bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II study of once-daily dasatinib for patients with castration-resistant prostate cancer (CRPC) (CA180085)
Authors: Yu E. , Massard C. , Gross M. , Wilding G. , Posadas E. , Culine S. , Carducci M. A. , Trudel G. , Paliwal P. , Sternberg C. 
Published: August 2020

5147 Background: Dasatinib is a potent oral SRC family kinase inhibitor that also inhibits c-KIT and PDGFR in vitro. The anti-proliferative/anti-metastatic activity as well as osteoclast inhibitory function of dasatinib in pre-clinical models supports its potential as a targeted therapy for prostate cancer. Previously we presented results on BID dosing of dasatinib in the treatment of CRPC (ASCO. 2008 Abstract 5156). A second group of patients (pts) was enrolled to investigate the activity, safety and bone effects of 100 mg once daily dosing. Methods: Male pts with progressive metastatic CRPC, rising PSA, castrate levels of testosterone (< 50 ng/dL) and no prior chemotherapy were enrolled. Dasatinib dose was 100 mg QD. Continuation of bisphosphonates was permitted. Primary endpoint was a composite of: PSA responses, bone scans and disease control by RECIST. Urinary N-telopeptide (uNTX) and bone alkaline phosphatase (BAP) were determined Q 4-weeks as indicators of bone metabolism. Results: 47 pts were treated (median treatment duration was 2.3 months). 11 patients were evaluable by RECIST; of these 64% achieved SD. The composite response rate was (8/47) 17%. Of 22 pts with bone scans, 50% were stable at 12 weeks and 3/9 (33%) were stable at 24 weeks. A prolonged PSA doubling time was observed in 32 of 39 pts (82%), including one pt with a PSA response. Of the pts with evaluable bone markers, including those who continued on bisphosphonate therapy, 20/41 (49%) had a ≥ 35% decrease in uNTX and 21/42 (50%) had a decrease from baseline in BAP. Grade 3/4 adverse events (AEs) were experienced by 13% of pts (diarrhea, asthenia, and pleural effusion [n=1]). Grade 1/2 AEs (≥ 15% of pts) were diarrhea, nausea, headache, fatigue, asthenia, anorexia and dyspnea. Conclusions: Fewer and less severe AEs were observed in all categories for the QD dosing group compared to the previously reported BID dosing cohort. In addition, preliminary clinical activity (tumor and PSA response; decreasing bone turnover [uNTX, BAP]), is now confirmed to be similar in pts treated with 100mg QD and BID dosing. These data support the relevance of further studies of dasatinib in metastatic CRPC. [Table: see text]
A phase I study of sorafenib in association with docetaxel-prednisone in chemonaive metastatic castration-resistant prostate cancer
Authors: Mardjuadi F. , Medioni J. , Kerger J. , Canon J. L. , Duck L. , Oudard S. , Clausse M. , D'Hondt L. , Moxhon A. , Machiels J. P. 
Published: August 2020

5153 Background: Docetaxel (D)-prednisone (P) is the standard regimen for metastatic castrate-resistant prostate cancer (mCRPC). Sorafenib (S) is a dual-action kinase inhibitor that blocks cell proliferation and angiogenesis with antitumor activity in CRPC. The objectives were dose limiting toxicities (DLTs)/recommended dose (RD) of S in combination with D-P, pharmacokinetics (PK), and safety at the RD in an expanded cohort. Methods: 6 pts were enrolled per dose level (DL). All pts received D 75 mg/m2/3 wks in 6 chemotherapy cycles and P 10 mg/d. S dose escalation included 4 DL. DL 1: S 200 mg bid from day 3 to 19 of each chemotherapy cycle. DL 2: S 200 mg bid started at day 3 of the 1st cycle and continued without interruption through the cycles. DL 3: S 400 mg bid from day 3 to 19 of each cycle. DL 4: S 400 mg bid started at day 3 of the 1st cycle without interruption through the cycles. DLTs were determined during the first cycle. Results: 24 chemo-naive mCRPC pts (median age 68) were included in the dose-escalation study. PK analysis showed that mean Cmax and AUC of D were increased at cycle 2 in cohort 2, 3, and 4 indicating a PK interaction dependent on the exposure to S. For the 24 pts, the main Gr 3–4 toxicities (N pts) were febrile neutropenia (8), uncomplicated neutropenia (5), and hand-foot syndrome (4). No DLT was found. PSA response (> 50% in PSA decrease) was recorded in 15 out of 20 pts. Conclusions: The RD of S in combination with D is 400 mg bid continuously. PK analysis revealed an interaction between D and S that may explain the high rate of febrile neutropenia and Gr4 neutropenia. 14 pts were included in an expanded cohort to further explore the safety of this regimen. Updated data will be presented. [Table: see text] No significant financial relationships to disclose.
