bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular pathways and gene ontology categories in association with response to combination chemotherapy plus bevacizumab in inflammatory and locally advanced breast cancer
Authors: Swain S. M. , Steinberg S. M. , Modrusan Z. , Smith V. , de Sauvage F. , Yang S. X.
Published: March 2020

509

Background: Inflammatory breast cancer (IBC) is an extremely aggressive subtype of locally advanced breast cancer (LABC) accounting for 1% to 6% of all breast cancers. The overall response rate to a combined modality therapy is 61.4%-83.5% and 15-year overall survival is 20%. Identification of Gene Ontology (GO) category or molecular pathway signature to distinguish subsets of patients with distinct clinical outcomes is imperative. Methods: 20 patients with IBC and 1 with LABC received one cycle of bevacizumab at 15mg/kg followed by six cycles of doxorubicin at 50mg/m2 and docetaxel at 75mg/m2 plus bevacizumab before surgery. Response to combination chemotherapy plus bevacizumab was measured with radiologic imaging modalities. Gene expression profiles from 20 tumor biopsies at baseline (1 with PD had inadequate biopsy) were measured with Agilent Whole Human Genome arrays and utilized to correlate with clinical response. Results: 14 (67%) of 21 patients (95% CI, 43%-85.4%) had a clinical partial response (PR), 5 had stable disease (SD) and 2 had progressive disease (PD). Of 103 molecular pathways, those of the stathmin and breast cancer resistance to antimicrotubule agents, and BTG family proteins and cell cycle regulation were significantly associated with response (PR versus SD+PD; P = .002 and .003). Members of the stathmin pathway are cyclin B1, cell division cycle 2, stathmin 1 (kinase interacting with leukemia-associated gene), and mitogen-activated protein kinase 13; BTG family members are retinoblastoma 1, CCR4-NOT transcription complex, subunit 7, and B-cell translocation gene 1. Sixteen of 965 GO classes were differentially expressed between patients with PR and PD plus SD (P < .005). Those include GO categories of transcription factor complex (14 genes; P = .00009), extracellular matrix (69 genes; P = .0006), and protein kinase activity (90 genes; P = .002). Tumor differentiation, ER, HER2/neu, and p53 were not associated with clinical response. Conclusions: Two pathways that regulate microtubule stability and cell cycle, and 16 GO categories are significantly associated with the response to the combination chemotherapy of docetaxel-doxorubicin plus bevacizumab.

No significant financial relationships to disclose.
Final results from phase II study of volociximab, an α5β1 anti-integrin antibody, in refractory or relapsed metastatic clear cell renal cell carcinoma (mCCRCC)
Authors: Yazji S. , Bukowski R. , Kondagunta V. , Figlin R.
Published: March 2020

5094

Background: A critical survival step for proliferating endothelial cells is the ligation of fibronectin in the extracellular matrix to integrin a5β1. Voloxicimab, a chimeric monoclonal antibody, blocks fibronectin binding to a5β1, and induces apoptosis of proliferating endothelial cells. Voloxicimab activity is independent of growth factor stimulus, suggesting that a5β1 signalling occurs downstream of growth factor signalling, and is possibly a final common pathway for the development of neovasculature. Methods: This is a multicenter, open label, phase II study in mCCRCC. Patients (pts) received volociximab 10 mg/kg IV every 2 weeks until disease progression. Pts were evaluated for efficacy every 8 weeks using RECIST criteria. Results: A total of 40 pts were enrolled. All pts were evaluable for safety and efficacy. Median time since first diagnosis was 2.5 years. ECOG score was 0–1 in all pts. Prior nephrectomy occurred in 38 (95%) pts. Nineteen (47.5%) pts had ≥ 2 prior therapy. Twenty one (52.5 %) pts had prior anti agiogenic therapy. Other prior treatment included IL-2 in 15 (37.5%), interferon alpha in 7 (17.5 %), IL-2 + interferon in 2 (5%) pts. Most frequent side effects were fatigue in 27 (67.5%) pts, nausea 14 (35%) pts, dyspnoea 8 (20%) pts and arthralgia 7 (17.5%) pts, of which none were grade 3 or 4. Seven (17.5%) pts had SAEs. Stable disease (SD) was observed in 32 (80 %) pts including 1 confirmed PR. Duration of SD ranged from 2–22 months (mo). Fourteen (35%) pts had time to progression (TTP) between 5.8 to 22 mo: Four (10%) pts had TTP ≥ 14 mo (range 14- 22 mo), 8 (20%) pts had TTP ≥ 6 mo (range 6- 12 mo) and 2 (5%) pts had TTP = 5.8 mo. Median TTP was 4 mo. Median overall survival (OS) has not been reached after 22 mo. OS at 6 mo was 79% and 68% at 22 mo. Six (15%) pts died in the study, 5 (12.5%) pts due to progressive disease and 1 with arrhythmia (unrelated to volociximab). Conclusions: Volociximab is well tolerated at 10 mg/kg q2w. Stable disease is noted in 80 % of pts. Based on clinical activity, a randomized controlled trial is being planned.

