Citations

Abstract Virtual care, introduced previously as a replacement for in-person visits, is now being integrated into clinical care delivery models to complement in-person visits. The COVID-19 pandemic sped up this process. The rapid uptake of virtual care at the start of the pandemic prevented educators from taking deliberate steps to design the foundational elements of the related learning environment, including workflow, competencies, and assessment methods. Educators must now pursue an informed and purposeful approach to design a curriculum and implement virtual care in the learning environment. Engaging learners in virtual care offers opportunities for novel ways to teach and assess their performance and to effectively integrate technology such that it is accessible and equitable. It also offers opportunities for learners to demonstrate professionalism in a virtual environment, to obtain a patient’s history incorporating interpersonal and communication skills, to interact with multiple parties during a patient encounter (patient, caregiver, translator, telepresenter, faculty member), to enhance physical examination techniques via videoconferencing, and ideally to optimize demonstrations of empathy through “webside manner.” Feedback and assessment, important features of training in any setting, must be timely, specific, and actionable in the new virtual care environment. Recognizing the importance of integrating virtual care into education, leaders from across the United States convened on September 10, 2020, for a symposium titled, “Crossing the Virtual Chasm: Rethinking Curriculum, Competency, and Culture in the Virtual Care Era.” In this article, the authors share recommendations that came out of this symposium for the implementation of educational tools in the evolving virtual care environment. They present core competencies, assessment tools, precepting workflows, and technology to optimize the delivery of high-quality virtual care that is safe, timely, effective, efficient, equitable, and patient-centered.

Abstract Background: Data supporting high tumor mutational burden (TMB-H) as a lone biomarker for an immune responsive tumor microenvironment (TME) or of response to immune checkpoint inhibition (ICI) in metastatic breast cancer (MBC) is weak; yet the tumor agnostic approval in TMB-H advanced tumors makes ICI an option in the clinic. PDL-1 positivity (PDL-1+) is the only consistent biomarker for ICI benefit in metastatic triple-negative BC (mTNBC). We sought to further evaluate concurrent predictors of an immune responsive or non-responsive TME within TMB-H MBC. Methods: Tumor samples (N=5621) obtained from patients with MBC were analyzed by next-generation sequencing (NGS) of DNA (592-gene panel or whole exome sequencing) and RNA (whole transcriptome sequencing) at Caris Life Sciences (Phoenix, AZ). Friends of Cancer Research TMB Harmonization Project (Merino et al., 2020) recommendations, with the TMB-H threshold set to ≥ 10 muts/Mb, were used. PDL-1+ (≥1% immune cells stained) assessed by IHC (Ventana SP142). Deficient-mismatch repair (dMMR) and high microsatellite instability (MSI-H) were determined by IHC and NGS, respectively. Gene expression profiling assessed 21 immune-related signatures and TMEs using MCP-counter (Betch et al., 2016) and quanTIseq (Finotello et al., 2019). Immune cell types were classified as immune-responsive (CD8+ and CD4+ T cells, B cells, myeloid dendritic cells, M1 macrophages, NK cells, and neutrophils) or non-responsive (Tregs, M2 macrophages, and monocytes). P-values adjusted by the Benjamini-Hochberg procedure. Exploratory p-values reported for sub-analyses of TMB-H responsive vs nonresponsive TME and PDL1+ vs PDL1- subgroups. Results: TMB-H was identified in 461/5621 (8.2%) MBC samples. TMB-H tumors exhibit significant enrichment of dMMR/MSI-H (7 vs 0%, p<0.0001) and IHC-PDL1+ (36 vs 28%, p<0.05) compared to TMB-L. TMB-H was not associated with increased abundance or proportion of immune responsive cell types or immune response gene signatures (e.g. antigen presentation), yet positive trends were observed. To identify predictive biomarkers of immune responsive (hot) or non-responsive (cold) TME profiles within TMB-H MBC, we generated a composite TME score representing the overall proportion of hot vs cold immune cell types. APOBEC mutagenesis was common in TMB-H tumors (72%) and was more frequently associated with an immune cold TME (77 vs 66% in hot TME subgroup, p=0.068). Within TMB-H tumors, cold TMEs were enriched with mutations (muts) in PIK3CA (61 vs 47%), CHEK2 (5 vs 0%), CBFB (4 vs 0%), amplifications (amp) of CCND1 (13 vs 4%), FGF19 (16 vs 5%), FGF4 (11 vs 4%), and MMLT6 (6 vs 0%), and expression of IHC-AR (75 vs 58%) compared to hot TMEs (all p<0.05). Hot TMEs had increased frequency of MSI-H (12 vs 5%) and KMT2D muts (12 vs 3%) compared to cold TMEs (all p<0.05). Amongst TMB-H and TMB-L tumors, PDL1+ was significantly associated with increased proportion of immune responsive cell types (ie CD8+) compared to PDL1- tumors (0.14 vs -0.08 TME score, p<0.0001). Comparison of TMB-H tumors by PDL1 status revealed enrichment of TP53 (67 vs 53%) and B2M (8 vs 0%) muts in PDL1+ tumors, while IHC-ER positivity (68 vs 54%) and CDH1 muts (32 vs 16%) were increased in PDL1- tumors (all p<0.05). Conclusions: High TMB alone does not strongly correlate with immune infiltrate or immune response gene signatures in MBC. Within TMB-H MBC, concurrent mutations in MSI-H and KMT2D are associated with an immune responsive TME while mutations in PIK3CA, CHEK2, CBFB, amplifications of CCND1, FGF19, FGF4, and MMLT6, and expression of IHC-AR are associated with an immune non-responsive TME. Co-occurring biomarkers within TMB-H breast cancer warrant evaluation in prospective cohorts for response or resistance to ICI to help develop composite biomarkers in breast cancer. Citation Format: Sarah Sammons, Andrew Elliott, Jeremy Force, Saranya Chumsri, Carey Anders, Antoinette R Tan, Daniel Magee, Jia Zeng, W. Michael Korn, Mustafa Kahsraw, Evanthia T Roussos Torres. Concurrent predictors of an immune responsive tumor microenvironment within tumor mutational burden-high breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-08-08.

