bluuebunny/crossref_metadata_2025 huggingface dataset:
Whole exome correlates in metastatic hormone sensitive prostate cancer (mHSPC): Results from E3805 CHAARTED.
Authors: Hamid Anis , Vergara Matias , Park Jihye , Chinsky Tyler M , Aldubayan Saud , Grist Emily , Attard Gerhardt , Van Allen Eliezer Mendel , Sweeney Christopher
Published: June 2024

5088

Background: The landscape and clinical impact of genomic variants in mHSPC are incompletely understood. We have shown that deleterious germline BRCA2 alterations (alts) associate with shorter time to castration resistant prostate cancer (TTCRPC) on androgen deprivation therapy (ADT), but not on ADT plus docetaxel (ADT+D) (ASCO 2023). Somatic variation from tissue of patients (pts) with mHSPC is not well characterized and may influence therapeutic outcomes. Methods: We performed whole exome sequencing of HSPC specimens obtained at initial diagnosis and germline DNA from whole blood from pts in the CHAARTED trial (NCT00309985) of ADT vs ADT+D. Somatic single nucleotide variants (SNV) and allele-specific copy number alts (CNAs) were identified, including estimation of tumor mutational burden (TMB) and copy number burden (CNB). Prognostic effects were evaluated in both arms. Loss of selected tumor suppressor genes was defined by monoallelic or biallelic loss. TTCRPC and overall survival (OS) were estimated by Kaplan-Meier method. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated by Cox models. Results: After quality control, 68 tumor-normal cases were analyzed. The majority of pts had synchronous (51.5%) and high volume (58.8%) disease. Most frequent somatic SNVs were TP53 (33.8%), PTEN (7.4%), PIK3CA (5.9%) and SPOP (5.9%). AR amplification was uncommon (4.4%), however frequent MYC gain (60.3%) was seen as well as monoallelic deletion of NKX3-1, TP53, PTEN and BRCA2. Whole genome doubling occurred in 14.7%. Median TMB and CNB were 4.7 mut/Mb and 9.1%, respectively. CNB was elevated in synchronous (p=0.01) and high volume (p=0.046) disease. CNB greater than median was associated with shorter TTCRPC in the overall cohort (HR 2.06, 95%CI 1.13-3.75, p=0.015) and ADT+D arm (HR 2.98, 95%CI 1.17-7.58, p=0.016). The effect in the overall cohort was reduced after adjustment for volume and presentation (HR 1.72, p=0.091). A compounding effect of PTEN and TP53 alts was seen in the ADT arm where median TTCRPC for wild-type (WT), 1-gene hit, 2-gene hit was 19.6 mos, 8.5 mos, 6.3 mos, respectively. The median OS of WT vs 1-hit/2-hit loss was 47.1 mos vs 26.8 mos (HR 2.05, 95% CI 0.90-4.68, p=0.087). Similar differences in TTCRP and OS by PTEN/ TP53 status were not observed with ADT+D. Conclusions: The genomic landscape of mHSPC is characterized by frequent alts in putative drivers known to be enriched in mCRPC (Table). We observed a low rate of genomic instability and AR amplification/mutation similar to non-metastatic HSPC. Concordant with the STAMPEDE trial, greater CNB confers a higher risk of progression. Combined tumor suppressor gene alts associate with prognosis in mHSPC, which may differ by therapy intensification. [Table: see text]
A phase II trial of enzalutamide (Enz) with 5-alpha reductase inhibitors (5-ARI) as an androgen deprivation therapy (ADT)–sparing approach for older men with castration-sensitive prostate cancer (CSPC).
Authors: Kilari Deepak , Kadambi Sindhuja G , Baran Andrea M. , Zittel Jason , Burfeind John D. , Messing Edward M. , Van Veldhuizen Peter J. , Bylow Kathryn A. , Sahasrabudhe Deepak M. , Mohile Supriya Gupta , Fung Chunkit
Published: June 2024

5089

Background: Older men with prostate cancer who have aging-related conditions are at high risk for adverse events (AEs) from ADT. 5-ARI inhibit the conversion of testosterone to dihydrotesterone and could be synergistic with Enz. In this phase II study, we evaluated Enz and Dutasteride (Dut) or Finasteride (Fin) in lieu of ADT for older men with CSPC who are at risk of AEs from ADT. Methods: Eligible patients were ≥65 years (y); deemed “not fit” by geriatric assessment (GA) or at high risk for side effects from ADT as determined by the treating physician; had metastatic (M1) or non-metastatic (M0) CSPC with a PSA doubling time ≤9 months and testosterone >50ng/dl. Enz 160 mg daily and Dut 0.5mg daily or Fin 5mg daily were administered until disease progression per Prostate Cancer Clinical Trials Working Group 2 guidelines. The primary study endpoint is PSA progression free survival (PFS). Key secondary endpoints include time to PSA nadir, absolute PSA nadir and evaluation of safety and toxicity of study treatments per CTCAE V4.0. Results: 43 men enrolled in the study. At study entry, subjects had the following baseline characteristics: median age was 78 y (range 66-94); 93% had ECOG 0-1; 63% had M1 CSPC with 30% of them having high volume disease per CHAARTED criteria; 23% had Gleason ≥ 8 CSPC; median PSA was 11.4 ng/ml (2-145), and median testosterone level was 342 ng/dl (56-639). Baseline GA at study entry showed that 18.6% had Instrumental Activity of Daily Living impairment; 9.8% had recent falls; 52.4% had Short Physical Performance Battery impairment; 40.5% had Older American Resources and Services (OARS) physical health and 31% had OARS medical social support impairments; 11.6% had Geriatric Depression Scale impairments; 65.9% had either Blessed Orientation-Memory-Concentration or Montreal Cognitive Assessment impairments; and 34.9% had Vulnerable Elders Survey-13 impairments. At a median follow-up of 5.9 y, 23 pts (53%) remained on study treatment and the median PSA PFS has not been reached for the entire group. The median time to PSA nadir was 8.1 months, with median PSA nadir at 0.02 ng/ml (range 0-2.75) and 98% having ≥90% PSA decline. The five most common any grade AE was fatigue (88%), gynecomastia (72%), hot flashes (42%), hypertension (40%), and falls (37%). No subject had treatment-related Grade 4 or 5 AEs. Four (9.3%) subjects withdrew treatment, 21% held treatments and 30.2% reduced dose of treatment due to AEs. Conclusions: The combination treatment with Enz and Dut/Fin appears to have clinical efficacy for older patients with CSPC who are at high risk for AEs from ADT. Clinical trial information: NCT02213107 .
Intensification of ADT with enzalutamide in high-risk patients with biochemical relapse following radical prostatectomy undergoing salvage radiation: Initial results from RTOG 3506 (STEEL).
Authors: Posadas Edwin Melencio , Gay Hiram Alberto , Rodgers Joseph P , Morgan Todd Matthew , Xiao Ying , Yu James , Michalski Jeff M. , Bouchard Myriam , Desai Neil B , Funk Ryan , Boike Thomas Pence , Jurgens Donald James , Wong Anthony C. , Shen Xinglei , Miyawaki Lloyd T , Bland Christopher S , Hairston John , Sandler Howard M. , Pugh Stephanie L , Feng Felix Y
Published: June 2024

