bluuebunny/crossref_metadata_2025_split huggingface dataset:
Progression-free survival (PFS) and second PFS (PFS2) by disease stage in patients (pts) with homologous recombination deficiency (HRD)-positive newly diagnosed advanced ovarian cancer receiving bevacizumab (bev) with olaparib/placebo maintenance in the phase III PAOLA-1/ENGOT-ov25 trial.
Authors: Pautier Patricia , Harter Philipp , Pisano Carmela , Cropet Claire , Hernando Polo Susana , Berger Regina , Matsumoto Takashi , Vergote Ignace , Colombo Nicoletta , Noettrup Trine Jakobi , Garnier Georges , Hillemanns Peter , Zamagni Claudio , Gonzalez Martin Antonio , Lefeuvre-Plesse Claudia , Denschlag Dominik , Lortholary Alain , Sehouli Jalid , Selle Frederic , Ray-Coquard Isabelle Laure 
Published: June 2021

5514 Background: In the Phase III PAOLA-1/ENGOT-ov25 trial (NCT02477644), the addition of maintenance olaparib to bev in pts with newly diagnosed advanced high-grade ovarian cancer (HGOC) resulted in a significant PFS benefit, particularly in HRD-positive (HRD+) pts (hazard ratio [HR] 0.33; 95% CI 0.25–0.45) (Ray-Coquard et al. NEJM 2019). We explored efficacy in HRD+ pts by disease stage. Methods: Pts with newly diagnosed, FIGO stage III–IV HGOC in response after platinum-based chemotherapy + bev received bev (15 mg/kg q3w for 15 months [mo]) + either olaparib (300 mg bid for 24 mo) or placebo (pbo). This exploratory analysis evaluated PFS (data cut-off [DCO]: Mar 22 2019) and PFS2 (DCO: Mar 22 2020) in HRD+ pts (tumor BRCA1/ BRCA2 mutation [tBRCAm] or genomic instability score [Myriad myChoice HRD Plus] ≥42) by FIGO stage. Results: 387/806 randomized pts (48%) were HRD+; 272/387 (70%) had stage III disease and 115/387 (30%) had stage IV disease. 153 (56%) HRD+ stage III pts and 61 (53%) HRD+ stage IV pts had a tBRCAm. Among HRD+ stage III pts, 172 (63%) had upfront surgery (51/172 [30%] had residual disease) and 90 (33%) had interval surgery (19/90 [21%] had residual disease); 52 (45%) HRD+ stage IV pts had upfront surgery (34/52 [65%] had residual disease) and 55 (48%) had interval surgery (18/55 [33%] had residual disease). Median follow-up for PFS and PFS2 was respectively 24.8 and 37.2 mo in HRD+ stage III pts and 24.0 and 37.0 mo in HRD+ stage IV pts. Median PFS, PFS2 and HRs are in the Table. Among HRD+ stage III pts, 36-mo PFS2 (olaparib + bev vs pbo + bev) was 74% vs 60%; among HRD+ stage IV pts, 53% vs 30%. Among HRD+ stage III pts with no residual disease after upfront surgery, HR (95% CI) for PFS was 0.15 (0.07–0.30) and for PFS2 was 0.22 (0.06–0.67). Among HRD+ stage III pts with residual disease after upfront surgery or who received neoadjuvant chemotherapy, or HRD+ stage IV pts, HR (95% CI) for PFS was 0.38 (0.27–0.53) and PFS2 was 0.68 (0.46–1.03). Conclusions: In the PAOLA-1 study, maintenance olaparib + bev provided a PFS and PFS2 benefit over pbo + bev in HRD+ pts, irrespective of FIGO stage and residual disease after upfront surgery. Clinical trial information: NCT02477644. [Table: see text]
Niraparib efficacy and safety in patients with BRCA mutated (BRCAm) ovarian cancer: Results from three phase 3 niraparib trials.
