The Effects of the Get Off Your Rocker Exercise Class on Balance for Patients following a CVA: A Case Study Approach

Background and Purpose: Cerebral vascular accident (CV A) is the leading cause of serious, long-term disability and the third leading cause of death in the United States. It is estimated that approximately 75% of people who have a stroke survive, many of whom live with some level of impairments that impact their activities of daily living and quality of life. One of the results of these impairments can be decreased balance. Limitations in balance may impact an individual\u27s risk of falls, ability to ambulate, and performance of functional activities. Exercises emphasizing balance training playa significant role in improving postural control. The purpose of this study is to determine if the six -week Get Off Your Rocker balance exercise class improves balance and quality of life in people who have had a CV A and who live in the community. If the Get Off Your Rocker exercise class is found to be effective for this population, it can be an additional tool for physical therapists in improving balance. Subjects: The two subjects who participated in the study had a neurological diagnosis of CVA. Both subjects were older than 20 years of age, lived in the community, and ambulated independently. Methods: Four measures were used to gather data regarding balance and quality of life. During the initial testing session, subjects completed the Timed Up and Go, Functional Reach, Berg Balance Measure, and Short Form 36 Health Survey. Subjects then participated in the Get Off Your Rocker balance exercise class three times a week for six consecutive weeks. Following the exercise class, the assessment measures were repeated. Results: Subjects demonstrated both quantitative and qualitative improvements. Both participants showed improvements on all four of the measures. Conclusion: Following participation in the six-week Get Off Your Rocker balance exercise class, we concluded that it was beneficial in improving balance for people following a CVA. This class can be an effective tool for balance training and increasing functional capacities leading to enhanced quality of life

Circulating Biomarkers and Resistance to Endocrine Therapy in Metastatic Breast Cancers: Correlative Results from AZD9496 Oral SERD Phase I Trial.

PURPOSE: Common resistance mechanisms to endocrine therapy (ET) in estrogen receptor (ER)-positive metastatic breast cancers include, among others, ER loss and acquired activating mutations in the ligand-binding domain of the ER gene (ESR1LBDm). ESR1 mutational mediated resistance may be overcome by selective ER degraders (SERD). During the first-in-human study of oral SERD AZD9496, early changes in circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) were explored as potential noninvasive tools, alongside paired tumor biopsies, to assess pharmacodynamics and early efficacy. EXPERIMENTAL DESIGN: CTC were enumerated/phenotyped for ER and Ki67 using CellSearch in serial blood draws. ctDNA was assessed for the most common ESR1LBDm by droplet digital PCR (BioRad). RESULTS: Before starting AZD9496, 11 of 43 (25%) patients had ≥5 CTC/7.5 mL whole blood (WB), none of whom underwent reduction to <5 CTC/7.5 mL WB on C1D15. Five of 11 patients had baseline CTC-ER+, two of whom had CTC-ER+ reduction. CTC-Ki67 status did not change appreciably. Patients with ≥5 CTC/7.5 mL WB before treatment had worse progression-free survival (PFS) than patients with <5 CTC (P = 0.0003). Fourteen of 45 (31%) patients had ESR1LBDm + ctDNA at baseline, five of whom had ≥2 unique mutations. Baseline ESR1LBDm status was not prognostic. Patients with persistently elevated CTC and/or ESR1LBDm + ctDNA at C1D15 had worse PFS than patients who did not (P = 0.0007). CONCLUSIONS: Elevated CTC at baseline was a strong prognostic factor in this cohort. Early on-treatment changes were observed in CTC-ER+ and ESR1LBDm + ctDNA, but not in overall CTC number. Integrating multiple biomarkers in prospective trials may improve outcome prediction and ET resistance mechanisms' identification over a single biomarker

Serial monitoring of genomic alterations in circulating tumor cells of ER-positive/HER2-negative advanced breast cancer: feasibility of precision oncology biomarker detection.

Nearly all estrogen receptor (ER)-positive (POS) metastatic breast cancers become refractory to endocrine (ET) and other therapies, leading to lethal disease presumably due to evolving genomic alterations. Timely monitoring of the molecular events associated with response/progression by serial tissue biopsies is logistically difficult. Use of liquid biopsies, including circulating tumor cells (CTC) and circulating tumor DNA (ctDNA), might provide highly informative, yet easily obtainable, evidence for better precision oncology care. Although ctDNA profiling has been well investigated, the CTC precision oncology genomic landscape and the advantages it may offer over ctDNA in ER-POS breast cancer remain largely unexplored. Whole-blood (WB) specimens were collected at serial time points from patients with advanced ER-POS/HER2-negative (NEG) advanced breast cancer in a phase I trial of AZD9496, an oral selective ER degrader (SERD) ET. Individual CTC were isolated from WB using tandem CellSearch® /DEPArray™ technologies and genomically profiled by targeted single-cell DNA next-generation sequencing (scNGS). High-quality CTC (n = 123) from 12 patients profiled by scNGS showed 100% concordance with ctDNA detection of driver estrogen receptor α (ESR1) mutations. We developed a novel CTC-based framework for precision medicine actionability reporting (MI-CTCseq) that incorporates novel features, such as clonal predominance and zygosity of targetable alterations, both unambiguously identifiable in CTC compared to ctDNA. Thus, we nominated opportunities for targeted therapies in 73% of patients, directed at alterations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), fibroblast growth factor receptor 2 (FGFR2), and KIT proto-oncogene, receptor tyrosine kinase (KIT). Intrapatient, inter-CTC genomic heterogeneity was observed, at times between time points, in subclonal alterations. Our analysis suggests that serial monitoring of the CTC genome is feasible and should enable real-time tracking of tumor evolution during progression, permitting more combination precision medicine interventions

nCirculating biomarkers and resistance to endocrine therapy in metastatic breast cancers: Correlative results from AZD9496 oral SERD phase I trial

