bluuebunny/crossref_metadata_2025 huggingface dataset:
A randomized phase II study: Pazopanib (P) versus lapatinib (L) versus combination of pazopanib/lapatinib (L+P) in advanced and recurrent cervical cancer (CC)
Authors: Monk B. , Mas L. , Zarba J. J. , Oaknin A. , Tarpin C. , Termrungruanglert W. , Alber J. A. , Ding J. , Stutts N. W. , Pandite L. N.
Published: August 2020

5520

Background: P and L are oral tyrosine kinase inhibitors. P targets VEGFR, PDGFR, and c-Kit. L targets EGFR and HER2 in CC, EGFR overexpression and markers of angiogenesis correlate with poor outcome; the prognostic value of HER2 overexpression remains unclear. Methods: Patients (pts) with measurable stage IVB, persistent or recurrent squamous or adenocarcinoma of the cervix not amenable to curative therapy; 0–1 prior regimens in the metastatic setting; ECOG PS 0–1; were randomized 1:1:1 to each of 3 treatment groups; not prescreened for EGFR or HER2 status. Treatment consisted of P 800mg QD; L 1,500 mg QD; L+P: P 400 mg + L 1,000 mg QD; the doses were escalated to P 800 mg + L 1,500 mg after 20 pts treated at 400 mg + 1,000 mg. Therapy continued until progression (PD), withdrawal due to adverse events (AEs), or withdrawal of consent. Primary endpoint was progression free survival (PFS); secondary overall survival (OS), tumor response (RR), safety. The study had 85% power to detect 80% improvement in PFS. A hierarchical testing procedure was applied comparing L+P vs L followed by L+P vs P and P vs L. The futility boundary was crossed for L + P vs L at the planned interim analysis and this arm was discontinued. Only the comparison of P vs L at the final analysis is reported. Results: Total N = 235 pts: 152 in the monotherapy arms: P (78); L (74). Baseline characteristics were balanced: median age 49 yrs (23–81). Stage IVB: 5%; recurrent 62%; persistent 34%. 86% had prior radiotherapy (45% with chemotherapy); 42% had prior chemotherapy for recurrent/persistent disease. P improved PFS (HR = 0.66; 90% CI 0.48, 0.91 p = 0.013) and OS (HR = 0.67; 90% CI 0.46, 0.99 p = 0.045; median OS for P is 50.7 wks; L is 39.1 wks) with RR for P of 9% and L 5%. Most common AEs (%) P/L were diarrhea (54/58), nausea (36/33), anorexia (28/32), vomiting (20/24); the most common Gr 3 AE was diarrhea (11/13); Gr 4 for any individual AE was ≤ 1%; 1 Gr 5 event of cachexia unrelated to L. Conclusions: PFS and OS were significantly prolonged with P compared to L. P and L both demonstrated a favorable toxicity profile in pts with advanced and recurrent CC. This study demonstrates the potential benefit of P in CC. Further exploration is indicated.

[Table: see text]
Somatic BRCA status in ovarian tumors
Authors: Hennessy B. , Timms K. , Carey M. S. , Gutin A. , Broaddus R. , Gonzalez-Angulo A. , Lanchbury J. , Lu K. , Mills G. B.
Published: August 2020

5528

Background: The combined prevalence of BRCA1/2 mutations in germline DNA derived from a population of invasive ovarian cancer patients is up to 15.3%. PARP inhibitor trials are ongoing in patients who carry germline BRCA1/2 mutations. It is important to know whether somatic (non-germline) BRCA changes are present in ovarian tumors, given the predicted sensitivity of BRCA mutation-carrying tumors to PARP inhibitors and other DNA damaging agents. However, a large cohort of ovarian tumor tissues has not been studied to determine the frequency of BRCA deficiency due to additional somatic changes. Methods: BRCA1/2 exons/flanking regions were sequenced in 235 high-grade ovarian cancers and 38 ovarian cancer cell lines. In 112 tumors, we also performed gene expression analysis and copy number arrays with ultradense probe tiling throughout both BRCA genes. Results: For BRCA1, 31 tumors (13.2%) harbored mutations: 23 known deleterious mutations, 1 suspected deleterious mutation, 3 novel indels, 1 novel mis-sense and 3 novel nonsense mutations. For BRCA2, 12/178 sequenced tumors (6.7%) harbored mutations: 8 known deleterious mutations, 1 suspected deleterious mutation and 3 novel indels. Only 3 BRCA1 mutations were detected in 2 cell lines, two known deleterious and 1 a novel 29 base pair deletion. One cell line thus appears to have both a germline and a somatic mutation. BRCA mutation status was associated with a trend to improved progression-free survival (PFS) in univariate analysis (p = 0.17). However, BRCA deficiency (defined by BRCA1/2 gene expression loss (4 tumors) and homozygous deletion (1 tumor) in addition to mutations) was associated with improved PFS in univariate (p = 0.04) and multivariate (p = 0.03) analyses. Conclusions: The frequency of BRCA1/2 mutations in ovarian tumors detected by sequencing regardless of family history is ≈20%, higher than the expected prevalence of germline mutations. In both BRCA1/2 genes, almost 25% of mutations in tumor tissue were novel and not previously seen in germline DNA. We are now sequencing corresponding germline DNA to determine the exact number of these novel mutations that are somatic. Direct analysis of ovarian tumor tissue is likely to expand the number of women with BRCA-deficient tumors beyond that detectable by germline sequencing.

