bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of ESR1 mutations in endometrial and ovarian cancers.
Authors: Gaillard Stephanie , Bayable Asnakech , Deshmukh Sachin Kumar , Nayar Utthara , Xiu Joanne , Ingram Lishann , Hubbard Gretchen , Sledge George W. , Herzog Thomas J. , Thaker Premal H. , Wu Sharon
Published: June 2024

5598

Background: Low-grade ovarian (OC) and endometrial (EC) cancers frequently express estrogen receptor (ERα, encoded by ESR1), and are considered hormonally responsive tumors. The use of endocrine therapy in the advanced and recurrent disease setting is common. In breast cancer, ESR1 mutations ( ESR1mt) convey resistance to endocrine therapy. Mechanisms for endocrine failure in gynecologic cancers are not well understood. In this study, we aim to evaluate the prevalence of ESR1mt, and associated characteristics, in EC and OC. Methods: 17,666 EC and 21,879 OC samples were analyzed by NGS of DNA (NextSeq, 592 genes and NovaSeq, WES) and RNA (NovaSeq, WTS) (Caris Life Sciences, Phx, AZ). Tumor mutational burden (TMB) totaled all somatic mutations (mt) per tumor (TMB-H: > 10 mt/MB). Statistical significance determined using chi-square and Mann-Whitney U test and adjusted for multiple comparisons (q<0.05). Real-world overall survival (rwOS) and time on treat (ToT) obtained from insurance claims data and calculated from first treatment to last contact or last of treatment, respectively. Results: L536, Y537, and D538 were the most common ESR1 hotspot mutations. ESR1mt (EC: 2.38%, OC: 0.22%) were more prevalent in endometrioid EC tumors (4.2%) compared to other EC histologies (1.7%)(p<0.05). Compared to high-grade serous (HGS) OC tumors (0.07%), ESR1mtmore prevalent in in low-grade serous (1.08%) and endometrioid (1.48%) (p<0.05). ESR1mt was associated with higher ESR1 RNA expression (EC: 1.19-fc, OC: 1-.28-fc), ER+ (EC: 94.1% vs 63%, OC: 80.9% vs 49.3%), and PR+ (EC: 90.8% vs 46.7%, OC: 36% vs 24.5%) (q<0.05). ESR1mt were associated with decreased TP53 mt (EC: 10.7% vs 50.9%, OC: 16.7% vs 78.3%), but increased PI3K pathway alterations (EC: PTEN mt: 70.4% vs 40%, PIK3R1 mt: 34.1% vs 19.6%, PIK3CA mt: 47.9% vs 36.6%, AKT1 mt: 11% vs 2.8%; OC: PTEN mt: 36.2% vs 4.%, PIK3CA mt: 32.7% vs 8.97%, AKT1 mt: 8.33% vs 0.62%), CTNNB1 mt (EC: 52.5% vs 13.9%; OC: 39.6% vs 3.09%), ARID1A mt (EC: 56% vs 32.2%; OC:28.6% vs 8.04%) and TGFBR1 mt (EC: 55.6% vs 9.16%) (q<0.05). ESR1mt was associated with TMB high (30.7% vs 21.6%) and high median IFN score (EC: -0.42 vs -0.35, OC: -0.48 vs -0.27) (q<0.05). ESR1mt enriched in patients with prior AI treatment (EC: 6.38% vs 2.65%, q=0.02; OC: 1.26% vs 0.18%), especially in EOC (14.7% vs 3.37%) (q<0.05). Conclusions: ESR1mt were more common in EC and were enriched in the endometrioid subtype, and in general associated with increased molecular alterations but a more cold immune microenvironment. Hotspot mutations known to confer endocrine resistance were most common and enrichment was observed in cases previously exposed to AIs, suggesting this may be a mechanism of resistance to endocrine therapy for some gynecologic malignancies.
Efficacy of olaparib combined to metronomic cyclophosphamide and metformin in patients with recurrent advanced/metastatic endometrial by molecular subtypes: ENDOLA phase I/II trial.
Authors: You Benoit , Leary Alexandra , Follana Philippe , Abdeddaim Cyril , Joly Florence , Bin Sylvie , Villeneuve Laurent , Alexandre Marine , Bonjour Maxime , Schwiertz Vérane , Boulai Anais , Rodrigues Manuel , Piffoux Max , Freyer Gilles , Callens Celine
Published: June 2024

