bluuebunny/crossref_metadata_2025 huggingface dataset:
Tumor-informed ctDNA as an objective marker for postoperative residual disease in epithelial ovarian cancer.
Authors: Paspalj Valentina , Grimm Christoph , Postl Magdalena , Tauber Christina Viktoria , Segui Nuria , Brueffer Christian , Alcaide Miguel , Oton Lucia , Chen Yilun , Saal Lao H. , Hofstetter Gerda , Muellauer Leonhard , Kessler Mirjana , Trillsch Fabian
Published: June 2024

5544

Background: The most important predictor of prognosis in patients with high-grade serous ovarian cancer (HGSOC) is complete tumor resection after primary surgery. The current practice for classifying postoperative residual disease is the subjective assessment by the physician at the end of surgery. To date, an accurate objective marker for postoperative tumor residuals is lacking. In this study we are evaluating circulating tumor DNA (ctDNA) as a predictive marker for postoperative minimum residual disease (MRD). Methods: In this prospective multi-center feasibility study, we included 52 patients with advanced HGSOC who underwent primary debulking surgery between July 2021 and December 2023. Intraoperatively, tumor tissue from several tumor locations was evaluated. Blood samples were examined preoperatively, on day two, and day ten postoperatively. Whole genome sequencing (WGS) was used to identify structural variants (SVs), single nucleotide variants (SNVs) and indels in fresh frozen or FFPE tumor tissue to develop personalized multiplex digital polymerase chain reaction (dPCR) fingerprint assays. Results: A high burden of SVs was detected (median 90 SVs, range 24-287) and dPCR assays successfully designed and orthogonally validated in all tumor samples. A unique dPCR fingerprint was generated for every patient, tracking one to eight biomarkers per patient (median 8). In a subset of 10 patients tissue biopsy samples from multiple tumor localizations were available. The personalized fingerprint was validated across all locations and shown to be consistent. In the overall cohort, ctDNA was positive in 96% (n=46/48) of patients preoperatively and in 87% (n=39/45) at postoperative day 10 (d10), when a plasma sample was available. Compared to patients without macroscopic residual disease, patients with postoperative tumor residuals expressed significantly higher ctDNA levels at d10 (p <0.001). Furthermore, for patients with macroscopic tumor residuals, ctDNA levels at d10 (% variant allele fraction (VAF)) remained comparable to preoperative ctDNA levels (4% decrease in median ctDNA levels). In contrast, patients with macroscopic complete resection were noted to have a 97% decrease in median ctDNA levels between pre-operative and d10 detection. Conclusions: The present tumor-informed dPCR SV fingerprint ctDNA approach demonstrated feasibility with remarkably high detection rates pre- and postoperatively. Postoperative ctDNA levels differed substantially based on postoperative tumor residuals. These findings suggest that this personalized approach could be used to develop a dPCR SV detection assay and may have clinical utility for postoperative MRD evaluation in patients with primary advanced HGSOC.
Gemcitabine plus cisplatin in recurrent ovarian, fallopian tube, and primary peritoneal cancer.
Authors: Eyada Mostafa , Fellman Bryan M. , Patel Shrina , Michael Victoria , Soliman Pamela T. , Sims Travis T. , How Jeffrey Andrew , Jazaeri Amir A. , Fleming Nicole D. , Ramondetta Lois M. , Westin Shannon Neville
Published: June 2024

5548

Background: Our objective was to explore safety and efficacy of gemcitabine plus cisplatin for treatment of patients with recurrent ovarian, fallopian tube and primary peritoneal cancer (OC). Methods: This single institution retrospective analysis conducted at MD Anderson Cancer Center, included patients with recurrent platinum sensitive (PSOC) or resistant (PROC) OC treated with gemcitabine plus cisplatin. Treatment doses were cisplatin 30-40 mg/m2 and gemcitabine 600-800 mg/m2. Utilized regimens were as follows: 1) cisplatin Day 1 (D1), gemcitabine D1 on 21-day cycle; 2) cisplatin D1, gemcitabine Day 8 (D8) on 21-day cycle; or 3) cisplatin/gemcitabine every 2 weeks on 28-day cycle. Objective response rate (ORR= complete response (CR) + partial response (PR)) was calculated along with 95% confidence interval (95%CI). Adverse events were collected and graded. Results: One hundred and seventy-six patients were included; 90% had high grade serous OC and 95% were stage III/IV at diagnosis. Subjects received a median of 3 prior lines of therapy (range 1-10). ORR was 44.1% (95% CI: 36.6-51.9) with 12 CR (7%), 64 PR (37%), 42 SD (24%) and 54 PD (31%). One hundred sixteen (66.6%) patients discontinued treatment due to disease progression after median 3 cycles (range 1-19). Among responders, median number of cycles with response was 3 (range 2-13). Twenty-three percent of subjects had PSOC with ORR of 61.5% and 76.1% had PROC with ORR of 39.4% (p =0.014). Number of prior lines of cytotoxic treatment or prior use of bevacizumab wasn’t associated with response to treatment. Median platinum free interval was associated with response to therapy (5 months in responders vs 3 months in non-responders; P=0.007). Forty-four percent of patients had adverse events, with most common being thrombocytopenia (12%), neutropenia (9%), and neurotoxicity (10%). Conclusions: Cisplatin in combination with gemcitabine demonstrates activity regardless of platinum sensitivity status in patients with recurrent ovarian cancer. However, longer platinum-free interval is associated with improved response to this therapy.
Evaluation of a novel extracellular vesicle (EV) based ovarian cancer (OC) screening test in asymptomatic postmenopausal women.
Authors: Manning Brendan , Banerjee Sanchari , Bortolin Laura T , Winn-Deen Emily S. , Hamzeh Bilal , Grimes Brittany , Santos-Heiman Timothy , Byrne Delaney M. , Hawkins Troy B , King MacKenzie Sadie , Salem Daniel P. , Smith Michael , Apostolidou Sophia , Gentry-Maharaj Aleksandra , Berg Christine D. , Skates Steven , Ransohoff David , Guettouche Toumy , Mattoon Dawn R , Menon Usha
Published: June 2024

