bluuebunny/crossref_metadata_2025 huggingface dataset:
KRAS and EGFR mutations to distinguish adenocarcinomas and squamous cell carcinomas of the cervix.
Authors: Wright Alexi A. , Hirsch Michelle S. , Wagle Nikhil , Howitt Brooke E , Palescandolo Emanuele , MacConaill Laura E. , Hummelen Paul Van , Shoni Melina , Hahn William C , Matulonis Ursula A
Published: March 2020

5011

Background: Cervical adenocarcinomas (AC) have higher rates of recurrence and distant metastasis, compared with squamous cell carcinomas (SCC), and decreased survival in advanced disease. Yet, tailored treatments for cervical cancers have not emerged. The aim of this study was to compare the frequency and type of somatic mutations in cervical AC and SCC to identify novel therapeutic targets for both subtypes. Methods: Tumors from 61 patients with cervical cancer (36 AC, 25 SCC) underwent genomic profiling by OncoMap, a multiplexed mass spectrometric genotyping technology that interrogates more than 400 known mutations in 33 cancer genes. Results: Overall, 31/61 (50.8%) tumors harbored candidate mutations, and 6/61 (9.8%) had ≥2 mutations. PIK3CA mutations were present in 21/64 (34.4%) of cervical cancers, with a trend towards higher rates in SCC compared with ACC (21/25 or 48.0% vs. 9/27 or 33.3%, p=0.10). KRAS mutations were present in 6/31 (16.7%) of AC, but none of the SCC (0%; 0/25). EGFR mutations were present in 9/25 (36.0%) of SCC, including G719S, but none of AC (0%; 0/31). Conclusions: The identification of distinct genomic alterations in SCC and AC of the cervix suggest different therapeutic rationales for each subtype. EGFR amplification in cervical SCC has been previously reported, but this is the first identification, to our knowledge, of activating EGFR mutations in cervical SCC. Together, this suggests that EGFR-inhibitors might be useful in selected patients with cervical SCC. Similarly, activating mutations in KRAS and PIK3CA in AC suggest that inhibition of the MAPK pathway (MEK inhibitors) and/or PI3K pathway may be beneficial in this subtype. Future studies should include more comprehensive genomic profiling strategies, such as targeted massively parallel sequencing, to detect multiple types of genomic alterations.
Lenalidomide (REV) in asymptomatic late recurrent ovarian cancer (ROC) patients with increasing CA 125: A GINECO phase II trial.
Authors: Selle Frédéric , Ray-Coquard Isabelle , Sevin Emmanuel , Mari Véronique , Berton-Rigaud Dominique , Bourgeois Hugues Pierre , Dohollou Nadine , Fabbro Michel , Floquet Anne , Lesoin Anne , Lortholary Alain , Hardy-Bessard Anne-Claire , Misset Jean-Louis , Mouret-Reynier Marie-Ange , Pujade-Lauraine Eric
Published: March 2020

5018

Background: REV is a thalidomide analogue, with both immunomodulatory and anti-angiogenic properties that could confer antitumor effect in ROC. Methods: The aim of this study was to evaluate REV efficacy as single agent in patients (pts) with asymptomatic late ROC (>6mos) with increasing CA 125, in 2nd or 3rd line. Primary endpoint was to estimate the rate of non-progressive disease at 4 mos. Pts were treated with REV 20 mg daily in oral continuous regimen with systematically recommended anti-thrombotic prophylaxis (ATP). Imagery and CA 125 were performed every 8 weeks. Results: From 05/2009 to 09/2010, 45 pts were included with a median age of 63 years. Pt characteristics were: serous (78%), previous lines (one 73%, two 27%), median platinum-free interval (PFI) (11.3 mos), PFI > 12 mos (42%), measurable disease (73%), and ECOG performance status 0 (84%). Efficacy: Rate of non progressive disease at 4 mos was 38% (95%CI, 23-53), 59 % (95%CI, 36-82) and 24 % (95%CI, 7-41) for the global population, pts relapsing over 12 mos and those relapsing between 6-12 mos, respectively. Results were independent of the number of previous lines. Median progression-free survival was 3.8 mos (95%CI, 2.1-5.6) and 6.4 mos in the subset of pts with PFI > 12 mos. Response evaluation according to CA 125 (Rustin criteria) was: complete response (CR) 2.4%, partial response (PR) 17%, stable disease (SD) 71%. When using RECIST criteria alone, response evaluation was: 9.5% PR and 45% SD. Median duration of biological response was 6.6 mos. REV efficacy will be correlated to immunological parameters (lymphocyte phenotypes and cytokines). Safety: Grade 3-4 toxicity in more than 5% of pts was neutropenia (29%) and thrombo-embolic events (TEE) (11%). TEE occurred only in pts without ATP. Reasons for stopping treatment due to toxicity were TEE (3), allergy (2), arrhythmia (1), dyspnea (1) and neutropenia (1). Conclusions: REV demonstrated encouraging activity in ROC with good tolerability and manageable adverse events. A phase I of REV combined with platinum-based chemotherapy is currently being conducted.
A phase II study of RO4929097 (RO), a gamma-secretase inhibitor, in advanced platinum (Pt)-resistant (R) ovarian cancer (OC): A study of the PMH, Chicago, and California phase II consortia.
Authors: Diaz-Padilla Ivan , Clarke Blaise A , Hirte Hal W. , Welch Stephen , Mackay Helen , Biagi James Joseph , Reedijk Michael , Weberpals Johanne Ingrid , Fleming Gini F. , Wang Lisa , Li Jennifer , Strevel Elizabeth Laureen , Eisenhauer Anne , Ivy S. Percy , Oza Amit M.
Published: March 2020