Conventional imaging has been the standard imaging modality for assessing prostate cancer recurrence and is utilized to determine treatment response to therapy. Molecular imaging with PSMA PET–CT has proven to be more accurate, sensitive, and specific at identifying pelvic or distant metastatic disease, resulting in earlier diagnosis of advanced disease. Since advanced disease may not be seen on conventional imaging, due to its lower sensitivity, but can be identified by molecular imaging, this reveals that metastatic prostate cancer occurs on a continuum from negative PSMA PET–CT and negative conventional imaging to positive PSMA PET–CT and positive conventional imaging. Understanding this continuum, the accuracy of these modalities, and treatment related outcomes based on imaging, will allow the clinician to counsel patients on management. This review will highlight the differences in conventional and molecular imaging in prostate cancer and how PSMA PET–CT can be used for the management of prostate cancer patients in different clinical scenarios, while providing cautionary notes for overtreatment.

TPS194 Background: Despite a growing number of treatment options for first line mCRPC, approximately 40% of patients (pts) have radiographic progression within the first year. Androgen receptor (AR) signaling inhibition increases genomic instability with double-strand DNA breaks & co-inhibition of AR & PARP induces synthetic lethality in multiple preclinical models. Homologous recombination repair (HRR) gene aberrations do not appear to be necessary for this synergy as demonstrated in a ph 2 clinical trial of abiraterone & olaparib where this combination improved radiographic progression-free survival (rPFS) in HRR-wild-type pts compared with abiraterone alone. A ph 1b trial has since shown that enzalutamide plus rucaparib has acceptable safety profile & no significant drug-drug interactions (S-DDI). Methods: CASPAR/A031902 (NCT04455750) is a ph 3 study in which 984 pts will be randomized 1:1 to enzalutamide plus rucaparib or placebo. HRR gene aberration is not required for enrollment. All pts will undergo next-generation targeted-exome sequencing from archival tumor tissue (new biopsy only required if no archival tissue available). Treatment will be continued until disease progression & crossover is not allowed. Key eligibility criteria are age ≥ 18 years, ECOG PS 0-2, biopsy-proven prostate adenocarcinoma, progressive (PSA or radiographic) disease per Prostate Cancer Working Group 3 guidelines, measurable or nonmeasurable disease per RECIST 1.1, no prior treatment for mCRPC (prior docetaxel, abiraterone, darolutamide, or apalutamide in non-mCRPC setting is allowed), no significant uncontrolled comorbidity, & no medications with S-DDI with enzalutamide/rucaparib. Hierarchical co-primary endpoints are rPFS & overall survival (OS). The OS analysis will be undertaken as a primary endpoint if the rPFS endpoint is met. For a one-sided logrank test with a type 1 error rate equal to 0.025, the study has 90% power to detect a hazard ratio (HR) of 0.71 in rPFS (median rPFS of 15 & 21 months in control & combination arms, respectively) & 80% power to detect an HR of 0.80 in OS (median OS of 32 & 40 months, respectively). Key secondary endpoints are rPFS & OS in pts with vs without pathogenic BRCA1, BRCA2, or PALB2 alterations; & differences in adverse events & quality of life (QOL) outcomes between the treatment arms. QOL assessments include Functional Assessment of Cancer Therapy–Prostate (FACT-P), Brief Pain Inventory Short Form (BPI-SF) & EQ-5D-5L. A key correlative endpoint is the sensitivity of ctDNA-based testing for alterations in HRR genes. Enrollment to CASPAR began in July 2021 & the study is available for participation to all US-NCTN sites with a projected enrollment of 3 years. Support: U10CA180821, U10CA180882, U24CA196171; U10CA180888; Clovis Oncology; http://acknowledgments.alliancefound.org Clinical trial information: NCT04455750.