5553

Background: Screening for OC that relies on CA125 and imaging lacks early-stage sensitivity, highlighting the need for a more effective test. EVs in blood may provide increased sensitivity from vesicles released in abundance and increased specificity from assessing multiple cancer-related markers colocalized on a vesicle surface. We report performance of an EV based OC Test in samples from asymptomatic postmenopausal women in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Methods: The OC Test (biomarkers, classifier, cutoff) was locked following a training study, after which we observed consistent assay performance in an independent cohort. Here we evaluated the OC Test in a blinded case-control study nested within the no screening (NS) and annual ultrasound screening (USS) arms of UKCTOCS. Cases were all women with a diagnosis (Dx) of high-grade serous carcinoma (HGSC) within 36 months following sample donation and were matched 10:1 by age at collection to women who had no OC detected before or within the trial follow up period (controls). In addition, samples drawn within 6 months prior to a false positive (FP) transvaginal ultrasound from women who underwent surgery for benign findings in the USS arm were evaluated. OC Test and research use CA125 test at previously established 98% specificity cutoff, were determined blinded to case-control status, with unblinding done by UCL only after all tests were completed. Results: We assessed 129 samples from women with HGSC, 1310 controls and 100 USS FP samples. Data from 160 samples were excluded due to operator error, low sample volume or quality issues. In healthy controls, we observed a 97.7% specificity for the OC Test, and 95.5% for CA125, P = 0.006 McNemar test. We observed a sensitivity of 82% for the OC Test in samples drawn 0-12 months prior to Dx, and 63% for CA125, P = 0.016 McNemar test. Additionally, only 2.3% (2/86, 95% CI 0.3-8.1) women who underwent surgery for false positive USS results were positive for the OC Test vs 10.4% (9/86, 95% CI 4.9-18.9) for CA125. Conclusions: The OC Test is capable of highly sensitive and specific detection of HGSC in asymptomatic postmenopausal women one year prior to Dx and can detect HGSC up to three years prior to Dx with superior sensitivity and specificity compared to CA125. The data supports further evaluation of the OC Test for OC screening. [Table: see text]
Anlotinib plus hormone therapy in patients with platinum-resistant recurrent ovarian cancer: A prospective, single-arm, open-label, phase II study.
Authors: Wang Xipeng , Li Jiarui , Zhang Ping , Wang Yizhi , Lu Xin , Xu Hong
Published: June 2024

5567

Background: Studies have suggested that estrogen regulates the malignant transformation of ovarian surface epithelial cells, stimulates the growth and migration of cancer cells. and promotes the VEGF expression in epithelial ovarian cancer. Anlotinib is a novel multi-target tyrosine kinase inhibitor, inhibiting tumor angiogenesis and proliferative signaling. In this study, we evaluate the activity of anlotinib combined with letrozole in patients with estrogen receptor positive, platinum-resistant recurrent ovarian carcinoma (NCT04720807). Methods: Patients who have previously received two or more chemotherapy treatments, with histopathologically confirmed high-grade serous ovarian cancer (including salpingo carcinoma and peritoneal carcinoma), estrogen receptor (ER) positive and ECOG 0-2 were considered eligible for enrollment. Anlotinib was taken orally (10mg mg qd, d1-14, 21 days per cycle), and letrozole was taken orally (2.5mg qd, d1-21, 21 days per cycle). The treatment was continued until disease progression, death, or intolerant toxicity. The primary endpoint was objective response rate (ORR) and the secondary endpoints included disease control rate (DCR), duration of remission (DOR) progression free survival (PFS), overall survival (OS) and safety. Results: Between September 2020 and December 2023, 30 patients with a median age of 61 years (range:50-79), FIGO histopathological stage I (11.1%), Ⅱ(3.7%), III (59.3%) and IV (25.9%) were enrolled. Twenty-seven of these patients have been evaluated for efficacy. In the efficacy-evaluable population (n=12), the therapeutic evaluation showed that 7 and 13 patients achieved partial response and Stable disease respectively(with the standards of GCIC), yielding the ORR of 16.7% (7/27 95% CI: 11.8% to 46.6%). The DCR was 74.1% (20/27, 95% CI: 53.4% to 88.1%). The median PFS was 4.24 months (95% CI: 3.71m to 5.09m) and the median OS was 18.96 months (95% CI: 8.34m to 31.05m).With subgroup analyses, Patients who had received PARPi before and patients with baseline CA125 level >500 had significant prolongations in mOS and mPFS, respectively. The most common adverse events (AEs) were grade 1 or 2, which included laryngitis (44.4%), stomatitis (37.0%), hand-foot syndrome (29.6%), and fatigue (25.9%), diarrhea (22.2%), hypertension (14.8%),. The grade 3 AEs were hypertension (37.0%), hand-foot syndrome (3.7%), diarrhea (3.7%) and hyperuricemia (3.7%). No higher AEs or treatment-related death were observed. Conclusions: As a chemo-free regimens, anlotinib plus letrozole showed a promising efficacy with a favorable toxicity profile for patients with platinum-resistant recurrent ovarian cancer. Research Sponsor: Chia Tai Tianqing Pharmaceutical Group Co. GYNECOLOGIC CANCER. Clinical trial information: NCT04720807 .
Targeting the CD47/TSP-1 axis: A promising strategy for patients with ovarian cancer (OC) that relapses on PARP inhibitors (PARPi).
Authors: Leary Alexandra , Jeanne Albin , Etiennot Marion , Henry Aubéri , Drelon Coralie , Schneider Christophe , Moniot Aurélie , Dedieu Stéphane
Published: June 2024