5019

Background: Notch signalling pathway plays a critical role in regulating cellular differentiation, proliferation, and apoptosis in preclinical cancer models. The Notch receptor, its ligands, and down-stream effectors are over-expressed in OC. Inhibition of γ-secretase-mediated Notch cleavage is a primary focus for the development of targeted therapeutics. Methods: Women (pts) with progressive, measurable (RECIST), Pt-R OC treated with ≤ 2 chemotherapy regimens for recurrent disease were treated with oral RO at 20mg od, 3 days on/4 days off every week, q3w. The primary objective was to determine the antitumor efficacy of RO in Pt-R OC by the progression-free survival (PFS) rate at the end of 4 cycles. Secondary objectives were to assess the safety of RO and to explore molecular correlates of outcome in archival tumor tissue. A Simon two-stage design was used. The study would open to second stage accrual if > 4 pts of the first 17 accrued remain progression-free at the end of 4 cycles. Results: 39 pts have been enrolled after first-stage criteria were met. Median age was 59 (range 26-81). Median number of cycles was 2 (range 1-18). 30 (83%) pts had high-grade serous OC. 34 pts were evaluable for response. 8 pts (20%) were progression-free after 4 cycles.12 pts (35%) had stable disease, with a median duration of 3.9 months (range 2.5-12.2). Median PFS was 1.3 months (1.2-2.3). The most common drug-related adverse events (AEs) of any grade (% pts) were: nausea (36), fatigue (28), anorexia (15), hypophosphatemia (15), anemia (13), and increased alanine aminotransferase [ALT] (13). There were 5 G3-4 AEs at least possibly related with RO: increased liver transaminases (2), diarrhea (1), headache (1), and hypophosphatemia (1). Intracellular Notch (NIC) and JAG1 protein expression on high-grade serous OC were correlated with response in 17 pts. Median PFS for pts with high NIC (n=6) was 3.3 months (1.0-not reached), compared to 1.3 months (1.1-2.6) for pts with low NIC (n=11), p=0.09. Conclusions: RO has limited clinical activity in unselected Pt-R OC as a single agent. Future studies need to assess potential for cohort enrichment using NIC expression.
Brief family history questionnaire for identification of Lynch syndrome in women with newly diagnosed endometrial cancer.
Authors: Ferguson Sarah E , Clarke Blaise , Mojtahedi Golnessa , Oza Amit M. , Gallinger Steve , Pollett Aaron , Mackay Helen , Bernardini Marcus , Aronson Melyssa
Published: March 2020

5026

Background: Endometrial cancer (EC) is often the sentinel cancer for women with Lynch syndrome (LS); however, it is underappreciated in this population. The Brief Family History Questionnaire (bFHQ) was developed to identify women with EC who have family histories suggestive of LS. The objective of our study was to evaluate the bFHQ compared to an extended family history (eFHQ) and medical record in identifying women with EC who may benefit from genetic cancer risk assessment. Methods: All women with newly diagnosed EC from July 2010 to June 2011 were asked to participate in a prospective screening protocol for LS which included completing two family history questionnaires; the bFHQ which is a 4-item self-report measure and the 37-item eFHQ administered by a research assistant. Family history was also extracted from the medical record. Using the bFHQ women were flagged as requiring additional investigation for LS based on predetermined criteria and the predictive ability of the flag was evaluated treating eFHQ as the gold standard. Comparisons were made between the bFHQ, eFHQ and medical record for families meeting Amsterdam II, Society Gynecologic Oncologist (SGO) 20-25% or the Ontario Ministry of Health (MOH) testing criteria for LS, using generalized estimating equation logistic regression models. Results: 119 (N = 182, 65%) consented to the study and 106 (89%) completed the bFHQ. The median age was 61 (26-91). The number of women who met testing criteria by the eFHQ was 17 (16%) and 33 (31%) were flagged by the bFHQ. The sensitivity, specificity, PPV and NPV of the bFHQ was 88.2%, 79.8%, 45.5% and 97.3%. There was no significant difference in the number of women who met Amsterdam II or SGO 20-25% testing criteria between the bFHQ, eFHQ and medical record (P > 0.05). The numbers of women meeting MOH criteria using the bFHQ (N=16, 15%) and the eFHQ were similar (N=17, 16%) (P = 0.7); however, more women met MOH criteria using the bFHQ and the eFHQ compared to the medical record (N=8, 7.6%) (P = 0.011; P = 0.006). Conclusions: The patient-administered bFHQ is a highly effective tool in identifying women who meet MOH testing criteria for LS and is a good screening tool to identify women with EC for further genetic assessment.
Correlative study of low serum creatinine and hematological toxicities in Japanese patients with ovarian cancer treated by dose dense TC therapy.
Authors: Matsumoto Koji , Onoe Takuma , Kitao Akihito , Tanioka Maki , Negoro Shunichi
Published: March 2020

5045

Background: Dose dense TC (ddTC) is a novel standard therapy for patients (pts) with advanced ovarian cancer, although hematological toxicities (hemTX), especially anemia, may increase as observed in NOVEL trial (JGOG3016). Low serum creatinine (LCr), especially below 0.7 mg/dl, may lead to overestimation of GFR. GOG announced that pts with LCr should use a minimum value of 0.7mg/dl to estimate GFR. The correlation between LCr and hemTX treated by ddTC is unknown. Methods: GFR was determined using the Cockcroft-Gault formula. Serum creatinine concentrations were measured using enzymatic assays. Minimum value of 0.7 mg/dl was not used during this period of time. The carboplatin clearance was then calculated by Calvert equation. HemTX were defined as, Grade 3 or 4 (by CTC-AE ver.4) neutropenia, anemia, and thrombocytopenia. Using electrical chart, frequency of hemTX and correlation between serum creatinine (less than 0.7 or not) were examined. Results: From Feb. 2010 to Dec. 2011, 61 consecutive pts were treated with ddTC. LCr was observed in 73% of pts. No treatment related death occurred. Among 61 pts, 50 (82%), 31 (51%), and 12 (19.6 %) pts experienced Grade3/4 neutropenia, anemia and thrombocytopenia, respectively. HemTX in pts with LCr and the others were as in the Table. Conclusions: LCr is frequent in Japanese female pts. ddTC in practice setting seems safe, and hemTX of ddTC are similar with those observed in NOVEL trial. The rationale using a minimum value of 0.7 mg/dl should be further studied by larger population, such as pts in NOVEL trial. [Table: see text]
NKTR-102 in patients with platinum-resistant ovarian cancer (PROC): Modeling CA125 response and its correlation with tumor response.
Authors: Chia Yen Lin , Hoch Ute , Leung Abraham C. F. , Eldon Michael A.
Published: March 2020

