bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.