bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of the radical prostatectomy surgical technique and surgeon experience on freedom from cancer recurrence
Authors: Bianco F. J. , Eastham J. A. , Vickers A. J. , Serio A. M. , Pontes J. , Kline E. A. , Scardino P. T.
Published: March 2020

4569

Background: We have shown a direct relation between positive margin (PM), morbidity outcomes and surgeon volume, technique after radical prostatectomy (RP). Significant variation occurs even among high volume providers. Our aim was to analyze the surgeon effects on cancer control after RP. Methods: We evaluated 8196 consecutive cT1–3NxMx naive men who underwent RP by one of 76 surgeons within 4 institutions between 1987 and 2003. We calculated the 5-yr probability of recurrence (BCR, PSA elevation >0.4 ng/ml × 2 or initiation of secondary therapy for a PSA rise) for each surgeon assuming a log-logistic survival distribution. A meta-analysis controlling for case mix: PSA, Gleason score, stage, PM and surgical expertise (i.e. cumulative number of surgeries performed) to evaluate for differences in BCR rates between surgeons was performed. We applied the I-square statistic to determine what proportion of the variation represented genuine differences v. chance alone. Results: 33 surgeons performed > 40 RP with 17 surgeons having > 100 procedures during the study period. BCR events were recorded in 1361 patients. The overall 5-yr freedom from BCR with 2524 patients remaining at risk was 80% (79%, 81%) . Extracapsular extension, seminal vesicle invasion, nodal metastasis, PM, Gleason score and PSA were independent predictors of BCR. The surgical volume also correlated independently with BCR. Importanntly we found significant variability on freedom from BCR between high volume surgeons. The I-squared statistic from the meta-analysis was 0.63. That is, approximately 63% of the difference in BCR rates among surgeons can be explained by genuine differences in surgical skill and approach, and approximately 37% is compatible with chance alone. For a sensitivity analysis, we repeated the analysis excluding surgeons who performed less than 100 procedures. In this sub-analysis, the I-squared statistic remained very significant at 0.48. Conclusions: Our data shows that in men treated by RP, the BCR outcomes of men are not exclusively determined by the biology and stage of prostate cancers (explained in most models), but to the surgical skill. Clinical trials evaluating BCR outcomes must prove equivalency among providers so that results are not biased by them.

No significant financial relationships to disclose.
Clinical impact of disseminated tumor cells in patients with non-metastatic prostate cancer treated by definitive radiotherapy
Authors: Berg A. , Berner A. , Lilleby W. , Bruland Ø. S. , Fosså S. D. , Nesland J. , Kvalheim G.
Published: March 2020

4575

Background: Detection of disseminated tumor cells (DTCs) in bone marrow (BM) has been proven to be an independent prognostic factor in breast cancer. To our knowledge, we here present the first larger study of radically treated prostate cancer (PC) with sufficiently long-term follow-up where the association between DTCs at diagnosis and clinical outcome has been studied. Methods: We screened 272 cT1–4pN0M0 PC patients for DTCs in BM-aspirates between 1994 and 2004. Monoclonal antibodies against cytokeratins (AE1/AE3) and standardized immunocytochemical methods were applied for detection. BM-status was compared with clinical and histopathological factors at diagnosis in all patients and with long-term clinical outcome in 131 patients. They all started treatment including definitive radiotherapy (RT) before June, 2000 and had a relatively poor prognosis defined as cT3–4 or Gleason score (GS) ≥ 7B (4 + 3) or PSA ≥ 10 μg/l. Kaplan-Meier plots were generated by BM-status with the following end-points: Overall death, cause-specific death, distant metastases (DM) as first clinical relapse, local failure as first clinical relapse and biochemical failure. Results: DTCs were detected in 18% of the patients and were significantly associated with increasing percentage Gleason grade 4/5 (p = .035, Mann-Whitney) but not with dichotomized GS, tumor-stage or PSA. In the follow-up cohort (median observation time 6.9 years), the 7-year cumulative risk of DM was 21% in BM-positive patients vs. 6% in BM-negative patients (p = .069, log rank). No association was found between DTCs and other end-points. A sub-group analysis of 73 patients with GS ≥ 7B yielded a 34% 7-year cumulative risk of DM in BM-positive patients vs. 10% in BM-negative patients (p = .039, log rank). DTCs did not predict DM in 55 patients with GS ≤ 7A (3 + 4). In a multivariate analysis, dichotomized GS (RR = 7.8 [95% confidence interval (CI) = 1.0–60.7], p = .049) and BM-status (RR = 3.0 [95% CI = .9–9.4], p = .066) had independent impact on DM. Conclusions: The presence of DTCs in BM at diagnosis of non-metastatic PC is associated with the histological differentiation of the primary tumor and seems to predict development of DM after definitive RT.

No significant financial relationships to disclose.
Can patients (pts.) with refractory germ cell tumors (GCT) be cured after progression following high dose chemotherapy (HDCT) with tandem transplant? Results with paclitaxel + gemcitabine
Authors: Lewis D. A. , Brames M. J. , Einhorn L. H.
Published: March 2020

