tbuckley/cabot-search huggingface dataset:
Evaluation of the prognostic/predictive value of HER2/TOP2A gene amplification and protein overexpression in patients with high-risk breast cancer treated with dose-dense sequential adjuvant chemotherapy.
Authors: O. Tzaida, C. Valavanis, M. Bobos, A. Batistatou, V. Kotoula, M. A. Dimopoulos, D. G. Pectasides, E. Timotheadou, G. Pentheroudakis, H. Gogas, E. Samantas, C. Christodoulou, P. Arapantoni, G. Fountzilas
Journal: Journal of Clinical Oncology (2011)

e21059 Background: The prognostic/predictive value of HER2 and topoisomerase II alpha (TOP2A) gene status in patients with breast cancer treated with adjuvant dose-dense sequential chemotherapy is not well defined. Anthracyclines and taxanes are considered to be important drugs in this setting. Methods: Formalin-fixed tumor tissue samples were obtained from 354 patients participating in a phase III trial, in which 595 high-risk breast cancer patients were randomized to receive postoperative dose-dense sequential chemotherapy with epirubicin and CMF, with or without paclitaxel. HER2 and TOP2A gene amplification was evaluated by chromogen in situ hybridization (CISH) using ZYMED (InVitrogen) technology in 285 and 266 patients, respectively and protein expression was assessed by immunohistochemistry (IHC) in 297 and 248 patients, respectively. Results: Among the 52 tumors classified HER2-positive by IHC (3+, strong membranous staining in ≥30% of the tumor cells), 50 tumors (96%) were amplified by CISH. As for TOP2A, among the 153 tumors classified positive by IHC (2+ and 3+, moderate and strong nuclear staining in ≥5% of the tumor cells), only 13 (9%) of the tumors were amplified by CISH. 64% of the HER2-positive tumors were also TOP2A-positive when assessed by IHC, while only 21% of the HER2-amplified tumors were also TOP2A-amplified by CISH. Univariate Cox regression analysis did not show any association of HER2 and TOP2A gene amplification or IHC-positivity with OS or DFS, except for an increased risk for progression (HR=1.71, 95% CI: 1.07-2.73, Wald p=0.024) in HER2-positive patients by IHC. No benefit from paclitaxel treatment was detected for HER2 or TOP2A gene amplified or protein overexpressing tumors. Conclusions: HER2 and TOP2A gene amplification or protein overexpression do not appear to be predictive for response to paclitaxel in high-risk breast cancer patients treated with dose-dense sequential adjuvant chemotherapy. Evaluation of mRNA expression and gene amplification of HER2 and TOP2A by RT-PCR and FISH is in progress and the data will be presented at the meeting.
Prevalence of RAS mutations among patients with metastatic colorectal cancer by country and region in randomized clinical trials: A pooled analysis.
Authors: Marc Peeters, George Kafatos, Aliki Taylor, Victor M. Gastanaga, Hua Yu, Kelly Smith Oliner, Gregory A. Maglinte, Jan-Henrik Terwey, Han H. J. M. Krieken
Journal: Journal of Clinical Oncology (2015)

520 Background: Global mCRC treatment guidelines for EGFR inhibitors require prior confirmation of wild-type RAS status (KRAS exons 2, 3, 4 and NRAS 2, 3, 4). The aim of this study was to estimate the prevalence of RAS mutations among mCRC patients by country, demographic characteristics, and clinical risk factors. A secondary aim was to estimate BRAF and KRASexon 2 mutation prevalence. Methods: Data from 5 published Amgen-sponsored randomized clinical trials (RCTs) were merged in a retrospective pooled analysis. There were 3 phase III, 1 phase II, and 1 phase Ib/II studies. For 4 out of 5 RCTs, RAStesting was conducted in a U.S. laboratory (Transgenomic Inc.) using Sanger sequencing on DNA extracted from tumor samples. For the remaining trial, a combination of next-generation sequencing and Sanger sequencing was used. Results: A total of 3,196 patients from 36 countries were included. The overall unadjusted prevalence of RAS mutations among mCRC subjects was 55.9% (95% CI, 53.9%, 57.9%); KRAS exon 2 mutation prevalence was 42.6% (40.7%, 44.5%). The prevalence by exon is given in the table below. BRAFmutation prevalence was 8.1% (6.7%, 9.6%). There were no statistically significant differences in RAS mutation prevalence by gender, age, or clinical factors such as performance status, tumour site, biopsy origin, or metastasis characteristics. Statistically significant differences in RAS mutation prevalence estimates were observed by country and by region with rates for Central West Europe being significantly lower than Eastern Europe (49.4% [44.4%, 54.3%] and 61.5%; [55.3%; 67.4%] respectively). Statistically significant RASmutation prevalence differences were observed between studies which could be due to varying patient characteristics. Conclusions: By merging data from RCTs, the analysis provides robust estimates of RASmutation prevalence. Studies using observational data are needed to confirm these findings. [Table: see text]
Measurements of 5-FU levels in plasma of patients with gastrointestinal cancer.
Authors: Martina Blaschke, Silke Cameron, Jutta Blumberg, Ulrike Wegner, Giuliano Ramadori
Journal: Journal of Clinical Oncology (2012)