No significant financial relationships to disclose.
Sunitinib therapy for patients (pts) with metastatic renal cell carcinoma (mRCC): Updated results of two phase II trials and prognostic factor analysis for survival
Authors: Rosenberg J. E. , Motzer R. J. , Michaelson M. D. , Redman B. G. , Hudes G. R. , Bukowski R. M. , George D. J. , Kim S. T. , Baum C. M. , Wilding G.
Published: March 2020

5095

Background: Two single-arm phase 2 trials reported a 42% objective response rate (ORR) with sunitinib as second-line therapy in mRCC pts (JAMA 2006;295:2516–24). Efficacy results were updated and an analysis of prognostic factors for survival was performed on pooled data. Methods: Eligibility criteria and treatment plan were nearly identical for both trials. Pts with mRCC who failed =1 prior cytokine-based therapy received sunitinib in repeated 6-week cycles of 50 mg/day orally for 4 weeks, followed by 2 weeks off treatment. Response was assessed by investigators according to RECIST. Pretreatment clinical and biochemical features were examined for prognostic factors by univariate and multivariate analysis (p<0.05 significance level was used in the backward stepwise selection procedure). Results: Updated efficacy data for 168 evaluable pts showed an ORR of 45% (95% CI: 39%, 54%), median progression-free survival (PFS) of 8.4 months (95% CI: 7.9, 10.7), and median overall survival (OS) of 22.3 months (95% CI: 14.8, 36.0). Twenty pts remain on treatment with sunitinib with the longest pt on the drug for >3.5 years with partial response for >3 years. The median duration of response was 11.6 months (95% CI: 9.9, 15.2), and included 1 pt with a complete response for >2 years. The proportion of pts alive at 2 years is 48%. Final prognostic factors for survival in the multivariate model were ECOG PS 0 vs. =1 (p=0.0034); time interval from diagnosis to sunitinib treatment =1 yr vs. <1 yr (p=0.0002); hemoglobin =13 vs. <13 g/dL for males and =11.5 vs. <11.5 g/dL for females (p=0.0002). Conclusions: Median survival is nearly 2 years, which compares favorably to the historical experience (12.7 months) in second-line therapy with other agents (JCO 2004;22:454–63). The influence of sunitinib therapy on patient survival is being investigated in a randomized phase 3 trial compared to interferon-a in first-line therapy for mRCC. Further study of prognostic factors to sunitinib therapy is warranted in the first-line setting.

No significant financial relationships to disclose.
Down-regulation of HIF-1α expression by letrozole in ER+ve breast cancer patients
Authors: Generali D. G. , Berruti A. , Fox S. B. , Brizzi M. , Bonardi S. , Milani M. , Bersiga A. , Dionisio R. , Dogliotti L. , Bottini A. , Harris A. L.
Published: March 2020

510

Introduction: Letrozole is a selective non steroidal aromatase inhibitor (AI) used for the treatment of estrogen positive (ER+ve) post-menopausal breast cancer (BC) women. HIF-1α, as marker of hypoxia, is involved in the selection of more aggressive phenotype being associated with both chemo and endocrine resistance Whether HIF-1α expression could be modulated by AI in BC is the subject of this investigation. Patients and Methods: 114 elderly women with T2–4 N0–1 and ER+ve BC were randomly assigned to 6 months of primary letrozole (2.5 mg/daily) (L) plus/minus oral “metronomic” cyclophosphamide (50 mg/daily) (LC). Tumor response was assessed clinically with a calliper. On TMAs HIF-1α was evaluated in tumor specimens collected before and after treatment. The intensity of the staining for TMAs marker was scored 0 (no staining), 1 (weak/moderate staining), 2 (strong staining) in nuclear intensity for HIF- 1α expression. Results: 107 patients had HIF-1a assessed at baseline, 80 patients had HIF-1α assessed both at baseline and after treatment. At baseline HIF-1α expression inversely correlated with tumor grade (p<0.01) and N positivity (p<0.01) while it did not correlate with stage, p53, bcl2, Ki67, progesterone ERa expression. HIF-1α expression was significantly reduced after treatment (p<0.004, Wilcoxon Rank sum test), with no difference between the arms. Reduction in HIF-1α did not showed any relationship with disease response. Conclusions: Letrozole was able to down-regulate HIF-1α expression and this may be a mechanism of its efficacy. These results should be taken into account when administering new target therapy able to modulate directly HIF-1α or indirectly via HIF- 1α related pathways in association with letrozole.

No significant financial relationships to disclose.
Randomized prospective phase II trial of two schedules of sorafenib daily and interferon-α2a (IFN) in metastatic renal cell carcinoma (RAPSODY): GOIRC Study 0681
Authors: Bracarda S. , Porta C. , Boni C. , Santoro A. , Artioli F. , Di Bartolomeo C. , Contu A. , Gasparro D. , De Angelis V. , Caserta C. ,   GOIRC Study Group
Published: March 2020

5100

Background: Sorafenib is an oral multi-kinase inhibitor with a demonstrated efficacy in MRCC (Eisen, ASCO 2006). IFN is a pleiotropic molecule with an antiangiogenic activity probably dose and schedule-dependent (Folkman, 1992). Aim of this study was to evaluate the activity and safety of sorafenib combined with IFN in two different schedules. Methods: Eligible patients had metastatic renal cell carcinoma (MRCC) with a clear cell component = 50%, previous nephrectomy, ECOG Performance Status 0–2, no cerebral metastases or previous treatment, measurable disease; any Motzer’s score was allowed. Patients received oral sorafenib 400mg BID continuously plus sc IFN, 9 MU three times a week (arm-A) or 3 MU five times a week (arm-B), started 7 days after sorafenib to increase compliance. Planned sample size of this single-stage study was 100 cases to be enrolled over 18 months. Primary end points: Progression Free Survival (PFS) in the two arms and safety; secondary end-points: overall response (intention-to treat analysis) and overall survival. Results: Between January 2006 and January 2007 all the expected cases were enrolled into the study (median age 63 years, range 34–82; male/female: 71/29). Of 63 patients for whom a post baseline assessment was available (31 in arm A and 32 in arm B), 16 achieved a partial response (25.4%: 29% in arm A, 95% CI 13.2–44.9 and 22% in arm B, 95% CI 7.6–36.2), 26 had a stable disease (41.3%: 29% in arm A and 53% in arm B) and 21 progressed (33.3%: 42% in arm A and 25% in arm B). Due to the short follow-up period PFS data are not yet available. The most common grade 3/4 toxicities affecting more than 5% of the pts were equally distributed between arms except for fatigue and skin rash (respectively 19% and 8%, only arm A): hypophosphatemia (43%), hand-foot syndrome (22%), anorexia, stomatitis, hyperamylasemia (11% each), diarrhea (8%) and hyperlipasemia (5%). Conclusions: With an overall response rate of 25.4% and a tumor control rate (partial response + stable disease) of 66.7% (58.1% in arm A, 95% CI 40.7–75.5 and 75.0% in arm B, 95% CI 60.0–90.0; p = ns) sorafenib plus IFN can be considered a promising regimen in MRCC. Further investigations of the active and safe low-dose IFN combination arm are warranted.

