bluuebunny/crossref_metadata_2025 huggingface dataset:
Fosaprepitant use in children and adolescents at Memorial Sloan Kettering Cancer Center.
Authors: Liu Dazhi , Horiates Krisoula , Mathew Sherry , Pozotrigo Melissa , Thackray Jennifer , Kussin Michelle , Yan Shirley Qiong , Seyboth Brian M. , Modak Shakeel
Published: September 2018

10575

Background: Recent NCCN guidelines recommend the addition of a neurokinin-1(NK1) receptor antagonist (e.g. fosaprepitant) to the serotonin 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist-corticosteroid combination for controlling both acute and delayed chemotherapy induced nausea and vomiting(CINV) associated with high emetogenic chemotherapy (HEC) in adults. Fosaprepitant is bioequivalent to aprepitant and could offer benefits to patients who are unable to tolerate oral antiemetics. However, little is known about the efficacy and safety of fosaprepitant in children. Methods: This retrospective chart review included all pediatric patients less than 18 years of age who received fosaprepitant at Memorial Sloan Kettering Cancer Center from July 2011 to November 2016. Results: Thirty-one patient charts representing a total of 105 doses of fosaprepitant were reviewed. Median age was 15 (range 2-17) years. Fifty-one doses (49%) were administered for primary prophylaxis for 11 patients; 40 doses (38%) for 12 patients who had a history of severe CINV and 14 doses (13%) as rescue for CINV in 10 patients after chemotherapy. Seventy-eight of the 101 chemotherapy cycles were highly emetogenic including 39 containing cisplatin. In the first two groups, patients did not have any episodes of vomiting in 97% and 88% of chemotherapy cycles respectively after fosaprepitant therapy. Seven of 12 patients receiving fosaprepitant for > 3 episodes of breakthrough vomiting within 24 hours had no vomiting episodes during the first 24 hours post fosaprepitant administration. No fosaprepitant-related side effects were reported. Conclusions: Fosaprepitant appears to be safe and tolerable in children with cancer in whom it may provide benefit as prophylaxis and treatment of CINV. However a phase III study is warranted to formally study its role in pediatrics.
Estimating the effects of patient-reported outcome (PRO) diarrhea and pain measures on PRO fatigue: Data analysis from a phase II study of abemaciclib monotherapy, a CDK4 and CDK6 inhibitor, in patients with HR+/HER2- breast cancer after chemotherapy for metastatic disease—MONARCH 1.
Authors: Boye Mark , Houghton Katherine , Stull Donald E , Ainsworth Claire , Price Gregory L
Published: September 2018

1060

Background: Investigators reporting treatment-emergent adverse events (TEAEs) in the 3rdline or greater abemaciclib MONARCH1 Phase 2 study observed Grade 1-3 diarrhea, fatigue, and abdominal pain in 90, 65, and 39% of the patients (n = 132). Unknown is the extent that diarrhea and overall pain add to fatigue in this setting. Using patient-reported outcome (PRO) measures, we conducted cross-sectional and longitudinal multivariate analyses to estimate these effects. Methods: Data came from a single-arm, open-label study of previously-treated patients with mBC. Throughout the study, the Brief Pain Inventory and the EORTC QLQ-C30 v3 were co-administered. All constructs and items from these two questionnaires –except EORTC Items 25 and 28 (memory and financial difficulties) - were used to estimate the Structural Equation Model (SEM) and the direct and indirect effects of pain and diarrhea on fatigue. Extended pattern mixture modeling (ePMM) – a latent variable modeling method that allows the explicit analysis of missing data and identifies subgroups with differential changes over time – was used to explore these relationships from screening through cycle 8. Results: SEM results showed that at cycle 2 of treatment, pain was a significant predictor of fatigue (b = 0.68; P < 0.001; CI 0.48 – 0.90); diarrhea was not a significant predictor of fatigue (b = 0.06; P = 0.12; CI -0.04 – 0.17). ePMM results across eight 30-day cycles found three fatigue subgroups: no change, improvement, worsening then improvement. Belonging to a similar pain subgroup predicted belonging to the corresponding fatigue subgroup (ref class was no change; improving b = 5.03, P = 0.004; worsening b = 22.01, P < 0.001); the same was not true for diarrhea and fatigue (ref class was no change; improving b = 0.213, P = 0.75; worsening b = 0.04, P = 0.97). Conclusions: These results suggest that for patients undergoing 3rd line or greater mBC treatment, pain is a significant predictor of fatigue early and over the course of the trial. However, diarrhea is not a significant predictor of fatigue. Clinical trial information: NCT02102490.
Prognostic significance of tumor subtypes in women with breast cancer according to stage: A population-based study.
Authors: Leone Jose Pablo , Leone Julieta , Zwenger Ariel Osvaldo , Vallejo Carlos Teodoro , Leone Bernardo Amadeo
Published: September 2018