Authors: Gonzalez Martin Antonio , Matulonis Ursula A. , Korach Jacob , Mirza Mansoor Raza , Moore Kathleen N. , Gupta Divya , Lechpammer Stanislav , Monk Bradley J. 
Published: June 2021

5518 Background: Niraparib has been approved for the maintenance treatment of patients with advanced ovarian, fallopian tube, or primary peritoneal cancer after front-line chemotherapy (CT) and in the recurrent setting. Here, we summarize niraparib efficacy and safety in patients with BRCAm OC across three phase 3 trials: PRIMA/ENGOT-OV26/GOG-3012 (PRIMA; NCT02655016), ENGOT-OV16/NOVA (NOVA; NCT01847274), and NORA (NCT03705156). Methods: Patients enrolled in the PRIMA trial had newly diagnosed advanced ovarian, fallopian tube, or primary peritoneal cancer. All patients had stage III or IV high-grade serous or endometrioid tumors and had a complete or partial response to their first-line platinum-based CT treatment. Subgroup analysis by tumor BRCAm status was prespecified. Patients enrolled in the NOVA and NORA studies had platinum-sensitive, high-grade serous ovarian, fallopian tube, or primary peritoneal cancer. Patients had already received at least 2 lines of platinum-based CT regimens. In both studies, subgroup analysis by germline BRCAm status was prespecified. The primary endpoint in all trials was progression-free survival (PFS) by blinded independent central review. Results: The BRCAm populations from each trial are as follows: 223 (148 BRCA1m and 75 BRCA2m) from the PRIMA trial, 203 (128 BRCA1m, 69 BRCA2m, and 13 BRCA1/2m) from the NOVA trial, and 100 (78 BRCA1m, 21 BRCA2m, and 1 BRCA1/2m) from the NORA trial. PFS results are shown in the Table. Across the 3 trials, the most common treatment-emergent adverse events were thrombocytopenia, anemia, neutropenia, and hypertension. Conclusions: Patients with BRCAm OC derived a significant PFS benefit from niraparib maintenance treatment across all 3 trials. No new safety signals were identified. Clinical trial information: NCT02655016, NCT01847274, NCT03705156. [Table: see text]
Anlotinib plus pemetrexed as a further treatment for patients with platinum-resistant ovarian cancer: A single-arm, open-label, phase II study.
Authors: Chen Jueming , Wei Wei , Zheng Lie , Li Han , Feng Yanling , Wan Ting , Qiu Jiaqi , Jiang Xingyu , Xiong Ying , Zheng Min , Li Jundong , Huang He , Song Libing , Liu Jihong , Zhang Yanna 
Published: June 2021

5533 Background: Non-platinum chemotherapy is widely used in platinum-resistant recurrent ovarian cancer treatment but with limited efficacy. Combing chemotherapy with angiogenic inhibitors is a new therapeutic choice. Anlotinib is a novel tyrosine kinase inhibitor targeting multiple receptors involved in tumor proliferation, vasculature, and tumor microenvironment. The study aimed to further assess the efficacy and safety of anlotinib combined with pemetrexed in platinum-resistant ovarian cancer. Methods: Patients who had received at least two different chemotherapy regimens (including the first line platinum-based regimen), with histologically proven recurrent platinum-resistant or platinum-refractory epithelial ovarian cancer (including salpingocarcinoma and peritoneal carcinoma), ECOG 0-2, were considered eligible for enrollment to receive six 21-days cycles of anlotinib (12 mg QD from day 1 to 14; 21 days per cycle) orally plus pemetrexed intravenously (0.5 g/m2 on day 1; 21 days per cycle). Subsequent maintenance treatment was anlotinib monotherapy (12 mg QD from day 1 to 14; 21 days per cycle) till disease progression or intolerant toxicity. The primary endpoint was objective response rate (ORR), and the secondary endpoints included disease control rate (DCR), progression-free survival (PFS) and safety. Results: As of Jan 2021, 27 patients were enrolled. The median number of chemotherapy was 4 (range, 2-10) and 51.9% (14/27) of patients had