[Table: see text]
Detection of chromosomal anomalies in uterine endometrial carcinoma using fluorescence in situ hybridization (UteroFISH)
Authors: Qian J. , Weber D. , Cochran R. , Hossain D. , Bostwick D. G.
Published: August 2020

5533

Background: Endometrial cancer is the most common pelvic gynecological malignancy. The diagnosis of well-differentiated endometrial adenocarcinoma, atypical hyperplasia, and marked hyperplasia is often challenging. We sought to investigate the utility of chromosomal anomalies for the detection of uterine endometrial carcinoma using multitarget fluorescence in situ hybridization (FISH). Methods: Samples were collected by endometrial brush and processed by liquid-based thin-layer cytological preparation protocol. For study, we collected cytology slides from consecutive cases to include 50 benign, 50 hyperplasia without atypia, 50 atypical hyperplasia, and 50 endometrial cancers. Each was hybridized using fluorescence labeled DNA probes to chromosomes 1, 8, and 10 (UteroFISH). The FISH signals were enumerated in 100 cells per case, and the chromosomal anomalies were correlated with pathologic findings, including histologic diagnoses on endometrial tissue samples. Results: Numeric chromosomal anomalies were found in 0% (0/50) of benign, 20% (10/50) of hyperplasia, 76% of atypical hyperplasia (38/50), and 86% (43/50) of carcinoma specimens. The mean percentage of cells with chromosomal changes was 54% in cancer specimens, significantly higher than that in hyperplasia without atypia (13%, p< 0.0001) and atypical hyperplasia (34%, p< 0.0001). The most frequent chromosomal anomaly was gain of chromosome 1. FISH anomalies had an overall sensitivity of 81% and specificity of 90% for the detection of atypical hyperplasia and/or endometrial carcinoma. There was no association with grade of endometrial carcinoma. Conclusions: Multi-target UteroFISH appeared to be useful for the differential diagnosis of reactive hyperplasia, atypical hyperplasia, and endometrial adenocarcinoma, with a high level of sensitivity and specificity. Endometrial hyperplasia with FISH-detected chromosomal anomalies may require close clinical follow-up.

No significant financial relationships to disclose.
Heparanase expression and angiogenesis in endometrial cancer: Analyses of RT-PCR and immunohistochemistry
Authors: Aoki Y. , Inamine M. , Hirakawa M. , Kudaka W. , Nagai Y.
Published: August 2020

5535

Background: The human heparanase has been shown to function in tumor progression, metastatic spread, and tumor angiogenesis. The aim of the present study was to assess heparanase expression in endometrial cancer in correlation with neovascularization and clinicopathological factors.Methods: Fifty-two endometrial cancers were obtained from previously untreated patients (median age, 56 years; range, 35–80 years). The expression of heparanase mRNA was evaluated using a semi-quantitative reverse transcriptase-polymerase chain reaction and immunohistochemical staining (IHC) with anti-heparanase polyclonal antibody. This antibody was raised by immunizing a rabbit with a peptide containing the amino acid residues from 238 to 250 of the Heparanase. Tumor angiogenesis was assessed using microvessel counting. The Mann-Whitney U test, one factor ANOVA test, and Spearman's test were used to determine the relationship between heparanase expression, microvessel density, and clinicopathological parameters. Results: The expression of heparanase mRNA was detected in 26 of 52 (50%) endometrial cancers, and was significantly correlated with FIGO stage IIIc (p = 0.0075), the presence of lymph-vascular space involvement (LVSI) (p = 0.0041), lymph node metastasis (LNM) (p = 0.0049), and histological tumor grade (p = 0.003). IHC showed that the heparanase was expressed in 23 of 52 (44.2%) endometrial cancers, which was significantly related to LVSI (p = 0.0028), depth of myometrial invasion (p = 0.0026), and histological tumor grade (p = 0.0135). Microvessel density was also associated with FIGO stage IIIc (p = 0.027), LVSI (p = 0.001), LNM (p = 0.038), ovarian metastasis (p = 0.03) and histological tumor grade (p = 0.003). Moreover, we found a strong positive correlation between heparanase expression and microvessel density (r2 = 0.475, p = 0.0001). Conclusions: These results suggest that the expression of heparanase can promote tumor angiogenesis and develop metastasis in endometrial cancer.

No significant financial relationships to disclose.
Effect of introduction of paclitaxel on survival among women with stage III and IV ovarian cancer
Authors: Dawood S. S. , Albaracin C. , Gonzalez-Angulo A. , Markman M. , Hennessy B.
Published: August 2020

5536

Background: The objective of this study was to evaluate survival over time in relation to FDA approval of paclitaxel (P) for second- and first-line treatment in a population-based cohort of women with stage III and de novo stage IV ovarian cancer. Methods: The Surveillance, Epidemiology, and End Results (SEER) program was searched to identify 8,267 and 10,746 women with stage III and stage IV epithelial ovarian cancer diagnosed between 1988–2004. Women were divided according to their year of diagnosis and year of FDA approval of P for second- (1992) and first-line(1998) treatment of ovarian cancer: Group1 (1988–1991; before P approval); Group2 (1992–1997; P approved for second-line); Group3 (1998–2003; P approved for first-line). Overall (OS) and ovarian-cancer-specific survival (OCS) were estimated using Kaplan-Meier product method and compared across groups with log rank statistic. Cox-proportional hazards models were fitted to determine the association of group year of diagnosis and survival after adjusting for patient/tumor characteristics. Results: Median age was 66 years. Median OCS was 44 and 18 months among women with stages III and IV disease, respectively. With stage III disease, 2-year OCS was 64%, 68%, and 70% for groups 1, 2, and 3, respectively (p < 0.0001). With stage IV disease, 2-year OCS was 39%, 41%, and 42% for groups 1, 2, and 3, respectively (p = 0.19). In the multivariable model for stage III disease, women in group 1 (HR = 1.4, 95% CI 1.2–1.5, p < 0.0001) and group 2 (HR = 1.2, 95% CI 1.1–1.3, p = 0.0003) had an increased hazard of ovarian-cancer-specific death vs. group 3. For stage IV disease, women in group 1 (HR = 1.2, 95% CI 1.12–1.3, p < 0.0001) had a significantly increased hazard of ovarian cancer-specific death, but no significant difference in group 2 (HR = 1.0, 95% CI 0.9–1.1, p = 0.88) vs. group 3. Similar trends were observed for OS. Conclusions: The survival of women with stages III and IV ovarian cancer has significantly improved with the introduction of P over the last two decades. However, the incremental improvement in survival with stage IV disease is clinically minimal and indeed not significant in the univariable analysis in the SEER patient cohort analyzed, suggesting a desperate need for new and more active drugs in these patients.