1070

Background: Tumor subtypes (TS) are an important prognostic tool in breast cancer patients (pts). However, with contemporary therapies the prognosis of different subtypes is unclear. Recently, the AJCC proposed to incorporate TS among other variables in the 8th edition of the staging manual. The aim of this study was to analyze differences in overall survival (OS) by TS according to stage compared with other factors. Methods: We evaluated women with microscopically confirmed invasive breast cancer between 2010 and 2013 with known estrogen receptor (ER) and progesterone receptor (PR) (together hormone receptor [HR]) status and human epidermal growth factor receptor 2 (HER2) status reported to the SEER program. Pts with other primary either before or after breast cancer were excluded. Pt characteristics were compared between TS. Univariate and multivariate analyses were performed to determine the effect of each variable on OS. Results: We included 166,054 pts. Median age was 60 years (range 18-108). Median follow-up was 21 months (range 1-48). TS distribution was: 72.5% HR+/HER2-, 10.8% HR+/HER2+, 4.8% HR-/HER2+ and 12% triple negative (TN). Pts with HR+/HER2- tumors were older, had lower grade and presented with earlier stage (all p < 0.0001). OS at 3 years for each subtype according to stage is shown in the table (p for interaction < 0.0001). These differences in OS by TS continued to be significant for each stage in multivariate analysis adjusted for age, race, grade, histology and marital status. Conclusions: In this cohort, we observed significant differences in pt characteristics according to TS. Although HR+/HER2- tumors had better clinicopathologic features, the HR+/HER2+ group had the best OS in most stages. OS was significantly different by TS in each of the 4 stages and these results remained significant in the multivariate model. Pts with TN stage 1 tumors had similar OS as pts with HR+/HER2+ stage 2 tumors. Our results support the incorporation of TS as part of the staging variables in breast cancer. [Table: see text]
Retrospective-prospective blinded evaluation predicting efficacy of epirubicin by a multigene assay in advanced breast cancer within a Danish Breast Cancer Cooperative Group (DBCG) cohort.
Authors: Buhl Anna Sofie Kappel , Christensen Troels Dreier , Christensen Ib Jarle , Nelausen Knud Mejer , Balslev Eva , Knoop Ann S. , Brix Eva , Svensson Else , Glavicic Vesna , Luczak Adam , Langkjer Sven Tyge , Linnet Soeren , Jakobsen Erik , Bogovic Jurij , Ejlertsen Bent , Rasmussen Annie , Hansen Anker , Knudsen Steen , Nielsen Dorte , Jensen Peter Buhl
Published: September 2018

1071

Background: Epirubicin remains a cornerstone in the treatment of primary and advanced breast cancer. This study evaluated the predictive effect of a multigene mRNA-based Drug Response Predictor (DRP) in the treatment of advanced breast cancer (ABC). We applied a mathematical method combining in vitro sensitivity with gene expression patterns in tumors. Previously the DRP has been broadly validated1, 2 including retrospective validation of epirubicin3. Methods: Among 838 consecutive patients from a DBCG cohort 137 patients were treated with epirubicin between May 1997 and November 2016 at one of the participating sites. Patients were examined every 9 to 12 weeks by CT scan and clinical evaluation. After patient informed consent, mRNA was isolated from formalin fixed paraffin embedded tumor tissue from diagnostic biopsies and analyzed using Affymetrix arrays. Blinded predictions of epirubicin efficacy were compared to clinical data collected retrospectively from patients’ medical records. Statistical analysis was done using Cox proportional hazards model adjusted for treatment line. Primary endpoint was progression free survival (PFS). Results: Median time to progression was 9.3 months (95% CI: 7.2-13.2). Of the 137 patients, four received epirubicin more than once. Scoring the DRP as a continuous covariate demonstrated that the DRP was significantly associated to PFS (p = 0.02). The estimated hazard ratio was 0.56 (90% CI: 0.35-0.89) comparing two patients with DRP score differing by 50 percentage points. The estimated median time to progression for a patient with a DRP value of 25% was 7 months versus 13 months for a patient with a DRP value of 75%. No interaction with previous adjuvant chemotherapy was observed (p = 0.98). Conclusions: The current study demonstrates a potential clinical value by being able to select patients that benefit from epirubicin against patients predicted not to benefit sparing the last patients unnecessary toxicity. Studies evaluating the predictor in an adjuvant setting will follow. 1 Knudsen et al PLoS ONE 9(2): e87415; 2 Buhl et al PLoS ONE 11(5): e0155123; 3 Wang et al JNCI 105(17): 1284-91
Characterization of bone only metastasis (BOM) patients (pts) with respect to tumor subtypes (TS).
Authors: Parkes Amanda Marie , Clifton Katherine , Al Awadhi Aydah , Oke Oluchi , Warneke Carla L. , Litton Jennifer Keating , Hortobagyi Gabriel N.
Published: September 2018

1072

Background: Metastatic breast cancer (MBC) pts with BOM are a unique population with limited characterization. Our goal was to characterize the TS of BOM pts, evaluating differences in sites and types of bone metastases (BM), treatment, and survival. Methods: We identified pts followed at MD Anderson Cancer Center from 01/01/1997 to 12/31/2015 for at least 6 months with a BOM diagnosis as first site of metastasis (met). TS was assessed by initial biopsy immunohistochemistry (IHC) (Table 1) with hormone receptor (HR) + defined as ER or PR >10%. Results: We identified 1445 pts with BOM, 1049 with initial biopsy IHC available to group into TS (Table 1). Among BOM pts, the majority had multiple BM at diagnosis (1141/79%), most in both the axial (Ax) and appendicular (App) skeleton (53%). Of the 808 pts with BM categorized on imaging at diagnosis, the majority were lytic (389/48%), with 21% sclerotic, 18% mixed, and 12% blastic. Time from breast cancer diagnosis to first met differed significantly by TS, χ2(3) = 94.33, P< .0001, with median time to met longer for pts with blastic (3.08 years; 95% CI 2.03, 4.24) versus lytic lesions (1.75 years; 95% CI 1.27, 2.17). Conclusions: BOM patients are a unique MBC subpopulation, more commonly found in luminal TS patients. Our study demonstrates prognostic differences in BOM pts specific to TS and emphasizes the need for further study of BOM patients. [Table: see text]
Use of serial multi-template liquid biopsies in triple negative breast cancer monitoring.
Authors: Song Paul Y. , Simmons Jill , Dempsey Paul W. , Klem Erich , Carter Chris , Tahvilian Shahram , Scollick Brian , Strauss William
Published: September 2018