5048

Background: NKTR-102 is a unique topoisomerase 1 inhibitor that provides continuous exposure to SN38. In heavily pretreated pts with PROC (median of 3 prior therapies; 27 pts were platinum refractory), 145 mg/m2 NKTR-102 given q14d or q21d demonstrated significant anti-tumor activity (JCO 28:7s, 5013). We present a PK/PD model for CA125 kinetics that can be used to project GCIG response as an aide to selecting dose and schedule. Methods: Data from 55 pts with PROC and elevated CA125 (median baseline = 515 U/mL) were fit with a PK/PD model developed to correlate CA125 dynamics with SN38 conc-time profiles predicted from individual pt dosing history: d[CA125]/dt = Kin*exp(beta*t)*(1-[SN38]/(IC50+[SN38]))-Kout*[CA125]. Results: CA125 profiles were well described by the model, with a population mean SN38 IC50 of 1.1 ng/mL. Typical min and max SN38 conc during treatment were 1.5 and 3 ng/mL for q14d and 0.9 and 2.4 ng/mL for q21d, indicating that both schedules resulted in SN38 exposure near the IC50. The half-life of CA125 decline was 6.4 days, similar to literature values. 46 of 55 pts had pre- and post-treatment tumor measurements for correlation of CA125 response and tumor size. Overall best response by GCIG and RECIST correlated in 57% of pts. 33% of pts with GCIG response showed declines in tumor size, albeit insufficient to classify as RECIST response. 72% of pts with GCIG SD showed at least SD by RECIST. CA125 vs time was simulated for 1000 pts receiving 145 mg/m2 NKTR-102 q14d or q21d, to allow comparison of CA125 and GCIG response between schedules (see table). The % pts per GCIG response was comparable between schedules, supporting use of the better-tolerated q21d regimen. Conclusions: The PK/PD model described CA125 profiles well, providing a tool to predict drug response from SN38 PK data. Close correlation of CA125 with tumor size is consistent with historical use of CA125 as a surrogate marker. Predicted CA125 profiles for NKTR-102 q14d or q21d were similar, suggesting that the better-tolerated q21d schedule will produce results consistent with those from Ph 2. [Table: see text]
Effect of tumor-infiltrating T-lymphocytes on the aggressiveness of epithelial ovarian tumors.
Authors: Vasconcelos Ines , Olek Sven , Gellhaus Katharina , Schwachula Tim , Braicu Ioana , Fotopoulou Christina , Chekerov Radoslav , Dimitrova Desislava , Sehouli Jalid
Published: March 2020

5053

Background: Borderline ovarian tumors (BOT) are a low-grade form of ovarian malignancy with significantly less aggressive behavior than epithelial ovarian cancer (EOC). Since there is neither convincing scientific evidence nor a marker capable of predicting BOT’s behavior, we analyzed the role of immune tolerance in differential disease outcome. EOC and BOT were chosen due to similar disease etiology, despite different disease courses. Increased numbers of T-cell subpopulations infiltrate malignant tumors, so we used epigenetic tests to determine the prevalence of regulatory T-cells (Treg) and overall-T-Lymphocytes (oTL) in EOC and BOT. Methods: The ovarian cancer samples were provided by the European multicentric OVCAD study. The BOT samples were obtained from Tumor Bank Ovarian Cancer at Charité Campus Virchow (Germany). Samples and clinical data were prospectively collected and documented using validated SOPs. DNA was bisulphite-converted and forwarded to methylation-specific RT-PCR for CD3 and FOXP3 loci. Results: We evaluated 90 high-grade EOC, 12 BOT with invasive implants and 25 non-invasive BOT samples. Higher oTL-values correlate with mortality (p=0.008) and recurrence (p<0.001), while higher Treg levels correlate with recurrence (p=0.028). Patients with non-invasive BOT have lower oTL (p=0.019) and Treg (p=0.0005) levels than patients with invasive BOT and EOC, while BOT (both invasive and non-invasive) patients have lower Treg-to-oTL ratios than EOC patients (p=0.0005). Finally, oTL levels associate with overall survival in EOC (p=0.042). Conclusions: We observed a strict correlation between tumor-type, Treg and oTL levels, as well as Treg-to-oTL ratio. This is in agreement with our hypothesis that disease aggressiveness is associated with the amount tumor-infiltrating lymphocytes and may provide the explanation for differing disease courses in EOC and BOT.
Treatment reality in elderly patients with advanced ovarian cancer: A prospective analysis of the OVCAD consortium.
Authors: Woelber Linn Lena , Eulenburg Christine , Braicu Ioana , Sehouli Jalid , Lambrechts Sandrina , Vergote Ignace B. , Hager Gudrun , Zeillinger Robert , Zeimet Alain G , Mahner Sven
Published: March 2020

