bluuebunny/crossref_metadata_2025_split huggingface dataset:
Feasibility of an adapted schedule of carboplatin plus paclitaxel in elderly women with advanced ovarian cancer: A retrospective cohort.
Authors: Nicaise Benjamin , Mebarki Soraya , Gisselbrecht Mathilde , Ashton Elisabeth , Azais Henri , Koual Meriem , Bats Anne-Sophie , Fournier Laure , Le Frère - Belda Marie-Aude , Medioni Jacques , Paillaud Elena , Oudard Stephane , Delanoy Nicolas 
Published: June 2021

5546 Background: The EWOC-1 trial compared Carboplatin monotherapy (C mono) to two different Carboplatin + Paclitaxel (CP) regimens (weekly or 3-weekly) in vulnerable elderly patients treated for advanced ovarian cancers (OC). This study was closed prematurely because of a worse outcome in the C mono group. Both CP regimens were equivalent in terms of feasibility and efficacy with different toxicity profiles. Optimal CP regimen in elderly patient is still unknown. Here we propose a study of another adapted regimen of CP (aCP) performed in elderly patients in our institution. Methods: We retrospectively analyzed OC patients ≥ 70 years who received a Carboplatin AUC 4-5 d1q3week + Paclitaxel 80 mg/m² d1-d8 q3week regimen between 2015 and 2019. Primary endpoint was treatment feasibility according to the EWOC-1 standard: completion of 6 courses of chemotherapy without early stopping for disease progression, death or unacceptable toxicity (adverse event (AE) related to chemotherapy or treatment procedure leading either to early treatment stopping, to an unplanned hospital admission or to death or to a dose delay lasting more than 14 days or more than 2 dose reductions). Results: We identified 36 pts with a median age of 79 years (table). All patient but one had an ONCODAGE-G8 score ≤ 14, 30.6% of patients had a comorbidity Charlson’s index > 4 and 52.5% had an albumin rate < 35 g/L. The feasibility endpoint was met in 58.3% of patients (IC95% = [25.6; 57.8]). Main causes of treatment failure (TF) were early discontinuation because of toxicity in 6 patients (16.7%) and progressive disease in 3 patients (8.33%). Median PFS was 35.3 months (IC95% = [22.7; NR]) and median OS was 62.1 months (IC95% = [31.4.0; NR]). The most frequent AE were asthenia (all grades = 94.4%, grade 3-4 = 13.9%), anemia (all grades = 94.4%, grade 3-4 = 27.8%), neutropenia (all grades = 66.7%, grade 3-4 = 38.9%) and neuropathy sensory (all grades = 61.1%, no grade 3-4). Non high-grade-serous histological type and a poor Charlson’s score were associated with a higher rate of TF (100% and 63.6%, respectively). Conclusions: These results are consistent with the findings of the EWOC-1 trial in both CP regimens and suggest that aCP could be non-inferior with an acceptable toxicity profile. Further prospective and comparative studies are mandatory to confirm this trend and to better identify predictive factors of TF in OC elderly patients.[Table: see text]
Dysregulation of soluble immune checkpoint proteins in newly-diagnosed early breast cancer patients.
