bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential benefit from fractionated dose-dense first-line chemotherapy for epithelial ovarian cancer (EOC) according to KELIM-evaluated tumor primary chemosensitivity: Exploratory analyses of ICON-8 trial.
Authors: You Benoit , Clamp Andrew , Cook Adrian David , McNeish Iain A. , Colomban Olivier 
Published: June 2021

5530 Background: ICON8 phase III trial did not show improvement in PFS or OS with first-line weekly dose-dense chemotherapy in EOC. This analysis evaluated the impact of tumor intrinsic primary chemosensitivity (assessed with modeled CA-125 ELIMination rate constant K (KELIM) based on the CA-125 kinetics during the first 100 days of chemo), on survival by treatment arms. Methods: Retrospective analysis of ICON8 where EOC patients were treated with chemo (Arm 1, standard (std) carboplatin AUC5-6 & paclitaxel 175mg/m2 q3weeks; Arm 2, carboplatin AUC 5-6 q3weeks and weekly paclitaxel 80 mg/m2; or Arm 3, weekly carboplatin AUC 2 & paclitaxel 80 mg/m2; ratio1:1:1) and debulking primary surgery (immediate (IPS), or delayed (DPS)). The association between standardized KELIM (dichotomized as favorable ≥ 1, or unfavorable < 1) and efficacy of treatment arms and surgery completeness was assessed univariate & multivariate analyses. Results: Of 1,566 enrolled patients, KELIM was calculated in 1,004 with ≥ 3 CA-125 available values. KELIM did not differ by treatment arm. Irrespective of surgical strategy, both KELIM and surgery completeness were significant prognostic factors, but treatment arms were not. In 354 IPS patients, 225 had unfavorable KELIM (63%). Weekly dose-dense carboplatin-paclitaxel (Arm 3) (compared to std chemo-Arm 1) was associated with improved survival in unfavorable KELIM patients (PFS:19.6 vs 11.0 months, HR 0.80 [0.54-1.17]; OS : 53.7 vs 40.1 months, HR 0.75 [0.50-1.14]), and worse survival in those with favorable KELIM (PFS: 26.7 vs 48.2 months, HR 1.27 [0.72-2.22]; OS: NR vs 69.2 months, HR 1.05 [0.53-2.06]). Maximum benefit was seen in highest-risk diseases (unfavorable KELIM + incomplete IPS; n = 116; PFS: 17.0 vs 7.4 months, HR 0.49 [0.29-0.82]; OS: 42.6 vs 27.0 months, HR 0.56 [0.33-0.96]). In 611 patients treated with neo-adjuvant chemo +/- DPS (279 unfavorable KELIM, 46%), the same trend for higher survival benefit from dose-dense carboplatin-paclitaxel was found in those with unfavorable KELIM (PFS: 10.8 vs 7.4 months, HR 0.84 [0.63-1.13]; OS: 26.4 vs 23.5 months, HR 0.80 [0.60-1.08]), and reversely. The higher KELIM, the higher the likelihood of complete surgery (OR 4.82 [3.21-7.37]). The prognostic impact of the surgery completeness was greater in unfavorable KELIM patients. Conclusions: In ICON8 trial, both the tumor primary chemosensitivity (by KELIM) and completeness of debulking surgery were major drivers of the prognosis & survival. Dose-dense fractionated chemotherapy in 1st-line setting may be beneficial for patients with lower tumor chemosensitivity, whilst it might be detrimental in those with highly chemosensitive disease. The greatest OS benefit (HR 0.56) from dose-dense chemotherapy was seen in highest-risk diseases (unfavorable KELIM and incomplete IPS).
Metronomic cyclophosphamide and bevacizumab for the treatment of recurrent gynecologic carcinosarcoma: A multi-institution, retrospective study.