4588

Background: A previously published ECOG study of paclitaxel (P) plus gemcitabine (G) in refractory germ cell tumors achieved a 21% response rate (6 of 28 pts.) (JCO 20:1859, 2002). Two patients are continuously NED for 4+ years. Neither had prior HDCT. High dose salvage chemotherapy with carboplatin + etoposide and peripheral blood stem cell transplant has curative potential. Subsequent chemotherapy after progression following HDCT has only rarely achieved durable remission. We have retrospectively reviewed pts. treated at Indiana University with P + G after failure to cure with initial cisplatin combination chemotherapy and salvage HDCT (± other salvage regimens). Methods: 184 patients received salvage HDCT from February 1996 to December 2004. After further progression, 33 pts. were treated with P 100 mg/M2 over 1 hour and G 1000 mg/M2 over 30 minutes days 1, 8, and 15 every 4 weeks for a maximum of 6 courses. Pts. were ineligible if they received prior P or G. 26 pts. received P + G as 3rd line, 6 as 4th line and 1 as 5th line chemotherapy. Results: Toxicity was primarily myelosuppression and neuropathy, as previously described with P + G (JCO 20:1859, 2002). There was no treatment related mortality. 10 of 33 pts. achieved objective response including 4 partial (2 to 6 months duration) and 6 complete responses (C.R.). 4 of the 6 C.R.s are continuously NED with P + G alone at 14+, 34+, 44+, and 45+ months from start of P + G. One additional C.R. is currently NED 54+ months after P + G, with 2 subsequent resections of carcinoma. Conclusions: Long-term disease free survival and potential cure is possible with P + G in this patient population after progression following HDCT.

[Table: see text]
The familial influence on bilateral testicular germ cell cancer: Medical Research Council study TER2
Authors: Harland S. J. , Daugaard G. , Horwich A. , Mead G. M. , Fossa S. D. , Sokal M. , Morgenstern D. , Oliver R. , Cook P. A. , Stenning S. P.
Published: March 2020

4590

Background: There is evidence that hereditary predisposition is important in the aetiology of testicular cancer but the mode of inheritance is unknown. Methods: To test the hypothesis that bilateral disease (5% of testis cancer) is a manifestation of hereditary predisposition, a family questionnaire was sent to patients with bilateral disease (cases) and responses compared with institutional controls with unilateral disease (two approached for every case), matched for year of first diagnosis. The primary outcome measure was the risk of testis cancer in the brothers of cases and controls, and a relative risk of between 4.1 and 5.0 was anticipated based on the model of Nicholson and Harland (BJC 1995 71:421–426). Results: Responses from 191 cases and 373 controls have been analysed. No evidence of reduced fertility was found in the parents or grandparents of cases compared to those of controls. Cases (48%) were less likely to have children than controls (64%). The mean (SD) age of onset of testicular cancer was lower in cases (31 (9)) than controls (35 (9)), p < 0.001. The incidence of testis cancer in the relatives of cases and controls are shown in the table . Conclusions: The 4.6-fold greater risk to brothers of cases confirms the role of a familial predisposition in bilateral testicular cancer. Given the incomplete ascertainment for brothers, there is likely to be a greater risk to brothers than fathers. No major effect of an X-linked gene is found. These findings are in keeping with previously described hereditary models for testicular cancer.

[Table: see text]

No significant financial relationships to disclose.
Bevacizumab, erlotinib, and imatinib in the treatment of patients with advanced renal cell carcinoma: Update of a multicenter phase II trial
Authors: Thompson D. S. , Greco F. A. , Spigel D. R. , Sosman J. A. , Burkett E. , O’Rourke T. J. , Hart L. , Hainsworth J. D.
Published: March 2020

4594

Background: Most patients with clear cell RCC have loss of von-Hippel-Lindau (VHL) gene function, ultimately leading to overexpression of VEGF, transforming growth factor (TGF-α), epidermal growth factor (EGF), and platelet-derived growth factor (PDGF). In this phase II trial, we evaluate the combination blockade of VEGF, and the EGF and PDGF receptors as treatment for metastatic RCC. Methods: Eligibility: metastatic clear cell RCC; 0–2 previous systemic regimens; ECOG PS 0–1; no previous anti-angiogenesis or EGF receptor inhibitor therapy; no active CNS metastases; adequate organ function; no history of thromboembolic disease; informed consent. All patients received bevacizumab 10 mg/kg IV q 2 wks, erlotinib 150 mg PO daily, and imatinib 400 mg PO daily. Patients were evaluated for response after 8 weeks; treatment continued until tumor progression. Results: 92 patients entered this trial between 6/04 and 4/05. Pertinent clinical characteristics: no previous systemic treatment, 71%; Motzer prognostic category low/intermediate/high 47%/50%/3%. 84 patients (91%) received at least 8 weeks of therapy. Objective responses were seen in 11 patients (12%); an additional 52 patients (57%) had stable disease/minor response at first reevaluation. After a median follow-up of 11 months, projected median and 1-year progression-free survivals are 9 months and 40%, respectively. One-year overall survival is 62%. The addition of imatinib to bevacizumab/erlotinib added substantial toxicity. Grade 3/4 toxicity included: diarrhea, 48%; skin rash, 27%; fatigue, 23%; nausea/vomiting, 20%. 2 patients discontinued treatment as a result of toxicity; all patients who received treatment for > 8 weeks required dose reductions of imatinib and/or erlotinib. Conclusions: The addition of imatinib, a PDGF receptor inhibitor, to bevacizumab/erlotinib does not appear to substantially improve the efficacy of the 2-drug combination. This 3-drug combination produced moderate to severe toxicity in the majority of patients, primarily exacerbations of diarrhea, fatigue, and skin rash. Further development of this 3-drug regimen is not recommended.

