bluuebunny/crossref_metadata_2025_split huggingface dataset:
Androgen receptor (AR) modulation strategies for recurrent prostate cancer (PC) without androgen suppression
Authors: Ferrari A. C. , Wang L. , Liu X. , Liu X. 
Published: March 2020

4657 Background: Prostate cancer (PC) progression is tightly linked to aberrant expression and activation of the androgen receptor (AR) gene and protein. Activation of AR is supported by increased/promiscuous ligand-binding to AR and cross-talk with activated growth factor receptor pathways and intracellular second messengers. Overexpression of AR mRNA has been linked to increased Sp1 and/or loss of AR suppressor protein (ARS) binding to the AR promoter (Oncogene, 2004). The purpose of this work was to test the hypothesis that down-regulation of AR levels and inhibition of ligand-dependent and ligand-independent activation can control androgen-dependent (AD) and -independent (AI) PC cells growth and sensitivity to apoptosis. Methods: AD and AI LNCaP cells treated with inhibitors of signal transduction pathways or inhibitors of Sp1, HDAC and/or DNA methylation were assessed for growth and apoptosis in the presence or absence of the anti-androgen bicalutamide. The combination index(CI)(CalcuSyn program) was used to measure activity: CI>1=antagonistic; CI=1, additive; CI<1,synergistic. Pertinent proteins were evaluated by Western blot. AR transactivation by transfection assays using AR and PSA reporter constructs. Results: Combinations of bicalutamide with inhibitors of Akt (Rapmycin), Sp1 (Mithramycin), HDAC (trichostatin A, Sodium butyrate) and DNA methylation (5’-Aza) were synergistic against AD and AI LNCaP cells while EGFR (Iressa) was additive. Decreased AR expression/phosphorylation and transactivation activity preceded the biologic effect. Some triplet combinations enhanced further AR modulation and biologic activity. Conclusion: a global strategy to simultaneously reduce AR levels and activation activity of downstream target genes might be an effective approach against androgen-dependent and androgen-independent clones present in recurrent, high-risk PC patients with potential to spare or postpone the need for castration. No significant financial relationships to disclose.
Baseline quality of life (QOL) as a predictor of tolerance to intraperitoneal (IP) chemotherapy for advanced epithelial ovarian cancer (EOC): A Gynecologic Oncology Group (GOG) study
Authors: Wenzel L. B. , Huang H. Q. , Armstrong D. K. , Walker J. L. , Cella D. 
Published: March 2020

5007 Background: A recent GOG randomized phase III trial demonstrated a 16 month improvement in survival for women with optimally debulked stage III EOC. Patients on the IP chemotherapy arm experienced a survival advantage but significantly worse toxicities, worse QOL during treatment, and more neurotoxicity (NTX) one year later, compared to those on the IV arm. We sought to determine whether baseline QOL and NTX and abdominal discomfort (AD) predict severity of IP treatment-related adverse effects and number of cycles completed. Methods: Three self-report QOL measures were utilized: the FACT-O (39 items), and FACT/GOG-NTX (11 items) and FACT/GOG-AD (4 items) subscales. Scoring was on a 5-point scale, with higher scores representing better QOL (FACT-O) whereas higher scores indicated worse symptoms (-NTX and -AD subscales). In addition to NTX and AD, we explored associations with fatigue. A logistic regression model was used for the analyses. Results: Of 205 patients randomly assigned to receive IP chemotherapy, 198 (97%) completed baseline QOL assessments, of whom 83 (42%) completed all 6 cycles and 16 (8%) completed none. Adjusting for age, performance status and residual disease, patients reporting higher baseline FACT-O and lower -NTX and -AD scores were more likely to complete more IP cycles. Categorizing FACT-O scores by quartiles (≤92, 93 to ≤108.8, 109 to ≤121.1, and >121.1), patients in the lowest quartile were significantly less likely to complete 6 cycles of IP therapy (odds ratio [OR] = 4.46; 95% CI: 1.95–10.21, p < 0.001). Higher FACT-O scores were also associated with less grade 3–4 fatigue (OR = 0.81 per 10 points; 95% CI: 0.67–0.99; p = 0.037); however, there was no relationship between baseline NTX and AD subscale scores and severity of physician-rated NTX and AD. Conclusions: Baseline patient-reported QOL and NTX and AD symptoms predict tolerance to IP chemotherapy. Patients with the poorest baseline QOL (FACT-O score <92) were least likely to complete IP therapy. No significant financial relationships to disclose.
