bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictive gene expression patterns of response to adriamycin and cyclophosphamide (AC) in human breast cancers
Authors: Makris A. , Creighton C. , Osborne K. C. , Hilsenbeck S. , Harrison M. K. , Ostler P. J. , Spears C. , Brown P. , Elledge R. , Chang J. C.
Published: March 2020

527

Background: Adriamycin and cyclophosphamide (AC) and docetaxel (D) are widely used in the treatment of breast cancer. We conducted a prospective, randomized, multicenter trial to discover predictive markers of AC and D and hypothesized that gene expression profiles can select appropriate patients who may respond to AC, and that these patterns are different from our published docetaxel (D) profiles Methods: One hundred and twenty patients were randomized to either 4 cycles of AC (60/600 mg/m2) or D (100mg/m2) prior to surgery. Core biopsies from 60 patients were obtained before treatment with neoadjuvant AC. Pathologic responses were assessed after AC. Gene expression patterns were determined using Affymetrix U133A GeneChips. Differential genes for AC response were then validated by QRT-PCR in an independent cohort of 33 patients treated with AC. Results: The median age was 48 yrs (range 30–72), clinical response rates were 57% (34/60), and pathological complete response (pCR) or near pCR (npCR) was observed in 22% (12/60) in AC arm. Differential expression between sensitive and resistant tumors with a low false discovery rate (FDR 5–10%) was obtained. Of these 82 differentially expressed genes, pathways up-regulated in sensitive tumors included TOP2A, metabolism (LYZ), survival (CFLAR, CASP3), cell cycle (MKI67), cytokines and other inflammatory genes. This molecular portrait for AC was not predictive of docetaxel response. By QRT-PCR of 4 genes (LYZ, CFLAR, MKI67 and TOP2A) in the independent tumor set, LYZ was predictive of AC pathologic complete response. Additional genes will be validated in the second cohort. Conclusions: The molecular profile for AC is different from the docetaxel expression profile. This potential predictive test may allow selection of the most appropriate chemotherapy schedule for women with breast cancer.

No significant financial relationships to disclose.
The National Epirubicin Adjuvant Trial (NEAT) and Scottish Cancer Trials Breast Group (SCTBG) br9601 randomized phase III adjuvant early breast cancer trials: The updated definitive joint analysis
Authors: Earl H. , Hiller L. , Dunn J. A. , Bathers S. , Grieve R. J. , Spooner D. , Agrawal R. K. , Foster L. , Twelves C. , Poole C. J.
Published: March 2020

534

Background: NEAT and the SCTBG BR9601 trial address the role of Epirubicin (E) as an adjunct to CMF in adjuvant chemotherapy for women with early breast cancer (EBC). Methods: NEAT compared E (100mg/m2 x4cycles) followed by classical (c)CMF (x4cycles) with cCMF (x6cycles); BR9601 compared E (100mg/m2 × 4cycles) followed by iv dose modified CMF q3w (750:50:600 ×4cycles) with iv CMF (x8cycles). Eligibility was completely excised EBC, requiring adjuvant chemotherapy, and start of treatment <10 wks from surgery. Primary outcome measures were relapse-free-survival (RFS) and overall survival (OS). A joint efficacy analysis of NEAT (n=2,021) and BR9601 (n=370) triggered by planned 5-year median follow-up (FU) and estimated 800 RFS events and 600 deaths has 85% power to detect 5% two-sided differences. Results: In 2,391 eligible patients, characteristics were balanced across treatments: 72% node +ve; 59% <50 years old; 47% pre-menopausal; 58% tumours grade 3; 55% >2cms; 32% ER-ve, 50% ER+ve (18% NA). At a median FU of 6.2 yrs, 710 relapses or deaths without relapse and 570 deaths are observed. Despite lower than anticipated event rates in the control arm, these updated results confirm a highly significant benefit in favour of ECMF for both RFS (HR 0.75 (95%CI 0.64–0.87) p=0.0002) and OS (HR 0.74 (0.62–0.87) p=0.0004), independent of trial and prognostic factors. In 1458 NEAT patients (in whom data are available), 68% were to receive tamoxifen; chemotherapy scheduling data is available for 843, of whom 46% were declared concurrent and 54% sequential. In a non-pre-planned retrospective analysis, sequential tamoxifen shows a trend for advantage on RFS (HR 0.78 (0.59–1.02) p=0.06). We have amenorrhoea data on 598 NEAT and BR9601 pre-menopausal women, of whom 72% became amenorrhoeic by the end of chemotherapy. In this instance, developing amenorrhoea showed no advantage for RFS (HR 0.90 (0.65–1.24) or OS (HR 0.99 (0.68–1.44)). Conclusions: This updated definitive analysis adds to the Overview in respect of an anthracycline advantage and confirms ECMF as an established and effective standard adjuvant therapy for EBC.

[Table: see text]
Anthracycline-based sequential adjuvant chemotherapy in operable breast cancer: Five-year results of a randomized study by the Michelangelo Foundation
Authors: Moliterni A. , Mansutti M. , Aldrighetti D. , Merlini L. , Zuccarino L. , Bari M. , Farris A. , Mariani P. , Fava S. , Gianni L.
Published: March 2020