ever received antiangiogenic therapy. The ORR was 36.4% (partial response (PR) in 8 patients; 95% CI, 17.2-59.3). The DCR was 100.0% (PR in 8 patients and stable disease (SD) in 14 patients; 95% CI, 73.5-100). The median time of the first response was 1.6 months (range, 1.3-4.4). The median PFS was 9.3 months (95% CI, NE-NE). Furthermore, the ORR of patients with and without prior antiangiogenic therapy was 16.7% (95%CI, 2.1-48.4) and 60.0% (95%CI, 26.2-87.8) respectively (P = 0.074). Any grades of adverse events (AEs) were observed in 92.6% (25/27) of patients, containing allergic eruption (33.3%), hand-foot syndrome (29.6%), hypertension (25.9%), and fatigue (25.9%). The grade 3-4 adverse events were only observed in 5 patients, including 1 with grade 3 proteinuria, 1 with grade 3 ascites, 1 with grade 3 fatigue, 1 with grade 3 edema limbs and 1 with grade 4 anemia. Conclusions: The treatment of anlotinib plus pemetrexed showed a promising antitumor activity with tolerable toxicity for patients in platinum-resistant and refractory ovarian cancer. Clinical trial information: ChiCTR2000029654.
Efficacy of niraparib maintenance therapy in Chinese women with platinum-sensitive recurrent ovarian cancer with and without secondary cytoreductive surgery: Results from the NORA trial.
Authors: Wu Lingying , Wu Xiaohua , Zhu Jianqing , Yin Rutie , Yang Jiaxin , Liu Jihong , Wang Jing , Liu Ziling , Gao Yunong , Wang Danbo , Lou Ge , Yang Hongying , Zhou Qi , Kong Beihua , Huang Yi , Chen Lipai , Li Guiling , An Ruifang , Tan Tao , Dong Juan 
Published: June 2021

5534 Background: NORA is the first, phase III, randomized controlled trial (RCT) that demonstrated individualized starting dose regimen of niraparib, which significantly improved PFS in Chinese patients with platinum-sensitive recurrent ovarian cancer (PSROC). This sub-group analysis evaluated the efficacy of niraparib maintenance therapy with and without secondary cytoreductive surgery (SCS) in PSROC. Methods: The NORA phase III RCT included adult (≥18 years) Chinese women with PSROC who were randomized in a 2:1 ratio to receive oral niraparib (n = 177) or matched placebo (n = 88). This retrospective subgroup analysis was based on the progression-free survival (PFS) of niraparib maintenance therapy in these two groups of patients with PSROC, patients with SCS, and patients without SCS. The PFS was assessed by blinded independent central review. The Kaplan-Meier (KM) estimator and log-rank test were performed to calculate the median PFS time. Results: Of the 265 evaluable patients, 69 (26.0%) patients received the SCS (niraparib, n = 48; placebo, n = 21), and 196 (74.0%) patients were without SCS (niraparib, n = 129; placebo, n = 67). Among patients with and without SCS, baseline characteristics for BRCA mutation were 26.1% vs 41.8%, complete response to last platinum-based chemotherapy were 68.1% vs 43.9%, time (6-12 months) to progression after penultimate therapy were 23.2% vs 34.7%, respectively. Treatment with niraparib led to a significant reduction of risk to disease progression compared with placebo in patients with SCS (Hazard ratio [95% CI]: 0.32 [0.13–0.78]; P = 0.0102) and without SCS (0.34 [0.23–0.50]; P< 0.001). Moreover, in the subgroups of patients who received SCS, niraparib maintenance therapy had a significantly longer PFS compared with placebo (Median [95% CI]: not reached [18.33 – not estimable] vs 5.75 months [3.68 – not estimable]; P = 0.0102). This trend was also similar in the subgroup of patients who did not receive SCS (Median [95% CI]: 10.28 months [7.49 – 18.37] vs 4.90 months [3.71 – 5.52]; P < 0.0001). Conclusions: The results from this retrospective sub-group analysis revealed that niraparib maintenance therapy provided significant clinical efficacy in patients with PSROC, irrespective of SCS. Clinical trial information: NCT03705156.