[Table: see text]
Relationship between VHL mutation status, tumor VEGF expression and plasma VEGF measurement in sporadic renal cell carcinoma
Authors: Fergelot P. , Rioux-Leclercq N. , Zerrouki S. , Bensalah K. , Patard J.
Published: March 2020

4602

Background: The relationship between VHL mutation status and prognosis in renal cell carcinoma (RCC) remains controversial. The aim of this study was to evaluate prospectively the association between VHL status, tumor VEGF expression, plasma VEGF levels and usual prognostic parameters in RCC. Methods: 70 patients with clear cell RCCs were included in this study. Genomic DNA was extracted using the QIAmp DNA mini kit (Qiagen) from frozen tumor samples. Four amplimers covering the whole coding sequence and exon/intron junctions of the VHL gene were synthetized by PCR followed by Big Dye sequencing (Applied Biosystems). Mutation bearing sequences were confirmed in a second round of PCR and sequencing reactions. Tumor VEGF expression was determined by immunohistochemistry and plasma VEGF was measured by enzyme-linked immunosorbent assay (Quantikine immunoassay, R&D systems). Results were expressed in pg/ml. Qualitative and quantitative variables were compared by using Chi-square (Fischer exact test) and Student t tests, respectively. Results: A VHL mutation was found in 46 cases (65.7%). VHL mutations were localized in exon 1, 2 and 3 in 23, 16 and 7 cases respectively. Median tumor VEGF expression was 45% (5–100). Median plasma VEGF was 104 pg/ml (13–1430). A significant association was found between VHL mutation and N stage (p: 0.01), Fuhrman grade, symptoms at presentation (p: 0.02) or tumor size (p: 0.007). A VHL mutation was found in 83.5% of low grade (G1–2) and 80% of incidental tumors respectively. A trend towards more frequent VHL mutations was observed in T1 tumors (87% mutation rate, p: 0.07) and in good performance status patients. Interestingly, VEGF tumor expression and plasma VEGF levels were not significantly different among patients with tumors having or not mutated VHL (p: 0.7). Conclusion: VHL mutations are more frequent in small incidental low stage or low grade tumors. Although VHL inactivation was not specifically determined in this study, we failed to show any association between VHL mutational status and VEGF tumor or plasma expression suggesting that other pathways than the VHL/HIF axis are required for explaining the angiogenic phenotype of RCC.

No significant financial relationships to disclose.
Randomized phase II study comparing 4 monthly doses of ipilimumab (MDX-010) as a single agent or in combination with a single dose of docetaxel in patients with hormone-refractory prostate cancer
Authors: Small E. , Higano C. , Tchekmedyian N. , Sartor O. , Stein B. , Young R. , Vestal J. , Moseley W. , Fischkoff S. , Lowy I.
Published: March 2020

4609

Background: Ipilimumab is a fully human anti-CTLA-4 IgG1 monoclonal antibody that blocks CTLA-4 and augments immune responses. The current study evaluated the safety and activity of ipilimumab alone or with a single dose of docetaxel in hormone-refractory prostate cancer (HRPC). Methods: 43 chemotherapy naïve patients (pts) with HRPC, were treated; 23 were in arm A (ipilimumab at 3 mg/kg q 4 weeks × 4 doses) and 20 in arm B (ipilimumab as in Arm A and one dose of 75 mg/m2 of docetaxel on day 1). Results: Six pts, 3 in each arm, demonstrated a decrease in PSA of > 50%. Three pts, 2 in arm A, and 1 in arm B had confirmed PSA responses with durations of 79+ days, 169+ days, and 280 days, respectively. There were no radiologic responses with these PSA responses. Thirty-six (84%) of the 43 pts experienced 1 or more adverse events considered to be related to treatment with ipilimumab. The most common adverse events included fatigue (44%), pruritus (26%), nausea (19%), rash (12%), constipation (12%), and weight loss (12%). Serious adverse events (SAEs) occurred in 18 patients (42%), who experienced 52 SAEs. The majority (42 out of 52, 81%) were judged by the Investigator to be unrelated or unlikely to be related to treatment with ipilimumab. Five of the 52 SAEs reported in 3 pts were considered to be possible immune breakthrough events (IBEs), associated with drug exposure and consistent with an immune-based mechanism of action. These were adrenal insufficiency (1), diarrhea, colitis, and melena (all in one patient) and colitis (1). One of these pts had a confirmed PSA response. Conclusions: Ipilimumab was well tolerated in this group of pts with HRPC. Three pts overall (6%) experienced an IBE, a phenomenon that has been correlated in other studies with efficacy. There were several confirmed responses as assessed by PSA, one of which was correlated with an IBE. There was no apparent enhancement of activity by coadministration of a single dose of docetaxel. Further studies exploring ipilimumab in prostate cancer are warranted, either as monotherapy at higher doses, or in combination with immune modulators or vaccines.

[Table: see text]
Skeletal related events (SREs) in metastatic androgen independent prostate cancer (AIPC) treated with docetaxel-based chemotherapy: Results from ASCENT
Authors: Chan J. S. , Ryan C. W. , Venner P. M. , Petrylak D. P. , Chatta G. S. , Ruether J. , Chi K. N. , Young J. , Shen C. , Beer T. M.
Published: March 2020

4614

Background: Docetaxel prolongs survival in AIPC patients and zoledronic acid (ZA) reduces the incidence of SREs. The SRE incidence of patients treated with docetaxel-based chemotherapy has not previously been reported. Methods: ASCENT was a randomized clinical trial that compared weekly DN-101 (calcitriol, 45 μg p.o. on day 1) plus docetaxel (36 mg/m2 iv on day 2 for 3 weeks of a 4-week cycle) to placebo plus docetaxel in patients with chemotherapy-naïve metastatic AIPC. ZA use was not restricted. SRE-free survival was described for the entire group and then compared for patients randomly assigned to DN-101 or placebo and stratified by ZA use. Statistical comparisons were conducted using Cochran-Mantel-Haenszel for incidence and log-rank for SRE-free survival. Results: With a median follow-up of 18.3 months, 33% of subjects experienced at least one SRE and the overall median SRE-free survival was 13 (95% CI 10.5–14.3) months. The incidence of SRE by type was: radiation to bone (18.8%), fracture (10%), spinal cord compression (4%), surgery to bone (0.4%). Eighty-five (34%) patients received ZA. The study was not adequately powered to measure the impact of DN-101 or ZA on SRE endpoints. Exploratory analyses showed a trend for an increase in SRE-free survival (HR 0.78, p = 0.13) of DN-101-treated patients. SRE-free survival and incidence for subgroups were examined ( Table ). Conclusions: This is the first report of SRE incidence in a large, prospective study of docetaxel-based therapy. Improved therapies for reducing SREs in AIPC are needed because the risk of SREs remains high despite the use of modern chemotherapy and ZA.