5058

Background: Approximately one third of women diagnosed with ovarian cancer are 70 years or older. Standard therapy of ovarian cancer including radical cytoreduction and combination chemotherapy has considerable morbidity and information regarding treatment reality in elderly patients with ovarian cancer is very limited. Methods: Patients with primary epithelial ovarian cancer FIGO-stages IIB-IV were prospectively included in 5 European cancer centers. All patients underwent surgery with the intent of maximal cytoreduction and platinum-based chemotherapy. To analyze treatment strategies and outcome in the elderly, patients were subdivided in <70 years and ≥70 years of age and compared regarding clinicopathological variables and prognosis. Results: A total of 275 patients were included and followed for a median of 25 months. Median age of the total cohort was 58 (18-85) years with only 47 patients (17.1%) ≥70 years old. Age itself was not a prognostic factor for progression free survival (PFS) in multivariate analysis. 30-days mortality rate after primary surgery was 3.6% in elderly patients compared to 0.6% in patients <70 years (p=0.153). Surgery was less radical in patients ≥70 (e.g. fewer lymph node dissections p<0.001) and the percentage of patients with residual disease after surgery was higher in elderly (44.7%) compared to younger patients (28.5%) despite similar FIGO stage distribution (p=0.029). Furthermore, elderly received more often mono-chemotherapy (p<0.001). Consequently, outcome was less favorable in patients ≥70 compared to patients <70 years (75% overall survival 16 vs. 28 months; p=0.002 and median PFS 14 vs. 20 months; p=0.182). Conclusions: In this prospective European multicenter study, ovarian cancer patients age 70 and older were treated significantly less radical and had unfavorable outcome compared to younger patients. Specific trials for elderly patients focusing on surgical as well as chemotherapeutic aspects are therefore highly desirable to gain more information in an aging society.
Factors associated with an increased risk of recurrence in women with ovarian granulosa cell tumors.
Authors: Suri Anuj , Horowitz Neil S. , Carter Ebony B. , Denslow Sheri , Gehrig Paola A.
Published: March 2020

5063

Background: There is emerging data in different malignancies, including gynecologic cancers, demonstrating factors independent of a patient’s tumor characteristics, which are associated with an increased risk of cancer recurrence. The goal of this study is to determine demographic and prognostic factors affecting recurrence of disease (RD) in women with ovarian granulosa cell tumors (GCT). Methods: A dual-institution retrospective analysis of patients diagnosed with GCT between 1995 and 2010. Demographics including age, race, BMI, stage, diabetes (DM), adjuvant treatment, and progression free survival (PFS) were extracted. Hazard ratios for recurrence were estimated by univariate and multivariate Cox regression models Results: One hundred nine women identified with a median age of 50 (range 12-87). Fifty-six (57.1%) were Caucasian, 32 (32.7%) African American, and 10 (10.2%) were other. Median BMI was 29 (range 12-57). Twenty-one patients had DM. The majority of women had stage I disease (89.0%), 7 (6.4%) had stage II/III disease, and 5 were unstaged. In univariate analysis, DM showed the strongest association with recurrence (HR 3.56, 95% CI: 1.57-8.11). Non-white race was also associated with higher risk of RD, though the association was not statistically significant (HR 1.74, 95% CI: 0.78-3.87). The association between DM and RD was also found in multivariate analysis controlling for all factors including non-white race and BMI (HR 2.99, 95% CI: 1.11-8.08). Only 19 (17%) patients received adjuvant chemotherapy consisting of one of two different adjuvant chemotherapy regimens bleomycin, etoposide, and cisplatin or paclitaxel and carboplatin, however there was no difference in outcome based on chemotherapy regimen (p=0.24). Conclusions: This is the largest study analyzing factors associated with risk of recurrence in women with ovarian GCT. Studies have demonstrated higher morbidity among diabetic patients with breast and colon cancer and this may be modifiable with metformin. Our results emphasize that diabetes is one of the strongest predictors of recurrent disease in patients with ovarian GCT. Further studies are necessary to evaluate the effect of other factors such as adjuvant chemotherapy.
Interval versus primary tumor debulking surgery in advanced ovarian cancer: Analysis of the European OVCAD data.
Authors: Fotopoulou Christina , Braicu Ioana , Vergote Ignace B. , Cadron Isabelle , Amant Frederic , Chekerov Radoslav , Castillo-Tong Dan Cacsire , Speiser Paul , Richter Rolf , Concin Nicole , Marth Christian , Mahner Sven , Trillsch Fabian , Zeillinger Robert , Sehouli Jalid
Published: March 2020

5071

Background: The international scenery around optimal primary treatment of advanced ovarian cancer (AOC) patients (pts) is currently being discussed, with large discrepancies and heterogeneity still existing between the national guidelines worldwide. Aim of the present study was to evaluate the differences in outcome of AOC-pts after primary (PDS) versus interval-debulking-surgery (IDS) based on a prospectively assessed multicenter data set. Methods: Overall outcome was analyzed from the OVCAD database; a prospective, observational, multicenter project. AOC-pts who underwent surgery in five specialized gynecological cancer centers across three European countries between 02/2005 and 12/2008 were evaluated. Overall (OS) and progression free survival (PFS) were calculated by Kaplan-Meier-curves. Univariate and Cox-regression-analysis were applied. Results: Overall, 256 AOC pts (FIGO-stage III/IV) were evaluated. Fifty pts (19.5%) underwent IDS and 206 pts (80.5%) PDS. Despite the non-randomized setting both groups were well balanced in terms of FIGO-stage, grading, histological subtype and presence of ascites. Different selection criteria were however present for each center. PDS pts presented significantly higher rates of intestinal resection (44.2% vs.24%; p=0.01) and lymphonodectomy compared to IDS ones (72.3%vs.48%; p=0.001), by equivalent complete tumor resection rates (67.5% vs.68%; p=0.82). Platinum response was significantly higher in PDS vs. IDS pts (80.6% vs. 54%; p<0.001). 3-years OS was with 66.7% (95%CI: 60.2-73.2%) significantly better in PDS- versus 48.3% (95%CI: 34.2-62.5%) in IDS pts (p<0.001). Also 2-years PFS was with 31.9% (95%CI:24.8-39.1%) significantly higher in PDS- vs. 11.4% (95%CI: 0.9-22%) in IDS-pts (p<0.001). In multivariate analysis PDS, but not age, ascites, FIGO-stage, grading, histology or residual tumor were of prognostic significance for platinum response. In addition, multivariate analysis identified PDS and no residual tumor to positively and ascites to negatively affect OS and PFS. Conclusions: PDS appears to be associated with a more favorable outcome compared to IDS in highly specialized centers according to this non-randomized data set.
Exposure-response relationship of open-label (OL) AMG 386 monotherapy in patients (pts) with recurrent ovarian cancer.
Authors: Karlan Beth , Lu Jianfeng , Navale Lynn , Rasmussen Erik , Sun Yu-Nien , Vergote Ignace B. , Kuchimanchi Mita , Warner Douglas , Weinreich David M.
Published: March 2020

