bluuebunny/crossref_metadata_2025_split huggingface dataset:
SWOG S0354: A phase II trial of CNTO328, a monoclonal antibody against interleukin-6 (IL-6), in chemotherapy pretreated patients (pts) with castration- resistant prostate cancer (CRPC)
Authors: Pinski J. K. , Goldman B. , Dorff T. , Mack P. , Lara P. , van Veldhuizen P. , Quinn D. , Hussain M. H. , Thompson I. M. 
Published: August 2020

5143 Background: IL-6 facilitates cancer cell survival via pleiotrophic effects on proliferation, apoptosis, angiogenesis, differentiation, and chemo-resistance. A multicenter phase II study of CNTO328 in chemo pretreated CRPC pts was conducted. Methods: Eligible pts had one prior chemotherapy, Zubrod performance status 0–2, and adequate end-organ function. Regimen: CNTO328 6 mg/kg IV q2 weeks x 12 cycles. Response assessment was q6 weeks. Primary endpoint was PSA response rate (RR) defined as ≥50% reduction. Accrual was completed in 2 stages, with planned accrual of 20 eligible pts in the first stage and 40 overall. Plasma cytokines were measured by Luminex in 44 pts. Results: Of 62 pts, 54 were eligible; all had received prior taxane therapy. Two (3.7%; 95% CI: 0.5%, 12.8%) had PSA response. Of 47 pts evaluable by RECIST, none had a response and 10 (21%) had stable disease (SD). With median follow-up of 6.6 months, median progression-free survival is 1.6 months (95% CI: 1.6, 1.7). Grade 4 toxicity included 1 case of DIC and 1 CNS ischemia; grade 3 toxicities included elevated AST (1), gastritis/esophagitis (2), thrombocytopenia (2), pain (2), leucopenia (1), and neuropathy (2). Median baseline IL-6 levels were 12.5 pg/mL (IQR: 2.5, 41.5). Pts with levels >12.5 pg/mL had worse 6-month survival vs. < 12.5 pg/mL (53% vs 94%, p = 0.02). Post-cycle 1, IL-6 levels were > 250-fold higher, indicating antibody-target complex formation. 33/39 pts had a decline in C-reactive protein (CRP) plasma levels at 6 weeks. Conclusions: CNTO328 was well-tolerated and resulted in a PSA RR of 3.7% and RECIST SD rate of 21%. Declining CRP levels during treatment reflect biologic activity. Elevated baseline IL-6 levels portend a poor prognosis. Additional translational studies will be presented. Additional study of CNTO328 in combination may be warranted. [Table: see text]
Preliminary report of an open-label, multicenter, phase I/II study of AT-101 in combination with docetaxel (D) and prednisone (P) in men with docetaxel refractory prostate cancer
Authors: Poiesz B. , Reeves J. , McNulty W. , Maleski J. , Holmlund J. , Leopold L. 
Published: August 2020

5145 Background: Antiapoptotic Bcl-2 family proteins are overexpressed in castrate resistant prostate cancer (CRPC) and contribute to resistance to therapy. AT-101 is a pan-Bcl-2 inhibitor (Bcl-2, Bcl-XL, Bcl-W, and Mcl-1) and potent inducer of proapoptotic proteins. AT-101 is active as a single agent and in combinations with standard therapies in in vitro and in vivo tumor models, as a single agent in a phase II trial in CRPC, and in combination with D/P as first-line therapy in CRPC, as demonstrated by declines in PSA and RECIST responses. Methods: Men ≥18 years of age with docetaxel-refractory CRPC were eligible. Patients (pts) must have PSA progression per the Bubley criteria or documented disease progression while receiving prior D/P therapy. Pts (n = 40) were treated with D (75 mg/m2 day 1), P (5mg b.i.d. on days 1–21) and AT-101 40mg b.i.d. on days 1–3 of each 21-day cycle. Safety (NCI CTCAE v3.0) and efficacy (Bubley Criteria for PSA) were assessed at 3-wk intervals. Radiological assessments were performed at 6-wk intervals for pts with soft tissue disease and bone scans were performed after cycle 6 and at the completion of