tbuckley/cabot-search huggingface dataset:
Utility of PCA3 and TMPRSS2: ERG urinary biomarkers to predict pathologic outcomes in African American men undergoing radical prostatectomy.
Authors: Allison H. Feibus, Oliver Sartor, Elisa M. Ledet, Eric Shaw, Krishnarao Moparty, Raju Thomas, Jonathan L. Silberstein
Journal: Journal of Clinical Oncology (2017)

e547 Background: Tremendous disparity exists between preoperative characteristics and pathologic outcomes in men electing radical prostatectomy (RP) for localized prostate cancer (PCa). We sought to determine the performance characteristics of urinary PCA3 andTMPRSS2:ERG (T2:ERG) to predict pathologic outcomes in a racially diverse group of men undergoing RP. Methods: Following IRB approval, post digital rectal exam (DRE) urine was prospectively collected in consecutive patients with known PCa prior to RP. PCA3 and T2:ERG RNA copies were quantified and normalized to PSA mRNA copies using the Progensa assay (Hologic, San Diego, CA). Nonparametric Mann-Whitney U tests were performed to determine the ability of PCA3 and T2:ERG to predict higher risk PCa and notable disease features. Results: The cohort consisted of 214 men with PCa who underwent RP, and 89 men (42%) were African American (AA). The men in the cohort generally had higher risk disease, with 75% having AUA risk stratification of intermediate/high-risk PCa. PCA3 discriminated between biopsy low- and intermediate/high-grade Gleason Score (p = .005) and pathologic low- and intermediate/high-grade Gleason Score (p = 0.001). For men with low-risk PCa, PCA3 also predicted Gleason Score upgrading from biopsy to prostatectomy specimen (p = 0.003). PCA3 could not predict the presence of perineural invasion, lymph node positivity, seminal vesical invasion, positive surgical margins or extraprostatic extension. When stratified by race, within the AA cohort, T2:ERG did predict upgrading from Gleason 6 disease at the time of biopsy to higher grade pathology at RP (p = 0.016). However, T2:ERG was not predictive for the overall cohort, nor was it predictive for any of the disease features found to be significant with PCA3. Conclusions: In a racially-diverse group of men undergoing RP, PCA3 and T2:ERG urinary assays have limited ability to characterize aggressive pathologic features at the time of RP regardless of race.
Age-specific differences in oncogenic pathway deregulation and chemosensitivity in patients with acute myeloid leukemia: Strategies to maximize response to induction chemotherapy
Authors: A. V. Rao, P. Valk, K. H. Metzeler, C. Acharya, D. A. Rizzieri, R. Delwel, S. H. Bohlander, C. Buske, A. Potti, B. Lowenberg
Journal: Journal of Clinical Oncology (2009)

7013 Background: Despite all the advances made in understanding the poor prognosis of acute myeloid leukemia (AML) in the elderly, the underlying biology at a molecular signaling pathway level has yet to be defined. Methods: Clinically annotated, microarray data from 425 patients with newly diagnosed AML from two publicly available datasets GSE1159 and GSE12417 were analyzed. Age-specific cohorts (young ≤45 years; n = 175 and elderly ≥55 years; n = 144) were prospectively identified. Gene expression analysis was conducted by applying previously defined and tested signature profiles reflecting deregulation of oncogenic signaling pathways, altered tumor environment, and signatures of chemotherapy sensitivity. Standard Kaplan-Meier survival curves were generated using the two-sided log-rank test and individual differences in the probability of oncogenic pathway deregulation between young vs. elderly were analyzed via the non-parametric Mann-Whitney U test and a one-sided p-value ≤ 0.05 was considered statistically significant. Results: Elderly AML patients had worse OS (median 8.8 months vs. 24.1 months in younger patients; p = 0.001) and EFS (median 7.1 months vs. 15.3 months in younger patients; p &lt; 0.0001). Analysis of oncogenic pathways revealed that older patients had higher probability of Ras, Src, and TNF pathway activation, p &lt; 0.0001. Older patients were also less sensitive to anthracycline compared to younger AML patients, p &lt; 0.0001. Unsupervised hierarchical clustering of younger AML patients revealed two clusters and clinically better survival for cluster 1 compared to cluster 2 (high Ras, Src, TNF pathway activation) and the latter were in turn less sensitive to adriamycin. However, in elderly patients those in cluster 2 also had high Ras, Src, TNF but this did not translate into differences in survival or chemotherapy sensitivity. Conclusions: AML arising in the elderly represents a distinct biologic entity characterized by unique patterns of deregulated signaling pathways that contributes to poor survival and resistance to adriamycin. We hope these findings will enable clinically meaningful adjustments of treatment strategies in the older patient population. No significant financial relationships to disclose.
Efficacy and safety of an anti-FLT3 antibody (LY3012218) in patients with relapsed acute myeloid leukemia.
Authors: David Sanford, William G. Blum, Farhad Ravandi, Rebecca B. Klisovic, Gautam Borthakur, Alison R. Walker, Guillermo Garcia-Manero, Guido Marcucci, William G. Wierda, Susan P. Whitman, Hagop M. Kantarjian, Jorge E. Cortes
Journal: Journal of Clinical Oncology (2015)