535

Background: Anthracycline-based sequential chemotherapy significantly improves efficacy outcomes compared to CMF alone. Methods: 806 eligible patients with operable breast cancer were enrolled into a randomized study (ratio 1:1:1:1) of sequential chemotherapy. In a 2×2-type design patients were allocated to first receive 4 cycles of AT (doxorubicin, A 60 mg/m2 iv + paclitaxel, T 200 mg/m2 as 3 h inf q 3wks) or EV (epirubicin, E 75 mg/m2 iv + vinorelbine, V 25 mg/m2 iv D1,8 q3wks) followed either by 4 monthly cycles of iv CMF or 6 cycles of q3w T alone (100 mg/m2 as 1h inf D1,8). Tamoxifen was recommended for 5 yr after chemotherapy in patients with HR+ tumors. Patients with tumors > 2 cm in diameter were allowed to start primary chemotherapy with 4 cycles of either AT or EV followed by surgery and postoperative systemic treatment as detailed above. Aim of the study was to test the role of T vs V when combined with an anthracycline during the first 4 cycles of the regimen as well as the role of CMF vs T during the last 4 cycles. Results: At a median follow-up of approximately 48 months, the 5 year freedom from progression (FFP) and overall survival (OS) for the main endpoints were as in the Table : The four treatment sequences were fairly well tolerated, with only 1 treatment-related death after EV. Type and severity of hematological toxicities were similar in all treatment arms. The incidence of reversible G2–3 neurotoxicity was 21.9% after AT, 5.3% after EV and 29.1% after sequential T. Chemical phlebitis was more frequent after EV (6.5%) then after AT (0.3). Conclusions: The results indicate that vinorelbine-epirubicin and classical CMF when appropriately used in a sequential modality for high-risk breast cancer are as valid and less neurotoxic an option of adjuvant therapy than the more widely used taxane-containing adjuvant regimens. Supported in part by Bristol-Myers Squibb, Pierre Fabre and Pharmacia.

[Table: see text]

[Table: see text]
Disease-free survival (DFS) as surrogate end point for overall survival (OS) in adjuvant aromatase inhibitors (AIs) trials for breast cancer (BC): Meta-analysis of 10 randomized clinical trials (RCTs) exploring the magnitude of the benefit
Authors: Ciccarese M. , Bria E. , Cuppone F. , Nisticò C. , Carlini P. , Sperduti I. , Lorusso V. , Terzoli E. , Cognetti F. , Giannarelli D.
Published: March 2020

539

Background. The issue regarding the eventual correlation of DFS with OS has not actually been explored in trials addressing the role of AIs. For this purpose, we meta-analyzed all RCTs in which patients were randomized to receive standard tamoxifen or AIs, whatever applied strategies. Methods. A literature-based meta-analysis was accomplished, and event-based relative risk ratios (RRs) with 95% confidence interval (CI) were derived. A fixed- (FEM) and a random-effect (REM) model and heterogeneity test were applied as well. Absolute benefits (AB) and the Number of patients Needed to Treat (NNT) were calculated. A linear regression model considering both each single outcome pair (5-years DFS and OS) has been adopted to explore for correlation, estimated according to Pearson, R2 (parametric) and Spearman (non-parametric) coefficients. Results. Ten RCTs were gathered (27,653 patients); two RCTs did not report the OS result, so they were not evaluable. DFS was significantly improved with AIs, with a AB of 2.3–3.5%, which translate into 29–43 NNT. OS was significantly improved in both overall and early switch strategy, with an AB of 0.8–1.61%, which translate into 120 and 62 NNT, respectively. A strong correlation was found between DFS and OS in the overall (r=0.78, R2=0.60, p=0.001; Rho=0.77, p=0.001) and in the early switch strategy (r=0.83, R2=0.68, p=0.003; Rho=0.84, p=0.002). Although a stronger correlation was found in the upfront strategy, the low number of RCTs did not allow to reaching statistical significance. Conclusions. The strong correlation between DFS and OS in AIs adjuvant endocrine treatment for early BC underlines the choice of DFS as a surrogate end-point for OS. The predictive value of earlier DFS (3-years) estimation for overall survival deserves a further analysis.

[Table: see text]

No significant financial relationships to disclose.
DUSP7 and DUSP8 promoter hypermethylations: Predictors of clinical outcomes in advanced epithelial ovarian carcinoma
Authors: Lim S. , Green J. A. , Wong H. , VanderBurg M. E. , Crook T.
Published: March 2020

5501

Background: The Dual specificity phosphatases (DUSPs) are a subclass of the protein tyrosine phosphatase (PTP) gene family which appears to be selective for dephosphorylating the critical phosphothreonine and phosphotyrosine residues within the mitogen-activated protein kinases (MAPKs) leading to inactivation. MAPK activation is a downstream target of several oncogenes and may give rise to oncogenic transformation, and hence DUSPs are potential tumor suppressor genes. The aim of this study was to investigate if DUSPs are subject to methylation-dependent silencing in epithelial ovarian cancer. Methods: In this study, promoter methylation and gene expression of the DUSPs genes (DUSP1, DUSP2, DUSP3, DUSP4, DUSP5, DUSP6, DUSP7, DUSP8 and DUSP10) were investigated in 9 ovarian cancer cell lines and in 74 primary epithelial ovarian tumors (Stage III/IV), using methylation specific PCR (MSP) and Reverse- transcription PCR (RT-PCR). The 74 clinical samples were retrospectively retrieved from a large Phase III RCT (the EORTC 55931/NCIC OV10) with clinical follow-up in excess of 6.5 years. Results: Ovarian Cancer Cell lines: Aberrant CpG methylation detected in DUSP1, DUSP2, DUSP4, DUSP6, DUSP7 and DUSP8. DUSP7 promoter methylation was associated with downregulation of mRNA expression. Primary Ovarian Tumors: Methylation of DUSP1, DUSP2, DUSP7 and DUSP8 was observed in 15–38% of the primary tumors. DUSP7 methylation is a predictor of adverse PFS in both univariate (median PFS 10.6 m versus 13.3m, p=0.002) and multivariate (Cox Regression HR 2.76, p<0.001) analyses, and is associated with a trend for poorer OS (22.1 m versus 29.3 m, p=0.07). In contrast, DUSP8 methylation is an independent predictor of favorable PFS (median 23.7m versus 11.5m; Cox Regression HR 0.30, p=0.006) and OS (HR 0.31, p=0.013). 5-year OS for DUSP8 methylated patients was 58.3% compared with 16.1% for DUSP8 unmethylated (HR 0.277, p=0.005). Conclusion: This is the first report of DUSP methylation in epithelial ovarian cancer. The study suggests that methylation-dependent transcriptional silencing of DUSP7 in advanced epithelial ovarian cancer may represent an independent predictor of adverse PFS. DUSP8 methylation, on the other hand, is a favorable clinical outcome marker.