therapy. Results: Efficacy data was available on 34 pts. Thirty-five percent (12/34) of pts treated had at least a 30% decrease in PSA level and 18% (6/34) of pts achieved a >50% PSA decline. Twenty one of 34 pts included in this analysis had measurable disease. Five pts (24%) with measurable disease had a PR or CR by RECIST criteria and one additional patient had tumor shrinkage of 29%. Two (2) RECIST PRs are unconfirmed. Thus far, 3 pts have been on therapy for 6 months or more and 15 pts remain on study. Safety data was available on 22 pts. The most common (>20%) adverse events (AEs) included fatigue (55%), anorexia, including weight decreased (45%), diarrhea and nausea (27%), vomiting and neutropenia (23%). The grade 3/4 AEs occurring in more than 1 pt were: neutropenia (5), anemia, anorexia, dyspnea and leukopenia (2 pts each). One partial small bowel obstruction was the only related, serious adverse event (SAE) reported to date. Conclusions: This data supports that AT-101 can be administered safely with D/P in pts with CRPC who are docetaxel-refractory. Durable PSA and RECIST responses were observed. [Table: see text]
Phase II trial of nab-paclitaxel as first-line therapy of hormone refractory metastatic prostate cancer (HRPC)
Authors: Kolevska T. , Ryan C. J. , Huey V. , Weisberg L. , Wang S. , Baer D. , Ghadialy A. , Goldstein D. , Fireman B. , Fehrenbacher L. 
Published: August 2020

5152 Background: Many patients with hormone refractory prostate cancer have poor tolerance to treatment. Docetaxel chemotherapy was shown to improve survival but has substantial toxicity, requires steroid administration, may cause poorly reversible neuropathy and requires long infusion times, all limiting its use. Nab-paclitaxel, an albumin-bound nanopaticle form of paclitaxel, delivers paclitaxel without steroids, requires only 30 minutes infusion time and has favorable toxicity profile that may be more tolerable but effective in patients with prostate cancer. The goal of this study was to evaluate the efficacy and toxicity of nab-paclitaxel in first line chemotherapy of men with castration resistant prostate cancer. Methods: nab-paclitaxel was given iv100 mg/m2 weekly x 3 of 4 weeks cycles. Main eligibility criteria include: hormone refractory metastatic prostate cancer, no prior chemotherapy, performance status 0–2. Primary endpoint was efficacy based on prostate-specific antigen (PSA) response. PSA response was PSA decrease of >50%, progressive disease (PD) was PSA increase of >25%, stable disease (SD) was <25% PSA increase or <50% decrease sustained longer that 8 weeks. Results: There are 38 patients enrolled, 35 were evaluable for response. Median age was 71 years old (range 57–86). One patient discontinued the treatment after 1 infusion due to toxicity (elevated ALT). PSA response was seen in 9 (25%) patients and SD in 15 patients (43%), with an overall response rate of 25% and clinical benefit of 68%. Seven patients received treatment for ≥ 6 months with minimal toxicity (range 6–10 months). Grade 3 related hematologic toxicity was reported in 7 (18%) patients (4 anemia, 4 neutropenia), grade 3 related non-hematologic toxicity was reported in 6 patients (1 hypokalemia, 1 muscle weakness, 2 fatigue, 1 fever, 1 neuropathy, 1 ALT elevation). Conclusions: Nab-paclitaxel has activity in patients with metastatic hormone refractory prostate cancer. This regimen was well tolerated, and may be useful in patients who are not suitable candidates for docetaxel based therapy. [Table: see text]
Phase I trial of RAD001 (R), bevacizumab (B), and docetaxel (D) for castration-resistant prostate cancer (CRPC)
Authors: Gross M. E. , Soscia J. , Sakowsky S. , Castellanos O. , Agus D. B. 