5605

Background: In patients with recurrent advanced endometrial carcinomas (EC), innovative treatments are needed after platinum chemotherapy and immunotherapy. EC are characterized by frequent defective DNA repair, along with alterations of PI3K-AKT-mTor, and IGF1R pathways. ENDOLA trial was meant to assess the safety and efficacy of the triplet olaparib (PARP 1-3 inhibitor) + metronomic cyclophosphamide + metformin in patients with advanced recurrent EC. We assessed the outcomes by the 4 molecular EC subtypes (POLE; dMMR/MSI-high; NSMP; P53mutated). Methods: ENDOLA trial (NCT02755844) was an academic French prospective multicenter phase I/II open-label dose-escalation study conducted in 6 French centers. The RP2D was defined as olaparib 300 mg BID combined to metformin 1500 mg/day and metronomic cyclophosphamide 50 mg/day (You et al. Proc AACR 2022). Alterations of POLE, MMR and p53 were assessed using local in-house assays. BRCA & HRD status were centrally defined using shallow Whole Genome Sequencing (sWGS) (HRP/HRD status defined as large genomic alteration (LGA) ≤ 7/≥8). Results: From Sept 2016to Nov 2019, 35 patients enrolled, and 31 were assessable for ITT (median age: 69, IQR: 62-72; endometrioid: n=18 (51.4%); serous: n=11 (35.5%); carcinosarcoma: n=2 (6.5%)). 2 patients (6.5%) were previously treated with immunotherapy. In the whole population, the non-progression rate at 10 weeks (NP10w, primary endpoint) was 61.5%, and median PFS (mPFS) was 5.1 months. The molecular subtype could be defined for 20 patients (64.5%): MSI-high, n=3 (15.0%); NSMP, n= 4 (20.0%); P53mutated, n= 13 (65.0%). The NP10w (& mPFS) were 18.2% (5.1 months), 27.3% (9.0 months), and 54.5% (5.1 months), respectively. The rates of patients with LGA ≤7 (non-HRD)/≥8 (HRD) were 15(48.3%)/8(25.8%). 100% patients with P53wild-type had low LGA≤ 7. No clear impact of LGA score alone was found (LGA≤ 7: NP10w 63.6%, and mPFS 5.1 month; LGA /≥8: NP10w 36.4% and mPFS 5.1 months). By combining LGA and P53, the worse mPFS was for patients with P53mutated & LGA≤ 7 (n=5, 3.1 months), and the best for patients with P53mutated & LGA≥8 (n=10, 8.5 months). Conclusions: In this heavily pre-treated population of patients with advanced EC (55% patients treated with ≥ 4 previous lines; and 50% were > 69 years old), the combination of olaparib + metronomic cyclophosphamide and metformin was highly effective, especially in those with NSMP or with P53mutated & HRD (LGA≥8) subtypes, with mPFS ~8 months. It might a promising therapeutic alternative in recurrent setting. Clinical trial information: NCT02755844 .
Prognostic assessment of simple hysterectomy versus radical/modified radical hysterectomy in clinically apparent stage II endometrial cancer: A multi-center cohort study.
Authors: Chen Yuliang , Liu Penglin , Bu Hualei , Song Kun , Kong Beihua
Published: June 2024

5611

Background: The extent of hysterectomy for endometrial cancer (EC) patients with suspected or gross cervical involvement remains controversial. This study aimed to compare the effect of simple hysterectomy (SH) and radical or modified radical hysterectomy (RH/mRH) on the prognosis in clinically apparent stage II endometrial cancer, stratified by aggressive and non-aggressive histological types. Methods: This multi-center retrospective study enrolled patients with clinically apparent stage II (macroscopically cervical involvement without pelvic extension based on the preoperative imaging examination and intraoperative exploration) from the largest endometrial cancer database in China between 2000 and 2019. The primary and secondary outcomes were cancer-specific survival (CSS) and disease-free survival (DFS), respectively. The prognostic difference was assessed using Kaplan-Meier analysis and Cox regression analysis, in total cohort and stratified by aggressive and non-aggressive histological subtypes. Propensity score matching (PSM) algorithm were applied. Results: A total of eligible 725 participants were enrolled, including 245 patients with aggressive histological types and 480 with non-aggressive subtypes. The Kaplan-Meier showed better CSS and DFS in the RH/mRH group than the SH group both in the before ( P=0.0014 and P=0.0038, respectively) and after PSM cohorts ( P=0.042 and P=0.046, respectively) among patients with aggressive histological types. Nevertheless, no significant difference was found (P>0.05) among the patients with the non-aggressive subtypes. Similarly, the multivariate COX analysis revealed that hysterectomy type was an independent prognostic factor for CSS (hazard ratio [HR] RH/mRH vs SH: 0.36, 95% confidence interval [CI] 0.14–0.95, P=0.039) and DFS (HR RH/mRH vs SH: 0.47, 95% CI 0.24–0.93, P=0.030) in patients with aggressive histological types. Conclusions: Compared to SH, RH/mRH were associated with better CSS and DFS in patients with aggressive histological types, but not in the non-aggressive histological types. Despite guidelines recommend SH as first-line treatment for patients with suspected or gross cervical involvement, RH/mRH might be a more reasonable and individualized choice for those with aggressive histological subtypes.
Real world effectiveness and safety of low dose nivolumab with metronomic chemotherapy in patients with advanced platinum-resistant head and neck cancer: An Indian institutional experience.
Authors: Kate Shruti , Sharma Richa , Nagarkar Rajnish Vasant , Shirsath Ankita Dadabhai , Choudhary Mukesh , Patil Roshan
Published: June 2024

6050

Background: Triple Metronomic chemotherapy (TMC) regimen of low-dose methotrexate, erlotinib, and celecoxib has been proven to improve overall survival (OS) of advanced platinum-resistant head and neck cancer (HNC) patients. The addition of low-dose nivolumab to metronomic chemotherapy is an alternative standard of care for those patients, who cannot access full-dose checkpoint inhibitors. In the present study, we aimed to assess the real world effectiveness and safety of low-dose nivolumab along with TMC. Methods: We performed a prospective analysis of advanced platinum-resistant HNC patients treated at our institute from June 2021 to June 2023 with TMC and low-dose immunotherapy consisting of capsule celecoxib (200 mg twice daily), tablet methotrexate (9 mg/m2/week), and erlotinib (150 mg once daily), along with intravenous nivolumab 20 mg (once every 2 weeks). Data was analysed descriptively and the Kaplan-Meier method was used to estimate OS, progression-free survival (PFS), and duration of response (DOR). Results: Overall, 85 patients of advanced platinum-resistant HNC were enrolled in this study. The median age of the patients was 54 years with male predominance. The most common primary sites were buccal mucosa (54%) and tongue (32%). The median follow-up was 6.5 months with 5 months of DOR to therapy. Median number of nivolumab doses received were 8 (IQR 2–48). The termination of therapy in the majority of patients was due to disease progression (55%). Most common adverse events reported were acneiform rash (62%), mucositis (52%), and fatigue (34%). Dose reduction for triple metronomic chemotherapy was required in 42% of patients for grade 3 and above adverse events. No grade 3/4 immune-related adverse events were reported throughout the study period. The median PFS and OS of the study population were observed to be 4.3 months and 8.8 months, respectively. Overall, 8 of 85 patients survived for ≥30 months and 20 (24%) patients were on treatment at the time of data analysis. Conclusions: Low-dose immunotherapy along with triple metronomic chemotherapy is a safe treatment option in real world advanced platinum-resistant HNC patients with acceptable outcomes.
Genomic characteristics of exceptional responders to treatment with PD-1 inhibitors in refractory/metastatic head and neck squamous cell carcinoma.
Authors: Chang Mark , Song Alexander , Deyo Logan James , Stamos Daniel , Bloomer Chance H. , Khoury Lara M. , Porosnicu Mercedes
Published: June 2024

