bluuebunny/crossref_metadata_2025 huggingface dataset:
Avelumab + axitinib vs sunitinib in patients (pts) with advanced renal cell carcinoma (aRCC): Final overall survival (OS) analysis from the JAVELIN Renal 101 phase 3 trial.
Authors: Motzer Robert J. , Penkov Konstantin , Uemura Hirotsugu , Campbell Matthew T , Kollmannsberger Christian K. , Lee Jae-Lyun , Venugopal Balaji , Van Den Eertwegh Alfonsus , Negrier Sylvie , Gurney Howard , Albiges Laurence , Berger Raanan , Haanen John , Rini Brian I. , Larkin James , Schmidinger Manuela , Sandner Robin , Wang Jing , Di Pietro Alessandra , CHOUEIRI Toni K.
Published: June 2024

4508

Background: The JAVELIN Renal 101 (NCT02684006) phase 3 trial compared first-line treatment with avelumab + axitinib vs sunitinib in aRCC. The trial previously met one of its primary objectives by showing significantly longer progression-free survival (PFS) with avelumab + axitinib vs sunitinib in pts with PD-L1+ tumors; longer PFS, higher objective response rate (ORR), and an acceptable safety profile were also observed in the overall population. OS data were immature. Here we report the final analysis. Methods: Pts with untreated aRCC (any IMDC risk score) were randomized 1:1 to avelumab + axitinib or sunitinib. OS and PFS (by blinded independent central review) in pts with PD-L1+ tumors (SP263 assay) were independent primary endpoints. OS and PFS in the overall population were key secondary endpoints; response and safety were also analyzed. Results: Of 886 pts randomized, 560 (63.2%) had PD-L1+ tumors. At data cutoff (August 31, 2023), median follow-up in the avelumab + axitinib and sunitinib arms was 73.7 and 73.6 months, respectively (≥68 months in all pts). Final efficacy data are shown in the Table. In the avelumab + axitinib and sunitinib arms, grade ≥3 TRAEs occurred in 66.8% vs 61.5%, respectively. Second-line therapy was received by 58.1% vs 69.4%, including a PD-(L)1 inhibitor in 18.8% vs 53.6%, respectively. Conclusions: The JAVELIN Renal 101 trial provides the longest follow-up for immune checkpoint inhibitor + tyrosine kinase inhibitor combination treatment from a phase 3 trial reported to date. OS analyses favored avelumab + axitinib vs sunitinib but did not reach statistical significance. PFS was longer with avelumab + axitinib vs sunitinib, and responses were durable in a subset of pts. Final analysis results confirm the long-term efficacy and manageable safety profile of avelumab + axitinib treatment in pts with aRCC. Clinical trial information: NCT02684006 . [Table: see text]
Systemic treatments in favorable and very favorable risk metastatic renal cell carcinoma (mRCC): Real world evidence from the International mRCC Database Consortium (IMDC).
Authors: Zarba Martin , Ferrier Evan , Wells Connor , El Zarif Talal , Basappa Naveen S. , Ebrahimi Hedyeh , McKay Rana R. , Wood Lori , Beuselinck Benoit , Suárez Cristina , Takemura Kosuke , Lalani Aly-Khan A. , Li Haoran , Spain Lavinia Anne , Templeton Arnoud J. , Powles Thomas , Bjarnason Georg A. , de Velasco Guillermo , CHOUEIRI Toni K. , Heng Daniel Yick Chin
Published: June 2024

4514

Background: The role of immunotherapy combinations in mRCC with IMDC favorable risk is controversial. A very favorable subgroup of favorable risk patients (primary diagnosis to systemic therapy ≥3yr, Karnofsky Performance Status 90 or 100% and absence of brain, liver, or bone metastasis) has been described by Schmidt A. et al., which require characterization in the immuno-oncology combination era. Methods: Using the IMDC, we selected mRCC patients with IMDC favorable risk who started systemic therapy during 2016-2023 and examined the favorable risk group and the subset of very favorable risk patients. First line systemic therapy was divided into 3 groups: Ipilimumab + Nivolumab (IPI/NIVO), combination of anti PD1/PDL1 and VEGF (IO-VEGF) (Pembrolizumab and Axitinib or Lenvatinib, Avelumab and Axitinib, or Nivolumab and Cabozantinib), and Vascular endothelial growth factor (VEGF) inhibitors (Pazopanib or Sunitinib). The primary outcomes were 2-year overall survival (2y OS) in the favorable and very favorable risk population. Secondary outcomes included Response Rate (RR), treatment duration (TD) and time to next treatment (TTNT). We used unadjusted survival rates at 2 years, with Cox regression model with TKI mono as reference. Results: 611 favorable risk patients were eligible for analysis, of which 165 (26.9%) had very favorable risk disease. Median age at diagnosis was 62 years, 73.8% were male, 87.1% had clear cell histology, 5% had sarcomatoid features, and 97,2% had a prior nephrectomy. With a median follow up of 33 months, outcomes are summarized in the table. Conclusions: No significant difference in survival between different treatment regimens in the favorable risk population was detected yet. In the very favorable risk population, there was a statistically significant decrease in 2 year overall survival with IPI-NIVO (HR 3.19) which, if validated, could underline the necessity of targeting the VEGF pathway in this population. Further prospective trials and longer follow-up are required to confirm these findings. [Table: see text]
Phase 1b study of tarlatamab in de novo or treatment-emergent neuroendocrine prostate cancer (NEPC).
Authors: Aggarwal Rahul Raj , Rottey Sylvie , Bernard-Tessier Alice , Mellado-Gonzalez Begoña , Kosaka Takeo , Stadler Walter Michael , Sandhu Shahneen , Yu Brian , Shaw Crystal , Ju Chia-Hsin , Thompson Corbin , Aparicio Ana
Published: June 2024