No significant financial relationships to disclose.
Final results of After-6 protocol 1: A phase III trial of observation versus 6 courses of paclitaxel (Pac) in advanced ovarian cancer patients in complete response (CR) after platinum-paclitaxel chemotherapy (CT)
Authors: Conte P. F. , Favalli G. , Gadducci A. , Katsaros D. , Benedetti Panici P. L. , Carpi A. , Scambia G. , Ballardini M. , Nanni O. , Pecorelli S.
Published: March 2020

5505

Background: The majority of advanced ovarian cancer patients (pts) in CR after debulking surgery and Platinum/Paclitaxel will eventually relapse. Role of maintenance CT is still questionable even if a SWOG/GOG trial has shown an improved progression free survival (PFS) with 12 vs 3 cycles of maintenance Pac. In March 1999, the After 6 Italian Cooperative Group initiated a phase III study to determine if maintenance Pac could prolong PFS in pts with a clinical (cCR) or pathological CR (pCR) after first line CT Methods: Pts with advanced ovarian cancer in cCR or pCR after 6 cycles of Platinum/Paclitaxel, were randomised to observation or 6 cycles of Pac 175 mg/sqm iv q 3 wks. Primary end point: PFS; secondary end points: overall survival (OS) and toxicities. Planned sample size: 250 pts to detect a 15% absolute increase in 2-yr PFS. Results: From 03/99 to 07/06, 200 pts were randomised. Due to the low accrual rate, an unplanned interim analysis of futility according to the Bayesian approach was performed. Main patient characteristics: median age 58 yrs, median PS 0 (neurotoxicity ≥ G 2 was an exclusion criteria), stage IIb/IIc 15%, stage III 79%, stage IV 6%; 105 pts (52.5%) were in pCR. 14% of pts randomised to observation received Pac; 22% of pts randomised to Pac stopped treatment after 2–5 cycles (progression or death: 3 pts; toxicity: 9 pts; refusal: 7 pts; others: 3 pts). A G ≥ 2 neurotoxicity was reported in 25% of pts treated with Pac; other toxicities were mild. After a median follow up of 44 months, 94 pts (47%) have relapsed and 42 pts (21%) died. Median PFS were 34 and 34.5 months in observation and Pac arm respectively; 3-yr OS was 88% in observation and 78% in Pac arm. Irrespectively of treatment arm, median PFS was 34.4 months for pts with pCR and 24.5 months for those with cCR; 3-yr survival rates were 87% and 79% respectively (p=0.04). Conclusions: Six courses of maintenance Pac do not prolong PFS or OS in pts in CR after first line platinum/paclitaxel. Irrespectively of assigned treatment, the outcome of these pts is more favourable than previously reported and significantly better in the pCRs. Maintenance CT remains an experimental treatment that should be tested in pts at high risk of relapse.

[Table: see text]
Phase II trial of the novel epothilone ZK-EPO in patients with platinum resistant ovarian cancer
Authors: Rustin G. J. , Reed N. S. , Jayson G. , Ledermann J. A. , Adams M. , Stredder C. , Wagner A. , Giurescu M. ,   The ZK- EPO Study Group in Platinum-Resistant Ovarian Cancer
Published: March 2020

5527

Background: The rationally designed, fully synthetic epothilone ZK-EPO has demonstrated significant activity against ovarian cancer cell lines. The results of the first completed phase I study (one 30-min infusion q3w) indicated good tolerability, with peripheral neuropathy as the most common toxicity; signs of activity, including objective responses, were reported. A randomised phase II trial was performed to determine the efficacy, safety and tolerability of 2 infusion durations in patients with platinum-resistant ovarian cancer. Methods: Eligible patients were at first or second relapse, had a platinum-free interval of <6 months, and disease evaluable by RECIST or, if not measurable, by CA125 (GCIG criteria). Patients were randomised to receive 3-hour or 30-min infusions of 16 mg/m2 ZK- EPO administered 3-weekly. Simon’s two-step design was used; 13–34 patients were to be accrued per arm. An arm would be continued if at least 2/13 patients responded. The drug would be considered efficacious if ≥6/34 patients responded. Results: To date, 63 patients have entered the study (accrual completed November 2006). Data is currently available on the 30 patients in step 1. Four patients were excluded from efficacy analysis due to tumor histology (clear or mucinous), as per protocol. 24 patients were taxane pre-treated. 4/13 patients responded in the 3-hour arm so accrual continued; in the 30-min arm 1/13 responded. A total of 101 infusions were administered to patients in step 1. The most common drug-related toxicity >grade 1 in the 3-hour and 30-min arm was grade 2–3 peripheral sensory neuropathy (3-hour: 9/15 patients, 30 min: 5/15 patients). Two patients withdrew because of neuropathy, both in the 3-hour arm. Other drug-related toxicities >grade 1 occurring in >1 patient were fatigue (n=3), arthralgia (n=3), nausea (n=3) and lethargy (n=2). Conclusion: Preliminary results indicate that ZK-EPO, administered as a 3-hour infusion at a dose of 16 mg/m2, has promising activity against platinum-resistant ovarian cancer. Updated response data on all patients will be presented. Peripheral neuropathy currently appears to be the only noteworthy toxicity of ZK-EPO.

