bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic validation of a digital pathology-based multi-modal artificial intelligence (MMAI) biomarker in patients with metastatic hormone-sensitive prostate cancer (mHSPC) from the CHAARTED trial (ECOG-ACRIN EA3805).
Authors: Markowski Mark Christopher , Ren Yi , Croucher Danielle , Royce Trevor Joseph , Yamashita Rikiya , Tierney Meghan , Huang Huei-Chung , Todorovic Tamara , Chen Emmalyn , Carducci Michael Anthony , Chen Yu-Hui , Liu Glenn , Parker Charles , Esteva Andre , Feng Felix Y , Attard Gerhardt , Sweeney Christopher
Published: June 2024

5077

Background: The ArteraAI MMAI prognostic biomarker leverages histopathology images and clinical data to risk stratify patients (pts) with localized prostate cancer. This study aimed to validate the MMAI biomarker in mHSPC. Methods: The validation cohort included a subset of pts from the CHAARTED phase III randomized trial with known age at diagnosis, baseline PSA, T-stage, and available histopathology images. Baseline characteristics were compared to examine the balance between included and excluded patients. Using the existing MMAI model, scores were generated, and prognostic ability was evaluated for overall survival (OS) in Cox proportional hazard model. Four defined prognostic groups based on tumor volume (high (HV) vs. low (LV)) and metastatic stage at diagnosis (M1 vs. M0) were included: 1. M0LV, 2. M0HV, 3. M1LV, 4. M1HV. These clinical groups were evaluated using multivariable analysis (MVA) which included MMAI risk group and treatment. Results: A subset of the CHAARTED patient population had evaluable digital histopathological images, allowing inclusion in this study (N=456/790, 57.7%), of which 370 (81.1%) were classified as MMAI-high and 86 (18.9%) as MMAI-intermediate/low risk. Data were available from 394/456 pts for classification into M0LV (N=57), M0HV (N=29), M1LV (N=66), or M1HV (N=242). MMAI-high proportion among groups were 56.1%, 69.0%, 86.4% and 92.6%, respectively. Median follow-up of the censored patients was 4.1 (IQR: 3.3-5.0) yrs. The estimated 5-yr OS across MMAI high, intermediate, and low groups was 39%, 58%, 83%, respectively (log rank p=<0.001). On MVA, the MMAI-high risk group model associated with OS (HR: 1.77 (95% CI: 1.10-2.84) p=0.02) adjusting for treatment arm, volume status, and stage at diagnosis (Table 1). When compared to M0LV, HV subgroups were also associated with OS on MVA. Conclusions: The ArteraAI MMAI model was found to be prognostic for OS among men with mHSPC in CHAARTED. This effect persisted when controlling for treatment, metastatic burden, and metastatic status at diagnosis. On MVA, M0HV and M1HV also maintained prognostic value. This analysis is exploratory in nature, to be followed by development of a model optimized for advanced prostate cancer.[Table: see text]
Long-term survival outcomes for hormonal therapy in premenopausal patients with clinical stage I endometrial cancer.
Authors: Suzuki Yukio , Huang Yongmei , Havrilesky Laura J , Blank Stephanie V. , Elkin Elena B. , Melamed Alexander , Ferris Jennifer S. , Saji Haruya , Miyagi Etsuko , Kong Chung Yin , Myers Evan R. , Wright Jason Dennis
Published: June 2024

5508

Background: As the number of young women with early-stage endometrial cancer is increasing, there is growing interest in use of progesterone-based therapy to allow fertility preservation. To date, there is a paucity of data on the safety and long-term outcomes of progesterone therapy. The objective of our study was to determine the safety and long-term outcomes of hormonal therapy for clinical stage I endometrial cancer in premenopausal women. Methods: The National Cancer Database was used to identify patients 18-49 years of age with clinical stage I, grade 1-2, endometrioid endometrial cancer diagnosed from 2004-2020. Primary treatment was defined as hysterectomy or hormonal therapy. Trends in the use of hormonal therapy were examined. A multivariable regression model was developed to examine the association between hormonal therapy and demographic factors. After propensity score matching, survival was compared between patients treated primarily with hormonal therapy and with primary hysterectomy. Results: A total of 15,849 patients, including 14,662 (92.5%) treated with primary hysterectomy and 1,187 (7.5%) who received primary hormonal therapy were identified. The use of hormonal treatment increased from 5.2% in 2004 to 13.8% in 2020 (P<0.0001). In a multivariable model, younger age, more recent year of diagnosis, non-White race, lower tumor grade, and earlier stage were associated with use of hormonal therapy (P<0.05 for all). After propensity score balancing, 5-year survival was 98.5% (95% CI, 97.3-99.2%) for hysterectomy and 96.8% (95% CI, 95.3-97.8%) for hormonal therapy (HR=1.84; 95% CI 1.06-3.21). Among patients <40 years of age, there was no difference in survival between hysterectomy and hormonal therapy (HR=1.00; 95% CI, 0.50-2.00). However, for patients age 40-49, hormonal therapy was associated with a significantly increased risk of death (HR=4.94; 95% CI, 1.89-12.91). There was no statistically significant difference in outcomes for hormonal therapy compared to hysterectomy in sub-set analyses stratified by grade (1 or 2) or stage (1A or 1B). Conclusions: The use of fertility-preserving hormonal therapy among reproductive age patients with early-stage endometrial cancer has increased over time. Among women age 40-49, hormonal therapy is associated with decreased survival. [Table: see text]
Final safety results from ATHENA–MONO (GOG-3020/ENGOT-ov45), a randomized, placebo-controlled, double-blind, phase 3 trial evaluating rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer.
Authors: O'Malley David M. , Monk Bradley J. , Lim Myong Cheol , Fuentes Pradera Jose , Buscema Joseph , Wilson Michelle K. , De Vivo Rocco , Herzog Thomas J. , Zagouri Flora , Oza Amit M. , Mikheeva Olga N. , Diaz John Paul , Lisyanskaya Alla Sergeevna , Morris Robert , Bruchim Ilan , Craib Marcia , Connor Christy , Shih Danny , Fujiwara Keiichi , Kristeleit Rebecca
Published: June 2024