7059 Background: LY3012218 (IMC-EB10) is a monoclonal antibody that binds FLT3 with high affinity and prevents binding of the FLT3-ligand and downstream signaling. Preclinical data using LY301228 demonstrates anti-leukemia activity which appears to be mediated via antibody dependent cell-mediated cytotoxicity (ADCC). Methods: We conducted a phase 1 trial to determine the safety, pharmacokinetics, and preliminary efficacy of LY3012218 in patients with relapsed/refractory acute myeloid leukemia (AML). Patients were eligible if they were ≥ 18 years, had a performance status < 3, adequate organ function, a life expectancy of > 3 months, and were not candidates for higher intensity therapy. Exclusion criteria included stem cell transplant within < 3 months, central nervous system leukemia or isolated extramedullary disease. Patients were treated in 4 dose cohorts (5 mg/kg (n = 3), 10 mg/kg (n = 13), 20 mg/kg (n = 3), 30 mg/kg (n = 5)) and received the drug intravenously weekly on days 1, 8, and 15 for cycle 1 and days 1, 8, 15, and 22 for subsequent cycles. Results: 31 patients were screened and 24 patients were treated. 14 patients were male (58.3%), the median age was 70.3 years (range 26-82), the median number of prior therapies was 2 (range 1-6) and 26% had a baseline FLT3 mutation. 12 patients reported 20 serious AEs with the most frequent including: pneumonia (n = 6, 25%), neutropenia (n = 3, 12.5%) and sepsis (n = 2, 8.3%). Dose limiting toxicities of infection, vomiting (10 mg/kg), and increased transaminases (30 mg/kg) were observed, although these were not clearly related to LY3012218. No MTD was defined. The serum trough concentrations for 5 to 30 mg/kg treatments (mean of Cmin: 41.9 to 739 μg/mL) following the third infusion were above the target trough concentration (33 μg/mL) associated with antitumor activity in preclinical models. Twenty one patients were evaluated for response and all were classified as treatment failures. Conclusions: Treatment with LY3012218 appears safe but did not demonstrate clinical activity as a single agent in relapsed/refractory AML. The lack of efficacy may be due to an absence of ADCC with LY3012218 or the presence of ligand-independent activation of signaling pathways down-stream of FLT3. Clinical trial information: NCT00887926.
Survival following stereotactic body radiation therapy or conventionally fractionated radiation for definitive non-operative treatment of stage I non-small cell lung cancer: A review of the National Cancer Data Base.
Authors: Cliff Grant Robinson, Aalok Patel, Jeffrey D. Bradley, Todd A. DeWees, Sana Rehman, Michael Charles Roach, Daniel Morgensztern, Traves Crabtree, Varun Puri
Journal: Journal of Clinical Oncology (2015)