[Table: see text]
Carboplatin plus paclitaxel versus carboplatin plus Stealth liposomal doxorubicin in patients with advanced ovarian cancer (AOC): Preliminary activity results of the MITO-2 randomized multicenter trial
Authors: Pignata S. , Scambia G. , Savarese A. , Breda E. , Sorio R. , Vernaglia Lombardi A. , Gebbia V. , Scollo P. , Lorusso D. , Morabito A.
Published: March 2020

5532

Background: The MITO-2 (Multicentre Italian Trials in Ovarian cancer) study is a randomized phase III study comparing the effect on progression-free survival of carboplatin/paclitaxel versus carboplatin/stealth liposomal doxorubicin (CLD) in 1st-line AOC patients. Due to the lack of published phase II data on the CLD schedule, safety and activity analyses were planned within the trial. The former, previously reported for the first 50 patients treated with CLD, showed mild haematological toxicity, while non-hematological events seldom were higher than grade 2. Methods: AOC patients with AOC (stage IC-IV), aged =75, ECOG PS =2, are randomized to CP (carboplatin AUC 5 / paclitaxel 175 mg/m2, d1q21) or to CLD (carboplatin AUC 5 + Stealth liposomal doxorubicin 30 mg/m2, d1q21), both treatments for 6 cycles. According to a phase 2 design with p0=30%, p1=50%, alfa=0.10, 50 patients with measurable target lesions as defined by RECIST criteria were required and ≥20 responses had to be observed in order to define that the experimental schedule was sufficiently active to warrant phase III continuation. Results: Out of the first 137 patients randomly assigned to CLD, 87 were not eligible for response assessment by RECIST (35 had only non target lesions; 28 had only Ca 125 increased; 23 had no lesion and normal Ca 125; 1 never started treatment). Out the 50 patients eligible for response assessment, overall 34 responses were recorded (14 complete, 20 partial) for a response rate of 68% (95% CI: 53.3–80.5). In addition, among 35 patients with all non-target lesions 9 (26%) complete responses and 18 (51%) nonCR- nonPD were observed. In the remaining 28 patients evaluable only for Ca 125, this normalized in 96% of the cases at the end of the 6 cycles. Conclusions: An a priori planned activity analysis showed that CLD every 3 weeks is feasible and active in AOC patients suboptimally debulked and with measurable lesions. The trial is ongoing; as of December 28th, 2006, 615 patients have been enrolled out of 810 planned.

No significant financial relationships to disclose.
The role of surgery in high-risk gestational trophoblastic disease patients
Authors: Lewin S. N. , Soslow R. A. , Kim M. J. , Derosa F. A. , Abu-Rustum N. R. , Sonoda Y. , Brown C. L. , Baines M. S. , Flores R. , Aghajanian C. A.
Published: March 2020

5541

Background: A survival rate of 81% has been reported in high-risk gestational trophoblastic disease (GTD) patients (pts) treated with multi-agent chemotherapy. We describe the surgical management in heavily treated pts with high-risk GTD. Methods: A retrospective chart review was performed of all pts receiving treatment for GTD at our institution from 1996–2006. High-risk pts who underwent surgery were selected. Results: Over the 10 year period, 32 pts with a median of two prior chemotherapy regimens (range 1–5) underwent 43 surgical procedures. 14 pts (44%) with undesired future fertility had hysterectomies to shorten their chemotherapy interval. 11 remain NED with median follow-up of 24 months (range 8–72). Surgeries to manage disease complications consisted of one craniotomy (for hemorrhage) and one laminectomy (for cord compression). Postoperatively the former received EMA/EP with interval hysterectomy followed by paclitaxel and carboplatin. She remains NED 75 months from diagnosis. The later died one month following laminectomy from pulmonary hemorrhage. Resection of solitary residual disease in chemotherapy refractory pts was attempted for cure in ten pts. Seven pts (70%) were cured following either thoracotomy with wedge resection or lobectomy (6) or radical abdominal trachelectomy (1) with median follow-up of 60 months (range 15 to 84). Of the remaining three, one developed brain metastasis following thoracotomy and was ultimately cured with EMA/EP. The other two with metastatic placental site trophoblastic tumor (PSTT) progressed and died, one and 60 months post-procedure. Planned hysterectomy due to non-metastatic PSTT was performed in two pts as their sole treatment. Both remain NED 19 and 26 months later. An additional seven PSTT pts had hysterectomies following EP/EMA treatment for metastatic disease. Three (43%) of the hysterectomy specimens had no residual disease. All required no further treatment and remain NED with median follow-up of 60 months (range 13 to 84 months). Conclusions: Surgical intervention during the management of high-risk GTD can be tailored to control disease complications, remove chemotherapy resistant disease or serve as therapy for PSTT. A multidisciplinary approach in specialized centers familiar with this disease entity is preferred.

No significant financial relationships to disclose.
Concomitant weekly carboplatin (CB) and paclitaxel (P) with pelvic radiotherapy (RT) for the treatment of advanced cervical cancer (ACC): A FNCLCC gynecologic group phase I trial
Authors: Lhomme C. , Petit T. , Largillier R. , Mayer F. , Floquet A. , Rey A. , Jimenez M. , Haie-Meder C.
Published: March 2020