Patient care and clinical trials in gynecological oncology: Implications of the COVID-19 pandemic.
Authors: Nasser Sara , Fotopoulou Christina , Guktekin Murat , Dimitrova Desislava , Morice Philippe , Sehouli Jalid 
Published: June 2021

5564 Background: This is a prospective international Survey to evaluate the impact of the COVID-19 Pandemic on the management of patients with gynecological malignancies from the multidisciplinary physicians' perspective, with particular focus on clincial infrastructures, and trial participation. Methods: The anonymous online survey consisted of 53 COVID-related questions. It was sent to all healthcare professionals in gynaecological oncology centres across Europe and the Pan-Arabian region from April 2020 to October 2020. All healthcare professionals treating women with gynecological cancers were able to participate in the survey. Results: A total of 243 answers were collected from 30 different countries. The majority (73%) of participants were gynecological oncologists from university hospitals(71%) with at least an Intensive care unit with cardiopulmonary support available at their institutions. Most institutions continued to perform elective surgeries only for oncological cases (98%). Patients had to wait on average 2 weeks longer for their surgery appointments compared to previous years(range 0-12 weeks). Cases that were prioritised for surgical intervention across all tumors (Ovarian, Endometrium, Cervical) were early stage disease (74%), primary situation (61%), and good ECOG status (63%). The radicality of surgery did not change in the majority of cases (78%) across all tumor types. During the pandemic, only 38% of clinicians stated they would start a new clinical trial. 45% stated the pandemic has negatively impacted the financial structure and support for clinical trials. 79% do not routinely screen patients included in trials for SARS CoV2. Overall, approx. 20% of clinicians did not feel well informed regarding clinical pathways for COVID-19 patients throughout the pandemic. The majority preferred regular updates and training via Webinars (75%), followed by tumorboards and interdisciplinary conferences (45%). 30% of clinicians stated that they are currently experiencing difficulties in providing adequate medical care due to staff shortage. Conclusions: Despite well-established guidelines for patient care and performing clinical trials in gynecological oncology, the COVID-19 pandemic has impacted clinical research, and financial structures. Longer waiting times for operative interventions, less support for clinical trials and concerns regarding provision of adequate medical care and triaging patients are very real. This survey underlines the necessity for building robust emergency algorithms tailored to gynecological oncology patients in the future.
HER2 in uterine serous carcinoma: Testing platforms and implications for targeted therapy.
Authors: Klc Tenley , Wu Sharon , Wilhite Annelise M. , Jones Nathaniel L. , Powell Matthew A. , Olawaiye Alexander , Simpkins Fiona , Girda Eugenia , Brown Jubilee , Puechl Allison , Ali-Fehmi Rouba , Winer Ira Seth , Herzog Thomas J , Korn Wolfgang Michael , Erickson Britt Kristina 
Published: June 2021