1091

Background: Triple negative breast cancer (TNBC) remains the most aggressive subtype of breast cancer in which up to 1/3 of all patients will relapse early and distantly. There remains no proven method to monitor and detect early recurrence. This study examines the utility of serial liquid biopsies using a multi-template approach (identification and analysis of cell-free DNA (cfDNA) and circulating tumor cells (CTCs)) as a solution. Methods: 210 patients (average 53 yrs.) with confirmed diagnosis of TNBC, within 3 years of completion of therapy (mean 25 mos.), and in full remission were enrolled. Liquid biopsies were performed quarterly to look for cancer specific genomic mutations not seen in germ line controls, but in cfDNA and CTCs using a custom 27-gene breast cancer panel. Prior validation of our gene panel demonstrated a false positive rate of 0.001-0.0007% in normal cfDNA and cell-based controls. Results: Each subject had on average 3.0 serial samples collected to date. 169 patients (80.4%) had evidence of mutations in at least one sample. Seventy-five percent of cfDNA and 36% of CTC samples examined have been found to bear mutations. The total number of samples with orthogonally (either between template or between draws) confirmed signal was 16.9%. Seven patients (3.3%) have developed documented evidence of recurrence, one in the axilla and the others with visceral/distant metastases. Of the patients that have recurred, all had a persistent mutation on consecutive blood draws or evidence of genomic mutations in both cfDNA and CTCs. Conclusions: The majority of TNBC patients in our study post-treatment were found to have genomic mutations on at least one liquid biopsy sample – either cfDNA or CTC. But, very few had a persistent presence of mutations in subsequent samples and 96.7% of our patients have remained NED. Unlike patients who remained NED, patients who recurred displayed persistent evidence of mutations on serial draws or in both cfDNA and CTC samples. To date our recurrence rate is lower than predicted. This study highlights the need for serial monitoring using a multi-template approach to better fully understand patient specific tumor biology and kinetics. The trial is ongoing. Clinical trial information: NCT02639832.
Immune gene signatures in triple-negative breast cancers characterized by varying levels of chromosomal instability.
Authors: Gyorffy Balazs , Bottai Giulia , Nagy Adam , Pusztai Lajos , Santarpia Libero
Published: September 2018

1096

Background: Triple-negative breast cancer (TNBC) is generally characterized by high levels of chromosomal instability (CIN) and an intense immune infiltration. However, the link between these two hallmarks and its implications for clinical practice has not been fully elucidated. Methods: We generated eight immune metagenes representing various immune components: natural killer [NK], dendritic cells [DC], T-cells [TC], B-cells [BC], cytotoxic T-cells [CT], interferon [IFN], nuclear factor-κB [NF-kB], and macrophages [M]. Publicly available gene expression data from forty-two data sets, including 862 TNBC samples, were collected. TNBC tumors were clustered in three main subgroups (Basal-Like [BL1/2], Immunomodulatory [IM], and Mesenchymal/Mesenchymal Stem-Like [MS]) using transcriptomic profiling. The CIN70 signature was used to stratify TNBC patients according to the levels of CIN. Statistical analyses were performed using Mann–Whitney U test and Kaplan-Meier analyses. Results: The majority of TNBC samples showed a high level of CIN (83%), and several immune modules were differentially expressed between CIN-high and CIN-low tumors. Specifically, CT, NK, DC, M, and NF-kB signatures were overexpressed in CIN-low TNBC ( p < 1.0E-04). We then evaluated the distribution of genomic instability among TNBC molecular subgroups. Noteworthy, the CIN-high group was composed by a comparable proportion of BL1/2 (39%) and MS (35%) tumors, while CIN-low TNBCs were consistently enriched for MS cancers (61%). Higher expression of the NK, M, and IFN metagenes lead to better survival in CIN-high tumors ( p = 1.9E-02, p = 2.1E-04, and p = 1.1E-03, respectively). Only IFN had the same correlation to survival in CIN-low ( p = 1.4E-02). Conclusions: TNBCs with low levels of CIN may principally enclose M/MSL tumors, which are characterized by an intense immune infiltration and overall good prognosis. Conversely, the TNBC CIN-high group is more heterogeneous in terms of both biological features and levels of immune infiltrates. Therapeutic strategies to promote and boost immune response in the genomically unstable TNBC subgroup warrant further investigation.
Influence of marital status on risk of mortality for 23,493 cases of triple negative breast cancer for four mutually exclusive race/ethnicities.
Authors: Parise Carol , Caggiano Vincent
Published: September 2018

1098

Background: Marital status has been associated with better breast cancer survival. However, breast cancer is a heterogeneous disease and it has not been determined whether marital status is a survival advantage for women with triple negative breast cancer (TNBC) and if this advantage holds for all race/ethnicities. The purpose of this study was to determine if being unmarried resulted in an increased risk of mortality for TNBC for four mutually exclusive race/ethnicities. Methods: We identified 23,493 cases of TNBC from the California Cancer Registry 2000-2014. Marital status at time of diagnosis was defined as: 1) married, 2) single, never married; 3) separated; 4) divorced; 5) widowed. Race/ethnicity was defined as white (n = 13,241), black (n = 2,775), Hispanic (n = 5,059), and Asian/Pacific Islander (API) (n = 2,418). Kaplan-Meier Survival Analysis and Cox Regression were used to assess the risk of mortality associated with marital status using married as the reference category. Marital status was considered a risk for mortality and hazard ratios (HR) and 95% confidence intervals reported if the Wald χ2 was statistically significant (p < 0.05). Models were adjusted for AJCC stage, age, grade, socioeconomic status, and treatment. Separate analyses were conducted for each race/ethnicity. Results: For allraces, single women had statistically significantly worse unadjusted survival (p < 0.05) than married women. However adjusted analyses showed that single (HR = 1.13; 1.01-1.27) and widowed (HR = 1.43; 1.27-1.61) white women had increased mortality when compared with married women. Single (HR = 1.50; 1.14-1.96) and divorced (HR = 1.75; 1.23-2.48) API women had an increased risk of mortality compared with married women. For black and Hispanic women, marital status was not associated with risk of mortality. Conclusions: Being married at the time of diagnosis of TNBC is a survival advantage only for white and API women but not for black and Hispanic women.
Beyond triple-negative breast cancer and African ancestry: Tumor phenotypes among internationally diverse patient populations.
Authors: Jiagge Evelyn Mawunyo , Jibril Aisha , Divine George , Gyan Kofi K. , Bensenhaver Jessica Miley , Oppong Joseph Kwaku , Awuah Baffour , Adjei Ernest , Merajver Sofia , Wicha Max , Newman Lisa A. ,   Henry Ford Health System International Center for the Study of Breast Cancer Subtypes
Published: September 2018