6062

Background: With the emergence of immune checkpoint inhibitors (ICIs), there are patients with advanced cancers experiencing exceptional treatment response with overall low treatment-associated toxicities. Despite success in refractory/metastatic head and neck squamous cell carcinoma (HNSCC), only a portion of patients experience benefit from the treatment with ICIs. Critical information on predictors of patient’s response to treatment is limited. At our institution we analyzed the genomic profiles of 36 patients with advanced HNSCC who demonstrated an exceptional response to treatment with PD-1 inhibitors. Methods: We reviewed patients with histologically confirmed HNSCC that had been treated with PD-1 inhibitors at Atrium Health Wake Forest Baptist Health. Treatment regimen included pembrolizumab 200mg every 3 weeks or nivolumab 240mg every 2 weeks. Response to therapy and duration of remission were monitored via CT scans and/or MRI scans at 3-month intervals, using RECIST 1.1 criteria. Exceptional responders were defined as achieving complete response (CR) or partial response (PR) for greater than six months, or stable disease (SD) for greater than one year. Progression free survival (PFS) and overall survival (OS) were measured from the date of PD-1 inhibitor initiation. PD-L1 level was measured via FoundationOne immunohistochemistry staining and reported as combined positive score (CPS). Additionally, next generation sequencing was performed on tumor (30/36 patients) and blood (33/36 patients) specimens via FoundationOne and Guardant360 testing platforms. Results: Out of 155 HNSCC patients treated with a PD-1 inhibitor, 36 patients demonstrated an exceptional response as defined above. 20 with CR, 9 with PR and 7 with SD. With an average follow up of 32 mo (95% CI, 26 mo-ongoing), the average OS was 33 mo (95% CI, 28 mo–ongoing) and the average PFS was 25 mo (95% CI, 20 mo-ongoing). These patients underwent an average of 27 treatments (range, 10-64 treatments to date). PD-L1 average score at 36 (95% CI, 22-49) and average TMB at 19 mut/mb (range, 0-90 mut/mb). Of 290 detected gene mutations, the most frequently mutated genes were TP53 (75%), PIK3CA (42%), CDKN2A (36%), EGFR (33%), TERT (25%), BRCA2 (22%), ERBB2 (22%), HNF1A (22%), MLL2 (22%), NOTCH1 (22%), and RAD21 (22%). Conclusions: There is limited data reporting the genomic profile of exceptional responders to PD-1 inhibitors in refractory/metastatic HNSCC. Higher TMB and single gene mutations such as TP53, PIK3CA, CDKN2A, EGFR, and TERT are frequently detected in exceptional responders and may provide future direction into the investigation of predictors of response to ICIs.
A novel and selective oral PI3Kα/δ inhibitor, TQ-B3525, in patients with relapsed and/or refractory follicular lymphoma: A phase II, single-arm, open-label study.
Authors: Wang Huaqing , Liang Aibin , Feng Jifeng , LIU YANYAN , Qian Zhengzi , Gao Da , Ran Xuehong , Zhou Hui , Liu Lihong , Wang Binghua , Fang Meiyun , Zhou Hebing , Huang Zhenqian , Tao Shi , Chen Zhuowen , Su Liping , Su Hang , Yang Yu , Xie Xiaobao , Li Zhiming
Published: June 2024

7057

Background: TQ-B3525 is a novel and selective oral PI3K α/δ inhibitor. In an earlier Phase I trial, TQ-B3525 achieved outstanding efficacy in subjects with refractory/relapsed follicular lymphoma (R/R FL) (2020 ASCO Abstract #8058). Here, we report the result from a single-arm, open-label, phase II registration study evaluating the safety and efficacy of TQ-B3525 in R/R FL patients. Methods: This phase II study included exploratory stage 1 and confirmatory stage 2. Patients with R/R FL after ≥2 lines therapies received oral 20 mg TQ-B3525 once daily in a 28-day cycle until disease progression or intolerable toxicity. Primary endpoint was independent review committee (IRC)-assessed objective response rate (ORR). Secondary endpoints were ORR by investigator assessment; the IRC- and investigator-assessed disease control rate (DCR), time to response (TTR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: Based on results (ORR, 88.0%; DOR, 11.8 months; PFS, 12.0 months) in 25 patients at stage 1, second stage study was initiated and included 82 patients for efficacy/safety analysis.Patients received a median of 3 prior lines, with 56.1% refractory to previous therapies; 73.2% experienced POD24 at baseline. At stage 2, ORR was 86.6% (71/82; 95% CI, 77.3%-93.1%), with 28 (34.2%) complete responses. Seven (8.5%) had stable disease for DCR of 95.1%. Median TTR was 1.8 months. Among 71 responders, median DOR was not reached; 18-month DOR rate was 51.6%. At median follow-up of 13.3 months, median PFS was 18.5 (95% CI, 10.2-not estimable) months; estimated 24-month OS rate was 86.1%. Response rates and survival data were consistent across all subgroups. Grade 3 or higher treatment-related adverse events occurred in 63 (76.8%) patients, with neutrophil count decreased (22.0%), hyperglycemia (19.5%), and diarrhea (13.4%) being common. Conclusions: TQ-B3525 exhibited favorable efficacy and manageable safety profiles, supporting its potential as a valuable treatment modality for heavily pretreated Chinese R/R/ FL patients. Clinical trial information: NCT04324879 . [Table: see text]
Assessing the prognostic value of transcriptomic data in multiple myeloma through machine learning methodologies.
Authors: Xu Xuan , Raza Shahzad , Ramachandran Remya Ampadi , Anwer Faiz , Tiger Yun Kyoung Ryu , Riviere Jim , Jaberi-Douraki Majid
Published: June 2024