Authors: Rapoport Bernardo Leon , Steel Helen C , Smit Teresa , Heyman Liezl , Theron Annette J , Hlatswayo T Nomsa , Kwofie Luyanda LI , Benn Carol , Anderson Ronald 
Published: June 2021

556 Background: Checkpoint proteins regulate the immune system. Breast cancer (BC) cells exploit the up-regulation or down-regulation of these proteins to evade anti-tumor immune responses. Soluble forms of immune checkpoint molecules (ICM) can be measured in human plasma, however their biological and clinical significance remains essentially unknown. The aim of the present analysis was to measure the pre-treatment ICM in newly- diagnosed BC patients (pts) and compare them to healthy controls. Methods: Soluble forms of ICM, as well as cytokines and chemokines, were measured using Multiplex bead array and ELISA technologies. Plasma samples from 98 BC pts and 45 healthy controls were analyzed for each protein. Data was prospectively obtained. Measured levels were compared between BC pts and healthy controls using a non-parametric test (Mann-Whitney). P-values below 0.05 were considered statistically significant. Results: Soluble stimulatory molecules GITR (p < 0,000002), GITRL (p < 0,007), CD27 (p < 0,002), CD28 (p < 0,003), CD40 (p < 0,003), CD80 (p < 0,009), ICOS (p < 0,0006), as well as inhibitory molecules PD-L1 (p < 0.0000001), CTLA-4 (p < 0,005), TIM-3 (p < 0,00006), HVEM (p < 0,00002) TLR-2 (p < 0,05), levels were significantly lower in early BC pts compared to healthy controls. When analyzed according to BC characteristics (TNBC vs. non-TNBC, tumor size, stage, nodal status and age) no significant difference was detected between the soluble levels of these ICM between the different subsets. Additionally, serum CXCL5 (p < 0,000001), CCL23 (p < 0,04), IL-16 (p < 0,00005), interferon-α (p < 0,03) and IL1-RA (p < 0,03) were significantly lower compared to healthy controls. Serum CX3CL1 or fractalkine (p < 0,024465) was significantly higher compared with healthy controls. Serum interferon-γ (p < 0,2), IL-6 (p < 0.6) and IL-2 (p < 0.6) levels were not significantly different between the BC pts and the healthy controls. Conclusions: We identified low levels of both the stimulatory and inhibitory immune checkpoint molecules, in newly-diagnosed, non-metastatic BC pts compared to healthy controls. These results indicate that early BC is associated with a down-regulation of both soluble stimulatory and inhibitory immune-checkpoint pathways. Newly-diagnosed early BC pts have a generalized immune-suppression independent of subtype (TNBC vs non-TNBC) and stage, which, to our knowledge, is the first study to describe soluble immune checkpoints in early BC pts.
Outcomes of ovarian cancer patients treated with platinum or non-platinum based chemotherapy after PARP inhibitor maintenance.
Authors: Brann Ralynn , Kremer Kevin Michael , Carlson Matthew , LoCoco Salvatore , Lea Jayanthi Sivasothy , Miller David Scott , Lee Jessica 
Published: June 2021

5563 Background: PARP inhibitors (PARPi) are approved for maintenance treatment of platinum sensitive ovarian cancers either after front-line therapy or after treatment for recurrence. Current recommendations include retreatment with platinum-based chemotherapy (PC) after progression on maintenance PARPi. There exists a theoretical concern that progression of disease (POD) on PARPi is indicative of the development of platinum resistance due to similar DNA targets of platinum chemotherapy and PARPi. Our objective was to evaluate the response to subsequent chemotherapy in patients who progressed on PARPi maintenance. Methods: All patients with ovarian, fallopian tube, or primary peritoneal cancer treated with PARPi treatment from 2017 to 2021 at two academic tertiary care centers were retrospectively identified. Patients were assessed for treatment time on PARPi, time to POD on PARPi (PFS), type of chemotherapy regimen following PARPi maintenance, and time to disease progression on subsequent therapy following PARPi (PFS2). Comparative statistical analyses were performed with appropriate two-sided statistical tests. Time to progression on chemotherapy after PARPi was calculated using the Kaplan-Meier method. Results: A total of 83 ovarian cancer patients treated with PARPi were identified, and of these, 61 (73.5%) were treated with PARPi in the maintenance setting. Among the patients treated with PARPi maintenance, 22 (36.1%) remain on treatment. 19 (31.1%) patients were started on PARPi maintenance after front-line chemotherapy. While on PARPi maintenance, 63.9% discontinued PARPi, the majority due to POD, and 26.2% due to patient intolerance of side effects. Following POD, 21/29 (72.4%) received subsequent PC and 8/29 (27.6%) received non-platinum based chemotherapy (NPC). Treatment time, PFS, and PFS2 are listed in Table. Of the patients who received PC, 14/21 (66.7%) had a PFS2 of over six months and 5/21 (23.8%) had a PFS2 of over 12 months. Of the patients who received NPC, 7/8 (87.5%) had a PFS2 of over six months and 2/8 (25.0%) had a PFS2 of over 12 months. Conclusions: Following POD on PARPi, patients responded to both PC and NPC. Time to progression on subsequent chemotherapy after treatment with PARPi does not differ significantly between PC and NPC regimens. Many patients continue to see benefit from PC after PARPi maintenance. Retreatment with PC following POD on PARPi maintenance should still be considered.[Table: see text]
Assessment of predictive biomarker prevalence in molecularly defined adult-type ovarian granulosa cell tumors.