5101

Background: Patients with high-risk features who experience biochemical relapse (BCR) after radical prostatectomy (RP) benefit from the addition of androgen deprivation therapy (ADT) to salvage radiotherapy (SRT). We hypothesized that intensification of androgen receptor (AR) blockade with enzalutamide would improve SRT outcomes for high-risk patients. Methods: Post prostatectomy prostate cancer patients who have had BCR (PSA ≥ 0.2 ng/mL) with at least 1 high-risk feature (Gleason 8-10, seminal vesicle invasion, pN1, persistent PSA >0.1 ng/mL after RP, and PSA ≥ 0.7 ng/mL) were eligible. Patients were randomized 1:1 to 24 months of ADT with an LHRH analog (LHRHa) or intensified ADT comprised of LHRHa + enzalutamide. The primary endpoint was progression free survival (PFS) with progression defined as PSA ≥ 0.05 ng/mL or initiation of new therapy following SRT. The target accrual of 170 patients provided 80% power to detect a HR=0.65 using a one-sided logrank test with a type I error of 0.10. Results: Between April 2019 and August 2022, 188 patients were enrolled. The patient characteristics were well balanced between the two arms. Median age was 64 years. Nodal involvement (pN1), pT3a-b, and Gleason 9 were noted in 22%, 77%, and 52% of patients, respectively. Over 70% had > 1 aggressive feature. Median follow-up time at the time of this report was 15.8 months. Prostatic fossa and pelvic SRT were mandatory. Para-aortic radiotherapy (RT), and lymph node and prostatic fossa lesion RT boosts were left at the discretion of the radiation oncologist. PFS favored the enzalutamide-intensified arm (HR=0.72, 80% confidence interval [CI]:0.56-0.94, one-sided p=0.14). Grade 3 adverse events (AEs) related to treatment in the standard versus enzalutamide arms were 11 vs. 23%, while Grade 4 AEs were 4% vs. 1%, respectively. The most common AEs (all grades, >15%) included hot flashes, fatigue, diarrhea, and decreased lymphocytes. The grade 3+ AEs (>3%) included decreased lymphocytes and hypertension. The largest differences (>7%) in AEs included insomnia, decreased lymphocytes. Diarrhea was less frequent with enzalutamide (40% vs 54%). Conclusions: The addition of enzalutamide to standard ADT did not meaningfully increase toxicity. While there was a trend toward PFS benefit from intensification, it has not yet met statistical significance. Updates on PFS and other clinical endpoints including quality of life will be reported with longer follow-up. Clinical trial information: NCT03809000 .
Efficacy and safety of cadonilimab plus anti-EGFR monoclonal antibody as de-chemotherapy regimen in persistent, recurrent, or metastatic gynecologic cancer.
Authors: Zhang Qiying , Liu Zi , Zhang Jing , Wang Fei , Fan Shi , Wang Juan , Wang Tao , Su Jin
Published: June 2024