[Table: see text]
Randomized phase II study of docetaxel with or without DMXAA (AS1404) in hormone-refractory metastatic prostate cancer (HRMPC)
Authors: Pili R. , Rosenthal M. ,   AS1404–203 study group investigators
Published: March 2020

5115

Background: DMXAA (AS1404) is a small-molecule agent that disrupts tumor vasculature. Combination of DMXAA with taxanes produces synergistic inhibition of tumor growth in animal models. A randomized phase II study in non-small cell lung cancer reported a substantial survival benefit when DMXAA was added to paclitaxel-based chemotherapy. This randomized phase II study examined the effect of adding DMXAA to docetaxel in HRMPC. Methods: Patients had progressive metastatic, androgen-independent, histologically confirmed prostate adenocarcinoma previously untreated with cytotoxics. Patients were randomized 1:1 to receive docetaxel (75 mg/m2) ± DMXAA (1,200 mg/m2) every 21 days for up to 10 cycles. Efficacy endpoints were prostate-specific antigen (PSA) response rate, objective response rate, time to tumor progression, duration of response and disease stabilization, time to PSA progression, and median and 1-year survival. Results: 74 patients were randomized: 34 to DMXAA plus docetaxel (DMXAA arm) and 40 to docetaxel alone (control arm). Median baseline PSA values were 83 ng/ml (range 6–3574 ng/ml) in the DMXAA arm and 87 ng/ml (range 1–570 ng/ml) in the control arm. PSA response data are available from 64 patients (see table ). Latest safety data show a similar number of serious adverse events reported across the treatment groups with 15 and 19 in the DMXAA and control arms, respectively. Conclusions: Addition of DMXAA to standard-dose docetaxel was well tolerated and the combination produced a substantially higher PSA response rate than docetaxel alone. DMXAA demonstrates promising activity in this patient population.

[Table: see text]

[Table: see text]
A phase II trial of docetaxel and samarium in patients with bone metastases from castration-refractory prostate cancer (CRPC)
Authors: Laplanche A. , Beuzeboc P. , Lumbroso J. , Massard C. , Plantade A. , Escudier B. , Di Palma M. , Bouzy J. , Haddad V. , Fizazi K.
Published: March 2020

5122

Background: Most patients (pts) with disseminated CRPC have bone metastases. Docetaxel is the current standard of care in CRPC. We assessed the association of docetaxel and samarium, a radio-pharmaceutical with a high affinity to bone, as consolidation treatment after docetaxel-estramustine. Methods: This is a prospective, bi-center phase II trial. Pts with bone metastases from CRPC received docetaxel 70 mg/m2 day 2 + estramustine 10 mg/Kg/day, day 1–5 (1 cycle/ 3 weeks). Pts with a response or stabilization after 4 cycles were given consolidation therapy: docetaxel 20 mg/m2/week × 6 weeks + samarium 37 MBq/Kg during week 1. Zoledronic acid was routinely used and was stopped 1 month before samarium infusion. A Simon design was used with a target of 39 pts receiving consolidation treatment. Response was defined according to the working group criteria (Bubley, J Clin Oncol 1999). The primary endpoint was progression-free survival (PFS). Results: From 01/04 to 12/05, 43 pts were included in the trial: 31 (72%), 11 (26%) and 1 (3%) achieved a PSA response, stabilization, and progression, respectively. After induction therapy, a pain response (defined as a decrease in pain intensity by at least 2/10 on a pain visual analog scale (VAS) in pts with a baseline pain level = 2/10) was achieved in 60% (18/30) and was confirmed in 69% (20/29) after consolidation therapy. Consolidation docetaxel-samarium was feasible with most pts experiencing a mild (grade 1–2) and rapidly reversible thrombocytopenia at week 5. The 7 months PSA-PFS rate was 48% (33–62%). While PSA relapse eventually occurred in all cases, this strategy resulted in an excellent long-term control of pain, with a median pain level on the VAS of 4/10, 1/10, and 0.5/10 at baseline, 12, and 18 months, respectively. With a median follow-up of 14 months, the median survival has not been reached and the 1-year survival rate is 71% (55–84%). Conclusions: Combining docetaxel and samarium is feasible and well-tolerated. It yields a major pain improvement that lasts long after consolidation therapy in pts with bone metastases from CRPC. Survival data are promising in this population of symptomatic metastatic CRPC. This approach should be tested in phase III trials.

No significant financial relationships to disclose.
Suberoylanilide hydroxamic acid (vorinostat) post chemotherapy in hormone refractory prostate cancer (HRPC) patients (pts): A phase II trial by the Prostate Cancer Clinical Trials Consortium (NCI 6862)
Authors: Hussain M. , Dunn R. , Rathkopf D. , Stadler W. , Wilding G. , Smith D. C. , Bradley D. , Cooney K. A. , Zweibel J. , Scher H.
Published: March 2020

