bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prospective observational trial of re-antiestrogen therapy after becoming resistant to ethinylestradiol treatment in hormone-dependent metastatic breast cancer.
Authors: Iwase Hirotaka , Yamamoto Yutaka , Ibusuki Mutsuko , Murakami Kei-ichi , Inao Touko , Okumura Yasuhiro , Omoto Yoko 
Published: February 2017

161 Background: After heavily treated estrogen deprivation therapy by aromatase inhibitors (AIs), an additional estrogen therapy may be useful in a certain condition. Furthermore, the estrogen therapy might sensitize a subsequent anti-estrogen therapy after the acquired resistance to estrogen. Methods: In the patients who obtained disease control (SD or more) by ethinylestradiol (EE2) therapy (1.5-3mg TID), the efficacy of anti-estrogen therapy using AI or fulvestrant was examined as a subsequent endocrine therapy. Primary endpoint was clinical benefit rate (CBR), and secondary endpoints were response rate (RR) and time to treatment failure (TTF). (Registration; UMIN000002831, prospective observational trial, sub-protocol analysis) Results: EE2 therapy was performed in 22 of postmenopausal breast cancer patients with ER-positive HER2-negative in primary or recurrent tumor, who had heavily pre-treated by endocrine therapies, including chemotherapies. At the median observation period of 13.6 months, RR of 41% (9/22) and CBR of 50% (11/22) were obtained (CR; 0, PR; 9, long SD; 2, SD; 4, PD; 3) and 4 patients withdrew this trial due to adverse events of early endocrine related symptoms and cerebral infarction. Although two patients were still ongoing, the median of duration of disease-control was 46 weeks (range; 23-62+). In thirteen patients who obtained disease control (SD or more) by EE2 therapy, fulvestrant for 6 patients or AI for 7 patients was used as a subsequent therapy. Fifty percent of fulvestrant group (3/6) and 43% of AI group (3/7) showed clinical benefit (PR or long SD). TTF of fulvestrant group was 15 weeks (median; range; 5-55+) and that of AI group was 19 weeks (median; range 5-33+). Furthermore, two patients who were responders to previous AI, got long SD to the subsequent EE2 re-treatment. Conclusions: EE2 therapy after resistance to estrogen deprivation therapy could be very useful, and a subsequent anti-estrogen therapy by AI or fulvestrant could be also effective in a certain condition. Thus, the changes of the endocrine environment by EE2 may induce the sensitization to hormone dependency in acquired hormone-resistant tumors. Clinical trial information: 000002831.
Low-dose metronomic cyclophosphamide/methotrexate (LDCM) and aspirin for patients without pathologic complete response (pCR) after neoadjuvant treatment for stage II-III breast cancer.
Authors: Burdette-Radoux Susan , Holmes Chris E. , Khan Farrah B. , Dittus Kim , Wilson Karen M. , Wood Marie 
Published: February 2017

163 Background: Patients (pts) who fail to achieve pCR after neoadjuvant chemotherapy have a 20% risk of recurrence at two years. Data for effective postsurgical chemotherapy in this population is lacking. LDCM is an all-oral chemotherapy regimen with anti-angiogenic activity and acceptable toxicity in metastatic breast cancer. Aspirin is associated with a lower risk of breast cancer recurrence in retrospective studies and has anti-angiogenic activity. Here we combine LDCM and aspirin for high risk pts with poor response to neoadjuvant chemotherapy. Methods: Pts with stage II-III HER-2 negative breast cancer who had residual invasive cancer after neoadjuvant chemotherapy were eligible. Pts completed surgery and radiotherapy prior to enrolment and began study treatment within 180 days of surgery. Pts received four 28-day cycles of LDCM (cyclophosphamide 50 mg po daily, and methotrexate 2.5 mg po twice daily on days 1 and 2 each week ). Aspirin 325 mg daily was added on cycles 3 and 4. Pts were evaluated for the primary endpoint of toxicity and safety every 28 days. Secondary endpoint was 2 year relapse free survival. Results: 10 of 13 planned pts were evaluable for toxicity as of May 4, 2013. Pathologic stage ranged from T2N0 to T3N3. 70% of tumors were chemoresistant (stable or upstaged at time of surgery). 60% of pts had hormone receptor positive tumors and received concurrent hormonal therapy. Median age was 59 years (range 38-76). All pts completed 4 cycles of study treatment without dose reduction. There were no grade 3 or 4 related toxicities. Worst hematologic toxicity was grade 2 leukopenia. Worst nonhematologic toxicity was grade 2 fatigue; all other related toxicities were grade 1. 9 pts were evaluable for recurrence and one had recurred at a median followup of 16 months (range 10-26). Conclusions: This antiangiogenic regimen is well tolerated in patients at high risk for recurrence after neoadjuvant chemotherapy, resulting in one recurrence at 16 months median followup, and it may be a candidate for future trials in this setting. Subsequent analyses will include longer term followup and biomarkers for angiogenesis. Clinical trial information: NCT01612247.
Safety and feasibility of adjuvant chemotherapy with S-1 and concurrent radiotherapy for Japanese patients with breast cancer after primary systemic chemotherapy.
Authors: Shigekawa Takashi , Osaki Akihiko , Sato Nobuaki , Kanbayashi Chizuko , Sano Hiroshi , Saeki Toshiaki 
Published: February 2017