A phase I open-label study using lenalidomide and docetaxel in castration- resistant prostate cancer
Authors: Petrylak D. P. , Resto-Garces K. , Tibyan M. , Mohile S. G. 
Published: August 2020

5156 Background: Based on efficacy of docetaxel (D) and possible synergism with antiangiogenic agents in AIPC demonstrated by results from a NCI trial of D ± thalidomide, a phase I trial evaluating escalating doses of D and lenalidomide (Ln), a derivative of thalidomide with immunomodulatory and antiangiogenic properties, was designed. Methods: Eligibility requirements include progressive measurable disease or rising PSA levels after antiandrogen withdrawal and < 2 prior chemotherapy regimens. All patients were required to have a castratete testosterone <50 ng/dl and to continue medical castration. Dose of D was 60 mg/m2 on Day 1 of 21-day cycle for dose level (L)1 and 75 mg/m2 for L 2–6. Ln dose levels were: 10 mg (L1–2), 15 mg (L3), 20 mg (L4), 25 mg (L5) and 30 mg (L6) for days #1–14. Pts were given prednisone 5 mg po |[BI]D continuously and 8 mg of decadron 12, 8 and 1 hour prior to D without prophylactic anticoagulation. 6 patients (pts) were entered at each level, escalation to the next level occurred if no more that 1 dose limiting toxicity|[(D]LT) was observed during cycle 1. Results: Thirty four pts were enrolled in L1–6; all pts are evaluable for toxicity. Pt characteristics include median age of 70 yrs (range 47–85), median baseline PSA of 101.9 ng/ml (range 5.9–7480), 14 pts (41%) had received prior chemotherapy (7 with 2 prior regimens). All had overt metastatic disease to viscera or bone; 21 pts had measurable disease. Median number of cycles for L1-L5 was 8 (range 2–19). DLT's observed: L2: Grade 4 Neutropenia (1 pt); L3–5 None. Of the 3 patients treated at L6, 2 developed DLTs (febrile neutropeina, grade 4 neutropenia) precluding further dose escalation. Other Grade 3/4 toxicities observed after cycle 1 included deep venous thrombosis (2 pts), grade 3 neutropenia (2 pts), grade 3 facial edema (1 pt) Of 31 pts evaluable for post treatment PSA declines; 8/17 (47%) untreated pts 7/14 (50%) previoustly treated pts had a >50% decline in PSA. Five pateints achieved a partial response in measurable disease, one had a near complete resolution of a biopsy proven metastatic pulmonary nodule. Conclusions: The recommended dose for is 75 mg/m2 D Q 3 weeks day 1 and Ln 25 mg PO D1–14. An expanded cohort of 10 patients will be treated at this level to further define toxicities. No significant financial relationships to disclose.
The prognostic significance of bone metastases and skeletal-related events (SREs) in prostate cancer survival: A population-based historical cohort study in Denmark (1999–2007)
Authors: Fryzek J. P. , Cetin K. , Nørgaard M. , Jensen A. Ø. , Jacobsen J. , Sørensen H. T. 