5568

Background: There is an urgent need for novel therapies for patients relapsing post-PARPi. CD47 is an attractive target due to its overexpression in OC, particularly under PARPi treatment, and its association with shorter survival and immune evasion. While most studies have focused on the CD47/SIRPa interaction (“don’t eat me” signal), our recent data from the randomized CHIVA trial (NCT01583322) uncovered the relevance of TSP-1, a matrix glycoprotein associated with poor prognosis, as a primary CD47-interacting ligand [ASCO 2023]. The TAX2 peptide selectively disrupts TSP-1 binding to CD47. Our aim was to investigate whether inhibiting the CD47/TSP-1 axis with TAX2 could overcome PARPi resistance in a syngeneic mouse model of BRCA2 mutant OC. Methods: Biodistribution studies of fluorescent TAX2 peptide were carried out in mice bearing ovarian tumors tracked through fluorescence molecular tomography. To assess the efficacy of TAX2 and/or PARPi (olaparib) treatment, we used ID8 cells harboring Trp53-/- and Brca2-/- mutations, as a pertinent syngeneic representation of intraperitoneal high-grade serous TP53 and BRCA2 mutated OC. Olaparib was administrated at 50 mg/kg orally daily, while TAX2 was administrated at 30 to 100 mg/kg intravenously thrice weekly. Survival curves were compared using the Gehan-Breslow-Wilcoxon's test. Results: We confirmed that TAX2 peptide binds directly to human TSP-1 with KD of 11 µM. In mice bearing tumors, TAX2 correlated with TSP-1 expression with prolonged accumulation at tumor sites, but none in healthy tissues. Using a relevant peritoneal carcinomatosis model exhibiting PARP inhibitor resistance, we demonstrated that administration of TAX2 alone significantly extended survival. Interestingly, post-olaparib administration of TAX2 substantially reduced tumor burden, even at the lowest TAX2 dosing, and prolonged survival (median survival: 44 vs 38 days). Remarkably, sequential use of TAX2 increased animal survival even under treatment conditions allowing olaparib efficacy. Indeed, post-olaparib discontinuation, mice survival increased from 10.6 to 15.7 days with administration of TAX2. This sequential approach improved the median survival to 56 days. Conclusions: Our findings propose TAX2 as a promising strategy for patients relapsing on PARP inhibitors. TAX2 displayed a selective biodistribution pattern in mice, concentrating at tumor sites. Our study showcased that while TAX2 alone exhibited significant but modest activity in PARPi-naive mice, its efficacy significantly increased post-PARPi exposure, irrespective of PARPi duration. A first in human trial in the post-PARP setting is planned.
Real-world biomarker testing, treatment patterns and outcomes in a US cohort of patients with advanced ovarian cancer.
Authors: Veljovich Dan Steven , Penson Richard T. , Birrer Michael J. , Luo Linlin , Pyrih Nick , Pack Simon , Iu Crystal , Hada Manila
Published: June 2024

5571

Background: Olaparib, a poly(ADP-ribose) polymerase inhibitor (PARPi), has shown efficacy as monotherapy for the treatment of BRCA mutated (BRCAm) advanced ovarian cancer (AOC) and in combination with bevacizumab for Homologous Recombination Deficient (HRD+) AOC. This study describes real-world (RW) characteristics, testing and treatment patterns in patients (pts) with AOC, including outcomes with olaparib first-line maintenance (1LM) therapy. Methods: A retrospective observational study utilizing the electronic health record-derived de-identified US-based Flatiron Health database was performed including women aged ≥18 y at AOC diagnosis (Jul 2018–Dec 2022) with ≥1 clinical visit. Pts were followed from diagnosis until Aug 31, 2023, cessation of dataset coverage, or death, whichever occurred first. Biomarker testing was defined as evidence of a test for BRCAm or HRD (inclusive of BRCAm). Estimated RW time to first subsequent therapy or death (TFST) and time to treatment discontinuation or death (TTD) are reported. Results: Demographic and clinical characteristics are shown in the Table. Of 1503 pts included, 80.8% (n=1214) were BRCAm tested and 36.3% (n=546) were HRD (inclusive of BRCAm) tested. Among pts who were either BRCAm or HRD tested (n=1220), 58.0% (n=708) were tested between AOC diagnosis and initiation of 1LM therapy. No 1LM therapy was recorded in 61.9% (n=931/1503) of pts. In both BRCAm and HRD+ pts, olaparib, either as monotherapy (44.5% [n=69/155] and 33.6% [n=100/298], respectively) or in addition to bevacizumab (7.1% [n=11/155] and 9.4% [n=28/298], respectively), was the most frequently used PARPi for 1LM therapy (Table). Median (95% CI) TFST and TTD was 44.7 (27.0, NA) and 22.7 (17.0, 47.0) mos, respectively in BRCAm pts receiving olaparib 1LM (n=69), and 29.1 (22.1, NA) and 22.1 (13.1, NA) mos, respectively in HRD+ pts receiving olaparib + bevacizumab 1LM (n=28). Conclusions: While most pts received BRCAm testing, a majority did not receive HRD (inclusive of BRCAm) testing. A sizeable proportion of pts with actionable biomarker results did not receive PARPi as 1LM therapy highlighting the need for education on the importance of genetic testing to guide AOC treatment. Time-to-event outcomes were comparable with those from the SOLO1 and PAOLA-1 clinical trials, thus supporting the real-world effectiveness of olaparib. [Table: see text]
Hospital challenges faced by frail patients with ovarian cancer and the adverse outcomes: A nationwide study.
Authors: Ortega Yaguachi Nataly , Javaid Saad , Frasier Kelly , Li Vivian , Vinagolu-Baur Julia , Rodriguez Evadne , Del Castillo Olivia , Batista Raquel , Jonas Kenlee , Palma Laura
Published: June 2024