Authors: Hillman Robert Tyler , Lin Douglas I. , Gershenson David Marc 
Published: June 2021

5567 Background: The FDA has separately approved pembrolizumab for all advanced solid tumors with either microsatellite instability or high tumor mutational burden (≥10 mutations per megabase), and homologous recombination deficiency is an established biomarker for response to poly ADP ribose polymerase inhibitors in epithelial ovarian cancer. The detection of these predictive biomarkers in adult-type ovarian granulosa cell tumors could identify novel treatment strategies in this rare disease. The primary objective of this study was to determine the prevalence of established predictive biomarkers among molecularly defined adult-type ovarian granulosa cell tumors. Methods: With institutional review board approval, we performed a cross-sectional study examining de-identified FoundationOne companion diagnostic molecular profiles for 423 women with molecularly defined (FOXL2 c.C402G positive) adult type ovarian granulosa cell tumors. The dataset was comprised of coding variants for up to 406 genes as well as genomic signatures including microsatellite instability, tumor mutational burden, and genome wide loss of heterozygosity. PD-L1 expression by immunohistochemistry was also available for a subset of tumors. Descriptive statistics were used for comparison between groups and all statistical tests were two-sided. Results: Women in this cohort had a mean age of 57 years (range 24-87) at the time of sample submission for molecular profiling. The median tumor mutational burden was 1.3 mutations per megabase [mut/Mb] (range 0-8.8 mut/Mb). TP53-mutated aGCT had a higher tumor mutation burden than TP53 non-mutated tumors (median 2.4 mut/Mb, 95% CI 1.7-3.0 mut/Mb vs median 1.3 mut/Mb, 95% CI 1.5-1.9 mut/Mb; P=.02). All 384 tumors with available microsatellite instability testing were microsatellite stable. Sixty-seven tumors had PD-L1 expression measured and of these 94% (63/67) were negative with the remainder “low positive.” No tumors were positive for genome wide loss of heterozygosity. Apart from FOXL2 c.C402G, the most frequent short variants were TERT promoter mutations (-124C>T: 190/423, 45.0%; -146C>T: 39/423, 9.2%). Other frequently observed variants included truncating mutations in KMT2D/MLL2 (71/423, 16.8%), pathogenic TP53 mutations (35/423, 8.3%), CDKN2A/B deletions (43/423, 10.2%), and activating PIK3CA mutations (23/423, 5.4%). Conclusions: No women with molecularly defined adult-type ovarian granulosa cell tumors in this large cross-sectional study would be eligible for FDA-approved pembrolizumab based on either microsatellite instability or high tumor mutational burden. No tumors exhibited evidence of homologous recombination deficiency and molecularly targetable mutations were rare. The development of novel precision treatment options remains a critical unmet need for this rare disease.
Final results of phase 1 evaluation of the safety and clinical activity of sapanisertib in combination with serabelisib and paclitaxel in patients with advanced ovarian, endometrial, or breast cancer.
Authors: Starks David , Rojas-Espaillat Luis Alexander , Dey Nandini , De Pradip , Leyland-Jones Brian , Williams Casey B. 