Authors: Bouberhan Sara , Hyde Jill S. , Foxall McKenzie , Penson Richard T. , Arend Rebecca Christian 
Published: June 2021

5532 Background: The recent findings from the GOG 261 trial established carboplatin and paclitaxel as the standard first-line therapy for advanced gynecologic carcinosarcoma (GCS). Response rates to alternative regimens are limited, and the optimal chemotherapy for later line treatment of gynecologic carcinosarcoma has not yet been determined. The objective of this retrospective study is to report clinical response to treatment regimens for patients with GCS treated at 2 large academic referral comprehensive cancer centers. Methods: This multi-institution, retrospective analysis identified patients with recurrent GCS treated between January 1, 2015 and August 1, 2020 at the Massachusetts General Hospital and the University of Alabama O’Neal Comprehensive Cancer Center. All eligible patients received platinum/taxane as their first-line treatment regimen and were subsequently treated for recurrent disease. Subsequent treatment strategies were investigated. Objective responses were determined based on the clinical radiologist’s interpretation. Time on treatment (TOT) and treatment toxicity were identified for each subject. Given the small number of patients in this series, descriptive statistics were employed. Results: 29 patients met inclusion criteria. 15 patients had recurrent uterine carcinosarcoma, and 14 patients had recurrent ovarian carcinosarcoma. The most commonly used treatment regimens were: liposomal doxorubicin (PLD)/bevacizumab (ORR: 13%; Range TOT: 2-7 months), metronomic oral cyclophosphamide (MOC)/bevacizumab (ORR: 17%; Range TOT: 1-18 months), weekly paclitaxel/bevacizumab (ORR 60%; Range TOT: 3-18.5 months), liposomal doxorubicin (PLD) (ORR: 0%; Range TOT: 1-3 months), and weekly paclitaxel (ORR: 33%; Range TOT: 4.5-5.5). All regimens were generally well tolerated, and only 3 patients discontinued treatment due to toxicity concerns. Conclusions: In summary, in our cohort of gynecologic carcinosarcoma patients, the most active regimen (defined by mean TOT) was paclitaxel/bevacizumab, but prolonged TOT was also observed in the patients treated with MOC/bevacizumab. Given the rarity and aggressive nature of this tumor, further studies into optimal second line chemo (and beyond) are warranted; although, the combination of MOC/bevacizumab should be considered given the tolerability and the duration of treatment in this patient population.
Clinical and molecular characteristics of ARIEL3 patients who derived exceptional benefit from rucaparib maintenance treatment for high-grade ovarian cancer (HGOC).
Authors: Kwan Tanya , Oza Amit M. , Lorusso Domenica , Aghajanian Carol , Oaknin Ana , Dean Andrew Peter , Colombo Nicoletta , Weberpals Johanne I , Clamp Andrew R. , Scambia Giovanni , Leary Alexandra , Holloway Robert W. , Amenedo Margarita , Fong Peter C.C. , Goh Jeffrey C. , O'Malley David M. , Maloney Lara , Goble Sandra , Ledermann Jonathan A. , Coleman Robert L. 
Published: June 2021

5537 Background: ARIEL3 is a placebo-controlled randomized trial of the PARP inhibitor (PARPi) rucaparib as maintenance treatment in HGOC patients (pts) who responded to the latest line of platinum therapy (NCT01968213). Rucaparib improved progression-free survival (PFS) across all predefined subgroups. Here, we present an exploratory analysis of clinical and molecular characteristics associated with exceptional benefit from rucaparib. Methods: Pts were randomized 2:1 to receive rucaparib 600 mg BID or placebo. At the data cutoff of Dec 31, 2019, 33/375 (9%) and 1/189 (0.5%) pts were still ongoing and receiving rucaparib or placebo, respectively. Molecular features (genomic alterations, BRCA1 promoter methylation) and baseline clinical characteristics were compared between pts who derived exceptional benefit (PFS ≥2 yrs), and those with disease progression on first scan (≈12 wks; the short-term [ST] subgroup) within each treatment arm. Results: Of 564 pts, 83 (15%) showed exceptional benefit: 79/375 (21%) in the rucaparib arm and 4/189 (2%) in the placebo arm. Within the rucaparib arm, exceptional benefit pts had more favorable clinical prognostic factors at baseline compared with the ST subgroup (Table). While BRCA mutations were enriched in the rucaparib exceptional benefit subgroup, 34/79 (43%) of these pts were BRCA wild type. Among other biomarkers, RAD51C/D mutations were associated with exceptional benefit; low genome-wide loss of heterozygosity was enriched within the ST subgroup; and high BRCA1 methylation was present at similar fractions. Trends were similar in the placebo arm (Table). Conclusions: Exceptional benefit in ARIEL3 was more common in, but not exclusive to, pts with favorable clinical characteristics and known mechanisms of PARPi sensitivity. Our results suggest that rucaparib can deliver exceptional benefit to a diverse set of HGOC pts. Clinical trial information: NCT01968213. [Table: see text]
Stage I Sertoli-Leydig cell tumors: An interim report from the International PPB/DICER1 & OTST Registry.
