Fox Chase Cancer Center

Designed small molecules that re-fold and re-activate destabilized mutant VHL Lead agent re-folds and re-activates multiple common VHL mutants This approach may apply to other destabilized proteins that underlie human disease.

Genetic counselors (GCs) utilize a variety of skills while counseling patients. However, it remains unclear whether the frequency or types of skills used impact patient outcomes. We explored the use of specific GC communication skills in cardiology and their impact on empowerment and therapeutic alliance. Adults attending an initial cardiovascular GC appointment completed pre-visit and post-visit surveys. Measures included the Genetic Counseling Outcomes Scale (GCOS) and the Working Alliance Inventory (WAI). GC appointments were audio-recorded, transcribed, and coded using the Genetic Counseling Skills Checklist (GCSC). WAI and change in GCOS scores following the GC visit were stratified into high- and low-scoring groups for comparative analyses. Descriptive analyses were used to identify GCSC code patterns across sessions with high and low WAI and GCOS scores. Seventeen participants (65% female, mean age: 61 years) completed the study. Cases from seven GCs were included across four indications: cardiomyopathy, arrhythmia, dyslipidemia, and aortopathy. There was an increase in empowerment after GC appointments (p = 0.0007), with nearly half (8/17) of participants exhibiting a clinically meaningful increase. Sessions showed a diverse set of skills used across eight domains on the GCSC. Skills around mutual agenda setting, focus on patients' emotions, and facilitating decision-making were used more frequently in higher WAI-scoring sessions. However, when comparing participants who exhibited clinically meaningful changes in empowerment to those who did not, there was little difference in the skills used in sessions, though some skills may have been used more frequently with patients who demonstrated smaller changes in empowerment (e.g., eliciting ways to overcome barriers to taking action). This is the first application of the GCSC in nonsimulated patient settings. We observed trends suggesting varying use of GC skills may contribute to differences in therapeutic alliance and that GCs alter the skills they use for different patients.

545 Background: The LITESPARK-013 study (NCT04489771) showed similar efficacy and safety between 200 mg and 120 mg (approved dose) doses of the HIF-2α inhibitor bel in pts with pretreated advanced ccRCC. We report exploratory biomarker analyses (including HIF-2α IHC, RNAseq, and WES) from this study. Methods: Pts with advanced ccRCC whose disease progressed after 1-3 prior systemic therapies (including an anti–PD-[L]1 therapy) were randomly assigned 1:1 to bel 200 mg or 120 mg QD. Treatment arms were pooled for biomarker analyses. Association of HIF-2α tumor proportion score (TPS; IHC D6T8V) and H-score (sum of each percentage multiplied by its corresponding intensity [0, 1+, 2+, 3+]) with clinical outcomes (ORR, PFS, OS) were tested at prespecified multiplicity-adjusted α = 0.05. Associations of RNAseq-based HIF-2α co-expression and HIF-2α cancer cell scores, glycolysis, angiogenesis, and other HIF-2α–related genes and signatures were tested at prespecified multiplicity-adjusted α = 0.10. Associations for molecular subtypes (Motzer et al. Cancer Cell . 2020;38:803) were tested at nominal α = 0.05. DNA mutations were evaluated by WES. Results: Of 154 pts, HIF-2α IHC was evaluable in 136, RNAseq in 109, and WES in 113 pts. HIF-2α TPS and H-score were positively associated with PFS ( P = 0.016 and 0.012, respectively), but not ORR or OS. HIF-2α cancer cell score was positively associated with ORR ( P = 0.085), but not PFS or OS. No associations with clinical outcome were observed for HIF-2α co-expression score. Glycolysis and angiogenesis were positively associated with ORR ( P = 0.036) and PFS ( P = 0.070), respectively, but these were no longer significant after adjustment of other signatures. ORR was consistent across molecular subtypes and by DNA mutation status (Table), with notably higher ORR in the BAP1 mutant vs wild-type group. Conclusions: In this first RNA and WES biomarker analysis of bel, HIF-2α TPS and H-score were potentially associated with PFS, and BAP1 mutation was potentially predictive of improved ORR in pts with RCC. Molecular subtypes, other RCC-related signatures, and VHL mutation showed no associations or trends with ORR, PFS, or OS. Prospective biomarker evaluations are needed to confirm these findings. Clinical trial information: NCT02853344 . n ORR, % (95% CI) All RNAseq evaluable 109 26.6 (18.6-35.9) Molecular subtypes Angiogenic 12 33.3 (9.9-65.1) Angiogenic/stromal 24 25.0 (9.8, 46.7) Immune/proliferative 22 27.3 (10.7-50.2) Stromal/proliferative 17 23.5 (6.8-49.9) Proliferative 17 23.5 (6.8-49.9) Other (unassignable to a subtype) 17 29.4 (10.3-56.0) VHL Mut 80 25.0 (16.0-35.9) WT 33 24.2 (11.1-42.3) PBRM1 Mut 59 23.7 (13.6-36.3) WT 54 25.9 (15.0-39.7) SETD2 Mut <jats:td colspan="1" rowspan=

