bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and safety of continued zoledronic acid every 4 weeks versus every 12 weeks in women with bone metastases from breast cancer: Results of the OPTIMIZE-2 trial.
Authors: Hortobagyi Gabriel N. , Lipton Allan , Chew Helen K. , Gradishar William John , Sauter Nicholas P. , Mohanlal Ramon W. , Zheng Ming , McGrain Beth , Van Poznak Catherine 
Published: February 2017

LBA9500^ Background: Zoledronic acid (ZOL, 4 mg) every (q) 4 wk reduces the risk of skeletal-related events (SREs) in patients (pts) with bone metastases from breast cancer (BC). The OPTIMIZE-2 trial examined whether ZOL q12 wk was non-inferior to ZOL q4 wk in pts who had previously received monthly IV bisphosphonate (BP) therapy for ~1 year or longer. Methods: This was a prospective, randomized, double-blind, multicenter trial in female pts with bone metastases from BC who previously received ≥9 doses of IV BP (ZOL or pamidronate) during the first 10-15 months of therapy. Pts were randomized (1:1) to receive ZOL 4 mg IV q4 wk or q12 wk (placebo between ZOL doses to maintain blind) for 1 year. The primary endpoint was the proportion of pts with ≥1 SRE on study (SRE rate). Primary analysis was non-inferiority (pre-defined margin of 10%) for the difference in SRE rates. Secondary endpoints included time to first SRE, skeletal morbidity rate (SMR), bone pain score, change in bone turnover markers, and safety. Results: 403 pts were randomized to ZOL q4 wk (n = 200) or q12 wk (n = 203). Median age was 59 years, and baseline characteristics were similar between arms. The SRE rate was 22% and 23.2% in the ZOL q4 and q12 wk arms, respectively. The difference in SRE rate between arms was 1.2% (95% CI, –7.5% to 9.8%; P = .724). The upper limit of this 95% CI (9.8%) is less than the predefined margin of 10%, which indicates non-inferiority of ZOL q12 wk vs q4 wk. Times to first on-study SRE (HR, 1.06; 95% CI, 0.70 to 1.60; P = .792) were similar in the ZOL q4 and q12 wk arms, and mean SMRs were also similar (0.46 vs 0.50, respectively; P = .854). Overall, changes from baseline in bone turnover markers, and the incidence of treatment-emergent adverse events (TEAEs), were similar in the 2 arms. Numerically more renal TEAEs were reported in the ZOL q4 wk vs q12 wk arm (9.6% vs 7.9%, respectively). Two cases (1.0%) of osteonecrosis of the jaw (ONJ) were reported in the q4 wk arm. Conclusions: Among pts who had received monthly IV BP therapy for 1 year or longer, the efficacy of continuing ZOL for an additional year at q12 wk was non-inferior to ZOL q4 wk. Fewer renal AEs and none of the ONJ events were observed in the ZOL q12 wk vs ZOL q4 wk arm. Clinical trial information: NCT00320710.
Increased detection of sentinel nodes in breast cancer patients with the use of superparamagnetic iron oxide tracer.
Authors: Rubio Isabel T , Diaz-Botero Sebastian , Esgueva Antonio J , Espinosa-Bravo Martin 
Published: February 2017