7513

Background: Multiple myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of plasma cells in the bone marrow. Identifying the characteristics within transcriptomic data of MM patients could be imperative for elucidating long-term cancer prognosis. Prediction and bioinformatic evidence could be valuable for therapeutic intervention. Methods: To discover a precise collection of biomarkers, a large-scale disproportionality analysis of MM patients using the FDA Spontaneous Reporting System database is conducted. This analysis aims to provide pharmacovigilance evidence regarding severe adverse events (AEs) due to medications. Additionally, pharmacogenomic insights from OMIM and MM drug targets are integrated into the analysis to carefully select 84 essential biomarkers. Seven different machine learning (ML) algorithms, namely AdaBoost, K-Nearest Neighbors (KNN), Decision Tree (DT), Gaussian Naïve Bayes (GNB), Support Vector Machine (SVM), Random Forest (RF), and Multilayer Perceptron (MLP) were then employed to assess the classification of disease outcomes. Specifically, the focus was on distinguishing deceased patients (due to MM) from surviving patients in the MM Research Foundation (MMRF) dataset based on the identified essential biomarker. Results: The classification involved a total of 787 patients from MMRF (624 alive and 163 deceased). Four sampling strategies (original raw data, undersampling, oversampling, and simultaneous sampling) were included in the training and testing process on ML models to alleviate the influence of imbalanced data. SVM achieved the highest accuracy while RF achieved highest mean across four sampling methods (Table). We then performed the Kaplan-Meier survival analysis of the prognostic values of essential genes. The expression of two genes (BRAC1 and CTLA4) from MMRF data when comparing deceased to survival patients was associated with patient outcomes. Additionally, seven genes were potentially prognostic factors in MM (Positive prognostic: ATM, CYBA, NR3C1, PIK3CA, and PIK3CG; Negative prognostic: IFNG and NTRK2). Conclusions: This study successfully showcased a computational methodology that holds potential for optimizing future clinical trials in MM. The approach includes identifying the most suitable patient population for a particular MM regimen, thereby contributing to improved patient care. It also offers strategies for reducing AEs, lowering mortality rates, and ensuring the optimal allocation of healthcare resources. [Table: see text]
Access to palliative care in patients with multiple myeloma in the USA: A National Cancer Database (NCDB) analysis of years 2004-2020.
Authors: Saba Ludovic , Fu Chieh Lin , Sarna Kaylee , Chaulagain Chakra Pani
Published: June 2024

7563

Background: Palliative care (PC) can improve the quality of life for patients with multiple myeloma (MM). Despite its recognized importance, research gaps persist in understanding factors influencing PC accessibility and utilization, particularly in the diverse MM patient landscape in the real-world setting. This study explores potential associations between race, ethnicity, socioeconomic factors, and PC access for MM patients in the USA. Methods: Utilizing the NCDB, we identified 202,949 MM patients diagnosed from 2004 to 2020. Multivariate logistic regression analysis was conducted with SAS version 9.4, to determine independent factors predicting PC access. Results: Analysis of 202,949 MM patients revealed notable disparities for access to PC. Female patients exhibited lower PC odds (OR: 0.94, p < 0.0001) compared to male patients, as did Black patients (OR: 0.80, p < 0.0001) and other racial groups (OR: 0.84, p < 0.0001) compared to White patients. Hispanic ethnicity was associated with lower PC utilization odds (OR: 0.84, p < 0.0001) compared to non-Hispanics. Earlier years (2004-2007) showed higher PC odds (OR: 1.12, p < 0.0001), while subsequent years (2008-2011, 2012-2015) exhibited lower odds (OR: 0.93, p = 0.0009; OR: 0.87, p < 0.0001, respectively) compared to the most recent years (2016-2020). Academic settings had lower PC odds than non-academic facilities (OR: 0.78, p < 0.0001). Insurance status varied, with no insurance (OR: 1.40, p < 0.0001), Medicaid (OR: 1.17, p < 0.0001), and other government insurance (OR: 1.38, p < 0.0001) linked to higher PC odds compared to private insurance. Lower annual household incomes (<$38,000, $38,000-$47,999, $48,000-$62,999) had increased PC odds compared to higher incomes (>$63,000) (all p < 0.0001). Areas with a higher percentage of individuals without a high school degree exhibited lower PC odds, notably 21% (OR: 0.83, p < 0.0001) and 13.0%-20.9% (OR: 0.94, p = 0.0222) compared to <7.0% without a high school degree. Greater distance (>30 miles) reduced PC odds compared to shorter distance (<10 miles) to treatment facility (OR: 0.83, p < 0.0001). A Charlson-Deyo score of 1 increased PC odds compared to a score of 0 (OR: 1.12, p < 0.0001). Conclusions: Our real-world analysis reveals substantial disparities in MM patients’ PC access and utilization. Female patients and minority groups (Blacks and Hispanics) face significant challenges. The dynamic trends over time and socioeconomic impacts underscore the need for integrating PC and targeted interventions for overall MM patient well-being. Our findings pave grounds for future prospective studies.
Neoadjuvant and perioperative immunotherapy in resectable non-small cell lung cancer (NSCLC): A systematic review and extracted individual patient data meta-analysis.
Authors: Trinconi Cunha Mateus Trinconi , Sperandio Rubens Copia , Chan Kelvin K. , Menjak Ines B.
Published: June 2024