7513 Background: Despite a dramatic increase in utilization of stereotactic body radiation therapy (SBRT) for non-operative treatment of clinical stage I NSCLC over the last decade, there are no reported clinical trials or large scale comparisons with standard conventionally fractionated radiation (CFRT). We sought to compare overall survival (OS) between these modalities using the National Cancer Data Base (NCDB). Methods: Patients with clinical stage I (AJCC 6th edition T1-T2N0M0) NSCLC who underwent definitive non-operative treatment with either SBRT or CFRT from 1998 to 2010 were identified from the NCDB. Cox regression was used to assess the impact of patient and treatment variables on OS. Inverse probability adjusted Kaplan-Meier survival curves were calculated to assess differences in OS while adjusting for baseline imbalances between the treatment groups. Results: A total of 19373 patients met inclusion criteria (5944 SBRT, 13429 CFRT). Median follow-up was 18.7 months. On multivariable analysis, improved OS was independently correlated with younger age, female gender, non-Caucasian race, lower Charlson comorbidity score, smaller tumor size, use of chemotherapy, treatment at an academic facility, and was most strongly associated with use of SBRT (HR .775, 95% CI, .737 to .817). Chemotherapy was delivered in 32.9% of CFRT patients and 4.2% of SBRT patients. Chemotherapy was correlated with improved OS on multivariable analysis for CFRT but not SBRT. In an adjusted Kaplan-Meier comparison, SBRT was associated with a significant increase in median (29.8 v 26.2 months) and 3-year (42.3% v 36.4%) OS compared with CFRT (P < .0001). Conclusions: In a large population-based analysis of outcomes in a modern cohort of patients with clinical stage I NSCLC treated with definitive non-operative therapy, SBRT was associated with a significant improvement in OS compared with CFRT.
Phase III randomized study of oral vinorelbine (oV) and gemcitabine (G) (oVG) versus docetaxel (D) and gemcitabine (DG) as first-line treatment of patients with advanced non-small cell lung cancer (NSCLC): A preliminary report
Authors: S. Agelaki, N. Androulakis, A. Agelidou, M. Agelidou, A. Kotsakis, S. Kakolyris, A. Polyzos, N. Kentepozidis, N. Ziras, D. Mavroudis
Journal: Journal of Clinical Oncology (2007)

7538 Background: Non-platinum based doublets are effective treatments for advanced NSCLC. We performed a multicenter phase III trial to compare the efficacy and tolerance of oVG and DG in NSCLC patients (pts). Methods: Chemotherapy-naive pts with stage IIIB/IV NSCLC and PS (WHO) 0–2 and adequate organ function were eligible. Pts received oV 70 mg/m 2 combined with G 900 mg/m 2 on days 1, 15 of a 4-week cycle or D 75 mg/m 2 on day 1 combined with G 1,000 mg/m 2 on days 1, 8 of a 3-week cycle. Primary endpoint was OS and secondary endpoints were response rate (RR), time to progression (TTP) and toxicity. Stratification was done for age, stage and PS. Results: 254 pts received oVG (n=121) or DG (n=133). Median age was 64 and 63 years, and PS was 0–1 in 94.2% and 94%, for oVG and DG, respectively. Most patients had disease stage IV and were =70 years (80.9% vs 74.4% and 74% vs 77%, in oVG and DG, respectively). After a median follow-up time of 6.1 months, median OS was 9.0 vs 10.7 months and 1-yr survival was 38% vs 46% for oVG and DG, respectively (p=0.486). Significantly more responders were observed in the DG arm (11% vs 23%, p=0.018). Median TTP was 3.1 vs 3.9 for oVG and DG, respectively (p=0.335). A similar toxicity profile was observed except for a trend for higher neutropenia grade 3–4 in DG compared to oVG (p= 0.066). There was no difference with respect to neutropenic infections (p= 0.124). An analysis of the influence of age (=70 and = 70) on OS and toxicity revealed that OS was similar for both arms in the two age groups but grade 3–4 neutropenia was lower in the oVG arm for pts =70 years. Conclusions: A higher RR that was not translated to a survival benefit was recorded for the DG arm. Both regimens were well tolerated without significant differences in toxicity. No significant financial relationships to disclose.
Intraventricular application of rituximab as a treatment option in patients with CNS lymphoma and leptomeningeal disease
Authors: H. Schulz, H. Pels, U. Schlegel, U. Zeelen, U. Germing, A. Engert
Journal: Journal of Clinical Oncology (2004)