5580 Background: HER2 is an emerging prognostic and therapeutic target in uterine serous carcinoma (USC). Testing algorithms and platforms in breast and gastric cancers are well studied and validated, but optimal HER2 testing in uterine cancer is not yet established. We aimed to assess the concordance of chromogenic in situ hybridization (CISH), immunohistochemistry (IHC), and next generation sequencing (NGS) platforms to aid in the development of USC specific testing guidelines. We also evaluated the rate of downstream mutations that may affect response to HER2 directed therapy. Methods: A total of 2,192 USC tumors were analyzed using NGS (NextSeq, 592 Genes and WES, NovaSEQ), a subset of 1,423 tumors were also tested by IHC and CISH (Caris Life Sciences, Phoenix, AZ). HER2 positivity through IHC (4B5, Ventana) and CISH (INFORM DUAL HER2 ISH Assay, Ventana) was determined based on 2007 and 2018 ASCO/CAP HER2 breast cancer guidelines. PD-L1 expression was tested by IHC using SP142 (Spring Biosciences) (positive cut-off >1%). Microsatellite instability (MSI) was tested by fragment analysis (FA), IHC and NGS. Tumor mutational burden (TMB) was measured by totaling somatic mutations per tumor (TMB-high cut-off > 10 mutations per Mb). Statistical significance was determined using chi-square. Results: Rates of HER2 positivity were comparable using the 2018 and 2007 breast cancer guidelines (19.5% vs 17.5%; p=0.25). Based on 2018 guidelines, the concordance between IHC and CISH was 98.9%. Specifically, 229/1423 patients (16%) were IHC+/CISH+, 5 patients (0.4%) were IHC+/CISH- and 11 patients (0.8%) were IHC-/CISH+ (Table). Common pathway alterations in HER2+ USC include TP53, RTK RAS, PI3K, NOTCH, chromatin remodeling and cell cycle genes. Single gene alterations in HER2+ tumors that may implicate HER2 therapy resistance (based on pathway analyses in other tumor types) included PI3K (36%), KRAS (2.6%), and PTEN (2.1%). HER2+ tumors had low immunotherapy biomarker profiles (0.3% MSI-H, 0.8% TMB, 17.1% PD-L1). Conclusions: High concordance rates were observed between CISH and IHC. Ultimately these testing platforms need to be validated by response to HER2 targeted therapies in order to develop USC specific HER2 testing guidelines.[Table: see text]
Potential impact of HPV vaccine on incidence of high-grade vulvar, vaginal, and anal precancers among females and males aged 15 to 39 years, United States 2000 to 2017.
Authors: Saraiya Mona , Senkomago Virginia 
Published: June 2021

5594 Background: Since introduction of HPV vaccine, cervical precancers have decreased, but the vaccine’s impact on non-cervical anogenital precancers is unknown. These precancers are identified opportunistically and are not routinely collected in most cancer registries. Methods: We examined high-grade vulvar (VIN3), vaginal (VAIN3), and anal (AIN3) precancers among persons aged 15-39 years using 2000-2017 data from select cancer registries covering 27.8% of the U.S. population. Incidence trends were evaluated with Joinpoint regression. Results: VIN3 rates declined 21% per year post-HPV vaccination introduction among women. VAIN3 rates declined 19.1% per year among women aged 15-29 years, also post-HPV vaccination introduction. Compared to the pre-vaccination period when AIN3 rates were increasing, AIN3 rates were stable among women aged 15-29 years and among men aged 30-39 years. Conclusions: Decreases in rates of VIN3 and VAIN3 after HPV vaccine introduction among younger age groups were similar to declines observed in cervical precancers, suggesting HPV vaccine impact.
Impact of different sequencing strategies of talazoparib and carboplatin combination upon efficacy and toxicity in BRCA-wild type and BRCA-mutant triple-negative breast cancer models.