Authors: Nelson Alexander , Harris Anne , Watson Dave , Pyper Sean Robin , Hall Nathan , Kamihara Junne , Stewart Douglas R , Dehner Louis P , Hill D. Ashley , Messinger Yoav H. , Frazier Lindsay Lindsay , Billmire Deborah F. , Schneider Dominik T. , Schultz Kris Ann Pinekenstein 
Published: June 2021

5547 Background: Sertoli-Leydig cell tumors (SLCT) are rare ovarian sex cord-stromal tumors which occur primarily in adolescents and young adults and are associated with DICER1 pathogenic variants. Methods: Informed consent for participation in the International PPB/ DICER1 or OTST Registry was obtained. When available, pathology was centrally reviewed. Staging was evaluated by Registry review using the International Federation of Gynecology and Obstetrics (FIGO) classification system. Results: Eighty-three patients with stage I SLCT were enrolled. Median age at diagnosis was 15 (range 1-60) years. Most (57/83) patients had germline DICER1 testing; 35/57 (61%) had germline pathogenic variants. Fifty-six patients had Ia and 27 had Ic SLCT. The distribution of patients receiving chemo based on histology and stage is displayed in Table. One patient with poorly differentiated stage Ia SLCT with sarcomatous elements and no chemo at diagnosis recurred 6 months after surgery and died of disease. Three patients with local diagnosis of stage Ia SLCT, with data unavailable for Registry confirmation of stage, developed a subsequent SLCT 33 to 74 months after diagnosis; of these, 2 died, and 1 remains in treatment for recurrence. Available records and molecular testing in these 3 cases have not provided a distinction between recurrent and metachronous disease. Excluding the latter 3 patients, 3-year overall survival was 97.3% for stage Ia SLCT. Six patients with stage Ic SLCT recurred (Stage Ic1=5 and Stage Ic2=1) with a median time to recurrence of 25 (range 3-53) months. In stage Ic1, 18% (2/11) recurred after upfront chemo compared to 33% (3/9) after surgery alone. Of the 5 patients with stage Ic1 disease that recurred, 4 had intermediate and 1 had poorly differentiated SLCT. One patient had sarcomatous elements and 2 received upfront chemo. Two of the 5 patients are alive, neither received upfront chemo. One patient with poorly differentiated stage Ic2 SLCT with sarcomatous elements and no upfront chemo recurred and died of disease. Three-year event free and overall survival were 86.9 and 88.6% for stage Ic SLCT. Four patients had metachronous SLCT in the contralateral ovary confirmed by clinical review or somatic testing at a median time from diagnosis of 33 (range 28-104) months. All 4 have germline pathogenic variants and no evidence of disease at last follow-up. Conclusions: Individuals with early stage SLCT generally fare well, however, ongoing surveillance for recurrence and metachronous disease is indicated. Novel therapies are needed to address recurrent SLCT.[Table: see text]
Next generation sequencing in ovarian cancer patients: Does personalized medicine improve oncological outcomes?