1521 Background: Most patients (pts) with primary central nervous system lymphoma (PCNSL) relapse after initial response to treatment, often presenting with leptomeningeal disease. Since the majority of PCNSL are B-cell neoplasms expressing the CD20 surface antigen treatment with the chimeric monoclonal antibody (Mab) rituximab might be reasonable. The primary objective was to evaluate feasibility and safety of direct administration of the anti-CD20 antibody into the cerebro spinal fluid (CSF). Methods: Pts with intracranial lesions and/or leptomeningeal involvement of B-cell neoplasms expressing the CD20 surface antigen were included. In order to define the tolerated single dose, injections of 10–40 mg rituximab in a volume of 1–4 ml were administered over two minutes via an ommaya reservoir (n=4) or intrathecally (n=2). Drug clearance from the CSF was determined by measuring rituximab levels in the CSF and blood by ELISA. Results: Treatment with rituximab at single dosis of up to 35mg thrice weekly was safe and well tolerated in 5/6 pts. Acute neurotoxicity in one pt (PN6) was probably related to a high tumor cell burden in the CSF and a rapid tumor cell lysis after intrathecal rituximab. Measurement of rituximab concentrations in the CSF showed severalfold higher values after intraventricular administration compared to those after intravenous rituximab application. Clearing of tumor cells in the CSF and a complete remission of leptomeningeal lymphoma manifestation was achieved in four pts. However, there was no effect of rituximab on parenchymal lymphoma. Conclusions: Taken together, these data suggest that direct administration of rituximab into the CSF may have a role in the treatment of leptomeningeal disease in pts with CNS lymphoma. However, the therapeutic value of systemic treatment with the antibody remains questionable. To better define the value of rituximab treatment in CNS lymphoma with lymphomatous meningitis, future studies should investigate dose intensification as well as combination with other chemotherapeutic drugs or radiotherapy. No significant financial relationships to disclose.
Oncotype-DX recurrence score distribution among breast cancer patients harboring a germline mutation in the BRCA1/2 genes.
Authors: Ron Lewin, Shulamith Rizel, Daniel Hendler, Victoria Neiman, Irit Ben-Aharon, Nicky Liebermann, David Margel, Dalia Zoref, Aaron Sulkes, Rinat Yerushalmi
Journal: Journal of Clinical Oncology (2015)

564 Background: In about 10% of breast cancer (BC) cases, a genetic mutation in the BRCA1/2 genes can be found. BCs associated with BRCA2 mutations present with positive estrogen receptor (ER) status in about 50% of all cases, whereas BCs associated with BRCA1 mutation are more aggressive and more likely to be ER-negative. Oncotype genetic profiling has become a standard of care to predict recurrence and the benefit from chemotherapy in ER positive BC. The role of Oncotype-DX in BRCA mutation-carriers is not clear. Our primary end-point is to compare the RS distribution of BRCA carriers to that of the General Population (GP). Methods: Two different data bases were crossed: the list of BRCA mutation-carriers at Rabin Medical Center (n=1,191) with the list of all the oncotype-DX tests which were performed through Kupat Holim Clalit, our HMO (n=5,491), between 2003 and 2015. Results: Patients and tumor characteristics, including Oncotype RS are shown in the Table. Conclusions: Our study indicates that among BC patients with mutations in the BRCA1/2 genes, the distribution of the RS is different from that of the GP. In these patients a larger portion of the population was shifted toward the intermediate- and high- risk groups. This was more pronounced in the BRCA1 carriers. To our knowledge this is the largest BRCA cohort in which the oncotype-Dx RS has been reported. *Non-BRCA n=1,031 BRCA1 n=16 P-value BRCA2 n=27 P-value Age (years) 60 54.1 0.015 58.3 0.37 ER index 2.59/3 2.2/3 0.013 2.5/3 0.45 PR index 1.65/3 0.98/3 0.017 1.03/3 0.004 Grade (%): I 16.7 0 < 0.0001 8.7 0.09 II 66.2 37.5 56.5 III 16.9 62.5 34.7 KI67 (%) 14.5 35.9 < 0.0001 19.2 0.13 Tumor size (cm) 1.64 1.62 0.91 1.44 0.18 Oncotype RS (%): Low 52.7 6.2 < 0.0001 25.9 0.0016 Intermediate 37.8 37.5 44.4 High 9.4 56.2 29.6 *All Oncotype tests which were performed for patients at our institute. **The BRCA groups were compared to the non-BRCA group.
Chemotherapy utilization in patients with resected colorectal cancer liver metastases (CRC LM): Does clinical practice follow the evidence?
Authors: Janarthanan Kankesan, Sulaiman Nanji, James Joseph Biagi, Monika K Krzyzanowska, William J. Mackillop, Christopher M. Booth
Journal: Journal of Clinical Oncology (2014)