100 Background: The use of superparamagnetic iron oxide (SPIO) tracer for sentinel node biopsy (SLN) has shown non inferiority compared with the radioisotope technique in early breast cancer. False negative rates of SLN biopsy after neoadjuvant treatment (NAC) have decreased with dual tracer (radioisotope/dye) and with the excision of > 2 SLNs. This study was designed to evaluate the outcome of SLN after NAC using a dual tracer (SPIO-Tc99) and to compare it with the SLN by same dual tracer in the adjuvant setting. Methods: Between July 2013 and March 2014, 30 patients with invasive breast cancer (IBC) and SLN biopsy after NAC (NAC- SLN), and 118 patients with IBC not treated with NAC (adjuvant SLN), whose SLN was traced by Tc99 and SPIO were included in the study. Patients were injected subareolar with Tc99 the day before surgery and with the SPIO intraoperatively. SLN was excised if it was radioactive, magnetic or palpable. Patients signed an inform consent. Results: Detection rate by Tc 99 was successful in 113 (95.7%) patients and by SPIO in 116 (98.3%) in the adjuvant SLN (P= 0.0833) while in the NAC-SLN group detection rate by Tc-99 was successful in 28 patients (93.3%) and by SPIO in 30 patients (100%) (P =0.1573). Concordance rates per patient in the adjuvant SLN between techniques was 98.2%, while in the NAC-SLN was 100%. (p = 0.4762) Mean number of SLNs excised by 99Tc and SPIO were 1.9 and 2.21 respectively in the adjuvant SLN, (p=0.001) while 1.533 and 2.60 respectively in the NAC-SLN group. (p=0.0016) In the adjuvant SLN, the SLN was positive in 36 patients (30%), and in the NAC-SLN in 9 patients (30%). In the adjuvant SLN, both techniques detected same number of positive nodes but in the NAC-SLN, 9 patients had a positive SLN by SPIO (> 2 SLNs by SPIO and 1 SLN by Tc99) and 7 patients had a positive SLN by Tc99. Conclusions: Detection of SLNs with SPIO allows for easy identification of axillary nodes and can be used to reliably identify SLNs in breast cancer. Even though the small sample size in the NAC-SLN, the higher number of SLNs excised by the SPIO may optimize the success of SLN after NAC.
Long-term outcome results of the phase III PROMISE-GIM6 study evaluating the role of LHRH analog (LHRHa) during chemotherapy (CT) as a strategy to reduce ovarian failure in early breast cancer (BC) patients.
Authors: Lambertini Matteo , Boni Luca , Michelotti Andrea , Gamucci Teresa , Olmeo Nina , Gori Stefania , Giordano Monica , Garrone Ornella , Levaggi Alessia , Poggio Francesca , Giraudi Sara , Bighin Claudia , Pronzato Paolo , Del Mastro Lucia 
Published: February 2017

105 Background: The PROMISE-GIM6 phase III randomized study showed that the use of triptorelin-induced temporary ovarian suppression during CT in premenopausal patients with early-stage BC reduced the occurrence of CT-induced early menopause (Del Mastro L, JAMA 2011). The 2013 ASCO and ESMO guidelines on fertility preservation in cancer patients consider this strategy still experimental due to the absence of data on long-term ovarian function and pregnancy rates, and some concerns exist on the safety of this procedure particularly for hormone-receptor positive BC patients. The present analysis reports long-term outcome results of the study. Methods: From October 2003 to January 2008, 281 premenopausal women with stage I through III BC who were candidates for adjuvant or neoadjuvant CT were randomized to receive CT alone or combined with triptorelin. The primary objective was to compare the incidence of CT-induced early menopause in patients treated with CT alone or combined with triptorelin. The present analysis considers data on recurrences, pregnancies and long-term ovarian function. Results: A total of 133 pts were enrolled in the CT alone arm and 148 in the CT + LHRHa arm; 82% and 79% of pts had hormone receptor positive-disease, respectively. The median follow-up at the time of the analysis was 7.3 years (interquartile range: 6.3-8.2 years). No differences in the 5-year disease-free survival (DFS) between treatment arms were observed (83.7% in CT alone arm vs 80.5% in CT plus LHRHa: HR=1.17; 95% CI 0.72-1.92, p=0.519). After the end of adjuvant treatments, 4 pregnancies (3.0%; incidence rate per 100 person-year=0.4) occurred in the CT-alone group and 8 pregnancies (5.4%; incidence rate per 100 person-year=0.8) occurred in the CT plus triptorelin group (CT + LHRHa arm vs CT alone: OR=1.84; 95% CI 0.54-6.27, p=0.39). Conclusions: The administration of LHRHa with CT was associated with the occurrence of more pregnancies; no differences in DFS were observed. The analysis on long-term ovarian function is still ongoing and will be presented at the meeting. Clinical trial information: NCT00311636.
Outcome of BRCA 1/2-mutated (BRCA+) and triple-negative, BRCA wild type (BRCA-wt) breast cancer patients in a phase I study of single-agent veliparib (V).
Authors: Pahuja Shalu , Beumer Jan Hendrik , Appleman Leonard Joseph , Tawbi Hussein Abdul-Hassan , Stoller Ronald G. , Lee James J. , Lin Yan , Kiesel Brian , Yu Jing , Tan Antoinette R. , Belani Chandra Prakash , Chew Helen K. , Garcia Agustin A. , Morgan Robert , Chen Alice P. , Giranda Vincent L. , Shepherd Stacie Peacock , Chu Edward , Puhalla Shannon 
Published: February 2017