[Table: see text]

[Table: see text]
The influence of nodal status on progression outcomes in patients with prostate cancer: Data from the Early Prostate Cancer program at 7.4 years
Authors: Iversen P. , Wirth M. P. , See W. A. , McLeod D. G. , Morris T. , Armstrong J.
Published: March 2020

4628

Background: The Early Prostate Cancer (EPC) program is an ongoing study of the effect of adding bicalutamide (CASODEX) 150 mg to standard care (radiotherapy [RT], radical prostatectomy [RP], or watchful waiting [WW]) for men with localized or locally advanced prostate cancer. At a median 7.4 years’ follow-up, bicalutamide significantly improved objective progression-free survival (PFS) in men with locally advanced disease, irrespective of standard care, and improved overall survival in the RT setting. There was no PFS benefit in patients with localized disease. Lymph-node involvement is an established risk factor for progression, so we conducted an exploratory analysis among patients with locally advanced disease to assess the influence of this risk factor on PFS. Methods: The EPC program (n = 8113) comprises 3 randomized trials designed for combined analysis. Patients with localized (T1–2, N0/Nx) or locally advanced (T3–4, any N; or any T, N+) non-metastatic prostate cancer received bicalutamide (n = 4052) or placebo (n = 4061) once daily plus standard care. This subanalysis studied the effect of nodal status (N−, N+, Nx) in locally advanced disease. Results: In patients with locally advanced disease, PFS improvements were irrespective of nodal status. The treatment effect increased as the risk of progression increased from N− to Nx to N+ disease. The greatest reduction in risk was seen in RP patients with N+ disease. Conclusions: The reduction in risk of progression with bicalutamide was seen irrespective of nodal status. The most significant reduction in risk of progression was in RP patients with N+ disease; survival data by nodal status for these patients will be presented.

[Table: see text]

[Table: see text]
Clinical benefit of atrasentan for men with metastatic hormone-refractory prostate cancer metastatic to bone
Authors: Sleep D. J. , Nelson J. B. , Petrylak D. P. , Isaacson J. D. , Carducci M. A.
Published: March 2020

4630

Background: Hormone-refractory prostate cancer (HRPC) metastasizes most commonly to bone. Treatment of advanced HRPC patients focuses on alleviating bone pain that afflicts 85% of patients. New therapies are needed that not only prolong survival but slow the progression of morbidity. Atrasentan, a selective endothelin A receptor antagonist that blocks the effect of endothelin in the bone microenvironment by slowing osteoblast proliferation, may slow disease progression in HRPC patients with bone metastases. Methods: Patients enrolled in a randomized, double-blind, placebo-controlled multinational trial of atrasentan 10 mg with independently confirmed bone metastases (N = 690) were followed until the first event of disease progression, which could be by radiographic (≥2 new lesions on bone scan) or clinical means (eg, pain requiring significant opioids or other interventions, spinal cord compression). Analyses were performed on time to disease progression and separately on time to clinical and radiographic progression. The difference between treatments was analyzed using Kaplan-Meier methods and Cox proportional hazards modeling. Results: N = 335 for placebo; N = 355 for atrasentan. Atrasentan therapy resulted in fewer disease progression events relative to placebo and reduced the risk of disease progression by 19% ( Table ). The differential effect of atrasentan on disease progression was most notable against clinical progression (32% reduction in risk vs placebo). Conclusions: In men with HRPC metastatic to bone, atrasentan delays disease progression, especially clinical events, relative to placebo.

[Table: see text]

[Table: see text]
Hormonal adjuvant treatment plus radiotherapy versus exclusive radiotherapy in locally advanced prostate cancer: Pooled analsys of 6 randomized trials
Authors: Carlini P. , Bria E. , Ciccarese M. , Milella M. , Arcangeli G. , Gallucci M. , Ruggeri E. , Terzoli E. , Cognetti F. , Giannarelli D.
Published: March 2020

4642

Background: The magnitude of the benefit of adding adjuvant hormonal treatment to radiotherapy for locally advanced prostate cancer is still unclear. We performed a pooled-analysis of phase III trials, to quantify the eventual benefit in recurrence decrease. Methods: All prospective phase III trials were considered eligible. A pooled analysis was accomplished, and event-based relative risk ratios (RR) with 95% confidence interval (CI) were derived through both a fixed- (FEM) and a random-effect model (REM) approach. Significant differences in primary outcome (recurrence rate), and secondary outcomes (overall survival), were explored. Magnitude outcome measures were: absolute benefits and number of patients needed to treat (NNT) for 1 patient to benefit. Heterogeneity test was applied as well. Results: Six trials designed to look if hormonal treatment plus radiotherapy decreases recurrence rate (3,571 patients) were gathered. In the primary outcome, the combined approach significantly improves the recurrence rate when applying the FEM (RR 0.72, 95% CI 0.68, 0.77, p < 0.0001), with an absolute benefit of 10.7%. The NNT was 9 patients. Although significant heterogeneity was found (p = 0.00001), the benefit remains significant at the REM as well (RR 0.67, 95% CI 0.54, 0.82, p < 0.0001). Although significant at FEM (RR 0.93, 95% CI 0.86, 1.00, p = 0.039) but heterogeneous (p = 0.0007), the overall survival demonstrated a not-significant trend in favour of the combined strategy at REM (RR 0.90, 95% CI 0.75, 1.10, p = 0.263). Conclusions: Considered all the available phase III trials, the combination of adjuvant hormonal treatment with radiotherapy over standard exclusive radiotherapy significantly decreases the recurrence rate in patients affected by localized prostate cancer. The significant heterogeneity in the analysis underscores the existing difference in patient’ characteristics. No significant benefit in overall survival was found.

