bluuebunny/crossref_metadata_2025 huggingface dataset:
Cognitive function in postmenopausal women receiving adjuvant letrozole or tamoxifen in the Breast International Group (BIG) 1–98 trial
Authors: Ribi K. E. , Phillips K. A. , Sun Z. , Stephens A. , Thompson A. , Harvey V. , Thürlimann B. , Cardoso F. , Coates A. S. , Bernhard J.
Published: August 2020

510

Background: Hormonal therapy for breast cancer (BC) may affect cognition. Methods: Post-menopausal women with hormone receptor positive, early-stage BC were randomized to receive either: A) tamoxifen for 5 years; B) letrozole for 5 years; C) tamoxifen for 2 years followed by letrozole for 3 years; or D) letrozole for 2 years followed by tamoxifen for 3 years, as adjuvant endocrine treatment. During the fifth year of trial treatment, objective cognitive function (speed of psychomotor function, visual attention, working and verbal memory, learning) was evaluated by computerized tests. The difference in the composite score for patients taking letrozole (B+C; N= 65) versus tamoxifen (A+D; N = 55) at the time of testing was the primary comparison. Scores for each domain were standardized according to age-specific norms. Two-way ANOVA controlling for language was used to test the effect of treatment on cognitive function. Self-reported subjective cognitive function, psychological distress, fatigue and quality of life were also assessed. Results: Patient characteristics were balanced between groups. Both groups performed below age norms on most domains. The group taking letrozole had better overall cognitive function than the tamoxifen group (difference in mean composite scores = 0.278, p = 0.038, 95% CI: 0.015–0.540) and outperformed patients on tamoxifen for all domains (n.s.). Comparison of monotherapy arms A versus B supported better cognitive function among letrozole patients. Subjective cognitive function, psychological distress, fatigue, and quality of life did not differ between groups. Conclusions: Although letrozole results in lower circulating estrogen levels than tamoxifen, in this study BC patients taking adjuvant letrozole during the fifth year of treatment had better cognitive functioning than those taking tamoxifen.

[Table: see text]
A phase II study of S-1 for the treatment of cytokine-refractory metastatic renal cell carcinoma
Authors: Naito S. , Eto M. , Shinohara N. , Tomita Y. , Fujisawa M. , Namiki M. , Nishikido M. , Usami M. , Tsukamoto T. , Akaza H.
Published: August 2020

5100

Background: S-1 is a novel oral anticancer agent, contains tegafur (FT), a prodrug of 5-fluorouracil (5-FU), with 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) at a molar ratio of FT: CDHP: Oxo = 1:0.4:1. The purpose of this study was to evaluate the efficacy and safety of S-1 in cytokine-refractory metastatic renal cell carcinoma (mRCC), and to examine the relation between response and mRNA expression levels of 5-FU-related enzymes. Methods: Eligible patients had a histologically confirmed diagnosis of clear cell or papillary type of RCC, measurable lesions, treatment histories with cytokines, an ECOG performance status of 0 or 1 (2 was allowed in patients with bone metastasis), an age of at least 20 years, prior nephrectomy, and adequate organ functions. Any prior treatment for mRCC was discontinued more than 4 weeks before registration. S-1 was administered orally at a dose of 40 mg/m2 twice daily for 28 days, followed by 14 days of rest. The primary endpoint was the objective response rate (ORR) as confirmed by an independent reviewer. The planned sample size was 44 patients. The threshold response rate was defined as 5%, and the expected rate was set at 17.5%. If the lower limit of the 95% CI exceeded the threshold rate (6 of the 44), S-1 was evaluated to be effective. Formalin fixed paraffin embedded specimens, which had been obtained by radical nephrectomy, were used for mRNA expression assay, performed by RT-PCR method. Results: Between April 2006 and May 2007, 45 patients were enrolled, and 31 assay samples were obtained. ORR was 24.4% (11/45, 95% CI: 12.9 - 39.5%). The median PFS was 9.2 months. The median OS could not be calculated, but the survival rate at 1 year was 87.5%. The most common grade 3–4 adverse events assessed according to the CTCAE v.3.0 included anemia (6.7%), neutropenia (8.9%), anorexia (8.9%), hyperglycemia (6.7%), stomatitis (4.4%), diarrhea (4.4%), and fatigue (4.4%). On mRNA expression analysis, the expression level of 5-FU-related enzyme correlated with ORR and PFS. Conclusions: S-1 is effective and well tolerated in patients with cytokine-refractory mRCC. Measurement of the mRNA level of 5-FU-related enzyme in tumors before treatment may facilitate prediction of the response to S-1.