135 Background: Veliparib (V) (ABT-888) is an oral, potent inhibitor of PARP 1/2. PARP inhibitors have preclinical and clinical efficacy in BRCA+ malignancies. There are genotypic and phenotypic similarities between BRCA+ cancers, serous ovarian cancer and basal-like breast cancer and we postulated that these tumors types may be similarly sensitive to single-agent PARP inhibition. This study sought to establish the maximum tolerated dose (MTD), dose -limiting toxicities (DLT), pharmacokinetic and pharmocodynamic properties, and preliminary efficacy of chronically-dosed V in 2 cohorts of patients, BRCA+ and BRCA-wt (consisting of serous ovarian cancer and triple-negative breast cancer (TNBC). Methods: A 3+3 dose escalation phase I trial was performed. Nine dose levels (DL) were planned, and dose escalation started at 50 mg BID to a maximum of 500 mg BID to determine a maximum tolerated dose (MTD) and recommended phase II dose (RP2D). V was administered orally continuously on a 28 day cycle. BRCA+ and BRCA-wt patients were enrolled in 2 separate cohorts with 2 separate escalations. Results: 98 (70 BRCA+ and 28 BRCA-wt) pts have been enrolled. The maximum administered dose (MAD) was 500mg BID and the MTD/RP2D is 400mg BID for both cohorts. 59 BRCA+ pts and 24 BRCA-wt pts (21 TNBC and 3 ovary) were evaluable for response. ORR was defined as CR+PR and clinical benefit rate (CBR) as CR+PR+SD > 6 months. Results are summarized in the table. Conclusions: There is evidence of anti-tumor activity with V comparable to that of other PARP inhibitors in the BRCA+ population. There was indication of dose responsiveness with greater activity in this population at higher doses. There is less activity in the mostly TNBC, BRCA-wt population, although there was evidence of benefit in a small number of patients. Ongoing tissue correlative studies will help to identify potential mechanisms of sensitivity and resistance. Clinical trial information: NCT00892736. [Table: see text]
Tumor infiltrating lymphocytes (TIL) to predict response to neoadjuvant chemotherapy in breast cancer: A systemic review and meta-analysis.
Authors: Mao Yan , Qu Qing , Zhang Yuzi , Liu Junjun , Shen Kunwei 
Published: February 2017

138 Background: Whether tumor-infiltrating lymphocytes (TILs) predict response to neoadjuvant chemotherapy (NAC) remains elusive. Methods: A systematic review and meta-analysis was undertook to establish the relationship between TIL and pathological complete response (pCR) rate in NAC of breast cancer. A PubMed and Web of Science literature search was designed. Studies were included, in which the predictive significance of intratumoral and/or stromal TIL, and/or CD3+, CD4+, CD8+, and FOXP3+ lymphocytes were determined . Pooled ORs and publication bias was evaluated by STATA software. Results: A total of 13 published studies (including 3,555 patients) were eligible. In pooled analysis, higher number of TIL in pre-treatment biopsy was correlated with higher pCR rate of neoadjuvant chemotherapy, and odds ratio (OR) was 3.82 (95% confidence interval (CI), 3.10-4.70), no matter tested in intratumor (OR=3.32, 95% CI: 2.52-4.37), in stroma (OR=4.15,95% CI: 2.94-5.86), or in combined sites (OR=8.98, 95% CI: 3.79,21.30). Moreover, TIL predicts higher pCR rate in triple negative (OR=5.03,95% CI: 2.31-10.97) and HER2+ (OR=5.54,95% CI: 1.39-22.12) patients, but not in hormonal receptor (HR) +/HER2- patients (OR=2.57, 95% CI: 0.20-33.24). For TIL subsets, CD8+ T-lymphocytes predict better pathological response to NAC no matter in pre- (OR=3.36,95%CI: 1.15-9.85) or post-NAC (OR=4.71,95%CI: 1.29-17.27) tissue, while FOXP3+ T-lymphocytes have similar predictive roles only when tested after NAC (OR=4.26, 95%CI: 1.83-9.92).With limited study, the predictive role of CD3+ and CD4+T-lymphoctes were unclear, more perspective studies were needed in future to establish the relationship. Conclusions: High level of TIL in pre-treatment biopsy could be a good marker indicates better pathological response to NAC in triple-negative and HER2+ breast cancer patients. Different subsets have different predictive roles in the pCR rate to NAC. However, significant heterogeneity and an insufficient number of studies underscore the need for further prospective studies on subsets of T lymphocytes and different subtypes of breast cancer to increase the robustness of the analyses.
Everolimus plus exemestane in patients with advanced invasive lobular carcinoma: Efficacy and safety results from BOLERO-2.
Authors: Hortobagyi Gabriel N. , Noguchi Shinzaburo , Neven Patrick , Puttawibul Puttisak , Heng Daniel , Brechenmacher Thomas , Ringeisen Francois Philippe , Saletan Stephen , Bachelot Thomas Denis 
Published: February 2017