5572

Background: Ovarian cancer is a leading cause of gynecological cancer-related deaths and one of the most common causes of cancer-related fatalities among women. Frailty has been identified as a predictor of unfavorable outcomes for cancer patients, but there is limited research on its impact on individuals with ovarian cancer. We examined the effects of Frailty in hospitalized ovarian cancer patients and the associated outcomes. Methods: National Inpatient Sample (NIS) 2020 was used to identify the patients with a primary diagnosis of ovarian cancer (local/regional and advanced metastatic) and was stratified into patients with and without Frailty. The primary outcome was mortality, and secondary outcomes included length of stay, the total cost of hospitalization, and other in-hospital adverse outcomes. Multivariate logistic regression analysis was used to calculate the outcomes after adjusting for confounding variables. Results: A total of 19790 patients were hospitalized with a primary diagnosis of Ovarian cancer, among which 3215 (16.24%) patients had the concurrent diagnosis of Frailty. The mean age of patients with and without Frailty was 65.76 (+/-13.10) and 60 (+/-14.45),p<0.001, respectively. After adjusting for confounding variables, Frailty was associated with an increased risk of mortality in patients with ovarian cancer (OR=3.01(1.83-4.95); p<0.001). Patients with Frailty were also at risk of increased length of stay (+3.80 Days (3.09-4.50; p<0.001) and total cost of hospitalization (+ $ 34662 (22973-46351); p<0.001). Frail patients also had an increased likelihood of Acute respiratory failure (OR=1.72 (1.22-2.42); p=0.002), Acute kidney injury (OR=2.40 (1.88-3.05); p<0.001), Sepsis (OR=4.97 (3.19-7.75); p<0.001), ICU admission (OR=2.23 (1.44-3.45); p<0.001), Pneumonia (OR=2.63 (1.69-4.10); p<0.001), total parenteral nutrition (OR=14.20 (7.80-25.83); p<0.001) and Intubation (OR=2.11 (1.21-3.69); p=0.008). However, there was no difference in the risk of noninvasive mechanical ventilation (OR=2.07 (0.95-4.52); p=0.48) or enteral feeding (OR=32.73 (0.63-1696); p=0.08). Conclusions: Frailty in ovarian cancer patients is considered an independent predictor of mortality. It is also associated with increased healthcare resource utilization and adverse in-hospital outcomes.[Table: see text]
Efficacy of niraparib in patients with advanced ovarian cancer: A meta-analysis of randomized controlled trials.
Authors: Marinho Alice , Lambert Fossen Eduardo , Caldeira de Freitas Maria Carolina , Coelho Itaya Gabriela , Da Costa Larissa Maria , Dias Yasmin , Celso Davi Said Gonçalves , Bonalumi Dos Santos Marcela , De Souza Mariana , Vilbert Maysa
Published: June 2024

5587

Background: Niraparib is a poly-adenosine diphosphate-ribose polymerase (PARP) inhibitor that has shown clinical benefits as a maintenance therapy for patients with advanced ovarian cancer. Methods: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating the efficacy of niraparib as maintenance therapy after platinum-based chemotherapy for patients with advanced ovarian cancer. PubMed, Embase, and Cochrane Central Register of Controlled Trials databases were searched for RCTs published up to January 17, 2024. Hazard ratios (HR) and Odds ratio (OR) with 95% confidence intervals (CI) were pooled using a random-effects model. The endpoints of interest were time to first subsequent therapy (TFST) and progression-free survival (PFS). We performed subgroup analyses for BRCA-mutation, HRD-positive, HRD-negative, response to platinum therapy, and newly diagnosed disease. Results: Four RCTs were included, comprising a total of 1,935 patients of whom 1,291 received niraparib and 644 received placebo. Niraparib significantly improved PFS in the overall population (HR 0.45; 95% CI 0.31-0.66; p < 0.0001; I2= 82%), in patients with BRCA mutation (HR 0.32; 95% CI 0.25-0.43; p < 0.00001; I2= 21%), HRD positivity (HR 0.39; 95% CI 0.30-0.51; p < 0.00001; I2= 40%), HRD negativity (HR 0.45; 95% CI 0.36-0,57; p < 0.00001; I2= 0%), and newly diagnosed cancer (HR 0.59; 95% CI 0.39-0.73; p < 0.0001; I2= 68%). The TFST was longer in the niraparib group (HR 0.48; 95% CI 0.33-0.68; p < 0.0001; I2= 80%). There was no statistical difference between complete and partial response to platinum therapy (OR 1.00; 95% CI 0.87-0.1.16; p = 0.98; I2= 0%). Conclusions: Niraparib improves PFS and lowers the time to first subsequent therapy in patients with advanced ovarian cancer. Outcomes and results by studies. [Table: see text]
Exploring the tumor microenvironment (TME) in patients with mismatch repair-deficient (MMRd) endometrial cancer (EC) undergoing immune checkpoint inhibitor (ICI) therapy: Proteomic insights into immune resistance mechanisms.
Authors: Grau Béjar Juan Francisco , Zeng Qinghe , Mehnert Martin , Colomba Emeline , Genestie Catherine , Le Formal Audrey , Edmond Elodie , Lachaud Antoine Amaury , Pautier Patricia , Michels Judith , Gouy Sebastien , Maulard Amandine , Yaniz Elisa , Leary Alexandra
Published: June 2024

