bluuebunny/crossref_metadata_2025 huggingface dataset:
NFKBIA deletion in triple-negative breast cancer.
Authors: Bredel Markus , Kim Hyunsoo , Thudi Nanda K. , Scholtens Denise M. , Bonner James A. , Sikic Branimir I.
Published: March 2020

1012

Background: While effective, target-directed therapies are available for ER-positive and HER2-amplified breast cancer, adjuvant therapeutic options for triple-negative breast cancer (TNBC) are limited in the absence of well-defined molecular targets. Constitutive activation of oncogenic nuclear factor kB (NFkB) has been associated with ER-negative or basal-like (BL) breast cancers, but the underlying mechanism of this activation remains undefined. We previously showed that deletion of the endogenous NFkB repressor gene NFKBIA associates with EGFR non-amplified glioblastoma multiforme and portends unfavorable clinical outcome (Bredel et al. NEJM 2011). Methods: We analyzed >5,000 human breast cancers for deletions, mutations and/or expression of NFKBIA. We studied tumor suppressor activity of NFKBIA and the effect of targeted NFkB inhibition in cell culture with various NFKBIA genotypes. We compared molecular results with outcomes of affected persons. Results: NFKBIA is often (10.8%) deleted but not mutated in breast cancer. NFKBIA deletions are significantly associated with TNBC (32.8%) and particularly frequent in the BL subtype (36.7%). Loss of NFKBIA exerts a haploinsufficient effect on NFKBIA expression and the transactivation of several NF-kB target genes with important roles in breast carcinogenesis. Restoration of NFKBIA expression or pharmacologic NFkB inhibition attenuates the malignant phenotype of cells cultured from TNBC with NFKBIA deletion. Deletion and low expression of NFKBIA are highly associated with unfavorable overall survival, independent of patient age, tumor stage, nodal status, and tumor subtype. Loss of NFKBIA expression portends significantly poorer disease-specific survival, recurrence-free survival, and distant metastasis-free survival. Moreover, NFKBIA expression is significantly associated with duration of metastasis-free survival in subgroups of patients with brain or lung metastases from breast cancer. Conclusions: NFKBIA is a new, prognostically relevant, molecular target in TNBC, which remains a clinically challenging subtype of breast cancer with limited treatment options.
Evaluation of flap endonuclease-1 (FEN1) as a prognostic, predictive, and therapeutic target in breast (BC) and ovarian cancer (OVC).
Authors: Abdel-Fatah Tarek M. A. , Russell Roslin , Maloney David J. , Mohan Vivek , Dorjsuren Dorjbal , Rueda Oscar , Gorguc Ipek , Mukherjee Abhik , Jadhav Ajit , Simeonov Anton , Wison III David M. , Agarwal Devika Ravindra , Ball Graham , Chan Stephen , Caldas Carlos , Ellis Ian O. , Madhusudan Srinivasan
Published: March 2020

1016

Background: FEN1 is a multifunctional protein with essential roles in long patch base excision repair (LP-BER), Okazaki fragment maturation during replication, resolution of tri-nucleotide repeat sequence-derived secondary structures, rescue of stalled replication forks, maintenance of telomere stability and apoptotic fragmentation of DNA. In the current study we have evaluated FEN1 as a prognostic, predictive and therapeutic target in BC and OVC. Methods: Clinico-pathological significance of FEN1 mRNA expression was evaluated in a BC training cohort [n=128], test cohort (n=249) and validated in a large cohort of 1,980 BC (METABRIC). Neural network analysis (NNA) was conducted to identify FEN1 interaction genes. FEN1 protein expression was investigated in three consecutive series of BC and OVC: 568 ER negative (ER- BC), 894 ER positive (ER+ BC) and 195 OVC cohorts. Pre-clinically, FEN1 deficient and proficient HeLa cell lines were investigated for chemotherapy sensitization. A high throughput screening (HTS) strategy was developed to identify FEN1inhibitors for therapeutic application. Results: FEN1mRNA overexpression is associated with adverse clinicopathological features such as high grade, high mitotic index, and triple negative (ps<0.0001). High FEN1 mRNA expression was highly significantly associated with PAM50 Her2, PAM50 Basal and PAM50 LumB (ps<0.0001) BC. FEN1 mRNA overexpression is associated with resistance to chemotherapy (p=0.019), endocrine therapy (p<0.0001) and independently with poor survival (p<0.0001). NNA revealed novel interaction genes with predominant roles in proliferation, cell growth, DNA repair, differentiation, invasion, migration, metabolism and apoptosis. FEN1 protein overexpression is significantly associated with aggressive clinico-pathological features and independently with poor survivals in ER+ BC, ER- BC and in OVC (ps<0.001). HTS assay has identified novel FEN1 inhibitors for therapeutic development. Conclusions: This is the first study to investigate FEN1 in BC and OVC. We provide confirmatory evidence that FEN1 is a promising biomarker as well as a therapeutic anti-cancer drug target for clinical application.
Impact of delaying initiation of adjuvant chemotherapy in breast cancer patients.
Authors: Gagliato Debora De Melo , Gonzalez-Angulo Ana M. , Lei Xiudong , Giordano Sharon Hermes , Theriault Richard L. , Valero Vicente , Hortobagyi Gabriel N. , Chavez-Mac Gregor Mariana
Published: March 2020