5012

Background: NEPC is an aggressive form of prostate cancer with poor prognosis and no standard treatment approach. NEPC can be characterized by late, treatment-emergent transformation from adenocarcinoma to high-grade neuroendocrine carcinoma (NEC), in 10–15% of mCRPC patients (pts). DLL3 is overexpressed in high-grade NECs, including NEPC, and minimally expressed on normal tissue. Tarlatamab, a bispecific T-cell engager immunotherapy with clinical activity in small cell lung cancer (SCLC), binds DLL3 and CD3 resulting in T-cell mediated tumor lysis. Here, we report primary analysis data of tarlatamab in NEPC (NCT04702737). Methods: This is an open-label phase 1b study evaluating tarlatamab monotherapy in adult (≥18 years [y]) pts with metastatic de novo or treatment-emergent NEPC by histologic, genomic, or immunohistochemistry (IHC) criteria. The starting dose was the highest safe and tolerable dose in the phase 1 SCLC trial (NCT03319940). Safety was the primary objective; anti-tumor activity and pharmacokinetics were secondary objectives. Exploratory analysis of DLL3 expression was assessed by IHC using the Ventana SP347 assay. Results: As of 28 March 2023, 40 pts received ≥1 tarlatamab dose (1 mg step dose, 100 mg target dose). Median (range) age was 64.5 (43–83) y, prior lines of therapy was 3 (1–9), prostate specific antigen at baseline was 0.2 (0.0–5000.0) μg/L. Treatment-related adverse events (TRAE) occurred in all patients, with no fatal TRAE. Most common TRAEs were cytokine-release syndrome (CRS; 65.0%), pyrexia (52.5%) and dysgeusia (42.5%). CRS occurred primarily in treatment cycle 1; events were mostly grade 1–2 (one grade 3 event). Treatment discontinuation due to TRAE was low (7.5%). Tarlatamab serum exposures were consistent with tarlatamab SCLC studies. Objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) was 10.5% (95% CI, 2.9, 24.8); median progression free survival (mPFS) was 1.9 months (m) (95% CI, 1.7, 3.5). Retrospective DLL3 IHC analysis showed that 18 of 32 (56.3%) biopsy evaluable pts had ≥1% DLL3 tumor positivity (DLL3+). As of 24 January 2024, ORR in DLL3+ pts was 22.2% (95% CI, 6.4, 47.6); durations of response in the 4 pts with response were 25.8 m, 9.2 m, 5.5 m, 3.7 m; mPFS in DLL3+ pts was 3.75 m (95% CI, 1.87, 11.01). Efficacy is shown in Table. Conclusions: Findings from this phase 1 study of tarlatamab in pts with NEPC demonstrated manageable safety with encouraging anti-tumor activity in DLL3 expressing NEPC. Further investigation is ongoing. Clinical trial information: NCT04702737 . [Table: see text]
Implications of HPV infection on survival outcomes in patients with penile squamous cell carcinoma: Insights from a nationwide study.
Authors: Garje Rohan , Ganiyani Mohammad Arfat , Khosla Atulya Aman , Ahmad Shahzaib , Podder Vivek , Bellur Shreyas S , Jayram Diya , Jatwani Karan , Ahluwalia Manmeet Singh
Published: June 2024

5045

Background: Human Papilloma Virus (HPV) infection is a favorable prognostic marker in certain cancers, particularly oropharyngeal and vulvar (SCC). Patients with pSCC have risk profile and clinical course like pSCC. However, the impact of HPV status on survival in pSCC remains uncertain. Methods: We conducted a retrospective study using the National Cancer Database and included patients with pSCC tested for HPV between 2004-2021. Survival outcomes were analyzed and reported as median overall survival (mOS, 95% CI). Multivariate analysis adjusting for age, disease stage, treatment modalities, and comorbidities, was performed using Cox proportional hazards models and reported as hazard ratios (HR, 95% CI). Results: Out of 1371 men with pSCC, 539 (39.3%) were HPV positive (HPV +ve). At diagnosis, most HPV +ve men with pSCC presented with early-stage cancer(I-III), and 6% were stage IV. The mOS for HPV +ve patients was 123.96 months (98.96 - 148.40) vs. 104.38 months (89.13 - 115.98) in HPV negative patients with pSCC (P=0.01). In the adjusted analysis, the presence of HPV infection was associated with HR for death of 0.79 (0.65-0.98; P = 0.03) compared to patients without HPV (table). Conclusions: HPV infection in patients with pSCC is associated with improved survival. These findings highlight HPV status as a prognostic Indicator in pSCC irrespective of clinical profile. Therefore, testing for HPV at the time of diagnosis should be performed routinely in patients with pSCC. [Table: see text]
PLATIPARP: A phase 2 study of induction docetaxel and carboplatin followed by maintenance rucaparib in treatment of patients with mCRPC with homologous recombination DNA repair deficiency.
Authors: Raychaudhuri Ruben , Gulati Roman , Schweizer Michael Thomas , Yezefski Todd , Khan Hiba M , Yu Evan Y. , Nelson Peter , Pritchard Colin C. , Montgomery Robert Bruce , Cheng Heather H.
Published: June 2024