5132

Background: Histone deacetylases (HDACs) are key regulators of histone acetylation status, which is critical to expression of genes implicated in the regulation of cell survival, proliferation, differentiation and apoptosis. Vorinostat is a potent oral HDAC inhibitor with anti-tumor activity in PC models and in phase I clinical trials. A phase II trial is assessing vorinostat in HRPC pts. Methods: Eligible pts had disease progression on 1 prior chemotherapy for HRPC, a PSA of ≥ 5ng/ml, and adequate organ function. Vorinostat was administered orally at 400 mg daily in 21-day cycles. Response was assessed every 12 weeks. The primary endpoint is proportion of pts without progression at 6 months by objective and biochemical measures. This study is designed to accrue 29 pts (80% power at the 5% significance level to distinguish between a rate of 10% vs 30%). If ≥ 7/29 pts are progression-free at 6 months, the drug will be recommended for further study. Secondary endpoints include safety, rate of PSA decline, objective response rate and overall survival. Correlative studies assessing the effect of vorinostat on serum levels of IL-6, soluble IL-6 receptor and gp130 levels were conducted. Results: To date 23/29 pts have been accrued. Median age is 68 years (range 54–77), 70% had performance status 1 and 78% are white. At registration disease progression was defined by: PSA in 83%, bone in 74% and soft tissue in 43%. Median number of cycles is 2 (range 1–6), 57% of pts required at least 1 dose reduction. At time of this report 39% of pts remain on therapy. 19 pts are toxicity evaluable. Most common treatment related adverse events (AEs) were: fatigue (74%), anorexia (63%), nausea (58%), diarrhea (32%), dehydration, taste alteration and vomiting (26% each). There was 1 grade (G) 4 thrombosis and 11 pts had G 3 AEs, the most common were: fatigue (32%) and nausea and anorexia (11% each). 3/9 response evaluable pts achieved stable disease. Conclusions: Vorinostat is feasible post chemotherapy in pts with HRPC, however it is associated with significant toxicities requiring dose reductions. Final efficacy, safety and correlative studies will be reported. Support: CTEP, N01-CM-62201, PC051375, PC 051382

No significant financial relationships to disclose.
Distinct patterns of PSA modulation by single-agent sunitinib before combination with docetaxel and prednisone in patients with metastatic castrate-resistant prostate cancer (CRPCa)
Authors: Zurita A. J. , Shore N. D. , Kozloff M. F. , Ryan C. W. , Beer T. M. , Maneval E. C. , Chen I. , Logothetis C. J.
Published: March 2020

5134

Background: We are conducting a phase I study of the oral, multitargeted tyrosine kinase inhibitor sunitinib malate in patients with CRPCa as a single agent lead-in, followed by combination with docetaxel and prednisone, to determine the optimal dose, safety, efficacy and pharmacokinetic profile of the combination. The lead-in with sunitinib alone was included to evaluate whether PSA is modulated differently than with imatinib (Mathew et al. JCO 2004;22:3323–9), and if this is predictive of response and toxicity to the combination. In addition to blocking PDGF signaling (imatinib), sunitinib also blocks VEGF. Preliminary safety and efficacy were previously reported (ASCO Prostate Symposium 2007). Here we present PSA modulation results. Methods: All patients receive a lead-in of daily sunitinib 50 mg for 4 weeks (wks) on, 2 wks off, prior to starting combination therapy. To date, 3 successive cohorts have received 60 mg/m2 docetaxel every 3 wks combined with prednisone 5 mg bid and escalating sunitinib doses (12.5, 37.5 or 50 mg/d) on a 2/1 schedule (2 wks on, 1 wk off). An ongoing cohort is receiving 75 mg/m2 docetaxel + 37.5 mg/d sunitinib. Dose-limiting toxicities (DLTs) are evaluated over the first 3-wk cycle. Results: PSA results are available for 21 patients (pts) enrolled across the 4 cohorts (median age 68 yrs, PSA 42 ng/mL, Gleason score 8). Preliminary data showed 3 patterns of sunitinib-induced PSA modulation during the lead-in: PSA reduction (6 pts; mean decrease 37.8%; >50% in 2 pts), initial increase followed by drop during the off-sunitinib period (10 pts; mean decrease 32.5%), and PSA increase (5 pts; mean increase 61%). Conclusions: Single-agent sunitinib induces PSA decline in a subset of patients with CRPCa in contrast to that observed with agents targeting PDGF or VEGF alone. The predictive value of the “lead-in PSA kinetics” in determining later response to the sunitinib plus docetaxel and prednisone combination will require completion of the study. These data support the hypothesis that blocking VEGFR may alter the phenotype of CRPCa and be synergistic with blocking PDGFR.

[Table: see text]
Elevated plasma TIMP-1 levels predict reduced survival in metastatic hormone-refractory prostate cancer patients
Authors: Oh W. K. , Leitzel K. , Kantoff P. W. , Regan M. M. , Hamer P. , Pierce K. , Brown-Shimer S. , Carney W. , Ali S. M. , Lipton A.
Published: March 2020

5143

Background: Tissue inhibitor of metalloproteinase-1 (TIMP-1) has been shown to have parodoxical multifunctional roles in tumorigenesis: inhibition of the catalytic activity of MMPs, growth promotion, inhibition of apoptosis, and regulation of angiogenesis. Increased TIMP-1 has been associated with an unfavorable prognosis in many cancers including breast, colorectal, gastric, head and neck, lung cancer, and lymphomas. Methods: EDTA plasma TIMP-1 was determined from 60 hormone-refractory prostate cancer (HRCaP) patients using the TIMP-1 ELISA from Oncogene Science / Bayer HealthCare, Cambridge, MA. Patients were identified from an institutional database and had metastatic, HRCaP at the time of blood collection, which ranged from <1 month to 14 yrs. after the start of androgen-deprivation therapy (ADT); some patients had also received several chemotherapy regimens by the time of blood collection. Median follow-up was 17 mo. after blood collection and 27/60 patients had died. Overall survival was analyzed using Kaplan-Meier method and Cox modeling on tertiles of the TIMP-1 distribution. Results: The median EDTA plasma TIMP-1 level from the 60 HRCaP patients was 335 ng/ml (range 21 - 1391 ng/ml). Median survival since time of blood collection was 14 mo. Survival differed across TIMP-1 levels (P<0.01, logrank test), in particular the upper tertile of plasma TIMP-1 had a significantly reduced overall survival from the time of blood collection compared to the lowest tertile: A larger confirmatory study which will include a multivariate analysis of known prognostic factors is planned. Conclusions: Elevated plasma TIMP-1 tertile level predicted reduced survival in HRCaP patients. Soluble TIMP-1 deserves further study to determine its predictive and prognostic biomarker potential in a larger cohort of prostate cancer patients.