Published: August 2020

5160 Background: Common among advanced prostate cancer patients, bone metastases indicate cancer progression and poor prognosis but few studies have quantified their influence on patient survival, particularly in the presence of subsequent skeletal-related complications. We therefore sought to examine this in a large population-based cohort of prostate cancer patients. Methods: Using data from the Danish National Patient Registry (covering all Danish hospitals), we studied 23,087 patients diagnosed with prostate cancer between 1999 and 2007, with follow-up through April 2008 (median follow-up: 2.2 years). We estimated the incidence of bone metastases following cancer diagnosis and the subsequent occurrence of SREs (radiation and surgery to the bone, fracture, spinal cord compression). We then computed and compared survival for three prostate cancer subgroups - no bone metastases, bone metastases, and bone metastases with SREs - using Kaplan-Meier and multivariate Cox proportional hazards models. Results: Across the study period, 14% (n = 3,261) of the prostate cancer patients developed bone metastases: 6.8% (n = 1,570) had bone metastases and no SRE and 7.3% (n = 1,691) had both bone metastases and at least one SRE (radiation to the bone was most frequent). One-year survival was lowest for prostate cancer patients with bone metastases and SREs (40%) compared to the groups with no bone metastases (87%) and with bone metastases but no SREs (47%). Similarly, after adjusting for age and the presence of comorbidities, short-term prognosis was poorest in patients with both bone metastases and SREs: compared to prostate cancer patients with no bone metastases, the 1-year mortality rate was 6.7 times greater for those with bone metastases and SREs (95% confidence interval (CI): 6.0–7.6) versus just 4.7 times higher in those with only bone metastases (95% CI: 4.3–5.2). Less than 1% of prostate cancer patients who developed bone metastases and suffered any SRE survived beyond five years. Conclusions: Although the presence of bone metastases confers a short-term prognosis in prostate cancer patients, survival is even poorer for patients who also experience skeletal-related complications. [Table: see text]
Impact of Asian American race on prostate cancer outcomes
Authors: Brassell S. A. , Raymundo E. , Chen Y. , Zhao J. 
Published: August 2020

5165 Background: The global increased incidence of prostate cancer (CaP) is of growing concern, notably in Asia where a 118% rise has been documented. Recent publications report that Asian Americans are more likely to have advanced clinical stage, higher tumor grades, and worse survival rates compared to other racial groups. It remains unclear if these adverse outcomes are attributable to intrinsic biologic differences of CaP in Asians or socioeconomic and cultural differences. Methods: Men registered into the Center for Prostate Disease Research multi-center military national database from 1989–2007 with biopsy-proven CaP and categorized as Asian American, Caucasian, or African American descent were included. Demographic and clinical characteristics were examined. Frequencies were reported for categorical features. Measures of central tendency and dispersion were reported for continuous features. Chi-square, ANOVA and Kruskal-Wallis test were used to examine association between race and clinico-pathologic features. Differences of PSA recurrence and overall survival rates were analyzed by Kaplan-Meier. The multi-variate Cox proportional hazard model was used to examine predictive value of clinico-pathologic features. Results: Included patients were 10,964: 583 (5.3%) Asian Americans, 2,046 (18.7%) African Americans, and 8,335 (76.0%) Caucasians. At diagnosis, Asian Americans had lower clinical stage (p<0.0001) but worse biopsy grade (p = 0.0006) than other groups. They had a higher percentage of organ confined disease (p < 0.0001) and were more likely to choose radical prostatectomy (RP) (p < 0.0001). Asian Americans had improved biochemical recurrence free (p<0.01) and overall survival (p < 0.001) compared to African Americans or Caucasians treated with RP or external beam radiation. Conclusions: Asian Americans with CaP treated in an equal access military health care system have improved pathologic outcomes and survival characteristics compared with other races. Asian ethnicity's negative impact on survival noted by others appears to be from factors other than the tumor's intrinsic behavior such as language barriers, socioeconomic status, and cultural norms. No significant financial relationships to disclose.