437 Background: 5-fluorouracil (5-FU) 50 years after its first introduction into therapy of gastrointestinal tumors is still one of the most effective anticancer drugs. Due to large interindividual metabolism optimal dosing has not yet been established. As 5-FU is mostly used in combination with other drugs elevated serum levels could be responsible for severe side effects. The aim of this study was to analyse intra- and interindividual variability of 5-FU levels in patients with 5-FU infusional therapy. Methods: 230 blood samples were obtained from 31 gastrointestinal cancer patients (esophagus (8), stomach (10), ileum (1), colorectum (12)) treated with 5-FU-infusional regimens, based on a 24 or 48 hour AIO treatment schedule. 5-FU was delivered using a Baxter pump. Intra- and interindividual differences in 5-FU plasma concentrations were analysed before (0h; n=115), at 2-3 hours after start of infusional 5-FU treatment (n=19) (early sampling) and towards the end of the infusion (n=96) (late sampling). 5-FU plasma concentrations were measured using an immunolinked Elisa assay (Saladax 5-FU PCM). Results: Early blood sampling resulted in lower 5-FU plasma concentrations (541±126,9 ng/ml) due to NaCl prefilling (4,5 ml) of the 5-FU tubing, as the Baxter pump delivers 4ml/h. Blood sampling at the later time-point resulted in reliable values (971±81,1 ng/ml). 5-FU concentrations did increase with elevated 5-FU doses. Measurements of 5-FU plasma concentrations lead to reproducible results. 5-FU concentrations were dose-dependent with low intra- and interindividual variability. However, care has to be taken, as the results can be influenced by inaccurate blood sampling (e.g at the port), early blood sampling (steady state-levels not reached), too late sampling (folfusor-pump already empty, i.e. in summer with elevated temperature), delayed centrifugation or hemolysis. Critical analysis of the measurements and correct performance of the sampling is therefore necessary. Conclusions: Measurement of 5-FU plasma concentrations may in the future allow to optimize the 5-FU dosing and to identify the cause of toxicity. Changes of 5-FU clearance in long-term therapy have to be studied.
Different risk factors for mortality in younger and older women after breast-conserving surgery.
Authors: G. G. Kimmick, F. Camacho, W. Hwang, H. B. Mackley, J. H. Stewart, R. T. Anderson
Journal: Journal of Clinical Oncology (2011)

6017 Background: We previously reported that death rates were higher among women who had breast conserving surgery (BCS) but no adjuvant radiation. Here, we investigate factors associated with overall survival after BCS in younger and older women. Methods: Women were included if they had BCS, according to the North Carolina Cancer Registry (1998 to 2002), for localized or regional, nonmetastatic breast cancer. Data were linked to Medicare and Medicaid claims, and National Death Index (NDI). Multivariate analyses, by age <70 and 70 and older, included: age; race; comorbidity; insurance status; tumor size; number of lymph nodes positive; hormone receptor status; receipt of optimal radiation (> 15 treatment sessions); adjuvant chemotherapy; receipt of preventive care - including mammography, Pap smear and primary care visits; and hospitalization. The primary outcome was overall death. Results: We identified 1,719 women (mean 71.3 years, range 29-101), with 615 (36%) over age 70 and older. In multivariate analyses, receipt of optimal radiation predicted overall survival for younger (HR 0.33, 95% CI 0.13-0.84) and older (HR 0.58, 95% CI 0.38-0.89) women. None of the other factors were significant predictors of overall survival in younger women, but in older women, older age (HR 1.07 95% CI 1.03-1.10), higher comorbidity level (HR 1.14, 95% CI 1.04-1.25), larger log tumor size (HR 1.64, 95% CI 1.24-2.18), and fewer primary care visits (HR 0.64, 95% CI 0.43-0.94) were significant. Conclusions: Receipt of suboptimal radiation therapy predicts higher mortality in young and old women managed with BCS in this sample of Medicare and Medicaid-insured women. Attention to primary care in older women may be important in decreasing mortality in older women surviving breast cancer.
Breast cancer (BC) in women ≤30 years of age: Tumour and patient characteristics and outcomes
Authors: A. Haddad, S. Verma, J. Caudrelier, P. Genest
Journal: Journal of Clinical Oncology (2008)