165 Background: Advanced breast cancer can respond to S-1. Other oral fluoropyrimidine-based regimen, tegafur-uracil (UFT) was proven to be effective as adjuvant chemotherapy in Japanese breast cancer patients. Adjuvant chemotherapy with S-1 was useful in gastric cancer patients and S-1 with concurrent radiotherapy was safe and effective in several kinds of cancer patients. We tested S-1 and concurrent radiotherapy as adjuvant therapy in curatively resected breast cancer patients after standard primary systemic chemotherapy. Methods: Adjuvant chemotherapy with S-1 consisted of eighteen courses (2-week administration and 1-week withdrawal), at 80-120 mg/body per day. In cases judged to require postoperative radiotherapy, it was concurrently initiated on day1 of the study (a fractional daily dose of 1.8 Gy, up to a total dose of 50.4Gy). If estrogen receptor and/or human epidermal growth factor receptor 2 were positive, endocrine therapy and/or trastuzumab were permitted concurrently. Results: Among 45 patients enrolled between September 2007 and September 2009 from 3 institutions, 43 patients were eligible. 32 patients (74.4%) received concurrent radiotherapy. 22 patients (51.2%) completed the scheduled courses of chemotherapy. The most common reason for withdrawal of treatment was the request to discontinue in 8 patients (38.1%) between 6 courses of the beginning due to subjective symptoms, such as anorexia. It was followed by the detection of recurrence in 7 patients (33.3%). Among 36 patients without recurrence, the planned courses of S-1 were administered to 22 patients (61.1%), and the cumulative rates of administration for 365 days were 66.4% (95%CI: 50.8-79.1%). Although grade 3 neutropenia (8.9%), leukopenia (4.4%), and diarrhea (4.4%) were observed, they were manageable, and no grade 4 adverse effects appeared. Conclusions: Except for a relative many withdrawal of treatment due to subjective symptoms in early courses, adjuvant chemotherapy with S-1 and concurrent radiotherapy have an acceptable toxicity profile, and it seems feasible. A phase III trial investigating the usefulness of adjuvant S-1 is now ongoing in Japan.
Inhibition of cardiomyocytes late INa with ranolazine to prevent anthracyclines cardiotoxicity in experimental models in vitro and in vivo.
Authors: Maurea Nicola , Coppola Carmela , Piscopo Giovanna , Cipresso Clemente , Rea Domenica , Tocchetti Carlo G. , De Laurentiis Michelino , Arra Claudio , Iaffaioli Rosario Vincenz 
Published: February 2017