1101

Background: Population-based incidence rates of breast cancers that are negative for estrogen receptor (ER), progesterone receptor (PR), and HER2/ neu(triple negative breast cancer {TNBC}) are higher among African American (AA) compared to White American (WA) women. Several studies show higher TNBC frequency among selected populations of African patients. The colonial-era trans-Atlantic slave trade resulted in shared West African ancestry between contemporary AA and Ghanaian (Gh) populations. The extent to which TNBC susceptibility is related to East African versus West African ancestry, and whether these associations extend to expression of other biomarkers such as Androgen Receptor (AR) and mammary stem cell marker ALDH1 is unknown. Methods: We used immunohistochemistry to assess ER, PR, HER2/ neu, AR and ALDH1 among WA (n = 153); AA (n = 76); Ethiopian (Eth)/East African (n = 90) and (Gh)/West African (n = 286) breast cancers through an IRB-approved international research program. Results: Mean age at breast cancer diagnosis was 43; 49; 60; and 57 years for the Eth; Gh; AA; and WA patients, respectively. Frequency of TNBC was significantly higher for AA and Gh patients (54% and 41%, respectively) compared to WA and Eth patients (23% and 15%, respectively); p < 0.001. These associations were unchanged when limited to patients age 50 and younger (47% and 49% for AA and Gh, respectively; versus 18% and 16% for WA and Eth, respectively); p < 0.001. Frequency of ALDH1 positivity was also higher for tumors from AA and Gh patients (32% and 36%, respectively) compared to those from WA and Eth patients (23% and 17%, respectively); p = 0.007. Significant differences were observed for distribution of AR positivity, which was 71%; 55%; 42% and 50% for the WA; AA; Gh; and Eth cases, respectively (p = 0.008). Conclusions: We found a correlation between extent of African ancestry and risk of particular BC phenotypes. West African ancestry was associated with increased risk of TNBC and breast cancers that are positive for ALDH1. Future studies of hereditary TNBC susceptibility among women with African ancestry are warranted.
Clinical, radiological and genetic features, associated with the histopathologic response to neoadjuvant chemotherapy (NAC) and outcomes in locally advanced soft tissue sarcoma (STS) patients (pts).
Authors: Cousin Sophie , Crombe Amandine , Stoeckle Eberhard , Brouste Véronique , Le Loarer Francois , Lucchesi Carlo , Kind Michèle , Toulmonde Maud , Sargos Paul , Michot Audrey , Kantor Guy , Soubeyran Isabelle , Coindre Jean Michel , Italiano Antoine
Published: September 2018

11014

Background: Two large phase III studies have shown an improved overall survival in soft-tissue sarcoma (STS) pts treated with neoadjuvant chemotherapy. The prognostic impact of pathologic response is not known neither the clinical, radiological and genetic features associated with response. Methods: Data from pts with localized STS of the extremities or trunk wall and treated with anthracyline-based NAC at Institut Bergonie (Bordeaux, France) were reviewed. Central pathology (diagnosis, histological response) and radiology (MRI, DCE-MRI) reviews were performed for all the cases. A good histological response (GR) was defined as <10% residual viable tumor. Exome and RNA sequencing of pre-treatment tumor samples was performed in order to identify genetic aberrations predictive of response. Results: 150 patients (88 male) were included in the study. Median age was 60 years (17-84). 40 pts (26.7%) were good responders. GR was associated with undifferentiated pleomorphic sarcomas and very large tumors (> 20 cm). Median OSwas 10.3 year [IC95 : 5.8 ; 14.9]. On multivariate analysis, only GR (HR= 0.36, 95%CI 0.184-0.703, p=0.0028) and performance status (PS) (HR= 3.799, 95%CI 1.72-8.387, p=0.001 for PS=2-3) were prognostic factors for OS. Early DCE- MRI parameters (after 2 cycles of treatment) such as, area under the contrast concentration vs. time curve for 90 seconds after contrast injection ( IAUC90) were strongly associated with histological response (p=0.027) whereas RECIST 1.1 was not. Conclusions: As for bone sarcomas, histological response to NAC is a crucial prognostic factor in STS. Multiparametric MRI parameters obtained post-2nd cycle of NAC are predictive of histological response and should be considered to adjust the therapeutic strategy. Genetic features (including the CINSARC signature) associated with response to NAC will be presented at the meeting.
Radiation-associated versus sporadic osteosarcoma: A single-institution experience.
Authors: Siontis Brittany , Roberts Emily , Zhao Lili , McHugh Jonathan B. , Owen Dawn , Baker Laurence H. , Biermann J. Sybil , Schuetze Scott , Chugh Rashmi
Published: September 2018