No significant financial relationships to disclose.
Multicenter randomized phase III trial of 3-weekly paclitaxel/platinum (PC3w) versus weekly paclitaxel/platinum (PCw) induction therapy followed by PC3w maintenance therapy in advanced epithelial ovarian cancer (EOC)
Authors: Burg M. E. , Janssen J. T. , Ottevanger P. B. , Kerkhofs L. G. , Valster F. , Stouthard J. M. , Onstenk W. , Termorshuizen F. , Verweij J.
Published: August 2020

5538

Background: Response rates (RR) up to 50% were found with PCw in platinum resistant EOC. We compared the efficacy of first-line PCw induction therapy to PC3w. Methods: 270 patients (pts) with FIGO stage II-IV, Performance status (PS) 0–2 were randomly assigned to 3 x PC3w (P 175mg/m2 with either cisplatin [Cis] 75mg/m2 or carboplatin [Car] AUC 6) or 6 x PCw (P 90mg/m2 with either Cis 70mg/m2 or Car AUC 4, day 1,8,15 and day 29,36,43) followed by up to 6 cycles PC3w in both arms. Pts were stratified for FIGO stage, PS, tumor size and center. Primary endpoints were progression free survival (PFS) and overall survival (OS). Secondary endpoints were RR and toxicity. A total of 225 events were needed to detect a 10–13% absolute difference in PFS/OS with a power of 84% (one-sided). Results: 267 pts (134 TC-3w and 133 TCw) were eligible (3 pts wrong tumor type). Pt characteristics were well balanced; median age 58 years, serous 62%, residual disease >1cm 66%, FIGO stage II 7%, III 64%, IV 29%. Median dose-intensity for PC3w was: P 58(47–58) and Cis 25(22.5–25) mg/m2/w, Car 2(1.6–2) AUC/w, for PCw: P 60(36–60) and Cis 44.7(30–44.7) mg/m2/w and for Car 2.7(1,6–2,7) AUC/w. After a median follow-up of 39 months (m) (range 0.03 - 93.3m) 206 pts (77%) had progressed and 164 pts (61%) had died. Median PFS was 18m for TC3w and 19m for TCw, 5-year PFS was 20% and 18%, respectively (logrank test: p = 0.63). Median OS was 44m for TC3w and 45m for TCw, 5-year OS was 36% and 37%, respectively (logrank test: p = 0.87). RR after induction therapy in 176 pts with measurable disease was 72% for TC3w and 74% for TCw (p = 0.68). TCw was well tolerated. Grade 3/4 toxicity for TC3w vs. TCw was respectively, platelets 1.75% vs.1.55% (ns), WBC 5.5% vs. 8.7 (p = <0.0001), granulocytes 16.7% vs. 11.7% (p = <0.001) and delay 3% vs. 9% of the cycles. TCw induced less grade 2/3 muscular and joint pain (TC3w 6.3% and 3.5% vs. TCw 0.3% and 0.8% of the cycles) and less neurotoxicity (TC3w 6% vs. 1.6% of the pts in TCw). The other toxicities were similar in frequency and severity in both arms. Conclusions: TCw was well tolerated and had less granulocytopenia, neurotoxicity, and muscular and joint pain but did not yield benefit in terms of OS, PFS or RR.

No significant financial relationships to disclose.
Cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for the management of peritoneal carcinomatosis from ovarian cancer: A multiinstitutional study of 246 patients
Authors: Bereder J. , Glehen O. , Habre J. , Desantis M. , Cotte E. , Mounier N. , Ray-Cocquard I. , Karimdjee B. , Bakrin N. , Bernard J. , Benchimol D. , Gilly F.
Published: August 2020

5542

Background: Optimal treatment of chemoresistant and recurrent ovarian cancer is debating with second line chemotherapies. For peritoneal carcinomatosis new treatment combining cytoreductive surgery with heated intraperitoneal per operative chemotherapy (HIPEC) may improve survival. Methods: Retrospective bicentric study of 246 patients with peritoneal carcinomatosis from ovarian cancer were performed to evaluate HIPEC and to identify prognostic factors. Peritoneal Cancer Index (PCI) assess tumor load and completeness cytoreductive score (CCS) was used to give quality of resection CC0 (no visible tumor), CC1 (persistent diffuse lesions < 2.5mm), CC2 (2.5mm < CC2 < 25mm) and over CC3 status. HIPEC is performed with platinum based regimen at 42°C. Endpoint was survival. Kaplan-Meier survival curve was fitted to the data. Cox's regression model was used for multivariate survival analysis. Results: The study included 268 procedures in 246 patients from 1991 to 2008. 206 procedures were performed in 184 patients with recurrence (Group 1) and 62 in chemoresistant patients (Group 2). After completion of resection the allocation of CCS was CC0 = 164, CC1 = 83, CC2 = 15, and CC3 = 5. Only 1 patient died in post operative course and procedure related morbidity rate was 12%. 5 years overall and free survival were respectively 35 % and 10%. Median overall survival was 49 months and the median disease free survival was 13 months. There was no difference between group 1 and 2 for survival. Independent prognostic factors for survival were the carcinomatosis extent, the completeness of cytoreductive surgery (HR = 2.26 IC95 [1.3–3.91]), performance status (HR = 4.3 IC95 [1.23–14.4]) and redo procedure (HR = 0.9 IC95 [0.001–0.9]). Conclusions: Hipec is a standardized and reproducible feasible method. Less extensive disease and the quality of cytoreduction remain an independent factor of better outcome. Morbidity is acceptable. To date in selected patients, HIPEC allows to reach the longest median time survival in recurrent peritoneal carcinomatosis from ovarian cancer.