5052

Background: Genes involved in homologous recombination DNA repair (HR) are inactivated in ~25% of patients with metastatic castration-resistant prostate cancer (mCRPC). Inactivation of HR has been associated with sensitivity to DNA damage by platinum chemotherapy and PARP inhibitors (PARPi). While both drug classes have shown efficacy, resistance and/or cumulative dose-limiting toxicities are inevitably observed. Here, we report results from a single-center phase 2 study investigating whether induction chemotherapy (IC) with docetaxel and carboplatin followed by maintenance PARPi would provide prolonged disease control. Methods: Patients with mCRPC tumors harboring a pathogenic alteration in an HR gene, who had received prior taxane and/or androgen receptor pathway inhibitor (ARPI), but not prior PARPi were eligible. Patients received IC with 4 cycles of docetaxel 60mg/m2 with carboplatin AUC 5 IV q21 days, followed by the PARPi rucaparib 600mg BID continuously as maintenance therapy until disease progression or unacceptable toxicity. The primary endpoint was clinical/radiographic progression free survival (PFS) compared to a historical control of 9.1 months with PARPi alone without prior platinum. 20 patients provided ~90% power to determine whether this treatment lowered risk of progression with a hazard ratio of 0.5 (implying PFS of 18.2 months), based on a 1-sided 1-sample log-rank test. Secondary endpoints included PSA50 response rate, safety, and overall survival. Post-hoc subgroup analysis was performed for the BRCA complex group (alterations in BRCA1, BRCA2, and PALB2) and for those refractory to IC. Results: 18 patients were enrolled between 2018 and 2021. Under-enrollment occurred due to loss of manufacturer support for rucaparib prior to study completion. 11/18 (61%) of patients had ≥2 prior ARPI, and 9/18 (50%) had previously received docetaxel. HR genes included on study were ATM (7), BRCA1 (3), BRCA2 (8), PALB2 (1), FANCA (1) and CHD1/ SPOP (1) with three tumors harboring two alterations. Clinical outcomes for the overall cohort and key sub-groups are reported in the table. 6/18 (33%) patients experienced grade ≥3 adverse events, including one patient with grade 4 thrombocytopenia. Conclusions: IC followed by maintenance rucaparib did not significantly increase PFS in patients with HR alterations compared to historical control. Results were more encouraging in the BRCA complex group. IC refractory patients were not rescued by subsequent PARPi, suggesting overlapping mechanisms of resistance when platinum is used prior to PARPi. Clinical trial information: NCT03442556 . [Table: see text]
Real-world baseline treatment patterns and overall survival (rwOS) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with olaparib in the United States.
Authors: Kariburyo-Yay Furaha , George Daniel J. , Aggarwal Himani , Tepsick Jon G. , Yu Rebekah , Li Weiyan , Orji Chinelo , Lal Lincy S. , Ghate Sameer R.
Published: June 2024

5054

Background: Olaparib is one of the first targeted therapies for pts with mCRPC. Real-world data on treatment patterns prior to receiving olaparib are limited in mCRPC pts with homologous recombination repair gene mutation (HRRm). This study describes real-world novel hormonal agent (NHA) use by clinical setting prior to receiving olaparib in mCRPC and rwOS in pts with HRRm mCRPC treated with olaparib monotherapy. Methods: HRRm+ pts with confirmed mCRPC diagnosis, age ≥21 years, treated with olaparib monotherapy (post May 19, 2020) and prior to abiraterone or enzalutamide were abstracted from electronic medical records in the ConcertAI Oncology Dataset with PC diagnosis between 1990 and 2023. HRR genes of interest were ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, RAD54L. Frequency of pts who progressed from metastatic hormone-sensitive PC (mHSPC) and from non-metastatic CRPC (nmCRPC) to mCRPC and treatment patterns prior to mCRPC were summarized. Kaplan-Meier analysis was used to describe the rwOS from the start date of earliest olaparib monotherapy treatment (index date). Results: A total of 144 mCRPC olaparib treated pts were identified [median age 73 years; any BRCAm including co-occurring HRRm 56.3%; White 73.6%; ECOG 0-1 at index 78.4%; Gleason ≥8 at index 66.7%]. Of the 144 pts, 80.5% of pts progressed from mHSPC, 11.8% of pts progressed from nmCRPC, and 7.6% of pts were identified in mCRPC setting. For pts who progressed from mHSPC, 62.1% were NHA-treated in the mHSPC setting. Overall, 43.8% initiated olaparib monotherapy in the first 2 lines of therapy after mCRPC diagnosis while 15.3% initiated olaparib in 5L+ (Table). Among pts diagnosed with mHSPC before mCRPC, olaparib was most frequently received in 2L (26.7%) and in 3L (22.4%). For mHSPC pts treated with NHA, olaparib was most frequently received in 2L (31.9%); in contrast, for mHSPC pts that were NHA-naïve, olaparib was most frequently received in the 5L+ (29.5%). The overall median rwOS from olaparib initiation was 16.5 (95% CI: 12.4, 21.1) months; and 20.3 (95% CI: 14.7, 26.8) and 12.9 (95% CI: 10.9, 16.9) months, respectively, for pts with and without any BRCA mutations. Conclusions: This real-world analysis indicates many mCRPC pts with HRRm are receiving several lines of therapy prior to olaparib, even when NHA are used prior to mCRPC. Earlier treatment with olaparib monotherapy may improve duration of therapy and overall survival. [Table: see text]
Race and decisional conflict about genetic testing in patients with advanced prostate cancer.
Authors: Purtell JP P , Ralston Avery , Rose Courtney M , McElyea Kyle , Ibrahim Farhan , Thompson Alexandra , Ghosh Sunita , Hwang Clara
Published: June 2024