5538

Background: Cadonilimab, an anti-PD-1/CTLA4 bi-specific antibody, and Nimotuzumab, an anti-EGFR monoclonal antibody, have demonstrated effectiveness in treating persistent, recurrent, or metastatic (P/R/M) cervical cancer individually. However, the exploration of combined bi-specific immunotherapy and anti-EGFR target therapy remains unexplored in P/R/M gynecological cancer. Methods: This open-label, prospective single-arm phase II study (NCT05606263). Eligible participants were P/R/M gynecological cancer patients who declined or couldn’t tolerate chemotherapy, or had failed first-line or subsequent treatments, irrespective of PD-L1 status. Patients received Cadonilimab at 6 mg/kg plus Nimotuzumab at a dose of 400 mg every two weeks. The primary endpoint included safety and objective response rate (ORR), with secondary endpoints comprising progression-free survival (PFS) and overall survival (OS). Results: From July 2022 to February 2024, twenty-nine P/R/M gynecological cancer patients received at least one dose of cadonilimab plus Nimotuzumab, including 22 (75.9%) with cervical cancer, 4 (13.8%) with endometrial carcinoma, and 3 (10.3%) with vulva cancer. The median age was 60 years (range: 39–80 years). Reasons for participating in this clinical trial included refusal of chemotherapy (7/29), inability to tolerate chemotherapy (7/29), and failure of first-line or subsequent lines of systemic therapy (15/29). Among them, 5 patients progressed after PD-1/PD-L1 treatment. After a median follow-up of 6 months (range: 1–18), the best response was observed in 17 patients, with 3 achieving complete response (CR) and 14 partial response (PR). Notably 2 patients relapsed after PD-1 treatment. The ORR was 58.6% (95% CI, 39.7–77.7). Additionally 6 patients achieved stable disease (SD), while 6 patients experienced disease progression. The median PFS and OS were not reached, but the 6-month PFS rate was 58.1% (95% CI, 35.5–75.2), and the 6-month OS rate was 76.5% (95% CI, 54.6–88.8). Adverse events (AEs) were generally manageable and tolerable (Grade 1-2), including hypothyroidism (13.8%), immune-mediated hepatitis (13.8%), rash maculo-papular (6.9%), thrombocytopenia (6.9%) and nephritis (3.4%). Conclusions: To the best of our knowledge, this represents the inaugural clinical report on the de-chemotherapy regimen of Cadonilimab plus Nimotuzumab for P/R/M gynecological cancer. The combination exhibited a promising tumor response rate (58.6%), surpassing the 32.3% observed with Cadonilimab alone, and demonstrated a manageable safety profile. These findings suggest the potential of bi-specific immunotherapy coupled with anti-EGFR target therapy especially in patients who are resistant to chemotherapy or intolerant to it, even in cases where single- specific immunotherapy has previously failed. Clinical trial information: NCT05606263 .
Maximizing cervical cancer prevention in safety-net settings of care: Resources from the Federal Cervical Cancer Collaborative for provider and patient engagement.
Authors: Segebrecht Jane , Hendrix Ellen , Chollette Veronica , K. McGee-Avila Jennifer K. , Loukissas Jennifer K. , Tookmanian Elise , Wentzensen Nicolas , Temkin Sarah M.
Published: June 2024

5542

Background: Uneven administration of cervical cancer prevention, screening, and management, and changing guidelines prompted the Health Resources and Services Administration (HRSA) Office of Women’s Health and federal partners to develop the Federal Cervical Cancer Collaborative (FCCC). The FCCC aims to achieve the vision of the Cancer Moonshot in safety-net settings, reduce disparities in cervical cancer, and bridge the U.S. government’s priorities of cancer research and health care delivery. The FCCC supported: i) a survey of NCI-Designated Cancer Centers on barriers and opportunities that influence how Cancer Centers partner and engage with HRSA-supported and other safety-net settings of care; ii) the development of resources for providers in safety-net settings of care to support equitable cervical cancer prevention, screening, and management; and iii) the development of health communications materials to foster patient engagement for improved access to preventive health services. Methods: From January-February 2022, the FCCC conducted a multiple-choice and open-ended survey of 72.3% of Cancer Centers (n = 47) to identify opportunities to strengthen collaborations with safety-net settings. From February 2022-June 2023, the FCCC convened nine roundtables, with stakeholders across U.S. territories and freely associated states, national organizations, academia, and federal agencies, to inform provider technical assistance and patient outreach materials. Results: Cancer Centers reported patient-level barriers as the most challenging, compared with clinician-level, organizational-level, and systems-level barriers. The most common barriers to management of abnormal cancer screening included: transportation/travel (98%), health literacy (96%), and caregiving responsibilities (95%). The roundtable series informed the development of two resources: a primary care provider toolkit and patient outreach materials to strengthen cervical cancer prevention, screening, and management of abnormal results in safety-net settings of care. Conclusions: Roundtables and survey findings can inform needed structural and public health interventions to overcome patient level barriers and strengthen partnerships between Cancer Centers and safety-net settings. The findings also guide the FCCC’s long-term commitments to support equitable cervical cancer prevention in safety-net settings. The toolkit offers practical tools and guidance to primary care providers to improve quality of care, train staff, and communicate with patients. Patient outreach materials can support patient engagement in care and access to care. Both freely available resources will be used in a national remote tele-mentoring initiative for providers in safety-net settings of care.
Using artificial intelligence-powered evidence-based molecular decision-making for improved outcomes in ovarian cancer.
Authors: Orr Brian Christopher , Uihlein Arlette Harper , Montgomery Robert , Radolec Mackenzy , Edwards Robert P.
Published: June 2024

5555

Background: High grade serous ovarian cancer (HGSC) is a complex deadly disease. Due to the lack of symptoms at early stages, vast majority patients present at stage III/IV. Frontline chemotherapy and surgery is effective with nearly all patients experiencing a remission, though over 80% patients will recur in the first 1-2 years and ultimately die of the disease in the next few years. Approximately 20% will be long-term survivors, but no current clinical data can predict who may be a short- or long-term survivor. Clinical management, monitoring, and systemic treatment decisions could be optimally individualized to patients if able to better define the prognosis. The goal of this study is to employ artificial intelligence multi-omic machine learning models to predict survival outcomes. Methods: Clinical data and tumor specimens from University of Pittsburgh Center from 2010-2016 were analyzed. Patient data, whole exome sequencing (WES), whole transcriptome sequencing (WTS), drug response profile, and digital pathology profile were used as input feature sets for training the multi-omic machine learning (ML) models. Hypothesis-free training of the ML models was utilized to classify patient survival at 2yr and 5yr threshold. Model performance was estimated using AUROC (area under the receiver operating characteristic curve) metric, scores >0.5 having higher prediction potential. Validation of the prediction results of each ML model with top performing models meeting statistical significance threshold of α=0.01. Results: 160 HGSC model builds were completed. ML models achieved high prediction accuracy for both short-term (2y) and long-term (5y) patient cohorts, identifying 7 models with ≥ 0.7 AUROC model performance for 2yr OS threshold and 13 models with ≥ 0.7 AUROC model performance for 5yr OS threshold. Addition of multi-omic feature sets to clinical profile improved the model’s ability to predict OS for both short-term and long-term thresholds. Multi-omic feature set inputs led to superior prediction and improved performance over clinical profile information alone, and top performing multi-omic models predicted better than any feature set in isolation. Comparison of top features identified by 2y and 5y OS threshold models, we found that molecular features (WTS followed by WES feature sets) predominantly drove 2y cohort while digital pathology imaging features were the driver the 5y cohort top performing models. Conclusions: Current clinical data does not accurately predict prognosis. Utilizing multi-omic machine learning models, superior prediction of short- and long-term survivors was achieved. The specific drivers of the top performing models were different for the short- and long-term cohorts, identifying future research opportunities as well as development potential of a clinical decision tool.
Systematic review of frailty assessment in ovarian cancer studies.
Authors: Madariaga Ainhoa , Alqaisi Husam , Castelo Alicia , Fazelzad Rouhi , Lheureux Stephanie , Oza Amit M.
Published: June 2024