No significant financial relationships to disclose.
Pegylated liposomal doxorubicin (PLD) with bevacizumab (B) in second-line treatment of ovarian cancer (OC): Pharmacokinetics (PK), safety, and preliminary outcome results
Authors: Muggia F. M. , Boyd L. , Liebes L. , Downey A. , Muller C. , Pothuri B. , Blank S. , Rutledge T. , Fishman D. , Verschraegen C.
Published: August 2020

5548

Background: PLD activity in platinum-resistant OC is modest. B, with its activity in platinum(Plat)-sensitive and Plat-resistant patients (pts), has not been combined with PLD. PLD intratumoral concentrations, if affected by B, might be reflected in PLD PK. This phase II study of PLD + B was started in 2007 to accrue 48 pts, unless 4 serious (> grade 3) adverse events (AEs) supervened. Methods: Improvement in progression-free survival (PFS) at 6 m from 25 to 40% at 6 m in Plat-resistant OC is primary endpoint. PK of PLD alone at 1h, d 7 and d 21 (cycle 1) vs with B (cycle 2), safety, and response rates (RECIST and CA125 criteria) were secondary endpoints. Dosing: PLD 30 mg/m2 followed by B 15 mg/kg on cycles 2–7 (with option to continue) d 1 every 3 w. Pts recurring within 6 m of platinum-based treatment for OC after < 3 prior regimens (but no PLD or B) were eligible. Exclusions: bowel obstruction, prior perforation, uncontrolled hypertension, or vascular disease. Hematologic, mucocutaneous and renal toxicities were evaluated prior to each cycle, MUGA scans every third cycle; disease status by CA125 and/or RECIST every third cycle. Results: 21 of 24 pts enrolled to date are evaluable. Median age is 65, range 52–83; most had 2 prior chemotherapy regimens. Median 6 (range 3–12) cycles were given with 6 off study with progression at 3–7 cycles. RECIST and CA125 responses are under review; in 11 pts with baseline CA125 of > 40 IU/mL, median increase was 31% by cycle 2; later falling to -57%. AEs did not exceed grade 3; hand-foot syndrome led to PLD dose reduction in 8 pts (33%); asymptomatic decreases in left ventricular ejection fraction (LVEF) >10% in 3 pts were noted, with treatment discontinuation in 1. The mean (±SEM) secondary PK parameter estimates for Cmax, AUC, and elimination half life were 4.5 ± 0.5 ug/mL, 651.7 ± 61 ug/mL x h, and 93.3 ± 19.7 h, respectively. Conclusions: Cycles 1 and 2 PLD PK do not differ. PLD + B is tolerable with PLD dose modifications. Declines in LVEF in 1 institution have uncertain causality. Midway into the trial, safety and time on study encourage completion for study primary endpoint.

[Table: see text]
Oxaliplatin plus continuous infusion topotecan: First stage of an ongoing phase II study for recurrent ovarian cancer: A New York Cancer Consortium study (#N01-CM62204)
Authors: LaNatra N. , Hochster H. , Muggia F. , Blank S. V. , Curtin J. , Fishman D. , Shapira I. E. , Goldberg G. L. , Parise S. , Tiersten A.
Published: August 2020

5556

Background: Topoisomerase-1 inhibitors and platinums are active in ovarian cancer. Our prior series described infusional topotecan as less myelosuppressive than bolus and more easily combined with oxaliplatin than cisplatin. An NYU phase I study of the combination in previously treated ovarian cancer patients (pts) showed promising activity and good tolerability (Hochster H, Gynecol Oncol 2008). Methods: Ovarian cancer pts treated with 1–2 prior regimens (1 platinum/taxane regimen, no topotecan) were treated with oxaliplatin 85 mg/m2 day 1, 15 and topotecan (0.4 mg/m2/day) continuous infusion x 14 days every 4 weeks (wks). Platinum resistant (stratum I = 10) and sensitive (stratum II = 17) pts are included in this two-stage trial (n = 52) to evaluate overall response rate (ORR) and toxicities. Results: From January 2006 to November 2008, 27 pts entered. Median age was 61 (37–79). Fifteen pts had 1 prior regimen and 12 pts had 2. Five pts discontinued before 2 cycles (3 for predefined toxicity, 2 by pt/physician choice). 102 cycles of chemotherapy were given (median 4, [1–6]). Grade 3/4 toxicities included thrombocytopenia (37% grade 3, 19% grade 4), neutropenia (37% grade 3, 11% grade 4), anemia (15% grade 3), neuropathy (7% grade 3), diarrhea (4% grade 3), transaminitis (4% grade 3), and fatigue (7% grade 3). Twenty-one pts had day 15 oxaliplatin held, 10 pts required dose reductions, and 21 pts had treatment delays mainly from thrombocytopenia. No pts had neutropenic fever. Twenty-one pts are now evaluable. Stratum I had 1 complete and no partial responses, 5 pts with stable disease and 2 with progressive disease. Stratum II had 3 complete and 6 partial responses, 4 pts with stable disease and none progressed. Median response duration is 41 wks (17–62); median duration of stable disease is 17 wks (4–70). Conclusions: Excluding thrombocytopenia, tolerance to this regimen confirms phase I results. In pts with creatinine clearances (CrCl) < 60 ml/min, the incidence of grade 3/4 thrombocytopenia was 75% versus 35 % for pts with CrCl > 60 ml/min. Pts with CrCl of 40–60 ml/min will now start topotecan 0.3 mg/m2/day x 14 days. Reaching our predefined ORR of at least 30% for stratum II and 20% for stratum I, the second stage of accrual has begun.

[Table: see text]
Weekly paclitaxel (wP) as single agent or in combination with weekly topotecan (wT) or carboplatin (C) in patients with resistant ovarian cancer (ROC): The phase II CARTAXHY randomized trial from GINECO
Authors: Gladieff L. , Lortholary A. , Largillier R. , Weber B. , Alexandre J. , Durando X. , Slama B. , Dauba J. , Paraiso D. , Pujade-Lauraine E.
Published: August 2020