5609

Background: MMRd status is a robust predictive biomarker for ICI in EC, however half of these pts do not respond. Most studies exploring biomarkers of response to ICI have focused on tumor or immune cell factors. We aimed to explore the tumor microenvironment (TME) in ICI-Responder (R) versus Non-Responder (NR) MMRd EC pts to identify new predictive biomarkers of response. Methods: Clinical data and outcomes of metastatic MMRd EC pts, treated with ICI at Gustave Roussy Institute (2016-2023), were retrospectively collected. Pts were classified as Rs (CR, PR, or SD ≥12 months) or NRs (PD or SD <12 months). Pre-ICI FFPE tumor samples were subjected to Biognosys UltraDeep TrueDiscovery™ Mass Spectrometry (MS) for the identification of differentially regulated protein expression between R and NR. Criteria for protein candidates’ selection were p-value < 0.01 and average absolute log2 fold change (absolute average Log ratio) > 0.58. CD8+ T cells were quantified in the intratumoral area and expressed as number of cells per mm2. Spearman correlation test (r) was used for lineal correlation calculations. Functional enrichment analysis was conducted to elucidate differentially expressed molecular signatures (Odds ratio; adjusted p-value) in Rs vs NRs, utilizing GO_Biological Process database. Results: Twenty-three tumor samples were included in the analysis: 15 from Rs and 8 from NRs. Overall, 11,187 proteins were quantified. Only 72 were found to be differentially abundant between Rs and NRs. Protein candidates present within the tumor microenvironment that were significantly UP-regulated in NRs related to: non-specific inflammation (CRP), arachidonic acid metabolism (LOX15, PTGR3), extracellular matrix synthesis (COL5A2, COL22A1, PXDN), and TGF-b (TFBR1). CRP, LOX15, PXDN and COL5A2, were negatively correlated with CD8+ T cell infiltration (r -0.23, r -0.33, r -0.51, r -0.21). Based on functional enrichment analysis, collagen fibril organization (OR 21.4; p 1.1 e-6), extracellular structure organization (OR 10.2; p 1.2 e-6), extracellular matrix (ECM) organization (OR 7.5; p 1.1e-6), supramolecular fiber organization (OR 3.4; p 0.03), and TGFBR signaling pathway (OR 6.4; p 0.08) were among the top 30 biological process upregulated in NRs. Conclusions: Our preliminary data on high throughput proteomic analysis identified the arachidonic acid pathway, ECM structural organization and TGF-b signaling as potential mediators of ICI resistance in MMRd EC, all of which may be actionable in an effort to enhance sensitivity to ICI.
Rising trends in HPV (+) & HPV (-) vulvar cancers among US non-Hispanic White and Hispanic White females 50 years and older.
Authors: Mata Zetina Ana Paola , Rajupet Sritha , Strange Theodore , Dhar Meekoo , Dhulipalla Lohitha , Mokhtar Asmaa , Castellanos Mario R
Published: June 2024

5620

Background: Our prior studies show that vulvar cancer in older females is increasing in the US, aligning with lengthened USPSTF cervical cancer screening intervals. Most medical societies do not recommend genital exams post-cervical cancer screening, and data on vulvar cancer is lacking to make comprehensive screening strategies. We utilized the SEER database to examine vulvar cancer, HPV status, and race/ethnicity to better understand the characteristics of patients who develop cancer. Methods: We examined vulvar cancer cases & data from 2000-2020, as reported in the SEER database. Estimations of HPV-positive vulvar cancer rates by age were derived using HPV attribution percentages from the HPV Centre Information United States Full Report, with younger females defined as < 54 years. Correspondingly, cases not within this percentage were classified as HPV-negative. Results: From 2000 to 2020, vulvar cancer incidence in the US increased by 14%, with rates rising from 2.18 to 2.40 per 100,000. This rise was most pronounced in Non-Hispanic White females over 50, whose rates grew from 2.41 in 2000 to 2.87 in 2020, more than any other race and ethnicity. For HPV-positive vulvar cancer, there was a 1.5% decrease in cases among females under 54. In contrast, there were significant increases in the 55-64 and 65+ age groups, with 53% and 14% rises, respectively. Additionally, the 55-64 age group experienced a notable 23% increase in HPV-negative cases, and those 65+ had a 9% rise. Conclusions: This study is the first to show a significant increase in vulvar cancer among non-Hispanic White females, particularly those aged above 50 years. Surprisingly, we observed that HPV (+) cancers, typically associated with younger demographics, are continuing to occur in older females. This is concerning since the HPV vaccine, introduced in 2007, wasn't available for HPV prevention in females now over 50. Concurrently, there is a rise in HPV-negative vulvar cancers within these older age groups. The current guidelines don't recommend routine genital exams for females over 65, indicating that there may be an opportunity to reexamine this recommendation given the US vulvar cancer trends in older females.
Treatment patterns of metastatic urothelial cancer in the United States.
Authors: Wang Xue , Chin Andi , Popadic Lyuba , Devine Francesca , Poretta Tayla , Schmidt Kerstin , Sierecki Mitch , Hoffman-Censits Jean H.
Published: June 2024