Published: June 2021

5569 Background: Evidence suggests that activation of the PI3K/AKT/mTOR pathway by paclitaxel may play a role in the development of taxane resistance. Conversely, PI3K inhibitors have been shown to sensitize tumors to the effects of paclitaxel. Therefore, the link between taxane resistance and activation of the PI3K/AKT/mTOR signaling pathway suggests inhibition of this pathway in combination with antimitotic drugs like paclitaxel may improve treatment outcomes in many malignancies. To further investigate this hypothesis we combined the TORC 1/2 inhibitor sapanisertib (TAK-228), the PI3Kα isoform inhibitor serabelisib (TAK-117), and paclitaxel in a phase I trial of heavily pretreated patients to determine the safety, efficacy, and RP2D. Methods: This is an open label, cohort study of sapanisertib (TAK-228) and serabelisib (TAK-117) given on days 2-4, 9-11, 16-18, and 23-25 with paclitaxel on days 1, 8, and 15 of a 28-day cycle. A traditional 3+3 dose escalation design with a maximum of 5 dosing cohorts was used. All 5 cohorts plus an expansion cohort are presented. Results: Enrollment has been completed and the overall results are summarized. Nineteen patients were enrolled; the majority were heavily pretreated with the average number of prior regimens exceeding 4. Based upon ITT, the ORR is 37%. The ORR is 47% in patients that completed at least 3 cycles. The clinical benefit rate is 73% and the PFS currently stands at approximately 11 months. Two patients with endometrioid endometrial adenocarcinoma achieved a complete response. All patients received comprehensive genomic profiling and 7 patients received prior mTOR inhibitor. Overall, the combination was well tolerated, except by patients in cohort 5. One DLT occurred in the last patient enrolled. The most common non-laboratory AEs were nausea (6%), fatigue (5%), and mucositis (5%). There were 45 (9%) grade 3 or 4 events, and the most common were decreased WBC and non-febrile neutropenia. Hyperglycemia was common in patients with a history of diabetes mellitus. Conclusions: Overall, the combination of sapanisertib, serabelisib, and paclitaxel was safe and efficacious throughout the first 4 cohorts. There were few serious adverse events, and most side effects were managed with routine supportive care interventions. Preliminary clinical results appear very promising, especially for patients with PI3K/AKT/mTOR pathway mutations. The positive effects of the combination were routinely seen in the lowest dosing cohorts and clinical benefit was even seen in patients that had previously failed everolimus or temsirolimus. All patients were either resistant or refractory to paclitaxel at time of enrollment, so further exploration of this combination to elucidate the mechanism of benefit is warranted. Clinical trial information: NCT03154294.
Exploring molecular profiles and survival in hormone receptor-positive uterine serous carcinoma.
Authors: Craig Amaranta , Wilhite Annelise M. , Wu Sharon , Xiu Joanne , Mantia-Smaldone Gina , Hernandez Enrique , Brown Jubilee , Jones Nathaniel L. 