5542

Background: Standard primary treatment for locally ACC is RT with concomitant chemotherapy (CT). CB and P are radiosensitizers with in vitro synergistic action. Methods: Patients (pts) with FIGO stage IIB-IVA negative paraaortic lymph nodes cervical cancer were treated with 6 weekly cycles of CT during pelvic RT (45 Gy) and brachytherapy (BT) according to Table 1 . Each dose escalation step followed a 30-day period of observation on cohorts of 3 to 6 pts depending on dose limiting toxicity (DLT): toxic death; garde (G) 4 neutropenia > 1 week; G 4 toxicity (other hematologic or non-hematologic); any toxicity requiring = 1 week delay in RT, or > 2 dose reductions of CT, or G 3/4 hematologic toxicity > 3 weeks after treatment’s end; unendurable G 3 non hematologic toxicity. Results: 23 pts were included by 5 centers in 5 dose levels (L). Stage distribution: IIB (10), III (11), IVA (2); 20 epidermoid and 3 adenocarcinoma; ECOG: 0 (16), 1 (7). 22 pts received the 6 planned cycles. Median dose of irradiation was 45 Gy (43.2–50) with no toxicity related interruption. 17 pts underwent BT, 2 had hysterectomy and 1 received complementary external irradiation 12 Gy. CT dose reduction was necessary in 4 pts (cycle 5 or 6) and cycles postponed for 10 pts (cycle. 5 or 6). One pt experienced paclitaxel allergy at L1. G 3 anemia and/or neutropenia were reported in 11 pts and G 4 neutropenia = 1 week in 2 pts. Radiodermatitis occurred in 5 pts, asthenia in 3 and nausea in 1. One DLT was observed: unendurable G 3 asthenia + G 3 neutropenia and leucopenia at L3. Clinical and radiological complete response was obtained in 13 pts, 5 PRs and 2 SDs in 20 evaluable pts. Conclusions: Acceptable toxicity and optimal irradiation were possible at L4 in 7 pts. These doses are recommended for future phase II studies of concomitant CT/RT in ACC.

[Table: see text]

No significant financial relationships to disclose.
Cervical cancer in patients infected with human immunodeficiency virus (HIV)
Authors: Leitao M. M. , White P. , Cracchiolo B. M.
Published: March 2020

5544

Background: The objective of this study was to compare the HIV viral load (VL), and CD4 counts (CD4) in patients infected with HIV with and without cervical cancer. We hypothesize that HIV positive women with inadequate HIV control, as reflected by the degree of immune suppression, will be at the highest risk of developing cervical cancer. Methods: We performed a case-control study of all patients seen at University Hospital from 1/1/95 - 4/30/06. All patients were HIV positive and were identified using an institutional electronic patient database and University Hospital Cancer Registry using ICD-9 codes. Cases were patients diagnosed with invasive cervical cancer and controls were patients without invasive cervical cancer. Patients were used as a control if there was documentation of a normal gynecologic exam without clinical or histopathologic evidence of cervical cancer. CD4 counts and viral loads were then abstracted from the electronic medical chart. Patients were kept as cases or controls if they had a CD4 count <6 months before or <1 month after the diagnosis of invasive cervical cancer (cases) or from the last gynecologic exam (controls). Controls were matched to cases on a 4:1 ratio according to current smoking history. Patients were considered immunocompetent if they had both CD4 counts >200 and VL <10,000. SPSS version 12.0 statistical software was used to analyze our data. Results: A total of 15 cases and 60 controls were identified. The majority (67 [89%]) of patients were African-American. The median CD4 count for the cases was 208 (range 18 - 1102) compared to 445 (range 20 - 1201) for the controls (p=0.03). The median VL was 16,918 (range 50 - 214,915) for the cases compared to 1,430 (range 50 - 571,000) for the controls (p=0.15). Only one (7.1%) of 14 cases was immunocompetent compared to 35 (63.6%) of 55 controls (OR 0.04 [95% CI: 0, 0.37; p<0.001]). This significance was maintained after adjusting for current highly active antiretroviral therapy (HAART) use, number of years known to be HIV infected, and patient age (p=0.002). Conclusions: Patients with HIV who are diagnosed with invasive cervical cancer appear to have a much greater degree of immunosuppression than women with HIV without invasive cervical cancer.

No significant financial relationships to disclose.
SCOTCERV: A phase II trial of docetaxel and gemcitabine as second-line chemotherapy in cervical cancer
Authors: Symonds R. , Davidson S. , Chan S. , Reed N. , McMahon T. , Paul J.
Published: March 2020

5548

Background: Concurrent Cisplatin chemotherapy along with radiotherapy is standard therapy for locally advanced cervical cancer. There is no established second line regimen. Taxanes and Gemcitabine are not thought to share drug resistance with Cisplatin. In combination they are reasonably tolerated; myelosuppression is the dose limiting toxicity. Response is more likely in recurrences outside the irradiated area. Methods: This was a multi-centre phase II trial of Docetaxel (75mg/m2 d1) and Gemcitabine (1,000 mg/m2 d1,d8) in relapsed patients (pts) after treatment with cisplatin alone or in combination (excluding with taxanes) and/or radiotherapy. A Gehan two-stage design was used (minimum response rate requirement 25%). Pts had to have disease assessable by RECIST outside the irradiated pelvis and adequate organ function. After 12 pts the Docetaxel dose was reduced to 60 mg/m2. Results: 26 eligible pts were recruited to the study; information is available currently for 24. The median age is 43 years (range 30–62) and the median time from prior treatment is 12 months (1–55). 23 pts had prior chemoradiotherapy. Performance status: 0 (15) or 1 (9). Histology: squamous 17, adenoCa (6) mixed (1). Major metastatic sites were lung (11) and para-aortic nodes (11). The principal toxicity was neutropenia (gd 3 (8), gd 4 (8)) with 4 pts experiencing grade 3 febrile neutropenia. Dose reductions occurred in 29% of pts (Docetaxel) and 25% of pts (Gemcitabine), primarily for neutropenic fever. Haematological toxicity resulted in d8 Gemcitabine being omitted in 41% of cycles. 1 patient had gd3 SOB and 1 patient gd 3 diarrhoea. Reduction of Docetaxel dose did not reduce haematological toxicity. 5 pts have not, as yet, had response reported. In 19 pts (16 completed therapy) there was 1 CR, 4 PR, 6 stable disease, 7 progressions and 1 unevaluable. The overall response rate is 26% (95% ci 9%-51%). Conclusions: This preliminary data shows this combination has activity against platinum resistant metastatic cervical cancer, although the ability to deliver d8 Gemcitabine is compromised. Final results will be available for the meeting.