176 Background: Despite androgen deprivation therapy, prostate cancer will develop resistance known as castrate resistant prostate cancer (CRPC). Androgen signaling is associated with pathways that influence cell proliferation and survival via cell cycle regulation. AR signaling results in inactivation of Rb tumor suppressor by way of AKT and reduction in intrinsic CDK4/6 inhibitors. Since PTEN loss is found in 40% of mCRPC and AKT pathway is a mechanism of CDK4/6 inhibitor resistance, we hypothesize adding an AKT inhibitor to a CDK4/6 inhibitor will have synergistic activity while delaying CDK4/6 inhibitor resistance. Preclinical xenografts have been shown to recapitulate patient response, therefore, can be used to guide clinical trials using novel combinations. Methods: We have established patient derived tumor xenograft models (GUR-017M, TMA-027 and PRJ-88T) from patients with mCRPC with each having a unique genomic alteration profile. In the clinical setting, GUR-017M was resistant to abiraterone, enzalutamide, cabazitaxel and had exposure to docetaxel. TMA-027 and PRJ-88T were resistant to enzalutamide. We combined a CDK4/6 inhibitor with an AKT inhibitor and treated each of these patient tumors in NOD-SCID mice for a total duration of 40 days. Mice were implanted and separated into 4 groups (placebo, CDK4/6 inhibitor, AKT inhibitor and CDK4/6 + AKT inhibitor) with 10-13 mice in each group. Tumor volumes were measured twice a week. For GUR-017M, abemaciclib (50 mg/kg) was combined with MK2206 (120 mg/kg) and was compared to each placebo and each single agent alone. For TMA-027, palbociclib (50 mg/kg) was combined with ipatasertib (50 mg/kg). After 40 days, tumors were harvested for immunohistochemistry analysis. PRJ-88T was grown as 3D spheroids in ultra-low attachment plates and treated with palbociclib + ipatasertib (10 uM-100uM) to evaluate for synergy. Results: GUR-017M and TMA-027 showed significant delayed tumor growth compared to placebo or either single agent alone. In the GUR-017M group, the final mean tumor volume for the combination group was 149 mm3, compared to 377 mm3 (abemaciclib), 358 mm3 (MK2206) and 527 mm3 placebo group, representing a percent decrease compared to control by 72%, 29%, and 32%, respectively. For TMA-027, the final mean tumor volume for the combination group was 102 mm3, compared to 259 mm3 (palbociclib), 416 mm3 (ipatasertib), and 402 mm3 placebo group, representing a percent decrease compared to control by 75%, 36%, and 4%, respectively. PRJ-88T 3D spheroids showed synergy with palbociclib + ipatasertib. In vivo experiments using PRJ-88T are in progress. Conclusions: The preclinical results show combining CDK4/6 inhibitors with AKT inhibitors is a promising treatment strategy and provides the basis for a clinical trial in patients with mCRPC.