5554

Background: Rucaparib provided a sustained progression-free survival benefit in patients (pts) with newly diagnosed advanced ovarian cancer after first-line treatment in the phase 3 ATHENA-MONO study (NCT03522246). We report final safety analyses (data cutoff 09 Mar 2023). Methods: Rucaparib was administered in 28-day cycles. Eligible pts were randomized 4:1 to oral rucaparib 600 mg BID (N=427) or placebo (N=111), with a treatment cap defined as 24 months. The safety population included randomized pts who received at least 1 dose of study drug (rucaparib, n=425; placebo, n=110). Results: All ATHENA-MONO pts discontinued treatment as of 24 Nov 2022 with a median treatment duration of 15 months and 35% of pts reaching the 24-month treatment cap. The median (range) relative dose intensity was 89% (30-110) for rucaparib. The rate of treatment-emergent adverse events (TEAEs), grade ≥3 TEAEs, TEAEs leading to interruption, dose reduction, or discontinuation with rucaparib remained consistent with the primary endpoint analysis with some minor changes (see Table below). Most common grade ≥3 TEAEs were anemia/decreased hemoglobin (28.7%), neutropenia/decreased neutrophils (14.6%), increased ALT/AST (10.6%), and thrombocytopenia/decreased platelets (7.3%). The most common TEAEs leading to discontinuation were anemia/decreased hemoglobin (3.5%), asthenia/fatigue (4.9%), and nausea (2.1%). Hypertension continued to be the most common TEAE observed in the placebo group (3.6%) compared with 1.6% in the rucaparib group. There were no changes in the incidence of serious adverse events or TEAEs leading to death since the primary endpoint analysis. Myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) were reported in a total of 3 pts in the rucaparib group (1 MDS during treatment [0.2%] and 1 AML and 1 MDS during long-term follow-up [0.5%]), of which the latter occurred since the primary readout. The initial MDS event that occurred during treatment, included in these incidence numbers, was considered resolved by the investigator since the initial analysis. Conclusions: Long-term maintenance treatment with rucaparib demonstrates a consistent and manageable safety profile in a broad population of pts with newly diagnosed ovarian cancer. No new safety signals were identified. Adverse events were generally manageable and led to discontinuation in a low proportion of pts. Clinical trial information: NCT03522246 . [Table: see text]
Consistent data about the predictive factors of the success of interval debulking surgery (CC0-IDS) in patients with advanced ovarian cancers in two large independent datasets.
Authors: You Benoit , Fagotti Anna , Colomban Olivier , Giannarelli Diana , Blanc-Durand Felix , Scambia Giovanni , Carrot Aurore , Lorusso Domenica , Pujade-Lauraine Eric , Ergasti Raffaella , De Rauglaudre Gaetan , Sassu Carolina Maria , Ray-Coquard Isabelle Laure , Capomacchia Filippo Maria , Combe Pierre , Apostol Adriana Ionela , Ferron Gwenael , Malapelle Umberto , Leary Alexandra , Marchetti Claudia
Published: June 2024

5560

Background: More than 50% of patients with FIGO stage III-IV epithelial ovarian cancers are treated with neoadjuvant chemotherapy (NACT) to achieve a complete interval debulking surgery (IDS), in the case of tumor response. Therefore, understanding the determinants of IDS success is crucial. The French GINECO and the Gemelli (Italy) groups analyzed 2 independent datasets to identify the predictive factors associated with low peritoneal carcinomatosis index (PCI) after 3or4 NACT cycles; complete IDS with no macroscopic residual lesion (CC0); high pathological chemotherapy response score (CRS3). Methods: The French dataset was built with the CHIVA (C) randomized phase II trial in 133 patients (NCT01583322). The Italian dataset was built with the Policlinico GEMELLI (G) real-life registry with 357 patients (ID5936–ProtN45). Univariate/multivariate logistic regression models were used to identify the clinical and biological covariates associated with: 1) low PCI after NACT (Sugarbaker PCI ≤ 10, or Fagotti score at IDS ≤ 2); 2) CC0 IDS; and 3) pathological CRS3. The tested predictors were the modeled CA-125 longitudinal kinetics parameter KELIM; the best radiological response according to RECIST 1.1; and BRCA mutation/ homologous recombination deficiency (HRD) status (C: ShallowHRD; G: Myriad&AmoyDx). The analyses were led independently in the 2 datasets. Results: Odds-ratios (OR) outcomes [95%CI] are presented in Table (*significant variables at multivariate). In both datasets, higher KELIM was the only predictor reproducibly associated with lower PCI after NACT (OR 4.08-4.44); higher probability of complete IDS (OR 4.66-7.29); and higher probability of pathology CRS3 (OR 2.97-12.43). The radiological response was inconsistently significant. The BRCA/HRD status was not predictive of IDS success elements. Conclusions: In 2 independent international datasets, the tumor primary chemosensitivity (assessed by CA-125 KELIM) was the only consistent predictor of IDS success after NACT in both datasets. Clinical trial information: NCT01583322 . [Table: see text]
The BEV1L study: Do real-world outcomes associated with the addition of bevacizumab to first-line chemotherapy in patients with ovarian cancer reinforce clinical trial findings?
Authors: Duska Linda R. , Lim Jonathan , Boyle Tirza Areli Calderón , Guinter Mark , Halloran Siobhan , Hartman John , Schilder Jeanne M. , Hurteau Jean A. , Golembesky Amanda
Published: June 2024