No significant financial relationships to disclose.
A phase II study of two dosing regimens of GSK 1363089 (GSK089), a dual MET/VEGFR2 inhibitor, in patients (pts) with papillary renal carcinoma (PRC)
Authors: Srinivasan R. , Linehan W. M. , Vaishampayan U. , Logan T. , Shankar S. M. , Sherman L. J. , Liu Y. , Choueiri T. K.
Published: August 2020

5103

Background: GSK089 is a potent, orally available small molecule inhibitor of MET and VEGFR2. Activating mutations and/or amplifications in MET have been described in pts with PRC. Two of 4 PRC pts treated with intermittent dosing of GSK089 on a Phase I study sustained partial responses (PR) for 1 and > 3 years respectively. The aim of the current study is to evaluate the efficacy, safety and tolerability of 2 dosing regimens of GSK089 as a single agent in pts with advanced sporadic PRC (SPRC) or hereditary PRC (HPRC). Methods: Adults with advanced PRC are enrolled in 2 cohorts with different dosing schedules of GSK089: cohort 1) 240 mg/day on days 1–5 of every 14 days (5-on/9-off); cohort 2) 80 mg daily. Pts are stratified based on status of MET-pathway activation (activating MET mutation, MET [7q31] amplification, or trisomy 7). The primary endpoint is RECIST response rate, assessed every 8 weeks. Plasma markers reflecting potential effects of MET inhibition and anti-VEGF therapy are analyzed. Results: As of December 15, 2008, 37 pts were enrolled in the 5-on/9-off cohort (19 with MET activation including 5 HPRC, 18 SPRC without MET activation or unknown MET status), and 16 pts in the daily dosing cohort (2 with HPRC, 14 SPRC with unknown MET status). Enrollment is ongoing in cohort 2. In cohort 1, of the 35 evaluable pts, 4 pts (2 HPRC and 2 SPRC) had confirmed PRs and 27 had stable disease (SD) as best response with 6 ≥12mo, 3 ≥ 9mo and 3 ≥ 6mo. Four of 5 HPRC pts (1 not evaluated) had shrinkage (15–53%) in all measurable tumors. Twenty-three SPRC pts had shrinkage (2–58%) in the sum of measurable tumors. In cohort 2, of the 9 evaluable pts, 2 (both SPRC) had confirmed PRs, and 7 had SD. The most frequent adverse events (AEs) associated with GSK089 were fatigue, hypertension, nausea, vomiting, diarrhea, and increased ALT/AST, primarily grades 1 and 2. Preliminary results from cohort 1 indicated that plasma shed Met (sMET) and VEGF increased and sVEGFR2 decreased after 2 cycles with changes maintained after 4 cycles. Conclusions: GSK089 is well tolerated and demonstrates anti-tumor activity in pts with PRC with both 5-on/9-off and daily dosing. VEGF, sVEGFR2, and sMET are promising pharmacodynamic markers for biological activity of GSK089.