170 Background: Anthracyclines are first line drugs against cancer, but produce a well-known cardiomyopathy through multiple mechanisms, which also include Ca2+ overload due to reduced SERCA2a activity and inappropriate opening of the RyR2, and impaired myocardial energetics. Anthracyclines generate Reactive Oxigen and Nitrogen Species, posing the heart at increased demand for oxygen, thus setting the stage for a metabolic ischemia that also activates late INa, the target of ranolazine (RAN). Here, we aim at assessing whether RAN, diminishing intracellular Ca2+ through its inhibition of late INa, and enhancing myocardial glucose utilization (and/or reverting impairment of glucose utilization caused by chemotherapy) blunts anthracyclines cardiotoxicity. Methods: To assess for cardiotoxicity in vitro, rat H9C2 cardiomyoblasts were pretreated with RAN (0.1-1µM) for 72 hours and then treated with doxorubicin (DOX, 0.1 µM)for additional 24 hours. Cells counts were assessed by Trypan exclusion test. To evaluate cardiac function in vivo, fractional shortening (FS) and ejection fraction (EF) were measured by echocardiography in C57BL6 mice, 2-4 mo old, pretreated with RAN (370mg/kg/day, a dose comparable to the one used in humans) per os for 3 days. RAN was then administered for additional 7 days, alone and together with DOX (2.17mg/kg/day ip), according to our well established protocol. Results: After DOX, only 68% of the cells were viable. RAN alone did not affected cell survival, but blunted DOX toxicity, rescuing % cell survival to 87% (p=.01 vs DOX alone). In our in vivo studies, after 7 days with DOX, FS decreased to 50±2%, p=.002 vs 60±1% (sham), and EF to 81+2%, p=0.0001 vs 91+1% (sham). RAN alone did not change FS (59±2%) nor EF 89+1%. Interestingly, in mice treated with RAN and DOX, the reduction in cardiac function was milder: FS was 57±1%, EF was 89+1%, p=0.01 and 0.0009, vs DOX alone. Conclusions: RAN blunts DOX cardiotoxic effects in 2 different models, in vitro and in vivo. We plan to test RAN as a cardioprotective agent with other antineoplastic cardiotoxic drugs in our experimental models, and to better characterize the cardioprotective mechanisms of RAN in all these settings.
Open-ended concept elicitation with breast cancer (BC) patient advocates to inform patient-reported outcome (PRO) endpoints in neoadjuvant and adjuvant trials of trastuzumab emtansine (T-DM1).
Authors: Campbell Alicyn K. , Guardino Ellie , Caplan Elyse S. , Glazer Jenna , Sabelko Kimberly , Smith Mary Lou , Venticinque Joan , Wohl Hope 
Published: February 2017

172 Background: There is no standard for measuring health-related quality of life (HRQoL) using PROs in (neo)adjuvant BC clinical trials. Further, in (neo)adjuvant treatment (tx), pre-surgical cytotoxic therapy may initially worsen HRQoL. The development of tools to measure PRO endpoints in (neo)adjuvant clinical trials could be improved with a better understanding of the issues that impact HRQoL in this population. Patient (Pt) advocates, many of whom are BC survivors, may provide valuable insight to inform PRO strategy and optimal selection of PRO endpoints in clinical trials. Methods: A workshop with BC pt advocates was conducted to inform T-DM1 BC PRO strategy. It consisted of open-ended concept elicitation to identify symptomatology, tx-related side effects, and common reasons for tx discontinuation during (neo)adjuvant therapy for BC. Results: For younger pts, hot flashes and issues with sexuality and fertility were described as the most concerning issues. For older pts, peripheral neuropathy was described as the most concerning issue. Regardless of age, most pts reportedly struggle with cognitive dysfunction, anxiety, and depression. Chemotherapy-associated side effects considered most distressing to pts of all ages were alopecia, fatigue, diarrhea, neutropenia, peripheral neuropathy, and hand-foot syndrome (HFS). Neutropenia was considered most likely to cause a physician-instigated tx break, and HFS was most likely to precipitate a pt-instigated tx break. Assessing post-operative pain and satisfaction with post-surgical tx outcome (whether breast conserving or mastectomy) were emphasized. Conclusions: Open-ended concept elicitation with pt advocates is a collaborative and informative way to identify the most relevant concepts for further study. Increased collaboration with advocates to support qualitative research may improve the ability of trial results to assist pts in making informed tx decisions. Earlier engagement of pts and advocates can support the development of new PROs that offer more precision and inform PRO instrument selection to adequately quantify tx impact.
dtectDx Breast: A serum biomarker test for breast cancer detection used in conjunction with traditional mammography screening.
Authors: Henderson Meredith C. , Sweeten Keri , Borman Sherri , Corn Christa , Gordon Lindsey , Reese David E. 
Published: February 2017

18 Background: Provista Diagnostics has developed a test that analyzes serum concentrations of 5 protein biomarkers in order to detect breast cancer. The dtectDx Breast test utilizes a proprietary algorithm that has been described previously (Weber et al. 2010). In this study, it was noted that the algorithm performs best in women under age 50. The aim of this study was to evaluate the performance characteristics of dtectDx Breast in women under age 50 in a commercial setting and compare the results with data from the previous clinical study. Methods: The dtectDx Breast test measures the concentrations of IL-8, IL-12, VEGF, CEA, and HGF via ELISA. These data combined with select patient characteristics and Provista’s proprietary algorithm result in a test value that is characterized as normal or elevated. dtectDx Breast test reports issued for women under age 50 were reviewed from a 3-year time period and prescribing physicians were interviewed regarding follow-up care and outcome measures (largely imaging studies, if warranted). Results: Of the 908 patients, 8 samples were rejected based on serum quality. Of the remaining 900 patients, 121 were reported as elevated (12.7%). In 4 cases, these elevated results were confirmed cases of breast cancer. Of these, 2 patients initially showed no screening evidence of cancer, but upon further evaluation (after receipt of dtectDx Breast results) were diagnosed with breast cancer. dtectDx correctly identified DCIS 66% of the time (n=2). Conclusions: These results describe the use of dtectDx Breast in a clinical setting and confirm that the assay behaves similarly to previously published results (Weber et al 2010). While the false-positive rate is higher than predicted (12.7% vs 6.8%), the assay correctly identified 4 of 4 invasive cancers and 2 of 3 DCIS cases. Since two of the invasive cancer cases were originally not detected via standard screening procedures, the assay has demonstrated important clinical utility when used in conjunction with mammography/standard of care. Here we show that, in the commercial patient population, when combined with standard of care, dtectDx Breast improves the detection of breast cancer in women under 50.
Methylation ESR1 as a potential factor of resistence to HER2/neu therapy in patients with breast cancer.
Authors: Martínez-Galán Joaquina , González Rivas Cynthia S. , Ruiz Vozmediano Julia , Portellano Lucia , Delgado Juan Ramón 
Published: February 2017