Authors: Beniey Michele , Cotte Alexia , Hubert Audrey , Bechir Nelly , Haque Takrima , Tran-Thanh Danh , Hassan Saima Noor 
Published: June 2021

586 Background: PARP inhibitors (PARPi) such as talazoparib and olaparib, have demonstrated an improvement in progression-free survival (PFS) amongst metastatic HER2-negative breast cancer patients with germline mutations in BRCA1/2 (BRCA-MUT). Clinical trials have evaluated PARPi in combination with carboplatin, but with mixed results. Earlier trials studied the combination of carboplatin and a low-dose PARPi of low potency, veliparib. The concomitant combination of carboplatin and talazoparib, a higher-potency PARPi, was also evaluated in solid tumors, using a heavily pre-treated population. Here, we perform a comparative evaluation of different sequencing strategies of talazoparib and carboplatin to determine efficacy and toxicity in BRCA-MUT and BRCA wild-type (WT) TNBC models. Methods: We used three orthotopic xenograft models in NSG (NOD scid gamma) mice, with 7-14 mice in each treatment group: MDAMB231 (BRCA-WT), HCC1806 (BRCA-WT), and MX1 (BRCA-MUT). We treated mice with carboplatin (C) (35 mg/kg intraperitoneally) in combination with talazoparib (T) (0.33 mg/kg oral gavage) using 2 dosing strategies: a) concomitant administration of C + T; and b) T first, followed by C three days later, each compared to vehicle control. We evaluated primary tumor inhibition and hematologic toxicity. Kruskal-Wallis test and Dunn’s multiple comparison test was used to assess statistical significance. Results: Using the MDAMB231 xenograft, we found the T-first approach led to a 66.7% (P < 0.0001), and the concomitant approach resulted in a 51.4% decrease in primary tumor volume, (P = 0.08), in comparison to control. In HCC1806, the T-first approach resulted in a 62.0% decrease in tumor volume (P < 0.0001), whereas the concomitant combination showed a 54.4% decrease (P = 0.002). In MX1, the T-first and concomitant approaches resulted in 72.7% (P < 0.0001) and 81.4% (P < 0.0001) decrease in tumor volume, respectively. With regards to neutrophil counts, T-first approach decreased neutrophils by 66.2% and 43.0% in MDAMB231 and HCC1806 xenografts respectively, similar to the trend with concomitant T + C: 61.4% and 38.0%. In the MX1 cohort, the T-first approach resulted in a 66.2% decrease in neutrophils (P = 0.001), and the concomitant approach led to a 77.5% decrease in neutrophils (P = 0.006). Conclusions: Our results demonstrate that the talazoparib-first approach is effective in two BRCA-WT models with no statistically significant neutropenia. While the concomitant combination approach demonstrated greater tumor inhibition in the BRCA-MUT model, this was also associated with significant neutropenia. This is suggestive that sequencing of talazoparib and carboplatin may have differential effect in BRCA-WT and BRCA-MUT tumors and may play an important role in improving efficacy in BRCA-WT tumors.
The association of skeletal muscle mass and cisplatin pharmacokinetics in head and neck cancer patients: The prospective PLATISMA study.
Authors: Molenaar-Kuijsten Laura , Chargi Najiba , Devriese Lot , de Bree Remco , Huitema Alwin 
Published: June 2021

6021 Background: Locally advanced head and neck squamous cell carcinoma (HNSCC) is commonly treated with cisplatin-based chemoradiotherapy (CRT). Cisplatin is associated with severe toxicity, which negatively affects survival. In recent years, a relationship between low skeletal muscle mass (SMM) and toxicity has been described. This increased toxicity may be related to an altered cisplatin distribution and binding in the fat-free body mass, of which SMM is the largest contributor. This study aims to investigate the association between cisplatin pharmacokinetics and SMM in HNSCC patients. Methods: We performed a prospective observational study in HNSCC patients treated with CRT with cisplatin. Patients received standard-of-care chemotherapy with three cycles of cisplatin, at a dose level of 100 mg/m2 per cycle. Quantitative data on body size descriptors including SMM, measured on computed tomography scans, and cisplatin pharmacokinetics (total and ultrafilterable plasma concentration) were collected, as well as data on toxicity. Results: 45 evaluable patients were included in the study. A large proportion of the study population had a low SMM (46.7%). The majority of patients (57.8%) experienced cisplatin dose limiting toxicities. Pharmacokinetic analysis showed a significant relationship between cisplatin pharmacokinetics and the body size descriptors SMM, weight, fat-free mass, and body surface area ( p< 0.005). In a simulation, patients with a low SMM were predicted to reach higher bound cisplatin concentrations. The higher concentration of bound cisplatin could be seen as a reflection of the smaller volume of distribution, and could thereby explain the increased toxicity in patients with a low SMM. Conclusions: We found an association between cisplatin pharmacokinetics and SMM. Patients with a low SMM were predicted to reach higher bound cisplatin concentrations, which could be an explanation for the increased toxicity in this patient group. Clinical trial information: Trial NL7469 (NTR7711).