Pharmacokinetic analysis of an all intraperitoneal carboplatin and paclitaxel regimen in ovarian cancer patients demonstrates favorable systemic bioavailability of both agents
Authors: Krasner C. N. , Seiden M. V. , Fuller A. F. , Roche M. , Verrill C. L. , D’Amato F. , Tretyakov O. , Tyburski K. , Matulonis U. A. , Supko J. G. 
Published: March 2020

5008 Background: A phase III trial (GOG172) demonstrated improved survival for patients with newly diagnosed and optimally debulked ovarian cancer treated with intraperitoneal (ip) cisplatin and paclitaxel (P), given both as a 24 h iv infusion and ip, as compared with standard iv dosing. Studies to further enhance efficacy and minimize toxicity of ip taxane/platinum regimens are needed. Because adequate systemic drug exposure is thought to be essential for maximum therapeutic benefit of ip chemotherapy, the pharmacokinetics (PK) and bioavailability of ip P and carboplatin (C) were determined in this pt population in a phase II trial to evaluate dosing by the ip route alone. Methods: P 60 mg/m2 once a week and C at an AUC 6 every weeks were infused over 1 h, iv in cycle 1 and ip in the 5 subsequent 21-day cycles. Plasma samples were collected during week 1 of cycles 1, 2 and 6. P was measured by LC/MS and free platinum (fPt) was determined by flameless atomic absorption. Results: PK data is available for 14 pts receiving at least 1 cycle of ip therapy and for 7 pts who received all 5 cycles. When given ip, P achieved a peak conc. in plasma (Cmax) of 0.086 ± 0.034 μM (mean ± SD) at 6.4 ± 2.2 h, 22-times lower than Cmax for iv infusion (1.92 ± 0.80 μM). Thereafter, P plasma levels were comparable for both routes and decayed at similar rates with a half-life of 13.9 ± 4.1 h for iv and 13.7 ± 2.2 h for ip dosing. The systemic bioavailability of ip P was 53 ± 19% for the initial dose and 46 ± 10% in cycle 6. P plasma levels exceeded 0.05 μM, the pharmacologic threshold conc., for >20 h upon ip dosing in 67% (10/15) and 71% (5/7) of pts in cycles 2 and 6, respectively. C was rapidly absorbed into systemic circulation when given ip with a Cmax of 83 ± 11 μM for fPt at 1.6 ± 0.2 h in cycle 2. Consistent with prior reports, systemic availability of fPt exceeded 100% (133 ± 22% in cycle 2; 142 ± 47% in cycle 6). Conclusions: Weekly ip P 60 mg/m2 with ip C (AUC 6) every 3 weeks achieved a potentially effective pattern of systemic exposure to both agents in a majority of pts. The cumulative time that P plasma levels are >0.05 μM per cycle of therapy is likely to be longer than provided by the iv/ip dosing regimen for P (135 mg/m2 24 h iv infusion day 1; 60 mg/m2 ip day 8) used in GOG172. No significant financial relationships to disclose.
Efficacy of a quadrivalent HPV (types 6/11/16/18) L1 virus-like particle (VLP) vaccine against vaginal and vulvar pre-cancerous lesions: a combined analysis
Authors: Paavonen J. 