1022

Background: The survival benefit of adjuvant chemotherapy in breast cancer is well established. However, the optimal timing to initiation of chemotherapy after definitive surgery is unknown. We evaluated the association between time to initiation of chemotherapy and survival outcomes according to breast cancer subtype and stage at diagnosis. Methods: Women diagnosed with stage I–III breast cancer between 1997-2011 who received adjuvant chemotherapy at our institution were included. Patients were categorized according to time from definitive surgery to adjuvant chemotherapy into one of three groups: ≤ 30 days, 31–60 days and more than 60 days. Descriptive statistics, Kaplan-Meier statistics and Cox proportional hazards models were used. Results: Among the 6,827 patients included, the 5-year Overall Survival (OS), Relapse-Free Survival (RFS) and Distant Relapse-Free Survival (DRFS) estimates were similar for the different time-to-chemotherapy categories. Among patients with stage I, there was no association between outcome and time to initiation of chemotherapy. Patients with stage II disease experienced an 18% and 22% increase in risk of RFS (HR 1.18; p=0.038) and DRFS (HR 1.22; p=0.02), when systemic treatment was started >60 days from surgery. Patients with stage III disease that started adjuvant chemotherapy >60 days after surgery had a 70% increase in the risk of death (HR 1.7; p=0.002), a 32% increase risk of relapse (HR 1.32; p=0.046) and a 34% increase risk of distant relapse (HR 1.34; p=0.044). Time to chemotherapy did not have a significant effect on outcome among Hormone Receptor (HR)-positive patients. Patients with triple negative (TNBC) and HER2-positive tumors treated with trastuzumab who started chemotherapy >60 days after surgery had lower 5 year-OS estimates (HR 1.52; p=0.016 and HR 2.62; p=0.005, respectively). Conclusions: Time to chemotherapy did not influence survival outcomes in the overall population. However, patients with stage III, TNBC and HER2-positive tumors treated with trastuzumab, experienced worse outcomes when chemotherapy was delayed. Among patients with tumors with aggressive biology and more advanced stages at diagnosis, early initiation of therapy should be favored.
Prospective evaluation of BRCA mutations in a large triple-negative breast cancer (TNBC) registry: Implications for germline testing.
Authors: Sharma Priyanka , Klemp Jennifer R. , Kimler Bruce F. , Ludlow Anna , Geier Larry , Elia Manana , Khan Qamar J. , Fabian Carol J. , McGinness Marilee , Connor Carol Sue , Mammen Joshua , Ranallo Lori , Knight Catie , Godwin Andrew K.
Published: March 2020

1026

Background: Although current NCCN guidelines recommend genetic testing (GT) for all TNBC patients aged <60 years (regardless of family history) however due to the lack of prospective information on prevalence of mutations in unselected TNBC patients, these guidelines have not been widely adopted by clinicians and insurance carriers (including Medicare). Data on BRCA mutations from unselected TNBC cohorts are lacking. Aims: In a large TNBC registry, to prospectively determine the 1) prevalence of germline BRCA mutations and 2) validity of current NCCN guidelines for GT. Methods: Patients with stage I-III TNBC presenting for treatment at an academic and surrounding community practices were approached for participation in a prospective registry. All patients underwent comprehensive BRACAnalysis (Myriad). Detailed FH was collected. Mutation prevalence in the entire cohort and in subgroups stratified by FH and age were calculated. A significant family history (SFH) was defined as 1st-/2nd-degree relatives with breast cancer aged <50 years or ovarian cancer at any age. Results: 165 patients with stage I-III TNBC have been enrolled from 2011-2013. Median age 54 (range 24-84yrs), 58% postmenopausal, 29% LN +, 33%, 58% and 9% had stage I, II, III disease respectively. 82% Caucasian, 14% AA, 2% Hispanic, 0.6% Ashkenazi Jewish. Deleterious BRCA1/2 mutations were identified in 13.1% patients (20/152, 15 BRCA1, 5 BRCA2; results pending in 13). 27% of patients had a SFH and 64% had any FH. Mutation rates in patients with or without SFH was 32.5% and 6.1%, respectively. When examined by age at diagnosis, the mutation rates were: 16.6% (<60yrs), 21.8% (<50yrs), 10.6% (51-60yrs), and 0% (>60 yrs). If SFH or age <50, were the only criteria used 35% and 30% of mutations would have been missed. All mutations were identified using the NCCN guidelines. Conclusions: This is the first study to prospectively evaluate BRCA mutations in an unselected TNBC cohort. In this large academic and community registry with negligible Ashkenazi representation, the overall BRCA mutation rate was 13%; 16.6% in those <60 years. These results validate GT based on current NCCN guidelines and support its use in routine clinical practice.
Body mass index (BMI), tumor subtype, and relapse-free survival (RFS) in CALGB 9741 (Alliance).
Authors: Ligibel Jennifer A. , Cirrincione Constance , Liu Minetta C. , Citron Marc L. , Ingle James N. , Gradishar William John , Martino Silvana , Sikov William M. , Michaelson Richard Alan , Hudis Clifford , Winer Eric P. , Barry William Thomas
Published: March 2020

1032

Background: Obesity is a predictor of poor outcomes in women with early-stage breast cancer (BC). Some reports suggest that obesity is associated with aggressive tumor histology. We examined the relationship between BMI at diagnosis and PAM50 subtype, and explored the interaction between BMI and subtype on prognosis in early BC. Methods: CALGB 9741 evaluated dose-density and sequence in node-positive BC. All patients received doxorubicin, cyclophosphamide and paclitaxel dosed by actual body weight without cap or dose adjustment. The primary endpoint was RFS. Height and weight at diagnosis were abstracted from patient records; the PAM50 assay was performed using the Nanostring platform. Association between PAM50 and BMI was assessed by a chi-squared test. The prognostic value of BMI conditional on PAM50 was tested as a continuous variable using Cox models for RFS adjusted for number of involved nodes, tumor size, menopausal status, drug sequence, and dose density. Results: Baseline height and weight were available for 1909 of 2005 enrolled patients; 1272 also had subtype determination by PAM50. Distribution of subtypes differed significantly by BMI (p=0.03), with all weight groups having similar proportions of Basal and HER-2 Enriched subtypes and with obese patients having lower rates of Luminal A (30 vs 35%) and higher rates of Luminal B (39 vs 26%) tumors as compared to normal-weight individuals. In multivariate analyses, BMI and subtype were independent predictors of RFS (p=0.011 and p<0.001, respectively). Exploratory analyses did not show a significant interaction between subtype and the relationship between increased BMI and RFS (p=0.15), although largest differences were seen among Luminal cancers (Table). Conclusions: Biologic subtypes were distributed differently in obese and non-obese individuals. The association between BMI and RFS did not differ significantly by subtype in this study. More work is needed to further explore the interaction of BMI and subtype, especially in a larger cohort of Luminal tumors. [Table: see text]
Efficacy of first-line bevacizumab (BEV)-based therapy for metastatic triple-negative breast cancer (TNBC): Subgroup analysis of TURANDOT.
Authors: Inbar Moshe J. , Lang Istvan , Kahan Zsuzsanna , Greil Richard , Beslija Semir , Stemmer Salomon M. , Kaufman Bella , Ahlers Silke , Brodowicz Thomas , Zielinski Christoph ,   Central European Cooperative Oncology Group
Published: March 2020