5062

Background: Guideline recommended genetic testing in advanced prostate cancer (PC) is underutilized and not always accepted by patients (pts). We assessed attitudes and decisional conflict (DC) surrounding genetic testing associated with subsequent test completion, and differences between white and nonwhite pts. Methods: Eligibility for this prospective single institution study included pts with N1 or M1 PC who had not yet completed genetic testing. Upon informed consent, pts were given a 24-question survey using a Likert scale of 0 (strongly agree) to 4 (strongly disagree) to assess attitudes toward genetic testing including a validated assessment of DC. DC and DC subscores (range 0-100, with 100 being highest DC) were calculated from subsets of survey responses. Self-identified race was obtained from the EMR. Two-group comparisons between white and nonwhite pts, and between those who completed genetic testing and who did not, were conducted with SAS v9.4 software using Fisher’s exact test for categorical variables and Wilcoxon rank sum test for Likert scale survey questions and DC score variables. Results: Of 42 enrolled pts (21 white, 17 black, 1 Asian, 3 declined), 22 (52.4%) completed genetic testing. Compared to white pts, nonwhite pts expressed more concern about test result privacy (mean = 1.72 v 2.95, p = 0.002), test results being used for non-healthcare purposes (1.78 v 3.00, p = 0.003), and trying unproven treatments (1.72 v 2.67, p = 0.01). Nonwhite pts felt more external pressure in decision-making compared to white pts (0.67 v 0.29, p = 0.04). No significant differences were appreciated in completion of testing, DC, or any subscore between racial groups. Compared to pts who did not complete testing, those who completed testing were more likely to report they knew which options were available (0.73. v 1.25, p = 0.05), knew the benefits of each option (0.77 v 1.30, p = 0.04), knew the risk and side effects of each option (0.95 v 1.50, p = 0.05), were clear about which benefits matter most to themselves (0.73 v 1.37, p = 0.02), and were clear about the best choice for themselves (0.73 v 1.35, p = 0.02). DC (28.59 v 18.11, p = 0.03) was higher in pts who did not complete testing, along with uncertainty (31.25 v 19.32, p = 0.02) and informed (31.25 v 20.45, p = 0.03) subscores. No differences were seen in values clarity, support, or effective decision subscores. Conclusions: In our study, nonwhite pts expressed greater concern about privacy, data misuse, and trying unproven treatments. Those who did not complete testing had more DC with greater uncertainty about knowledge and decision making. These findings will help direct targeted interventions to increase knowledge, trust, and decisional certainty about genetic testing in pts with advanced PC. Ongoing studies will assess the impact of these interventions on rates of testing completion at our institution.
Independent blinded validation of an AI-based digital histology classifier for prostate cancer recurrence and metastasis risk prediction.
Authors: Fay Magdalena , Liao Ross , Lone Zaeem M , Reddy Chandana A. , Muhammad Hassan , Xie Chensu , Jain Parag , Huang Wei , Basu Hirak S , Nguyen Jane , Nair Sujit S. , Chakravarty Dimple , Williamson Sean R. , Gupta Shilpa , Weight Christopher , Roy Rajat , Wilding George , Tewari Ashutosh K. , Klein Eric A. , Mian Omar Y.
Published: June 2024

5098

Background: Artificial intelligence (AI) tools which identify pathology features from digitized whole slide images (WSI) of prostate cancer (CaP) generate data to predict risk of disease recurrence and metastasis. PathomIQ and ISMMS have developed an AI-enabled prognostic test, PATHOMIQ_PRAD, which predicts risk of biochemical recurrence (BCR) and distant metastasis (DM) using WSIs. The objective of this study was to evaluate the clinical validity of PATHOMIQ_PRAD using a retrospective clinical cohort at Cleveland Clinic. We also compared the test's performance to Decipher, an established genomic risk classifier. Methods: We conducted a retrospective PATHOMIQ_PRAD analysis of CaP WSIs of patients who underwent prostatectomy at Cleveland Clinic from 2009-2022 and did not receive any adjuvant therapy before BCR. 263 patients in the cohort received definitive treatment with radical prostatectomy and had a median follow-up of 50 months. Of these patients, 65 patients had BCR, and 14 patients developed DM as of last follow up. WSIs were de-identified, anonymized, and patient outcomes were blinded during the study. Patients were stratified into high-risk and low-risk categories based on pre-determined thresholds for PATHOMIQ_PRAD scores (0.45 for BCR and 0.55 for DM). The Kaplan-Meier method with log-rank was used to compare biochemical recurrence-free survival (BCRFS) and metastasis-free survival (MFS). Multivariable Cox proportional hazards regression was used to identify factors associated with BCR. Results: The rate of BCRFS and MFS were associated with both PATHOMIQ_PRAD score (BCR: >0.45 vs. <0.45, p<0.0001; DM: >0.55 vs. <0.55, p<0.0001) and Decipher score (BCR: >0.6 vs. <0.6, p=0.0009; DM: >0.6 vs. <0.6, p=0.0095). All 14 patients who had DM during the follow up time had a high PATHOMIQ_PRAD score. Univariate analysis shows that PATHOMIQ_PRAD reliably identifies patients at risk of BCR (HR: 4.19, p< 0.0001), and had comparable prognostic performance to Decipher (HR: 2.83, p=0.0013). Multivariate analysis (Table) shows that there was an increased risk of BCR in both the high-risk PATHOMIQ_PRAD (HR: 3.58, p=0.0005) and Decipher (HR: 2.20, p=0.0159) groups relative to the low-risk groups, which suggests that combining the two tests may further improve risk stratification. Conclusions: These results show that PATHOMIQ_PRAD continues to demonstrate clinical validity in predicting risk of BCR and DM with favorable performance compared to a commonly used genomic classifier. PATHOMIQ_PRAD may identify patients for early treatment intensification, as well as inform clinical trial patient selection. [Table: see text]
Nimotuzumab plus concurrent chemoradiotherapy for locally advanced cervical squamous cell carcinoma: The randomized, phase 3 CC3 study.
Authors: Wang Jun jie , Jiang Ping , Qu Ang , Wei Lichun , Zou Lijuan , Li Xiaofan , Wang Chunyan , Sun Xiaoge , Ding Li , Yuan Xiangkun , Cheng Huijun , Wu Dehua , Cai Rong , Yin Rutie , Zhang Jidong , Qiu Hui , Wang Tiejun , Gao Kun , Zhuo Yanhong , Zhang Yun Yan
Published: June 2024