[Table: see text]
A phase I study of sorafenib and RAD001 for metastatic clear cell renal cell carcinoma
Authors: Harzstark A. L. , Rosenberg J. E. , Weinberg V. K. , Sun J. , Ryan C. J. , Lin A. M. , Fong L. , Brocks D. R. , Small E. J.
Published: August 2020

5104

Background: Both RAD001 and sorafenib have activity against advanced clear cell renal cell carcinoma (ccRCC). Inhibition of both mTOR and angiogenesis may improve outcomes; therefore, a phase I trial combining sorafenib and RAD001 was undertaken. Methods: Cohorts of 3 or 6 patients with ccRCC were treated with a 7 day run-in period of sorafenib 400 mg PO BID continuously followed by RAD001 (dose level I: 2.5 mg, dose level II: 5 mg) PO QD and sorafenib 400 mg PO BID continuously. Pharmacokinetic sampling of sorafenib was obtained on day -1, and of both RAD001 and sorafenib on day 15 of combination therapy. Dose-limiting toxicity (DLT) was defined as occurring within the first 28 days of therapy. Results: Fifteen patients with a median age of 65 (range 51–75) have been enrolled. Two patients were not evaluable for response or DLT evaluation. Five pts were treated with sunitinib previously. Zero of 6 pts on dose level 1 experienced a DLT. Two of 9 pts treated at dose level II have experienced protocol-defined DLTs (grade 4 uric acid and grade 3 lipase with grade 2 pancreatitis). Independently-reviewed best objective responses in 13 evaluable pts include 3 confirmed partial responses (10, 17+, and 23+ months), 6 stable disease (2+, 4+, 4.5, 6+, 13, and 23+ months), and 4 progressive disease. Steady state dosing of RAD001 demonstrated a steady state AUC0–24h of RAD001 of 193.3 (± 32.9) ng h/mL at a dosage of 5 mg QD, comparable to the single agent 5 mg QD steady state dosing AUC0–24h of 238 (± 77) ng h/mL, suggesting there is no pharmacokinetic interaction between RAD001 and sorafenib. Linear pharmacokinetics between the 2.5 and 5 mg QD dosages of RAD001 were observed. The AUC0–24h of sorafenib was not significantly changed by concomitant dosing with RAD001 with a steady state AUC0–24h of 134600 (±42072) ng h/mL pre-RAD001 and a post-sorafenib steady state AUC0–24h of 131451 (±53838) ng h/mL. Conclusions: Combination therapy with sorafenib and RAD001 is safe and feasible. No clinically relevant pharmacokinetic interaction was observed. Activity for the combination has been observed and a phase II study is planned at the 5 mg QD dosage of RAD001.

No significant financial relationships to disclose.
The effect of zoledronic acid on bone metastasis in patients suffering from renal cell cancer (RCC): A German prospective single-arm clinical trial
Authors: Tunn U. , Stenzl A. , Kindler M. , Strauss A. , Miller K. , Ruebel A. , Albrecht M. , Gruenwald V.
Published: August 2020

5107

Background: The incidence of RCC increased over the last decades and about 30% of patients will develop bone metastasis. These pts. face considerable skeletal morbidity e.g. bone pain, pathologic fractures, spinal cord compression or tumor induced hypercalcemia (TIH). A prospective trial was initiated in RCC metastatic to bone evaluating the SRE (skeletal related event) rate under therapy with zoledronic acid (ZA). Primary objective was the proportion of pts. with at least one SRE after 12 months. Methods: Patients with RCC must have had ≥1 bone metastasis and ≤2 prior applications of a bisphosphonate. Bone lesions were diagnosed by bone scan and ≥1 lesion was confirmed using X-ray, CT or MRI. Pts. passed a 12 months treatment period receiving 4 mg ZA every 3 weeks. Pts. were followed every 3 weeks for 54 weeks for development of SREs (radiation or surgery to bone, spinal cord compression, pathologic bone fractures) and TIH. A bone scan was done, if AP or LDH were >2xULN or symptoms occurred. Suspected SRE was confirmed by X-ray, CT or MRI. After end of treatment patients entered a survival follow-up. Results: 51 pts. participated in the study. Median age was 63 years and 2/3 were male. Proportions of MSKCC risk groups good/intermediate/poor for pretreated pts. were 8%, 56%, and 18%, respectively. 78% of pts. suffered from ≤6 bone metastases. 18% had already experienced at least one SRE before study entry. 26% obtained prior medications, mainly interferons (20%), interleukins (16%) and chemotherapy (16%). 25 pts. completed the 12 months treatment period. Based on a preliminary analysis 13 pts. (26%) experienced at least one SRE with an absolute number of 23 events. No TIH was observed. Bone lesions response was observed in 3 pts. (2 CR, 1 PR) out of 33 pts. currently available. Final efficacy and safety results of the 12 months treatment phase will be shown at presentation. Conclusions: Pts. with mRCC and bone metastases are at high risk for experiencing an SRE with a reported incidence of up to 74%. This is the first study prospectively evaluating SRE rate in patients with mRCC and bone lesions receiving ZA. A preliminary analysis indicates an SRE-rate of 26% and no TIH was observed. Final results of this trial could further support the use of ZA in mRCC.