5557

Background: For ROC patients (pts) with early progression during or after (< 6 months) platinum and 3 weekly P, use of single non-platinum agent including wP is standard (Kristensen G, et al. J Clin Oncol 26: 2008 abstr 5508). Few randomized trials have explored combination therapy in this setting. Methods: Pts with ROC after a first or second line including a platinum and a taxane were randomized to receive wP (80 mg/m2/week) alone or in combination with wT (3mg/m2/week) or C (AUC 5 every 4 weeks). The primary end-point was the comparison of progression-free survival (PFS) between single non-platinum agent and combination therapy (wP+wT or wP+C). Secondary objectives included safety, QoL, response rate (RR) and overall survival. Results: From April 2004 to August 2008, 165 pts were accrued (wP 57, wP+wT 57, wP+C 51). Median number of cycles and P dose-intensity (mg/m2/week) was 4.6 and 70, 4.2 and 63 in monotherapy and combination therapy arms respectively. Non-hematological toxicity was not different between the arms, except an excess of hypersensitivity reactions in the wP+C arm. Grade 3–4 neutropenia (48 vs 13% of pts), and anemia (24 vs 6%) were more frequent in combination therapy than in single agent arm and similar with wT or C combination. Febrile neutropenia was experienced by 5 pts treated with combination therapy. Discontinuation from drug treatment was more frequent with combination therapy (24% of pts) than with monotherapy (4%), mainly due to hematotoxicity. RR was 34, 38 and 39% for wP, wP+wT and wP+C respectively. Median PFS of pts treated with single agent (112 days) was not significantly different from those treated with combination therapy (149 days) (p = 0,62) and was similar in wP+wT (152 days) or wP+C (146 days) arms. Treatment with single non-platinum agent or combination therapy was not found an independent parameter when added to a Cox model including prognostic variables. Conclusions: Combination therapy (CT) in platinum resistant ovarian cancer was found more toxic than weekly paclitaxel and the PFS advantage from CT was not statistically significant.

No significant financial relationships to disclose.
A phase II trial of voreloxin in women with platinum-resistant ovarian cancer
Authors: Hirte H. W. , McGuire W. , Edwards R. , Husain A. , Hoskins P. , Michels J. , Matulonis U. , Sexton C. , Michelson G.
Published: August 2020

5559

Background: Voreloxin is a naphthyridine analog that intercalates DNA and inhibits topoisomerase II, inducing apoptosis. Clinical activity has been observed in ovarian cancer and AML. Results are reported from a fully enrolled phase II study of 3 dose levels of single agent voreloxin in patients (pts) with 1° or 2° platinum-resistant or refractory ovarian cancer. Methods: Pts may have received ≤ 3 prior platinum regimens plus one additional non-platinum regimen. PS of 0–1 was required. Voreloxin regimens: Cohort A 48 mg/m2q3weeks (wk) (N = 65), Cohort B 60 mg/m2q4wk (N = 35), and Cohort C 75 mg/m2q4wk (N = 35) by short IV infusion. BRCA status is reported by pt consent. Results: Cohort A: 2CRs, 5PRs; ORR 11%; median PFS 82 days (52–98 days 95%CI); Cohort B: 1CR, 3PRs; ORR 11%, median PFS too early to evaluate (TETE); Cohort C - TETE. Cohort A: Febrile neutropenia (FN) incidence was low (8%). Other common G3 or G4 AEs reported (≥ 5%) were fatigue (14%) and nausea (5%). Dose delays or reductions (40%) occurred typically at Cycle 1, largely due to neutropenia. Cohort B: Dose was increased to 60 mg/m2 and dosing interval was lengthened to 4 wk, maintaining dose intensity (DI) and allowing adequate time for marrow recovery. ANC dosing criterion was changed from ANC ≥ 1,500 to ≥ 1,000. There was a marked decrease in dose delays and reductions (14%) with only 3% incidence of FN. Common G3 or 4 AEs reported (≥ 5%) were fatigue (11%) and nausea (5%). The safety profile supported further dose escalation to 75 mg/m2q4wk (Cohort C- DI increased by 25%). Data are TETE. Conclusions: Preliminary data suggest Cohorts A and B have similar safety and efficacy profiles as anticipated based on comparable DI. Fewer dose reductions and delays occurred in Cohort B, due to revised dosing criteria and increased cycle length to 4 wk. Accrual to Cohort C is complete. Efficacy and safety data for all cohorts will be reported.

[Table: see text]
A phase II study evaluating the safety and efficacy of patupilone in patients with platinum refractory/resistant ovarian, primary fallopian, or peritoneal cancer
Authors: Smit W. M. , Sufliarsky J. , Werner T. L. , Dizon D. , Wagnerova M. , Hirte H. W. , Delaney R. , Li J. , Weber D. , Schellens J. H.
Published: August 2020

5563

Background: Patients with ovarian cancer that relapse or recur within 6 months after platinum plus taxane therapy have a poor prognosis. Patupilone, a natural epothilone isolated from myxobacterium, is a microtubule targeting agent that was found to be safe and well tolerated, with clinical activity in refractory or resistant ovarian cancer. Methods: Patients were treated with a dose of patupilone 10 mg/m2, given intravenously over 10–20 minutes once every 3 weeks, which was found safe in a previous phase I study. Results: Total 113 women enrolled and 112 were treated. The median age was 56 years (range 18–85 years), and 11 % had WHO Performance Status (PS) of 2. Most patients (104) had ovarian cancer, while 5 were peritoneal and 2 each of fallopian or other origin. All patients had received prior platinum and taxane, and 50% had progressed in less than 3 months after prior platinum therapy. Patients received a median of 4 cycles (range 1–16) of patupilone with median average dose per cycle of 9.97 mg/m2, resulting in a median dose intensity of 100%. The most common grade 3/4 toxicity was diarrhea (21%/3%), fatigue (10%/1%), intestinal obstruction (5%/3%), anorexia (5%/1%), and vomiting (8%/0%). About 38% patients developed neuropathy, which was mostly grade 1 (in 22%), with only 4% patients at grade 3. A total of 6 patients (5.4%) discontinued due to serious adverse event. There were 4 (3.6%) deaths on study, none of which were considered treatment related. The best overall response rate (by RECIST criteria) was 7.1% (95% CI: 3.0%, 14.0%) with no patient having complete response and 8 patients with partial response. Also, 46 patients (41%) had stable disease and 39 (34.8%) progressed, while response was unknown or could not be evaluated in 19 patients. The median PFS is 2.5 months (95% CI: 1.4, 3.5), and median overall survival is 11.2 months (95% CI: 8.3, 14.9), with 33% patients censored. Conclusions: Patupilone 10mg/m2 administered at q3wk was safe and well tolerated. It showed promising activity in patients with refractory/resistant ovarian cancer.