Published: June 2021

5579 Background: Hormone receptor (HR) positivity has been reported as a good prognostic indicator in endometrial cancer. This study investigated estrogen receptor (ER) and progesterone receptor (PR) positivity as indicators of platinum response and improved survival in uterine serous carcinoma (USC), and determined differences in molecular profiles between these tumors and hormone receptor negative tumors. Methods: Tumor profiling was done with immunohistochemistry (IHC), next generation sequencing (NGS), and whole transcriptome sequencing (WTS). PD-L1 expression was determined by IHC using SP-142 (cut-off >1%). Microsatellite instability (MSI) status was evaluated with IHC and NGS, and tumor mutational burden (TMB) by totaling somatic mutations per tumor (high if > 10 mutations/ MB). Immune-cell fraction was determined with QuantiSeq. We used insurance claims data to calculate Kaplan-Meier estimates for overall survival (OS). Statistical significance was determined with chi-square and Wilcoxon rank sum test and adjusted for multiple comparisons. Results: 2806 USC tumors were available for molecular profiling with 717 HR+/966 HR-, 1559 ER+/1059 ER- and 805 PR+/1809 PR-. Median OS for HR+ patients was longer than patients who were HR- regardless of treatment (1152 v 797 days; hazard ratio 0.68, 95% CI 0.58-0.80, p < 0.01). This OS benefit of HR positivity remained for patients receiving platinum therapy (1134 v 889 days; hazard ratio 0.75, 95% CI 0.58-0.98, p < 0.01). HR+ status trended towards improved OS in those treated with hormone therapy (407 vs 771 days, hazard ratio 0.78, 95% CI 0.59-1.02, p = 0.07). In addition to increased androgen receptor expression (54.2 vs 6.2%, p = < 0.001), PTEN mutations were more common in the HR+ group (10.3 vs 5.1%, p = 0.016). This resulted in in more frequent alterations of the PI3K pathway when compared to HR- tumors 64.5 vs 52.2%, p = < 0.001). PD-L1, TMB, and MSI status were similar between the two cohorts. Checkpoint inhibitor gene expression was notable for higher IDO expression in the HR+ group, but lower CD80, CD86, HAVCR2, IFNG, and PDC1 expression. The immune micro-environment was notable for less B-cells and M1 macrophages, but more M2 macrophages. Breaking the ER and PR positive cohort down to individual expression of each gene resulted in similar OS and molecular findings. Conclusions: HR positivity is associated with improved survival in allcomers with USC and those treated with platinum therapy, and there was a trend to improved OS with hormone therapy. More data is needed to determine if HR status is a prognostic marker for IO treatment response. This cohort had a distinct molecular profile compared to HR- tumors.
Molecular determinants of response to immune-oncology therapy in uterine carcinosarcoma.
Authors: Wilhite Annelise M. , Wu Sharon , Xiu Joanne , Erickson Britt Kristina , Rocconi Rodney Paul , Brown Jubilee , Herzog Thomas J. , Holloway Robert W. , Wallbillich John , Winer Ira Seth , Powell Matthew A. , Korn Wolfgang Michael , Jones Nathaniel L. 
Published: June 2021

5582 Background: Uterine carcinosarcoma (UCS) is subtype of endometrial cancer (EC) with aggressive behavior and poor prognosis. UCS has not traditionally been included in EC clinical trials and treatment options are limited. Immune-oncology (IO) therapy has shown promise UCS, but it is unknown which patients benefit most. We sought to identify immunogenic markers in UCS and explore treatment response to IO therapy. Methods: Tumor samples were analyzed using Nex-Gen sequencing of the DNA (NextSeq, 592 genes or NovaSeq, whole exome sequencing) and RNA (NovaSeq, whole transcriptome sequencing) and immunohistochemistry (IHC) (Caris Life Sciences, Phoenix, AZ).PD-L1 IHC used SP-142 (cut-off >1%). MSI was tested by FA, IHC and NGS. TMB was measured by totaling somatic mutations per tumor (high > 10 mutations per MB). Immune cell fraction was calculated by QuantiSeq. Overall survival (OS) information was obtained from insurance claims data and Kaplan-Meier estimates were calculated for molecularly defined patient cohorts. Statistical significance was determined using chi-square and Wilcoxon rank sum test and p values adjusted for multiple comparisons (q) to be <0.05. Results: A total of 1,144 UCS tumors underwent comprehensive tumor profiling. 68.4% of samples were obtained from primary tumors and 31.6% from metastatic sites. 21.6% of tumors expressed PD-L1, 8.5% were TMB-H and 6.8% were MSI-H/MMRd. UCS patients treated with IO had longer median overall survival than those not treated with IO (months: 31.2 vs 19.4; HR(95% CI): 0.39 (0.17-0.76) p=0.005). Median OS was also increased for dMMR/MSI-H (OS not yet reached vs 18.9 months); HR(95% CI): 0.56 (0.36-0.92) p=0.019) and TMB-H (OS not yet reached vs 18.9 months); HR(95% CI): 0.62 (0.38-0.99) p=0.047). More patients are needed to determine if these markers predict response to IO therapy. The most common mutations in UCS led to pathway dysregulation in the PI3K, RAS, chromatin remodeling, HR, and WNT pathways. dMMR/MSI-H tumors have distinct molecular profiles compared to MSS tumors (table). Additionally, dMMR/MSI-H tumors had higher TMB (96.9% vs 2.2%, q<0.01) and increased frequency of PDL-1 (23.6% vs 13.8%; q=0.04). Immune checkpoint genes were more often expressed in MSI-H tumors, though this was non-significant except for IFNG (4.66-fold increase; q=0.01). Conclusions: IO therapy is associated with improved survival in USC. MSI and TMB are markers of improved OS in patients with UCS. MSI tumors have a distinct molecular profile compared to MSS tumors, and they appear to be more immunogenic, which could contribute to the improved survival seen in patients who received IO therapy.[Table: see text]
Tumor-associated immune cells and progression-free survival in advanced endometrial cancer (EC), results from the PHAEDRA trial (ANZGOG 1601).