No significant financial relationships to disclose.
Bevacizumab in patients with advanced platinum-resistant ovarian cancer
Authors: Cannistra S. A. , Matulonis U. , Penson R. , Wenham R. , Armstrong D. , Burger R. A. , Mackey H. , Douglas J. , Hambleton J. , McGuire W.
Published: March 2020

5006

Background: Bevacizumab (BV), a recombinant, humanized monoclonal antibody directed against vascular endothelial growth factor, has demonstrated clinical benefit in multiple tumor types. Activity in ovarian cancer (OC) has been reported in phase II studies in patients (pts) with recurrent disease. We now describe the activity/safety of BV in pts with platinum-resistant OC (PROC) that progressed after topotecan or liposomal doxorubicin (LD). Methods: Eligibility criteria for this multicenter, Phase II study included primary or secondary PROC that progressed within 3 months of topotecan or LD, 3 or fewer prior chemotherapy regimens, and a performance status (PS) 0 or 1. BV was dosed at 15 mg/kg q 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) as defined by RECIST. A two-stage design was utilized with H1 set at 15%. Secondary endpoints included progression-free survival (PFS), duration of response, overall survival (OS), and safety. Results: The study enrolled 44 of the intended 53 pts, closing early due to a higher than expected rate of gastrointestinal perforations (GIP). Baseline characteristics included median age 60 yrs (range 31–87); PS 0 in 26 pts, 1 in 18 pts; 2 prior chemotherapy regimens in 20 pts, 3 in 24 pts. Preliminary efficacy: ORR (CR+PR), 7/44 (16%). Median duration of response was 12 weeks, with 2 pts continuing on study >5 months. Serious adverse events (SAEs) were reported in 18/44 pts (41%). Selected SAEs included GIP 5 (11%; one occurred more than 30 days after coming off study while on paclitaxel and commercial Avastin®), bowel obstruction 5 (11%), arterial thromboembolic events 4 (9%), delayed wound healing 2 (5%), and one case each of pulmonary hypertension, hypertensive encephalopathy, and hypoxia. Conclusions: BV has single agent activity in women with PROC, but is associated with substantial toxicity in this population. Trials are ongoing in less heavily treated, newly diagnosed pts with OC to evaluate the efficacy and safety of BV in these disease settings. Identification of risk factors for BV-associated adverse events requires further study.

[Table: see text]
Phase I trial of KOS-953, a heat shock protein 90 inhibitor, and trastuzumab (T)
Authors: Modi S. , Stopeck A. , Gordon M. S. , Solit D. , Ma W. , Wheler J. , Cropp G. , Johnson R. G. , Hannah A. L. , Hudis C.
Published: March 2020

501

Background: KOS-953 (17-AAG in Cremophor) is a potent Hsp90 inhibitor that in vivo induces rapid degradation of Her2, loss of pAKT and tumor growth inhibition in a Her2+ breast cancer xenograft. Objectives: Define the phase 2 dose of KOS-953 + T. Define toxicity and PK of KOS-953, its active metabolite and T. Assess changes in intracellular signaling proteins (such as Hsp70) in leucocytes. Describe antitumor activity. Methods: Eligible pts with advanced solid tumors (Her2 + was not required) received standard weekly doses of T followed by IV KOS-953 in escalating doses over 2 hrs. Results: 25 pts enrolled in 4 cohorts (225, 300, 375 and 450 mg/m2; 4, 3, 8 and 10 patients per cohort), receiving a total of 94 cycles (median 3, range <1 - 12+). Demographics: 21 female (17 with Her2+ metastatic breast cancer ‘MBC‘, 1 Her2 status unknown); median age/KPS 66 yrs/90; # prior T-containing regimens for MBC pts (n=18) equaled 2 (range 0–5). DLT was observed at the 3rd and 4th cohort (1 pt each): 2-week dose delay for recovery from Grade 4 fatigue/Grade 2 nausea & anorexia at 375 mg/m2; delayed recovery of platelets at 450 mg/m2. Drug-related Grade 3 toxicity: emesis, increased ALT and hypersensitivity (n=2); Grade 4 drug-induced thrombocytopenia in a pt with Hashimoto’s disease after 7 cycles. In general the drug was well tolerated. Grade 1 or 2 toxicities included fatigue, nausea, diarrhea, emesis, headache, rash/pruritus, increased AST/ALT and anorexia. Most toxicities (except headache) were not dose dependent. PK of parent (n=21): t½ 3.0 ± 2.1 h; clearance 31.8 ± 12.8 L/h; Vz 164 ± 101 L. Metabolite: Tmax 30–60 min after end-of-infusion with similar AUC and longer t½ of 6.1 ± 1.7 h. PK of T showed no changes compared to previous reports. Among 17 pts with Her2 + MBC s/p multiple regimens of T: PR= 1, MR = 3, 5 pts with SD (5, 7+, 9 and 12+ months). Pts with PR and MRs had confirmed progression of disease prior to study on T-containing regimen. Pharmacodynamic testing showed reactive induction of Hsp70/72 in leucocytes at all dose levels. Conclusions: KOS-953 added to T is active in refractory Her2 + MBC with no change in PK compared to single-agent therapy. The phase 2 dose of KOS-953 is 450 mg/m2; enrollment to the phase 2 trial of this combination in Her2+ MBC is on-going.