1040

Background: The randomized phase III TURANDOT trial compared first-line BEV plus paclitaxel (PAC) vs BEV plus capecitabine (CAP) in HER2-negative metastatic BC (mBC). BEV-based regimens are often favored in TNBC [Dawood 2012] because of efficacy in subgroup analyses and a lack of effective treatments. We performed an exploratory subgroup analysis of TURANDOT to provide more data on BEV-based therapy in TNBC. Methods: Patients (pts) with HER2-negative mBC who had received no prior chemotherapy for mBC were randomized to either BEV–PAC (BEV 10 mg/kg d1 and 15 + PAC 90 mg/m2 d1, 8, and 15 q4w) or BEV–CAP (BEV 15 mg/kg d1 + CAP 1000 mg/m2bid d1–14 q3w). The primary endpoint was overall survival (OS); secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and safety. Results: Of 561 pts treated, 130 had TNBC. Baseline characteristics were typical of a poor-prognosis population and generally balanced between treatment arms, although fewer pts receiving BEV–PAC than BEV–CAP had ECOG PS 1/2 (25% vs 40%, respectively), positive lymph nodes (56% vs 72%), metastatic disease at first diagnosis (19% vs 30%), and liver metastases (27% vs 43%). Median age was 54 vs 56 years, respectively. At data cut-off, median follow-up was 21.4 vs 19.2 mo for BEV–PAC and BEV–CAP, respectively. The safety profiles in the TNBC subgroup were similar to the overall population. The predominant grade ≥3 AEs were hematologic AEs and neuropathy with BEV–PAC and hand-foot syndrome and diarrhea with BEV–CAP. Conclusions: One-year OS rates up to 78% in TURANDOT are among the highest seen in TNBC. BEV-based therapy is a valid option in a setting with limited active treatments. BEV–PAC may be favored based on 1-year OS, PFS, and ORR. Clinical trial information: NCT00600340. [Table: see text]
TGFb signature at 2 weeks to predict response to preoperative therapy (PT) with bevacizumab (B) and chemotherapy (CT) in early breast cancer (EBC).
Authors: Williams Nicole , Varadan Vinay , Vadodkar Aditi , Miskimen Kristy , Gilmore Hannah L. , Beckloff Nicholas , Edelheit Simone , Prabhakar Dhivya , Janevski Angel , Banerjee Nila , Kamalakaran Sitharthan , Abu-Khalaf Maysa M. , Sikov William M. , Dimitrova Nevenka , Harris Lyndsay
Published: March 2020

1046

Background: Gene expression profiles from core biopsies taken during PT for EBC may identify markers associated with benefit. B was recently shown to improve pathologic complete response (pCR) to CT in two randomized trials, but is associated with increased toxicity. Predictive signatures are critical to optimizing benefit. We have shown that changes in TGF-β pathway activity after one dose of B are associated with pCR. To confirm these results and understand the mechanism of alteration of the TGFb pathway, we evaluated the 61-gene TGFb signature by RT-PCR, measured markers of TGFb pathway activation and assessed TGFb gene mutations. Methods: Real-time PCR was performed on paired (pre/post) core biopsy RNA samples from 21 patients (pts) who received B, trastuzumab (T) or nab-paclitaxel prior to combined CT and targeted therapy using Custom RT2 Profiler PCR Arrays (384-well plate, 64x6 format) containing 60 genes from our TGF-beta signature and 3 housekeeping genes, IPO8, ALAS1, and SDHA. RT- PCR reactions containing Qiagen RT2SYBR Green qPCR Mastermix and 5 ng of amplified cDNA were run on a Roche LightCycler480 machine. Cp values were determined using the Roche LightCycler480 software. Antibodies to p-Smad2, TGFBR1 and TGFBR2 were analyzed in FFPE IHC pre and post therapy. TGFb pathway genes with known mutations in TCGA were assessed using an Illumina Custom Amplicon and miSeq next generation sequencing. Results: The log 2 FPKM value of the 60 genes correlated well with the ΔCP values calculated normalized to ALAS1 housekeeping gene. The ΔΔCP values was determined by subtracting the 60 gene ΔCP values of baseline samples from post-exposure samples. Patients were clustered using the ΔΔCP. Pts exposed to B who achieved a pCR showed down-regulation of signatures genes, in contrast to a strong non-pCR cluster. Signature evaluation showed no association with response in the T arm. TGFb pathway protein expression and mutation frequency is under analysis. Conclusions: TGFb signature predicts response to B containing chemotherapy after one dose of B and is validated by RT- PCR as a potential predictive tool. TGFb pathway activation and gene mutation analysis will be presented. Clinical trial information: NCT00617942.
Phase II study of neoadjuvant chemotherapy with a metronomic regimen of paclitaxel + cyclophosphamide + capecitabine followed by 5-fluorouracil + epirubicin + cyclophosphamide in operable triple-negative breast cancer (JBCRG-13 study).
Authors: Higaki Kenji , Masuda Norikazu , Takano Toshimi , Matsunami Nobuki , Morimoto Takashi , Ohtani Shoichiro , Mizutani Makiko , Miyamoto Takeshi , Kuroi Katsumasa , Ohno Shinji , Morita Satoshi , Toi Masakazu
Published: March 2020