Published: March 2020

5011 Background: In the US, 6000 cases of vulvar or vaginal cancer are diagnosed annually. HPV is detected in 75–100% of vulvar cancers in younger women. The most common HPV type detected is HPV 16, followed by HPV 18. These two types also cause a majority of HPV-related vaginal cancers. Treatment to prevent progression to vaginal/vulvar cancer is challenging. Here, we present a combined analysis of 3 randomized, placebo-controlled trials to evaluate the impact of a prophylactic quadrivalent HPV vaccine on the rates of HPV 16- and 18-related vulvar and vaginal neoplasia grade 2/3 (VIN 2/3 and VaIN 2/3). Methods: 18,150 women (16–26 yrs) from the Americas, Europe and Asia were enrolled in 1 of 3 trials. Subjects were randomized to either quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine or placebo. For all trials, vaccination occurred at day 1, and months 2 and 6. Genital tract specimens were obtained at day 1 and at 6–12 month intervals thereafter for a maximum of 48 months. Colposcopy referral was algorithm-based. Biopsies were HPV-typed. Cytology, histology, and HPV detection were conducted centrally. Analyses were done per protocol (PP) (subjects received 3 doses, had no major protocol violations, were HPV 16 or 18 seronegative at Day 1 and HPV 16 or 18 DNA negative Day 1 through month 7) and modified intention to treat (MITT) (received ≥1 dose and were HPV 16 or 18 negative at Day 1 by serology and DNA). Endpoint counts began after Month 7 and Day 30 in the PP and MITT analyses, respectively. Results: In PP analysis, after an average of 18 months of follow-up, the vaccine was 100% effective (95% CI: 56–100%) in preventing HPV 16- or 18-related VIN 2/3 or VaIN 2/3. There were 10 cases in the placebo group and 0 cases in the vaccine group. In the MITT population, after an average of 2 years of follow-up, there were 24 histologically confirmed cases of HPV 16- or 18-related VIN 2/3 or VaIN 2/3, all in the placebo group (100% efficacy; 95% CI: 83–100%). Conclusions: Quadrivalent HPV VLP vaccine prevented HPV 16 and 18-related vaginal and vulvar high-grade precancerous lesions for at least 2 years post-immunization. This intervention is expected to greatly reduce the risk of vulvar and vaginal cancers. [Table: see text]
A multi-institutional evaluation of the safety and efficacy of bevacizumab for recurrent, platinum-resistant ovarian cancer
Authors: Wright J. D. , Alvarezsecord A. , Numnum T. M. , Rocconi R. P. , Powell M. A. , Berchuck A. , Alvarez R. D. , Trinkaus K. , Rader J. S. , Mutch D. G. 
Published: March 2020

5019 Background: Bevacizumab has shown activity in recurrent ovarian cancer with an acceptable adverse event profile. However, the incidence of bowel perforation in a recent trial of heavily pretreated ovarian cancer patients was higher than expected from prior experience with bevacizumab. Whether the difference in the rate of bowel perforation was due to refractory disease, treatment history, disease burden, or location of tumor is uncertain. We sought to review our multi-institutional experience with bevacizumab in patients with recurrent ovarian cancer. Methods: A retrospective review of patients with recurrent ovarian cancer treated with single agent or combination bevacizumab therapy was undertaken. Toxicity was assessed using standard criteria. Response was determined radiographically and through serial CA125 measurements. Statistical analysis to determine factors associated with toxicity and response was performed. Results: Sixty-two eligible patients were identified. All had failed prior platinum-based therapy and had received a median of 5 prior chemotherapy regimens and 2 prior platinum-containing regimens. Single agent bevacizumab was administered to 12 (19%) women, while 50 (81%) received the drug in combination with a cytotoxic agent. The most common toxicities were myelosuppression (60%), proteinuria (19%) and hypertension (16%). Grade 3–5 toxicities occurred in 15 (24%) patients, including grade 3–4 hypertension in 4 (7%). Gastrointestinal perforations were identified in 4 (7%) subjects. Nine (15%) patients discontinued therapy due to toxicity. Fifty-eight patients were assessable for response. The overall response rate was 36% (4 CR, 17 PR) with stable disease in 40%. Clinical benefit (CR, PR, stable disease) was seen in 83% of patients treated with single agent therapy and 74% of those treated with bevacizumab-combination regimens. Conclusions: Bevacizumab demonstrates significant activity for recurrent, platinum-resistant ovarian cancer. Life threatening bowel perforations were noted in 7% of our subjects. The frequency of perforations in our cohort suggests that this complication is more likely to occur in heavily pretreated patients. No significant financial relationships to disclose.