[Table: see text]
EGF103009, a phase II trial of lapatinib monotherapy in patients with relapsed/refractory inflammatory breast cancer (IBC): Clinical activity and biologic predictors of response
Authors: Spector N. L. , Blackwell K. , Hurley J. , Harris J. L. , Lombardi D. , Bacus S. , Ahmed S. B. , Boussen H. , Frikha M. , Ayed F. B.
Published: March 2020

502

Background: Data from preclinical studies and small numbers of IBC patients inPhase I clinical trials suggest that IBC may be particularly sensitive to the anti-tumor effects of lapatinib, an inhibitor of ErbB1/ErbB2 tyrosine kinases. EGF103009 was initiated to confirm and expand these initial observations and identify a tumor profile predicting for the sensitivity of IBC to lapatinib. Methods: Patients with relapsed/refractory IBC based on clinical criteria, were assigned to Cohort A (ErbB2 overexpressors: 2/3+ IHC/FISH+) or B (ErbB1 +/ErbB2 non-overexpressors) after analysis of a fresh tumor biopsy in a central reference lab. Patients received lapatinib daily (1500mg/d). Clinical response was documented at day 56 and in the case of CR/PR, confirmed on day 84 and every 8 weeks thereafter. Target lesions were assessed according to RECIST criteria and response in skin disease documented by digital photography. Tumor expression of ErbB2, p-ErbB2, ErbB1, p-ErbB3, IGF-IR, PTEN, ER/PR, E-cadherin, β-catenin, and Rho B/C was analyzed by quantitative IHC from a fresh, pre-treatment biopsy. Results: Of 34 patients enrolled, clinical response data is available from 22 patients of which 17 had biopsies analyzed at a reference lab and assigned to Cohorts A (N=11) and B (N=6). Eight of 11 patients (72%) in Cohort A had a clinical response (CR/PR) to lapatinib documented by RECIST, skin disease, or both. There were no responders in Cohort B. All responders (i) overexpressed ErbB2 (2/3+ IHC or FISH+), (ii) increased p-ErbB2 (2/3+), (iii) co-expressed IGF-IR, and (iv) expressed activated, p-ErbB3. PTEN status did not affect response to lapatinib. Toxicity was generally grade I/II skin and G.I. with one grade III cardiotoxicity necessitating withdrawal from study. Conclusions: ErbB2 overexpression but not ErbB1 expression alone, predicts for sensitivity to lapatinib in IBC. High ErbB2, p-ErbB2 and IGF-IR co-expression predict for clinical response to lapatinib monotherapy in patients with relapsed/refractory IBC, illustrating the importance of selecting patients based on biology rather than histology alone, to maximize the clinical efficacy of ErbB kinase inhibitors in breast carcinomas.

[Table: see text]
Prognostic impact of MAD1L1 promoter hypermethylation in advanced ovarian cancer
Authors: Jansen R. A. , Liu J. C. , Liyanarachchi S. , Crijns A. P. , Yan P. S. , Huang T. H. , Cohn D. E. , Fowler J. M. , Van der Zee A. G. , Brown R.
Published: March 2020

5021

Background: Aberrant methylation of GC-rich gene promoters is a frequent epigenetic event in ovarian cancer leading to silencing of tumor suppressor genes. Identification of methylation biomarkers holds promise for impacting patient survival. Methods: High-throughput screening of hypermethylated CpG islands was conducted by differential methylation hybridization on stage III and IV epithelial ovarian carcinomas. Tumor DNA methylation status was interrogated by methylation-sensitive restriction enzymes, followed by co-hybridization on a custom promoter CpG island array with pooled normal ovarian surface epithelial cell (nOSE) DNA. Microarray findings were validated by quantitative methylation-specific PCR (qMSP) on 55–79 tumor samples. Results: Methylation levels of 6 novel genes (CYP39A1, EBP, FOXD4b, GTF2A1, MAD1L1 and YY1AP1) functioning in cell cycle control, transcription and drug metabolism/transport were identified as hypermethylated in ovarian cancer versus nOSE (nonparametric Wilcoxon rank sum test, p < 0.005). Using Fisher’s exact test, patients with shorter progression-free survival (PFS) (≤18 months) had higher methylation levels compared to those with longer PFS (p = 0.015) for the gene MAD1L1, a mitotic checkpoint protein and antagonist of c-myc that regulates cell proliferation and differentiation. Cox regression analysis of methylation levels and PFS identified a negative correlation for MAD1L1. This correlation achieved statistical significance when MAD1L1 methylation levels combined with chemotherapy response was tested against PFS (p = 0.021), suggesting an interaction of this gene in patient response to chemotherapy. Conclusions: Induced overexpression of MAD1L1 has been shown to delay cell proliferation and inhibit growth. Downregulation via hypermethylation of this gene results in cell cycle dysregulation, a pathway for disease progression. This epigenetic modification in MAD1L1 renders it a potential target for intervention therapies that could improve patient survival.