Authors: Smith Deborah , Robledo Kristy , Yip Sonia , Cummins Michelle , Kok Peey-Sei , Lee Yeh Chen , Friedlander Michael , Baron-Hay Sally E. , Shannon Catherine M. , Coward Jermaine , Beale Philip James , Goss Geraldine , Meniawy Tarek , Lombard Janine Margaret , Spurdle Amanda B. , Andrews John , Stockler Martin R. , Mileshkin Linda R. , Antill Yoland Catherine 
Published: June 2021

5584 Background: Activity of durvalumab in patients with deficient mismatch repair (dMMR) advanced endometrial carcinoma (EC) was confirmed in the PHAEDRA trial (ANZGOG 1601). This study investigated the association between immune biomarkers and clinical outcomes in PHAEDRA. Methods: Formalin-fixed paraffin embedded sections immunohistochemically stained for PD-L1 using the Ventana platform, were with matched H&E slides scored independently by two pathologists according to the Ventana PD-L1 (SP263) algorithm for urothelial carcinoma (UC). Immune biomarkers assessed were PD-L1 staining of tumor cells (TCP) and immune cells (IC), and presence of tumor-associated immune cells (ICP). Results: Sixty-seven of the 71 patients had sufficient tumor for PD-L1 testing. AUC were 0.667, 0.726 and 0.644 for TCP, ICP and IC, respectively for predicting tumor response. Optimal cutpoints were TCP≥1%, ICP≥10% and IC≥35%. ICP≥10% achieved the highest sensitivity (53%) and specificity (82%) of the individual cutpoints. The optimal cutpoint algorithm was able to identify patients who would not respond, (sensitivity 88%, negative predictive value 92%), but had low specificity (48%) and positive predictive value (37%). Differences in PFS were found using ICP≥10% (logrank p = 0.01), compared to TCP (p = 0.25), IC (p = 0.48) and the UC algorithm (p = 0.08) (Figure 1). PFS was shorter in patients with pMMR than dMMR after adjusting for ICP (HR 2.99, 95%CI: 1.61-5.57, p < 0.001). Adjustment for MMR reduced the prognostic significance of ICP≥10% for PFS (HR 0.59, 95% CI: 0.28-1.23, p = 0.16). For OS, differences were seen for the UC algorithm (p = 0.02), but not ICP (p = 0.07), TCP (p = 0.18) or IC (p = 0.23). Similarly to PFS, adjustment for MMR reduced the prognostic significance of the UC algorithm for OS (HR: 0.53, 95% CI: 0.25-1.12, p = 0.10). Conclusions: In this exploratory analysis, ICP was more closely associated with tumor response and PFS than TCP or IC. ICP alone was better than the UC algorithm for predicting PFS. The optimum cutpoint algorithm was promising for identifying non-responders, but requires external validation. Clinical trial information: ACTRN12617000106336.