[Table: see text]
Bortezomib as brief neoadjuvant therapy for localized high-risk prostate cancer (PCa) followed by radical prostatectomy (RP)
Authors: Sonpavde G. , Frolov A. , Macdonell V. , Hayes T. G. , Mims M. P. , Ayala G. E. , Wheeler T. M. , Thompson T. C. , Ittman M. M. , Kadmon D.
Published: August 2020

5127

Background: Neoadjuvant therapy may provide an important paradigm for the discovery of active agents for the therapy of PCa. Bortezomib is a proteasome inhibitor with preclinical activity in PCa. A rationale can be made to study brief preoperative bortezomib before RP to determine feasibility and biologic activity. Methods: A phase II trial was designed to evaluate bortezomib 1.6mg/m2 as intravenous bolus weekly for 4 weeks followed by RP 24–72 hours after the last dose. Histological evidence of adenocarcinoma of the prostate was required with clinical stage T1c or T2a with Gleason 8–10 disease, or clinical stage T2b-T2c with Gleason grade 7 and PSA of >10 ng/mL, or clinical stage T3. Results: Accrual is complete with 40 patients enrolled, of whom 38 completed neoadjuvant bortezomib followed by RP and are evaluable. The median age was 60.2 years. No pathologic complete responses were noted. Cytopathic effects (cytolysis, nuclear pyknosis) were commonly seen compared to baseline tumor. Upregulation of apoptosis, proliferation and phosphorylated (p)-Akt have been previously reported in a subset of patients by our group (Ayala GE et al, Clin Cancer Res. 2008;14:7511–8). Two of 8 evaluable patients had a >50% decrease in serum PSA with bortezomib treatment; 3 others had PSA declines of 14%, 25%, and 45%, respectively; 1 patient had no change, and 2 displayed PSA increases. Therapy was feasible with generally manageable toxicities, and surgical morbidities did not increase. A comprehensive toxicity analysis will be presented. Feasibility of surgery, extraprostatic extension, positive margin and lymph node positive rates will be compared with matched historical controls and these data will be presented. Conclusions: Bortezomib is feasible as neoadjuvant therapy preceding RP for PCa and demonstrates biologic activity. Given the upregulation of proliferation and pAkt, the further evaluation of bortezomib may be warranted in randomized trials in combination with chemotherapy or Akt inhibitors.

[Table: see text]
Comparability of health-related quality of life (HRQOL), treatment decision making, and treatment satisfaction after PSA recurrence among prostate cancer patients who receive hormone therapy (HT) versus observation (OBS): Results from the COMPARE registry
Authors: Luu T. , Sartor O. , Dandade N. , Halabi S. , Bennett C.
Published: August 2020

5131

Background: HT may lower PSA, but it may also cause hot flashes and sexual dysfunction. OBS is not associated with hot flashes or lower testosterone production, but PSA may rise. Examining patient satisfaction with treatment decision making, treatment choice, and HRQOL may help improve disease management. We compared treatment satisfaction and HRQOL of patients who chose OBS over HT. Methods: The Comprehensive Multicenter Prostate Adenocarcinoma Registry (COMPARE) is an observational registry of men with PSA failure. Data from patient-reported questionnaires were analyzed for patients treated with OBS or HT. Results: 674 patients (82%) chose OBS; 147 (18%) chose HT. The median time between cancer diagnosis and registry enrollment was 6 years. Of men on OBS, 85%, 83%, and 71% were satisfied with treatment decision process, treatment choice, and treatment outcome, respectively. Men on HT had similar rates of satisfaction (82%, 75%, and 71%). Men initially treated with brachytherapy/surgery were less satisfied with OBS. Men initially treated with external beam radiation were less satisfied with HT. Patients reported similar problems with urinary, sexual, and bowel function. Conclusions: Men with PSA failure seem content with treatment choice and decision making and have low rates of urinary/bowel problems. Rates of sexual dysfunction in both groups are similar. Clinical trials may help determine if HT improves long-term outcomes (e.g. overall survival), since short-term patient reported satisfaction is similar between OBS and HT. The reported rate of sexual dysfunction is lower than expected.