11086 Background: Several authors have noted aggressive tumour characteristics and poor outcomes in women diagnosed with BC under the age of 35. To provide further insight, we have undertaken a comprehensive multi-decade review of the demographics, tumour features and outcomes in very young women at our institution. Methods: Of 238 women ≤ 30 years (yrs) with BC seen at our institution between 1962 -2005, 204 were eligible for this study. Charts were reviewed for risk and genetic factors, presenting symptoms, tumour characteristics and therapy. Where possible, tumour blocks were retrieved for review and estrogen receptor (ER) and HER-2 profiles. Outcomes included recurrence rates, time to recurrence (TTR) and survival (OS). Results: 201 patients (pts) with invasive BC were included in this analysis. Median age was 28 (r: 19–30). Median tumour size was 2.5 cm (r: 0.3–11.1). 10%, 36% and 54% were grade 1, 2 and 3, respectively. 46% had axillary node involvement. Overall stage distribution was: I-31%, II-42%, III-24% and IV-3%. Lympho-vascular invasion was present in 67%. 48% of 124 cases were ER+ and HER-2 over-expression was noted in 26% of 34 cases tested. 24% were ‘triple negative’. 44% of those tested for BRCA mutations (18 cases) were positive. Overall, 50% of stage I-III pts experienced recurrences: 22% local-regional, 47% systemic and 31% had both. TTR and OS for the entire group and for ER + and ER- subsets were analyzed and compared for 3 time periods: 1962–1985, 1986–1995 and 1996–2005. A trend towards improvement was noted over time. Conclusions: This >40-year retrospective study represents one of the largest reviews of very young women with BC. When compared to historical subsets (>35 or >50 yrs of age), very young patients appear to present more frequently with poor prognostic markers. We have observed higher recurrence rates and lower 5-year OS compared to older subsets but an important evolving impact of adjuvant therapy over time. Although a rare group, young women with BC merit further study to optimize outcomes. No significant financial relationships to disclose.
Preliminary results from a phase I study of substance P-saporin in terminal cancer patients with intractable pain.
Authors: Arthur E. Frankel, Hugh Nymeyer, Douglas A. Lappi, Denise Higgins, Chul Ahn, Carl Noe
Journal: Journal of Clinical Oncology (2014)

191 Background: For 10-15% of cancer patients, pain cannot be controlled using existing therapies (Zech et al., Pain, 63, 65-76, 1995). SP-SAP is the first targeted toxin to undergo phase I testing for pain. SP-SAP (Wiley and Lappi, Neurosci Lett, 230, 97-100, 1997) covalently linkes substance P (SP), a neuromodulator that binds to NK1 receptors on laminae I and X of the dorsal horn, and saporin (SAP), a ribosomal toxin that ablates cells that express NK1 and endocytose the toxin. Intrathecal injections of SP-SAP in rats reduce chemically or thermally induced pain, thermal hyperalgesia, and mechanical allodynia, with no signs of motor, sensory, or behavioral dysfunction (Mantyh et al., Science, 278, 275-9, 1997; Nichols et al., Science, 286, 1558-61, 1999; Suzuki et al., Nature Neurosci, 5, 139-26, 2002; Vierck et al., Neurosci, 199, 223-32, 2003). In canines, intrathecal injections into the lumbar region – 45 mcg for 10-15 kg (Allen et al., Toxicol Sci, 91, 286-98, 2006) or 15 mcg for 8-12 kg (Wiese et al., Anesthesiol, 119, 1163-77, 2013) – produce no neurological, behavioral, or histological deficits. A double-blinded RCT of SP-SAP for the treatment of bone pain in canines (Brown and Agnello, Anesthesiol, 199, 1178-85, 2013) showed that a single injection of 60 mcg (above 30 kg) or 40 mcg (below 30 kg) significantly reduced pain as measured by time to owner unblinding (p=0.002) or number of canines unblended (p=0.001). Methods: A single intrathecal injection of SP-SAP is made at the L5-S1 interspace of cancer patients with intractable sub-umbilical pain. Single subject cohorts are at doses of 1, 2, 4, 8, 16, 32, 64, and 90 mcg. Primary outcomes are assessed by pain survey (VAS “bothersome pain”, VAS “pain intensity”, ODI, EQ-5D, and BDI) and medication use log. Patients are monitored for toxicity, neurological and cardiac abnormalities, and SP-SAP antibodies for 6 months. Results: This report presents the results from the first three subjects of the phase I study. No evidence of toxicity or neurological or cardiac abnormalities were found. No clear evidence for pain reduction was observed. Conclusions: At existing doses (&lt; 4 mcg), SP-SAP appears safe for human use. The study is continuing with dose escalation. Clinical trial information: NCT02036281.
Health care providers’ perspective on communication of cancer diagnosis and treatment plan to geriatric patients.
Authors: Himabindu Lanka, William Zirker, Igor Dorokhine
Journal: Journal of Clinical Oncology (2016)