[Table: see text]
Phase I feasibility study of carboplatin plus capecitabine followed by maintenance capecitabine in patients (pts) with recurrent platinum-sensitive epithelial ovarian cancer (EOC)
Authors: Montes A. , Sandhu S. K. , Rothermundt C. , Coombes I. , A'Hern R. , Keyzor C. , Thomas A. , Kaye S. , Gore M.
Published: August 2020

5564

Background: In a previous study, we noted a response rate (RR) of 61% for the 3 drug combination of carboplatin, epirubicin and capecitabine in platinum-sensitive recurrent EOC. This combination however resulted in excessive grade (G) 3–4 haematological toxicity (55%) (BJC 2006; 94:74). The current trial therefore assessed the feasibility and efficacy of the 2 drugs, carboplatin and capecitabine as second- or third-line treatment. Methods: Pts were administered carboplatin (AUC5) day 1 and capecitabine at a starting dose of 750 mg/m2 bd, days 1–21, q21 (dose level 1). The capecitabine dose was deescalated to 625 mg/m2 (dose level -1) and 500 mg/m2 (dose level -2) according to toxicity. Pts with an objective response or stable disease received maintenance capecitabine (at the same dose level) for up to 12 months or until progression. Responses were assessed with RECIST criteria and CA-125. Results: 19 of the 20 pts enrolled were evaluable for toxicity and response. Dose-limiting toxicity was observed at dose level 1 (G3 fatigue, G3 diarrhoea, G3 neutropenia of > 14 days; n = 3/5), dose level -1 (G3 angina (n = 2), G3 vomiting, G3 palmar plantar erythema; n = 4/7) and dose level-2 (diarrhoea / fatigue; n = 1/7). One patient had a G3 carboplatin hypersensivity reaction. 8 pts received maintenance capecitabine which was well tolerated. The overall RR was 53% with 10 partial responses and 5 stable diseases. The median progression free survival (PFS) was 6.5 months (m) and the 6mPFS was 63% with 2 pts currently ongoing treatment. The median PFS on maintenance was 3.2 m. Conclusions: The combination was well tolerated at the recommended phase II dose of carboplatin (AUC 5) and capecitabine (500 mg/m2 bd) with partial responses in over half of the cases.

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Cost-effectiveness of zoledronic (ZOL) acid plus endocrine therapy (ET) in premenopausal women with early breast cancer (EBC) from a Canadian perspective
Authors: Ougari K. E. , Taneja C. , Sofrygin O. , Kaura S. , Delea T.
Published: August 2020

557

Background: The Austrian Breast and Colorectal Cancer Study Group Trial 12 (ABCSG-12) examined the efficacy of 3 years (yrs) of treatment with goserelin in combination with ET (anastrozole or tamoxifen) with or without ZOL 4 mg q6 mos in 1,803 premenopausal women with EBC (median age 45 yrs). After a median follow-up of 47.8 mos (max 84 mos), risk of disease-free survival (DFS) events was reduced by 36% (HR = 0.64; p = 0.01) in patients (pts) who received ZOL (ZOL+ET) compared with those who did not (ET). Methods: A Markov model was used to estimate the cost per quality adjusted life years (QALYs) gained of 3 years treatment duration of ZOL+ET versus ET-only in premenopausal women with EBC based on results of the ABCSG-12. A Canadian healthcare system perspective and a lifetime timeframe were used. Outcomes and cost of breast cancer recurrence were based on recent published studies. Results were generated under 2 scenarios regarding duration of benefit (reduction in risk of recurrence) with ZOL: (1) Benefits persist to maximum follow-up in ABCSG-12 (trial benefit); (2) Benefits persist until death (lifetime benefit). Results: The cost of 3 years of ZOL (medication and administration) is 4 191 $CDN. Under the lifetime benefit scenario, 73% of these costs are offset by savings in the cost of recurrences. Under the trial benefit scenario, 12% are offset. QALYs gained are 1.63 yrs and 0.52 yrs under the lifetime and trial benefit scenarios respectively; cost-effectiveness is 1 122 $CDN and 3 675 $CDN per QALY gained respectively, which is well below the 50 000 $CDN per QALY threshold frequently used to assess whether therapies are cost-effective. Conclusions: The combination of ZOL + ET is a cost-effective use of healthcare resources from a Canadian healthcare system perspective.

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Antiangiogenic therapy for granulosa cell tumors of the ovary
Authors: Tao X. , Sood A. K. , Deavers M. T. , Schmeler K. M. , Nick A. M. , Coleman R. L. , Gershenson D. M. , Brown J.
Published: August 2020

5574

Background: Sex-cord stromal ovarian tumors (SCSTs) tend to respond poorly to chemotherapy agents. Therefore, we examined the clinical efficacy of bevacizumab with or without concurrent chemotherapy and evaluated the angiogenic characteristics of these patients’ tumors. Methods: We conducted an IRB-approved retrospective review of all patients with SCSTs seen at our institution from February 2004 to October 2008. Eligible patients underwent pathologic confirmation and clinical evaluation, and received bevacizumab. VEGF and CD31 immunohistochemical staining (IHC) was performed when tissue was available; microvessel density (MVD) was measured based on CD31 counts. Results: We identified 8 eligible patients treated with bevacizumab. Of these, 7 had adult granulosa cell tumors (GCT) and one had a juvenile GCT. Of the 8 patients, 4 had early stage disease (I or II), 2 had advanced stage disease (III), and 2 were unstaged. All patients were treated for recurrent disease and had been previously treated with cytotoxic chemotherapy, with a median of 3.5 prior regimens (range, 1–6). Of the 8 patients, one patient had a complete clinical response, 2 patients had a partial response, 2 patients had stable disease, and 3 patients progressed, yielding a response rate of 38% and a clinical benefit rate of 63%. The median progression-free survival (PFS) was 7.2 months and the overall survival (OS) was not reached at a median follow-up after starting bevacizumab of 23.6 months. Of the 8 patients, 5 had tissue available for IHC. VEGF expression was noted at some level in all samples; overexpression was present in 1 of the 5 patients (upper tertile of score), and moderate expression was observed in 3 of the 5 patients (middle tertile). VEGF overexpression correlated with shorter PFS (p = 0.006) and shorter overall survival (p = 0.02). High MVD (>12.3 per previous data based on ROC analysis) was present in 3 of the 5 patients, and correlated with VEGF overexpression (p = 0.007) and shorter overall survival (p = 0.004). Conclusions: Anti-VEGF therapy is highly effective in patients with ovarian granulosa cell tumors. On the basis of these observations, a prospective trial has now been initiated using single agent bevacizumab in patients with recurrent disease.