Authors: Safra Tamar , Hershkovizh Dov , Shachar Eliya , Adar Lyri , Brezis Miriam R. , Raviv Yuval , Galmor Lee , Peleg Hasson Shira 
Published: June 2021

5553 Background: Ovarian cancer (OC) is the second most common gynecologic malignancy and the most common cause of gynecologic cancer mortality in the United States. Homologous recombination deficiency (HRD), including the BRCA mutations, are found in 50% of OC tumors. Next generation sequencing (NGS) provides understanding the underlying molecular and genetic patterns to improve OC treatment. This study examines the prognostic and predictive biomarkers identified with NGS in hopes to improve OC patients outcomes. Methods: The patient cohort included 890 consecutive OC patients treated between 2002 and 2020,at the Tel-Aviv Medical Center. We retrospectively evaluated patients with histopathologically confirmed OC. Cox models were used to analyze the clinical impact of various mutations and biomarkers among OC patients with and without FoundationOne CDx NGS testing, by assessing overall survival (OS), progression free survival (PFS), and physicians' timing preferences for referral to NGS testing. Results: Among the 890 OC patients, 103 (11.57%) completed NGS molecular testing. The median OS among patients with and without NGS testing, adjusted for age, stage and recurrence status, was 73.36 and 68.50 months, respectively (P =.02). The median PFS was 17.23 and 17.43 months, respectively (P =.77). We also evaluated physicians' preferences regarding timing of molecular profiling, upon diagnosis, after first recurrence and at advanced line of treatment in 31.95%, 36.08% and 26.8% of practitioners, respectively. Of the patients who completed NGS, 48 (52.75%) harbored actionable mutations, and 21 patients (43.75%) received matched targeted therapy. Forty-five patients were microsatellite stable (MSS) (45%), 55 with undetermined status (55%) and 0 patients with MSI-H. Forty-one (71.93%) patients had low ( < 5) tumor mutation burden status (TMB), 16 (28.07%) intermediate (5-15) and none with high ( > 15) TMB. There was no noticeable survival difference when comparing low with intermediate TMB (P = 0.3). Loss of heterozygosity (LOH) was a significant prognostic biomarker. Patients with high LOH (hLOH > = 16%) had longer OS compared to low LOH (lLOH < 16%), 99.02 vs. 50.23 months, respectively (P <.005). Patients with hLOH and BRCA mutations (BRCA+) had longer OS compared to hLOH/BRCA WT (BRCA-), lLOH/BRCA+, and lLOH/BRCA-, with an unreached median OS of 91.5 vs. 60.48 vs. 45.21 months, respectively (P =.005). Conclusions: Our work demonstrates the clinical benefit of NGS personalized medicine as a cornerstone of future treatment strategies in OC. Our study suggests an OS benefit among the NGS tested cohort. We identified LOH as a prognostic biomarker. Prospective studies evaluating larger cohorts are necessary to generate a more extensive evaluation of additional prognostic and predictive biomarkers among OC patients.
Does aggressive surgery only benefit patients with less advanced ovarian cancer?