[Table: see text]

[Table: see text]
A decision analytic model of prostate cancer screening using prostate-specific antigen and digital rectal exam
Authors: Hayes J. H. , Barry M. J. , Kantoff P. W. , Stahl J. E.
Published: March 2020

5155

Background: PSA-based screening has been widely adopted in the US although a mortality benefit has yet to be demonstrated. The disutility of screening and quality of life of men diagnosed and treated after screening are critical issues in assessing its benefit and harm. The purpose of this model is to estimate the effect of one-time screening for prostate cancer using Prostate Specific Antigen (PSA) and DRE (digital rectal exam) on life expectancy (LE) and Quality Adjusted Life Expectancy (QALE) in the context of current diagnostic and treatment practice. Methods: A semi-Markov state transition simulation describes the relevant health states. Two strategies were compared: 1) Screening - single screening PSA and DRE; 2) No Screening - patients diagnosed after developing symptoms. Markov cycle length was 1 year. Transition probabilities and utility weights were developed from review of the literature and expert opinion. Sensitivity analyses were performed on all parameters. A PSA threshold of 4 ng/mL and age 65 were used for the base case. The model was created using TreeAge software. Results: For our base case, a single screening conferred a LE benefit of 0.37 y (15.86 vs 15.49 y) and a QALE benefit of 0.20 QALYs (15.62 vs 15.42 QALYs). Predicted 10 y cancer specific survival for screen-diagnosed men was 95.7% vs SEER 97.7%. The model predicted 9.5% of screened patients would have metastatic disease at diagnosis vs 5% in SEER (4% unknown stage); in unscreened men, this rate was 18/100,000 vs 15/100,000 in SEER. Sensitivity Analyses of Utilities (SA): The single screen model was relatively insensitive to SA of utilities: a 20% single cycle toll on one-time PSA screening disutility was required to eliminate the benefit of screening. The disutility of positive PSA with negative biopsy slightly affected QALE: a toll of 0.25 QALYs decreased QALE from 15.62 to 15.61 QALYs. Conclusions: Our model reveals a modest benefit to one-time screening for prostate cancer. This one-time screening model is relatively insensitive to utility SA; however, the importance of incorporating psychological effects of PSA screening in recurrent screening is to be determined. The impact of serial screening, lead time, PSA threshold, and cost effectiveness on LE and QALE is being analyzed.

No significant financial relationships to disclose.
BRCA1 as a predictive marker of survival in sporadic ovarian cancer
Authors: James C. R. , Quinn J. E. , Mullan P. B. , Johnston P. G. , Harkin D. P.
Published: March 2020

5512

Background: First line treatment of ovarian cancer (OC) involves both Platinum and Taxane based chemotherapy and reduced BRCA1 mRNA and protein expression levels are observed in up to 70% of sporadic ovarian tumours. We, therefore, investigated whether BRCA1 may represent a biomarker of response to chemotherapy in sporadic ovarian cancer. Methods: As in vitro models of sporadic ovarian cancer, we used both antisense and siRNA to abrogate BRCA1 expression in BG-1 and OVCAR5 ovarian cancer cells, respectively. Apoptotic responses to DNA damaging agents and antimicrotubule agents were measured using dose inhibition assays and Annexin V flow cytometry. Quantitiative real time PCR analysis (qRTPCR) was employed to measure BRCA1 mRNA expression in 54 surgically resected ovarian tumours. Univariate analysis provided an evaluation of the effect of BRCA1 mRNA expression and response to platinum or platinum/Taxane containing chemotherapy. Results: We provide in vitro evidence that BRCA1 differentially modulates chemosensitivity in sporadic ovarian cancer. Specifically, we demonstrate that antisense and siRNA inhibition of BRCA1 expression in both BG1 and OVCAR5 ovarian cancer cells, respectively, results in increased sensitivity to both cisplatin and carboplatin and decreased apoptotic response to both paclitaxel and docetaxel. Subsequently, by retrospective clinical analysis of 54 fresh frozen sporadic ovarian tumours we demonstrate that patients with low levels of BRCA1 have a significantly improved overall survival when treated with a platinum based chemotherapy regimen in comparison to patients with high levels of BRCA1 (30.4 months vs 21 months, p=0.047, HR 0.5). In addition, overall median survival for high BRCA1 expressing patients was found to double upon the addition of a taxane containing regimen (46.82 months vs 21 months, p=0.068, HR 0.44). Conclusions: We demonstrate both in vitro and in vivo evidence to support a role for BRCA1 as a predictive marker of response to chemotherapy in sporadic ovarian cancer. We believe that this study is significant given the high incidence of reduced BRCA1 mRNA and protein levels observed in sporadic ovarian cancer and may therefore have implications for the future management of this disease.