5072

Background: AMG 386, an investigational peptibody, inhibits tumor angiogenesis by preventing angiopoietins 1/2 and Tie2 receptor interaction. A phase II, double-blind, controlled study (NCT00479817) evaluated toxicity and efficacy of AMG 386 + paclitaxel (P) in recurrent ovarian cancer pts. Increased AMG 386 exposure in that study was associated with longer progression-free survival (PFS; Lu et al., JCO 2010; 28 [Suppl]: 5042). Here, these analyses were applied to pts electing OL AMG 386 monotherapy after progression in the placebo group. Methods: Pts with recurrent epithelial ovarian, fallopian tube, or peritoneal cancer (≤3 prior anticancer therapies, GOG ≤1) were randomized 1:1:1 to P IV QW (3 on/1 off) + AMG 386 (3 or 10 mg/kg) or placebo IV QW. In the placebo group, pts who progressed and stayed eligible could receive OL AMG 386 10 mg/kg IV QW monotherapy. In pts receiving AMG 386 monotherapy, post-hoc analyses evaluated PFS per RECIST, objective response rate (ORR), adverse events (AEs), and the relationships between high and low AMG 386 exposure (based on a median AUCSS of 10.6 mg*hr/mL) and efficacy (PFS per RECIST, ORR). Results: 161 pts were randomized. 18 pts received OL AMG 386 monotherapy (range: 1-56 infusions). At the time of analysis, PFS was 3.2 mo. ORR was 0%. 6 pts had stable disease (SD), 7 had progressive disease (PD). Common AEs were abdominal pain (n = 6), fatigue (n = 5), peripheral edema (n = 5), nausea (n = 5), urinary tract infection (n = 5), and vomiting (n = 5); grade ≥ 3 AEs in more than 1 pt were pleural effusion (n = 2; all grade 3), small intestinal obstruction (n = 2; all grade 3), and ovarian cancer (n = 2; all grade 5). PFS was longer in the high- (n = 9) vs low-exposure (n = 9) group (7.2 vs 1.8 mo; HR = .266, p = .041). Precrossover PFS was similar between high- and low-exposure groups (5.5 vs 4.5 mo; HR = 1.146, p = .812). For both groups, ORR was 0%. In the high-exposure group, 4 pts had SD, 3 had PD. In the low-exposure group, 2 pts had SD, 4 had PD. Conclusions: In line with results from a phase II study of AMG 386 + P, pts with recurrent ovarian cancer who received AMG 386 monotherapy and had high AMG 386 exposure had longer PFS than pts with low exposure. Toxicity was similar in both groups.
A matched pair analysis of intra- and postoperative catumaxomab in patients with ovarian cancer from a multicenter, single-arm phase II trial versus a consecutive single-center collective of ovarian cancer patients without immunotherapy.
Authors: Pietzner Klaus , Chekerov Radoslav , Reinthaller Alexander , Reimer Daniel , Reimer Toralf , Angleitner-Boubenizek Lukas , Tschirschmann Miriam , Lindhofer Horst , Braicu Elena Ioana , Fotopoulou Christina , Sehouli Jalid
Published: March 2020

5080

Background: Advanced ovarian cancer is still connected to high mortality rates due to intraperitoneal tumor cells that survive radical cytoreductive surgery as well as adjuvant chemotherapy. These persistent tumor cells need to be targeted in order to improve survival. Catumaxomab has demonstrated the ability to kill EpCAM-positive intraperitoneal tumor cells of ovarian cancer patients in studies aiming to controll malignant ascites in the recurrent setting. This analysis was conducted to investigate the efficacy of intraperitoneal catumaxomab at the timepoint of primary cytoreductive surgery and postoperative period, prior to standard adjuvant chemotherapy. Methods: Ovarian cancer patients undergoing radical surgery received one intraoperative (10 μg) followed by four subsequent intraperitoneal (i.p.) dosages (10, 20, 50 and 150 μg) of catumaxomab on days 7, 10, 13, and 16, respectively. Because of the single arm design of the study, the patients treated with catumaxomab were compared in a matched pair analysis to consecutive patients with primary ovarian cancer who received standard treatment without catumaxomab in a large center, in order to compare survival. The two main prognostic factors of stage and level of tumorreduction were chosen as matching criteria. Results: Of 58 patients screened, 41 were treated with catumaxomab and available for survival evaluation. Median age was 57 years in the catumaxomab group and 59 years in the matched-pair control group. The most comon histology was the serous subtype with 70.7 % in the catumaxomab and 80.5 % of the patients in the control group. The median for overall survival was reached for the historical consecutive matched-pair control collective, but is not yet reached for the catumaxomab group. However, 3-year survival data were available for both groups and showed survival of 85.4% (35) in the catumaxomab group and 63.4% (26) in the matched-pair control group (p-value: 0.041; HR 2.073) Conclusions: There seems to be a trend to beneficial 3-year survival in the catumaxomab group, suggesting that a phase III trial is warranted.
Final results of a phase II trial of weekly nab-paclitaxel with GM-CSF as chemoimmunotherapy for platinum-resistant epithelial ovarian cancer.
Authors: Swensen Ron E. , Goff Barbara Ann , Childs Jennifer , Higgins Doreen , Gooley Theodore , Fintak Patricia A , Buening Barbara , Disis Mary L.
Published: March 2020