Authors: Tate Shinichi , Nishikimi Kyoko , Matsuoka Ayumu , Otsuka Satoyo , Shozu Makio 
Published: June 2021

5556 Background: The recent SCORPION trial showed that aggressive primary debulking surgery (PDS) did not improve survival outcomes in patients with advanced ovarian cancer and was associated with a high incidence of perioperative morbidity. We compared survival outcomes and morbidity between patients who underwent highly aggressive and less aggressive surgery at our hospital; patients with high tumor loads were treated with neoadjuvant chemotherapy (NACT), followed by aggressive surgery. Methods: This retrospective study included 209 patients with a surgical complexity score (SCS) ≥8, who underwent aggressive surgery between January 2008 and December 2018. PDS, followed by chemotherapy was performed in this study, and NACT followed by interval debulking surgery (IDS) was performed in patients with excessively high tumor loads, a poor general condition, or unresectable lesions in whom PDS was contraindicated. Based on the median SCS, patients were categorized into highly aggressive surgery and less aggressive surgery groups, and we performed an intergroup comparison of progression-free survival (PFS), overall survival (OS), and perioperative morbidity. Results: The median SCS was 13 in all cohorts. The less aggressive surgery group (SCS < 13) and the highly aggressive surgery group (SCS≥13) included 83 and 126 patients, respectively. The peritoneal cancer index in the highly aggressive surgery group was higher than that in the less aggressive surgery group (20 vs. 9). Notably, 52 patients (63%) underwent PDS in the less aggressive surgery group, and 104 patients (83%) underwent IDS after NACT in the highly aggressive surgery group. No intergroup difference was observed in patients without any residual disease (less aggressive surgery group: 74 patients [89%] vs. highly aggressive surgery group: 118 patients [94%], p = 0.245). The median PFS in the less- and highly aggressive surgery groups was 32 months (95% confidence interval [CI] 24–45) and 31 months (95% CI 27–34) (log-rank test, p = 0.622; Wilcoxon test, p = 0.926), respectively. The median OS in the less- and highly aggressive surgery groups was 99 months (95% CI 59–not reached) and 75 months (95% CI 56–106) (log-rank test, p = 0.390; Wilcoxon test, p = 0.799), respectively. Severe perioperative complications (Clavien-Dindo grade ≥IIIb) occurred in 4 patients (4.8%) and 8 patients (6.4%) in the less- and highly aggressive surgery groups, respectively (p = 0.767). Conclusions: Aggressive surgery benefits both patients with less advanced and advanced ovarian cancer. Selection of the optimal timing of debulking surgery may lead to better survival outcomes without an increase in perioperative morbidity in patients with high tumor loads, who undergo highly aggressive surgery.
Anlotinib in combination with TQB2450 in patients with recurrent ovarian cancer (ACTION): A multicenter, single-arm, open-label, phase Ib trial.
Authors: Lan Chunyan , Zhao Jing , Yang Fan , Li Rong , Huang Yu , Wang Jing , Zhao Weihong , Zhang Li , Liu Chang , Bi Xuehan , Jin Haihong , Meng Jin , Huang Xin 
Published: June 2021

5557 Background: Combination of antiangiogenic therapy and immune checkpoint inhibitor therapy is reported as an effective antitumor strategy. TQB2450 is a humanized IgG1 monoclonal antibody against programmed death-ligand 1 (PD-L1). We aimed to assess the activity and safety of TQB2450 plus the antiangiogenic multi-target tyrosine kinase inhibitor anlotinib in patients with recurrent advanced ovarian cancer. Methods: The study with ClinicalTrials.gov identifier NCT04236362 is an open-label, multicohort, and multicenter phase Ib trial evaluating the efficacy and safety of anlotinib combined with TQB2450 in patients with advanced gynecologic cancer. The present study (ACTION study) reports the ovarian cancer cohort. We enrolled patients aged 18–70 years with platinum-resistant or platinum-refractory epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, an Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST). Eligible patients received anlotinib 12 mg per day orally on days 1 to 14 and TQB2450 1200 mg intravenously on day 1, every three weeks. Treatment continued until disease progression, unacceptable toxicity, and withdrawal of consent. The primary endpoint was objective response rate (ORR) assessed by investigators according to RECIST version 1.1. Secondary endpoints included progression-free survival (PFS), duration of response (DOR), overall survival (OS) and safety. Results: Between 21 Feb 2020 and 15 Jan 2021, 33 patients with a median age of 55 years (range, 26-71) were enrolled and received study treatment. Patients had received at least once platinum-based chemotherapy, and the median number of previous chemotherapy lines was 3 (range, 1–6). 30.3% patients had bevacizumab therapy before enrollment. At data cutoff (15 Jan 2021), the median follow-up was 5.1 months (range, 0.1–10.8). In the 25 efficacy-evaluable patients, 13 of them achieved partial response, yielding the ORR of 52.0% (95% CI, 30.4%–71.6%). The median PFS was 6.7 months (95% CI, 4.5 months to not reached). The median duration of response and the median OS were not reached. The treatment-related grade 3 or 4 adverse events (AEs) occurred in 54.5% patients, and the most common ones were palmar-plantar erythrodysesthesia syndrome (21.2%) and hypertension (18.2%). The most potential immune-related AEs included grade 1 to 2 hypothyroidism (24.2%) and fatigue (9.1%). No treatment-related death was recorded. Conclusions: Anlotinib plus TQB2450 showed encouraging antitumor activity and tolerable toxicity in patients with recurrent advanced ovarian cancer. Clinical trial information: NCT04236362.