8045

Background: Neoadjuvant and perioperative immunotherapy are emerging approaches for resectable NSCLC. However, survival outcomes are still immature and subgroup analyses are underpowered. We report extracted individual patient (pt) data (eIPD) and trial-level (TL) meta-analyses of phase II and III randomized controlled trials (RCTs) in this setting. Methods: The systematic review included Cochrane, Embase, and major oncology conferences (ASCO annual meetings, ESMO meetings, WCLC meetings). Primary objectives were eIPD event-free survival (EFS) and overall survival (OS). Secondary objectives included eIPD and TL meta-analysis of subgroups. Kaplan-Meier plots of time-to-event outcomes were reconstructed with WebPlotDigitizer (v4.6, 2022), and eIPD was estimated with IPDfromKM (v0.1.10, 2020) stratified by study. Comparisons between arms were made in a 1-stage model with a Cox Proportional Hazards model stratified by study. The difference of restricted mean survival time (D-RMST), a quantification of the postponement of an event during a specified interval, was used to compare survival when the proportional hazard assumption (PHA) was violated, tau being the shortest follow-up time of the available trials. TL meta-analysis was performed with a random effects model. This meta-analysis was registered in the PROSPERO database under CRD42024502150. Results: Seven RCTs (AEGEAN, CM816, CM77T, KN671, NADIM II, NeoTorch, and Lei et al. [ESMO IOTECH 2022, #56O]) were identified, comprising 2995 pts. EFS analysis included all pts, with HR of 0.58 (0.52-0.65; p<0.01). OS analysis (1645 evaluable pts from 4 trials) showed a D-RMST of 5.17 mo. (p<0.01) due to PHA violation. Full eIPD analysis in the table. TL meta-analysis showed benefit in all subgroups, including PD-L1 expression, histology, stage, smoking status, sex, and age. TL EFS and OS results were comparable to results obtained from eIPD analysis, with low heterogeneity measures. Conclusions: This meta-analysis provides robust and nuanced insights into the positive impact of immunotherapy in resectable NSCLC. While evidence supports its efficacy, uncertainty surrounding the benefit in stage < III disease highlights the need for additional research and more mature results to guide clinical decision-making effectively. [Table: see text]
Annotations-free survival prediction with WSIs using graph convolutional neural networks.
Authors: Kong Qianqian , Li Ruilei , Zhang Jiaran , Li Ke , Ge Chunlei , Yan Xieqiao , Yao Hong , Guo Jun , LI Chen
Published: June 2024

e16501

Background: Survival prediction of cancer patients has always been an challenging problem.Tumor microenvironment (TME) Analyzation based on whole-slide-images (WSIs) has provide an effective perspective for survival prediction. However, most existing TME analyzation based on cell segmentation or classification relies heavily on labor-intensive cell-level annotations of pathologists. Furthermore, except for each individual cell or local pathological feature, survival prediction also involves local-level pathological features interactions in tumor microenvironments. This requires context-awareness based on histological features to fully infer the patient's survival risk. Therefore, we explored a model based on graph convolutional neural networks (GCNN) to perform survival prediction of cancer patients using WSIs. Methods: We utilized WSIs collected from The Cancer Genome Atlas (TCGA) to develop a graph convolutional neural network for survival prediction of cancer patients. The model leverages the advantages of graph structures to autonomously learn the histopathological contextual features in WSIs, and therefore can incorporate additional and crucial tumor microenvironment interaction information while avoiding the labor-intensive annotations. WSIs of two different cancers, KIRC and LUAD, were randomly divided into training, validation, and testing sets in a ratio of 7:1:2. The performance of the constructed model is evaluated using the test set and the results are compared with other state-of-art methods. Results: Our work is compared with other state-of-art weakly supervised learning methods for survival prediction in computational pathology. Abundant experimental results shown that our method outperformed previous methods on these two cancer types (achieving a 2.9% improvement compared to Multiple Instance Learning (MIL) and a 2.6% improvement compared to Attention MIL), with an overall c-index of 0.646. Additionally, we evaluated the interpretability of our model through attention heatmaps of low-risk and high-risk patients. Conclusions: We have developed a GCNN based model, combined with attention mechanisms, to learn features of heterogeneous tumor microenvironments and their contextual information from memory-efficient representations of highly correlated image patches for cancer patients survival prediction. This model is applicable to any weakly supervised learning task in computational pathology that involves slide-level or patient-level labels, making it an effective supplementary diagnostic tool for oncologists and pathologists.
Prediction of immune checkpoint inhibitor (ICI) response in patients with urothelial cancer (UC) by a novel RNA-based ICI response signature (ICI-PRS).
Authors: Shepherd Jonathan , Mayhew Gregory , Guo John , Beebe Kirk , Eisner Joel Robert , Milburn Michael Vance
Published: June 2024