5082^

Background: Ovarian cancer patients with an anti-tumor immune response have a prolonged survival, suggesting that augmenting anti-tumor immunity may be therapeutic. We hypothesized that weekly nab paclitaxel (nabP) followed by GM-CSF may enhance anti tumor immunity and prolong time to progression (TTP). Methods: Eligible subjects had platinum resistant ovarian, primary peritoneal or fallopian tube cancer, and an elevated CA125. Conditional power estimate after 11 subjects showed 22 subjects had 80% power to show a response rate (RR) >21% if the true study RR is 35%. Study end points were RR and TTP. Progression (DP) was doubling of CA125 above the nadir. Complete response (CR) was a decline of CA125 below institutional normal. Partial response (PR) was a decline of >50% from baseline. Stable disease (SD) was all other scenarios. Subjects received nabP, 100mg/m2 days 1,8,15 followed by GM-CSF 250mcg days 16-26 of a 28 day cycle until progression or 6 cycles were complete. Responding subjects received up to 6 more cycles of GM-CSF on days 14-28. Results: 21 subjects received at least one dose of study medications. Median age was 61 (30-91) and had a median of 3 (1-13) prior regimens. Among those completing the study, the median TTP was 132 days vs. 272 days on the prior platinum regimen. 9/21 (43%) had a PR and 4/21 (19%) had a CR. Subjects with a response had a median TTP of 140 days. Assay of serial T-lymphocyte counts against CEA, MUC1, CA125 and tt and influenza controls are planned. Conclusions: Weekly nabP with GM-CSF had manageable toxicity and induced a high response rate (62% by CA125) in patients with platinum resistant ovarian cancer, however this regimen did not prolong the TTP beyond the TTP observed in the prior platinum regimen.
Prospective multicenter study evaluating the survival of patients with locally advanced cervical cancer (LACC) and negative positron emission tomography with computerized tomography (PET-CT) in the para-aortic area undergoing laparoscopic para-aortic (PA) lymphadenectomy before chemoradiation therapy.
Authors: Gouy Sebastien , Morice Philippe , Narducci Fabrice , Uzan Catherine , Rey Annie , Martinez Alejandra , Pautier Patricia , Deandreis Desiree , Querleu Denis , Haie-Meder Christine , Leblanc Eric
Published: March 2020

5083

Background: In three comprehensive cancer centers, patients with LACC were systematically staged using conventional and PET-CT imaging before chemoradiotherapy. If patients had no uptake in the PA area, laparoscopic extraperitoneal PA surgery was then performed to define radiation field limits more accurately. The aim of this study was to evaluate the therapeutic impact of this management. Methods: A prospective multicenter series of 237 patients treated from 2004 to 2011 for LACC with a negative PET-CT of the PA area and undergoing laparoscopic PA lymphadenectomy. Radiation fields were extended to PA area when PA nodes were involved. Chemoradiotherapy modalities were homogeneous between Institutions. Patients with a poor prognosis histologic subtype, peritoneal carcinomatosis or ovarian metastasis were excluded. Results: Clinical stages were IB2 (n=79), IIA (n=10), IIB (n=120), III (n=23), IVA (n=5). The histologic types were squamous carcinoma (n=197), adenocarcinoma (n=34) and others (n=6). Twenty-nine (11%) patients had nodal involvement (false negative PET-CT results): 16 with PA nodal metastasis measuring > 5 mm and 13 < 5 mm. With a median follow-up of 18 (range, 0-67) months, disease-free survival (DFS) at 2 years in patients without and with PA involvement was respectively 76% (68%-83%) and 61% (37%-80%)(p=.007). DFS at 2 years in patients without PA involvement or with PA metastasis measuring < or > 5 mm was respectively 76% (68%-83%), 89% (57%-98%) and 38% (14%-68%)(p=.0006). Conclusions: This is the largest series of patients reported undergoing such strategy. We obtained a similar survival rate for patients with PA nodal metastasis < 5 mm and patients without PA lymph node involvement suggesting that this strategy is highly efficient in such patients. Conversely, the survival of patients with PA nodal involvement > 5 mm remained poor, despite no extrapelvic disease at PET-CT imaging in this subgroup. Other treatment modalities should be evaluated for these patients.
The impact of racial disparity on outcomes of patients with early-stage uterine endometrioid carcinoma in an equal-access environment.
Authors: Robbins Jared R. , Laser Benjamin S. , Bhat Neal , Cogan Chad , Munkarah Adnan , Elshaikh Mohamed A.
Published: March 2020

5088

Background: To determine if racial disparity exists between African American (AA) and non-African American (NAA) patients with early stage uterine endometrioid carcinoma who had similar multidisciplinary management. Methods: Our prospectively-maintained database of 1,450 uterine cancer patients was reviewed for this IRB-approved study. We identified 766 consecutive patients with endometrioid carcinoma 1988 FIGO stages I-II who underwent hysterectomy between 1987-2009. Patients with non-endometrioid carcinoma, mixed histologies and those who received preoperative treatments were excluded. For the purpose of data analysis, patients were divided into two groups; AA and NAA. Recurrence-free survival (RFS), disease specific (DSS) and overall survival (OS) was calculated from the date of hysterectomy using the Kaplan-Meier method. Cox regression modeling was used to explore the risks of various factors on recurrence. Results: Median follow-up was 5.1 years. 27% were AA and 73% were NAA. All patients underwent hysterectomy and oophorectomy. 80% had peritoneal cytology and 69% underwent lymphadenectomy. AA patients were more likely to have higher grade tumors, and more lymphovascular space involvement (LVSI). Although the two groups were balanced in regards to surgical staging and adjuvant treatment received, the five-year RFS and DSS were significantly lower in AA compared to NAA patients (91% vs 84%, p=0.030; 95% vs 88%, p=0.011, respectively). Between the two groups, OS was not significantly different. On multivariate analysis and after adjusting for other prognostic factors, race (AA vs NAA) was not a significant predictor of outcome. Grade 3 tumors and the presence of LVSI were the only two independent predictors of RFS and DSS with p=<0.001 and p=<0.001, respectively. Conclusions: In this large hospital-based study, AA race was associated with a higher incidence of adverse pathological features and worse recurrence-free and disease-specific survival. However, on multivariate analysis race was not an independent prognostic factor. Further studies are needed to elucidate possible underlying molecular mechanisms for these poorer outcomes.
Neoadjuvant chemotherapy plus radical surgery followed by chemotherapy in locally advanced cervical cancer.
Authors: Angioli Roberto , Plotti Francesco , Terranova Corrado , Angelucci Michela , Oronzi Irma , Montera Roberto , Damiani Patrizio , Cafà  Ester Valentina , Guzzo Federica , Montone Eva , Ricciardi Roberto , Aloisi Alessia , Hyseni Entela , Luvero Daniela , Scaletta Giuseppe , Capriglione Stella , Lopez Salvatore , Miranda Andrea , Li Destri Marta , Benedetti Panici Pierluigi
Published: March 2020