5563

Background: Data from the GOG-0218 (NCT00262847) and ICON7 (NCT00483782) trials suggest that adding bevacizumab (bev) to first-line (1L) chemotherapy (CT) for treatment of stage III/IV ovarian cancer (OC) improves progression-free survival (PFS) among the overall population, but an improvement in overall survival (OS) may be limited to patients (pts) with high-risk clinical factors. Real-world (rw) evidence assessing the impact of adding bev to 1L CT may help identify subgroups of pts who may benefit from 1L CT alone vs CT + bev. Methods: This retrospective study included pts from the US nationwide Flatiron Health electronic health record–derived deidentified database who were diagnosed with stage III/IV epithelial OC on/after 1/1/2016 and initiated 1L CT ± bev on/after 1/1/2017. Pts with high-risk clinical factors were defined as those with stage IV disease or stage III disease with either visible residual disease or no evidence of surgery. Rw endpoints included time to next treatment (rwTTNT), rwPFS, and rwOS. Kaplan-Meier methods were used to estimate unadjusted median outcomes, indexed to 1L start date. Results: Among 1752 pts, median age was 68 years (IQR, 60–75 years), and median follow-up time was 18.5 months (IQR, 8.0–36.6 months). Among pts with high-risk clinical factors, median rwTTNT was significantly longer with 1L CT + bev than with CT alone; no differences were seen with median rwPFS, although a trend toward longer rwOS was observed with 1L CT + bev vs with CT alone (Table). Among pts without high-risk clinical factors, no significant differences were observed in median estimates of rwTTNT, rwPFS, or rwOS between pts receiving 1L CT + bev and pts receiving CT alone. Conclusions: This rw study provides support for findings from ICON7 and GOG-0218, suggesting that the benefit of adding bev to 1L CT may be limited to pts with high-risk clinical factors. [Table: see text]
Artificial intelligence to predict homologous recombination deficiency in ovarian cancer from whole-slide histopathological images.
Authors: Frenel Jean-Sebastien , Bossard Céline , Rynkiewicz Joseph , Thomas Florian , Salhi Yahia , Salhi Sanae , Chetritt Jérôme
Published: June 2024

5578

Background: In the field of ovarian cancer diagnosis, predicting Homologous Recombination Deficiency (HRD) holds paramount importance for personalized treatment strategies. Histopathology tissue analysis is considered as the gold standard in cancer diagnosis, prognosis, and theranostic. Whole Slide Imaging, i.e the scanning and digitization of entire histology slide, is now being adopted in numerous pathology labs, allowing development of deep-learning analysis of the large amount of morphological features contained in these WSI. The aim of this study is the development of a cutting-edge deep learning model designed to predict HRD status directly from WSIs of ovarian cancer tissue samples. Methods: We introduce a DNN designed to predict the HRD status for patients with ovarian cancer from whole slide images (WSI), using a fusion-like model using both cellular information and tissue-level morphological features. The algorithm has been trained and evaluated using a cross-testing and cross-validation technique on 151 patients with at least one WSI from a discovery dataset using a 5-fold stratified framework. We then externally validated the model onto The Cancer Genome Atlas (TCGA) from which the HRD status is available (n=93). Results: The performance of HRD status prediction was assessed on the basis of area under curve (AUC).The proposed architecture achieved an AUC of 0.74 on the discovery cohort and 0.67 on the TCGA. Results to the pathologist could be provided immediately and integrated into the pathologist report. External validation on the PAOLA cohort dataset is ongoing. Conclusions: By harnessing the power of deep neural networks (DNN), we provide a rapid and scalable solution for HRD prediction, circumventing the limitations of traditional molecular assays. Successful integration of this deep learning model into routine pathology workflows could significantly enhance diagnostic efficiency, reduce the turnaround time and financial cost compared with molecular assay. It could finally inform clinicians in tailoring targeted therapeutic interventions for ovarian cancer patients, thereby advancing precision medicine in the context of HRD-associated ovarian cancers.
Phase II study of pembrolizumab and lenvatinib in platinum sensitive recurrent ovarian cancer.
Authors: Bauer Smadar , Saad Akram , Greenhouse Inbal , Rapoport Anna Ruth , Shahar Shir , Barnatan Tania , Satchi-Fainaro Ronit , Shapira-Frommer Ronnie
Published: June 2024