24 Background: Estrogen receptor (ER)-positive breast cancers are considered prognostically more favorable than ER-negative tumors and are often responsive to anti-estrogen therapy. Whereas tumors overexpressing HER2 are endocrine resistant and they require the blockage of the HER2 pathway in addition to estrogen deprivation. To evaluate epigenetics differences in tumor-related genes to ESR1 and HER2/neu status in primary breast cancer is the objective of this study. Methods: We quantified methylation levels of promoter of ERS1 which are to confer growth adventage to cells in 107 women with breast cancer. Real Time QMS-PCR SYBR green (methylation-specific PCR) was used to analyze the hypermethylation. Tumours were classified as phenotype basal, luminal A, Luminal B, and phenotype HER2+. Results: Presence of methylated ESR1 in serum of breast cancer patients was associated with ER-negative phenotype (p=0.0179). Of the available cases, 60 pts (56%) were Luminal A, 10 pts (9.3%) Luminal B, 13 pts (12%) Basal like, and 9 pts (8.4%) HER2+. We observed that methylated ERS1 was preferably associated with phenotype Basal Like and worse interval progression free and survival global though p > 0.05 and the amplification HER2+ was correlation with significant more frequent methylation gene (p<0.05). Thet hypermethylation of normal ERS1 and 14-3-3σ combined differentiated between breast cancer patients and healthy controls (p = 0.0001) with a sensitivity of 81% (95% CI: 72–88%) and specificity of 88% (95% CI: 78–94%). Conclusions: This study identifies the presence of variations in global levels of methylation promoters genes in healthy controls and breast cancer with different phenotype classes and shows that these differences have clinical significance. These showed that frequent methylation had a strong association with molecular phenotype of breast cancer and perhaps in the future can explain therapy resistance related to RE and HER2/neu status and this may be of significance in the assessment of targeted therapy resistance related to ER and HER2/neu status in breast cancer patients.
Recurrence Score across the age spectrum: Is there an age discrimination?
Authors: Smith Franz Omar , Lee Marie Catherine , Acs Geza , Fulp William J. , Lee Ji-Hyun , Khakpour Naznin , Kiluk John , Laronga Christine 
Published: February 2017

27 Background: Treatment planning for early-stage estrogen receptor (ER) positive, lymph node negative breast cancer was based on prognostic factors with limited predictive power such as age. The Recurrence Score (RS) from the Oncotype DX assay (ODX) provides predictive power transcending age but is rarely applied to the elderly or young patients (pts). We examined our experience with RS along the age continuum. Methods: Retrospective review was conducted of prospectively gathered breast cancer pts having a RS obtained as part of their cancer care. Eligibility for performance of the ODX was based on NCCN guidelines or physician discretion. Comparisons on RS were made by age groups (young: <45yrs; middle: >45yrs -<70yrs: elderly: >70yrs) using general linear regression model and the exact Wilcoxon Rank Sum Test. Results: 677pts had 681 tumors with RS available (89 young, 476 middle and 112 elderly pts). Median RS for the study pts was 17 (range 0-85) and 16, 17, and 15 for the young, middle, and elderly respectively. Median age was 58yrs (range: 27-95); young, middle, and elderly was 42, 58, and 74yrs respectively. Age as a continuous or categorical variable was not predictive of RS (p value = 0.38, 0.58 respectively). No significant differences were seen between age cohorts for histology, mitotic rate, lymphovascular invasion (LVI), grade, nodal status, stage, or strength of ER positivity. Mastectomy rates were higher in the young (57.5%), compared to the middle (42.5%) and elderly (39.6%) (p=0.02). Median invasive tumor size was 1.6, 1.5, and 1.5cm for young, middle, and elderly. Larger tumor size, as a continuous variable, equaled higher RS (p=0.046). Other significant factors predicting higher RS were increased mitosis (p<0.001), LVI (p=0.013), high grade (p<0.001), and weak (<10%) ER positivity (p<0.001). Nodal status, stage, and histology did not affect RS. Conclusions: Age has limited predictive power for treatment planning for breast cancer. Age alone should not preclude recommendations for performance of ODX in estrogen receptor positive lymph node negative early stage breast cancer as the RS distribution across the spectrum of age is well matched.
Integrated analyses of DNA copy number variations and gene expression in inflammatory breast cancer (IBC).
Authors: Xie Mian , He Chao-sheng , Wei Shen-hai 
Published: February 2017