1048^

Background: Triple-negative breast cancer (TNBC) is generally associated with a poor prognosis. Combination therapy with anthracyclines and taxanes is widely used as preoperative systemic chemotherapy (PST), but pathological complete response (pCR) rate is ≤50%. We conducted metronomic PST in TNBC patients. Methods: Patients had primary breast cancer (T1C-3N0M0 or T1-3N1M0) with low ER expression (<10%) diagnosed with either a triple-negative or HER2-negative invasive tumor. They received 4 cycles of a metronomic PCX regimen followed by 4 cycles of 5-fluorouracil (500 mg/m2, q3w) + epirubicin (100 mg/m2, q3w) + cyclophosphamide (500 mg/m2, q3w) (FEC regimen). The metronomic PCX regimen includes weekly administration of paclitaxel (80 mg/m2; days 1, 8, 15), cyclophosphamide (50 mg/body; po, days 1-21) and capecitabine (1200 mg/m2; po, daily), with one cycle set to 21 days. Primary endpoint was pCR rate. Results: Between March 2010 and September 2011, 41 patients were enrolled and 40 patients were treated. Characteristics of these 40 pts (ITT population) were: median age 52 years (range, 33-69), median tumor size 23.7 mm (range, 3.5-82), N(+) in 16 pts (40%), and estrogen receptor weakly positive (ER;1-9%) in 7 pts (17.5%). Median dose intensity for paclitaxel, cyclophosphamide and capecitabine was 89.7%, 92.1% and 89.8%, respectively. Five pts requested discontinuation of PST during PCX and 2 during FEC, primarily due to adverse events, leaving a per protocol population of 33 pts. pCR (ypT0/Tis ypN0) rate was 54.5% (18/33). 22 pts achieved CR, and ORR was 93.9% (95% CI, 79.8-99.3) as assessed by MRI or CT. Breast conservation rate was 72.7% (24/33), and 5 of 13 pts changed to partial resection from pre-planned total mastectomy. Grade 3-4 adverse events were neutropenia (35%), febrile neutropenia (25%), leucopenia (25%), and hand-foot syndrome (7.5%). There was no SAE report, and most pts completed treatment as outpatients. Conclusions: Metronomic PCX followed by FEC provided a high pCR rate and was manageable as PST in patients with TNBC. Clinical trial information: UMIN000003570.
Quality of life (QoL) in patients (pts) with locally advanced or metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes who received eribulin mesylate or capecitabine: A phase III, open-label, randomized study.
Authors: Cortes Javier , Awada Ahmad , Kaufman Peter Andrew , Yelle Louise , Perez Edith A. , Velikova Galina , Wanders Jantien , Olivo Martin S. , He Yi , Dutcus Corina , Simons W. Robert , Twelves Christopher
Published: March 2020

1050^

Background: In a phase III trial comparing eribulin (E) vs. capecitabine (C) in pts with locally advanced or MBC, a trend for improved OS was observed but a statistically significant superiority was not demonstrated with E vs. C for OS or PFS. The AE profiles were consistent with known side effects. We now report QoL results from this trial. Methods: Pts received eribulin mesylate 1.4 mg/m2 on Days 1 and 8, or C 1.25 g/m2 BID orally on Days 1-14, of a 21-day cycle. Eligible pts had received prior therapy including an anthracycline and taxane, and were receiving study drug as 1st-, 2nd-, or 3rd-line therapy for advanced disease. QoL, a secondary objective, was assessed using EORTC QLQ-C30 and QLQ-BR23 questionnaires at baseline, 6 weeks, 3, 6, 12, 18, and 24 months after starting treatment (or until progressive disease or treatment change), and at unscheduled visits. Longitudinal analyses were carried out using weighted generalized estimating equations adjusted for non-random attrition due to death within 12 months. Model covariates were time (visit), region, and baseline QoL. The primary endpoint was change from baseline for Global Health Status (GHS)/overall QoL; exploratory endpoints were change from baseline for each functional domain, and signs/symptoms. Results: 1,102 pts were randomized (E 554; C 548). GHS/QoL scores were low at baseline for E (56.3) and C (54.7) on a scale of 0 (worse) to 100 (best). GHS/QoL and cognitive functioning improved significantly more in pts receiving E vs. C, (6.5 [p=0.048] and 15.3 [p<0.001], respectively). Emotional functioning improved significantly for pts receiving C vs. E (3.3; p=0.033). Pain was comparable at baseline, and was lower at subsequent visits with both treatments. Patient-reported signs/symptoms in favor of E included nausea and vomiting (E1.9; p=0.043) and diarrhea (-3.7; p=0.001); systemic side effects (5.2; p<0.001) and upset by hair loss (9.3; p=0.023) favored C. Conclusions: GHS/QoL scores improved more in pts receiving E than C. E showed advantages in terms of gastrointestinal effects while C had advantages in relation to hair loss. Clinical trial information: NCT00337103.
Mutational analysis of plasma DNA from patients (pts) in the phase III GRID study of regorafenib (REG) versus placebo (PL) in tyrosine kinase inhibitor (TKI)-refractory GIST: Correlating genotype with clinical outcomes.
Authors: Demetri George D. , Jeffers Michael , Reichardt Peter , Kang Yoon-Koo , Blay Jean-Yves , Rutkowski Piotr , Gelderblom Hans , Hohenberger Peter , Leahy Michael Gordon , von Mehren Margaret , Joensuu Heikki , Badalamenti Giuseppe , Blackstein Martin E. , Le Cesne Axel , Schoffski Patrick , Maki Robert G. , Xu Jian-Ming , Nishida Toshirou , Kuss Iris , Casali Paolo Giovanni
Published: March 2020