5581

Background: Ovarian cancer (OC) is characterized by a high recurrence rate following primary surgical and systemic therapy with decreasing efficacy of subsequent treatment lines and accumulating toxicity. Immunotherapy had shown limited efficacy in recurrent OC with 8% response rate in a notable cohort study (Keynote 100).The combination of Pembrolizumab (P) with Lenvatinib (L) was evaluated in a small cohort of platinum resistant OC (LEEP 005) with a 32% response rate. This study assessed the P+L combination’s effectiveness in the platinum sensitive recurrence setting. Methods: In this investigator initiated phase 2 study (NCT04519151), we enrolled patients with platinum sensitive recurrent OC. Inclusion criteria were high grade serous or endometrioid histology, maximum of two previous treatment lines, measurable disease per RECIST 1.1, reserved organ function, and ECOG of 0 or 1. Patients received P (200mg every three weeks) and L (20mg daily) until disease progression or unacceptable toxicity or up to 35 cycles of P. L treatment could be maintained beyond 35 courses of P per investigator decision. Study's primary end point is response rate (RR), and secondary end points encompass progression-free survival (PFS), overall survival (OS), duration of response (DOR), safety, and quality of life. Correlative study explored archival/fresh tumor tissue and blood biomarkers for response as well as fecal and vaginal microbiome. Results: Between May 2021 and July 2023 24 patients were treated. Median age was 65 years (range 43-77). 11(46%) received 1 prior treatment line and 11(46%) received prior bevacizumab. At a median follow up of 30 months, 12/24 (50%) had RECIST 1.1 response, 2 (8%) with CR and 10 (42%) with PR. Median PFS was 8 months. Median OS and DOR were not reached. At 6 and 12 months, response persisted in 10 and 3 patients, respectively. Treatment-related adverse events were noted in all patients, predominantly hypertension and fatigue. Dose reduction of L occurred in 19 (79%) patients mainly due to hypertension 8(33%), fatigue in 7(30%) and arthralgia in 5(21%). Discontinuation due to adverse event occurred in three patients (hepatitis, nephrotic range proteinuria, diabetic keto-acidosis). There was no treatment-related death. Data on the QOL analysis and biomarker study will be presented later. Conclusions: L+P combination showed meaningful responses and manageable toxicity in platinum sensitive recurrent OC patients thus potentially provides a non chemotherapy alternative. Effect on survival and response to subsequent therapies is yet to be evaluated. Further research is essential to pinpoint the patient subset that can benefit the most from this combination. Clinical trial information: NCT04519151 .
Phase 2, single arm clinical trial to evaluate the safety and activity of oregovomab and niraparib as a combinatorial immune priming strategy in subjects with platinum sensitive recurrent ovarian cancer: FLORA-4 study.
Authors: Duska Linda R. , Secord Angeles Alvarez , Richardson Debra L. , Jada Srinivas Rao , Gupta Sunil
Published: June 2024

5586

Background: Oregovomab, a murine IgGκ1 MAb, with high affinity binding (1.16 x 1010/M−1) to the tumor associated antigen CA125 acts as a therapeutic vaccine inducing indirect immunization by cellular and humoral immune responses directed against CA125. We hypothesize that T cells which have been immune sensitized by oregovomab may be further activated in the presence of niraparib mediated induction of STING (STimulator of INterferon Genes). The primary objective was to assess the safety and activity of combination oregovomab and niraparib in platinum sensitive EOC. Methods: An open-label single arm Phase 2 evaluation of the combination of oregovomab and niraparib in subjects previously treated with 1 to 3 lines of platinum-based chemotherapy. All subjects received the niraparib and oregovomab. The daily dose of niraparib was weight based (200-300 mg) taken orally from Day 1 Week 1 to at least the end of Week 12. Oregovomab (2 mg) was administered at Day 1 of Weeks 1, 4, 7, 12, and 20. This study endpoints were disease control rate (DCR) defined as patients that achieved CR, PR and SD; early humoral response; and safety. Results: Between July 2022 and June 2023, 10 eligible patients with a median age was 67.5 years were enrolled, and all patients were included in this analysis. 6 patients had received 2 prior lines and 4 patients had received 1 prior line of chemotherapy. Five patients received prior PARP inhibitors, 1 patient with HRD, and 1 patient with gBRCA mutation. The median number of oregovomab doses administered were 5 (range, 2.0 to 5.0) and median niraparib doses were 118.5 (range, 28.0 to 168.0). Of the 10 patients enrolled, 1 patient (10%) achieved an objective partial response (PR) and 5 patients had disease stabilization (SD), for an overall DCR of 60% at 12 weeks assessment. Of the 5 patients with SD, 2 maintained SD until week 24 assessment while the remaining patients progressed. The duration of response in the 1 patient with objective response was 2.9 months and the median duration of DCR is not evaluable (range 2.9 months - NE). Treatment related all grades adverse events (AEs) to niraparib included anemia (30%), thrombocytopenia (30.0%) and hypertension (30.0%), and oregovomab related all grades AEs included urticaria in 1 patient (10%). Conclusions: Combination oregovomab and niraparib in patients with platinum sensitive EOC was well tolerated with no new safety signals. Translational research is ongoing to assess biomarkers of early humoral response. Clinical trial information: NCT04498117 .
Benmelstobart (TQB2450) combined with anlotinib hydrochloride capsule in the treatment of advanced, recurrent, or metastatic endometrial cancer: A multicohort, open label, multicenter, phase II clinical trial (TQB2450-II-08).
Authors: Wu Xiaohua , Chen Xiaojun , Wang Ke , Wang Dong , An Ruifang , Hou Jianqing , Yang Ying , Wang Danbo , Qu Pengpeng , Zhang Bingzhong , Duan Wei , Li Xiumin , Zang Ai-min , Yu Guohua , Lou Hanmei , Yao Desheng , Wang Shuzhen , Yan Dong , Li Liang , Liu Xiaowei
Published: June 2024