11018

Background: Osteosarcoma (osarc) can be a rare complication from radiation (rt) therapy. Radiation-associated osarc (RAO) is reported to have a worse prognosis than non rt-associated osarc with limited objective data comparing the two. We conducted a retrospective study comparing demographics, therapy and outcomes of sporadic osarc (SO) to RAO. This study was confined to adults. Methods: We identified patients (pts) > age 18 years (yr) with osarc treated at our institution between 1990 and 2016 using an institutional database. We categorized tumors as SO or RAO based on history of prior rt within field of osarc. We extracted data on demographics, treatment, and primary malignancy characteristics. Results: We identified 159 pts with osarc, 28 were RAO tumors. Results are in Table 1. Median follow-up was 2.8 yr (0.1-19.6 yr). For RAO, median time from rt to diagnosis was 11.5 yr (1.5-28 yr) with a median cumulative dose of 60 Gy (44-75.8 Gy). Median progression free survival (PFS) and overall survival (OS) were not significantly different in pts presenting with metastatic osarc; PFS 10.3 mo vs 4.8 mo (p=0.45) and OS 15.6 mo vs 6.1 mo (p=0.96) in SO vs RAO pts, respectively. For pts with localized osarc, median relapse-free survival (RFS) and OS were significantly different, not reached vs 12.2 mo (p<0.001) and not reached vs 27.6 mo (p=0.001) in SO vs RAO, respectively. Conclusions: In our series, there was a significant difference in age, size and location of RAO vs non rt-associated osarc. Overall, all osarc pts with metastatic disease at diagnosis fared poorly. Pts presenting with localized RAO had worse outcomes than patients with localized SO. This was not associated with a detectable difference in therapy rendered or treatment effect in resection specimens. [Table: see text]
Toxicity and efficacy of bolus (BOL) versus continuous intravenous (CIV) dosing of doxorubicin (DOX) in soft tissue sarcoma (STS): Post hoc analysis of a prospective randomized trial.
Authors: Cranmer Lee D. , Lu Yao , Ballman Karla V. , Loggers Elizabeth Trice , Pollack Seth
Published: September 2018

11023

Background: DOX remains critical in STS treatment. Controversy exists regarding its optimal administration route (BOL vs CIV). BOL vs CIV could affect toxicity and/or efficacy. A randomized trial to assess this is unlikely. We conducted a post hoc analysis to explore differences in these routes of DOX administration. Methods: Data from a prospective randomized phase III study of doxorubicin with or without evofosfamide (TH-302) were used. At the discretion of treating physician, BOL or CIV DOX could be used. Grade 3-5 hematologic, non-hematologic and cardiac toxicities and treatment response were explored using multivariable logistic regression. OS and PFS were analyzed using Kaplan-Meier and Cox proportional hazards. Results: 640 subjects were enrolled (556 BOL, 84 CIV). Baseline differences in age, extent of disease and prior radiotherapy were controlled for in regression models. Hematologic toxicity was associated with age, performance status (PS) and cumulative (CUM) DOX dose. Non-hematologic toxicity was associated with age, PS, receipt of prior radiotherapy and CUM TH-302 dose. Cardiac toxicity was only associated with CUM DOX dose. Odds of response were strongly associated with CUM DOX dose (mg/m2, OR = 1.011, p < 0.0001), and, to a lesser extent, with CUM TH-302 dose (g/m2, OR = 1.081, p = 0.0008), STS subtype and prior radiotherapy. Comparing CIV to BOL DOX, neither OS (median 21.7m vs 18.3m, HR = 0.85, p = 0.29) nor PFS (median 6.1m vs. 6.1m, HR = 0.89, p = 0.43) was affected by manner of DOX administration (CIV vs BOL). Cox analyses indicated that factors reflecting tumoral biology and host status, rather than treatment received, were associated with OS (PS, histologic STS subtype, histologic grade, receipt of prior radiotherapy) and PFS (PS, treatment-related toxicity). Conclusions: Our analyses provide no evidence for superiority of either BOL or CIV administration of DOX as regards toxicity or efficacy in STS treatment. Thus, the logistically simpler BOL administration of DOX should be favored over CIV administration.
Neoadjuvant denosumab treatment of locally advanced giant cell tumor of bone (GCTB).
Authors: Rutkowski Piotr , Gaston Louie , Borkowska Aneta , Stacchiotti Silvia , Baldi Giacomo Giulio , Palmerini Emanuela , Casali Paolo Giovanni , Gronchi Alessandro , Parry Michael , Gelderblom Hans , Ferrari Stefano , Dijkstra P.D.Sander , Pienkowski Andrzej , Grimer Robert
Published: September 2018