10503

Background: The phase III GRID study showed that REG provides a significant improvement in progression-free survival (PFS) compared with PL in pts with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib (IM) and sunitinib (SU; HR 0.27, p<0.0001). Determining GIST genotype in TKI-refractory disease has proven challenging due to inter-tumoral heterogeneity and pt preference to avoid serial biopsies. To overcome this, we analysed circulating DNA in plasma as a source of tumor DNA and studied the correlation between mutational status and clinical outcome. Methods: DNA was isolated from both archival tumor tissue (n=102) and plasma at baseline (n=163) and analyzed for mutations via Sanger sequencing (tissue) or BEAMing (plasma). Results: Mutational frequencies for tumor tissue samples were: KIT, 66%; PDGFRA, 3%; KRAS, 1%; BRAF, 0%. For plasma, frequencies were: KIT, 58%; PDGFRA, 1%; KRAS, 1 out of 2 samples, BRAF, 0%. Detection of primary KIT mutations showed 84% concordance between tissue and plasma. Secondary KIT mutations were more commonly detected in plasma (47%) than in tissue (12%). Subgroup analysis based on mutational status showed an improved PFS in REG-treated pts vs PL in all subgroups by both central and local review of imaging studies. The presence of a secondary KIT mutation in plasma was associated with shorter PFS in pts receiving PL (HR 1.82, p=0.05). Pts with a KIT-exon 9 mutation received IM for a shorter period of time, and SU for a longer period of time, relative to other GIST genotypes. Pts with a PDGFRA mutation showed variable clinical responses, while 1/1 KRAS-mutant GIST did not respond well to IM, SU, or REG. Conclusions: KIT mutational status correlated to IM and SU treatment duration. While consistent with prior reports using tissue sampling, this validates the utility of plasma-based circulating DNA analysis of target oncogenes. Secondary KIT mutations appear to have a negative prognostic impact in GIST, while the clinical benefit of REG vs PL was not influenced by KIT mutational status. Clinical trial information: NCT01271712.
A randomized, double-blind, placebo (Pbo)-controlled phase III study of ombrabulin plus cisplatin in patients (pts) with advanced-stage soft-tissue sarcoma after failure of anthracycline and ifosfamide chemotherapies.
Authors: Papai Zsuzsanna , Tolcher Anthony W. , Italiano Antoine , Cupissol Didier , Lopez-Pousa Antonio , Chawla Sant P. , Bompas Emmanuelle , Penel Nicolas , Isambert Nicolas , Staddon Arthur P. , Thyss Antoine , Santoro Armando , Franke Fabio A. , Cohen Patrick , Le-Guennec Solenn , Demetri George D. , Blay Jean-Yves
Published: March 2020

10506

Background: Ombrabulin (AVE8062) is a vascular disrupting agent that damages established tumor vasculature and has demonstrated synergistic antitumor activity with cisplatin in vivo. In a phase I study, ombrabulin 25 mg/m² plus cisplatin 75 mg/m² was identified as the recommended dose in pts with solid tumors (AACR 2008; Abs 08-AB-4925). This phase III study evaluated the efficacy and safety of ombrabulin plus cisplatin in pts with advanced soft-tissue sarcoma (NCT00699517). Methods: Pts (aged ≥18 yrs, ECOG PS ≤2) with metastatic soft-tissue sarcoma who had received prior anthracycline and ifosfamide, with ≤2 prior chemotherapies for advanced disease, were randomized (1:1) to receive either ombrabulin 25 mg/m² or Pbo plus cisplatin 75 mg/m² every 3 weeks. The primary objective was to compare progression-free survival (PFS) between arms; secondary objectives included overall survival (OS) and safety. Results: Overall, 355 pts (median age 52 yrs; 51.5% male) were randomized (176 ombrabulin, 179 Pbo) in 44 centers worldwide. Median duration of follow-up was 27.9 and 30.5 months in Pbo and ombrabulin arms, respectively. PFS analysis showed a statistically significant improvement with ombrabulin (median 1.54 vs 1.41 months Pbo; HR=0.76, 95% CI 0.59–0.98; p=0.0302), with 3- and 6-month rates in favor of ombrabulin vs Pbo: 35.4% vs 24.9% and 19.3% vs 10.6%, respectively. A trend for an improvement with ombrabulin was observed in 3 of the 4 prespecified histology strata: liposarcoma, leiomyosarcoma, and “other”, but not for pleomorphic. Analysis of OS did not show statistically significant improvement with ombrabulin (median 11.43 vs 9.33 months Pbo, HR=0.85, 95% CI 0.67–1.09). OS rates at 1 year were in favor of ombrabulin (48.6% vs 42.4% Pbo). Grade 3/4 TEAEs more frequently seen with ombrabulin included neutropenia (19.2% vs 7.9% Pbo) and thrombocytopenia (8.5% vs 3.4% Pbo). Conclusions: Although this trial met its primary efficacy endpoint, the combination of ombrabulin and cisplatin did not demonstrate sufficient clinical benefit in pts with advanced soft-tissue sarcoma to warrant further study. Clinical trial information: NCT00699517.
Detection of mutant-free circulating tumor DNA in the plasma of patients with gastrointestinal stromal tumor (GIST) harboring activating mutations of C-Kit or PDGFRA.
Authors: von Bubnoff Nikolas , Kerle Irina , Specht Katja , Bruegel Melanie , Wickenhauser Claudia , Jost Philipp , Niederwieser Dietger , Peschel Christian , Duyster Justus , Lange Thoralf , Maier Jacqueline
Published: March 2020

10508

Background: In gastrointestinal stromal tumor (GIST), there is no biomarker available that indicates success or failure of therapy. We hypothesized that tumor specific CKIT or PDGFRA mutant DNA fragments can be detected and quantified in plasma samples of GIST patients. Methods: We prospectively collected 291 plasma samples from 38 subjects with GIST harbouring activating mutations of CKIT or PDGFRA detected in tumor tissue, irrespective of current disease status or treatment. We used allele-specific Ligation PCR to detect mutant free circulating (fc)DNA. Results: We were able to detect fcDNA harbouring the tumor mutation in 15 out of 38 patients. Patients with active disease displayed significantly higher amounts of mutant fcDNA compared to patients in CR. The amount of mutant fcDNA correlated with disease course. We observed repeated positive test results or an increase of mutant fcDNA in five patients with progressive disease or relapse. A decline of tumor fcDNA or conversion from positive to negative was seen in five patients responding to treatment. A negative to positive conversion was seen in two patients with relapse and one patient with progression. In two cases, we aimed to identify additional mutations, and found four additional exchanges, including mutations not known from sequentially performed tumor biopsies. Conclusions: Our results indicate that free circulating DNA harbouring tumor specific mutations in the plasma of patients with GIST can be used as tumor-specific biomarker. The detection of resistance mutations in plasma samples might allow earlier treatment changes and obviates the need for repeated tumor biopsies. Clinical trial information: NCT01462994.
Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified liposarcoma.
Authors: Dickson Mark Andrew , Tap William D. , Keohan Mary Louise , D'Angelo Sandra P. , Gounder Mrinal M. , Chi Ping , Antonescu Cristina R. , Landa Jonathan , Qin Li-Xuan , Rathbone Dustin D. , Ustoyev Yelena , Crago Aimee Marie , Singer Samuel , Schwartz Gary K. , Condy Mercedes M.
Published: March 2020