5593

Background: The treatment options after first-line chemotherapy for endometrial cancer (EC) are very limited. Several immune checkpoint inhibitors or combined with antiangiogenic drugs have shown antitumor activity and been approved in EC. Anlotinib is a multiple-targeted tyrosine kinase inhibitor that has been approved for the treatment of several solid tumors. Benmelstobart (TQB2450) is a humanized monoclonal antibody targeting programmed death-ligand 1 (PD-L1). This multicohort, open label, multicenter, phase II study aims to evaluate the efficacy and safety of TQB2450 injection or combined with anlotinib hydrochloride capsule in the treatment of recurrent or metastatic advanced EC. Methods: Patients with pathologically confirmed recurrent or metastatic advanced EC failed at 1 or 2 prior lines of therapy will be enrolled. Non-MSI-H/dMMR patients were treated with TQB2450+anlotinib therapy (TQB2450 1200mg, IV D1/Q3W; anlotinib 12mg PO QD, D1-14/Q3W) (cohort 1) or anlotinib (cohort 3), MSI-H/dMMR patients were treated with TQB2450 (cohort 2), until disease progression or intolerable toxicity experienced. Cohort 1 is divided into two stages for enrollment. In the first stage, 22 patients are enrolled. If the lower limit of the confidence interval is greater than 15%, indicating that there are at least 8 patients achieved CR/PR, consideration can be given to proceeding to the next stage. In the second stage, 85 patients are enrolled. The primary endpoint was the objective response rate (ORR) by independent review committee (IRC). Key secondary endpoints include ORR by investigator, disease control rate (DCR), duration of response (DoR), progression free survival (PFS), overall survival (OS) and safety. Results: As of November 09, 2023, 170 patients were enrolled and treated (cohort 1 N=107, cohort 2 N=32, cohort 3 N=31). In the first stage, 22 patients enrolled, 8 achieved CR/PR, and the study progressed to the second stage in cohort 1. Antitumor activities are shown in the table. Treatment-emergent adverse events (TEAEs) occurred in 99.07%, 100% and 100% of patients. Grade ≥3 TEAEs were reported in 74.77%, 40.63% and 87.10% of patients, respectively, with the most common ones being weight loss (46.73%, 25%, 29.03%), white blood cell decreased(47.66%, 12.5%, 19.35%), blood corticotrophin increased (44.86%, 15.63%, 22.58%), thyroid stimulating hormone increased (37.38%, 3.13%, 25.81%). Conclusions: TQB2450 plus anlotinib showed promising antitumor activity with a manageable safety profile in the treatment of recurrent or metastatic advanced EC. Clinical trial information: NCT04574284 . [Table: see text]
Combined uterine and colorectal screening: A call for action.
Authors: Jiang Ruolin Lorraine , Johnson Caitlin Ruth , Francoeur Alex Andrea , Mann-Grewal Amandeep Kaur , Kapp Daniel Stuart , Chan John K
Published: June 2024

5615

Background: Colon cancer is currently one of the top three malignancies in the US with routine screening guidelines in place. With the current rise in uterine cancer incidence and mortality, there is currently no screening for uterine cancer. We propose to evaluate the demographics and trends in uterine and colorectal cancer incidences among women in the United States. Methods: Uterine and colorectal cancer incidence data among U.S. women were collected from the United States Cancer Statistics (USCS) database from 2001-2019. Annual estimated uterine and colon cancer incidence data among women was obtained from the American Cancer Society (ACS) from 2015-2024. SEER*Stat 8.3.9.2 and Joinpoint regression program 4.9.0.0 were used to calculate cancer incidences and trends per 100,000. Average annual percentage change (AAPC) was used to describe trends. Age-adjusted incidences were adjusted by the U.S. 2000 standard population. SAS Enterprise Guide v 7.1 was employed to analyze estimated cancer incidences. Results: From 2001-2019, 904,032 incident uterine cases were identified from USCS. Regarding race, 76.5% identified as non-Hispanic White, 10.5% as non-Hispanic Black, 8.38% as Hispanic, and 3.42% as non-Hispanic Asian/Pacific Islander. Of the 1,337,470 incident colorectal cancer cases obtained from USCS, 76.4% identified as White, 12.1% as Black, 7.10% as Hispanic, and 3.23% as Asian. Using ACS data from 2015-2024, the estimated number of annual incident uterine cancer cases increased from 54,870 to 67,880 while colorectal cancer incidence changed from 63,610 to 71,270 cases over the past 10 years (p<0.0001). Using a projection model, we predict that the incidence of uterine cancer will surpass colon cancer by 2025 at 40.17 and 37.07/100,000 respectively (Table). Given that Black women have a high rate of increasing uterine cancer incidence (AAPC 2.88%; p<0.0001), we predict that uterine cancer incidence among Black populations will surpass their rate of colon cancer by 2025 (42.97 vs 35.10/100,000). Conclusions: These findings suggest that uterine cancer incidence is increasing at a concerning rate and will likely surpass colon cancer by 2025. The impact of health disparities on Black women calls for research on the need for screening and novel therapies. [Table: see text]
Genomic alterations and clinical outcomes in patients with non-clear cell RCC: Indiana University experience.
Authors: Taza Fadi , Tran Mya , Hassoun Rebecca , Althouse Sandra K. , Fausel Christopher A. , Schneider Bryan P. , Salous Tareq , Logan Theodore F. , Adra Nabil , King Jennifer
Published: June 2024