5564

Background: Frailty is a state of vulnerability to poor resolution of homeostasis following a stressor event, such as chemotherapy or surgery. Better knowledge of frailty assessments (FA) in ovarian cancer could help drive a global and individualized care strategy. Methods: A search was performed in 10 databases including Medline, Embase and Cochrane (up to March 2022). The search strategy utilized a combination of keywords and controlled vocabulary related to ovarian cancer, frailty/geriatric assessment. Studies performing FA in patients with ovarian cancer on systemic therapy, surgery and surveillance were included. The 2020 PRISMA checklists were followed, and the study was registered in PROSPERO (CRD42022323409). Primary objective was to identify frailty scales used in ovarian cancer studies. Secondary objectives were to describe impact of results on decision making and outcomes, adherence to ASCO Vulnerability Assessment (VA) guidelines. Results: 2,259 articles were screened, and 48 included in the final analysis. Studies were published between 2004-2022 and included 84,575 patients. 23 studies (48%) had an age limit for inclusion (≥65 to ≥80 years). Six studies were interventional (1 phase 3 clinical trial [CT], rest phase 2) and 42 were observational (45% retrospective). FA were highly variable. Median number of tests to assess frailty were 3 (range 1-13). Most studies used a combination of tests (several may apply): validated frailty scales (21 studies, 43.7%), nutritional/sarcopenia status (20 studies, 41.7%), functionality/physical performance (19 studies, 39.6%), geriatric assessment (7 studies, 14.6%). Global measures with all the comprehensive assessment items of the ASCO VA guideline were included in 14.6% of studies. FA was not used for decision making in any study. One FA designed for ovarian cancer was identified, the GINECO Geriatric Vulnerability score. Frailty was the primary objective in 26 studies (54%), out of which 12 were retrospective. Among them, study objectives were highly variable including survival, complications, or cost of surgery (13 studies) and systemic therapy (7 studies), prognosis (4 studies), treatment compliance and dependence (1 each). All but one (a prognostic study) met its primary outcome demonstrating worse outcomes in frail patients. Conclusions: Frailty assessments are heterogeneous in ovarian cancer studies. Most studies do not adhere to the ASCO vulnerability assessment guidelines. An association between frailty and poor outcomes was detected in surgical and systemic therapy studies. There is room for improvement, as none of the assessed studies used the frailty for decision making.[Table: see text]
Phase Ib INEOV neoadjuvant trial of durvalumab +/- tremelimumab with platinum chemotherapy for patients (pts) with unresectable ovarian cancer (OC): Survival outcomes and immune correlates.
Authors: Leary Alexandra , Chardin Laure , Lortholary Alain , Asselain Bernard , Alexandre Jerome , Lebreton Coriolan , Savoye Aude-Marie , Oudard Stephane , Gavoille Céline , You Benoit , D'hondt Veronique , Grenier Julien , Yaniz-Galende Elisa , Roussel-Simonin Cyril , De La Motte Rouge Thibault , Pujade-Lauraine Eric
Published: June 2024

5569

Background: Ineov was a phase Ib randomized trial of neoadjuvant carboplatin/paclitaxel (NACT) + durvalumab (D) +/- tremelimumab (T) in unresectable OC. We previously reported safety and encouraging complete resection rates (CC0=70%) and complete pathological response rates (pCR=18%) at interval debulking surgery (IDS). However there were no significant differences with the addition of T to D+NACT. Here we report survival outcomes and immune correlates with a focus on long-term responders. Methods: Pts with unresectable stage IIIC/IV OC were randomized to NACT + D (1125mg) alone (arm A) or with T (75mg once at C2) (arm B). IDS was planned after C3, or delayed after C6. Pts in arm A not operable after C3 crossed over to arm B, pts in arm B crossed over to standard of care (SOC) and assessed for delayed IDS after C6. PFS was assessed by Kaplan-Meier and PFS compared between arms A and B by Log-Rank test. Intra-epithalial CD8+ lymphocytes were scored as nb/mm2 and HLA-I expression was scored by H-score. Results: 70 patients were randomized to Arm A (N=36) or Arm B (N=34). 4 pts were replaced for early toxicity and one early death attributed to COVID. Median PFS in all pts was encouraging at 18mo but not different between arms. CCO at IDS was associated with significantly improved PFS (mPFS 25mo vs 14mo; p 0.0008). NACT+D+/-T significantly increased intra-epithelial CD8+ infiltration (p<0.0001) and HLA-I levels (p=0.007), but the changes were no different in arm A vs B. While high ieCD8 predicted improved pathological response (p=0.0014), neither ieCD8 nor HLA-1 levels at baseline or IDS predicted improved PFS. 8 (12.5%) pts were disease free at >40months. When compared to the other patients in the trial, this subset of long-responders was characterized by higher pCR (38% vs 11%), higher CC0 rates (100% vs 66% ) but showed no differences in immune profile. Among pts with known BRCA status, 43% of long-responders had a BRCAm (vs 20%). Conclusions: NACT combined with immunotherapy resulted in encouraging CC0, pCR and PFS in pts with unresectable OC, however the addition of T to D did not improve immune infiltration or outcomes. Features associated with long response were pCR, CC0 and BRCAm, not immune features. Clinical trial information: NCT03249142 .
Molecular and immune characterization of squamous cell ovarian cancers for identification of therapeutic targets.
Authors: Hollingsworth Jessie , Wu Sharon , Adkoli Anusha , Farrell Alex Patrick , Hodges Kurt , Oberley Matthew James , Karnezis Anthony , Thaker Premal H. , Girda Eugenia
Published: June 2024