11026

Background: Retrospective study on locally advanced GCTB patients (pts) treated with neoadjuvant Denosumab (Db) outside clinical trials in 6 European reference centers. Methods: From 138 pts (median age 30yrs) with histologically confirmed advanced GCTB treated with Db(2011-2016), we included into analysis 87pts who underwent surgery after preoperative Db. All 87 patients had locally advanced tumors with extensive soft tissue involvement(54) or penetration to joint, not amenable to limb-sparing surgery/primary curettage or with high risk of recurrence. In 39/42(93%) cases diagnosis was confirmed by H3F3Agene mutation. Median follow-up time -22 months. Results: Primary tumor was located in lower limb(54%; n = 47) -mostly in tibia(25%) and femur(23%), upper limb(33%; n = 29), and pelvis/axial skeleton/ribs(13%; n = 11). 68(78%) patients had primary tumors, 19(22%) recurrent tumors after surgery (+/-radiotherapy). Median Db duration was 7months (range 1.5-35months), 17pts received also Db postoperatively. 39(45%) had wide en-bloc resection -WE (+17 implantation of prosthesis), 48(55%) cases had intralesional curettage -C, no extremity amputation. Pts who underwent prosthetic replacement had longer median preoperative Db therapy as compared to pts without prosthesis. All pts demonstrated a response to Db Progression after surgical treatment was observed in 15 pts -13 of them after intralesional curettage (13/48, 27%); 9 patients underwent D re-challenge -all responded. Two-year progression-free survival (PFS; from Db start) rate was 80%, 91% in WE group vs 73% in C group (p = 0.04), one-year PFS (from operation date) rate was 84%: 92% in WE and 79% in C group(p = 0.01). Treatment was well tolerated with only 1 grade 3 toxicity. Conclusions: Our study confirms that Db is active in a neoadjuvant setting with excellent efficacy and short-term tolerability. It implies that neoadjuvant therapy with Db is the option for treatment of initially locally advanced tumors to facilitate complete surgical resection or avoid mutilating surgery. The risk of recurrences after curettage of GCTB following Db raises questions about the optimal duration of preoperative treatment and if Db is indicated postoperatively.
Characterizing the end-of-life period in young patients with sarcomas.
Authors: Movva Sujana , von Mehren Margaret , Handorf Elizabeth , Tetzlaff Eric Daniel , Albanese Anjali , Murphy Kathleen , Chwistek Marcin
Published: September 2018

11027

Background: There is a paucity of data surrounding the end-of life transition (EOLT) in young adult (YA) patients with sarcoma. Discussions surrounding prognosis, goals of care (GOC), hospice and death can be challenging in these patients as they may be at a particularly hopeful stage of their life. The purpose of this study is to better understand the EOLT in YA patients with sarcoma by determining the survival and number of lines of treatment at different periods in the disease course. In addition, the study aims to determine what impacts the decision to discontinue anti-cancer therapy. Methods: Fox Chase Cancer Center (FCCC) patients, 18-39 years old who died from sarcoma between January 2013 and December 2016 were included in this study. Patient demographics, tumor specific data, treatment and treatment decisions were collected from electronic medical records and retrospectively analyzed. Results: 38 FCCC patients who were diagnosed between the ages of 18-39 died between January 2013 and December 2016. Of these 21 patients were between the ages of 18-39 at the time of their death. Median age at death was 30 (range: 22-40). The most common histologies were Ewing Sarcoma, GIST (n = 3) and osteosarcoma, synovial sarcoma (n = 2). Median time from diagnosis of metastatic disease to death was 21.4 months. Median time from metastatic disease to discussion of GOC and hospice by any provider was 9.6 and 16.7 months respectively. The hospice discussion was held by the treating oncologist 87.5% (n = 16) of the time (outpatient 35.7% and inpatient 64.3%). 60% (n = 15) of patients/family selected hospice when it was originally presented to them (multi-organ failure, unarousable, paralysis). The hospice discussion was held at a median of 21 days prior to death and median time on hospice was 13 days (range: 1-63). Patients were treated a median of 54 days prior to their death (range: 6-1823). Median times on first, 2ndto last and last treatments were 273, 67 and 22.5 days respectively (P = 0.002). Conclusions: Focusing on this particular group of patients will generate benchmark data that can help counsel them about their specific expected survival and changes in clinical status as their disease progresses. We plan to compare this data with that of older patients.
Does MGMT (O6-methylguanine–DNA methyltransferase) have a role in metastatic Ewing sarcoma (ES) patients (pts) undergoing temozolomide (TMZ) and irinotecan (IRI)?
Authors: Palmerini Emanuela , Pasello Michela , Jones Robin Lewis , Manara Maria Cristina , Parra Alessandro , Picci Piero , Grignani Giovanni , Marchesi Emanuela , Cesari Marilena , Longhi Alessandra , Abate Massimo , Paioli Anna , D'Ambrosio Lorenzo , Fagioli Franca , Dorin Asaftei sebastian , Ferrari Stefano , Scotlandi Katia
Published: September 2018

11030

Background: TMZ+IRI has significant activity in metastatic ES. Epigenetic silencing of the MGMT DNA gene by promoter methylation has been associated with response to TMZ in glioblastoma. Our aim was to assess if MGMT methylation 1) has a role in ES progression and 2) is predictive of response to TMZ. Methods: 1) In 10 ES cell lines presence of MGMT gene (Real-time PCR), methylation of its promoter (methylation-specific PCR) and protein expression (western blot) were assessed. MGMT protein (IHC) and methylation of its promoter was searched in 97 ES pts samples (74 localized; 23 metastatic). 2) In metastatic ES pts treated with TMZ+IRI, with pre-treatment FFPE tissue and measurable disease, the relation between RECIST response, PFS and MGMT expression (IHC) was assessed. Results: 1) The expression of MGMT gene and its protein was detected and concordant (p = 0.02) in all ES cell lines evaluated; methylation was a rare event. In ES tissue samples the methylation of the MGMT gene was found at a low intensity as compared with the unmethylated gene, but the protein expression was relatively low: 36% in localized, 65% in metastatic pts (p 0.03). 2) 24 pts (median age 19 years, range 3-50 years; F/M: 7/17) treated with TMZ + IRI from 2010 to 2015 were identified. Line of treatment: 8 patients were in 1st line; 16 ≥ 2nd line. Median n of cycles was 6 (range: 2-31). Pattern of metastases: 16 multiple sites, 4 lungs, 3 multiple sites + bone marrow, 1 bone. MGMT was positive in 63% of cases. ORR: 16.5% (1 CR , 3 PR); SD: 50% (13 pts); PD: 33.5% (7 pts). According to MGMT expression the ORR was 11% in negative and 20% in MGMT positive patients (p = 0.8). 6-mos PFS rate was 59% (38-80 %IC), no differece according to MGMT expression (pos 61% vs neg 56%, p 0.7). Conclusions: Whereas in cell lines the MGMT gene and its protein expression is a generalized event, in tissue samples MGMT protein is present in a minority of localized pts, and might be associate with tumor progression. Methylation of MGMT gene does not seem responsible for its regulation in ES, and post-transcriptional mechanisms are more likely to be involved. The presence of MGMT protein does not predict the response to TMZ + IRI in this small series.
Multicentric randomized phase II trial of gamma knife surgery (GKS) versus image-guided, intensity-modulated radiation therapy (IG-IMRT) in patients with sacrococcygeal chordoma.
Authors: Lu Shun , Lang Jin Yi , Wang Weidong , Feng Mei , Zou Bingwen , Peng Xinhao
Published: September 2018