[Table: see text]
Oxaliplatin plus paclitaxel for recurrent and metastatic cervical cancer (CC): New York Cancer Consortium Trial P5840
Authors: Kuo D. Y. , Blank S. V. , Kobrinsky B. , Christos P. , Caputo T. A. , Runowicz C. D. , Pothuri B. , Ivy P. , Muggia F. , Wadler S.
Published: March 2020

5549

Background: Although cisplatin (cis) is an effective radiosensitizer, its activity in patients (pts) with advanced and recurrent CC is disappointing. Oxaliplatin (O) might exhibit greater activity and be suitable for combination with paclitaxel (P). Methods: Pts with advanced and recurrent CC who had not received prior chemotherapy except radiosensitizing cis were treated with P 175 mg/m2 IV and O 130 mg/m2 IV every 21 d. Response (R), as determined by RECIST criteria and confirmed at 9 weeks (wk), and toxicity were primary outcomes. If R in = 8 patients (pts) of 18, accrual to 46 could ensue. Results: Of 17 pts enrolled, 16 were treated. Histology: 7 adeno/10 squamous.The median age was 57 (range 33–78) and 13 had had prior radiation (10 with cis). Median cycles: 3 (0–8). One CR and 4 PRs were achieved for an overall response rate of 29% (95% confidence interval: 10.3%, 56.0%). Additionally, 4 had stable disease, but this was not confirmed at 15wk. Time to progression in those responding was 21 wk (range 11–51). 7 pts are alive. 6 pts experienced grade (gr) 3/4 hematologic toxicity. Neuropathy occurred following cycle 3 in 2 pts (gr3). Additonal gr 3/4 toxicities were gastrointestinal (GI)/metabolic in 6, thrombotic in 1 and hypersensitivity in 1. There were no treatment-related deaths. Conclusions: In the stage I of our Phase II trial, O and P demonstrate a 29% response rate when used to treat advanced and recurrent CC. Toxicities of this regimen are hematologic, gastrointestinal, and neurologic. Supported by N01-CM-62204.

No significant financial relationships to disclose.
A stromal-associated gene expression signature predicting for survival in a series of patients with advanced high-grade serous ovarian cancer
Authors: Bonome T. , Samimi G. , Randonovich M. , Brady J. , Ghosh S. , Ng S. , Mok S. C. , Birrer M. J.
Published: March 2020

5552

Background: Prognostic gene expression signatures have been derived for undissected serous ovarian epithelial tumors, yet the specific contribution of stromal cells to patient survival has not been addressed. The aim of this study is to identify stromal genes impacting patient survival in the context of serous ovarian cancer. Methods: Expression profiling utilizing Affymetrix U133 Plus 2.0 oligonucleotide arrays was completed for 50 microdissected stromal samples derived from high-grade, late-stage serous tumors displaying a broad spectrum of survival endpoints. A semi-supervised dimension reduction method employing multivariate Cox regression and principal components analysis was applied to the expression data to identify genes associated with patient survival and establish a predictive model. qRT-PCR was employed to validate the microarray expression data. Results: Cox regression analysis identified 267 significant genes. The first 6 principal components of these genes, representing >65% of total variance, entered a multivariate Cox model through which the relative hazard of future patients can be predicted. To confirm our finding, the microarray data underwent leave-one-out validation. The patients were equally divided into low- and high-risk groups and non-parametric Kaplan-Meier analysis and log rank test demonstrated the two groups were significantly different in survival (p = 0.0115). Genes associated with cell survival and migration were identified in the prognostic signature. For validation, qRT-PCR data for all 50 specimens was correlated with microarray expression values for a series of select prognostic genes. Conculsions: In this study, we characterized and validated a stromal dervied prognostic signature associated with poor patient survival. Contained in this novel predictor may be stromal targets suitable for the design of new therapeutic interventions, or use as independent diagnostic markers.

No significant financial relationships to disclose.
A phase I study of MORAb-003, a fully humanized monoclonal antibody against folate receptor alpha, in advanced epithelial ovarian cancer
Authors: Bell-McGuinn K. M. , Konner J. , Pandit-Taskar N. , Gerst S. , Nicolaides N. , Sass P. , Grasso L. , Weil S. , Phillips M. , Aghajanian C.
Published: March 2020

5553

Background: Folate receptor alpha (FRA) is over-expressed in the majority of epithelial ovarian cancers (EOC) but is largely absent from normal tissue. MORAb-003 is a humanized monoclonal antibody (MAb) to FRA. Binding of MORAb-003 to FRA can prevent phosphorylation of substrates specific for Lyn kinase, suppress proliferation of cells over-expressing FRA, mediate FRA-positive tumor cell killing via antibody-dependent cellular and complement-dependent mechanisms, and suppress tumor growth in vivo of FRA-expressing tumors in rodent xenograft models. Toxicology studies in non-human primates found no evidence of toxicity with MORAb-003 at supra- pharmacological doses. This open-label, multiple-infusion, first-in-human, dose-escalation trial evaluates the safety, pharmacokinetics (PK), and anti-tumor activity of MORAb-003 in patients with platinum-resistant EOC. Methods: Sequential cohorts of patients received four weekly infusions at escalating dose levels of MORAb-003 from 12.5 mg/m2 to 400 mg/m2. Eligible patients had platinum-resistant EOC, acceptable organ function, KPS = 70%, and measurable disease by GOG-RECIST criteria. A subset of subjects received a tracer dose of 111In-labelled MORAb-003 and SPECT-CT and planar imaging. Human anti-human antibody (HAHA) and PK analyses were performed. Results: To date, 18 subjects have been dosed with up to 200 mg/m2. No dose limiting toxicity or significant related adverse events have been observed. Four subjects had rigors (2 grade 1) or fevers (3 grade 1, 1 grade 2) following the first infusion. Nine subjects have had radiologically stable disease, and 7 subjects have had stable or declining CA125. Two subjects have received extended therapy for an apparent clinical benefit. Radiolabelled tracer studies have demonstrated significant tumor uptake of labeled MORAb-003. The 400 mg/m2 dose cohort is currently enrolling. Conclusions: The FRA-specific MAb MORAb-003 appears to be well tolerated in patients with EOC and may have activity in platinum-resistant patients. These results support further evaluation of the efficacy of MORAb-003 in a phase 2 study which is ongoing.