No significant financial relationships to disclose.
A phase II study of sunitinib in recurrent or metastatic endometrial carcinoma: A trial of the PMH Phase II Consortium
Authors: Welch S. , Mackay H. J. , Hirte H. , Fleming G. F. , Morgan R. , Wang L. , Blattler C. , Ivy S. P. , Oza A. M.
Published: August 2020

5576

Background: Endometrial cancer (EC) is the most common gynecologic malignancy. Vascular endothelial growth factor (VEGF) overexpression in EC correlates with poor outcome, thus targeting VEGF is a rational therapeutic approach. We have conducted a two-stage open-label phase II study in advanced EC with sunitinib, an oral tyrosine kinase inhibitor of multiple VEGF receptors. Methods: Eligible pts have recurrent or metastatic EC and have received up to 1 prior chemotherapy (CT) regimen for metastatic disease. Sunitinib is given at 50 mg daily (OD) for 4 consecutive weeks (wks) followed by 2 wks off. Dose could be reduced to 37.5 mg OD and then 25 mg OD in the setting of toxicity. Imaging is repeated every 12 wks. Primary objectives are objective response rate (ORR by RECIST) and rate of 6-month progression-free survival (PFS). If 1 or more responses occur in the first 15 evaluable pts, the study would continue to a second stage (total = 30 pts). Secondary objectives are time to progression (TTP), overall survival (OS), and safety. Results: We report the results of the first stage of this study. Sixteen pts have been treated (median age: 63; range 41–74) with 37 cycles of sunitinib (median 2; range: 1–7). Baseline ECOG PS was 0 (7 pts), 1 (8 pts), or 2 (1 pt). Histology was endometrioid (7 pts), serous (5 pts), clear cell (1 pt), or mixed/other (3 pts). Most pts had high-grade histology (G3: 8; G2: 4; G1: 2; GX: 2). Nine pts had prior adjuvant CT, 8 pts had 1 prior CT for advanced EC, 4 pts had prior hormones and 7 pts had prior radiotherapy. Partial response was achieved by 2 pts (ORR = 12.5%), and 2 other pts had a best response of stable disease; 3 of these pts remained progression-free > 6 months. Median TTP = 2.5 months (95% CI: 2.47-NR), and median OS = 6.2 months (95% CI: 5.1-NR). Grade 3/4 adverse events (AE) in >10% of pts were fatigue (7 pts, 44%) and hypertension (5 pts, 31%). Dose reduction was required for 11 of 16 pts (69%). Two pts were inevaluable after receiving <2 cycles due to AE (grade 4 hyponatremia; grade 3 fatigue) and 1 other pt has yet to complete 2 cycles. Conclusions: Sunitinib shows preliminary activity in EC. This trial will proceed to a second stage of accrual to further explore the efficacy and safety of sunitinib in advanced EC.

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Phase II study of MKC-1 in patients with metastatic or resistant epithelial ovarian cancer or advanced endometrial cancer
Authors: Elser C. , Hirte H. , Kaizer L. , Mackay H. , Bindra S. , Tinker L. , MacAlpine K. , Wang L. , Sidor C. , Oza A.
Published: August 2020

5577

Background: MKC-1 is a novel oral cell cycle inhibitor with preclinical activity in xenograft models of human ovarian and endometrial cancers. MKC-1 also reduces pAKT, an attractive target in endometrial cancer due to frequent PTEN mutations. Methods: The objective of this phase II study is to assess the efficacy of MKC-1 in 2 patient (pt) populations: metastatic or recurrent platinum-resistant ovarian cancer (EOC) and advanced endometrial cancer (EC). Three prior lines of treatment were allowed in both groups. A two arm, parallel group multicenter 2-stage design was used. The primary endpoint was tumor response by RECIST or CA-125. MKC-1 125 mg/m2 was administered orally twice daily for 14 days in 28-day cycles. Results: Accrual to stage one is complete with 21 pts in each arm. 19 pts with EOC (median age 56 yrs, range 31–71) and 9 patients with EC (median 63 range 50–74) were available for efficacy. A total of 66 cycles (EOC/EC: 39/27cycles) median 2 per patient (range 1–8) were delivered. 11/4 pts had prior adjuvant CT, 14/10 had prior systemic CT for advanced disease, and 2/6 received prior radiation. In pts with EOC, 7 pts have stable disease (SD), 12 progressive disease (PD), 2 remain on study. Median time to progression is 1.8 months. In pts with EC 4 pts had SD, 5 PD, 6 remain on study. Toxicity data are available in 28 pts (17/11). Most common adverse events (AE) possibly related to MKC-1 were fatigue, nausea, elevated ALT or AST, urine discoloration, anemia, anorexia, elevated AP and gastrointestinal disorder in 55%, 39%, 36%, 24%, 23%, 21%, 21%, and 21 % of cycles respectively. The only possibly related grade 3+ AEs were neutropenia, leucopenia and hyponatremia in 9 %, 3 %, and 2% of cycles. Conclusions: MKC-1 was well tolerated in both patient populations. Single agent MKC-1 has insufficient activity in platinum resistant EOC to warrant further investigation. Updated clinical data for both patient groups will be presented at the meeting.