10512

Background: Approximately 90% of well-differentiated / de-differentiated liposarcomas (WD/DDLS) have CDK4 amplification. The selective CDK4/CDK6 inhibitor PD0332991 inhibits growth and induces senescence in liposarcoma cell lines and xenografts. Our prior phase II study demonstrated that treatment with PD0332991 (200mg daily x 14d every 21d) results in clinical benefit in WD/DDLS but moderate hematologic toxicity (48% Grade 3/4 neutropenia; dose reduction in 24%). Aiming to reduce toxicity, we conducted a phase II study to assess progression-free survival (PFS) and toxicity with PD0332991 at a new dose and schedule, 125mg daily x 21d every 28d. Methods: Participants were patients with advanced WD/DDLS. Eligibility criteria were age ≥ 18 years, measurable WD/DDLS (RECIST 1.1), documented progression on at least one systemic therapy directly before enrollment, CDK4 amplification by fluorescence in situ hybridization and retinoblastoma protein expression by immunohistochemistry (≥1+). Pts received oral PD0332991 at 125mg daily for 21 days in 28-day cycles. The primary endpoint was PFS at 12 weeks. Based on historical data, a promising result was defined as a 12-week PFS of ≥40% and not promising as ≤20%. The sample size was up to 28 evaluable patients. If 9 patients were progression free at 12 weeks, then PD0332991 would be considered to have activity in WD/DDLS. Results: 29 pts were enrolled and 25 were evaluable for the primary endpoint. Median age was 62 (range 42-85); 55% were male; median ECOG score was 0 (range 0-1). PFS at 12 weeks was 56% (14/25 patients; 90% CI 41-100%), and thus the study significantly exceeded its primary endpoint. Median PFS was 23.6 weeks (95% CI: 11.6 to Not Reached). There was 1 confirmed partial response lasting > 1 year. Grade 3 and 4 adverse events included anemia (grade 3, 21%), thrombocytopenia (grade 3, 7%; grade 4, 3%), and neutropenia (grade 3, 34%). Dose reduction was required in only 1 patient. Conclusions: In patients with WD/DDLS with CDK4 amplification, PD0332991 treatment was associated with a favorable PFS and objective tumor response. This dose and schedule appears active and may have less toxicity than 200mg x 14d. The 125mg x 21d schedule warrants evaluation in a phase 3 study. Clinical trial information: NCT01209598.
Potentially actionable kinase fusions in inflammatory myofibroblastic tumors.
Authors: Lovly Christine Marie , Lipson Doron , Otto Geoff , Brennan Tina , Sankar Sabita , Stephens Philip J. , Miller Vincent A. , Coffin Cheryl M.
Published: March 2020

10513

Background: Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal neoplasm that harbors anaplastic lymphoma kinase (ALK) gene rearrangements in approximately 50% of cases. ALK inhibitors have been validated as an effective therapeutic approach in this subset of IMTs. The goal of this study was to characterize a series of IMTs using both immunohistochemistry (IHC) and next generation sequencing (NGS). Methods: 30 formalin-fixed, paraffin-embedded IMT specimens from 28 patients were evaluated by IHC for ALK expression using standard techniques. DNA was extracted and sequenced using a targeted capture-based NGS assay for 3769 exons of 236 cancer-related genes and 47 introns of 19 commonly rearranged genes, including 8 tyrosine kinases in a CLIA laboratory (Foundation Medicine). Selected specimens were also evaluated for ALK fusions by fluorescence in-situ hybridization (FISH). Results: 20 samples were ALK positive and 10 samples were ALK negative by IHC. Targeted NGS was successfully performed in 16/20 ALK positive and 10/10 ALK negative cases. Among the 16 ALK positive cases analyzed by NGS, 12 harbored ALK fusions with various 5’ gene fusion partners, including LMNA, TPM3, TPM4, SEC31A, TFG, RANBP2, and CLTC. The remaining 4 were also negative by FISH suggesting a different mechanism of ALK overexpression. Among the 10 ALK negative cases, 2 harbored ALK fusions (EML4-ALK, TPM3-ALK). In the other 8 ALK negative samples, 2 contained distinct ROS1 fusions (YWHAE-ROS1, TFG-ROS1) and 1 contained a PDGFRβ fusion (NAB2-PDGFRβ), none of which have been described in IMT samples to date. Overall, kinase gene fusions were identified in 18/26 (69%) evaluable samples. Conclusions: This study represents the most comprehensive NGS analysis of IMTs. 12/12(100%) ALK IHC and FISH positive cases contained ALK fusions, while 5/8 (63%) of distinct ALK IHC negative cases harbored kinase fusions, involving ALK, ROS1, or PDGFRβ. Since these fusions are all targetable with existing kinase inhibitors (i.e. crizotinib, dasatinib), this study suggests that IMTs should be routinely profiled for kinase fusions and not just by ALK IHC. Efforts are ongoing to identify “driver mutations” in the fusion-negative specimens.
Results of the randomized phase III trial of trabectedin (T) versus doxorubicin-based chemotherapy (DXCT) as first-line therapy in patients (pts) with translocation-related sarcoma (TRS).
Authors: Hendifar Andrew Eugene , Chawla Sant P. , Leahy Michael Gordon , Italiano Antoine , Patel Shreyaskumar , Santoro Armando , Staddon Arthur P. , Penel Nicolas , Piperno-Neumann Sophie , Demetri George D. , Hayward Larry , White Jeff , Gouw Launce G. , De Miguel Bernardo , Lardelli Pilar , Soto Arturo , Nieto Antonio , Blay Jean-Yves
Published: March 2020