5514

Background: Cervical cancer is the fourth common malignancy in women, with a 5-year overall survival rate of 24%-76.1%. At present, there are few studies on targeted drugs combined with concurrent chemoradiotherapy (CCRT) for locally advanced cervical cancer (LACC) and the survival results were not satisfactory. This CC3 study is the first randomized, controlled, multicenter phase 3 trial of EGFR combined with CCRT for advanced cervical cancer, aims to evaluate the efficacy and safety of nimotuzumab (humanized EGFR) in combination with CCRT for LACC. (NCT04678791). Methods: All patients with locally advanced cervical squamous cell carcinoma were randomized (1:1) to receive nimotuzumab (400mg, iv, weekly, for 6 weeks) combined with CCRT (cisplatin: 40 mg/m2, weekly, for 6 weeks; IMRT/VMAT: 45-50.4 Gy/25-28f; high-dose rate brachytherapy: 30-40 Gy, in 8 weeks) or CCRT alone. The primary endpoint was 3-year progression free survival (PFS) per RECIST 1.1. The secondary endpoints were 3-year overall survival (OS), objective response rate (ORR), complete response (CR) rate per RECIST v1.1, and safety per CTCAE v5.0. Results: Totally 286 patients were enrolled. 142 patients in the Nimo group (nimotuzumab combined with CCRT) and 144 in the CCRT group (CCRT alone). The baseline characteristics were balanced between the two groups. The 1-year PFS rate of the Nimo group was longer than that of CCRT group (96.1% vs. 92.1%, P=0.506). There was no significant difference in the risk ratio between the two groups (HR=0.76, 95% CI: 0.33-1.72, P=0.507), the 3-year PFS and 3-year OS were not reached. A total of 62 (43.99%) patients achieved partial response (PR) and 57 (40.14%) achieved CR in the Nimo group, 50 (34.72%) and 57 (39.58%) in the CCRT group, respectively. The ORR was 83.80% vs. 74.31% (P=0.049). The most common AEs were graded 1-2 as reported before. Follow-up is ongoing. Conclusions: Nimotuzumab combined with CCRT showed significant ORR improvement, longer trend in PFS and good safety in the treatment of LACC patients. Clinical trial information: NCT04678791 . [Table: see text]
Assessing the risk of uterine serous carcinoma in survivors of triple-negative breast cancer: Is BRCA1 the link?
Authors: Manning William , Li Siguo , Bregar Amy , Gockley Allison Ann , Clapp Mark C. , Wilke Roni Nitecki , Dioun Shayan , Rauh-Hain Jose Alejandro , Melamed Alexander
Published: June 2024

5602

Background: Uterine serous carcinoma (USC) is a rare and deadly form of endometrial cancer. It is unclear whether BRCA1 pathogenic variants (PV) are associated with an increased risk of USC. Because patients with triple-negative breast cancer (TNBC) have a high prevalence of BRCA1 PV, we hypothesize that if BRCA1 PV are causally related to the development of USC, survivors of TNBC would be at an increased risk of subsequent USC. This cohort study compares USC incidence rates in TNBC survivors with population-based controls. We estimate the magnitude of the association between BRCA1PV and USC that must exist if the excess risk of USC among TNBC survivors is attributable to differences in the prevalence of BRCA1 PV between TNBC survivors and controls. Methods: Using the Surveillance, Epidemiology, and End Results 17 registry data, we identified patients with TNBC diagnosed between Jan 2010 and Dec 2020 and population-based controls. Due to limited data on BRCA1 PV prevalence among non-white TNBC survivors, we restricted this analysis to White women. We estimated the probability of having a BRCA1 PV based on reported age-based prevalence for the general population and cohorts of patients with TNBC. We fit Poisson regression models to estimate age-specific incidence rates and age-adjusted relative risk of USC among TNBC survivors compared with controls and to estimate the relative risk of USC among BRCA1 PV carriers. Results: We identified 48,082 patients with TNBC accounting for 202,074 person-years. The median age at diagnosis was 61 years. The control population contributed 215,813,524 person-years of follow-up. There were 19 incident diagnoses of USC among TNBC survivors and 8,056 among controls, corresponding to crude rates of 9.4 and 3.7 cases per 100,000 person-years, respectively (Figure). After adjusting for age, TNBC survivors had a 59% increase in rate of developing USC (incidence rate ratio 1.59; 95% CI 1.02 to 2.50) compared to controls. We attributed the excess risk of USC among TNBC survivors to differences in BRCA1 PV prevalence. Given this, we estimated that BRCA1 PV was associated with an approximately 30-fold increase in the incidence of TNBC (95% CI 1.1 to 790). Conclusions: Survivors of TNBC, a population with a high prevalence of BRCA1 mutations, are at increased risk of USC compared with population-matched controls. This observation is concordant with an association between pathologic BRCA1 mutations and USC.
Exploring genetic ancestry and tumor mutation profiles in renal clear cell carcinoma: A comprehensive analysis using The Cancer Genetic Ancestry Atlas.
Authors: Lee Michelle J , Vemuru Shalini , Rhee Christopher H , Moses Marcus , Patel Deven , Nazha Bassel , Bilen Mehmet Asim , Brown Jacqueline T
Published: June 2024