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Different expression of progesterone receptor between uterine serous carcinoma and ovarian serous carcinoma
Authors: Matsuo K. , Eno M. L. , Abouzied A. M. , Im D. D. , Rosenshein N. B.
Published: August 2020

5578

Background: Clinical presentation and progression of uterine serous carcinoma (USC) often mimicks that of ovarian serous carcinoma (OSC), making the diagnosis difficult. The aim of this study is to compare characteristics of biomarker expression of USC to OSC. Methods: We evaluated all patients with FIGO stage III-IV USC and OSC, who underwent initial cytoreductive surgery between January 1, 1995, and March 31, 2008. Cases that received neoadjuvant chemotherapy were excluded. Patient demographics and clinico-pathologic data were abstracted from the medical records. Biomarker expression results were evaluated for mutation of p53 (m-p53), DNA profiling, multi-drug resistance gene-1 (MDR-1), estrogen receptor, and progesterone receptor. In-vitro drug resistance assay results were compared among platinum, taxane, cyclophosphamide, doxil, etoposide, gemcitabin, and topotecan (EDR Assay, Oncotech, Inc.). Results: There were 19 cases of USC and 185 cases of OSC identified. USC and OSC showed similar biomarker expressions except for the DNA index and expression of progesterone receptor. Biomarker expressions were: m-p53, 83.3% vs 68.7%, p = 0.28; DNA aneuploidity, 88.8% vs 80.8%, p = 0.53; DNA index, 1.7 (1.0–2.7) vs 1.5 (0.8–3.2), p = 0.044; S-phase fraction, 8.1% (3.1–19) vs 8.6% (0.3–19.2), p = 0.5; MDR-1, 33.3% vs 19.1%, p = 0.21; and estrogen receptor, 82.3% vs 82.9%, p = 1.0. Increased progesterone receptor expression was seen in USC compared to OSC (29.4% vs 9.2%, odds ratio 4.1, 95%CI 1.25–13.7, p = 0.028). In the in-vitro drug resistance assay, proportions of extreme drug resistance were similar in all tested drugs, including: cisplatin, 7.7% vs 7.2%, p = 0.5; carboplatin, 11.1% vs 9.5%, p = 0.3; paclitaxel 26.7% vs 23.5%, p = 1.0; doxil, 44.4% vs 33.9%, p = 0.69; and topotecan, 15.4% vs 18.5%, p = 1.0. Conclusions: Advanced uterine serous carcinoma was associated with increased expression of progesterone receptor compared to advanced ovarian serous carcinoma. The different expression potentially could be used to differentiate the two conditions and as a target in treatment therapies for uterine serous carcinoma.

No significant financial relationships to disclose.
DNA mismatch repair protein defects and endometrial cancer in women age 40 and younger
Authors: Shih K. K. , Garg K. , Levine D. A. , Kauff N. , Abu-Rustum N. R. , Soslow R. A. , Barakat R. R.
Published: August 2020

5579

Background: The significance of the hereditary basis of endometrial cancer is apparent in young women with endometrial cancer. The objective of this study was to describe the incidence and prognostic implications of DNA mismatch repair protein defects in a series of patients age 40 years and younger with endometrial cancer. Methods: We performed a retrospective cohort study of patients age 40 years or less who were diagnosed with endometrial carcinoma between 1/93 and 5/08. Clinical and pathologic data were extracted from medical records. Paraffin-embedded slides from hysterectomy specimens were obtained and DNA mismatch repair (MMR) immunohistochemistry (IHC) was performed. Cases were analyzed according to presence of DNA MMR protein defects. Standard two-sided statistical tests were performed. Results: Of the 71 identified patients, the median age was 37 years (range, 24–40), with a median follow-up of 47 months (range, 1–178). The majority were of endometrioid histology (94%), stage I (73%), and FIGO grade 1 (61%). IHC was performed with available blocks (n = 56), and loss of DNA MMR was found in 9 cases (16%). Cases with loss of DNA MMR were more likely to have high-grade (FIGO 2 or 3) tumors (p < 0.001), be advanced stage (III or IV) at the time of diagnosis (p < 0.001), and have a family history suggestive of hereditary non-polyposis colorectal cancer (p = 0.01). There was no difference between the groups in histology, obesity (BMI>30), parity, or history of infertility. Analysis of clinical outcomes revealed that cases with loss of DNA MMR had significantly worse overall survival (median survival not reached, log rank p = 0.018). At the time of last follow-up, 2 (22%) patients with loss of DNA MMR were dead of disease compared with 2 (4%) patients with retained DNA MMR. Conclusions: Endometrial cancer is rare in young women age 40 years or less. In these patients, loss of DNA MMR was associated with worse clinicopathologic factors (high-grade and advanced-stage tumors) and worse outcome. Other clinical risk factors associated with endometrial cancer were not associated with loss of DNA MMR. The data suggest that MMR testing in women 40 years of age or younger with endometrial cancer may have clinically useful prognostic information.

No significant financial relationships to disclose.
A survival comparison between women with uterine serous and/or clear cell carcinoma with and without a history of breast cancer
Authors: Mendivil A. , Vogel T. J. , Bae-Jump V. L. , Gehrig P. A.
Published: August 2020

5580

Background: The association between breast and uterine is well known. However, the effect that a prior breast cancer diagnosis may have on women with a new endometrial cancer diagnosis is less well described. The goal of our study was to determine the effect that a prior history of breast cancer would have on the outcome for women with type II uterine cancer. Methods: After obtaining IRB exemption, a retrospective chart review was performed. All women treated for uterine carcinoma between 1994 and 2007 were identified and we identified women with either uterine serous (UPSC) or clear cell carcinoma (UCCC) as the study group. The patients were then divided between those with and those without a prior breast cancer diagnosis. Patient demographics, cancer histologies, and stage of disease data were collected. Fisher's exact test and unpaired t test were used as appropriate. Progression-free (PFS) and overall survival (OS) were calculated using the Kaplan Meier method. Results: Approximately 1,083 patients were treated for uterine carcinoma during the study period of which 74 had pre-existing breast carcinoma (6.9%). One hundred and fifty women had USC and/or UCCC (13.8%) of whom 23 also had pre-existing breast carcinoma (13.3%). The women with breast cancer where older at the time of their uterine cancer diagnosis (77 y.o.) compared to those without breast cancer (68 y.o.) (p = 0.0089); were more likely to develop USC/UCCC (OR 2.56; 95% CI 1.47–4.44); and were more likely to be white compared to black (OR 4.6; 95% CI 1.74–11.99). At five years, there was no significant difference in PFS or OS between those women with and without a prior history of breast cancer. Conclusions: Women with a history of breast cancer have more the twice the likelihood of developing USC and/or UCCC. While having two primary malignancies can be devastating, our study indicated that women who developed a type II uterine cancer and also had a history of a prior breast cancer had the same outcomes as those women without a prior cancer diagnosis. This finding may help to allay patients’ fears about developing another malignancy and its impact on their prognosis.

No significant financial relationships to disclose.