[Table: see text]
High plasma levels of fenretinide (4-HPR) were associated with improved outcome in a phase II study of recurrent ovarian cancer: A study by the California Cancer Consortium
Authors: Reynolds C. P. , Frgala T. , Tsao-Wei D. D. , Groshen S. , Morgan R. , McNamara M. , Scudder S. , Zwiebel J. A. , Lenz H. J. , Garcia A. A.
Published: March 2020

5555

Background: 4-HPR is a synthetic retinoid with dose-dependent cytotoxicity in vitro for ovarian cancer cell lines, especially at concentrations > 10 μM. We previously reported preliminary results of a phase II trial (Garcia et al, Proc ASCO 2004: a5056) that showed encouraging stabilization of disease. Methods: 4-HPR capsules were given orally (900 mg/m2/bid for 7 days every 21-days) to women with recurrent ovarian cancer. Steady-state plasma concentrations of 4-HPR were determined by HPLC. Patients were required to have uni-dimensionally measurable disease, 0–2 chemotherapy regimens for recurrent disease, and performance status 0–2. The primary endpoint was response rate by RECIST criteria; secondary endpoints were progression-free survival (PFS) and overall survival (OS). Results: 31 patients were enrolled to the first stage; 28 patients were evaluable for response, with a median of 3 prior chemotherapy regimens (range: 1–3); 24 patients were evaluable for pharmacokinetics. A total of 172 4-HPR treatment cycles were given. Eleven patients experienced at least one grade 3 toxicity and one patient had grade 4 fatigue. No objective responses were observed, leading to study closure. Best response was stable disease in 13 patients (42%) with a median duration of 7.9 months (2.1–25.8 months). 4-HPR steady-state plasma levels ranged from 3.1–12.5 μM. PFS at 6 months was 26% (± 0.08 SE), 42 % (± 0.14 SE) for patients with 4-HPR plasma levels = 9 μM (n=12), and 17% (± 0.11 SE) for plasma levels < 9 μM (n=12). OS with plasma levels = 9 μM was significantly higher than for those with 4-HPR levels < 9 μM (66% vs. 13% at 18 months, adjusted p-value = 0.016). Conclusions: 4-HPR may provide clinical benefit to patients with recurrent ovarian cancer who obtain high 4-HPR plasma levels. Trials in ovarian cancer of 4-HPR focused on progression-free survival as an endpoint are justified using formulations with improved bioavailability. Supported by N01-CM-62209.

No significant financial relationships to disclose.
Randomized, multicenter, two-dose level, open-label, phase IIa study with the intraperitoneally infused trifunctional bispecific antibody catumaxomab (anti-EpCAM × anti-CD3) to select the better dose level in platinum refractory epithelial ovarian cancer patients
Authors: Belau A. , Pfisterer J. , Wimberger P. , Kurzeder C. , Du Bois A. , Sehouli J. , Loibl S. , Burchardi N. , Vergote I. , Wagner U.
Published: March 2020

5556

Background: The trifunctional antibody catumaxomab specifically binds EpCAM+ tumor cells, CD3+ T lymphocytes and accessory cells via the Fcγ RI/III thereby inducing a tumor specific cell mediated cytotoxicity in vitro and in vivo. This study was conducted to evaluate efficacy and safety of two different regimens of catumaxomab. Methods: Women with platinum-refractory (progressing during or ≤ 6 mos. after the last platinum containing regimen) epithelial ovarian cancer and measurable recurrent disease were randomized to receive either 10 -10 -10 - 10 μg or 10–20–50–100 μg of catumaxomab over 6h i.p on days 0, 3, 7 and 10. Results: 45 pts. were entered (22 high dose (HD)-arm, 23 low dose (LD)-arm). Both groups were well balanced concerning ECOG-perfomance score, with a median age of 65.6y in the HD- and 57.6y in the LD-arm and with a median diameter of measurable lesions of 90mm in the HD- and 104mm in the LD-arm. Based on the AEs, changes in laboratory parameters and other safety variables observed in the safety population in the course of this study, the accumulated safety experience is consistent with the key features of the mode of action of catumaxomab. Their intensity on median level was mostly mild to moderate. A clinical benefit was detectable in 27.3% of pts. for the HD- (1PR/5SD) and 8.7% of pts. for the LD-arm (2SD). After a median follow-up of 4.96 months, the median overall survival time was 182 d for the HD- and 114 d for the LD-arm. Conclusion: The results demonstrate that catumaxomab is safe with acceptable toxicity when administered as a sequence of 4 IP infusions at 10, 20, 50 and 100 μg. A modest dose effect is observed for the higher doses of catumaxomab.