Purpose: Common resistance mechanisms to endocrine therapy (ET) in estrogen receptor (ER)-positive metastatic breast cancers include, among others, ER loss and acquired activating mutations in the ligand-binding domain of the ER gene (ESR1LBDm). ESR1 mutational mediated resistance may be overcome by selective ER degraders (SERD). During the first-in-human study of oral SERD AZD9496, early changes in circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) were explored as potential noninvasive tools, alongside paired tumor biopsies, to assess pharmacodynamics and early efficacy. Experimental Design: CTC were enumerated/phenotyped for ER and Ki67 using CellSearch in serial blood draws. ctDNA was assessed for the most common ESR1LBDm by droplet digital PCR (BioRad). Results: Before starting AZD9496, 11 of 43 (25%) patients had >= 5 CTC/7.5mLwhole blood (WB), none of whom underwent reduction to = 5 CTC/7.5 mL WB before treatment had worse progression-free survival (PFS) than patients with = 2 unique mutations. Baseline ESR1(LBD)m status was not prognostic. Patients with persistently elevated CTC and/or ESR1(LBD)m(+) ctDNA at C1D15 had worse PFS than patients who did not (P = 0.0007). Conclusions: Elevated CTC at baseline was a strong prognostic factor in this cohort. Early on-treatment changes were observed in CTC-ER+ and ESR1(LBD)m+ ctDNA, but not in overall CTC number. Integrating multiple biomarkers in prospective trials may improve outcome prediction and ET resistance mechanisms' identification over a single biomarker

Abstract 3143: Monitoring circulating tumor cell (CTC) and circulating tumor DNA (ctDNA) genomic alterations in ER positive (POS)/HER2 negative (NEG) advanced breast cancer during endocrine therapy: correlative study of AZD9496 oral SERD phase I trial

Abstract Purpose: The vast majority of advanced ER POS breast cancers eventually cease responding to endocrine (ET) and other therapies leading to evolution of lethal disease. However, timely monitoring of the molecular events associated with response/progression in tissue biopsies is logistically difficult. The use of liquid biopsies, such as CTC and ctDNA, in this context has been of recent interest. Patients and Methods: Individual CTC and ctDNA were obtained at different time points from patients with advanced ER POS/HER2 NEG breast cancer enrolled in a Phase I trial of AZD9496, an oral selective estrogen receptor degrader (SERD) ET. The CTC, purified using tandem CellSearch®/DepArray™ technologies, were genomically profiled by DNA single cell next generation sequencing (scNGS). Plasma ctDNA was isolated from blood collected in Streck BCT tubes. Genomic profiling was performed by targeted gene panel scNGS for CTC and ddPCR for ERα gene (ESR1) mutations in ctDNA. Results: 123 high-quality CTCs from 12 patients profiled by scNGS showed 100% concordance with ctDNA in detection of driver ESR1 somatic mutations. CTC scNGS additionally revealed extensive intra-patient heterogeneity of driver alterations, that would have been unresolvable by bulk ctDNA profiling, including separate subclonal CTC populations emerging within the same patient. ScNGS revealed potential opportunities for targeted therapies in 73% of patients, directed at alterations in PIK3CA, FGFR2, KIT and BRAF, at times present as 2 or more targets in the same or different cell populations. In one patient, an emergent, distinct, BRAF p.V600E targetable alteration was detected in a subpopulation of CTCs collected at the progression time point but not at baseline. Conclusion: Serial monitoring of CTC and ctDNA genomic alterations is feasible and should enable real-time tracking of response/progression, tumor evolution and opportunities for precision medicine interventions. Citation Format: Andi K. Cani, Emily M. Dolce, Elizabeth P. Darga, Kevin Hu, Martha Brown, Chia-Jen Liu, Jackie Pierce, Kieran Bradbury, Kimberly Aung, Gaia Schiavon, Danielle Carroll, T. H. Carr, Teresa Klinowska, Justin Lindemann, Gayle Marshall, Vicky Rowlands, Elizabeth A. Harrington, J. Barrett, Anne Armstrong, Richard Baird, Erika Hamilton, Seock-Ah Im, Komal Jhaveri, Manish R. Patel, Caroline Dive, Scott A. Tomlins, Aaron M. Udager, Daniel F. Hayes, Costanza Paoletti. Monitoring circulating tumor cell (CTC) and circulating tumor DNA (ctDNA) genomic alterations in ER positive (POS)/HER2 negative (NEG) advanced breast cancer during endocrine therapy: correlative study of AZD9496 oral SERD phase I trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3143.</jats:p