Results of a multicenter pilot study of weekly nab-paclitaxel, carboplatin with bevacizumab, and trastuzumab as neoadjuvant therapy in HER2+ locally advanced breast cancer with SPARC correlatives
Authors: Yardley D. A. , Raefsky E. , Castillo R. , Lahiry A. , LoCicero R. , Thompson D. , Shastry M. , Trieu V. , Knauer D. , Desai N. 
Published: August 2020

527 Background: The addition of targeted therapies to standard chemotherapy has resulted in improved outcomes in metastatic, neoadjuvant and early stage breast cancer. A phase III study in MBC demonstrated improved efficacy with nab paclitaxel (nab-P) compared with standard solvent-based paclitaxel. The secreted protein acidic rich in cysteine (SPARC) is a poor prognostic factor for survival and may mediate enhanced intratumoral accumulation of nab-P via an interaction with albumin. This multicenter phase II pilot study was designed to evaluate the feasibility, safety, and preliminary efficacy of dual VEGF and HER-2 monoclonal antibodies of bevacizumab (B) and trastuzumab (T) administered in with neoadjuvant nab-P and carboplatin (C) with SPARC tumor correlatives. Methods: Eligibility: clinical T1c-T4d and/or N0–3, M0 (T1N0M0 excluded) chemo naive, ECOG PS 0–2, normal LVEF, adequate organ function. Treatment: nab-P 125 mg/m2 D1, 8, 15 with C AUC 6 D1 q28 days plus T 4 mg/kg load followed by 2 mg/kg/wk and B 5 mg/kg/wk x 6 cycles followed by surgery. Post surgery T and B continued for 52 wks. SPARC tumor expression was measured by immunohistochemistry. Results: 29 pts are enrolled and evaluable for safety. Median age: 52 years (29–76), ECOG PS 0–93%, median tumor size 3.2 cm, 54% ER-/PR-, 72% node positive. G3/4 neutropenia was 38% with no febrile neutropenia. Nonheme toxicity: G3/4 hyperglycemia 10%, proteinuria and hypertension, each in 7%. 8 pts were hospitalized (infection-4, ↓LVEF-1, wound dehiscence-1 pt, other-2). 5 pts did not complete neoadjuvant therapy (↓LVEF-1, noncompliance-1, pt request-3) and 10 pts did not complete post op therapy ((pt request-2, toxicity-3, wound-2, unk-3). Pathologic responses are available for 20 pts. pCR was noted in 13/20 pts (65%) and PR was noted in 7/20 pts (35%). 77% of the pCR pts (10/13) and 86% of the PR pts (6/7) were positive for SPARC. Conclusions: Neoadjuvant B, T with nab-P and C is feasible and highly active with a remarkable pCR of 65%. SPARC tumor correlations with pathologic response data reveal a concordance between the high response rate and high incidence of SPARC positivity. [Table: see text]
DNA repair gene expression profile and risk of locoregional relapse in locally advanced breast cancer patients
Authors: Le Scodan R. , Cizeron-Clairac G. , Fourme E. , Meseure D. , Vacher S. , Spyratos F. , Cvitkovic F. , de la Lande B. , Lidereau R. , Bieche I. 