152 Background: In BOLERO-2 (NCT00863655), everolimus plus exemestane (EVE + EXE) more than doubled median progression-free survival (PFS) vs placebo (PBO) + EXE (by local assessment: 7.8 vs 3.2 mo; hazard ratio [HR], 0.45; P < 0.0001; by central assessment: 11.0 vs 4.1 mo; HR, 0.38; P < 0.0001) in patients (pts) with hormone-receptor–positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC). This exploratory analysis assessed the efficacy and safety of EVE + EXE in a subset of pts with baseline invasive lobular carcinoma (ILC) (elderly pts with predominantly peritoneal, gastrointestinal, and ovarian metastases [mets]). Methods: Pts with HR+, HER2– ABC recurring or progressing on/after prior nonsteroidal aromatase inhibitor therapy were randomized 2:1 to receive EVE 10 mg/day + EXE 25 mg/day or PBO + EXE. Primary efficacy end point was PFS (by local assessment). Results: Of 724 pts, 77% (n = 556) had ductal carcinoma and 14% (n = 104; EVE + EXE, n = 64; PBO + EXE, n = 40) had ILC. In ILC subset, median age was 63 years, 47.1% had measurable disease, and majority of baseline characteristics were similar to overall study population with exception of main mets sites. In pts with ILC, 36% reported visceral mets (lung, liver, pleural, pleural effusions, peritoneum, and ascites), 10% lung mets, and 23% liver mets when compared with 59% visceral mets, 31% lung mets, and 33% liver mets in overall study population. Median PFS was higher with EVE + EXE vs PBO + EXE (6.9 vs 4.2 mo; HR, 0.59; 95% CI, 0.37-0.95). Objective response rates were 14.1% (EVE + EXE arm) and 0% (PBO + EXE arm) vs 12.6% and 1.7%, respectively, among overall study population. Clinical benefit rates were 45.3% (EVE + EXE arm) and 30.0% (PBO + EXE arm); 51.3% vs 26.4% in overall study population. The safety profile of EVE + EXE in pts with ILC was similar to overall study population. Most common adverse events (all grades) in EVE-treated pts with ILC were stomatitis (50%), diarrhea (41%), nausea (36%), fatigue (34%), and rash (33%). Conclusions: EVE + EXE prolonged PFS in pts with ILC who had different patterns of mets. Other outcomes were similar to those in overall study population. Clinical trial information: NCT00863655.
Vitamin D levels, triple-negative histology, and geography in breast cancer: A retrospective analysis of a large database of oncology practices in the United States.
Authors: Habib Joyce Georges , Espirito Janet L. , Harrell Robyn K. , Turnwald Brian , O'Shaughnessy Joyce , Epstein Ervin H. , Patt Debra A. 
Published: February 2017

17 Background: The UVB-vitamin D-breast cancer (BC) hypothesis is supported by ecological studies demonstrating an inverse correlation between sunlight exposure and BC incidence and mortality. Observational studies also favor an inverse association between vitamin D status and BC risk, recurrence and mortality. Yet controversies remain regarding the role of vitamin D in BC. We examined associations between vitamin D levels, geographic location, clinical, and pathologic characteristics of BC patients (pts). Methods: This was a retrospective analysis from the electronic health record database of pts diagnosed with BC between 1/2007 and 5/2013 across US Oncology Network practices categorized based on their geographic location into: northern (> 40° N), central (35 to 40°N) and southern (< 35°N) latitude. We collected age at diagnosis, BMI, smoking history, stage, estrogen receptor (ER), progesterone receptor (PR), HER2 status, and the first documented serum 25-hydroxyvitamin D (25-(OH)D) level, categorized as 30 optimal. Statistical comparison was performed using Chi-squared tests for categorical variables and Kruskal-Wallis tests for continuous variables. Logistic regression was used to predict the likelihood of vitamin D deficiency. Results: 20,338 BC pts with a documented vitamin D level were identified. Mean age at diagnosis was 58. Stage and receptor status distribution were: 8%, 41%, 32%, 11% and 4% for stage 0, I, II,III, and IV respectively; 63%, 13%, and 10% for ER+/HER-2-, HER-2+ and TNBC, respectively. 17.6% and 27.8% of pts had deficient or suboptimal vitamin D levels. The covariates of age < 60 years (OR 1.24), advanced stage (OR 1.32 stage II, OR 1.51 stage III, and OR 1.81 stage IV), TNBC (OR 1.45), BMI ≥ 25 (OR 2.02), current smoker (OR 2.11), and lower latitudes (OR 1.36 and 1.19 for central and southern latitude respectively) were independent predictors of a first documented vitamin D deficiency in a multivariate model. Conclusions: Vitamin D deficiency may be associated with TNBC and central and southern latitudes. The possible influences of differential vitamin D supplementation and timing of testing require further investigation.
DNA methylation array analyses to identify HYAL2 methylation in peripheral blood as a marker for the detection of early breast cancer.
Authors: Yang Rongxi , Pfuetze Katrin , Zucknick Manuela , Sutter Christian , Marme Frederik , Schneeweiss Andreas , Schmutzler Rita K. , Bartram Claus , Burwinkel Barbara ,   Methylation Collaboration Group
Published: February 2017