Phase I study of MORAb-003, a humanized anti-folate receptor-alpha monoclonal antibody, in platinum resistant ovarian cancer
Authors: Konner J. A. , Ahmed S. , Gerst S. , Vander Els N. , Pezzuli S. , Sabbatini P. , Hensley M. , Dupont J. , Tew W. , Aghajanian C. 
Published: March 2020

5027 Background: Folate receptor alpha (FRA) is over-expressed in the majority of epithelial ovarian cancers (EOC) but largely absent from normal tissue. MORAb-003 (M3) is a humanized monoclonal antibody (MAb) to FRA. Binding of M3 to FRA can prevent phosphorylation of substrates specific for the 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 M3 at supra-pharmacological doses. This open-label, multiple-infusion, first-in-human, dose-escalation trial evaluates the safety, pharmacokinetics (PK), and antitumor activity of M3 in patients with platinum-resistant EOC. Methods: Sequential cohorts of patients receive four weekly infusions at escalating dose levels of M3, from 12.5 mg/m2 to 100 mg/m2. Human anti-human antibody (HAHA) and PK analyses are performed. Eligible patients have EOC that relapsed < 6 months after platinum-based therapy, acceptable organ function, Karnofsky Performance Status ≥ 70%, and measurable disease by GOG-RECIST criteria. Patients undergo pulmonary function testing (PFT) at baseline, and at end of study. Results: To date, 7 women have been treated with M3: 3 at the 12.5 mg/m2 dose, 3 at 25 mg/m2, and 1 at 37.5 mg/m2. Median age was 60. Neither dose limiting toxicity nor HAHA has been observed. Grade 1 rash occurred in 1 patient. Grade 1/2 fever following drug administration occurred in 2 patients. Grade 2 FEV1 decrease was observed in a patient with likely pulmonary lymphangitic metastasis. One subject at 25 mg/m2 had radiographically stable disease. At low doses, the PK analysis demonstrated the half-life to be shorter than anticipated based on animal studies, possibly due to tumor binding. Radiolableled imaging studies are underway to determine the distribution of M3. Conclusions: The FRA-specific MAb MORAb-003 appears to be well tolerated in patients with EOC. Enrollment continues and updated results will be presented. No significant financial relationships to disclose.
Secondary cytoreductive surgery for localized recurrent epithelial ovarian cancer: Analysis of prognostic factors and survival outcome
Authors: Salani R. , Santillan A. , Zahurak M. , Giuntoli R. , Gardner G. J. , Armstrong D. K. , Bristow R. E. 