e16500

Background: Bladder cancer is the sixth most prevalent malignancy in the United States, of which urothelial carcinoma (UC) is the predominant histologic type. The prognosis of metastatic UC (mUC) is generally poor with standard platinum-based chemotherapy (PBC) regimens. With approvals of immunotherapy (IO) and antibody drug conjugates (ADCs) in recent years, the treatment landscape has been evolving substantially. This study aimed to describe current, real-world treatment patterns of mUC. Methods: This retrospective study used de-identified, open and closed administrative claims data from Komodo’s Healthcare Map between 1/1/2016 and 5/31/2023. Adult patients were required to have ≥2 claims for UC diagnosis and ≥2 secondary neoplasm claims (within 30 days before or any time after the first UC claim). In closed claims, patients were required to have continuous enrollment during the 6-month baseline period, whereas patients in open claims were required to have at least the median number of claims among all patients in open claims. Index date was defined as the earliest date of a secondary neoplasm claim following UC diagnosis. Patients were observed until death or end of study, whichever occurred first. Treatment patterns, including duration of treatment (DOT), were evaluated in patients who initiated first line (1L) treatment on or after 1/1/2020. A sensitivity analysis was conducted in closed claims alone. Results: Among 38,557 patients who were diagnosed with mUC, 44% received at least one line of treatment at any time. After removing patients who started 1L before 1/1/2020, 28,576 patients meeting eligibility criteria were included at baseline. Median age was 74 years; 77% patients were male; 38% had diabetes or hyperglycemia at baseline; 67% had de novo mUC. PBC with or without IO maintenance, were the most common 1L treatment regimens (47%). IO (39%) and enfortumab vedotin (EV, 21%) were the dominant regimens in 2L. Sacituzumab govitecan (SG) was predominantly administered in 3L (17%). Median DOT was generally longer in earlier versus later lines for most therapies, including PBC followed by IO maintenance, ADCs, FGFR targeted therapy and EV+Pembrolizumab (P), and were similar for other therapies (Table). Findings were similar in the sensitivity analyses. Conclusions: Novel therapies, such as IO and ADCs, have provided additional treatment options for patients diagnosed with mUC. Future studies with longer follow-up are needed to characterize the shifting treatment paradigm, as EV+P becomes a standard of care in 1L mUC. [Table: see text]
Perceptions and expectations: A study on prognostic perception and quality of life in patients with metastatic renal and bladder cancer.
Authors: Bolek Hatice , Arslan Cagatay , Basaran Mert , Cicin Irfan , Özgüroğlu Mustafa , Tural Deniz , Ürün Yüksel
Published: June 2024

e16505

Background: In metastatic cancers, treatments are aimed at palliation, focusing on life extension and quality of life (QoL) improvement rather than cure. This study aims to investigate the alignment between patient expectations and the realistic outcomes of treatment in metastatic renal cell carcinoma (mRCC) and metastatic bladder cancer (mBC). Methods: Between 15.03.2023-15.01.2024, an online survey was conducted targeting patients with mRCC and mBC. The primary objective was to evaluate the patients’ understanding and expectations concerning curability and the anticipated outcomes of their treatments in a metastatic setting. Additionally, the study aimed to explore the impact of patients' QoL and levels of optimism on their perceptions of cure and treatment outcomes. EORTC 30.3 QoL questionnaire and Life Oriented Test (LOT) were administered. Results: A total of 169 patients participated, with a median age of 63 years.72.2% of patients assessed their general health state as "good", 13.6% as "excellent", 11.8% as "fair", and 2.4% as "poor." Out of the patients surveyed, 40.2% considered cure as "very likely," 45% as "likely," 4.7% as "a little likely," and one as "not possible." The table shows patients' perspectives on improving disease symptoms, doing daily tasks easier, and living longer with treatment. Patients' perception of cure was not affected by gender, age, treatment modality, or general health status. While only 9 patients perceived cure as "a little likely" or "not possible," this group has lower median QoL and LOT scores than those who believed cure was "very likely" or "likely." This pattern is observed in their perceptions regarding the improvement symptoms, ability to make daily life activities easier, and expectations of living longer. Conclusions: Patients with mRCC and mBC have expectations of cure from treatments that may not align with clinical realities. Prioritizing clear communication and patient participation in treatment planning, particularly around palliative care is essential for effective care delivery. [Table: see text]
Site of metastasis and clinical outcomes in patients with advanced renal cell carcinoma treated with TKI monotherapy or combination therapy: A real-world analysis.
Authors: Nuvola Giacomo , Navarro Victor , Mollica Veronica , Marmolejo Castañeda David Humberto , González Macarena , Morales-Barrera Rafael , Vega Sharela , Santoni Matteo , Catalan Laia , Trilla Enrique , Carles Joan , Massari Francesco , Suárez Cristina
Published: June 2024

e16513

Background: Tyrosine kinase inhibitors (TKIs), either in monotherapy or in combination with immunotherapeutic agents (IO), have become the standard of care for the first-line treatment of advanced or metastatic renal cell carcinoma (RCC). Common sites of metastasis in RCC include the lymph nodes, lungs, liver, pancreas, bones, and brain. This study aims to analyze the clinical outcomes of patients treated with TKI monotherapy and TKI-IO combination therapy based on the site of metastasis. Methods: A retrospective analysis was conducted on the clinical characteristics and outcomes of RCC patients treated with first-line TKI and TKI-IO in Spanish and Italian institutions. The study employed a descriptive analysis, calculating the median follow-up using the reverse Kaplan-Meier method. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared using the log-rank test. Cox proportional-hazard models were utilized to determine hazard ratios (HRs) with a 95% confidence interval. Results: Out of 369 eligible patients, 285 received TKI monotherapy, and 84 were treated with TKI-IO. The median follow-up was 84.34 months (95% CI; 73.82 - 101.91) in the TKI group and 17.58 months (95% CI; 13.11 - 45.77) in the TKI-IO group. PFS was significantly longer with TKI-IO compared to TKI in patients with lung metastasis (48.79 months vs. 21.95 months) (HR 0.59 [0.39;0.91]; p=0.02). While PFS was longer in patients with bone metastasis (41.3 months vs. 19.09 months) (HR 0.56 [0.28 ; 1.13]; p=0.11), liver metastasis (41.3 months vs. 15.97 months) (HR 0.52 [0.25 ; 1.06]; p=0.07), and lymph node metastasis (32.82 months vs. 20.14 months) (HR 0.67 [0.43 ; 1.04]; p=0.08) with TKI-IO, these differences were not statistically significant. TKI monotherapy showed longer PFS in patients with pancreatic metastasis (41.64 months vs. 22.7 months) (HR 1.37 [0.5 ; 3.72]; p= 0.54). OS was numerically longer in TKI-IO-treated patients across various subgroups but did not reach statistical significance. Notably, OS was significantly higher in patients with pancreatic metastasis compared to those with other metastatic locations (139 months vs. 42.74 months) (HR 0.35[0.18;0.69]; p<0.01). Conclusions: Our study underscore the superiority of TKI-IO combination therapy over TKI monotherapy, revealing consistently favourable outcomes across various metastatic sites. Notably, an intriguing exception emerged in the context of pancreatic metastasis, where patients exhibited an extended PFS with TKI monotherapy. The implications of our data suggest a tailored approach for this specific subset, wherein frontline immunotherapy may not be the optimal choice.
Single cell RNA sequencing to reveal genetic biomarkers and immune microenvironment of patients with aggressive small renal cell carcinoma.
Authors: Park Jee Soo , Kim Eun Chae , Song Seol , Kim Jongchan , Jang Won Sik , Hwang Byungjin , Ham Won Sik
Published: June 2024