5584

Background: Squamous cell carcinoma (SCC) represents <1% of all Ovarian cancers (OC) and is associated with poor prognosis. This study seeks to identify prognostic factors and molecular markers associated with OSCC compared to Endometrioid OC (EOC), Clear Cell OC (CCOC), HPV16/18-negative vulvar SCC (VSCC) and HPV16/18-negative cervical SCC (CSCC). Methods: 812 EOC, 846 CCOC, 32 OSCC, 15 malignant BT, 500 HPV16/18- CSCC, and 472 HPV16/18- VSC were analyzed using next-generation sequencing of DNA (NextSeq, 592 genes and NovaSeq, WES) and RNA (NovaSeq, WTS) (Caris Life Sciences, Phx, AZ). Tumor mutational burden (TMB) was measured by totaling all somatic mutations (mt) per tumor (TMB-H: > 10 mt/MB). PD-L1 IHC positivity was determined by a cut-off of >1% CPS (22c3, Agilent) and >2|5% (SP142, Spring Biosciences). HPV status determined by WES for HPV16 and 18. Statistical significance determined using chi-square and Mann-Whitney U test and adjusted for multiple comparisons (q<0.05). UMAP was used to visualize differences or similarities in transcriptomic profiles. Real-world overall survival (rwOS) obtained from insurance claims data and calculated from first treatment to last contact. Hazard ratio (HR) was calculated by Cox proportional hazards, with p-value calculated using log-rank test. Results: OSCC had the highest rate of TP53-mt and CDKN2A-mt compared to BT, EOC, CCOC, and CSCC (TP53-mt: 71.9%, 33.3%, 25.1%, 11.6% and 27.1%, CDKN2A-mt: 25%, 0%, 1.49%, 0.48%, and 4.45%) but lower than VSCC (TP53-mt: 80%, CDKN2A-mt: 38.9%). OSCC had lower mt of Chromatin Remodeling (CR) genes ARID1A (3.13%) compared to EOC (39.3%) and CCOC (58.2%) but higher mt of CR gene KMT2D (19.4%) compared to CCOC (3.62%) (q<0.05). OSCC had increased TMB-H than EOC, CCOC and VSCC (41.9% vs 13.6% vs 5.7% vs 8.84%) and PD-L1 IHC (all q<0.05). There was no ER/PR staining in OSCC. Median interferon (IFN) score was higher in OSCC compared to EOC, CCOC and BT (-0.24 vs -0.44 vs -0.46 vs -0.51, q<0.05) but similar to CSCC (-0.29) and VSCC (-0.17). Pathway analysis showed enrichment of IFNγ Response, Inflammatory Response, EMT and TNFα Signaling (NES: 1.53-2.05, FDR<0.25) in OSCC compared to EOC and CCOC. UMAP showed OSCC clustering more closely with CSCC and VSCC compared to EOC and CCOC. OSCC had worse post-Carboplatin survival (19.6 mo) compared to EOC (71.6 mo, p<0.01) and CCOC (46.9 mo, p<0.01), similar post-Carbo survival to TP53-mt CSCC (22.5 mo; p=0.80) but improved post-Carbo survival compared to TP53-mt VSCC (9.05 mo; p=0.01). Conclusions: The molecular and transcriptomic profile of OSCC is distinct from EOC, CCOC, and BT but similar to CSCC and VSCC. OSCC demonstrated a more immune hot phenotype. Further studies are needed to investigate the potential use of immunotherapy in OSCC.
Durvalumab + carboplatin/paclitaxel (CP) followed by durvalumab ± olaparib as first-line treatment for newly diagnosed advanced or recurrent endometrial cancer (EC) in DUO-E: Results by BRCA1/BRCA2 mutation (BRCAm) status.
Authors: Van Nieuwenhuysen Els , Baurain Jean-Francois , Chon Hye Sook , Thomes Pepin Jessica , Sundborg Michael J. , Gold Michael A. , Kim Byoung-Gie , Blank Stephanie V. , Liu Ji-Hong , McCollum Michael , Mori Masahiko , Jonuškienė Goda , Moore Kathleen N. , Novák Zoltán , Ramos Pedro , de Padua Charles Andreé Joseph , Gil-Martin Marta , Kowgier Matthew , del Rosario Paula Michelle , Westin Shannon Neville
Published: June 2024