e16502

Background: Immune checkpoint inhibition (ICI) shows great promise, including approval of pembrolizumab, nivolumab and avelumab in urothelial cancer (UC). However, the overall percentage of UC patients with clinical benefit is relatively small, despite biomarker use to select patients (e.g., PD-1 expression and TMB). Recently, several accelerated approvals (atezolizumab and durvalumab) were subsequently withdrawn following failure to show improved survival compared to standard of care (SOC) treatment in Phase 3 +/- biomarker use. To address the need for better ICI biomarkers, we developed an RNA-based predictive response signature (ICI-PRS) with the primary objective of being prognostic for ICI-treated patients, but not for SOC treatment (Shepherd et al, 2024 ASCO GU). ICI-PRS uses a novel ICI-specific survival signature with tumor-derived and immune associated features to evaluate the likelihood of responding and having longer survival with ICI therapy independent of non-ICI therapy. Herein we report the initial clinical validation of the ICI-PRS using independent datasets of patients with UC treated with ICI. Methods: RNA expression and clinical data were retrospectively evaluated in two independent cohorts of patients with UC treated with ICI: Bladder Cancer Advocacy Network (BCAN) UC-GENOME cohort (dbGaP phs003066.v1.p1 and cBioPortal (n=105) [PMID36333289]) and BACI cohort (Gene Expression Omnibus (GEO;GSE176307 (n=84 for patients treated with >1 cycle) [PMID: 34294892])). ICI-PRS was applied and an optimal cutoff value to designate binary response prediction (complete response + partial response (PR/CR) vs. stable disease + progressive disease (SD/PD)) was derived with Youdin’s method using the receiver operator characteristic (ROC) curve of the original IMVigor210 training set. Results: Samples predicted to be ICI-PRS positive show consistent associations with overall survival (OS) when receiving ICI treatment. A lower hazard ratio (HR) was found for both BACI [HR (95% CI): 0.455 (0.24-0.86); and BCAN 0.540 (0.30-0.98)]. Response to ICI therapy was also associated with ICI-PRS scores, as patients achieving either CR or PR had significantly lower ICI-scores than those with SD or PD in both BACI (p=0.001) and BCAN (p=0.012). Conclusions: Herein we describe initial clinical validation of ICI-PRS in two independent cohorts of UC patients treated with ICI. It provides ICI-treatment specific prognostic and predictive value for patients with UC and may have application alone or in combination with other signatures when determining treatment sequencing or rational combination strategies. These results support further evaluation of the ICI-PRS and potential development as a diagnostic test for selecting UC patients most likely to benefit from ICI therapy either alone or in combination with non-ICI therapy.
Real-world survival outcomes associated with immunotherapy followed with anti-vascular targeted therapy for metastatic clear cell renal cell carcinoma.
Authors: Zhang Hui , Hou Zhiwei , Lai Long , Wu Huaguo
Published: June 2024

e16507

Background: The Food and Drug Administration (FDA) has approved a variety of drugs for the treatment of advanced metastatic renal cell carcinoma, including anti-vascular tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). Options for initial therapy range from monotherapy to combination therapy. However, the challenge of choosing the most effective first- and second-line treatments to enhance overall survival persists. Methods: In this retrospective, propensity-matched cohort study, we included 135 patients with metastatic clear cell renal cell carcinoma (mRCC) treated at Shandong Cancer Hospital between January 1, 2017, and December 31, 2022. These patients received ICIs as part of their first or second line of therapy. Statistical analysis was conducted from June 1, 2023, to August 1, 2023. The primary endpoint was OS, measured from the date of diagnosis to death or the last follow-up. PFS was assessed during treatment. Survival analysis was performed using Cox proportional hazards regression and Kaplan-Meier estimates. Results: The final cohort comprised 135 patients, of whom 84 received first-line therapy with ICIs. The remaining 51 patients were treated with ICIs as second-line therapy following an initial regime of TKIs. Patients were initially categorized based on whether ICIs were used in the first-line treatment. It was observed that the OS for patients receiving first-line targeted therapy was higher than for those receiving first-line immunotherapy, with median OS figures of 33 months versus 15 months. To investigate this outcome, we further refined the patient groups based on the sequence of ICIs and TKIs in the treatment regimen. We discovered that the median PFS following first-line anti-vascular targeted therapy combined with immunotherapy was 3.5 months, compared to 14.5 months when immunotherapy followed first-line anti-vascular targeted therapy (p=0.0092). The median PFS for second-line treatments was 6.5 months versus 15 months (p=0.0014). Similarly, the median OS figures were 16.66 months and 31.88 months, respectively (p=0.008). Conclusions: This study suggests that administering immunotherapy after the progression of anti-vascular therapy significantly improves both OS and PFS compared to other sequences of immunotherapy. These findings offer valuable insights and strong empirical support for clinical decision-making regarding the sequencing of treatments for mRCC.
Phase II clinical study of the safety and efficacy of sintilimab in combination with axitinib and stereotactic radiotherapy in the treatment of local-regional recurrent renal cell cancer.
Authors: Liu Ruiqi , Liu Yang , Zhang Zhiling , Gao Jianming , Zhang Xinyue , Pan Qiwen , Li Yilin , Cai Lingling , Guo Shengjie , Han Hui , Zhou Fangjian , Dong Pei , He Liru
Published: June 2024

e16511

Background: Currently, targeted agents and immunotherapy are applied to local-regional recurrent renal cell carcinoma (LRRCC). The combination with systemic therapy and stereotactic radiotherapy (SBRT) is worth exploring. In the present study, we aimed to investigate the efficacy and safety profile of sintilimab plus axitinib combined with SBRT in the treatment for LRRCC. Methods: This was a single-arm, phase II study enrolled LRRCC patients (pts), for whom the SBRT can be safety applied for all the recurrent lesions visible on imaging. Eligible pts received sintilimab (200mg, day 1) and axitinib (5mg, bid, day 1-21) in a 21d cycle. SBRT (35-45Gy/5 fractions) was performed before the third administration of sintilimab. The primary endpoint was progression-free survival (PFS). Results: From Oct 2021 to Jan 2024, 19 pts with a median age of 58 (range: 33-74) were enrolled. Among them, 9 (47.37%) pts had clear cell carcinoma. Nine (47.37%) pts were IMDC intermediate (7 pts) or high risk, and 8 (42.11%) pts recurred in less than 1 year after surgery. Seven(36.84%) pts received at least one prior systemic therapy. Four (21.05%) pts had recurrence in the renal fossa, while 3(15.79%) pts in retroperitoneal lymph node, 2(10.53%) pts in retroperitoneal lymph node with renal fossa and 10(52.63%) pts in intra-abdominal soft tissue. With a median follow-up of 9.5 months (range: 3.0-27.1m), 18 pts were evaluable for response. The median tumor volume was 37.47cc (range: 2.44-493.19cc). The overall response rate was 55.56% with 4 complete responses and 6 partial responses per RECIST v1.1. The median time-to-response was 5 months. The local control rate and the disease control rate were 100% and 94.44%, respectively. The median PFS was not reached, and the 9-month PFS rate was 94.44%. All 19 pts were evaluable for toxicity. Any-grade treatment-related adverse events (TRAEs) occurred in 16(84.21%) pts. The most common TRAEs were albuminuria (8/19; 42.11%), nausea (8/19; 42.11%), hypertension (7/19; 36.84%), and diarrhea (7/19; 36.84%). Grade 3 or higher TRAEs occurred in 6/19(31.58%). Conclusions: Sintilimab plus axitinib combined with SBRT showed promising antitumor activity and manageable toxicity in pts with LRRCC. Clinical trial information: ChiCTR2100049523 .
Real-world clinical and toxicity outcomes in older Veterans with metastatic renal cell carcinoma (mRCC) treated with front-line systemic therapy.
Authors: Aly Ragia , Yang Ziyi , Schmitt Jordan Marie , King Jennifer
Published: June 2024