e16506

Background: Non-clear cell RCC (nccRCC) represents a heterogeneous group of tumors with sparse data on the clinical features and genomic landscape. Here, we describe a real-world cohort of nccRCC patients, characterize the genomic makeup, and report on clinical outcomes utilizing contemporary therapeutic strategies. Methods: Patients with nccRCC treated at Indiana University and who underwent genomic sequencing between 2015-2023 were included in this analysis. Baseline demographic and disease characteristics were summarized. Kaplan-Meier method was used to analyze progression-free survival (PFS) and overall survival (OS) using the log rank test to compare groups. Results: 55 patients were included. The median age at diagnosis was 56 years. 48 patients (87%) had metastatic disease. 25 (45.5%) had de novo metastatic disease. The most common histology subtypes included were unclassified (n=18; 32.7%), papillary (n=14; 25.5%), chromophobe (n=6; 10.9%), translocation (n=5; 9.1%), renal medullary (n=3; 5.5%), collecting duct (n=3; 5.5%), and other (n=6; 11.0%). Rhabdoid and/or sarcomatoid features were present in 32% (n=18). First-line systemic therapy for metastatic disease was single agent tyrosine kinase inhibitor (TKI) in 14 patients (29.2%), combination immunotherapy (IO-IO) for 11 patients (23.0%), combination IO-TKI for 11 patients (23.0%), single agent IO for 2 patients (4.2%), cisplatin-gemcitabine in 5 (10%), and other in 5 patients (10%). Genomic alterations are summarized in the table. Overall, diverse mutations were detected across variant subtypes, including alterations in TP53, CDKN2A, NF2, chromatin modulation ( SETD2, BAP1, PBRM1), PI3K/AKT (PIK3CA, PTEN, mTOR), and VHL/HIF pathway. Median PFS was 0.6 (0.3-0.9) years. No statistical difference was observed in the median PFS between the histology subgroups. 2-year OS for chromophobe histology was 100%, unclassified was 62.2%, papillary was 56%, and other histologies was 40.4%. 2-year OS for all patients treated with IO-TKI was 85.7%, single agent TKI was 47.9%, IO-IO was 38.6%, and NE for single agent IO. Conclusions: In this real-world cohort of patients with nccRCC, unclassified histology had the highest frequency of the most common genomic alterations evaluated. There was a trend with improved 2-year OS for patients with chromophobe histology and patients treated with IO-TKI. [Table: see text]
The impact of smoking status on genomic profile in patients with renal cell carcinoma.
Authors: Pham Phillip , Hassoun Rebecca , Althouse Sandra K. , Tran Mya , Fausel Christopher A. , Schneider Bryan P. , Logan Theodore F. , Salous Tareq , Adra Nabil , King Jennifer
Published: June 2024

e16521

Background: Cigarette smoking is a known risk factor for the development of renal cell carcinoma (RCC), and active smoking has been associated with decreased survival in patients (pts) receiving systemic targeted therapies for RCC. The impact of smoking status on tumor genomics in other malignancies has been evaluated, particularly in urothelial carcinoma. Here, we investigated the impact of smoking status on genomic alterations and outcomes in pts with RCC. Methods: Pts with history of RCC who underwent genomic sequencing between 2015-2023 at Indiana University were included. Baseline demographic and disease characteristics were summarized. Pts were classified by smoking history into either no smoking history or history of smoking, which included both pts who currently or previously smoked. Comparisons between groups were done using the Chi-square test for categorical variables and Wilcoxon test for continuous variables. Kaplan-Meier method was used to analyze progression free survival (PFS) and overall survival (OS), using the log rank test to compare groups. Results: 144 pts were included. 63 (43.8%) were never smokers, 58 (40.3%) previously smoked, and 23 (16.0%) currently smoked. 103 (71.5%) were male. Median age at diagnosis was 58yrs (range: 24-83). Pts who currently smoked had a median age of 52 yrs vs. 59yrs for both pts who previously smoked and who never smoked (p=0.021). 133 pts (92.4%) were white. Histology was 69.4% clear cell, 9.0% unclassified, 9.1% papillary, 2.1% translocation, 2.1% collecting duct, 1.4% renal medullary, 1.4% chromophobe, 1.4% poorly differentiated, 0.7% mixed, and 3.4% other. Histology did not differ based on smoking status. Rhabdoid and/or sarcomatoid features were present in 28.8% of pts. 138 pts (95.8%) had metastatic disease. 65 pts (47.1%) presented with de novo metastatic disease. Metastasis sites included lung 56.9%, regional lymph nodes (LN) 40.3%, bone 31.9%, liver 17.4%, distant LN 18.8%, and brain 6.9%. The table lists genomic alterations in patients with and without a smoking history. Overall, 2-yr PFS was 9.2% and 2-yr OS was 86.5%. 2-yr PFS in pts with a smoking history was 9.2% vs. 8.6% in pts without a smoking history. 2-yr OS in pts with a smoking history was 90.1% vs. 82.3% in pts without a smoking history (p=0.49). Conclusions: In this cohort of pts, there was a trend toward more frequent PBRM1 mutations, which have been associated with improved response to immunotherapy, in pts with a history of smoking. Larger datasets are needed to further evaluate potential genomic differences based on smoking history that may reflect increased sensitivity to particular systemic therapies. [Table: see text]
HALP index in patients with metastatic clear-cell RCC treated with nivolumab.
Authors: Palacka Patrik , Obertova Jana , Chovanec Michal , Sycova-Mila Zuzana , Stefanikova Katarina , Slachtova Eva , Zak Monika , Savka Alexander , Hrncar Matej , Mego Michal , Rejlekova Katarina
Published: June 2024