5093

Background: The aim of this study is to evaluate the efficacy, in terms of overall survival and progression free survival, and safety of adjuvant chemotherapy after neoadjuvant chemotherapy followed by radical surgery both in patients with and without node metastases. Methods: Between June 2000 to May 2007, all patients with diagnosis of locally advanced cervical cancer referred to the Division of Gynecologic Oncology of the University Campus Bio-Medico of Rome were elegible for this protocol.All enrolled patients received 3 cycles of platinum-based chemotherapy every 3 weeks according to the scheme cisplatin 100 mg/mq and paclitaxel 175 mg/mq. After neoadjuvant chemotherapy all patients with stable or progression to treatment were excluded from the protocol, all other were submitted classical radical hysterectomy and bilateral systematic pelvic lymph node dissection, and after to adjuvant treatment with 6 cycles of platinum based chemotherapy with cisplatin 100 mg/mq and paclitaxel 175 mg/mq. Results: 110 patients with local advanced cervical cancer received the treatment with neoadjuvant chemotherapy followed by radical surgery and adjuvant chemotherapy.Our study focused on clinical and operative data , in terms of overall survival and disease free survival at 5 and 3 years. 5-year OS of our series was 78% at five years and 86% at 3-years, with encouraging results also in subgroup with and without node mestastases. Conclusions: The adjuvant chemotherapy regimen after neoadjuvant chemotherapy and radical surgery rappresents a valid treatment option for patients with locally advanced cervical cancer without lymph node involvement, both in terms of overall survival than in terms of disease-free interval, the results have also confirmed the validity of this approach in lymph node metastases, with a complication rate lower than the standard radio-chemotherapy regime.
The novel biomarker HE4 versus CA125 in detecting endometrial cancer: A case control prospective study.
Authors: Plotti Francesco , Zullo Marzio Angelo , Angelucci Michela , Oronzi Irma , Damiani Patrizio , Montera Roberto , Dugo Nella , Guzzo Federica , De Oronzo Maria Antonietta , Ricciardi Roberto , Aloisi Alessia , Hyseni Entela , Luvero Daniela , Portuesi Rosa Alba Valentina , Scaletta Giuseppe , Capriglione Stella , Miranda Andrea , Li Destri Marta , Benedetti Panici Pierluigi , Angioli Roberto
Published: March 2020

5094

Background: In endometrial cancer, there are no markers routinely used in clinical practice. This study prospectively investigates the sensitivity and specificity of new marker HE4 in detection of endometrial cancer. Methods: Serum samples were prospectively obtained 24 hours before surgery from 25 patients with endometrial cancer and from 25 patients with uterine benign pathology, operated from January 2011 to October 2011 at University Campus Bio-Medico of Rome. Preoperative CA125 levels were evaluated by a one-step “sandwich” radioimmunoassay. HE4 levels were determined using the HE4 enzymatic immune assay. The CA125 normal value is considered less than 35 U/mL. Two HE4 cut-off are considered: less than 70 pmol/L and less than 150 pmol/L. The specificity analysis was performed using the parametric T-Test for comparing the HE4 series and the Mann-Whitney test for the CA125 series. The level of statistical significance is set at p < 0.05. Results: The sensitivity of CA125 in detecting endometrial cancer is 16% whereas the sensitivity of HE4 is 48% and 28 % for 70 pmol/L and 150 pmol/L cut-off respectively. The specificity of HE4 is 100% (positive predictive value = 100%, negative predictive value = 65.79% and 58.14% considering the two HE4 cut-off, respectively), whereas the CA125 specificity is 72 % (positive predictive value = 36.36%, negative predictive value = 46.15%) in detection of endometrial cancer. Conclusions: HE4 has a good sensitivity and a specificity of 100% in detection of endometrial cancer and may be useful for detecting early stage endometrial cancer. In particular the HE4 at cut-off of 70 pmol/L yields the best sensitivity and specificity.
Association of adjuvant therapy in early-stage low-risk endometrial cancer with increased mortality: A statewide cancer registry analysis.
Authors: Milam Michael R. , Huang Bin , Moghadamfalahi Mana , Parker Lynn , Metzinger Daniel , Tucker Thomas
Published: March 2020