No significant financial relationships to disclose.
Survival with adjuvant surgical oophorectomy and tamoxifen in premenopausal women with operable breast cancer
Authors: Love R. R. , Dinh N. V. , Quy T. T. , Linh N. D. , Hade E. M. , Young G. S. , Jarjoura D.
Published: March 2020

552

Background:
Reports of randomized trials evaluating adjuvant ovarian suppression or ablation with and without tamoxifen are limited in number, useful comparative data and long-term follow-up.
Methods:
From 1993–99 we recruited 709 Vietnamese and Chinese premenopausal women with clinical stage II-III operable breast cancer to a multi-site randomized prospective clinical trial of immediate pre-mastectomy adjuvant surgical oophorectomy followed by tamoxifen for 5 years (n=356) or mastectomy alone with the same combined hormonal therapy on recurrence of disease (n=353).The primary study endpoints were disease-free and overall survival.This report provides analyses for an extended follow-up period after 5 years.
Results:
With a median follow up of 7 years, disease-free and overall survival were significantly better with adjuvant therapy (log-rank p-values of 0.0003 and 0.0002). Ten year DFS probabilities of 62% and 51% (95%CI 4–22%), and OS probabilities of 70% and 52% (95% CI 6–34%) between adjuvant and observation groups were observed. In the estrogen receptor positive patient subset, 5 and 10 year DFS probabilities were 83% and 61%, and 66% and 47%; and 5 and 10 year OS probabilities were 88% and 74% and 82% and 74% in adjuvant and observation groups respectively.
Conclusions:
In women with estrogen receptor positive operable breast cancers, 5 and 10 year disease free and overall survival rates following adjuvant oophorectomy and tamoxifen compare favorably with those from other adjuvant regimens. In estrogen receptor positive patients, the hazard function with adjuvant therapy increases after year six.

No significant financial relationships to disclose.
Intraperitoneal carboplatin in icodextrin 4% as first-line treatment for epithelial ovarian cancer: A phase I/II trial
Authors: Hofman L. , Sludden J. , Boddy A. V. , Murphy D. J. , Ferry D. R.
Published: March 2020

5522

Background: First line intraperitoneal (IP) chemotherapy improves survival in epithelial ovarian cancer (EOC). Problems with IP delivery are not uncommon; in the GOG 172 study, 34% of patients discontinued IP therapy due to catheter complications. Icodextrin 4% is a high molecular weight solution for IP use, which produces a prolonged pharmacological ascites and reduces both post-surgical and post-chemotherapy adhesions. Methods: This phase I study investigated IP carboplatin in icodextrin 4% in optimally debulked EOC. Immediately post operatively, 1.5L Icodextrin 4% was infused IP. This was repeated on a weekly basis. Carboplatin was added 3-weekly, over 6 cycles. Carboplatin target AUC started at 5 mg/ml.min based on 51Cr EDTA clearance and the Calvert formula, and increased by increments of 1 mg/ml.min until dose limiting toxicity (DLT) was reached. Three to 6 patients were treated per dose level. IP fluid samples and blood samples were obtained immediately prior and after IP administration of carboplatin in icodextrin 4% and 1, 2, 4, 8, 12, 24, 48 h and 1 week after. Results: Fourteen patients were treated; 4 at AUC 5, 3 at AUC 6, 3 at AUC 7, 4 at AUC 8. DLT was reached at AUC 8. Myelosuppression was the DLT. The mean AUCs, measured in plasma ± SEM (and peritoneal fluid ± SEM), were: 5.8 ± 0.80 (55.2 ± 14.3), 4.9 ± 0.92 (43.0, 1 sample), 5.3 ± 1.3 (74.4 ± 25.3) and 7.5 ± 0.28 (135.3 ± 9.48) mg/ml.min for the target AUCs of 5, 6, 7 and 8 respectively. Two patients were withdrawn at the start of the 2nd cycle due to vaginal leaking of the IP installed icodextrin. The other 12 patients completed all 6 cycles without significant catheter problems or abdominal pain. Conclusions: The pharmacokinetic data suggest that carboplatin in icodextrin 4% is associated with a considerable IP pharmacokinetic advantage. Compared to data obtained on IP carboplatin in 5% glucose, icodextrin 4% does not seem to alter the pharmacokinetics of IP installed carboplatin. Icodextrin 4% appears to be an excellent carrier solution for IP carboplatin, with the potential to reduce catheter associated complications. To complete the phase II part of the study, 20 further patients will be treated at the maximum tolerated dose (MTD), AUC 7 mg/ml.min.

No significant financial relationships to disclose.
Phase III randomized trial of pegylated liposomal doxorubicin (PLD) plus carboplatin versus carboplatin in platinum-sensitive (PS) patients with recurrent epithelial ovarian or peritoneal carcinoma after failure of initial platinum-based chemotherapy: Southwest Oncology Group Protocol S0200
Authors: Alberts D. S. , Liu P. Y. , Wilczynski S. , Clouser M. , Lopez A. , Lange M. , Lanzotti V. , Markman M.
Published: March 2020

5551

Background: There is a continuing debate over the role of combination, platinum-based chemotherapy for PS, recurrent ovarian cancer (OC). Although this phase 3 trial was closed prematurely by the SWOG Data Safety and Monitoring Committee (DSMC) due to slow patient accrual, it provided provocative results nonetheless. Methods: Patients with recurrent stage III or IV OC, with a progression-free and platinum-free interval of 6- 24 months after completion of first-line platinum-based chemotherapy, and up to 12 courses of non-platinum containing chemotherapy or biologic therapy as consolidation treatment after the first-line regimen were eligible and observed for progression-free survival (PFS) and overall survival (OS). Patients were randomized to either IV PLD (30 mg/m2) plus IV carboplatin (AUC=5 mg/mL × min) once every 4 weeks (PLD arm) or IV carboplatin (AUC=5mg/ML × min) once every four weeks alone. Results: The PLD arm enrolled 31 patients and the carboplatin alone arm enrolled 30 for a total of 61 patients out of the 900 planned. The response rates were 67% (18/27) for the PLD arm and 32% (9/28) for the carboplatin only arm (Fisher’s exact p=0.02). The estimated median PFS on the PLD arm was 12 months and 8 months on the carboplatin only arm. The estimated median OS on the PLD arm was 26 months and 18 months on the carboplatin only arm (p=0.02). 26% of the patients on the PLD arm reported grade 4 toxicities, all hematological in nature. Conclusions: Although this study was closed early, because of slow patient accrual the results for the PLD arm are intriguing for response rates, median progression-free survival and overall survival. These data suggest that there may be an advantage to the PLD plus carboplatin combination treatment in patients with PS, recurrent disease.