e16523

Background: To evaluate the prognostic value of the index combining hemoglobin and albumin levels with lymphocyte and platelet counts (HALP) in patients with metastatic clear-cell RCC treated with nivolumab. Methods: We enrolled 149 subjects (38 females), median age 62 years, treated with nivolumab 240 mg biweekly or 480 mg each 28 days following progression on at least one TKI from 2016 to 2024. The study population was dichotomized based on the median of HALP index (24.12), which was calculated as hemoglobin (g/L) x albumin (g/L) x absolute number of lymphocytes / platelets (g/L) at initiation of immunotherapy. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method with differences analyzed by the log-rank test. Multivariate Cox proportional-hazards model was used to evaluate the prognostic value of the HALP, ECOG performance status and lactate dehydrogenase (LDH). Results: At the median follow up 17.4 months, 122 patients progressed on nivolumab and 87 died. ECOG 2 v ECOG 0 and 1 was associated with significantly worse PFS and OS ( P < 0.0001, HR 0.21 and P < 0.0001, HR 0.15, respectively). Both survivals were shorter in patients with serum LDH higher than 1.5-time of normal range compared to lower levels ( P = 0.0034, HR 0.47 for PFS and P < 0.007, HR 0.45 for OS). Low HALP correlated with worse PFS ( P = 0.0121, HR 0.62) and OS ( P = 0.0025, HR 0.50). The independent prognostic value of HALP index was showed in multivariate analysis. Conclusions: HALP index determined at initiation of nivolumab in second or third line was an independent prognostic factor for survival of metastatic clear-cell RCCs. A nomogram based on the HALP could accurately predict prognosis of these patients. Key Words: Blood Counts. Albumin. Metastatic Disease. Renal-Cell Carcinoma. Nivolumab.
Improved overall survival with immune checkpoint inhibitors in the treatment of metastatic urothelial carcinoma: A national retrospective comparative study.
Authors: Yu Chih-Chin , Su Po-Jung , Tsai Yao-Chou
Published: June 2024

e16550

Background: Numerous randomized trials have illustrated the survival advantages of immune checkpoint inhibitors (ICI) in metastatic urothelial carcinoma. However, the application of ICI varies in different trials, encompassing first-line, second-line, monotherapy, combination with chemotherapy, or maintenance therapy. Real-world clinical practices often diverge from trial criteria. This study aims to evaluate the effectiveness of any ICI regimen in treating metastatic urothelial carcinoma using real-world data. Methods: This retrospective comparative study included patients diagnosed with locally advanced or metastatic urothelial carcinoma between January 2015 and July 2023, sourced from the Taiwan Upper Tract Urothelial Cancer and Bladder Cancer Collaboration Database. Patients with prior neo-adjuvant or adjuvant systemic therapy were excluded. Results: Among 427 patients, 152 (35.6%) who received any ICI as the first-line or second-line regimen constituted the ICI group, while the remaining 275 (64.4%) patients receiving only chemotherapy formed the chemotherapy group. Within the ICI group, 55 (36.2%) patients received monotherapy, 49 (32.2%) received combination therapy with chemotherapy, and 4 (2.6%) received maintenance therapy as the first-line regimen. The remaining 44 (28.9%) patients received ICI as the second-line regimen. No significant differences were observed in age, sex, performance status, renal function, tumor site, ratio of locally advanced disease, ratio of visceral metastasis, and ratio of previous radical surgery between the two groups. Median overall survival (OS) from the start of the first-line therapy was 15.8 months in the ICI group and 10.2 months in the chemotherapy group. Kaplan-Meier curves demonstrated that the ICI group exhibited superior OS and cancer-specific survival compared to the chemotherapy group (log-rank p= 0.009 and 0.004, respectively). In the multivariable analysis, the ICI group also demonstrated favorable outcomes in OS [hazard ratio (HR) 0.726, p=0.011] and cancer-specific survival (HR 0.67, p=0.004). Conclusions: Our study confirms the clinical efficacy of ICI in metastatic urothelial carcinoma. The use of ICI monotherapy or combination in the first-line or second-line regimen for metastatic urothelial carcinoma improves patient survival. [Table: see text]
Immunotherapy plus chemotherapy versus chemotherapy alone as first-line treatment for advanced urothelial cancer: A systematic review and meta-analysis of randomized controlled trials.
Authors: Alves Ana Caroline Fonseca , Silva Isadora Mamede Mendes da , Escalante Romero Lorena , Celso Davi Said Gonçalves , Reis Pedro Cotta Abrahão , Dacoregio Maria Inez , Stecca Carlos
Published: June 2024

e16554

Background: Platinum-based chemotherapy (CTX) has stood as the cornerstone in the treatment of advanced urothelial cancer (aUC) for decades, with limited alternative options available. The landscape shifted with the integration of PD-1 and PD-L1 inhibitors into the therapeutic arsenal, emerging as pivotal post-platinum therapies. The exploration of their potential role in the initial treatment of aUC is now a subject of active investigation. In response to these advancements, we conducted a meta-analysis to evaluate the effectiveness of immunotherapy in the first-line management of aUC patients. Methods: A systematic search across PubMed, Embase, and Cochrane identified randomized controlled trials (RCTs) comparing PD-1 and PD-L1 inhibitors combined with CTX versus CTX alone for aUC. Outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and treatment-related adverse events (TRAE). Heterogeneity was assessed using I2 statistics, employing a random-effects model for analysis. Statistical analyses were performed using R software version 4.3.2. Results: Among 2,162 patients from three RCTs, 1,106 (51.16%) received immunotherapy. Combining immunotherapy to CTX demonstrated substantial improvements in both PFS (HR 0.78; 95% CI 0.70-0.86; p < 0.01) and OS (HR 0.84; 95% CI 0.75-0.93; p < 0.01) compared to CTX alone in the entire cohort. Enhanced PFS was observed in both Cisplatin (HR 0.71; 95% CI 0.62-0.82; p < 0.01) and Carboplatin (HR 0.85; 95% CI 0.73-0.98; p = 0.03) subgroups. Significant OS benefit was restricted to the cisplatin subgroup (HR 0.80; 95% CI 0.69-0.93; p < 0.01), while in the Carboplatin subgroup, the benefit was only numerical (HR 0.87; 95% CI 0.75-1.01; p = 0.06), with no significant differences between subgroups (pinteraction = 0.44). Additionally, immunotherapy exhibited a higher ORR (RR 1.20; 95% CI 1.06-1.36; p < 0.01), with no significant differences in grade ≥ 3 TRAE (RR 1.06; 95% CI 0.98-1.15; p = 0.13). Conclusions: These findings underscore the effectiveness of combining PD-1 and PD-L1 inhibitors with CTX, revealing improved progression-free and overall survival in aUC compared to CTX alone. As anticipated, outcomes were better in patients treated with cisplatin, reaffirming its possible superiority over carboplatin regimens. Our results provide compelling evidence supporting the combination of immunotherapy and CTX as a first-line treatment option for patients with aUC.
Single-center retrospective analysis of safety and efficacy of dose-reduced enfortumab vedotin (EV) in frail patients with metastatic urothelial carcinoma (mUC).
Authors: Song Wilbur , Tao Yu , Luo Jingqin , Roth Bruce J. , Reimers Melissa Andrea
Published: June 2024