Published: August 2020

5154 Background: Targeting of mTOR and vascular endothelial growth factor (VEGF) alone or with chemotherapy has been reported for CRPC. We report a dose finding study combining mTOR and VEGF inhibitors along with docetaxel for advanced CRPC. Methods: Eligible patients (pts) had progressive, metastatic, chemo-naive CRPC. A modified adaptive design was used to explore 3 dose levels. 3 pts were treated in each cohort, expanded by 3 pts if a dose limiting toxicity (DLT) was observed. If no DLT occurred after all pts completed 2 cycles in a cohort, pts were enrolled at the next dose level. If a DLT was seen in 2 pts, that dose level was closed. Dose levels included: cohort 1 (D 75 mg/m2, R 2.5 mg, B 15 mg/kg); cohort 2 (D 75 mg/m2, R 5 mg, B 15 mg/kg); and cohort 3 (D 65 mg/m2, R 5 mg, B 15 mg/kg). D+B was given IV day (d) 1 and R PO days 1–21 on a 21 d cycle. Efficacy is explored as: maximal confirmed PSA decline; partial or complete response (PR+CR) by RECIST criteria; and/or changes in bone scintigraphy. Results: 12 patients have been enrolled to complete the dose-finding phase. Baseline median (range) values include: age 70 (58–78) yrs, PSA 115 (4–1336) ng/mL, alkaline phosphatase 107 (37–763) U/L. All pts had PSA elevations, 5 pts had metastasis to lung and/or lymph nodes. 9 pts had bone metastases. Common toxicities were fatigue and mucositis. DLTs by dose level is summarized as: cohort 1, DLT in 1 of 6 pts (neutropenic fever/grade (Gr) 3, pneumonia/Gr 3, 1 individual pt); cohort 2, DLT in 2 of 2 pts (neutropenic fever /Gr 3, 2 pts); cohort 3, DLT in 3 of 4 pts (neutropenic fever /Gr 3 and Gr 5, pulmonary embolism/ Gr 3, 3 pts). A pt in cohort 3 died from neutropenic fever and sepsis at cycle 3 despite dose modifications and growth factor support. Preliminary measures of efficacy by method of assessment and cohort assignment are summarized ( Table ). Conclusions: We conclude that the cohort 1 dose level of D 75 mg/m2, R 2.5 mg, B 15 mg/kg is safe and demonstrates anti-cancer efficacy. Pt accrual continues at this dose level for the dose-expansion phase of the study. [Table: see text] No significant financial relationships to disclose.
Chronic fatigue in prostate cancer patients after radical prostatectomy (RP) or high-dose radiotherapy (RAD)
Authors: Kyrdalen A. E. , Hernes E. , Fossa S. D. , Dahl A. A. 
Published: August 2020

5164 Background: Chronic fatigue (CF) is frequent in cancer patients, but has been less studied in prostate cancer patients (PCPs). This study compares CF in PCPs treated with RP or RAD(≥70Gy), who have never received any hormonal therapy. Methods: In 2006 we addressed all Norwegian PCPs who had been diagnosed in 2004 and were alive (N = 2,997). Among the 2,194 PCPs (73%) responding we identified 332 patients with RP and 183 with RAD 12–32 months before our survey. The PCPs returned a mailed questionnaire covering fatigue, quality of life, urinary and bowel bother, sexual function, comorbidity, and lifestyle. Hormonal therapy identified by the national prescription database or self-report, lead to exclusion. Caseness of CF was based on the Fatigue Questionnaire. Results: Caseness of CF was observed in 13.6% of men with RP (95%CI 9.9–17.2%) and in 25.7% after RAD (95%CI 19.4–32.0%) (p = 0.001). The prevalence in the RP group was similar to the norm observed in Norwegian men >60 years. PCPs with RP or RAD had similar prevalence of bother regarding urinary symptoms (13 vs 16%, p = 0.13), while more RAD than RP patients reported bother due to bowel symptoms (24 vs 4%, p < 0.001). Sexual functioning showed a better score in the RAD versus the RP group (p < 0001). In multivariate regression analysis treatment modality did not show any significant association with CF (p = 0.25). In contrast, physical and mental quality of life (both p < 0.001) and bother due to bowel problems (p = 0.005) were associated with CF caseness. No significant associations were found between urinary bother, sexual function and CF caseness. Conclusions: This national study of PCP treated with curative intention showed a much higher prevalence of CF after RAD compared to RP. In multivariate analysis treatment modality was not significantly associated with CF caseness. Bowel bother was more common after RAD, and showed a significant association with CF caseness, however, with a wide confidence interval. No significant financial relationships to disclose.