5595

Background: DUO-E (NCT04269200) showed statistically significant, clinically meaningful improvement in progression-free survival (PFS) with addition of durvalumab to CP, followed by durvalumab ± the PARP inhibitor olaparib, vs CP alone for patients (pts) with EC (Westin SN et al. J Clin Oncol 2024;42:283–99). PARP inhibitors are an established approach to targeting tumors with homologous recombination deficiency, so we performed post hoc exploratory analyses of PFS by BRCAm status. Methods: Pts with newly diagnosed FIGO Stage III/IV or recurrent EC and naïve to first-line systemic treatment were randomized 1:1:1 to CP (CP + durvalumab placebo [pbo; 6 cycles] followed by durvalumab pbo + olaparib pbo), CP+D (CP + durvalumab [1120 mg q3w; 6 cycles] followed by durvalumab [1500 mg q4w] + olaparib pbo) or CP+D+O (CP + durvalumab [6 cycles] followed by durvalumab + olaparib [300 mg bid]). Tissue BRCAm status was determined retrospectively (FoundationOneCDx assay, Foundation Medicine). Results: Of 718 pts randomized, 19.9% were mismatch repair deficient (dMMR) and 80.1% MMR proficient (pMMR). At primary analysis (April 12, 2023), PFS improvement was observed for CP+D and CP+D+O vs CP irrespective of BRCAm status (Table). BRCAm prevalence was low overall (dMMR: 12.6% BRCAm, 61.5% non-BRCAm, 25.9% unknown; pMMR: 4.0% BRCAm, 65.9% non-BRCAm, 30.1% unknown). PFS outcomes for CP+D+O vs CP in pMMR non-BRCAm pts (HR 0.57, 95% CI 0.42–0.78) were consistent with the overall pMMR subgroup (HR 0.57, 95% CI 0.44–0.73); BRCAm subgroup analyses were descriptive due to small sample size. Conclusions: Clinical benefit with addition of durvalumab to CP, followed by durvalumab + olaparib, vs CP alone was observed in the ITT and pMMR populations irrespective of BRCAm status. Clinical trial information: NCT04269200 . [Table: see text]
Cadonilimab plus lenvatinib in patients with advanced endometrial cancer: A multicenter, single-arm, phase II trial.
Authors: Lan Chunyan , Yang Xielan , Zhao Jing , Zheng Min , Yang Fan , Xie Zhiwen , Wu Xiaoliu , Yang Hongying , Wang Wenyan , Huang Xin
Published: June 2024

5600

Background: Lenvatinib plus pembrolizumab is the standard treatment for patients with advanced endometrial cancer with mismatch repair-proficient (pMMR) disease who had disease progression after the receipt of prior systemic platinum-based therapy. Cadonilimab is a PD-1/CTLA-4 bi-specific antibody. We aimed to assess the combination of cadonilimab and lenvatinib in patients with advanced endometrial cancer who had previously received at least one platinum-based chemotherapy. Methods: In this phase II study with a safety-run in, eligible patients were aged 18 years or older with advanced endometrial cancer of any histologic subtype, except sarcoma, progressed after at least one prior platinum-based chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0 or 1. In the safety run-in period, a 3+3 dose de-escalation design was used to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of lenvatinib (16 mg or 12 mg once daily) combined with cadonilimab 10 mg/kg every 3 weeks. After the completion of safety run-in period, the phase II cohort at the RP2D will open. Approximately 29 patients are planned to receive treatment at the RP2D. The primary endpoint was objective response rate (ORR) at the RP2D. Key secondary endpoints included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: Between 8 May 2023 and 18 December 2023, 24 patients were enrolled. As of 31 December 2023, enrollment was ongoing. No DLTs were observed during the safety run-in period. The RP2D of lenvatinib is 16 mg once daily. Among 21 efficacy-evaluable patients, the ORR was 52.4% (95% CI: 29.1–75.7), and the DCR was 90.5% (95% CI: 69.6–98.8). The Medians for DOR, PFS, and OS were not reached. Grade 3–4 treatment-related adverse events included increased ALT (2 [8.3%]), increased AST (1 [4.2%]), increased creatine phosphokinase (1 [4.2%]), hypertension (1 [4.2%]), and intestinal perforation (1 [4.2%]). Conclusions: Cadonilimab plus lenvatinib showed promising antitumor activity in patients with advanced endometrial cancer who have experienced disease progression after prior systemic platinum-based therapy. The combination therapy had a favorable and manageable safety profile. Clinical trial information: NCT05824481 . [Table: see text]
Endometrial carcinoma in Black vs Asian women: Racial disparities and opportunities to improve survival in 219,301 patients in the USA.
Authors: Becerra Henry Alberto , Ilerhunmwuwa Nosakhare Paul , Wasifuddin Mustafa , Uche Ifeanyi , Osorio Juan C. , Wang Jen Chin C.
Published: June 2024

5608

Background: Endometrial Carcinoma (EC) is the most prevalent gynecological malignancy in the USA (1,2). Incidence and mortality has been increasing, making it a growing public health problem (2-4). While hysterectomy-corrected studies have revealed racial differences for EC (5,6), factors that influence the poor prognosis among black women with EC in the USA remain. The objective of this study is to describe sociodemographic characteristics, survival outcomes and prognostic factors based on race in EC patients. Methods: Cases of EC from the Surveillance, Epidemiology, and End Results (SEER) Research Plus Data, 17 Registries, from 2000 to 2020, were analyzed in SPSS v25. Variables were compared with Chi-squared test. Median Overall Survival (OS) was done using Kaplan-Meier method. Cox Regression analysis was done to identify independent prognostic factors influencing survival. A two-sided p-value ≤0.05 was considered statistically significant. Results: 219,301 patients with EC were included. Median follow up: 64 months. Median age of diagnosis: 62 years. 69.5% were whites, 8.6% blacks and 8.4% asians. Treatments were surgery (91.8%), radiotherapy (26.1%) and chemotherapy (18.1%). The median OS was 209 months (95%CI:207.1-210.9). Notably, the shortest median OS was observed in blacks (118 months), followed by 205 months for whites, while it was not reached for asians. Multivariate analysis showed that, compared to whites, blacks exhibit the poorest prognosis (HR=1.39, 95%CI:1.35-1.43), whereas asians demonstrated the most favorable prognosis across all races (HR=0.88, 95%CI:0.85-0.91). Independent poor prognostic factors found for EC included older age, low income and advanced stage. Differences in the distribution of these factors were observed among races. When comparing to asians, there was a higher proportion of blacks ≥60 years-old (66.9% vs 44%, p<0.001), with incomes <$60,000 (31.3% vs 3.6%, p<0.001) and diagnosed at more advanced stage (37.4% vs 28.9%, p<0.001). Surgery-based treatments showed the best prognosis (HR<0.3 independent of race, p<0.01). However, the distribution of these treatments stratified by race and stage showed that asians were more prone to receive surgical treatment independent of stage compared to blacks (p<0.001). Conclusions: Our findings contribute novel information on distribution of prognostic factors across races and their impact on survival. Notably, compared to asians, blacks appear to face delayed diagnosis, lower income, and less frequent use of surgery-based treatments. This highlights the importance of early access to diagnosis and treatment as potential avenues to improve survival. Limitations include the lack of other potential prognostic factors such as obesity in the database. References (PMID):1. 37147968; 2. 33127429; 3. 34277441; 4. 27741565; 5. 35511145; 6. 31116674.
Prognostic utility of YBX1-mediated genes in clear cell renal cell carcinoma outcomes.
Authors: Ali Waleed , Tawagi Karine , Balla Andre
Published: June 2024