153 Background: The prognostic significance of DDR alterations in mCRPC remains unclear, with conflicting data from prior reports. Whether DDR alterations are predictive of outcomes with therapeutic agents other than PARP inhibitors in mCRPC is also poorly understood. With increasing use of molecular profiling in mCRPC, understanding the full prognostic and predictive utility of plasma DDR alterations is paramount. Methods: A next-generation sequencing Predicine liquid biopsy assay was used to profile cfDNA and germline DNA in 407 mCRPC patients (pts) from two independent international cohorts (n=162 Australia, n=245 US). DDR genes profiled were BRCA2, ATM, BRCA1, MLH1 and MSH2. Kaplan-Meier survival estimates and multivariable Cox regression analyses were used to assess associations between DDR alterations and clinical outcomes including PSA response rate (PSA RR), progression-free survival and overall survival (OS). Results: Median age was 74 (IQR 67-79), with median follow up 74 months and median OS 23 months. 65/407 (16%) harboured pathogenic DDR alterations, including 21 patients with ³1 alteration. Frequency of genomic aberrations are shown in the table. BRCA2 alterations were further classified as heterozygous loss (66%), homozygous loss (14%), monoallelic mutation (11%) and biallelic mutation/loss of heterozygosity (9%). Aberrations in any DDR gene, ATM, MLH1 + MSH2 or BRCA2 were associated with shorter OS on univariable analysis, but only any DDR or BRCA2 aberration remained significant upon adjusting for clinical prognosticators and ctDNA fraction (Table). Pre-treatment BRCA2 aberration was associated with significantly shorter OS and lower PSA RR compared to BRCA2 wt for pts receiving an AR pathway inhibitor (ARPI) (18 vs 32 months, p=0.006; 36 vs 60%, p=0.04 respectively) but not for taxane chemotherapy (17 vs 20 months, p=0.3; 45 vs 66, p=0.1 respectively). Conclusions: Detection of an aberration in any DDR gene or BRCA2 was an independent poor prognostic factor across 2 large independent cohorts of mCRPC patients. Intriguingly, patients with a BRCA2 alteration appeared to have worse outcomes with ARPI but not chemotherapy, suggesting predictive utility of DDR profiling. Our data collectively speak to the potential role of DDR alterations, in particular BRCA2, as prognostic and/ or predictive biomarkers in mCRPC.[Table: see text]

150 Background: With the evolving use of targeted therapies exploiting genomic vulnerabilities in mCRPC, screening patients for sensitizing alterations is of increasing relevance. However, the influence of age on the detection of relevant genomic alterations is incompletely understood. In this study, we compared the cell-free DNA (cfDNA) profiles of younger (age <70) versus older (age ≥70) men with mCRPC and assessed the relative prognostic impact of common genomic alterations. Methods: A next-generation sequencing-based Predicine cfDNA assay was used to profile 276 mCRPC patients from two independent international cohorts. The frequency of genomic alterations across age categories was compared using the chi-squared test, while circulating tumour DNA fraction (ctDNA%) was compared using the Mann–Whitney U test. Cox proportional hazards analysis with interaction testing was used to assess the association between age, genomic alteration and overall survival. Results: The median age of the combined cohort was 72 years (IQR 66-78), with 170 (62%) patients ≥70 years old. Despite differences in baseline characteristics (poorer performance status in older patients, higher Gleason score and de novo metastatic disease in younger patients), there was no significant difference in ctDNA% (median 22% vs 30%, p=0.6). We observed similar frequencies of genomic alterations across the 10 most commonly aberrant genes, including AR (<70 vs ≥70: 46% vs 49%, p=0.6), TP53 (40% vs 36%, p=0.6), BRCA2 (29% vs 21%, p=0.13) and PTEN (39% vs 35%, p=0.5). This similarity persisted when analysing mutations and copy number alterations in isolation. While driver alterations in both age categories were strongly associated with unfavourable outcomes (Table), an exploratory analysis revealed that copy number gain in PIK3CA may have a worse prognostic impact in younger men ( p for interaction = 0.03), with a lesser effect observed in AR gain ( p = 0.1) and MYC gain ( p = 0.1). Conclusions: The genomic profiles of pertinent alterations between younger and older men are comparable. Certain genomic alterations may carry a worse prognosis in younger men. Patients should be considered for precision medicine assessment and directed therapies, regardless of age. [Table: see text]