No significant financial relationships to disclose.
Pazopanib (GW786034) is active in women with advanced epithelial ovarian, fallopian tube and peritoneal cancers: Initial results of a phase II study
Authors: Friedlander M. , Hancock K. C. , Benigno B. , Rischin D. , Messing M. , Stringer C. A. , Tay E. H. , Kathman S. , Matthys G. , Lager J. J.
Published: March 2020

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Background: Pazopanib is a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/β, and c-kit that blocks tumor growth & inhibits angiogenesis. Clinical studies have demonstrated activity of anti-angiogenesis agents in ovarian carcinoma. Methods: Pts with epithelial ovarian, fallopian tube or primary peritoneal carcinoma; ECOG PS 0–1 with complete CA-125 response to initial platinum-based chemotherapy with subsequent rise to = 42 U/mL; no disease on CT; or non-bulky disease (masses ≤ 4 cm) were eligible. All pts must have received 1–2 prior regimens. Treatment consisted of pazopanib 800mg QD until PD, withdrawal due to AEs, or withdrawal of consent. Two-stage Green-Dahlberg design was employed requiring 2 CA-125 responses in Stage I (20 pts) to proceed to Stage II (15 pts). Primary endpoint was CA-125 response (= 50% decrease from 2 baseline samples, confirmed ≥ 21 d after initial response sample). Results: Data were available from 15/17 pts enrolled. Median age was 60 yrs (46–79). Majority of pts had platinum-sensitive disease to first line therapy (74%) and had 1 prior line of therapy (60%). 40% of pts relapsed < 6 mos, 27% relapsed 6–12 mos; 27% relapsed > 12 mos. CA-125 responses were seen in 7 pts (47%) with a median time to response of 29 d (5 pts have continuing response of 56–140 d and 2 pts had response duration of 56 & 112 d). SD was observed in 4 pts (27%) and PD in 4 pts (27%). Most common AEs were fatigue, diarrhea, nausea, vomiting, and headache. Most common Gr 3/4 AEs were diarrhea (n=2) and ALT elevation (n=2). Five pts (33%) withdrew due to an AE; 1pt (7%) withdrew due to a potentially disease-related AE (Gr 3 ascites) and 4 pts (26%) withdrew due to toxicity (Gr 3 fatigue, Gr 2 vomiting, Gr 3 double vision, Gr 3 AST/ALT elevations). Conclusions: Preliminary review of Stage I suggests that pazopanib monotherapy demonstrates biologic activity in pts with ovarian cancer with biochemical relapse following prior platinum chemotherapy. The study has met the response criteria to proceed to stage II of enrollment.

No significant financial relationships to disclose.
Gefitinib in combination with paclitaxel (P) and carboplatin (C) as second-line therapy for ovarian, tubal or peritoneal adenocarcinoma: Final results of a phase II study
Authors: Pautier P. , Joly F. , Kerbrat P. , Bougnoux P. , Fumoleau P. , Petit T. , Rixe O. , Ringeisen F. , Lhommé C.
Published: March 2020

5566

Background: High EGFR expression occurs in 35–70% of primary ovarian tumors and is often associated with poor prognosis. This Phase II, open-label, non-comparative multicenter study investigated the efficacy and tolerability of gefitinib (Iressa) in combination with paclitaxel (P) and carboplatin (C) for second-line treatment of patients (pts) with ovarian, tubal or peritoneal adenocarcinoma. Methods: Women (>18 years) with platinum-resistant/refractory (relapsed <6 months after first-line platinum-based and P chemotherapy), or platinum-sensitive (relapsed >6 months) disease were enrolled. Pts received gefitinib (500 mg/day), P (175 mg/m2) and C (AUC 5) every 3 weeks for 6–8 cycles, after which pts could continue to receive gefitinib. The primary endpoint was objective response rate (ORR) assessed using RECIST or Rustin criteria. Results: Sixty-eight pts (26 resistant/refractory and 42 sensitive) were enrolled (median age [range]: 57 [34–72] years; ECOG performance status 0/1/2: 41/26/1). ORR and disease control rates were 19.2% and 69.2%, respectively, for resistant/refractory; and 61.9% and 81.0%, respectively, for sensitive pts (see table ). Grade 3/4 toxicities (in =10% pts) were neutropenia (59%), diarrhea (25%), leukopenia (22%), anemia (13%), and acne (13%). Two myelodysplastic syndromes (MDS) and one acute biphenotypic leukemia were observed during treatment. Another pt developed MDS 34 months after study treatment discontinuation. Conclusions: Gefitinib (Iressa) in combination with P and C has promising activity as second-line treatment for ovarian, tubal or peritoneal adenocarcinoma and is generally well tolerated. The hemopathies are under further investigation.

[Table: see text]

No significant financial relationships to disclose.
A clinical pathway for patients undergoing primary cytoreductive surgery with rectosigmoid colectomy for advanced ovarian or primary peritoneal cancer
Authors: Gerardi M. A. , Santillan A. , Meisner B. , Diaz-Montes T. P. , Gardner G. J. , Giuntoli R. L. , Bristow R. E.
Published: March 2020

5569

Background: To evaluate the safety, feasibility, and economic impact of a clinical pathway including rapid diet advancement for patients undergoing rectosigmoid colectomy as part of cytoreductive surgery for advanced ovarian or primary peritoneal cancer. Methods: Post-operative management was dictated by surgeon preference in 45 consecutive patients (Group 1) and according to the prescribed clinical pathway in 19 consecutive patients (Group 2). Critical elements of the clinical pathway included: rapid diet advancement, early discontinuance of nasogastric suction, criteria-based utilization of parenteral nutrition, selective laboratory testing, and deferring initiation of chemotherapy until after discharge. Results: The median age was 58 years for Group 1 patients and 67 years for Group 2 patients. Median time to flatus was 6 days for both groups; however, the median time to tolerating diet was 6 days for Group 1, and 4 days for Group 2. Patients in Group 1 had a median length of hospital stay of 12 days (range=5–30 days), a median total 30-day post-operative hospital charge of $42,868 (range=$19,960-$130,252), and a 30-day readmission rate of 33%, compared to 8 days (range=4–28 days) (p=0.020), $32,840 (range=$18,353-$140,283) (p=0.016), and 21% (p=0.379) for Group 2, respectively. Clinical pathway-directed management was associated with a median reduction in hospital charges of $10,027 per patient. Conclusions: A critical pathway incorporating rapid diet advancement for patients undergoing primary cytoreductive surgery with rectosigmoid colectomy for ovarian or primary peritoneal cancer is feasible, safe, and associated with a significant reduction in length of hospital stay and hospital-related charges and did not increase morbidity.

No significant financial relationships to disclose.