Published: August 2020

528 Background: The cytotoxicity of radiation therapy appears mainly mediated through the induction of DNA-double strand breaks. We explore whether DNA repair gene expression could be associated with the risk of locoregional recurrence (LRR) in locally advanced breast cancer patients. Methods: mRNA levels of 21 selected DNA repair genes were measured in tumors samples of 97 locally advanced breast cancer patients included in a phase III trial (CRH cohort), using quantitative reverse-transcriptase polymerase chain reaction. Normalized mRNA levels were evaluated for association with LRR-free survival (LRR-FS) and overall survival (OS). Results were validated in an independant cohort (Netherlands Cancer Institute: NKI cohort). Multivariate analysis, including known prognostic factors, was done to assess the association between gene expression profile of DNA repair genes and outcomes. Results: Overexpression of RAD51, PRKDC, and XRCC6 were associated with a higher risk of LRR in the CRH cohort. RAD51 was the only gene associated with LRR in the NKI cohort. With a median follow-up of 126 months (CRH cohort), the 5-year LRR-FS rates were 100% in patients (n = 61) with low RAD51, compared with 70% in patients (n = 36) with high RAD51 (p < 0.0001). The 5-year OS rates were 95% in patients with low RAD51, compared with 69% in patients with high RAD51 (p = 0.00026). RAD51 overexpression was associated with a higher risk of LRR (multiadjusted hazards ratio [HR], 12.83, 95% CI: 3.6 - 45.6) and a higher risk of death (multiadjusted hazards ratio [HR], 4.10, 95% CI: 1.7 - 9.7). RAD51 was also significantly associated with shorter LRR-FS and OS in the NKI cohort. Conclusions: Our results suggest that overexpression of RAD51, a key component of the homologous recombination and the DNA DSBs repair, is associated with a higher risk of LRR and death, and may be a prognostic marker of LRR in locally advanced breast cancer patients. No significant financial relationships to disclose.
The influence of margin width and volume of disease near margin on benefit of radiation therapy after breast-conserving surgery for DCIS: Results of long-term follow-up
Authors: Rudloff U. , Brogi E. , McCormick B. , Brockway J. P. , Goldberg J. I. , Wynveen C. A. , Reiner A. S. , Patil S. , Van Zee K. J. 
Published: August 2020

531 Background: There remains variation in the use of radiation (RT) in women with DCIS, despite prospective randomized trials documenting its benefit in reducing the risk of ipsilateral breast tumor recurrence (IBTR). Methods: Patients with DCIS treated with excision alone or excision plus radiation at our institution from 1991–1995 were identified. A dedicated breast pathologist assessed margin width, number of involved ducts at closest margin, nuclear grade, and presence of necrosis and lobular neoplasia. Pathological variables, age, and presence of palpable mass were tested in uni- and multivariate analysis for association with risk of IBTR and added value of RT. Results: 294 patients with a median follow-up of 11 years had actuarial 10- and 15-year overall IBTR rates of 22 and 29%. For lesions excised with margins of <1mm, 1–9mm, and ≥10mm, the actuarial 10-year IBTR rates were 28, 21, and 19%, respectively. RT reduced adjusted IBTR rates by 62% (12 vs. 28%; p=0.002) for all patients; 83% for lesions with <1mm margins (p=0.002), 70% for 1–9mm (p=0.05), and 27% (p=0.55) for ≥10mm. Following adjustment for other variables, higher volume of disease near the margin was associated with risk of IBTR in the no RT group (HR=3.37, p=0.002) and greater benefit of RT (HR 0.14; p=0.004). Conclusions: Effect of RT on local recurrence risk is influenced by both margin width and number of involved ducts at nearest margin. Patients with higher volume of disease near the margin derive a greater benefit from the addition of RT. Despite margins of ≥10mm, the risk of local recurrence remains substantial in patients with DCIS. [Table: see text] No significant financial relationships to disclose.
Serum 1-OH vitamin D (D) and prognosis of postmenopausal breast cancer (BC) patients: NCIC-CTG MA14 trial
Authors: Piura E. , Chapman J. W. , Lipton A. , Zhu L. , Leitzel K. , Wilson C. F. , Pritchard K. I. , Shepherd L. , Pollak M. N. 