28 Background: Inflammatory breast cancer (IBC) is an aggressive form of BC poorly defined at the molecular level. We aim to perform genome-wide analyses of copy number variation and gene expression to identify genes reproducibly associated with survival in IBC patients. Methods: We performed concurrent genome-wide microarray analyses of copy number variable regions (CNVRs) and gene expression in IBC patients. Fifty-six pairs of breast cancer and normal specimens from IBC patients were analyzed by using Affymetrix SNP 6.0 and Affymetrix U133 plus 2.0 microarrays. To investigate genomic alterations, we used an Affymetrix Genome-Wide Human SNP 6.0 array containing 1.8 million SNP and CNV probes in total. The microarray data were imported into the Partek Genomic Suite to perform CNV analysis. Ingenuity Pathway Analysis was carried out to describe gene-gene interaction networks and canonical pathways. Cox regression model was used to evaluate the association between expression of these CNV-driven genes and survival outcomes. Results: The genomic landscape of frequent copy number variable regions (CNVRs) in at least 35% of samples was revealed. Further statistical analysis for genes located in the CNVRs identified 387 genes differentially expressed between tumor and normal tissues (p < 0.001). We demonstrated the concordance between copy number variations and gene expression changes by elevated Pearson correlation coefficients. Fisher’s exact test identified five canonical pathways that were significantly enriched among the 387 CNV-driven genes. Pathway analysis revealed two major dysregulated functions in IBC: survival regulation via Rac/PAK and PTEN/PI3K/AKT signaling pathway. Further validation using three independent cohorts demonstrated prediction of survival. Conclusions: We identified genes/pathways that may serve as prognostic markers for IBC patients by integrating gene expression profiles and copy number variations.
21-gene Recurrence Score testing and subsequent treatment decisions in patients (pts) with estrogen-receptor-positive (ER+) early-stage breast cancer (ESBC).
Authors: Manders Jennifer B. , Burkhart Joan , Campbell Debra , Devitt James J. , Vacchino Judith , Sing Amy Pratt 
Published: February 2017

30 Background: The utilization of the 21-gene Recurrence Score (Oncotype DX) in community settings is now well established for ER+, node negative (N-) pts with ESBC. The utility of the Recurrence Score result is to guide treatment decisions and spare exposure to chemotherapy (CT) in pts that have little likelihood of benefitting. To better understand physician behavior as it relates to OncotypeDX testing, we examined the characteristics of pts tested versus not tested, the Recurrence Score distribution and treatment patterns in approximately 160 pts with ESBC seen in 2010. In addition, provider utilization and treatment patterns were also assessed. Methods: Using data from 2010, the number of pts who were eligible to undergo OncotypeDX testing was compared to the number of pts who underwent testing. Pts were considered eligible for testing if they had node-negative, ER+, HER2-negative ESBC. We determined the number of pts with a Recurrence Score value in the low (RS <18), intermediate (int; RS 18-30), and high-risk (RS ≥31) groups along with the number of pts who subsequently received chemotherapy in each category. Results: Of the 233 pts identified with ESBC, 158 were eligible for OncotypeDX testing and 107 (67.7%) underwent testing. Fifty-five percent of pts were low, 37% int, and 7.7% high-risk, respectively. Nineteen percent of low, 56% of int, and 100% of high-risk pts received CT. In the 11 pts with a low Recurrence Score result that received CT, the reason cited was pt decision in 4 and young age in 3. Conclusions: Oncotype DX use in the community is well established. Recurrence Score-guided use of CT in the low- and int-risk groups was as expected based on adjuvant chemotherapy guidelines; however, there were still some physicians treating low Recurrence Score pts with CT-mostly based on younger age or larger tumors. Data from 2011 and 2012 will be included in the final presentation allowing greater insight into pt groups less represented in the single year experience.