e277 Background: Physician communication with patients is vital to deliver a proper diagnosis. In addition, it is important to appropriately answer questions to improve the quality of care especially with geriatric patients with cancer. However, patients feel their questions are not being answered in a timely manner. Multiple international studies involving oncologists have identified communication barriers such as cultural differences, paternalistic views and family dynamics. Furthermore, barriers to communication in geriatric patients are cognitive impairment and hearing loss. The aim of this study is to assess health care providers’ perspective on communicating cancer diagnosis and treatment plan in geriatric population. Methods: A ten-question survey was created and was emailed to health care providers using Survey Monkey. Data analysis consisted of distribution frequency and Chi-squared test/Fischer test. Results: 69 health care providers’ participated in the survey. 13 of the 69 (18.8%) did not see any geriatric patients with cancer and were excluded from the study. Amongst the communication parameters assessed, 85% of them said they had a particular approach to diagnosis. 76.9% of them included side effects of chemotherapy, risks and benefits of treatment and an option of no treatment in their initial treatment plan. Also, 67.3% of them included advance directives, hospice and prognosis in their initial plan. (Table 1) An adequate comparison was not possible due to the small sample size. Conclusions: In communicating cancer diagnosis and treatment plan, health care providers’ feel that they adequately answer questions and address needs of their geriatric patients. [Table: see text]
Effect of supportive care consultation on reducing 30-day readmissions to oncology inpatient services at an academic hospital.
Authors: Mark W. Knestrick, Carl Grey, Dheeraj Kodali, Sijin Wen, Michael D. Craig, Alvin Howard Moss
Journal: Journal of Clinical Oncology (2016)

181 Background: Decreasing 30-day hospital readmissions is an important quality care measure and signifies high-quality care. This study seeks to identify the benefits of Supportive Care consultations on 30-day readmissions to oncology inpatient services in an academic hospital. Methods: A retrospective review of all patients that had at least one 30-day readmission to the medical oncology or hematological malignancy service during a 2 year period (2011-2012). Data was collected on age, sex, cancer type, stage, number of readmissions, and presence of inpatient Supportive Care consultation. Results: During the study period 410 patients were identified with at least one 30-day readmission to an oncology service. Patients with a supportive care consult, 111 (27.7%), had an average of 2.5 readmissions and patients without a consultation, 299 (72.9%), had an average of 2.0 readmissions (p = 0.014). After Supportive Care consultation a reduction of 0.87 admissions (p &lt; 0.001) was observed. Stage IV disease was observed in 203 (49.5%) of patients studied. Conclusions: Supportive Care is often consulted for patients with significant symptoms and suffering during advanced illness. The higher observed average readmissions in patients seen by Supportive Care may reflect the complex assistance needed by this patient population. This study demonstrates a benefit of Supportive Care consultation in reducing 30-day readmissions after consultation.
A single arm, open-label, phase II study to assess the efficacy of lucitanib in patients with <i>FGFR1</i>-amplified squamous NSCLC (sqNSCLC).
Authors: David R. Spigel, Roberta Cereda, Jason B. Litten, Andrew R. Allen, Giuseppe Giaccone, Mark A. Socinski, D. Ross Camidge, Benjamin Besse
Journal: Journal of Clinical Oncology (2014)