No significant financial relationships to disclose.
Development of a gene signature for earlier detection and diagnosis of ovarian cancer
Authors: Vansant G. , Pezzoli P. , Goldstein W. , Monforte J. , Birrer M.
Published: March 2020

5573

Background: Ovarian cancer is the 5th leading cause of death from cancer among women and is the most fatal cancer among the gynecological malignancies. One of the major reasons for poor prognosis among ovarian cancer patients is the disease is often detected at stages III and IV, where survival rates are very low. For patients at these stages, less than 25% will survive 5 years and ultimately 75% of women diagnosed at these late stages will die. The current biomarker predominantly used for detection of ovarian cancer and monitoring of patients for relapse during therapy is the mucin 16 gene product CA125. The utility of this biomarker is limited because its expression is not always isolated to tumor tissue and in fact its expression is not associated with 40% of stage I tumors. Methods: Genes were selected that have been shown to have significant expression differences in primary ovarian tumors versus normal surface ovarian epithelium and were used to develop a multiplex RT-PCR assay for monitoring the expression of these genes. We extracted RNA from samples representative of patients with cancers of various stages (1A through 4B) and diagnoses as well as disease free subjects and monitored the expression of the potential genetic biomarkers in these samples with the developed multiplex assay. Results: Cluster analysis of the gene expression data successfully grouped the different stages together with very high specificity including the samples from the stage I patients. One stage I sample clustered with the stage III and IVs. This was from a patient with a poorly differentiated serous adenocarcinoma, a characteristically aggressive tumor which may be physiologically more similar to the later stage tumors. Conclusions: In these experiments we sought to identify and evaluate potential biomarkers that could be used in parallel for early detection and for monitoring patients during treatment. Initial results from this study revealed genes that have the potential to be part of a gene signature assay panel for early detection and patient treatment monitoring for ovarian cancer.

No significant financial relationships to disclose.
Cyclin-dependent kinase (CDK) activity as a prognostic marker in primary epithelial ovarian cancer
Authors: de Souza J. A. , Wei C. , Noguchi S. , Lu K. , Ishihara H. , Aoki D. , Ueno N. T.
Published: March 2020

5575

Background: The unpredictable nature of primary epithelial ovarian cancer (EOC) response to treatment necessitates the identification of factors that predict long-term outcome. CDK activity is the core regulator of the cell-cycle checkpoint for cancer cells. We previously found that cell death induced by taxanes requires increased activity of CDK1 and CDK2- fundamental kinases in cell proliferation. Thus, we hypothesized that CDK1/2 activities can determine the prognosis of patients with primary EOC. Methods: We retrospectively analyzed frozen ovarian cancer specimens from 72 women treated with cytoreductive surgery and adjuvant chemotherapy for newly diagnosed EOC. Median patient age was 61 years (range, 38–80), 91% had FIGO stage III/IV disease, and 86% were treated with platinum- or taxane-based regimens. Median follow-up was 32 months; median time to treatment failure (TTF), defined as time from surgery to first relapse for patients who had achieved complete response or time to disease progression for those who had persistent disease, was 15 months. Enzymatic activity of CDK1/2 in the tumor tissues was determined by a modified in vitro kinase activity assay using a C2P device (Sysmex Inc.). Recursive partitioning and regression trees algorithm (RPART) was used to identify the cohorts based on CDK1/2 activities. Results: In the univariate analysis, disease stage (p=0.021), type of surgery (optimal vs. suboptimal) (p=0.004), presence of ascites (p=0.043), and CA125 after the adjuvant therapy (p=0.005) were significant predictors of TTF. The cohort with CDK2 activity = 87.3 had a significantly shorter TTF (p=0.014) and the cohort with CDK1 activity = 226.35 showed a trend toward longer TTF (p=0.094). Multivariate Cox proportional hazards regression analysis revealed CDK2 activity (<87.3 vs. = 87.3) (p=0.012) and CA125 level at completion of the adjuvant chemotherapy regimen (p=0.02) to be independent predictors of TTF. Conclusion: Our data supports kinase activity of cell cycle as a clinically significant prognostic factor. To extend these findings, we plan to conduct a large prospective study to determine whether CDK1/2 profiling can predict long-term outcome in primary EOC.

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Phase II trial of single-agent cetuximab in patients with persistent or recurrent epithelial ovarian or primary peritoneal carcinoma with the potential for dose escalation to rash
Authors: Schilder R. J. , Lokshin A. E. , Holloway R. W. , Alvarez R. D. , Pathak H. , Aghajanian C. , Drescher C. W. , Godwin A. K.
Published: March 2020

5577

Background: Data in other tumor types showed a correlation between severity of acneiform rash and cetuximab (Cet) response. This study evaluated if Cet dose escalation to cause Grade 2 rash correlated with anti-tumor activity and if sera-based markers could predict likelihood of response. Methods: A 2-stage design was used with 50 patients (pts) planned. Eligibility: persistent/recurrent ovarian or primary peritoneal carcinoma; up to 2 prior regimens, including 1 platinum/taxane-based regimen; ECOG PS = 2; measurable EGFR-positive tumors. Pts received an initial dose of Cet 400 mg/m2, then 250 mg/m2 weekly for two 3-week cycles. Pts who had SD and < Grade 2 rash were dose escalated in 75 mg/m2 increments every 3 weeks until Grade 2 rash or maximum 400 mg/m2. Blood, pre- and/or post-treatment, was obtained from 13 of 25 pts with measurable response and the sera evaluated for potential predictive markers of response. Results: The study was stopped due to inadequate number of responders among the first 25 pts. Median age: 58 years (range: 31–79); median number of cycles: 2 (range: 1–11). At first assessment, 4 pts remained at 250 mg/m2; 8 pts were dose-escalated to 325 mg/m2; of these, 4 were increased to 400 mg/m2. One pt achieved PR; 9 pts had best response of SD. Median PFS: 2.1 months; 4-month PFS rate: 25%; 1-year survival rate: 54.8%. Rash (96%) was the most common drug-related adverse event (2 pts with Grade 3); 1 pt had Cet-induced Grade 4 hypersensitivity. Serologic markers including cytokines, chemokines, and growth and angiogenic factors were analyzed in sera from 9 pts exhibiting PD and 4 pts with SD. In pre-treatment samples, the average values of 9 of these markers were significantly reduced in pts exhibiting SD vs PD (P=0.052 to 0.00018, t-test). Changes in marker levels after Cet treatment were not significant indicators of SD. Conclusions: Single-agent Cet showed minimal activity in these previously treated pts. However, the low number of dose-escalated pts limits complete evaluation of the hypothesis regarding response and dose escalation to rash. We did identify that pts with reduced levels of 9 serologic markers at baseline were more likely to have disease control on Cet treatment.