e16525

Background: The United States veteran population represents a unique group of patients with distinct health care challenges, particularly for older veterans. Here, we describe a real-world cohort of veterans with mRCC treated with systemic therapy and assess if outcomes and toxicities with front-line systemic therapy differ for older adult veterans. Methods: Veterans diagnosed with mRCC between 2010- 2023 at the Richard L. Roudebush VA in Indianapolis and treated with front-line systemic therapy were identified. Patients were classified as £65yo and >65yo. Comparisons between groups were done using Chi-square tests for categorical variables or Wilcoxon test for continuous variables. Kaplan-Meier method was used to analyze progression-free survival (PFS) and overall survival (OS), with Cox model used to adjust for confounders. Results: A total of 73 patients with mRCC were identified. Median age was 67.4. 31 patients (42%) were £65yo and 42 (58%) were >65. 99% of patients were male. 69% of patients had clear cell histology, 11% papillary, 11% poorly differentiated, 5% unclassified, 2% chromophobe, 2% sarcomatoid, and 2% other. 52% of patients ≤65yo had IMDC int/poor risk disease vs. 85% of patients >65 (p=0.016). There was no statistically significant difference in disease grade, stage, or presence of sarcomatoid/rhabdoid features between groups. The table lists and compares therapies received and toxicity outcomes. The median PFS was 18.7 months in pts ≤65yo vs. 7.1 months in pts >65 (p=0.24). The median OS was 58.1 months in pts ≤65 vs. 12.6 months in pts >65. (p=0.048). When using the Cox model to adjust for IMDC risk, the OS difference was not maintained, with a hazard ratio of 1.16 (CI 0.59, 2.27; p=0.664). Conclusions: In this cohort of veteran patients with mRCC, older veterans had higher rates of IMDC int/poor risk disease, likely leading to decreased survival outcomes. Front-line systemic therapies used were similar to younger veterans without an apparent difference in toxicity. This material is the result of work supported with resources and the use of facilities at the Richard L. Roudebush VA in Indianapolis. [Table: see text]
Impact of β-adrenergic blockade on efficacy of immunotherapy in patients with metastatic clear cell renal cell carcinoma.
Authors: Semaan Karl , Eid Marc , Saad Eddy , Issa Wadih , Saliby Renee Maria , Paul Morgan , Zhong Caiwei , Gunenc Damla , Phillips Noa , Nawfal Rashad , Machaalani Marc , El Hajj Chehade Razane , Yekeduz Emre , Labaki Chris , El Zarif Talal , Baca Sylvan C. , Xie Wanling , McGregor Bradley Alexander , Zhang Tian , CHOUEIRI Toni K.
Published: June 2024

e16529

Background: Immunotherapy (IO) has become a cornerstone in the standard of care of patients (pts) with metastatic clear cell renal cell carcinoma (mccRCC). Recent studies suggest concomitant beta-blockers (BB) use may improve the effectiveness of IO in melanoma by increasing CD8+ T cells tumor infiltration through β-adrenergic blockade. Herein, we assess the impact of BB on the clinical outcomes of pts with mccRCC treated with IO-based regimens in first-line (1L) settings. Methods: Real-world data from Dana-Farber Cancer Institute and the University of Texas Southwestern Medical Center were collected retrospectively. Pts with mccRCC who received 1L standard of care IO-based regimens, including dual-IO or IO in combination with vascular endothelial growth factor-targeted therapies (IO+VEGF-TT) were included. Pts receiving BB at the 1L initiation were classified as BB-treated pts, while pts who were not on BB at 1L initiation were labeled as BB-untreated pts. Time to treatment failure (TTF) and overall survival (OS) were compared between groups using a multivariable Cox regression adjusting for age at 1L start, body mass index (BMI), and IMDC risk group. Objective response rate (ORR; responders vs. non-responders/not evaluable) per RECIST 1.1 criteria was compared between groups using a Chi-Squared test. Results: Our cohort included 171 pts with mccRCC, 134 (78.4%) were male, and the median (Q1-Q3) age was 62 (56-68) years. A total of 55 deaths were observed. The median follow-up of pts was 28.1 months. At 1L treatment initiation, 52 (30.4%) pts were receiving BB. BB-treated pts (vs. those not) were older (65.1 vs 60.8; p=0.003) and had higher BMI (31.1 vs. 29; p=0.004) at 1L initiation. BB-treated pts (vs. those not) had comparable TTF (adjusted HR (aHR) = 1.0; 95% confidence interval (CI): 0.7-1.5; p=0.88) and comparable OS (aHR=1.1; 95%CI: 0.6-2.0; p=0.67). BB-treated pts (vs. those not) had a numerically increased ORR, but this difference was not statistically significant (31/52, 59.6% vs. 59/119, 49.6%; p=0.29). A sensitivity analysis within each of dual-IO (n=83, 48.5%) and IO+VEGF-TT (n=88, 51.5%) subgroups showed similar results (Table). Conclusions: This is the first effort to investigate the impact of β-adrenergic blockade on IO activity in pts with mccRCC. While previous data suggest concomitant BB use may enhance IO efficacy in pts with melanoma, our results show that the use of BB was not associated with better IO effectiveness in pts with mccRCC. Limitations of the study arise from its retrospective design. [Table: see text]
Cabozantinib outcomes for metastatic renal cell carcinoma at a tertiary NHS hospital in the United Kingdom (UK).
Authors: Arumugam Shanmugasundaram Guhan , Holden Emily , Al-Husban Hadeel , Kazmi Farasat , Maskell David , Kapur Gaurav
Published: June 2024