e16556

Background: EV is a Nectin-4 directed ADC with activity in mUC. EV monotherapy increased PFS and OS compared to salvage chemotherapy in pretreated mUC. EV + pembrolizumab increased PFS and OS compared to chemotherapy as first-line therapy and is being explored in the perioperative setting. Thus, EV will likely have an increasingly prominent role in the management of UC. However, EV is given until disease progression and has significant toxicities, especially for elderly or frail patients. Other than the initial dose escalation, no studies have reported the efficacy or safety of starting EV at a dose lower than the approved dose of 1.25 mg/kg. Methods: We performed a single-center retrospective analysis of patients treated with EV from 1/1/2020 to 12/25/2023. Data were collected by chart review including labs, imaging, and clinical documentation. Grades of toxicity were assigned based on CTCAE v5.0 criteria with available data. Radiographic response was determined by the investigator. We evaluated outcomes including ORR, PFS, OS, and EV-associated AEs, and compared these between patients who received 0.75 mg/kg (“low-dose”) and patients who received higher doses (“standard-dose”). Given the small sample size, we present only descriptive statistics. Results: We analyzed data from 18 patients treated with standard-dose EV and from 9 patients treated with low-dose EV. The low-dose group, compared with the standard-dose group, had a similar number of females (33% vs 44%) and non-whites (33% vs 28%), and higher median age at first EV dose (81 vs 68). The low-dose group had a lower rate of prior curative intent surgery (55% vs 78%) and upper tract disease (11% vs 50%), and fewer prior lines of treatment in the palliative setting (median 1 vs 2). In the low-dose group, ORR was 78% with CR in 33%. With a median follow up of 15.9 months, median PFS and median OS from EV initiation were not estimable. In the standard-dose group, ORR was 78% with CR in 28%. With a median follow up of 28.2 months, median PFS was 8.9 months and median OS was 24.1 months. The low-dose group had similar or lower grades of EV-associated AEs (Table). Conclusions: Patients treated with low-dose EV 0.75 mg/kg had similar responses compared to historical controls and a same-institution cohort of patients treated with standard-dose EV, with lower rates of GI toxicities, rash, and peripheral neuropathy. Findings are limited by small sample size, retrospective nature, and differences in baseline characteristics. Low-dose EV in elderly or frail patients with baseline comorbidities warrants prospective study. [Table: see text]
Preliminary results of bladder sparing by short-course radiotherapy combined with toripalimab in high-risk/extremely high-risk non-muscle invasive bladder cancer (HOPE-04).
Authors: Wen Feng , Tan Ping , Lin Tianhai , Zeng Hao , Wei Qiang , Zhang Peng , Shen Yali
Published: June 2024

e16557

Background: To evaluate the treatment safety and efficacy of short-course radiotherapy combined with PD-1 antibody (Toripalimab) as a potential bladder-preserving therapy for high-risk / extremely high risk non-muscle invasive bladder cancer (NMIBC). Methods: HOPE-04 is a single-arm open-label, phase II trial, which designs to evaluate the safety and efficacy of short-course radiotherapy (5 × 5 Gy) and Toripalimab as a novel bladder sparing treatment in patients with high-risk / extremely high risk NMIBC. Fifty-five pathological and imaging diagnosed NMIBC patients with or without BCG treatment will be recruited. Radiotherapy of 5× 5 Gy/fractions will be given to the whole bladder followed by a focal tumour bed boost and concomitant administration of Toripalimab of 240 mg intravenous infusion every 21 days for 12 cycles (about one year). The primary endpoints are disease free survival (DFS) and safety. The secondary endpoint is overall survival. Additional indicators include implementation rate of salvage surgery and quality of life. Results: Until now, 11 patients were included successfully, with 2 female patients and 9 male patients. And the median age was 62.36 years old. Of them, 5 patients were low grade differentiation, and 6 patients were high grade. The median follow-up time was 12.56 months. Two patients with history of multiple recurrence sites repeatedly suffered from local recurrence after radiotherapy and received radical cystectomy. The pathologic stagings were pT1N0 for both patients after surgery. Therefore, the one year- bladder intact DFS rate was 62.5% and the median RFS was not achieved. No patient died so far. For safety analysis, 4 patients suffered from immune-related adverse event, namely, grade 2 arthritis, grade 1 rash and grade 1 hyperthyroidism which led to treatment interruption of Toripalimab. And 2 patients experienced radiotherapy related toxicities, including grade 1 frequent urination and urgency, grade 1 erythra and grade 1 anal sagging sensation. No treatment related dose reduction happened. Conclusions: HOPE-04 is the first encouragement of short-course radiotherapy and Toripalimab combination in the treatment of high-risk / extremely high risk NMIBC, which extends the therapeutic options of bladder preservation treatment for this population. Our preliminary results show a promising effect both in prevention of local recurrence as well as distant metastasis, and toxicities were manageable, which would be verified by the final analysis. Clinical trial information: ChiCTR2200059970 .