TPS8119^ Background: Lucitanib, a potent, oral inhibitor of the tyrosine kinase activity of Fibroblast Growth Factor Receptors 1/2 (FGFR1/2), Vascular Endothelial Growth Factor Receptors 1-3 (VEGFR1-3) and Platelet-Derived Growth Factor Receptors A/B (PDGFRA/B), is being developed for the treatment of lung cancer and breast cancer. FGFR1-amplification is a hallmark genomic alteration in sqNSCLC, observed at a frequency of 10-20%. As such, inhibition of the FGF-axis represents a promising potential target for therapy of sqNSCLC. Methods: The current study evaluates daily oral lucitanib monotherapy in patients (pts) with FGFR1-amplified sqNSCLC. This is an international, multicenter, open-label, single-arm study. The primary endpoint is objective response rate (ORR; RECIST1.1) with secondary endpoints of response duration, clinical benefit rate, progression-free survival, and safety evaluation. Exploratory objectives include volumetric assessment of tumor growth kinetics, serial circulating tumor DNA measurement, and identification of additional biomarkers of lucitanib activity including determination of FGFR1 or FGF ligand RNA or protein expression using in-situ hybridization or immunohistochemistry. A Simon's minimax two-stage design will be used to provide 80% power to test the hypothesis H0: p ≤ 10% versus H1: p ≥ 25%, with a type I error at 5% (one sided). A minimum of 22 and maximum 40 pts will be enrolled. Key inclusion criteria include: pts aged ≥ 18 years with stage IV sqNSCLC and tumor FGFR1-amplified, tumors that are not invading or abutting a major vessel and/or tumors that are not cavitary. FGFR1 amplification will be assessed centrally by FISH but local FGFR1 testing is sufficient for enrollment. Pts should have measurable disease and have had at least one previous treatment for advanced disease. This study will begin enrolling pts in the United States and Europe in early 2014 at a network of centers skilled in the identification of pts with relatively uncommon tumor characteristics. Clinical trial information: 2013-003874-29.
Pain palliation as an oncology label indication: Lessons learned in custirsen phase III development.
Authors: Tomasz M. Beer, Sebastien J. Hotte, Johann Sebastian De Bono, Philippe Beuzeboc, Nashat Y. Gabrail, Daniel Cain, Cindy Jacobs, Karim Fizazi
Journal: Journal of Clinical Oncology (2014)

222 Background: Durable pain palliation (dPP) in metastatic castrate-resistant prostate cancer (mCRPC) is a measure of clinical benefit suitable for a label indication. A randomized, double-blind, placebo-controlled, phase III study developed with FDA under a Special Protocol Assessment (SPA) compared custirsen/taxane (cust/tax) to placebo/taxane (plac/tax) as second-line chemotherapy for patients (pts) with mCRPC with disease progression during or after first-line docetaxel. Primary efficacy was 12-week or more dPP. Other endpoints included overall survival (OS), serious adverse events (AEs), and ≥Gr 3 AEs. Methods: Patients were randomized (1:1) to second-line taxane (docetaxel retreatment or cabazitaxel; based on prior docetaxel response, progression) + 640 mg custirsen or placebo. Eligible pts had to have baseline stable pain on consistent opioid-analgesic regimen. With a one-sided alpha of 0.025, power of 90%, and estimated difference in proportion of 25% vs. 10% dPP, the trial required 292 pts. Results: Trial was activated at a total of 62 sites and was stopped after 20 months (mo) with only 35 pts screened/14 pts enrolled. Requirements for baseline stable pain/analgesic use proved too restrictive to complete enrollment. Demographics were comparable. Prior response to first-line docetaxel occurred in 93% pts. Disease progression after first-line docetaxel based on bone scan (n=10) or prostate-specific antigen (n=4); median time from end of first-line to progression one mo. Treatment of a median thre cycles plac/tax arm compared to six cycles cust/tax arm. Three pts achieved dPP (n=1 [14%] plac/tax; n=2 [29%] cust/tax). Median OS (95% CI) was 7.8 (3.2, 11.5) mo plac/tax vs. 11.8 (9.8, 15.7) mo cust/tax. AEs greater than or equal to Gr 3 reported for two pts or more included: back pain (0 plac/tax; 2 cust/tax), hyperesthesia (0,2), asthenia (2,1). Serious AEs reported for nine subjects (4,5). Only serious AE reported in more than 1 pt was hyperesthesia, leading to study discontinuation (0, 2). Conclusions: Enrollment was not feasible due to restrictive trial criteria of stable baseline pain/consistent analgesia, which were too difficult to achieve. Thus, a survival based study has been launched and is recruiting, with monitoring of pain/analgesic use. Pragmatic criteria for oncology pain studies are needed. Clinical trial information: NCT01083615.