No significant financial relationships to disclose.
Phase II study of exemestane (E) in refractory ovarian cancer (ROC)
Authors: Verma S. , Alhayki M. , Le T. , Baines K. , Rambout L. , Hopkins L. , Fung Kee Fung M.
Published: March 2020

5026

Background: Despite biologic rationale, endocrine therapeutic strategies have been under investigated in ovarian cancer. This is the first study to report the efficacy of an aromatase inhibitor, E, in patients (pts) with ROC. Methods: This was a pilot, phase II, single-centre, non-comparative, open-label study. Pts with ROC stage II - IV who had received no more than 2 lines of prior chemotherapy, had ECOG PS ≤ 2, and measurable disease or non-measurable disease with a CA 125 ≥ 30 U/mL and/or ascites were eligible. All pts must have received prior platinum and taxane chemotherapy. Treatment consisted of E 25mg p.o. daily until disease progression. The primary endpoint was objective response rate (ORR) and secondary endpoints were time to progression (TTP), duration of response (DR) and toxicity. Results: 24 pts have been enrolled to date. Only 2 pts who withdrew consent or never started E were excluded from this analysis. Subjects had stage III (77%) or IV (18%) ovarian cancer, the majority were grade 3,serous histology. 15 pts (68%) had 2 prior lines of therapy and 7 pts (32%) had only 1 prior line of therapy. Treatment was commenced in the majority immediately after progression on chemotherapy. There were no objective clinical responses; however 8/22 (36%) pts had stable disease (SD) >14 weeks (med. duration 23 wks). One pt remains with SD > 95 wks duration. The median TTP was 8.8 wks. Receptor status was available in 16/22 pts: ER+ (41%), PgR+ (32%), BCL-2+ (23%) and HER2+ (0%). Correlation of ORR/SD with receptors and CA 125 will be presented. Toxicity was evaluated in all pts who received at least one dose of E. Hyponatremia (gr 4), attributed to disease, was observed in 1 pt. All other toxicities were NCI CTC grade ≤ 2: fatigue (14%), hot flashes (9%), skin reaction (5%), and fluid retention (5%). Conclusions: In this highly refractory ROC pt population, E was associated with an impressive, clinically meaningful SD rate of 36%. As this potentially represents a less toxic, well-tolerated therapeutic option for women with ROC, further investigation is warranted. Supported by a grant from Pfizer Canada

No significant financial relationships to disclose.
Phase I trial of intraperitoneal (IP) administration of a measles virus (MV) derivative expressing the human carcinoembryonic antigen (CEA) in ovarian cancer patients
Authors: Galanis E. , Hartmann L. C. , Cliby W. , Zollman P. J. , Peethambaram P. P. , Long H. J. , Kaur J. S. , Sloan J. A. , Peng K. W. , Russell S. J.
Published: March 2020

5028

Background: Edmonston vaccine strains of MV have significant antitumor activity against ovarian cancer xenografts (Peng et al, Cancer Res, 2002). Oncolytic selectivity is due to overexpression of the MV CD46 receptor in ovarian cancer cells. Furthermore, engineering the virus to express the marker peptide CEA (MV-CEA) allows real time monitoring of viral gene expression/propagation in vivo. Methods: We are conducting a Phase I trial of MV-CEA in patients (pts) with recurrent, taxol and platinum refractory, ovarian or primary peritoneal carcinoma. Eligible pts should have protective anti-MV antibody (ab) titers and normal CEA levels. A standard phase I cohorts of three statistical design is employed. MV-CEA is administered IP via a port-a-cath, q 4 wks for up to 6 cycles. Results: To date, 12 pts have received viral doses from 103 to 106 TCID50. No dose-limiting toxicity has been observed. Most common toxicities included grade 1–2 nausea (4 pts); grade 1–2 fatigue (4 pts); grade 1 fever (3 pts); grade 1 abdominal pain (2 pts). One pt had grade 2–3 arthralgias in cycles 4–6. There was no treatment induced immunosuppression as assessed by DTH, CD4, CD8, immunoglobulin and complement levels, no significant increase in the titers of anti-MV abs in serum or ascites in response to treatment, and no development of anti-CEA abs. Viral genomes were detected in the peripheral blood mononuclear cells of 2 asymptomatic pts by QRT-PCR. No CEA elevation in the serum was observed in the dose range tested, and there was no viral shedding in urine or mouth gargle specimens. Testing of pt tumor samples for CD46 by IHC demonstrated overexpression of the target receptor in 7/8 pts. Best objective response was stable disease (2 - 9 mo duration) in 5 pts, while 3 pts had significant decrease in CA125 levels, of 44%, 72%, and 78%, respectively. Conclusions: In this first human application of an engineered oncolytic MV strain, we have observed excellent tolerance after repeat IP administration of the virus. Despite the low doses employed so far, there is early evidence of biologic activity. Dose escalation continues to the target dose of 109 TCID50.

No significant financial relationships to disclose.
The outcome of patients with relapsed gestational trophoblastic neoplasm (GTN) after the completion of chemotherapy
Authors: Powles T. , Young A. , Short D. , Savage P. , Pappin C. , Schmid P. , Seckl M.
Published: March 2020

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Background: Women requiring chemotherapy for GTN are stratified into low risk and high risk disease and treated accordingly. The vast majority of patients are cured with chemotherapy. Despite this a small number relapse after completing treatment. The prognostic factors predictive of outcome for these relapsed patients are unclear and are investigated here. Methods: Clinical data at presentation and at the time relapse on patients with relapsed GTN was collected from a prospective data base at the Charing Cross Hospital. This included stage of disease, time to relapse, treatment details and rate of HCG rise. Statistical analysis was performed using the Kaplan Meier method. Univariant and multivariant analysis was performed on the data. Results: Between 1980 and 2004 1708 patients were treated with chemotherapy for GTN. Sixty of these patents have relapsed. The median age of these 60 patients was 29 years (range 30–51) and the median follow up was 10 years. The overall 5 year survival for patients with relapsed GTN was 91% (84–99%). All deaths were tumour related. Patients who initially presented with low risk disease (n = 27) had an overall survival of 100% while those who presented with high risk disease had an overall survival of 91% (66–96%) (p < 0.05). Five patients progressed during treatment for relapsed disease, all of these patients died. Ten patients relapsed for a second time. All of these patients are currently alive and disease free with a median of 11 years of follow up. Significant prognostic factors included stage of disease at presentation, the presence of metastatic disease at relapse and the rate of rise of HCG at relapse. Conclusions: The outcome for patients with relapsed GTN is good especially those who relapse after initially having low risk disease. Failure to obtain a complete remission on 2nd line chemotherapy is a poor prognostic indicator.