Idiopathic pulmonary fibrosis (IPF) is an aging-associated disease characterized by myofibroblast accumulation and progressive lung scarring. To identify transcriptional gene programs driving persistent lung fibrosis in aging, we performed RNA-Seq on lung fibroblasts isolated from young and aged mice during the early resolution phase after bleomycin injury. We discovered that, relative to injured young fibroblasts, injured aged fibroblasts exhibited a profibrotic state characterized by elevated expression of genes implicated in inflammation, matrix remodeling, and cell survival. We identified the proviral integration site for Moloney murine leukemia virus 1 (PIM1) and its target nuclear factor of activated T cells-1 (NFATc1) as putative drivers of the sustained profibrotic gene signatures in injured aged fibroblasts. PIM1 and NFATc1 transcripts were enriched in a pathogenic fibroblast population recently discovered in IPF lungs, and their protein expression was abundant in fibroblastic foci. Overexpression of PIM1 in normal human lung fibroblasts potentiated their fibrogenic activation, and this effect was attenuated by NFATc1 inhibition. Pharmacological inhibition of PIM1 attenuated IPF fibroblast activation and sensitized them to apoptotic stimuli. Interruption of PIM1 signaling in IPF lung explants ex vivo inhibited prosurvival gene expression and collagen secretion, suggesting that targeting this pathway may represent a therapeutic strategy to block IPF progression.

AbstractBackgroundThere is a paucity of data regarding the sex‐related differences in the trends and outcomes of trans‐septal transcatheter mitral valve replacement (TS‐TMVR).MethodsThe Nationwide Readmissions Database (2015–2018) was queried for admissions for TS‐TMVR. Propensity matched analysis was conducted to compare outcomes with hospitalizations for TS‐TMVR among women versus men. The main study outcome was in‐hospital mortality.ResultsOur final analysis included 2063 hospitalizations for TS‐TMVR; of whom, 58.1% were women. The proportion of women among those undergoing TS‐TMVR increased from 50% in 2015 to 60.2% in 2018 (Ptrend = 0.04). Compared with men, women undergoing TS‐TMVR were slightly younger, and had a distinct profile of comorbidities. After matching, there was no significant difference in in‐hospital mortality among women versus men undergoing TS‐TMVR (7.8% vs. 6.1%, OR = 1.30; 95% CI: 0.79–2.13). Subgroup analyzes showed an interaction toward higher mortality with women versus men among patients with CKD (Pinteraction = 0.07). There were no significant differences between women and men in in‐hospital complications or length of stay after TS‐TMVR. Compared with men, women undergoing TS‐TMVR were more likely to be discharged to a nursing facility (17.7% vs. 11.5%, p = 0.01) and had higher rates of 30‐day readmissions (22.4% vs. 13.6%, p = 0.01).ConclusionThis nationwide analysis showed an increase in the proportion of women among patients undergoing TS‐TMVR during the study years. There were no differences in in‐hospital mortality, in‐hospital complications, or length of stay between both sexes following TS‐TMVR. Women were more likely to be discharged to nursing facilities and had higher rates of readmission at 30 days even after propensity matching.

AbstractBackgroundFrontotemporal lobar degeneration (FTLD) refers to a group of neurodegenerative conditions, affecting the frontal and/or temporal lobes. Ongoing research has provided insight into developing clinical trials for FTLD and key clinical measures such as structural MRI. To inform clinical trial design and optimize participation, it is imperative to explore facilitators and barriers for potential candidates.ObjectiveThe objective of this study is to explore facilitators and barriers to participating in future clinical trials for FTLD.MethodsAdvancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) are observational studies focused on characterizing FTLD syndromes in preparation for clinical trials. The 584 participants enrolled across 18 research sites in the United States and Canada completed a survey assessing interest in clinical trial participation.Results29% of respondents self‐reported as patients (63±10 years), 26% self‐reported as caregivers answering on behalf of patients (65±10 years), and 45% self‐reported as healthy but at risk for FTLD (48±14 years). Travel reimbursement was the most common factor reported to positively influence participation (≧66%), with the healthy but at risk group showing the strongest endorsement (83%). Cost and time involved in travel were possible barriers for about half of the patients (48%) and healthy but at risk respondents (53%). The respondents value receiving feedback on the study findings (≧80%) and being informed of their individual disease progression (≧75%). Particularly, keeping participation confidential was very important for the healthy but at risk group (62%). In regard to research assessments, most participants demonstrated a high interest in physical and neurological exams at a research center (≧87%) whereas only half were interested in doing more invasive procedures such as the lumbar puncture (≧52%). Overall, respondents showed a positive attitude and support for research participation (≧77%) and trusted that their health information would remain confidential in a clinical trial (≧53%).ConclusionsFavorable attitudes and interest towards medical research exist among participants. To optimize participation, clinical trials should allocate funding for travel and involve participants in feedback about study results and their disease progression. Alternatives to invasive assessments may increase participation.