[Table: see text]

[Table: see text]
Development of risk groups in metastatic castration-resistant prostate cancer (mCRPC) to facilitate the identification of active chemotherapy regimens
Authors: Armstrong A. J. , Halabi S. , Tannock I. F. , George D. J. , DeWit R. , Eisenberger M.
Published: August 2020

5137

Background: Our aim was to develop and validate clinically applicable predictive factors for a >30% PSA decline 3 months following chemotherapy initiation, and to assess the performance of a risk-group based classification in predicting PSA declines and overall survival (OS) in men receiving chemotherapy for mCRPC. Methods: In TAX327, 1006 men with mCRPC were randomized to receive docetaxel (D) in two schedules, or mitoxantrone (M), each with prednisone: 989 provided data on PSA decline at 3 months. Predictive factors for a >30% 3-month decline in PSA levels were identified using multivariate logistic regression in D treated men (n = 656) and validated in M treated men (n = 333). Risk factors were combined to form risk groups to predict PSA declines, OS, tumor, and pain responses. Prostate Cancer Working Group (PCWG2) disease states were evaluated for these outcomes in docetaxel treated men. Results: In multivariate analysis, four independent risk factors predicted for absence of >30% decline in 3-month PSA: significant baseline pain (OR 0.63 p = 0.02), visceral metastases (OR 0.66, p = 0.03), anemia (hemoglobin <13 g/dl, OR 0.72 p = 0.07), and bone scan progression at baseline (OR 0.60 p = 0.009). Predictive accuracy was moderate with a concordance index (c-index) of 0.61. Risk groups (good, intermediate, poor) were developed with median OS of 25.7 (95% CI 23.3–28.6), 18.7 (17.3–19.7), and 12.8 (11.5–14.6) months, respectively (p < 0.0001), and >30% PSA decline in 78, 66, and 58 percent of men (p < 0.001). In the validation M cohort, similar trends for PSA declines and OS were noted across risk groups (OS 22.5, 16.0, 11.8 mo, p < 0.001). PCWG2 subtypes (node only, bone metastatic, and visceral disease), were also highly prognostic and predictive but did not predict OS as well as the TAX327 risk groups (c-index 0.56). Conclusions: Risk groups have been identified and internally validated that predict PSA decline and OS in men with mCRPC. This classification may facilitate evaluation of new regimens of systemic therapy that warrant definitive testing in comparison to docetaxel and prednisone in phase III trials. Prospective validation of these risk groups is needed.

[Table: see text]
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.

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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.
Management of bone loss in breast cancer patients: 24-month results from the ARBI trial of anastrozole with risedronate
Authors: Markopoulos C. , Tzorakoleftherakis E. , Polychronis A. , Venizelos V. , Xepapadakis G. , Kalogerakos K. , Papadiamantis J. , Zobolas V. , Janinis J. , Dafni U.
Published: August 2020