No significant financial relationships to disclose.
Anti-tumor activity of letrozole in patients with recurrent advanced low malignant potential or low-grade serous ovarian tumors
Authors: Kavanagh J. J. , Hu W. , Fu S. , Deavers M. , Moore C. , Coleman R. L. , Levenback C. F. , Shen D. , Zheng H G. , YF Li , Mueller P. , Gershenson D. M. , Zheng H. , Li Y. F.
Published: March 2020

5582

Purpose: To evaluate the clinical activity of oral Letrozole in patients with recurrent and advanced low malignant potential or low grade serous ovarian tumors and to determine the impact of steroid receptor expression on this observed activity. Methods: In a phase II design, we recruited patients with confirmed recurrent advanced stage low malignant potential tumors and recurrent low-grade serous carcinomas. Measurable disease was required. Steroid hormone expression (ER and PR), EGFR, and Her2/neu expression were determined on available pathological material by IHC from the initial surgery or at documentation of recurrent disease and blood was obtained before enrollment and every other month while on therapy. Letrozole was administered orally at a dose of 2.5 mg once a day. The endpoints were objective response rate assessed by Response Evaluation Criteria in Solid Tumor. Adverse events were graded using the National Cancer Institute Common Toxicity Criteria. Results: Thirteen patients meeting eligibility have been enrolled are evaluable for response and toxicity. From objective clinical parameters (RECIST) no patients had a CR or PR; five patients (38%) had disease stabilizations, eight patients had progressive disease. However, using criteria for CA 125 response, we obtained a complete serologic response in 2 of 13 patients (15%), and a partial serologic response in 2 additional patients (15%); marker stabilization was seen in 5 other patients (38%). CA125 increased in four patients (31%). We also detected the presence of ER, PR, EGFR, Her-2/Neu by IHC, and estradiol in the plasma by ELISA. No significant correlation was observed between tumor marker response and ER expression alone. However, when we evaluated the co-expression of ER/PR we found 3 of 5 (60%) patients had a serologic response compared to just 1 of 8 patients with ER+/PR- tumors (P=0.07). We observed no severe adverse events. Conclusion: Our preliminary data suggests that oral Letrozole has some antitumor activity in recurrent advanced low grade or borderline ovarian tumors and is well tolerated. The analysis of correlation between objective response and combined prediction markers including phosphorylated ER, PR, AKT, and IGFR is ongoing (Supported by CTRF).

No significant financial relationships to disclose.
A phase II trial of concurrent chemoradiaiton with paclitaxel/carboplatin in high-risk cervical cancer patients after radical hysterectomy: A multicenter prospective Korean study
Authors: Lee T. , Kang S. , Kim Y. , Park B. , Kim Y. , Lee J. , Kim S. , Kim Y. , Kim J. , Kim K.
Published: March 2020

5598

Background: In 1999, five randomized studies demonstrated that cisplatin based chemoradiation had a benefit over radiotherapy in cervical cancer. However, paclitaxel has been known to be safe and effective as a radiosensitizer, and carboplatin to be less toxic than cisplatin with simpler administration. Therefore, the object of this study was to evaluate the 2 year disease free survival and toxicity of high risk cervical cancer patients who received chemoradiation with paclitaxel/carboplatin. Methods: Seventy-one patients with at least one high risk factor after radical hysterectomy (metastasis to pelvic lymph nodes (LNs), invasion of parametrial tissue (PMs), positive vaginal resection margin) were administered 135 mg/m2 of paclitaxel, carboplatin (AUC = 5) every 3 weeks for 3 cycles as an adjuvant treatment. Radiotherapy was concomitantly administered to the whole pelvic region in 28 fractions totaling 4.5∼5.4Gy. Results: Median age was 49 (range: 26–80). Seven women were dropped from the study due to noncompliance and two patients did not complete treatment due to anaphylactic shock and prolonged infection. In total, sixty-two patients completed the protocol treatment. Of 211 chemotherapy cycles administered, grade 3 or 4 neutropenia occurred in 85 (40.3%) and the majority were transient. Dose reductions were in 7 cycles due to prolonged (over 4 days) neutropenia (6), and elevated liver enzyme (1). Febrile neutropenia occurred in only two patients. 14 patients experienced grade 3 or 4 non-hematologic toxicities: 1 sensory neurotoxicity, 2 fatigue, 4 diarrhea, 3 allergic reaction, 2 genitourinary, 2 hepatic, with no treatment related deaths. With a median follow-up of 20.1 (16–28) months, 8 patients experienced recurrences, 2 distant lung metastasis and 6 pelvic side wall or paraaortic recurrences (DFS: 87.1%, 95CI:78.8∼95.4). Conclusions: Concurrent chemoradiation with paclitaxel/carboplatin is well tolerated and appears effective in early stage high risk cervical cancer patients. Considering the advantages of lower toxicity and shorter treatment schedule, this regimen shows promise and should be further tested on a larger number of patients with a prolonged follow-up.

No significant financial relationships to disclose.