e16510

Background: The Y-box-binding protein1 (YBX1) transcription factor has been linked to a variety of biological processes such as mRNA stabilization and localization and cell-cycle progression. YBX1 has been shown to have pro-oncogenic effects in some cancers, possibly also modulating cisplatin’s effects in others. However, comparatively less regarding YBX1 has been explored in kidney renal clear cell carcinoma (ccRCC), the most common kind of kidney cancer. This in silico study explores the relationship between YBX1 and associated regulatory targets in ccRCC cases. Methods: The MSig database was utilized to generate a list of genes which contained one or more YBX1 binding sites in their promoter region based on ChIP-seq data. Kaplan-Meier plots of overall survival in ccRCC cases based on YBX1 and YBX1-regulated gene expression were generated using TCGA data on the KMPlot platform with “high” and “low” expression cutoffs based on quartiles. Multiple hypothesis testing was corrected by adjusting the significant p-value cutoff to a FDR >0.05 (adjusted p-value cutoff is 0.023). Enrichment and network analysis was then conducted on genes shown to be differentially expressed in respect to outcome through the Cytoscape and Metascape platform to see which over-represented biological pathways may mediate outcome (p<0.01 for significance). Results: Out of 76 initial genes, 33 showed differential expression in regards to survival, including YBX1 itself. Enrichment analysis highlighted biological processes such as negative regulation of mRNA metabolic processes and Nop56p-associated rRNA complex formation as possible ways YBX1 and its related targets can affect outcomes. A variety of genes were highlighted by the network analysis, such as the membrane trafficking gene YIF1A and acetyltransferase KAT8 among others. Conclusions: Similar to what has been shown in other types of cancers, YBX1 and its regulatory constituents have been linked to ccRCC outcomes, possibly due to its role regarding mRNA regulation as highlighted by our enrichment analysis. Other interactions mediated by genes such as the cell cycle regulator CCAR2 offer other pathways through which YBX1 can mediate outcome. Previously being linked with cisplatin resistance in other cancers such as breast, YBX1 offers a suitable target for further wet-lab research regarding its role in ccRCC.
A new four-tiered grading scheme for postoperative prognostication in renal cell carcinoma with local recurrence.
Authors: Lei Chang , Qu Le , Wang Linhui , Ge Jingping , Zhou Wenquan
Published: June 2024

e16524

Background: Renal cell carcinoma (RCC) patients suffering from local recurrence (LR) herald variable risk of second progression even after curative surgery for LR. Further risk stratification of these patients will facilitate selection of candidates for adjuvant immunotherapy. Here we evaluate the prognostic significance of tumor grade variation (GV) between the primary tumor (PT) and LR tumor in nonmetastatic RCC in the largest study to date. Methods: We reviewed Research of Multi-institution in East-China on Malignant and Benign Epithelial Renal Tumors (REMEMBER) database to identify ccRCC or pRCC patients who underwent surgery for LR. All pathology slides were centrally reviewed by three independent senior genitourinary pathologists and patients were assigned to groups based on GV as upgrading (WHO/ISUP Ⅰ/Ⅱ for PT grade and Ⅲ/Ⅳ for LR grade), downgrading (WHO/ISUP Ⅲ/Ⅳ for PT grade and Ⅰ/Ⅱ for LR grade), stable low-grade (WHO/ISUP Ⅰ/Ⅱ for both PT and LR grade) and stable high-grade groups (WHO/ISUP Ⅲ/Ⅳ for both PT and LR grade). To evaluate the predictive value of GV, four tumor grade measures (PT grade, LR grade, highest grade for the PT and LR, GV) were separately incorporated for model development. The primary end point was overall survival (OS), defined as the time from LR surgery to death from any cause or last follow-up. A multivariable cox regression analysis was performed to explore associations between timing and survival. Results: 345 patients were identified 114 stable low-grade (33.1%), 56 downgrading (16.2%), 97 upgrading (28.1%), and 78 stable high-grade (22.6%). Median OS were highest among patients with stable low-grade (114 [stable low-grade] vs. 86 [Downgrading] vs. 59 [Upgrading] vs. 33 [Stable high-grade] months). Univariate analysis indicates that PT, LR and GV were significant correlated with poor OS (all P values < 0.05). After separately constructing the PT grade model (#1) via LASSO cox regressions for predicting OS, LR grade model (#2), highest grade model (#3) and GV model (#4) were built by simply replacing the variable of PT grade, it turned out that GV model (#4) achieved the better discriminatory ability (AUC of model (#4) vs. model (#1), 0.812 vs. 0.743; model (#4) vs. model (#2), 0.812 vs. 0.788; model (#4) vs. model (#3), 0.812 vs. 0.762, all p values < 0.05). Conclusions: This is the first study showing that GV is independently associated with clinical outcomes in patients with LR. Routine reporting of LR upgrading or downgrading in relation to the PT and assessment of GV can facilitate more informed treatment decisions by tailoring strategies to an individual patient's risk of progression.
Renal cell carcinoma post-kidney transplant: An analysis of OPTN/UNOS database.
Authors: Savani Saloni , Patel Het , Pawa Arpita , Dhaibar Hemangini , Master Samip R. , Singh Neeraj
Published: June 2024