Predicting the efficacy of anthracyclines in breast cancer (BC) patients: Results of the neoadjuvant TOP trial
Authors: Desmedt C. , Azambuja E. , Larsimont D. , Rouas G. , Di Leo A. , Delaloge S. , Duhem C. , D'Hondt V. , Piccart M. , Sotiriou C. 
Published: August 2020

523 Background: Anthracycline-based regimens are among the most active and used chemotherapies in BC. Here, we report the results of the prospective TOP trial ( NCT00162812 ) which was specifically designed to identify markers of response/resistance to preoperative epirubicin (100 mg/m2 q2 or q3wks) in estrogen receptor-negative (ER-) BC patients. Methods: Using pre-epirubicin biopsies, we analyzed TOP2A by fluorescence in situ hybridization (Abbott triple probe) and by immunohistochemistry (KiS1) and generated gene expression profiles (HG133Plus2.0). We used publicly available gene expression data from the BIG1–00, trial (EORTC-10094), which compared in a preoperative setting an anthracycline-based (A) to a taxane-based (T) regimen, to validate some of our results. Results: 149 patients were included in the TOP trial and 14.5% had a complete pathological response (pCR). TOP2A amplification (11% of the cases) was exclusively observed in HER-2 amplified cases (33% of the cases), and was highly predictive of pCR (k = 0.35, p = 0.0002 - half of the patients with TOP2A amplification experienced pCR). Neither the protein levels nor the mRNA levels were predictive of pCR. Chromosome17 (Ch17) polysomy was observed in 68% of the samples and was not associated with pCR. TOP2A gene expression module (made of genes located closely to TOP2A), was predictive of response both in the HER-2+ patients of the TOP trial and in the ER-/HER-2+ of the BIG1–00 patients treated with A but not with T [Area Under the Curve (AUC): 0.86 (p = 0.00001) in TOP trial and 0.81 (p = 0.0005) in A-arm BIG1–00 trial]. Stroma expression module defined previously was associated with pCR in both trials (TOP and in the ER- BIG1–00 patients treated with A but not with T, especially in HER-2- patients [AUC: 0.31 (p = 0.01) in TOP trial and 0.33 (p = 0.02) in A-arm/BIG1–00 trial]. Conclusions: This trial, which is the first to prospectively evaluate the predictive value of TOP2A, supports TOP2A gene amplification as predictive marker of response. Ch17 polysomy, observed in ∼2/3 of these ER- patients, was not predictive of response. Finally, our results suggest that gene expression modules also predict relative response/resistance to anthracyclines, both in HER-2+ and HER-2- patients. No significant financial relationships to disclose.
Expression profile of CTC and corresponding tumors in primary breast cancer patients
Authors: Tanja F. N. , Hoffmann O. , Aktas B. , Solomayer E. , Wallwiener D. , Becker S. , Kimmig R. , Kasimir-Baur S. 
Published: August 2020

538 Background: The target of adjuvant therapy in breast cancer is minimal residual disease (MRD). However, treatment decisions are based on expression of predictive markers (ER; PR, HER-2) of the primary tumor. Based on current studies, presence of MRD may be reflected by the detection of circulating tumor cells (CTC). Therefore, the aim of the study was to characterize CTC by multiplex-PCR for the expression of HER-2, ER, and PR and compare the expression profiles of CTCs with those of the corresponding primary tumors. Methods: CTC from blood of 431 patients with primary breast cancer were analyzed for EpCAM, MUC1, and HER-2 transcripts with the AdnaTest BreastCancer (AdnaGen AG, Germany). A blood samples was CTC positive when at least one of the markers was detected. Expression of the ER and PR receptor was assessed in an additional RT-PCR. The ER, PR and HER2 receptor status of the primary tumors was determined by immunohistochemistry. The DAKO-Score for the expression of HER-2 was determined with the HercepTest. Results: The overall detection rate for CTC was 13% (58/431 patients) with the expression rates of 38% for HER-2 (22/58 patients), 25% for ER (12/48) and 4% for PR (2/48), respectively. ER positivity of the primary tumor was demonstrated in 45/58 (78%) of these patients, PR positivity in 41/58 (71%) patients and HER-2 in 9/58 (16%) patients, respectively. The concordance rate between ER, PR, and HER-2 status of CTCs and the primary tumor was 29%, 25%, and 53%, respectively Interestingly, the spread of CTC was mostly found in triple negative tumors (p = 0.01) and CTC in general were mostly found to be triple-negative regardless of the ER, PR, and HER-2 status of the primary tumor. Conclusions: Since the expression profile between CTC and the primary tumor differs, the consequence for the selection of adjuvant treatment targeting minimal residual disease has to be further evaluated in clinical trials. No significant financial relationships to disclose.
