in both groups. In this population, the value of P seems limited. These data may serve as a benchmark for trials of novel agents in ES. [Table: see text]