5095

Background: National Comprehensive Cancer Network (NCCN) guidelines state that patients with early stage low risk endometrial cancer (defined with 2009 criteria as stage IA endometrioid endometrial cancer) may be managed with observation with consideration of adjuvant therapy.The premise of this study is to review the patterns of care of those patients who received adjuvant therapy and its impact on survival. Methods: This is a retrospective cohort analysis of 1044 women from 2004-2008 in the Kentucky Cancer Registry (KCR) one of the affiliates utilized in the Surveillance, Epidemiology and End Results (SEER) Program database. Inclusion criteria for the patients in this analysis were those women with 2009 Stage IA uterine cancer of endometrioid histology, moderate and well differentiated tumor grade, who received definitive primary surgery. Adjuvant therapy was defined as any postoperative radiotherapy and/or chemotherapy after definitive surgical treatment. Patients with adjuvant therapy after surgery (AT) were compared to those patients who underwent surgery only (SO). Chi-square tests were used to identify associations between type of treatment and clinical/demographic factors. K-M plots and Cox regression models were used to examine survival between the two treatment groups. Results: 5.3% (55/1044) of patients with early stage low risk endometrial cancer were treated with AT compared to 94.7% (989/1044) of SO patients.No statistical differences in mean age, race, tumor size, smoking status, insurance status, lymph node dissection and gynecologic oncology care were found among the AT or SO groups. Five year survival was significantly better in the SO cohort compared to the AT cohort (92% alive at 5 years for SO vs. 66% alive at 5 years; p<0.0001). Controlling for other confounders in the multivariate Cox regression analysis, SO patients had substantially less risk for death compared to the AT groups (HR: 0.21; 95%CI 0.12-0.38; p<0.0001). Conclusions: In this statewide cancer registry analysis, adjuvant therapy after surgery in early stage low risk endometrial cancer patients is uncommon and is associated with an increased risk of mortality.
Neoadjuvant chemotherapy of docetaxel and carboplatin in patients with stage Ib2 to IIb nonsquamous cervix cancer of the uterus.
Authors: Nagao Shoji , Shimada Muneaki , Fujiwara Keiichi , Takeshima Nobuhiro , Takizawa Ken , Shoji Tadahiro , Sugiyama Toru , Yamaguchi Satoshi , Nishimura Ryuichiro , Kigawa Junzo
Published: March 2020

5103

Background: Non-squamous carcinoma of the uterine cervix has a resistance to radiation therapy and chemotherapy, and this is associated with worse prognosis compared with squamous carcinoma. This is a phase II study to assess an efficacy and safety of neoadjuvant chemotherapy of docetaxel and carboplatin (DC therapy) in patients with stage Ib2 to II non-squamous cervix cancer of the uterus. Methods: Patients with histologically confirmed, stage Ib2-II non-squamous uterine cervix cancer were received DC therapy prior to type III radical hysterectomy. IV doceaxel was administered at 60 mg/m2 followed by IV carboplatin administration based on AUC=6. The treatment was repeated every 21 days for a total of 1 to 3 cycles. Surgery was performed as soon as sufficient response was obtained. Results: Fifty-three women with non-squamous cervical carcinoma (FIGO stage Ib2,15; IIa, 7; IIb, 31) received DC therapy. Median age and tumor size were 49 years old (range: 27-71) and 52mm (range: 10-92), respectively. Fourty of 47 patients (74%) received 2 cycles of chemotherapy. Clinical response occurred in 69.8% of patients (complete response, 5; partial response, 32; stable disease, 15; disease progression, 1), and 96% (52/54) of patients completed the surgery. Incidences of grade 3/4 hematological toxicities were 98% (53/54) for neutrocytopenia, 4% (2/54) for thrombocytopenia, and 9% (5/54) for anemia. Febrile neutropenia was observed in three patients. Observed grade 3/4 non-hematological toxicities included were 5 for nausea, 2 for vomiting, 3 for constipation, 4 for allergic reaction. Median follow-up duration was 860 days with a range of 147- 1635 days. The 2-years progression-free survival rate and 2-years overall survival rate were 63% and 79% in stage IB2, 71% and 86% in stage IIA2, and 67% and 86% in stage IIB, respectively.Twenty patients recurred and twelve patients died. Conclusions: Neoadjuvant chemotherapy using DC therapy was well tolerated and had good response. It seems to be benefical in patients with satge Ib2 to II nonsquamous cervical cancer.
Prognostic significance of high-risk human papilloma virus (HPV), p16, and p53 status in women with vulvar squamous cell carcinoma (VSCC).
Authors: Allo Ghassan , Yap Mei Ling , Cuartero Julie , Mackay Helen , Milosevic Michael , Murphy Joan , Kamel-Reid Suzanne , Pintilie Melania , Clarke Blaise
Published: March 2020

5105

Background: The incidence of VSCC is increasing. Studies suggest the presence of two histologically and molecularly distinct subsets of VSCC; one contingent on and another independent of HPV infection. However, it is uncertain if HPV status has prognostic significance. HPV oncoproteins can result in degradation of the tumor suppressor p53, cell cycle deregulation and abnormal expression of cyclin dependant kinase inhibitor p16. The aim of this study was to investigate HPV infection, p16 and p53 in relation to clinical parameters in women with VSCC. Methods: Sequential cases of VSCC from patients (pts) treated at Princess Margaret Hospital (PMH) from 2000 to 2008 were reviewed. HPV infection was evaluated by Roche Linear array. A tissue microarray was constructed. p16 and p53 immunohistochemistry was performed. Clinical data was abstracted from medical records and PMH Cancer Database. Survival analysis was performed using Kaplan-Meier curves and log rank test. Results: We identified124 pts with VSCC. HPV was detected in 43/123 (35%) pts (median age 71 ± 16 yrs). HPV16 was the most common serotype (38/43; 88.4%). p16 was expressed in 30/115 (26%) pts and p53 in 59/117 (50.4%) pts. Median age of pts was not different in relation to HPV, p16 and p53 status. Expression of p16 (p<0.0001) and loss of p53 (p=0.007) were associated with HPV infection. Pts with HPV positive tumors were less likely to recur (recurrence rate at 5 years (RR) 12.5% vs 50.3%, p=0.009). HPV positive VSCC were not associated with better 5 yr disease free survival (DFS), 58% vs 31%; p=0.15, or overall survival (OS), 61% vs 61% ; p=0.94. p16 positive tumors had a lower RR at 5 yrs, 23.8% vs 59%, p=0.006 and better 5yr DFS (61% vs 27% ; p=0.009) but not significant for OS (65% vs 59%; p=0.94). Among pts with HPV positive VSCC, OS and DFS were not different between p16 positive and negative VSCC. In the 46 pts treated with radiotherapy, HPV and p16 positive tumors were associated with a lower RR (p=0.004 and 0.005). p53 expression was not prognostic in any pt group. Conclusions: Women with HPV-positiveVSCC have a lower risk of disease recurrence. p16-expressing VSCC are associated with reduced disease recurrence and improved DFS.