Correlation of HRD status with clinical and survival outcomes in patients with advanced-stage ovarian cancer.
Authors: Sims Travis T. , Sood Anil K. , Westin Shannon Neville , Fellman Bryan M. , Unke Jenna , Rangel Kelly M , Hilton Tyler , Fleming Nicole D. 
Published: June 2021

5568 Background: Nearly 50% of patients with high grade ovarian cancer (HGOC) harbor a germline or somatic mutation in BRCA1/BRCA2 or have tumors characterized by homologous recombination deficiency (HRD). HRD is associated with response to poly(ADP-ribose) polymerase inhibitors (PARPi) in HGOC. Although PARPi show great promise, there is interest in investigating how HRD status affects outcomes and can be used to objectively tailor other treatment strategies. We aimed to compare clinical and survival outcomes in HGOC stratified by HRD status. Methods: We performed a retrospective analysis of all advanced HGOC from April 2013 to June 2019. Patients were included if germline BRCA and HRD status was known. Clinical outcomes were analyzed and stratified by (1) germline BRCA+ (2) germline BRCA - and somatic BRCA/HRD+, or (3) BRCA-/HRD-. Progression free (PFS) and overall survival (OS) were estimated using Kaplan-Meier methods stratified by HRD status and modeled via Cox proportional hazards regression. Results: 1271 patients with advanced HGOC presented during the study period of which 187 met inclusion criteria. 106 patients had germline BRCA mutation, 26 somatic BRCA/HRD+, and 55 BRCA/HRD-. Patients who had HRD- tumor had older median age at diagnosis (63 vs. 54 and 60 years, p<0.001), white race (89% vs. 74% and 68%), non-serous histology (20% vs. 6% and 0%, p=0.04), required more NACT chemotherapy cycles (4 vs. 3 and 3 cycles, p=0.03), and less complete gross resection (R0) at tumor reductive surgery (TRS) (60% vs. 83% and 77%, p=0.02). Patients who had BRCA/HRD- tumor had worse PFS (14.9 months) compared to germline BRCA+ (23.5 months) or somatic BRCA/HRD+ (20.2 months, p<0.001). Patients with BRCA/HRD- disease also had worse OS (42.3 months) compared to germline BRCA+ (68.8 months) or somatic BRCA/HRD+ (69.2 months). Multivariate analysis for PFS revealed that age (HR 1.02, 95% CI 1.00-1.04), p=0.01), stage (HR 5.7, 95% CI 1.39-23.4, p=0.02), R0 resection at TRS (HR 0.41, 95% CI 0.21-0.83, p=0.01), and BRCA/HRD- status (HR 1.63, 95% CI 1.07-2.48, p=0.02) were significant factors impacting PFS. Multivariate analysis for OS revealed that age (HR 1.07, 95% CI 1.03-1.10, p<0.001) and R0 resection at TRS (HR 0.19, 95% CI 0.08-0.44, p<0.001) were significant factors impacting OS. Conclusions: Germline BRCA-mutant, somatic BRCA/HRD+ HGOC was associated with improved PFS and OS regardless of primary TRS or NACT. BRCA-/HRD- was a negative prognostic factor for survival in HGOC.