e16538

Background: Kidney cancer remains the seventh most common solid organ cancer in the UK, USA and Europe, with renal cell carcinoma forming most of these cases [1]. In the UK, kidney cancer accounts for 3% of all new cancer diagnoses of which 25–31% present with metastatic RCC (mRCC) at initial diagnosis. [2] Methods: The METEOR trial was used as the comparator for response rates and progression-free survival to evaluate our outcomes. In the METEOR trial, treatment with Cabozantinib was associated with significantly better overall survival (OS) (21.4 months (m) with Cabozantinib vs 16.5m Everolimus), progression-free survival (PFS) (7.4m vs 3.9m), objective response rates (ORR) (17% vs 3%), and an equivalent safety profile when compared to Everolimus, a second-line treatment for patients with advanced renal cell carcinoma. [3] We present the results of Cabozantinib outcomes in the first to third line setting for mRCC at an NHS tertiary hospital. A direct comparison of OS is not feasible, as the METEOR data was for Cabozantinib in the second line. In contrast, Cabozantinib was used in first, second and subsequent line settings according to the NHS funding in our hospital trust. Results: From 16 April 2018 to 13 November 2023, 43 patients with mRCC received Cabozantinib at our NHS trust. Compared to the METEOR study, the median follow-up for our NHS tertiary centre patients was 7.5 m, as opposed to 18.7 m. Comparing the real-world data from our NHS centre with the METEOR trial, the ORR (partial response according to RECIST criteria) was 25% compared to 17%, whilst the PFS was 10.6m vs 7.4m. Interestingly, we observed that patients who had received immunotherapy before Cabozantinib had significantly better PFS (12m OS = 22% vs 0%; Log Rank = 0.03). Grade 3 and above toxicities was 32.5% vs 71% (NHS hospital vs METEOR trial). Conclusions: Overall, Cabozantinib showed better than expected response rates, and the toxicities in our NHS tertiary hospital were less severe than in the METEOR trial. Significantly, we observed that individuals who had received immunotherapy before Cabozantinib had higher survival outcomes. References: 1. U.S. Cancer Statistics Working Group. U.S. Cancer Statistics Data Visualizations Tool, based on 2022 submission data (1999-2020): U.S. Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute; https://www.cdc.gov/cancer/dataviz , released in November 2023; 2. Cancer Research UK [Internet]. Kidney cancer statistics. Available from: http://www.cancerresearchuk.org/healthprofessional/cancer-statistics/statistics-by-cancer-type/kidney-cancer. [Cited: 2019 Jan 15]; 3. Choueiri, Toni K., et al. "Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial." The Lancet Oncology 17.7 (2016): 917-927.
Clinical features, genomic alterations, and survival outcomes for variant histology urothelial carcinoma.
Authors: Sevgi Mert , Hassoun Rebecca , Althouse Sandra K. , Tran Mya , Fausel Christopher A. , Schneider Bryan P. , Salous Tareq , Adra Nabil , King Jennifer
Published: June 2024

e16549

Background: Twenty-five percent of urothelial tumors exhibit variant histology. Each variant exhibits unique genomic composition and has a distinct clinical course. While there is emerging work describing the clinical and genomic features of variant histology, the integration of both with their impact on clinical outcomes remains less studied. Here, we describe the clinical features, genomic alterations, and outcomes of a real-world cohort of variant urothelial histology. Methods: This was a retrospective review of patients with variant histology urothelial carcinoma who underwent genomic sequencing and were treated at our institution between 2016-2023. Genomic data was derived from standard of care CLIA-next generation sequencing. Demographics and outcomes were derived from chart review. Kaplan-Meier method was used for progression free survival (PFS) and overall survival (OS). Results: 78 patients (pts) were included. Median age was 68.6 (33.7-90.7). 69.2% were male. Variant histology included 15 pts with squamous cell component, 14 pts with plasmacytoid component, 13 pts with micropapillary component, 8 pts with adenocarcinoma. The remaining variant histologies are listed in table 1. 10 pts (12.8%) had more than one variant histology present. 60 pts (76.9%) had metastatic disease; 24 (40%) of them with de novo metastatic disease. Metastatic sites were distant lymph nodes (LN) in 37 pts, lung in 25 pts, bone in 22 pts, and liver in 14 pts. The table lists genomic findings by variant histology. Overall, 2-yr PFS was 29% and 2-yr OS was 69.4%. Median PFS was 0.3 yrs for plasmacytoid vs. 0.4 for adenocarcinoma vs. 0.7 for micropapillary vs. 0.8 for squamous. Median OS was 1.5 yrs for plasmacytoid vs. 2.9 for adenocarcinoma vs. 3 for micropapillary vs. not evaluable for squamous. Conclusions: In this cohort of patients with variant urothelial histology, the most common genomic alterations were TERT and TP53 mutations. Several targetable alterations including KRAS, PIK3CA, and TSC1 were detected across various histology subtypes and suggest a potential avenue for further therapeutic research. Though not statistically significant, PFS and OS were shorter for patients with plasmacytoid and adenocarcinoma variants. [Table: see text]