e16512

Background: Addressing health disparities in renal cell carcinoma (RCC) has been an enduring challenge globally, with notable variations in incidence and outcomes among different racial groups. Genomic ancestry serves as a valuable tool in capturing biological variations among diverse populations and offers insights into clinical, histopathological, and molecular distinctions. We utilized The Cancer Genetic Ancestry Atlas (TCGAA) to investigate tumor mutation profiles of RCC with focus on the influence of genetic ancestry on the intricate genomic landscape of this malignancy. Methods: Genomic and clinical data of TCGA PanCancer Atlas KIRC were downloaded through the GDC Data Portal. We utilized The Cancer Genome Ancestry Atlas (TCGAA) and the STRUCTURE algorithm for estimation of genetic ancestry. Primary ancestry was specified as comprising greater than or equal to 50% of genetic ancestry from a single reference population. Statistical analyses were performed using chi-square, Cox proportional hazards models, and Kaplan-Meier methods. Results: 64.5% were male and 41% were locally advanced or metastatic (stage III-IV). Genomic analysis revealed 438 individuals with European ancestry (mean European ancestry of 95.78%), 50 patients with African ancestry (mean African ancestry of 77.7%), and 8 patients with Asian ancestry (mean Asian ancestry of 92.5%). The mean age of patients was 61.0, 58.5, and 49.5 for the European, African, and Asian ancestry groups, respectively. African ancestry correlated with a trend towards reduced overall survival (OS) compared to European ancestry (median OS 62.89 vs 90.48 months). African ancestry patients harbored lower frequency of VHL and PBRM1 alterations, but with significant enrichment in MTOR, FREM2, UNC80, LRP2 alterations compared with European ancestry group. Conclusions: This study reveals genetic heterogeneity in RCC across diverse ancestry groups, indicating presence of distinct oncogenic genes and pathways in African American populations.These findings suggest potential contributions to racial disparities in clinical presentation, outcomes, and treatment responses. Future research should include exploring the role of genetic ancestry in tumorigenesis and disease progression, alongside developing targeted therapies to mitigate health inequities and enhance outcomes for all populations. [Table: see text]
The prognostic value of Meet-URO score in patients with metastatic clear cell renal cell carcinoma receiving second or third-line tyrosine kinase inhibitors/immune checkpoint inhibitors combination therapy: A real-world study.
Authors: He Sike , Liu Haoyang , Chen Junru , Sun Guangxi , Liu Zhenhua , Zeng Hao
Published: June 2024

e16516

Background: A novel prognostic predictive model based on inflammatory indices and clinical factors; Meet-URO Score has been validated in patients with metastatic clear cell renal cell carcinoma (mccRCC) receiving immunotherapy. Here we investigate its prognostic value in Clear Cell Renal Cell Carcinoma (ccRCC) patients receiving second and third-line tyrosine kinase inhibitors-immune checkpoint inhibitors (TKIs-IOs) combination treatment. Methods: Baseline and follow up data from patients with mccRCC were obtained retrospectively from a single institution. Neutrophil-to-lymphocyte ratio (NLR), the International Metastatic RCC Database Consortium (IMDC) score and bone metastases were assessed before treatment. The primary outcomes were overall survival (OS). Harrell’s c-index was estimated to compare the accuracy of the prediction ability of the two models and Cox proportional hazard-regression model was used for univariable and multivariable analyses. Results: A total or 72 patients received TKIs-IOs combination treatment as second- and third-line therapy (88.89% and 11.11%) were included in this study. A significant shorter median overall survival (mOS) was observed in the IMDC poor risk group. Applying Meet-URO score, four groups were found and stratified (p=0.0016). The c-index in Meet-URO was higher than in IMDC (0.676 vs 0.585) and indicated that Meet-URO score had a higher discriminative ability than the IMDC score. In the Cox regression model, nephrectomy was found to be a protective factor (HR=0.21, 95% confidence interval: 0.05 - 0.93, p=0.04). Conclusions: Meet-URO score presents more accurate prognostic stratification than the IMDC score in mccRCC patients receiving TKIs-IOs combination treatment as second or further line therapy. More research is necessary to validate these findings in the future.
Clinical outcome differences based on gender in patients with advanced renal cell carcinoma (aRCC) treated with immune checkpoint inhibitors (ICIs).
Authors: Choi Yujin , Goswamy Rohit Vivek , Wei Mengting , Liu Yuan , Yildirim Ahmet , Brown Jacqueline T. , Nazha Bassel , Martini Dylan J. , Hartman Caitlin , McClintock Greta Russler , Zhuang Tony , Kissick Haydn , Harris Wayne B. , Carthon Bradley Curtis , Kucuk Omer , Master Viraj A. , Bilen Mehmet Asim
Published: June 2024