552

Background: The management of bone mineral density (BMD) in postmenopausal, breast cancer (BC) patients (pts) receiveing anastrozole was investigated in this phase III, multicenter, open label trial. Methods: Pretreatment BMD of 217 eligible pts with hormone receptor-positive BC scheduled to receive anastrozole was evaluated at lumbar spine (LS) and hip (HP). Pts with T-score<-2.0 in LS or HP, received anastrozole 1mg/day plus oral risedronate 35 mg/week (A+R) and pts with T-score>-1 in both sites received anastrozole only (A). Pts with T-score<-1 in either site but T-score>-2.0 in both sites were randomized to receive A+R or A alone. All pts received Calcium and Vit D daily. BMD was then assessed at 12 and 24 months. Results: Comparison of randomized arms (A = 33 pts, A+R = 37 pts): T-score change from baseline was significantly different only for LS at 24 months (-0.23 in A vs 0.41 in A+R, Wilcoxon test p = 0.007) and was significantly higher from baseline for the A+R arm (Signed rank test p = 0.01). At 12 months, among A only pts, 4 (12.1%) had a T-score<-2.0 without becoming osteoporotic, while 2(6.1%) moved to the normal BMD region; from A+R pts, only 2(5.4%) had a T-score<-2.0 without becoming osteoporotic, while 9 (24.3%) moved to the normal BMD region. The same trend in BMD changes was also observed at the 24 month evaluation. Group with T-score<-2.0 in either LS or HP (A+R, n = 99): a significant increase for LS both at 12 and 24 months was detected (median increase of T-score by 0.45 and 0.37, p<0.01 for both time points) with a corresponding non-significant change in HP (p = 0.91 and p = 0.15). BMD in 13(13.3%) pts improved to the osteopenic region (-2.0<T-score<-1.0). Group with T-score>-1 in both sites (A, n = 48): significant decrease was detected for HP and LS, both at 12 and 24 months; however, only 11 (22%) pts became osteopenic and 1(2%) became osteoporotic. Conclusions: The addition of oral risedronate in postmenopausal BC patients with osteopenia receiving anastrozole has a favourable effect in BMD at lumbar spine at 24 months.

[Table: see text]
Phase II evaluation of cisplatin plus cetuximab in the treatment of recurrent and persistent cancers of the cervix: A limited access phase II study of the Gynecologic Oncology Group
Authors: Farley J. H. , Sill M. , Walker J. L. , Schilder R. J. , Thigpen J. T. , Coleman R. L. , Miller B. E.
Published: August 2020

5521

Background: A majority of cervical cancer patients overexpress epidermal growth factor receptor (EGFR), which is a poor prognostic factor. Cetuximab (C225) is a murine monoclonal antibody that binds to EGFR and competes with ligand binding and tyrosine kinase activation.Given the evidence of activity in squamous carcinomas of the head and neck, the purpose of this study was to evaluate the safety and efficacy of cisplatin and cetuximab chemotherapy. Methods: Women with advanced, persistent, or recurrent carcinoma of the cervix not amenable to cure were eligible for this study. Only prior chemotherapy (CT) administered in conjunction with primary radiation as a radiosensitizer was allowed. Women could not have received prior anti-EGFR antibody therapy or therapy with a tyrosine kinase inhibitor that targets the EGFR pathway. All women had measurable disease and a GOG performance status ≤ 2. The women received cisplatin at 30 mg/m2 days 1 and 8. The first dose of C225 was given at 400 mg/m2. All subsequent doses of C225 were given at 250 mg/m2. C225 was given on days 1, 8, and 15. Each cycle was 21 days. Adverse events were assessed with CTCAE v 3.0. Primary measure of clinical efficacy was the frequency of tumor response. The study was stratified by prior CT. The design required at least 16 responses in a sample of 40 with prior CT and 29 without prior CT before the regimen was considered for phase III testing. Results: Between September 2004 and March 2008, 76 patients were entered onto the study. Of these, 69 were eligible and evaluable. Three patients were on study at the time of the analysis. 56 (81%) patients had received prior radiation. 40 (58%) patients previously received prior CT. There were 8 (12%) responses. The response rate was 8% among patients with prior CT, and 17% among CT naïve patients. One woman had grade 4 anemia. The most common grade 3 toxicities were metabolic (14), dermatologic (8), fatigue (6), and gastrointestinal (6). Conclusions: The combination of cetuximab with cisplatin was adequately tolerated but did not indicate additional benefit beyond cisplatin therapy. Stratification of patients based upon K-ras mutation and/or EGFR status may select a group for which this regimen is most effective.

No significant financial relationships to disclose.