Published: March 2020

5029 Background: To evaluate prognostic factors and survival outcome of patients undergoing secondary cytoreductive surgery for recurrent epithelial ovarian cancer with ≤ 5 sites of recurrence on pre-operative imaging studies. Methods: Patients undergoing secondary cytoreduction for recurrent epithelial ovarian carcinoma between 9/1997–3/2005 were retrospectively identified from tumor registry databases. Inclusion required: complete clinical response to primary therapy, ≥12 months between initial diagnosis and recurrence, and ≤5 recurrence sites on pre-operative imaging studies. Univariate and multivariate logistic regression analyses were used to evaluate the effect of clinico-pathologic variables on overall post-recurrence survival. Results: Fifty-five patients met study inclusion criteria. The median age at recurrence was 57.7 years and the median diagnosis-to-recurrence interval was 32 months (range 12 to 164 months). Complete cytoreduction was achieved in 41 patients (74.5%). On multivariate analysis, the statistically significant and independent predictors of overall survival were diagnosis-to-recurrence interval ≥18 months (median survival=49 months vs 3 months, p = 0.001), the number of radiographic recurrence sites (median survival: 1–2 sites=50.0 months vs 3–5 sites=12.0 months, p < 0.03) and residual disease (median survival: no gross residual=50 months vs macroscopic residual=7.2 months, p < 0.01). Age, tumor grade, histology, CA-125 level, ascites, and tumor size were not significantly associated with survival. Conclusions: These data support the definition of localized recurrent ovarian cancer as patients with 1–2 radiographic recurrence sites. In this select population, a diagnosis-recurrence interval ≥18 months and complete secondary surgical cytoreduction, which was achievable in the majority of cases, were associated with a median post-recurrence survival time of approximately 50 months. No significant financial relationships to disclose.
ABCF2 expression in endometrial cancer and breast cancer
Authors: Tsuda H. , Ogawa Y. , Nishimura S. , Kajitani K. , Kawamura N. , Hashiguchi Y. , Berkowitz R. S. , Mok S. C. 
Published: March 2020

5035 Background: ABCF2 is a new member of the ATP-binding cassette transporter superfamily gene. We previously reported that ABCF2 protein is new biomarker in clear cell adenocarcinoma (CC) of the ovary and its expression may predict the response to chemotherapy and survival of CC patients (Proc ASCO 2005, Clin Cancer Res 2005). Both breast cancer (BC) and endometorial cancer (EC) are estrogen-dependent tumors, however, their biological behavior differ. In this study, we examined ABCF2 expression in EMCA and BC and evaluated the relationship between ABCF2 expression and clinical factor. Methods: Formalin-fixed surgical samples from 100 EMCA and 191 BC patients were included in this study. ABCF2 expression was investigated by immunohistochemistry. Positive expression of ABCF2 was > 10% based on the cytoplasmic staining. Results: Histologic types and stage were as followed: EMCA: (Endometrioid (EM): 92; Adenosquamous (AS): 8), (I: 63; II: 5; III: 30; IV: 2). BC: (Papillo tu (PP): 60; Solid tub (SL): 38; Scirrhous (SC): 77; Other (OT): 15). Breast cancer was sub-classified into 3 types according to the criteria of the Japanese Breast Cancer Society. The relationship between ABCF2 expression and histologic type was shown in table. In EMCA and BC, there were no significant relationship between ABCF2 expression and clinical factor like stage, histologic type, grade and estrogen receptor (ER). In EMCA, ABCF2 expression was not related with disease free survival (DFS). However, in BC, ABCF2-positive tumors had longer DFS than ABCF2-negative tumors (p = 0.03). The ABCF2 expression were correlated with further biological variables such as tumor stage, lympho node metastasis, nuclear grade and ER status for DFS by univariate and multivariate Cox regression analysis. Multivariate analysis revealed that ABCF2 was an independent prognostic factor (HR 0.46; p = 0.018). Conclusion: The role of ABCF2 protein may differ between EMCA and BC. [Table: see text] No significant financial relationships to disclose.
ABCF2 expression may predict the prognosis of cervical cancer
Authors: Nishimura S. , Tsuda H. , Kajitani K. , Hashiguchi Y. , Kawamura N. , Berkowitz R. S. , Mok S. C. 