e16528

Background: Renal cell carcinoma (RCC) is the most common form of kidney cancer in adults, accounting for 90-95% of primary malignant kidney tumors and representing around 3% of all cancers worldwide.Kidney transplant recipients (KTRs) have a higher incidence of developing RCC compared to the general population but lower compared to ESRD population. In 2018, the incidence of RCC was 1.6/10,000 in the general population and 45-50/10,000 person years in ESRD patients, with an increased incidence in patients with risk factors like old age, African American descent, hypertension, and smoking. With this study, we sought to identify high-risk patients among KTRs who may benefit from surveillance imaging. Methods: The UNOS/OPTN database was used to select kidney transplant recipients between 1/1/2010 to 12/31/2022. Pediatric patients, patients with simultaneous multi-organ transplants, and those with other malignancies were excluded. The study computed the incidence of RCC during the first 5-year and between 5 to 10-year post-transplant periods. Additionally, univariate, and multivariable logistic regression analysis was conducted to identify predictors for the development of RCC. Results: A total of 202,837 patients were included in the study, of them 1042 developed RCC during the follow-up period. The mean time to diagnose RCC was 3.3 (SD:2.7) years. The incidence rate was 11.59 and 11.57 during the first 5 years of follow-up and during the next 5 years per 10,000 person-years respectively. The major risk factors associated with the development of RCC were age 35-49 (OR: 1.88, p<0.001), age 50-64 (OR: 2.79, p<0.001), age >=65 (OR: 2.86, p<0.001), BMI >=30 (OR: 1.27, p=0.004) and race (African American (OR: 1.74, p<0.001) or Caucasian (OR: 1.39, p=0.002)). In addition, underlying hypertension (OR: 1.23, p=0.01), pre-transplant RCC (OR:3.85, p<0.001), and glomerulonephritis (OR: 1.28, p=0.009) causing ESRD were the significant risk factors for the occurrence of RCC during the 10-year follow-up period. The median graft survival and patient survival from the time of diagnosis to graft failure and patient mortality was 466 (109 – 1243) days & 437 (109 – 1058) days respectively. Conclusions: The risk of developing RCC in the first 5 years of kidney transplant increases by 7-fold compared to the general population. Obese, middle-aged, African American, or Caucasian patients with a history of hypertensive nephrosclerosis, pre-transplant RCC, or glomerulonephritis are at a higher risk for developing RCC during the post-transplant period. RCC also increases the risk of early graft failure and death. RCC surveillance for post-kidney transplant patients is not currently recommended due to absence of the studies showing a cost benefit with this approach. Based on this study, further studies are warranted to assess the risks and benefits of initiating RCC surveillance in these select group of patients.
Anlotinib plus everolimus as first-line treatment for advanced non–clear cell renal cell carcinoma: A single-center, single-arm, phase II trial.
Authors: Zhang Hailiang , Ye Dingwei
Published: June 2024

e16533

Background: For patients (pts) with recurrent or stage IV non-clear cell renal cancer (nccRCC),the medical treatment guidelines recommend the first choice to participate in clinical trials, or use TKI drugs such as sunitinib, and mTOR inhibitors such as everolimus. Anlotinib is a novel multi-target tyrosine kinase inhibitor (TKI). It’s antitumor targets include vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR) and c-kit. ALTER-UC-001 is a single-center, single-arm, phase II trial which evaluated the efficacy and tolerability of anlotinib plus everolimus as first-line therapy in pts with nccRCC (NCT05124431). Methods: Patients with advanced nccRCC and no prior systemic drug therapy for advanced disease were eligible for this trial; Eastern Cooperative Oncology Group (ECOG) performance status 0-1. The patients received 12mg anlotinib once daily on days 1-14 every 3 weeks by oral, and 5mg everolimus orally once daily. The primary endpoint was objective response rate (ORR). Secondary endpoints included overall disease control rate (DCR), progression free survival (PFS), and over survival (OS). Adverse events will be monitored throughout the study and graded according to CTCAE V5.0. Results: Between Jan 2022 and Dec 2023, 24 pts were enrolled and received study treatment. The median age was 56 years old (range: 20 to 79 years). Nineteen pts (79.2%; 19/24) had a ECOG PS score of 1, and five pts (20.8%; 5/24) had a ECOG PS score of 0. All pts had not received prior treatment. In addition, 17 (70.8%) had received surgical treatment and 1 (4.2%) had received radiotherapy. The data cutoff was Dec 2023, with a median follow-up of 6.04 (range, 1.34-18.1) months.14 pts had the best overall response (unconfirmed) assessments which inferred the ORR of 57.1%(PR in 8 pts 95% CI, 29.6-81.2)and the DCR of 100% (PR in 8 pts and SD in 6 pts; 95% CI, 73.2-100). The median PFS has not reached. Any grades of adverse events (AEs) were observed in 91.7% (22/24) of pts, the most common of which were mucositis (29.1%), hypertension (25.0%) , creatinine increased(16.7%), proteinuria (16.7%) and glutamic-pyruvic transaminase increased (12.5%).Seven (29.1%) pts experienced grade 3 TRAEs, including hypertension (8.3%), proteinuria (8.3%), mucositis (4.2%), platelet count decreased (4.2%), creatinine increased (4.2%), chronic gastritis (4.2%) and bleeding (4.2%). No treatment-related deaths occurred. Three (12.5%) and two (8.3%) pts had suspension of treatment because of TRAEs caused by everolimus and anlotinib respectively. Conclusions: Anlotinib plus everolimus as first-line therapy is efficacious and safe for pts with advanced nccRCC. We will report more data in the future. Clinical trial information: NCT05124431 .