e14522 Background: Initial clinical trials (reported in 2002) showed a trend favoring post-operative 5-FU in patients with resected colorectal cancer liver metastases (CRC LM). A pivotal RCT was reported in 2007 showing improved outcomes with peri-operative FOLFOX. Here, we report trends in the chemotherapy delivered in routine clinical practice and describe the extent to which practice followed emerging evidence. Methods: All cases of CRC in Ontario who underwent surgical resection of liver metastases in 1994-2009 were identified using the population-based Ontario Cancer Registry (OCR). We linked electronic records of treatment to the registry and reviewed all surgical pathology reports. Physician billing and electronic records of chemotherapy drug delivery were used to identify neoadjuvant (NACT), adjuvant (ACT) or peri-operative (PERI-OP) chemotherapy delivery. We defined three study periods (1994-2001, 2002-2006, and 2007-2009) based on when the pivotal clinical trials were reported. Results: Between 1994-2009, 2,717 patients underwent resection of CRC liver metastases in Ontario. Fifty four percent of all cases (1,471/2,717) were treated with NACT, ACT, or PERI-OP. Overall use of chemotherapy increased over the three study periods: 46% (466/1,006), 53% (511/957), 66% (494/754) (p<0.001). Use of ACT did not increase after reporting of trials in 2002 (34%, 347/1,006 1994-2001 vs. 31%, 296/957 2002-2006, p<0.093). Use of PERI-OP increased from 11% (103/957) in 2002-2006 to 25% (185/754) in 2007-2009 (p<0.001). Details of drug delivery were available for 57% (841/1471) of cases. During 1994-2001, 68% (110/161) of cases received single-agent 5-FU. From 2002-2009, most patients received FOLFOX (46%, 316/680) or FOLFIRI (23%, 156/680). Among all cases, treatment was delayed in 23-41% and dose-reduced or discontinued in 24-56%. Delays and dose modifications were more common with ACT FOLFOX (41% and 56% respectively) than with ACT FOLFIRI (30% and 36%). Conclusions: While use of chemotherapy among patients with resected CRC LM has increased over time, practice patterns demonstrate incomplete adoption of therapies established in key clinical trials. There is a high rate of dose delays and/or modifications in routine clinical practice.
Patient-Reported Outcomes 1 Year After Immediate Breast Reconstruction: Results of the Mastectomy Reconstruction Outcomes Consortium Study
Authors: Andrea L. Pusic, Evan Matros, Neil Fine, Edward Buchel, Gayle M. Gordillo, Jennifer B. Hamill, Hyungjin M. Kim, Ji Qi, Claudia Albornoz, Anne F. Klassen, Edwin G. Wilkins
Journal: Journal of Clinical Oncology (2017)

Purpose The goals of immediate postmastectomy breast reconstruction are to minimize deformity and optimize quality of life as perceived by patients. We prospectively evaluated patient-reported outcomes (PROs) in women undergoing immediate implant-based or autologous reconstruction. Methods Women undergoing immediate postmastectomy reconstruction for invasive cancer and/or carcinoma in situ were enrolled at 11 sites. Women underwent implant-based or autologous tissue reconstruction. Patients completed the BREAST-Q, a condition-specific PRO measure for breast surgery patients, and Patient-Reported Outcomes Measurement Information System–29, a generic PRO measure, before and 1 year after surgery. Mean changes in PRO scores were summarized. Mixed-effects regression models were used to compare PRO scores across procedure types. Results In total, 1,632 patients (n = 1,139 implant, n = 493 autologous) were included; 1,183 (72.5%) responded to 1-year questionnaires. After analysis was controlled for baseline values, patients who underwent autologous reconstruction had greater satisfaction with their breasts than those who underwent implant-based reconstruction (difference, 6.3; P &lt; .001), greater sexual well-being (difference, 4.5; P = .003), and greater psychosocial well-being (difference, 3.7; P = .02) at 1 year. Patients in the autologous reconstruction group had improved satisfaction with breasts (difference, 8.0; P = .002) and psychosocial well-being (difference, 4.6; P = .047) compared with preoperative baseline. Physical well-being of the chest was not fully restored in either the implant group (difference, −3.8; P = .001) or autologous group (−2.2; P = .04), nor was physical well-being of the abdomen in patients who underwent autologous reconstruction (−13.4; P &lt; .001). Anxiety and depression were mitigated at 1 year in both groups. Compared with their baseline reports, patients who underwent implant reconstruction had decreased fatigue (difference, −1.4; P = .035), whereas patients who underwent autologous reconstruction had increased pain interference (difference, 2.0; P = .006). Conclusion At 1 year after mastectomy, patients who underwent autologous reconstruction were more satisfied with their breasts and had greater psychosocial and sexual well-being than those who underwent implant reconstruction. Although satisfaction with breasts was equal to or greater than baseline levels, physical well-being was not fully restored. This information can help patients better understand expected outcomes and may guide innovations to improve outcomes.