10517

Background: T is the first of a new class of anticancer agents with a transcription-targeted mechanism of action. In vitro,T interferes with the aberrant transcription factors binding to DNA promoters in TRS. Methods: Pts with advanced TRS of the subtypes: myxoid liposarcoma (ML), alveolar soft part sarcoma, angiomatoid fibrous histiocytoma, clear cell sarcoma, desmoplastic small round cell tumor, low grade endometrial stromal sarcoma, low grade fibromyxoid sarcoma, myxoid chondrosarcoma and synovial sarcoma, stratified by performance status (0 vs 1-2) and subtype (ML vs other TRS) were randomized (1:1 ratio) to T (1.5 mg/m2 in 24h iv infusion q3wk) or doxorubicin, either single agent 75 mg/m2 q3wk, or 60 mg/m2 combined with ifosfamide (6-9 g/m2 q3wk) as 1st line treatment. Primary endpoint: efficacy of T vs DXCT by comparing progression-free survival (PFS). Secondary: PFS at 6 months (PFS6), response rate (RR), PFS/RR by subtype (ML vs other TRS); overall survival (OS), safety. Results: 121 pts enrolled from 22 centers, 88 were confirmed by central pathology review and evaluable for the primary efficacy endpoint by independent review assessment (IR), and all 121 pts randomized were evaluable by investigators’ assessment (IA). The main limitation of the study analyses in both arms was high censoring rate (70% IR; 61% IA) mostly due to surgery (~30%) or chemotherapy/ radiotherapy (~30%). PFS results are shown in the Table. PFS6 was not different between arms (IR: 66.4% vs 80.8% p=0.18/IA: 60.7% vs 62.4% p=0.88). Current median OS:not reached (NR) for T (24.1-NR) and 21.7 mo. for DXCT (21.2-NR).Safety: Most frequent AEs in both arms were nausea (70% vs 65%), vomiting (44% vs 26%) and fatigue (64% vs 63%). ALT increase G4 occurred in 10% pts treated with T and neutropenia G4 in 25% of pts in the T arm vs 52% in the DXCT arm. Conclusions: Although with a high censoring rate, this prospective study suggests thatPFS/OS with trabectedin are not significantly different from DXCT in first-line treatment. Clinical trial information: NCT00796120. [Table: see text]
A model for multi-institutional, multidisciplinary sarcoma videoconferencing.
Authors: Attia Steven , Maki Robert G. , Trent Jonathan C. , Okuno Scott H. , Indelicato Daniel J. , Webber Nicolas P , Curtis Kelly Kevelin , Kozak Kevin Robert
Published: March 2020

10521

Background: Sarcomas are rare cancers, with > 50 subtypes, and require multi-disciplinary care. Their management benefits from multi-institutional input due to the paucity of concentrated experience with each subtype. However, sarcoma tumor boards, wherein a patient-specific, consensus treatment approach is determined, are predominantly conducted in isolation at individual centers. Methods: Since March 2010, we have conducted a weekly multi-institutional, multi-disciplinary sarcoma tumor board to combine knowledge and experience in the management of our most challenging patients. The Mayo Clinic bridge links sites by interactive videofeed. Each site may contribute cases. De-identified history, radiology and pathology are reviewed. A didactic series reviews a rotation of seminal papers, newly published research, or our own data. An “Expert Guest" series allows outside experts to connect to one conference. A yearly participant survey assesses quality. Conference is free to sites and is CME accredited. Results: Currently, 8 sarcoma programs connect Mondays from 8-9am ET. Median attendance is 20 (range: 8-27). In 2012, 342 cases were reviewed over 43 conferences (median: 8 cases/conference; range: 4-12 cases/conference). The 2012 survey revealed 96% (25/26) agreed HIPAA rules are followed; 93% (25/27) agreed conference is educational; 93% (25/27) agreed recommendations are evidenced-based or reasonable; 100% (27/27) agreed participants are respectful; and 86% (18/21) agreed input from other sites has changed their management. Staff attendance (quantity) rated as meets/exceeds needs was 100% (25/25) for medical oncology; 96% (26/27) for pathology; 93% (25/27) for orthopedic oncology; 92% (23/25) for radiation oncology, surgical oncology and radiology; and 61% (17/23) for thoracic oncology. Conclusions: To our knowledge, this is the only weekly multi-institutional sarcoma tumor board in existence. It permits consistent oncology care across a wide geographic area, and is a model for providing consensus recommendations regardless of the remoteness of the patient and care team. Future plans for this group include prospective collection of outcomes data.
Phase II trial of ifosfamide in combination with sorafenib in patients with advanced soft tissue sarcoma: A Spanish Group for Research on Sarcomas (GEIS) study.
Authors: Garcia del Muro Xavier , Maurel Joan , Martinez Trufero Javier , Lavernia Javier , Lopez-Pousa Antonio , De Las Penas Ramon , Cubedo Ricardo , Fra Joaquin , Casado Antonio , De Juan Ana , Jimenez Colomo Laura , Martin Broto Javier
Published: March 2020