689 Background: Enfortumab vedotin (EV) and pembrolizumab have emerged as first-line combination therapy for locally advanced or metastatic urothelial carcinoma (UC). In retrospective studies of EV monotherapy, higher relative dose intensities (RDI) in the initial treatment cycles have been associated with improved response rates and prolonged progression-free survival (PFS), whereas cumulative RDI across the entire treatment course has not shown a consistent relationship with outcomes. The impact of EV RDI on outcomes in combination therapy treated patients remains unclear. Our single-center, retrospective study aims to assess the relationship between RDI within the first 3 and 6 cycles and PFS and overall survival (OS). Methods: We conducted a retrospective analysis of patients treated with EV + pembrolizumab. Only patients who received &gt;1 cycle of EV were included. Data on PFS, OS, and dosing were collected from the EMR. For each patient, cumulative RDI was calculated through cycle 3 (RDI-3) and cycle 6 (RDI-6) as: (delivered EV dose) / (standard EV dose during that timeframe) x 100%. The primary analysis evaluated RDI as a continuous variable in Cox regression models using 63-day and 126-day landmark analyses, corresponding to the completion of 3 and 6 cycles, respectively. Models were adjusted for ECOG status and assessed PFS and OS as endpoints. RDI-3 and RDI-6 were selected to capture early versus later effects of RDI and to align with institutional restaging practices. The Kaplan-Meier method was used to analyze survival by RDI group (RDI &gt;80% and &lt; 80%). The 80% threshold was selected as it represents the typical first EV dose reduction from 1.25 mg/kg to 1.00 mg/kg, consistent with prior EV monotherapy studies. These analyses were exploratory and supplemental to the primary analysis. Results: 104 patients met inclusion criteria. Of these, 90 and 99 were evaluable for RDI-3 PFS and OS landmark analyses, and 78 and 89 for RDI-6, respectively. The median follow-up time was 17.2 months. In adjusted landmark Cox models, higher RDI-3 and RDI-6 showed no significant difference in PFS (RDI-3: HR 0.903, p = 0.152; RDI-6: HR 0.987, p = 0.859) or OS (RDI-3: HR 0.891, p = 0.155; RDI-6: HR 0.895, p = 0.218). Unadjusted Kaplan–Meier analyses similarly showed no association between RDI and PFS or OS (RDI-3: PFS p = 0.61, OS p = 0.23; RDI-6: PFS p = 1, OS p = 0.48). Conclusions: In adjusted analyses, RDI over the first 3 and 6 cycles did not significantly correlate with PFS or OS. These findings contrast with prior EV monotherapy data, suggesting that, within the EV + pembrolizumab paradigm, early EV dose intensity may be less critical, allowing flexibility in dosing without compromising efficacy, potentially reflecting a compensatory effect from immunotherapy combination. HR (95% CI) p-value RDI-3 PFS 0.903 (0.79-1.04) 0.152 OS 0.891 (0.76-1.04) 0.155 RDI-6 PFS 0.987 (0.86-1.14) 0.859 OS 0.895 (0.75-1.07) 0.218

Introduction: why Discover Aging?Welcome to Discover Aging, a journal within the fully open access Discover series, dedicated to advancing research on aging across biomedical, clinical, technological, and social research areas.Aging is the greatest risk factor for the world's most prevalent diseases and a defining demographic trend of our century [1].Our mission is to serve as a comprehensive resource for researchers, clinicians, policymakers, and the public by publishing aging studies of the highest integrity.

The use of neoadjuvant chemotherapy (NAC) in breast cancer management has increased, leading to uncertainties in adjuvant treatment benefits. We reviewed (cN +) stage II-III breast cancers that underwent NAC and breast-conserving treatment (BCT) between 2010 and 2020 in the National Cancer Database (NCDB). Overall survival (OS) was compared between those who did and did not receive regional nodal irradiation (RNI). The 7137 cN + patients had a mean age of 54.3 ± 10.9. Breast and nodal pCR rates were 25.9% and 35%. RNI was administered in 57.7% (50.0% of the ypN0 and 61.9% of the ypN +). The mean number of nodes removed was 10.3 ± 7.7 in the RNI + and 9.5 ± 7.6 in the RNI- groups (p < 0.01). The mean number of positive nodes was 2.5 ± 4.0 in the RNI + and 1.8 ± 3.5 in the RNI- groups (p < 0.01). In a median follow-up of 68months, RNI + patients had a worse OS than RNI- patients (79.9% vs. 84.4%, p < 0.001). In the ypN0 population, there was no OS difference between RNI + and RNI- groups (p = 0.4), however, ypN + patients had worse OS if they were RNI + than RNI- (p = 0.007). RNI does not improve OS in cN + patients undergoing a complete response from NAC after BCT. Although recurrence cannot be assessed via this data set, these results support individualized decisions to omit RNI in ypN0 patients following NAC and BCT and emphasize the need for further investigation into the potential benefits or harms of RNI in ypN + patients treated with NAC and BCT.