Published: March 2020

5045 Background: ABCF2 is a new member of the ATP-binding cassette transporter superfamily gene. We previously reported that ABCF2 protein is new biomarker in clear cell adenocarcinoma (CC) of the ovary and its expression may predict the response to chemotherapy and survival of CC patients (Proc ASCO 2005, Clin Cancer Res 2005). In this study, we examined ABCF2 expression in cervical cancer (CACX) and evaluated the relationship between ABCF2 expression and clinical factor. Methods: Formalin-fixed surgical samples from one hundred fourty CACX were included in this study. ABCF2 expression was investigated by immunohistochemistry. Positive expression of ABCF2 was >10% based on the cytoplasmic staining. Results: One hundred fourty patients were included in this study. The clinical stage was I in 86 patients, II in 38 patients, III in 10 patients, and IV in 6 patients. Histologic types were squamous cell carcinoma (SC) in 101 patients and non-squamous cell carcinoma (NSC) in 39 patients. The positive rate of ABCF2 in advanced stage (III + IV) was significantly higher than it in early stage (I + II) (p = 0.03). However, histologic type was not related with ABCF2 expression (SC 49.5% vs NSC 59.0%, p = 0.35). ABCF2-negative tumors had longer overall survival (OS) than ABCF2-positive tumors (p = 0.0014). The ABCF2 expression were correlated with further biological variables such as age, tumor stage, and histologic type for OS rate by univariate and multivariate Cox regression analysis. Multivariate analysis revealed that stage and ABCF2 were independent prognostic factor (Hazards ratio (HR) = 4.66, p = 0.0005; HR = 0.34, p = 0.025). Conclusions: The role of ABCF2 protein may predict the prognosis of CACX. [Table: see text] No significant financial relationships to disclose.
Report of first-stage accrual for NCI 5886, a phase II study of erlotinib, carboplatin and paclitaxel as first-line treatment of ovarian cancer
Authors: Blank S. V. , Curtin J. P. , Goldman N. A. , Runowicz C. D. , Speyer J. L. , Tiersten A. D. , Dancey J. , Wadler S. , Muggia F. M. 
Published: March 2020

5076 Background: Abnormalities in the EGFR pathway are thought to play a major role in the dysregulated growth of ovarian and related epithelial cancers. The purpose of this study is to determine whether the addition of erlotinib (erl) to the standard first line regimen of paclitaxel (T) and carboplatin (CB) encourages pathologic complete response (pCR) in patients (pts) with ovarian (OC), fallopian tube (FTC) or primary peritoneal (PPC) cancers. Tolerability and toxicity data have been previously reported (ASCO 2005). Correlative studies of EGFR and related pathways are being performed, but data is insufficient currently for presentation. Methods: Pts with a histologic diagnosis of OC, FTC or PPC Stage III or IV with either optimal (≤ 1 cm) or suboptimal residual disease within 12 weeks of initial surgery were eligible for enrollment. Pts received T (175 mg/m2) and CB (AUC 6) every 21 days, along with erl (150 mg) by mouth, daily, continuously, for a planned 6 cycles, after which pts underwent surgical reassessment to determine pCR. Data were analyzed as two parallel phase II trials in the strata of Stage III optimal (Op) and Stage III suboptimal/Stage IV (S). Both trials followed Simon’s two-stage design, with planned first stage sample sizes of 28 (Op) and 19 (S). Early stopping rules applied for ≤ 11 pCR in Op pts, and ≤3 responses in S pts. Results: Since June 2003, 47 pts have been accrued, 29 Op and 18 S. In the Op stratum, 19 second looks (SL) were performed: 10 negative, revealing pCR, and 9 positive. Two patients elected not to have SL. Six Op pts discontinued treatment prior to completion, and four pts in this group continue treatment. In the S stratum, 7 pts were treated neoadjuvantly, and 1 pt is Stage IV. Surgical reassessment was performed in 5 of the 18 S pts, all of whom had dramatic responses, but not pCR. One pt’s disease did not respond enough to the regimen to warrant surgical reassessment. One pt was ineligible, 8 discontinued treatment, and 3 continue treatment. Conclusions: First stage accrual goals have been met, and demonstrate enough activity of erl, T and Cb in OC, FTC and PPC to proceed with second stage accrual. In the S cohort, criteria for proceeding with the study are being reassessed to account for early dropouts and neoadjuvant treatment. No significant financial relationships to disclose.