10523

Background: Recent studies suggest that VEGFR inhibition could play a role in the treatment of soft tissue sarcoma (STS). Prior studies by our group showed that the combination of ifosfamide with sorafenib resulted in preclinical additive activity and that was feasible and safe in the phase I trial. Methods: Patients (pts) with advanced STS, previously treated with doxorubicin, no prior ifosfamide, ECOG PS 0-2, and adequate hematological, renal and hepatic function, were enrolled in this multicenter phase II study, receiving sorafenib 400 mg bid po continuously and ifosfamide 2 g/m2 iv for 3 days together with mesna 400 mg/m2 every 3 weeks. The primary endpoint was progression-free rate (PFR) at 3 months. A one-sample binomial design was used (PFR P0=40%, P1=60%, α=0.10, β=0.20), requiring at least 19 of 35 pts free of progression at 3 months to be considered positive. Results: From September 09 to March 12, 35 pts were enrolled at 11 centers. Median age was 55 (18-73). PS: 0-13, 1-18; 2-4 pts. Histologic types were: LMS 12, Lipo 6, SS 5, MPNST 2, other 10 pts. . The median number of cycles administered per patient was 4. PFR at 3 months was 67%, with 23 pts being free of progression at 3 months. Median progression-free survival was 4.8 months (95% CI, 1.9-6.3) and median overall survival was 16.2 months. PR was achieved in 17% pts. Most common grade 3-4 toxicities were asthenia (25%), hand-foot syndrome (11%) and neutropenia (20%) resulting in 3 episodes of neutropenic fever. Other common toxicities (G1-4) included emesis (34%), rash (22%), diarrhea (34%), hypertension (11%) and mucositis (9%). Conclusions: The combination of ifosfamide and sorafenib is active and has acceptable toxicity in pts with doxorubicin pretreated STS. The PFR at 3 months might exceed the expected with ifosfamide alone warranting further investigation. Clinical trial information: EudraCT: 2007-002176-34.
Neo/adjuvant doxorubicin (A) and ifosfamide (I) versus gemcitabine (G) and docetaxel (T) in patients (PTS) with localized, high risk soft tissue sarcoma (STS): A randomized phase II comparative effectiveness trial.
Authors: Davis Elizabeth J. , Chugh Rashmi , Zhao Lili , Biermann J. Sybil , Wong Sandra L. , Feng Mary Uan-Sian , Lucas David Robert , Featherstone D'Andra , Reinke Denise , Zalupski Mark M. , Schuetze Scott
Published: March 2020

10524

Background: Approximately 50% of pts with localized, >5 cm, high grade STS develop metastatic disease. Although controversial, adjuvant chemotherapy has demonstrated improved disease-free (DFS) and overall survival (OS). AI can cause significant toxicities that often lead to hospitalization. GT is active in metastatic STS pts and as compared to AI has a favorable schedule and toxicity profile. Methods: In a single-institution phase II study, pts with localized, resectable, high grade STS >5 cm were randomized to receive AI or GT. Pts were stratified by neo- or adjuvant treatment and extremity or non-extremity tumor. Pts received A (75 mg/m2 over 48 hrs) and I (2.5 g/m2/d on D1-3) or G (900 mg/m2 over 90 min on D1,8) and T (100 mg/m2 on D8), both arms with GCSF, for 4 cycles unless progression. Radiation was given after chemotherapy. The primary endpoint of the trial was hospitalization rate during chemotherapy and was compared using a chi square test and multiple logistic regression adjusting for other variables. The trial was powered to detect a reduction in hospitalization rate from 35% to 10% using GT. Survival functions were estimated using Kaplan-Meier method. Results: 84 pts were enrolled from 11/04-8/12 with 80 pts evaluable. The median age is 56 yrs (19-76) and tumor size is 7.8 cm (3.2-25). 55 pts received neoadjuvant therapy and 48 had extremity STS. In the AI arm, 13/37 (35%) pts were hospitalized vs. 11/43 (26%) in the GT arm (p=0.25). The most frequent reason for hospitalization in AI arm was febrile neutropenia (7 events) and in GT arm was hypersensitivity reaction (4 events). The median DFS of pts treated with AI vs GT is 24 months vs not reached, respectively; median follow up is 30 (1-87) months. The 2-year DFS rate is 53% (SD 9%) in the AI arm vs. 71% (SD 7%) in the GT arm and remains marginally significant after adjusting for age, gender, neoadjuvant therapy, tumor site and size (p=0.054). OS rates are not significantly different between arms. Conclusions: Hospitalization rate was not significantly lower with GT compared to AI, although toxicity profile was different. DFS but not OS is marginally improved with GT. Clinical trial information: NCT00189137.
Wnt antagonists in osteosarcoma patients.
Authors: Bravo Dalibel , Shogren Kristen L. , Riester Scott M. , Wagner Eric R. , Herrick James L. , Okuno Scott H. , Yaszemski Michael J. , Maran Avudaiappan
Published: March 2020

10531

Background: Osteosarcoma (OS) is a clinically challenging primary malignant bone tumor that has a high rateof local recurrence and metastasis. Disease free survival has been reported to be as low as 19% despite contemporary chemotherapy regimens and surgery. Wnt signaling is known to play a role in osteogenesis and cancer pathogenesis, therefore is a promising target for therapeutic intervention in OS. Secreted Frizzled Related Proteins (sFRPs), Dickkopf-1 (DKK1), and Sclerostin (SOST) are secreted Wnt inhibitor proteins that regulate Wnt signaling in bone. This study investigates the activity of sFRP3, DKK1, and SOST in serum from OS patients with the goal of developing therapeutic Wnt inhibitors and clinically useful biomarkers. Methods: Enzyme linked immunosorbent assayswere used to quantify sFRP3, DKK1 and SOST levels in human serum (n=40 pairs; 20 OS patients, 20 aged matched non-diseased controls). Patients were stratified into 2 age groups: >35 (n=26 pairs) and <30 (n=14 pairs) years of age. Clinical data from the medical records was correlated with experimental results. Using a Wilcoxon signed rank test, a p–value <0.05 was significant. Results: sFRP3 levels were significantly decreased in 55% (22/40) of diseased samples compared to 20% (8/40) of the non-diseased controls (p= 0.007). DKK1 levels were elevated in 40% (16/40) of OS samples compared to 30% (12/40) of the non-diseased controls (p= 0.08). SOST levels were increased in 42.5% (17/40) of diseased samples compared to 32.5% (13/40) of the non-diseased controls (p= 0.38). When stratified by age, the younger patients showed a statistically significant decrease in sFRP3 expression (p<0.001). Serum levels of sFRP3, DKK1, and SOST were not statistically significant between metastatic and non-metastatic OS. Conclusions: Serum sFRP3 levels were significantly decreased in OS patients, a difference that was even more pronounced in the pediatric strata. Since sFRP3 is differentially expressed in patient serum it has potential as a clinical biomarker for initial tumor diagnosis and early detection of recurrence. Decreased sFRP3 expression may be responsible for the up regulation of Wnt signaling in OS. Wnt inhibitors such as sFRP3 have potential as therapeutic agents in OS warranting further investigation.