11033

Background: Chordoma is a rare slow-growing neoplasm arisen from cellular remnants of the notochord. About 30% occur in the sacrococcygeal region. Surgical resection is recommended treatment. Due to the high recurrence rate, adjuvant radiation therapy was suggested to receive as an effective method to improve local control rates. Methods: Thirty eight patients were pathologically diagnosed as non-metastatic sacrococcygeal chordoma from Aug. 2003 to May. 2015 were recruited retrospectively to analysis. All patients received surgical resection after diagnosed. Initial surgery included subtotal resection (24% of patients), and gross total resection (76% of patients). Among these patients, 25 patients treated with adjuvant IG-IMRT, while 13 patients treated GKS after surgical resection. The median follow-up was 40 months (range, 6–151 month) for all patients, The PTV of IG-IMRT group received total doses were 60 Gy (range, 56-74Gy), delivered with 2-2.2 Gy/fraction, while GKS group underwent a total of 6-8 sessions treatment. Results: For the IG-IMRT group and the GKS group, the 5-year overall survival and local control rates were 87.5% and 67.7%, respectively. And 5-year local control rates were 35% and 22.2%, respectively. In total, 18 patients progressed locally: 11 were in the IG-IMRT group and 7 in the GKS group. In comparison with GKS group, the IG-IMRT group has a better overall recurrence-free survival (p = 0.03), the significance remained after adjusted for surgery results, age and gender. Moreover, there is no significant difference of overall survival was found between these two groups. Conclusions: We report favorable local control and adverse event rates following IG-IMRT, and suggested IG-IMRT is the first choice of adjuvant radiation therapy for sacrococcygeal chordoma treatment.
Numerical, dimensional or mixed progression disease to imatinib as prognostic factor in patients with metastatic GIST.
Authors: Badalamenti Giuseppe , Incorvaia Lorena , Galvano Antonio , Assanto Giovanni Manfredi , Musso Emmanuela , De Luca Ida , Cesarin Alessandra , Ancona Chiara , Passiglia Francesco , Vincenzi Bruno , Grignani Giovanni , Pantaleo Maria A. , Gatto Lidia , Bartolotta Tommaso Vincenzo , Taibbi Adele , Russo Antonio
Published: September 2018

11040

Background: The majority of GIST patients with advanced disease initially achieves disease control from imatinib treatment. Approximately 10% of patients progresses within 6 months of starting therapy (primary resistance) and also 50-60% of the responding patients develops progression disease within two years (secondary resistance). Progression disease (PD) can be numerical, dimensional or mixed. The known prognostic factors of risk stratification in local disease are tumor size, mitotic activity and anatomic site. In this retrospective analysis we explore several clinical factors affecting survival in metastatic setting. Methods: The population included in this large database of 128 patients with metastatic GIST was obtained examining data collected from four Oncologic Centres with expertise for the GIST management. The clinical factors analyzed were sex, tumor size, mitotic activity, anatomic site, KIT and PDGFRa mutational status, site of metastasis, FDG-PET status at progressing disease and pattern of tumor progression to I line imatinib 400, II line Imatinib 800 or Sunitinib, evaluated with CT scan or MRI: PD with dimensional growth (dimensional, dPD), with new lesions appearance (numerical, nPD) and with both numerical and dimensional growth (Mixed, mPD). Every factor has been correlated with Overall Survival (OS) measured in months. Survival analyses were performed by using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazard regression models were executed to search for association with the outcome. Results: Univariate analysis showed significant value for primary tumor site (p < 0.0001), mitotic activity (p = 0.02), tumor size (p = 0.05) and PD pattern (p = 0.008): OS nPD group was 102.7 months, in dPD group 87 and in mPD group 70. The multivariate analysis confirm significant prognostic factors for OS tumor site (p = 0.0004) and PD pattern (p = 0.02). Conclusions: with the limitations of a retrospective analisys, this study shows for the first time the impact of pattern of progression on OS: patients with dPD have a worse prognosis than those with nPD or mPD, suggesting type of PD as an independent prognostic factor for OS in advanced GISTs.
Impact of pharmacogenomics on imatinib toxicity in gastrointestinal stromal tumors.
Authors: Zhuang Wei , Qiu Haibo , Wang Xueding , Xin Shuang , Huang Min , Zhou Zhiwei
Published: September 2018