26 Background: Early detection is crucial to improve the survival rate and quality of life of breast cancer (BC) patients. Changes in DNA methylation in peripheral blood could be associated with malignancy at early stage. We aim to identify BC-associated DNA methylation signatures in peripheral blood. Methods: We identified a BC-associated differentially methylated locus by genome-wide investigation using Illumina 27K Methylation Assay. Two validation studies and replications in leucocytes and T cells were carried out using MassARRAY. The RNA expression levels were measured by real-time PCR. Results: The methylation level of CpG site cg27091787 in hyaluronoglucosaminidase 2 gene (HYAL2) in peripheral blood was significantly lower in BC cases than in controls (discovery round, 72 BC case and 24 controls, p = 2.61 × 10-9 adjusted for cell-type proportions; first validation round,338 BC case and 507 controls, p < 0.0001; second validation round,189 BC case and 189 controls, p < 0.0001). Compared to the highest quartile, the lowest quartile of cg27091787 methylation was associated with a more than 40-fold increased risk of BC (p < 0.0001). In addition to cg27091787, the decreased methylation of a 650 bp CpG island shore of HYAL2 was also associated with BC. Moreover, the expression and methylation of HYAL2 in leucocytes were inversely correlated (p = 0.006). To note, the BC-associated decreased HYAL2 methylation was replicated in T cell fraction (p = 0.034). The cg27091787 methylation level enabled a powerful discrimination of early stage BC cases from healthy controls (area under curve (AUC) = 0.88), and was also robust for the detection of BC in younger women (AUC = 0.87). Conclusions: Validating the epigenome-wide study by independent cohorts, we have revealed a strong association between decreased HYAL2 methylation in peripheral blood and BC. Our results have given an answer to the debate on the origin of BC-associated differential methylation in blood, which is not only because of the change of cell type proportions, but more importantly due to altered methylation in specific blood cell fragments, like in T cells. And thus, we provide a promising blood-based marker for the detection of early BC.
A multivariate model to predict cancer upgrade from atypical ductal hyperplasia by core needle biopsy.
Authors: Pena Alvaro , Fazzio Robert T. , Shah Sejal , Hoskin Tanya L. , Brahmbhatt Rushin D , Visscher Daniel W. , Hieken Tina J. , Jakub James W. , Boughey Judy Caroline , Degnim Amy C. 
Published: February 2017

3 Background: Atypical ductal hyperplasia (ADH) is a high-risk breast lesion usually diagnosed with core needle biopsy. Although upgraded to cancer at surgical excision in ~15 to 25% of cases, routine excision is questioned due to cost and overtreatment. We evaluated clinical, imaging, and histologic features associated with cancer upgrade and developed a multivariate model to predict risk of upgrade. Methods: With IRB approval a single institution retrospective review was performed of patients who underwent surgical excision of ADH diagnosed by core biopsy from 06/2005 to 06/2013. Review was performed of electronic records, breast imagin,g and biopsy slides. Multiple imputations were used for missing data. Association of cancer upgrade with various features was assessed with logistic regression. Results: 409 biopsies with ADH on core biopsy, with later surgical excision, were included. The overall upgrade rate was (16.1%, 95% CI:12.9-20.0%); 10 patients had invasive cancer at excision and 56 DCIS only. Features on core biopsy most strongly associated with upgrade were imaging estimated percent of lesion removed (upgrade 9% for 90% removed, 14% for 50 to 75%, and 27% for < 50% removed), individual cell necrosis (upgrade 34% with necrosis vs. 9.5% without), and # foci of ADH (22% for >1 focus vs 8% for 1 focus). A multivariate predictive model (see Table) showed an average C-statistic of 0.77. Women with no necrosis and either 1 focus with ≥ 50% removal or >1 focus with 90% removal (36% of the sample) have low risk of upgrade (5.0%, 95% CI:1.3-8.7%). Conclusions: ADH on core biopsy with low risk of upgrade to cancer is defined by percent of imaging lesion removed, # of foci of ADH, and lack of individual cell necrosis. If findings are validated, women whose biopsies meet low-risk criteria might be considered for chemoprevention and surveillance rather than surgical excision.[Table: see text]