e16517

Background: While active surveillance for small renal cell carcinoma (RCC) gained acceptance due to harmless behavior, controversy still continues on aggressive potential of small RCC. Despite small tumor size, there still remains a risk for distant metastasis and recurrence. The biology of small RCC, especially the risk factors for metastasis and recurrence, has not been fully elucidated. It is therefore important to evaluate the aggressive potential of small RCCs to ensure that necessary treatments are given, but also to avoid overtreatment. Therefore, we used bulk RNA sequencing and single cell RNA sequencing (scRNA-seq) to reveal genetic biomarkers and distinct immune microenvironment in aggressive small RCC patients. Methods: Five cases of T1a (≤ 4cm) clear cell RCCs (ccRCCs) that were reported to have synchronous metastasis or recurrence were identified as an aggressive group and four cases with age, sex, and tumor size-matched ccRCCs patients with no metastasis or recurrence were identified as a non-aggressive group among prospective cohort (ClinicalTrials.gov Identifier: NCT03694912) RCC database. For the control, two healthy kidney donors were enrolled. We performed scRNA-seq using the 10X Genomics platform and bulk analysis for the total eleven cases of peripheral blood mononuclear cell (PBMC) samples. We demultiplexed pooled 11 samples using Souporcell and sequencing reads were normalized and analyzed using R/Seurat package. Cellular components of each sample were determined based on known marker genes. Bulk analysis involved differential gene expression analysis and pathway enrichment analysis. Results: The mean tumor size and age was 2.6 cm and 63 years old, respectively. Among 5 aggressive ccRCC patients, two patients had synchronous lung metastasis and two patients had synchronous bone metastasis. One patient had recurrence after partial nephrectomy. We analyzed 36,303 cells and identified 31 cell subpopulations. Our single-cell analysis unveiled distinct variations in T cell and natural killer (NK) cell proportions among aggressive, non-aggressive, and normal groups, highlighting significant differences in these ratios. Additionally, a notable pattern of gene expression levels was found between non-aggressive and aggressive groups, with a substantial increase in the expression levels of GSTP, ASRG, and SNORD142 genes in aggressive group. Conclusions: As T1a ccRCCs present low but non-negligible risk of metastasis and recurrence, patients with small RCCs should be counseled on such risk when offered active surveillance. Patients with higher NK cells and lower naïve CD8+ T cell are associated with higher risk of metastasis and recurrence in T1a RCC. This study suggests a promising potential for leveraging genetic markers and immune cell dynamics in the diagnosis of aggressive ccRCC using non-invasive screening methods.
Clinical characteristics of renal cell carcinoma in the transplanted kidney in renal transplant recipients: A systematic scoping review.
Authors: Tanariyakul Manasawee , Saowapa Sakditad , Aiumtrakul Noppawit , Wittanakorn Onsinee , Wannaphut Chalothorn , Polpichai Natchaya , Yingchoncharoen Pitchaporn , Acoba Jared David
Published: June 2024

e16518

Background: Renal transplant recipients are at a 100-fold increased risk of developing renal cell carcinoma (RCC), with a higher incidence of RCC in native kidneys than in allografts. Given that kidney transplant recipients typically possess only one functional kidney, it is critical for clinicians to heightened disease awareness. This systematic scoping review aims to provide an updated overview of the clinical characteristics, treatment, and outcomes of RCC in the allograft kidneys. Methods: We comprehensively searched the databases of MEDLINE and EMBASE until January 2024. Included studies were case reports, case series and retrospective analyses reporting RCC in the allograft kidney of renal transplant recipients. The review delineates the clinical presentation, time between kidney transplant and diagnosis, donor characteristic, mass size, histopathology and treatment outcome of RCC in the allograft kidneys. Results: Forty-two case reports and case series, along with eleven retrospective cohorts were found. 65 patients were identified in the case reports and case series, while 209 patients were reported in the retrospective study reviews. The review emphasizes that 75.4% of patients with allograft RCC were asymptomatic at the time of diagnosis, with the majority diagnosed through imaging surveillance. Symptomatic patients most commonly presented with gross or microscopic hematuria, elevated creatinine, abdominal or graft pain, respectively. 61.9% of recipients received their allograft from deceased donors, and 38.1% from living donors. The average time interval between kidney transplantation and the diagnosis of RCC spans 11.6 years, ranging from 6 months to 30 years. Papillary RCC and clear cell RCC (ccRCC) were the two most common histopathological diagnoses, with papillary RCC accounting for 53.3% and ccRCC for 34.2% of cases. A potential limitation is the inconsistent of long-term follow-up data for most of the subjects, which makes the outcome of this population uncertain. Conclusions: This systematic scoping review identified an average time interval of 11.6 years between kidney transplantation and RCC diagnosis, with a range from 6 months to 30 years. The majority of kidney transplant recipients with allograft RCC (75.4%) were asymptomatic, while the remainder presented with symptoms such as hematuria, elevated creatinine, abdominal or graft pain, weight loss, fever, malaise, or hypertension. The incidence of asymptomatic allograft RCC among kidney transplant recipients underscores the importance of vigilant post-transplant screening. Future research should investigate clinical outcomes and the cost-effectiveness of the screening practices in allograft kidney to develop preventive strategies.
Efficacy and safety of first-line TKI plus ICI therapy in metastatic non-clear cell renal cell carcinoma: A real-world multiple-centre study.
Authors: Zhong Xi , Huang Tingxuan , Peng Yulu , NG Cheoklong , Liu Xuhao , Jing Taile , Wei Wensu , Zhang Zhiling , Han Hui , Chen Minfeng , He Liru , Huang Jiwei , Dong Pei
Published: June 2024