Assessment of trastuzumab-related cardiac dysfunction in the Herceptin Adjuvant (HERA) Trial with 3.6 years median follow- up
Authors: Procter M. J. , Suter T. , de Azamuja E. , Muehlbauer S. , Dafni U. , van Veldhuisen D. J. , Muscholl M. , Piccart-Gebhart M. 
Published: August 2020

540 Background: The Herceptin Adjuvant (HERA) Trial is a three-group randomized trial that compared 1 year or 2 years trastuzumab with observation. We investigated cardiac dysfunction in HERA patients randomized to observation or 1 year trastuzumab and report results at a median follow-up of 3.6 years. Methods: Only patients who after completion of (neo)adjuvant chemotherapy with or without radiotherapy had normal left ventricular ejection fraction (LVEF > 55%) were eligible. Cardiac function was monitored throughout the trial. A repeat LVEF assessment was required in case of cardiac dysfunction. Results: There were 1,698 patients randomized to observation and 1,703 randomized to 1 year trastuzumab. The incidence of discontinuation of trastuzumab due to cardiac disorders was low (5.1%). The incidence of cardiac endpoints was low (severe CHF 0.77% in the trastuzumab group). The incidence of cardiac endpoints was higher in the trastuzumab group compared to observation (severe CHF 0.77% vs 0.00%; confirmed significant LVEF drops 3.57% vs 0.64%). In the trastuzumab group, there were no occurrences of severe CHF after the end of the scheduled treatment period of 1 year. Among the patients in the trastuzumab group with confirmed significant LVEF drop, the first occurrence was within the scheduled treatment period of 1 year for 55 out of 60 patients (91.7%). In the trastuzumab group, 59 of 73 patients (80.8%) with a cardiac endpoint reached acute recovery and of these 59 patients 52 (88.1%) were consider to have a favourable long term outcome. Conclusions: The incidence of cardiac endpoints remains low even with longer term follow-up. The cumulative incidence of any type of cardiac endpoint increases during the scheduled treatment period of 1 year, but appears to remain approximately constant after the scheduled treatment period of 1 year is completed. [Table: see text]
Neoadjuvant cisplatin and bevacizumab in triple negative breast cancer (TNBC): Safety and efficacy
Authors: Ryan P. D. , Tung N. M. , Isakoff S. J. , Golshan M. , Richardson A. , Corben A. D. , Smith B. L. , Gelman R. , Winer E. P. , Garber J. E. 