e16542

Background: Current first-line therapy for aRCC involves ICIs, often administered with another ICI or tyrosine-kinase inhibitors (TKIs). While there has been some literature on the association between gender and clinical outcomes in patients with aRCC, some results are contradictory and thus the true association remains unknown. We explored the role of gender in the difference in clinical outcomes of patients undergoing therapies involving ICIs. Methods: We conducted a retrospective analysis on adult patients with advanced RCC treated with ICIs at Emory Winship Cancer Institute between 1/1/2018 and 8/31/23. Overall survival (OS) and progression-free survival (PFS) was calculated from the date of treatment initiation to death and progression, respectively. Progression was determined by RECIST v1.1 or clinical progression. Clinical benefit (CB), including stable disease, partial response, and complete response, was determined by RECIST v.1.1. CB, OS, and PFS were used to identify the association between gender and clinical outcome through univariate (UVA) and multivariate (MVA) analyses. Results: Analysis was conducted on a total of 401 patients, consisting of 283 (70.6%) males and 118 (29.4%) females. Their median age was 66 (range = 18-95). Treatment plan involved 139 (34.6%) patients for single ICI therapy, 131 (32.6%) patients for ICI/ICI therapy, 108 (26.9%) patients for ICI/TKI therapy, 6 (1.5%) patients for ICI/ICI/TKI therapy, and 17 (4.23%) patients for therapy with ICI plus an experimental drug. CB, OS, and PFS all confirmed no difference in clinical outcomes of the patients based on gender in UVA and MVA. Female patients had hazard ratios (HR) close to 1 for both OS and PFS and odds ratios (OR) close to 1 for CB. Results from Kaplan-Meier (KM) plots also support the lack of difference in clinical outcomes between genders. The KM plot indicated similar OS and PFS for female and male patients, with the median OS for female and male patients being 36 and 28.2 months and the median PFS for female and male patients being 7.4 and 7.1 months, respectively. Conclusions: Patients treated with ICIs had similar clinical outcomes based on gender as indicated by insignificant differences in CB, OS, and PFS. However, prospective studies are still needed to validate such findings. [Table: see text]
Integrative genomic analysis examines molecular and clinical disparities between bladder urothelial carcinoma and upper tract urothelial carcinoma.
Authors: Choi Yoon Ji , Kim Jwa Hoon , Lee Jae-Lyun , Bae Woo Kyun , Kim Miso , Park Ji Hyun , Choi Jonggwon , Park Inkeun , Shin Sang Joon , Jo Jungmin , Park Se Hoon , Park Kwonoh , Kim Jiwon , Sa Jason
Published: June 2024

e16553

Background: The clinical outcome of urothelial carcinoma presents significant variability, reflecting its intricate molecular composition, epidemiologic attributes, and primary site of origin. Despite histological similarities, upper tract urothelial carcinoma (UTUC) and bladder urothelial carcinoma (BLCA) represent two distinct disease entities with disparate treatment responses and mutational patterns. Methods: To assess the impact of molecular heterogeneity on treatment outcomes, we conducted a comprehensive genomic analysis of 231 Korean BLCA and UTUC patients from the K-MASTER cohort. Results: Our investigation unveiled dynamic molecular properties and mutational patterns in key molecules, including TP53, FGFR3, CREBBP, and SPEN. BLCA patients demonstrated enrichment of APOBEC mutational signature activities, whereas UTUC patients were characterized by activation of the cell cycle pathway. Transcriptome analysis uncovered unique biological signatures, highlighting increased cell migration and WNT signaling in BLCA, while FGFR3 and stem-cell-like pathways predominated in UTUC. Moreover, our study identified increased treatment resistance to both platinum-based chemotherapy and immunotherapy in UTUC patients. Notably, tumor mutational burden (TMB) and microsatellite instability score independently demonstrated robust predictive capabilities for immunotherapy response in BLCA and UTUC, respectively. Lastly, a machine learning-based multivariable model identified FGFR3 mutation as a molecular determinant associated with favorable clinical outcomes, contrasting with mutations in FGFR2 linked to increased resistance to chemotherapy. Conclusions: Collectively, our findings provide important insights into the significance of molecular and clinical disparities in urothelial carcinoma, facilitating disease-specific treatment interventions.
Estimated impact of novel immune checkpoint inhibitors on reducing cancer mortality in patients with locally advanced or metastatic urothelial carcinoma in Russia.
Authors: Alekseev Boris , Alekseev Boris , Avxentyev Nikolay , Makarova Yuliya , Andreiashkina Irina
Published: June 2024

e16560

Background: The standard first-line treatment for patients with locally advanced or metastatic urothelial carcinoma (UC) is platinum-based chemotherapy. Other available therapeutic option are immune checkpoint inhibitors (ICIs) such as pembrolizumab, nivolumab, atezolizumab, and avelumab. However, unlike other drugs in this class, avelumab can be used as maintenance therapy in patients without disease progression after first-line platinum-based chemotherapy. Objective: In this study we sought to evaluate the effects of using ICIs in treating adult patients with locally advanced or metastatic urothelial UC on reducing overall and one-year cancer mortality in Russia. Methods: A mathematical model based on overall survival and progression-free survival data from clinical trials has been proposed. This model describes duration of therapy and treatment outcomes for treatment without ICIs (historical approach), with pembrolizumab and atezolizumab in first-line in cisplatin-ineligible PDL1-positive patients; nivolumab and pembrolizumab, atezolizumab in second-line therapy according to real-life clinical practice (current approach), and with avelumab as maintenance therapy after platinum-based chemotherapy (suggested approach). The model was applied to assess the healthcare expenses and the increase in saved lives when shifting from historical to current approaches and from current to suggested methods over a three-year timeframe. This analysis considered the annual population of patients in Russia with locally advanced or metastatic UC who might initiate platinum-based therapy. Results: Annually, up to 4,182 patients with locally advanced or metastatic UC in Russia can initiate platinum-based chemotherapy. Compared with historical approach, the use of pembrolizumab, nivolumab, and atezolizumab in the first and second lines of therapy according to real-life clinical practice, allows reducing mortality from malignant neoplasms by 553 cases over a 3-year horizon. Over the same period, avelumab-based treatment would additionally save 2,506 lives. Shifting to suggested practice with avelumab maintenance therapy may lead to decrease in one-year cancer mortality from 20.3% to 20.25% and one-year bladder cancer mortality from 13.8% to 12.12%. Furthermore, the cost of saving one life with avelumab amounts to 6.0 million rubles, which is 9% lower compared to the cost of saving one life with other ICIs (6.6 million rubles). Conclusions: The use of avelumab maintenance in advanced or metastatic UC patients without progression after platinum-based chemotherapy has a significant and quantifiable impact on reducing cancer-related mortality in Russia.
Neoadjuvant immunotherapy-driven bladder preservation for muscle-invasive bladder cancer: A multicenter, propensity score-matched cohort study.
Authors: Hu Jiao , Ou ZHENYU , Chen Minfeng , Liu Jinhui , Yan Luzhe , Chen Jinbo , Liu Peihua , Zu Xiongbing
Published: June 2024