e16519

Background: The combination of immune checkpoint inhibitor (ICI) and tyrosine kinase inhibitor (TKI) has emerged as the standard first-line therapy for metastatic renal cell carcinoma (mRCC), however, limited clinical trials have investigated the role of ICI plus TKI in the treatment of metastatic non-clear cell renal carcinoma (mnccRCC) for its heterogeneity and low incidence. Our study presents multiple center real-world data with the optimal sample size so far to assess the efficacy and safety profile of ICI plus TKI in patients with mnccRCC. Methods: We performed a retrospective analysis including patients previously untreated with mnccRCC receiving TKI plus ICI or TKI in four institutions participated in this study. The primary endpoint was progression-free survival (PFS) according to the Response Evaluation Criteria in Solid Tumors version 1.1, others including overall survival (OS), the objective response rate (ORR) and treatment related adverse events (AEs). Results: A total of 214 patients were included for this study with 122 patients receiving TKI monotherapy and 92 patients receiving TKI plus ICI. Median follow-up time was 29.4 months (IQ1-IQ3, 15.7-48.5). The median age of patients was 49 years, with the majority being male (70.6%) and intermediate/poor risk. The most prevalent pathological subtype of nccRCC was papillary RCC (44.4%), followed by MIT family translocated RCC (16.4%), fumarate hydratase RCC (10.3%), chromophobe RCC (9.3%), other nccRCC (6.5%), and unclassified RCC (13.1%). The median PFS of the TKI monotherapy group and the TKI plus ICI combination group were 5.9 months (95%[CI], 4.3-7.5) versus 15.2 months (95%CI, 6.6-23.7), while mOS was 38.5 months (IQ1-IQ3=17.1-70.0) for TKI cohort and unreached (IQ1-IQ3=23.4-N) in TKI plus ICI cohort. The ORR and disease control rate (DCR) was 16.4% versus 29.4% and 48.4% versus 78.3% in the two cohorts. Any grade of AEs was 93.44% and 96.74% occurred in the monotherapy group and combination therapy group, while the incidence of grade ≥3 AEs was 23.77% and 35.87%, respectively. Conclusions: The findings from our retrospective real-world cohort of mnccRCC patients demonstrate that the combination of ICI plus TKI could significantly enhance PFS, ORR and OS compared to TKI monotherapy and no new safety signals were found. [Table: see text]
Cabozantinib (CABO) after prior immune checkpoint inhibitor (ICI) and tyrosine-kinase inhibitors (TKI) therapy in metastatic renal cell carcinoma (mRCC): Real-world evidence (RWE) from a Moscow observational program.
Authors: Polshina Natalya , Filonenko Daria , Karulina Sofia , Zhukova Lyudmila
Published: June 2024

e16526

Background: Cabozantinib is approved for metastatic renal cell carcinoma (mRCC). Data of CABO efficacy after prior ICI/ICI-TKI therapy are limited by several RWE trials. Here we report real-world evidence of CABO in Russian patients from a Moscow observational program. Methods: Patients (pts) with mRCC treated with CABO monotherapy through the Moscow observational prospective program between Feb’2022 and Jan’2024 were identified. All pts received 1-3 prior lines of therapy, all received prior ICI and TKI, either in combination or consequently. Pts with active CNS metastases were excluded from the program. Baseline clinical and treatment characteristics were collected. Rates of partial response (PR), stable disease (SD), progressive disease (PD), and disease control rate (DCR, PR+SD) were analyzed, and survival outcomes (overall survival (OS) and progression-free survival (PFS)) were calculated. Results: A total 59 patients (pts) treated with CABO were included in our analysis. Median age was 59 years (range 40-78), 46 (78%) pts were male, 54 (91,5%) pts had clear-cell histology. At time of CABO start 5 pts (8,5%) had the ECOG PS 0, 37 pts (62,7%) had ECOG PS 1, 17 pts (28,8%) had ECOG PS 2. 40 pts (67,8%) had intermediate International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk, 19 pts (32,2%) had poor IMDC risk. 45 (76,3%) pts had prior nephrectomy. 15 pts (25,4%), 27 pts (45,8%), 17 pts (28,8%) had 1, 2 and ≥3 previous treatment lines respectively; 22 pts (37%) received prior treatment with combination of ICI and TKI. 4 pts (7%), 26 pts (44%), 29 pts (49%) had 1, 2-3 and > 3 sites of metastases respectively. 31 pts (53%) had bone metastases. Median (min-max) follow-up was 14 (1-22) months (mo). Rates of best response were: PR - 20%, SD - 56%, PD - 19%. Overall DCR was 76%. Median PFS was 14 mo (12,3-15,7) with 12-mo PFS 59%. Median OS was not reached, and the 12-mo OS rate was 76%. 41% of patients had a dose reduction, 32% needed treatment interruption and 19% of pts discontinued treatment due to toxicity. Conclusions: The effectiveness of CABO observed in this real-world observational program was consistent with results from clinical trials: DCR – 76%, median PFS – 14 mo with 12-mo PFS 59% and 12-mo OS 76%. Dose modifications may be required to optimize CABO use in routine clinical practice.