11043

Background: Imatinib-induced side effects are common, although most of these side effects are mild, some will be severe and lead to disruption of Imatinib treatment in gastrointestinal stromal tumor (GIST). It is necessary to explore a biological predictors to predict and optimal therapeutic strategy. But there were few studied conducted to explore the mechanisms of Imatinib-induced side effects. The present study comprehensively investigated the effects of genetic polymorphisms of cytokines involved in cell proliferation and metabolic enzymes and transporters involved in Imatinib metabolism on these side effects. Methods: A total of 154 GSIT patients treated with Imatinib were enrolled. 22 SNPs (single nucleotide polymorphisms) in KIT/ PDGFRA/ PDGFRB/ SHC1/ FLT1/ MAPK1/ EGFR/ CCL5/ CXCL14were detected using Agena Massarray matrix-assisted laser desorption / ionization-time of flight (MALDI-TOF) platform. Logistic regression analyses were performed to evaluate their effects on Imatinib-induced toxicities. This study was approved by the ethical committee of Sun Yat-Sen University Cancer Center. Results: Imatinibdose, FLT1 rs9951465, MAPK1 rs13515, PDGFRB rs55712339 and SHC1 rs3766920 were found to be correlated with the incidence of myelosuppression ( P= 0.027, 0.009, 0.002, 0.008, < 0.001, respectively), moreover, FLT1 rs9554314 was correlated with severe myelosuppression (Grade 0,1 vs. 2+, P= 0.009, OR (95%CI) = 3.042 (1.314-7,042)). Meanwhile, EGFR rs10228436 was found to be correlated with the incidence of skin rash ( P= 0.027), moreover, CCL5 rs4796120 and CXCL14 rs7716492 were correlated with severe skin rash (Grade 0,1 vs. 2+), with OR (95%CI) and p value were 8.542 (0.934-78.107), 13.504 (2.308-79.004) and 0.057, 0.020, respectively. Conclusions: This is the first comprehensive report on the biomarkers for Imatinib toxicities. These biomarkers might be able to distinguish patients with mild or more severe forms of Imatinib toxicities, thus enabling the optimization of Imatinib therapy and lead patients benefit from Imatinib treatment in a long-term.
Combined peripheral natural killer (NK) cell and circulating tumor cell (CTC) enumeration to enhance prognostic efficiency in patients (pts) with triple-negative breast cancer (TNBC).
Authors: Liu Xiao-ran , Shao Bin , Li Hui-ping , Yang Yan-lian , Rugo Hope S. , Kong Wei-yao , Song Guo-hong , Jiang Han-fang , Liang Xu , Yan Ying , Hu Zhi-yuan , Xu Guo-bing
Published: September 2018

1105

Background: CTCs have emerged as an independent prognostic factor for metastatic breast cancer. However, the prognostic value of baseline CTCs regarding PFS in TNBC is still controversial, especially beyond first-line. We evaluated a novel combined NK cell/CTC detection system for enumeration to better understand the impact of cell count on prognosis in TNBC. Methods: 83 consecutive patients with metastatic TNBC were enrolled and received a new line of therapy (median=2, range: 1~5). Baseline circulating CTCs and NK cells were isolated and enumerated simultaneously prior to starting a new line of therapy using our previously published method targeting EpCAM (Bai et al. J Mater Chem B, 2014) and flow cytometry (antibodies against CD3-, CD45+, CD56+) respectively. The NK cell level was expressed as the proportion of total lymphocytes (%). Patients with normal to high NK cell proportion (≥ 9.15%) and > 2 CTC/2 ml were defined as NK resistant CTC, the rest were defined as non-NK resistant CTC. Results: 33 out of 83 TNBCs had first-line of therapy. Pts with ≤ 2 CTC/2 ml had a significantly longer median PFS than those with > 2 CTC/2 ml ( P = 0.028). The differences in median PFS were not significant ( P=0.110) for the entire group of pts with TNBC receiving different lines of therapy. Pts with non-NK resistant CTCs had a significantly longer median PFS than those with NK resistant CTCs ( P= 0.025), regardless of line of therapy. Conclusions: Including peripheral NK cell level into consideration can improve CTC prognostic efficiency in predicting PFS for TNBCs receiving different line of therapy. Further analysis of the unique biological features of NK-resistant CTCs and associated clinical consequence holds promise in guiding clinical practice. [Table: see text]
The incidence of other malignancies before and after sarcoma diagnosis: A population-based study.
Authors: Van Der Graaf Winette T.A. , Olga Husson , van Houdt Willem J. , Desar Ingrid M.E. , Ho Vincent K.Y.
Published: September 2018

11076

Background: Sarcomas encompass a group of rare and heterogeneous mesenchymal malignancies with mostly unknown origin. Both exogenous risk factors, in particular radiotherapy, as well as genetic risk factors have been described. Second tumors next to sarcomas suggest associated risk factors. In the current study, we investigate the incidence of sarcomas and other malignancies by using population-based data from the Netherlands Cancer Registry. Methods: In 29,638 patients diagnosed with sarcoma between 1989 and 2015, with a median age of 59 years, we quantified the risk of other malignancies after sarcoma diagnosis using standardized incidence ratios (SIRs). In assessing associations with malignancies before sarcoma diagnosis, we focussed on previous radiotherapy. Skin carcinomas, with the exception of melanomas, were excluded. Results: In total, 3,381 (11.4%) sarcoma patients, median age 71years, had a previous malignancy (at a median age of 66 years). The most frequent sarcomas associated with prior tumors were angiosarcoma (34.5%) and gastrointestinal stromal tumours (20.6%). In the angiosarcoma group, 78.6% of patients had received prior radiotherapy for their previous tumors. Subsequent tumors (diagnosed in patients with median age of 69.5 years) after sarcoma diagnoses were detected in 2,523 patients with median age of 63 years (SIR 1.13; 95%CI: 1.09–1.18). Risks appear notably elevated for breast cancer (SIR 1.19; 95%CI: 1.06–1.34), lung cancer (SIR 1.15; 95%CI: 1.04–1.27), cancers of the urinary tract system (SIR 1.33; 95%CI: 1.14–1.53) and hematological cancers (SIR 1.31; 95%CI: 1.13–1.51). Median time until diagnosis of subsequent cancer was 52.7 months. Conclusions: Sarcoma patients have a markedly increased risk on another malignancy, either before or after the sarcoma diagnosis. Further research into genetic and exogenous risk factors may help to explain the associations.