e16598

Background: The rise of neoadjuvant immunotherapy has brought neoadjuvant immunotherapy-driven bladder preservation (Neoimmu-CMT) into the spotlight, yet its application is hampered by a scarcity of robust clinical evidence. There are no comparative studies on the effectiveness of Neoimmu-CMT versus traditional trimodal therapy (TMT) or neoadjuvant chemotherapy-driven bladder preservation (NAC-CMT). To address this gap, our study (ChiCTR2300069303) aims to assess Neoimmu-CMT's viability and identify suitable candidates through a multicenter, propensity score-matched (PSM) analysis. Methods: The study included 163 patients from 14 hospitals, categorized into Neoimmu-CMT (n=97), TMT (n=30), and NAC-CMT (n=36) subgroups. PSM was utilized to mitigate baseline variability. Primary outcomes were disease-free survival (DFS), bladder-intact DFS (BI-DFS), and overall survival (OS). Univariate and multivariate Cox analyses were used to identify potential prognostic factors. Biomarker assessment comprised immunohistochemistry and single-cell RNA sequencing. Results: Post-PSM, Neoimmu-CMT significantly outperformed NAC-CMT in DFS (HR: 2.112, 95% CI: 1.247-3.576, P=0.005) and BI-DFS (HR: 2.329, 95% CI: 1.138-4.770, P=0.021), with a 2-year BI-DFS rate of 90.28% compared to NAC-CMT's 71.59%. However, Neoimmu-CMT and TMT showed no significant difference in DFS and BI-DFS, with Neoimmu-CMT marginally surpassing TMT in 2-year BI-DFS rates (86.42% vs. 80.89%). Clinical complete response to neoadjuvant treatment and lower clinical T stage were positive prognostic factors for Neoimmu-CMT. Interestingly, regardless of being combined with ADC (HR: 1.283, 95% CI: 0.224-7.359, P=0.780) or chemotherapy (HR: 0.769, 95% CI: 0.255-2.323, P=0.642), the DFS outcomes did not surpass those received with sole immunotherapy. Furthermore, conventional clinical parameters such as tumor-associated hydronephrosis, tumor number, and histology type did not emerge as significant predictors for bladder preservation outcomes. Biomarker analysis showed the tumor microenvironment immune phenotype closely relates to bladder preservation outcomes. Conclusions: Neoimmu-CMT is a promising bladder preservation strategy, comparable to TMT and superior to NAC-CMT. Its advancement could significantly broaden bladder preservation treatment options.
Preliminary results of sexual quality of life (QOL) outcome for intermediate-high risk prostate cancers treated by stereotactic radiotherapy (SBRT) and androgen deprivation therapy (ADT): Clinical and dosimetric factors.
Authors: Basu Trinanjan , Sahu Jay Prakash , Gnair Ratheesh , Kamat Shounak Jairam
Published: June 2024

e17085

Background: There has been numerous evidence about ADT and radiotherapy on sexual QOL among prostate cancer (Pca) patients. This study analyzed the impact of SBRT on sexual health of Pca treated by SBRT and ADT. This also monitored dosimetry related to penile bulb (PB) and neurovascular bundles (NVB). Methods: Consecutive series of 40 Pca patients of intermediate and high-risk group (NCCN) were included. Baseline sexual function was assessed using Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC‐CP) questionnaire for sexual symptoms score. Patients received ADT as per risk groups. Radical SBRT was 36.25Gy in 5 fractions (Pelvic nodal 25 Gy in 5 fractions for high risk) on alternate days or weekly. Mean Dose to penile bulb and dose received by bilateral NVB were documented. Sexual function by EPIC-CP monitored at baseline and then 6 monthly till last follow up. Results: With median age of 61 years and median follow up of 20 months, 20% (8) patients belong to NCCN intermediate favourable risk category,15% (6) Intermediate unfavourable risk category and 65% (26) High risk category. All high risk Pca received elective pelvic nodal radiotherapy. Mean dose to penile bulb was in range of 9.5-29.4Gy. NVB Dose ranged from V34.4 (83.3% - 91.8%), V32 (94.5-99.16%) V28(99.76-100%). The EPIC‐CP for sexual symptoms score reported (out of 12) median score at baseline of 3 (range2-4), at 6 months 4.5 (range3-6)), at 12 months 5 (range 3-7), at 24 months 5.5 (range 4-7) and at 30 months 7 (range 6-8). The higher score represented worsening sexual function QOL. Till last follow up 38/40 patients were biochemically controlled with acceptable gastro-intestinal and genito-urinary late effects. Both the median and mean score of EPIC-CP sexual domain declined over follow up period representing clinical effect of ADT and dose received to PB and NVB. Sexual function scores declined gradually in both risk groups (High risk > intermediate risk) and vitality/hormonal scores were unchanged from baseline in both groups at 3 and 6 months. Few patients beyond 3 years of follow up reported some degree of recovery in EPIC-CP score in sexual function domain. Conclusions: A substantial group of patients in our study had mild or no erectile dysfunction at base-line but compromised sexual health after ADT and SBRT. The technical challenge of sparing NVB for high risk Pca patients combined with effect of ADT remains a concern. However, PB dosage were in the acceptable range signifying multitude of factors besides only dosimetric features. Late recovery of sexual function to some extent probably a possibility. There are limitations in documentation of sexual QOL by EPIC-CP in our cohort and future prospective documentation and pragmatic sparing of NVB can highlight specific issues related to sexual QOL.