Published: August 2020

534 Background: In vitro, D has demonstrated regulatory functions in breast cancer cells and the bone microenvironment. Higher serum D levels were associated in some prior studies with favorable BC prognosis. We previously found that the baseline serum bone resorption marker, beta C-terminal telopeptides of type I collagen (B-CTx), was associated with bone-only first relapse, and that higher levels of insulin secretion as estimated by c-peptide level was associated with reduced event-free survival (EFS). We hypothesized that baseline serum D might be associated with relapse of breast cancer in bone and/or other metastatic sites. Methods: Baseline D was determined for the phase III MA.14 trial of adjuvant tamoxifen (20 mg/day oral for 5 years) ± octreotide (90 mg/month depot injection for 2 years). Stratification was by adjuvant chemotherapy, axillary lymph node status, and hormone receptor status. EFS, time from randomization to recurrence, second malignancy, or death due to any cause, was the primary endpoint. Recurrence-free survival (RFS), time from randomization to recurrence of the primary disease alone, was a secondary endpoint. For both endpoints, step-wise forward multivariate Cox regression adjusted for stratification factors was used to examine the association of D and outcome; a factor was added if p < 0.05. Results: Baseline D levels were available for 607 (91%) patients. As expected, D levels for a population far from the equator varied with month of blood draw (p = 0.007), which gives confidence in assay performance. Continuous D was not associated with RFS of any relapse (p = 0.57), bone only relapse (p = 0.19), bone + other site of relapse (p = 0.73), or all bone relapse types (p = 0.66). D was not associated with EFS (0.43), even when adjusted by season (p = 0.64), level deficiency/insufficiency vs sufficiency/toxicity (p = 0.69), age (p = 0.54), and BMI (p = 0.32). As well, interactions between D and season, age, and BMI were non-significant (respectively, p = 0.90, 0.84, 0.23). Conclusions: D was not associated with EFS or RFS in postmenopausal breast cancer patients in this well controlled hormonal therapy study, a result consistent with some, but not all, studies of this issue. No significant financial relationships to disclose.
Correlation of levels of Akt phosphorylation at Ser473 with benefit from paclitaxel chemotherapy in NSABP B-28 patients with node-positive breast cancer
Authors: Yang S. X. , Costantino J. P. , Nguyen D. , Jeong J. , Mamounas E. P. , Wolmark N. , Kim C. , Kidwell K. , Paik S. , Swain S. M. 
Published: August 2020

537 Background: We investigated the levels of tumor phospho-Akt(Ser473) (pAkt) and treatment outcome of patients with node-positive breast cancer after adjuvant treatment with doxorubicin/cyclophosphamide (AC) followed by four cycles of paclitaxel (PTX) (AC→PTX) compared with AC chemotherapy alone in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-28 trial. Methods: The primary tumors on B-28 tissue microarray were available from 1581 of 3060 patients enrolled. pAkt status was examined by immunohistochemistry with the antibody to pAkt(Ser473) (Cell Signaling Technology) at the National Cancer Institute. Levels of pAkt were quantitatively scored with the assistance of an Automated Digital Imaging System blinded to clinical outcome, and categorized by the staining index (intensity X % of staining /100) of > 2 (high) and ≤ 2 (low). The association between tumor pAkt level and clinical outcome at 10 years was assessed using multivariate Cox modeling adjusting for age, tumor size, number of positive nodes, tumor grade, estrogen receptor and HER2 status. Results: Among patients with low tumor pAkt levels (n = 975), there was no DFS difference between those treated with or without PTX (adjusted HR = 1.02, p = 0.81). However, among patients with high tumor pAkt levels (n = 606), those treated with AC→PTX had a 26% reduction in DFS event rate compared to those treated with AC only (adjusted HR = 0.74, p = 0.02). There was no OS difference between treatment groups for those with low pAkt cancer (HR = 0.97, p = 0.80). In patients with high pAkt cancer, those treated with AC→PTX had a 20% reduction in death rate compared to those treated with AC only but this difference did not reach statistical significance (adjusted HR = 0.80, p = 0.17). Conclusions: High levels of Akt phosphorylation at Ser473 independently predict a DFS benefit from the sequential addition of paclitaxel to adjuvant doxorubicin plus cyclophosphamide in node-positive breast cancer. Patients with low levels of pAkt breast cancer may not benefit from the sequential addition of PTX to doxorubicin plus cyclophosphamide. [Table: see text]