No significant financial relationships to disclose.
Biomarker discovery in endometrial carcinoma using novel proteomic methods
Authors: Borgia J. A. , Frankenberger C. , McCormack S. E. , Kaiser K. A. , Usha L. , Rotmensch J. , Coon J. S.
Published: March 2020

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Background: A practical serum-based screening test for endometrial and ovarian carcinomas could greatly improve their early diagnosis, but developing such a test has proved elusive. Herein, we describe methods offering increased statistical power over conventional ‘batch’ analyses, via paired patient serum samples to identify biomarkers specific for uterine endometriod carcinomas (UEA). Methods: Paired serum samples (collected pre- and post- surgery) were prepared from patients undergoing UEA resection. A Ciphergen SELDI-TOF mass spectrometer was used to generate the patient serum proteomic profiles with data acquisition optimized to the 5,000–40,000 m/z (mass) range. Spectra quality was assessed using a specific function within the R-project statistical platform (v2.2.0), whereas data analyses were performed using Bioconductor, an extension of the R statistical platform; all in a blinded manner. Raw spectra were processed as follows: spectra pair normalization, baseline subtraction, and differential peak detection (with calibrated alignment). Aligned peaks were sorted into groups, based on tumor pathology and pre- vs. post-operative specimen type, and compared using a two tailed homoscedastic t-test in Microsoft Excel 2003. Results: Pre- and post-operative serum from 10 patients with UEA had their serum proteomic profiles evaluated for peaks lost after surgery. These values were then compared with a set of ‘normal’ samples (i.e. patients undergoing surgery for benign gynecologic disease). Even with our small sample size we identified 16 serum components that were significantly reduced or absent (p < 0.04) after tumor resection; 10 unique to UEA (p <0.04). From this group, species at m/z values of 4291.9, 4414.2, 5036.1, 9,615.0, and 25,508.8 seem most promising, based on their high level of significance (p < 0.02), for 10/10 patients. Conclusions: These results validate the power of our pre-and post-operative sample sets for the identification of new serum biomarker candidates for UEA. Work is in progress to increase the patient sample size, expand the study to patients with serous uterine and ovarian carcinomas, and identify the reported biomarker candidates via tandem mass spectrometry

No significant financial relationships to disclose.
Relationship between CYP2D6 and estrogen receptor alpha polymorphisms on tamoxifen metabolism in adjuvant breast cancer treatment
Authors: Grabinski J. L. , Smith L. S. , Chisholm G. B. , Drengler R. , Rodriguez G. I. , Lang A. S. , Kalter S. P. , Garner A. M. , Fichtel L. M. , Pollock B. H. , Kuhn J. G.
Published: March 2020

505

Background: Tamoxifen (TAM) and its metabolites display large inter-individual variation with profound implications for breast cancer outcomes. Tamoxifen is hydroxylated to the potent metabolites, 4-hydroxytamoxifen (4-OH TAM) and endoxifen, by various cytochrome P450 (CYP450) genes including CYP2C9 and CYP2D6. The SULT1A1 gene is involved in the conjugation of 4-OH TAM. Tamoxifen’s binding site is the estrogen receptor (ER). Methods: Clinical data and blood samples were collected for 301 patients (299 female, 2 male) receiving at least 8 weeks of adjuvant tamoxifen therapy. HPLC analysis assessed TAM, N-desmethyltamoxifen (N-DMT), and 4-OH TAM levels. Genotyping of the CYP2C9 (*2,*3), CYP2D6 (*2, *3, *4, *6, *7, *8, *14) and SULT1A1 (*2) genes was determined by Pyrosequencing. CYP2D6 genotypes were subdivided into poor (PM), intermediate (IM), and extensive (EM) metabolizers. Genotyping of ER alpha polymorphisms, Pvu II and Xba I, utilized a Taqman Allelic Discrimination Assay. The Wilcoxon Rank Sum test was used to test associations of genotype and quantitative metabolite levels, within genotype associations, and ethnicity. Results: The majority of our patients were Caucasian (68%) and Hispanic (26%). The mean (± SD) levels for TAM, 4-OH TAM and N-DMT were 111.7 (± 58.4 ng/ml), 2.2 (± 1.5 ng/ml) and 204.7 (± 104.1 ng/ml), respectively. The CYP2D6 genotype was statistically associated with 4-OH TAM levels (p=0.0002). Differences were detected between EM and PM (p=0.0001) and IM and PM (p=0.0029). ER alpha Pvu II genotypes were shown to influence TAM levels (p=0.02). Significant differences were identified between the PP and Pp genotypes (p=0.0064) and between PP and pp genotypes (p=0.03). Hispanics had significantly higher levels of TAM (p=0.02) and 4-OH TAM (p=0.007) than Caucasians. Conclusions: Genotype and ethnicity are significantly associated with levels of TAM and 4-OH TAM and may explain clinical variation in response to TAM treatment.

No significant financial relationships to disclose.