Published: August 2020

551 Background: We have previously shown that neoadjuvant cisplatin has activity in TNBC, a subtype of breast cancer for which there is no effective targeted therapy. Bevacizumab adds to the efficacy of chemotherapy in metastatic breast cancer; however, there is limited data on the safety or efficacy of bevacizumab in combination with chemotherapy in the neoadjuvant or adjuvant setting. Thus, we sought to explore the safety and efficacy of the addition of bevacizumab to cisplatin in the treatment of TNBC. Methods: 51 patients (pts) with confirmed TNBC provided informed consent and were enrolled in a single arm phase II trial of neoadjuvant cisplatin 75 mg/m2 q 3 weeks x 4 cycles and bevacizumab 15 mg/kg q 3 weeks x 3 cycles prior to definitive surgery. Only 3 cycles of bevacizumab were delivered to allow 6 weeks between the last dose of bevacizumab and surgery. Research biopsies were obtained and breast MRI performed before treatment and at surgery. Postoperatively, pts received doxorubicin and cytoxan (AC) plus bevacizumab or AC/Taxol plus bevacizumab. Median age was 50 yrs (range 30 to 66 yrs); tumors were clinical T1 (2%), T2 (80%), T3 (18%). Results: Forty-six pts are evaluable for response and 5 pts are still receiving neoadjuvant therapy. Clinical responses to date: 12/46 (26%) clinical complete response (cCR), 24/46 (52%) clinical partial response (cPR), 5/46 (11%) stable disease (SD), and 1/46 (2%) progressive disease (PD). Non-responders included 4/46 (9%) pts who discontinued protocol therapy for toxicity. To date, 7/46 (15%) pts achieved a complete pathological response (Miller-Payne 5) and an additional 10/46 (22%) were Miller-Payne 4. Five pts did not complete neoadjuvant therapy, 2 with tinnitus/hearing loss and 3 with grade 4 toxicities consisting of refractory hypertension in 1 pt and pulmonary embolism (PE) in 2 pts. Tissue-based assays to predict platinum/bevacizumab responses, including BRCA1/2 status, are underway. Conclusions: Cisplatin and bevacizumab has some activity in TNBC as demonstrated by 37% of evaluable pts with a Miller-Payne 4 or 5 pathological response. However, toxicity, including tinnitus/hearing loss, hypertension and PE, limited completion of neoadjuvant therapy in 11% of pts. No significant financial relationships to disclose.
Improved outcomes in advanced stage uterine carcinosarcoma (mixed mullerian tumor [MMT])
Authors: O'Malley D. M. , Nagel C. , Cantrell L. A. , Havrilesky L. , Liotta M. , Alvarez Secord A. , Nickles A. , Cohn D. E. , Wallace A. , Rose P. , Gehrig P. 
Published: August 2020

5518 Background: There is currently no consensus regarding the management of advanced stage uterine MMT. In an effort to better define postoperative treatment modalities and their associated outcomes, we retrospectively reviewed factors that influence progression and survival. Methods: A retrospective, multi-institution study of women diagnosed from 1997–2007 was performed. Post-operative treatment included either observation (OBS), RT (brachytherapy, whole pelvic, or combination), chemotherapy (CT) alone or with RT (CT+RT). The majority of chemotherapy regimens included carboplatinum/paclitaxel, Ifosfamide/cisplatin, cisplatin/adriamycin, Data collected included time to recurrence, overall survival and sites of recurrence. Statistics included t-test, ANOVA and Kaplan Meier. Results: 119 patients were identified with late stage uterine MMT. 81 had stage III disease and 38 had stage IV disease. The median age at diagnosis was 67 years (range: 30–86). 70 (59%) were Caucasian and 48 (40%) were African-American. 116 (87%) were optimally debulked and their survival further analyzed. 18 (15%) were observed and 9 of these patients recurred. This group had the poorest median progression free survival (PFS) of 3.4 months. The majority (N = 50, 49%) of late stage patients underwent adjuvant CT with a median PFS of 13.3 months and median OS of 15.6 months. Of these patients 33 (66%) recurred. 18 (17 %) patients underwent RT alone with a median PFS of 12.4 months and OS of 14.9 months. 14 (78%) of these patients recurred. 20 patients (19%) underwent a combination of CT and RT and 11 (55%) experienced recurrences . The combination therapy group had the longest median PFS of 14.3 months and OS of 17.2 months (p = 0.27). Conclusions: Chemotherapy had become the standard therapy for advanced stage MMT however the addition of radiation has not been established. Patients diagnosed with advanced stage MMT can achieve long-term DFS in a minority of patients (33%) treated with chemotherapy. We showed that the addition of radiation to adjuvant chemotherapy showed a slight improvement over chemotherapy alone yet the optimal therapy has yet to be defined. This retrospective review highlights the need for prospective trials of new therapeutic agents and treatment regimens for women with advanced stage uterine MMT. No significant financial relationships to disclose.