Browsing by Author "Thomas, Alexandra"
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Item Open Access An FDA-Approved Antifungal, Ketoconazole, and Its Novel Derivative Suppress tGLI1-Mediated Breast Cancer Brain Metastasis by Inhibiting the DNA-Binding Activity of Brain Metastasis-Promoting Transcription Factor tGLI1.(Cancers, 2022-08) Doheny, Daniel; Manore, Sara; Sirkisoon, Sherona R; Zhu, Dongqin; Aguayo, Noah R; Harrison, Alexandria; Najjar, Mariana; Anguelov, Marlyn; Cox, Anderson O'Brien; Furdui, Cristina M; Watabe, Kounosuke; Hollis, Thomas; Thomas, Alexandra; Strowd, Roy; Lo, Hui-WenThe goal of this study is to identify pharmacological inhibitors that target a recently identified novel mediator of breast cancer brain metastasis (BCBM), truncated glioma-associated oncogene homolog 1 (tGLI1). Inhibitors of tGLI1 are not yet available. To identify compounds that selectively kill tGLI1-expressing breast cancer, we screened 1527 compounds using two sets of isogenic breast cancer and brain-tropic breast cancer cell lines engineered to stably express the control, GLI1, or tGLI1 vector, and identified the FDA-approved antifungal ketoconazole (KCZ) to selectively target tGLI1-positive breast cancer cells and breast cancer stem cells, but not tGLI1-negative breast cancer and normal cells. KCZ's effects are dependent on tGLI1. Two experimental mouse metastasis studies have demonstrated that systemic KCZ administration prevented the preferential brain metastasis of tGLI1-positive breast cancer and suppressed the progression of established tGLI1-positive BCBM without liver toxicities. We further developed six KCZ derivatives, two of which (KCZ-5 and KCZ-7) retained tGLI1-selectivity in vitro. KCZ-7 exhibited higher blood-brain barrier penetration than KCZ/KCZ-5 and more effectively reduced the BCBM frequency. In contrast, itraconazole, another FDA-approved antifungal, failed to suppress BCBM. The mechanistic studies suggest that KCZ and KCZ-7 inhibit tGLI1's ability to bind to DNA, activate its target stemness genes Nanog and OCT4, and promote tumor proliferation and angiogenesis. Our study establishes the rationale for using KCZ and KCZ-7 for treating and preventing BCBM and identifies their mechanism of action.Item Open Access Delivery of an ectonucleotidase inhibitor with ROS-responsive nanoparticles overcomes adenosine-mediated cancer immunosuppression.(Science translational medicine, 2022-06) Mao, Chengqiong; Yeh, Stacy; Fu, Juan; Porosnicu, Mercedes; Thomas, Alexandra; Kucera, Gregory L; Votanopoulos, Konstantinos I; Tian, Shaomin; Ming, XinTumor evasion of immune destruction is associated with the production of immunosuppressive adenosine in the tumor microenvironment (TME). Anticancer therapies can trigger adenosine triphosphate (ATP) release from tumor cells, causing rapid formation of adenosine by the ectonucleotidases CD39 and CD73, thereafter exacerbating immunosuppression in the TME. The goal of this study was to develop an approach to facilitate cancer therapy-induced immunogenic cell death including ATP release and to limit ATP degradation into adenosine, in order to achieve durable antitumor immune response. Our approach was to construct reactive oxygen species (ROS)-producing nanoparticles that carry an ectonucleotidase inhibitor ARL67156 by electronic interaction and phenylboronic ester. Upon near-infrared irradiation, nanoparticle-produced ROS induced ATP release from MOC1 cancer cells in vitro and triggered the cleavage of phenylboronic ester, facilitating the release of ARL67156 from the nanoparticles. ARL67156 prevented conversion of ATP to adenosine and enhanced anticancer immunity in an MOC1-based coculture model. We tested this approach in mouse tumor models. Nanoparticle-based ROS-responsive drug delivery reprogramed the immunogenic landscape in tumors, eliciting tumor-specific T cell responses and tumor regression, conferring long-term survival in mouse models. We demonstrated that TME reprograming sets the stage for response to anti-programmed cell death protein 1 (PD1) immunotherapy, and the combination resulted in tumor regression in a 4T1 breast cancer mouse model that was resistant to PD1 blockade. Furthermore, our approach also induced immunological effects in patient-derived organotypic tumor spheroid model, suggesting potential translation of our nanoparticle approach for treating human cancers.Item Open Access Developing a biomechanical model-based elasticity imaging method for assessing hormone receptor positive breast cancer treatment-related myocardial stiffness changes.(Journal of medical imaging (Bellingham, Wash.), 2021-09) Miller, Caroline E; Jordan, Jennifer H; Thomas, Alexandra; Weis, Jared APurpose: Assessing cardiotoxicity as a result of breast cancer therapeutics is increasingly important as breast cancer diagnoses are trending younger and overall survival is increasing. With evidence showing that prevention of cardiotoxicity plays a significant role in increasing overall survival, there is an unmet need for accurate non-invasive methods to assess cardiac injury due to cancer therapies. Current clinical methods are too coarse and emerging research methods have not yet achieved clinical implementation. Approach: As a proof of concept, we examine myocardial elasticity imaging in the setting of premenopausal women diagnosed with hormone receptor positive (HR-positive) breast cancer undergoing severe estrogen depletion, as cardiovascular injury from early estrogen depletion is well-established. We evaluate the ability of our model-based cardiac elasticity imaging analysis method to indicate subclinical cancer therapy-related cardiac decline by examining differences in the change in cardiac elasticity over time in two cohorts of premenopausal women either undergoing severe estrogen depletion for HR-positive breast cancer or triple negative breast cancer patients as comparators. Results: Our method was capable of producing functional mechanical elasticity maps of the left ventricle (LV). Using these elasticity maps, we show significant differences in cardiac mechanical elasticity in the HR-positive breast cancer cohort compared to the comparator cohort. Conclusions: We present our methodology to assess the mechanical stiffness of the LV by interrogating cardiac magnetic resonance images within a computational biomechanical model. Our preliminary study suggests the potential of this method for examining cardiac tissue mechanical stiffness properties as an early indicator of cardiac decline.Item Open Access E2112: Randomized Phase III Trial of Endocrine Therapy Plus Entinostat or Placebo in Hormone Receptor-Positive Advanced Breast Cancer. A Trial of the ECOG-ACRIN Cancer Research Group.(Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2021-10) Connolly, Roisin M; Zhao, Fengmin; Miller, Kathy D; Lee, Min-Jung; Piekarz, Richard L; Smith, Karen L; Brown-Glaberman, Ursa A; Winn, Jennifer S; Faller, Bryan A; Onitilo, Adedayo A; Burkard, Mark E; Budd, George T; Levine, Ellis G; Royce, Melanie E; Kaufman, Peter A; Thomas, Alexandra; Trepel, Jane B; Wolff, Antonio C; Sparano, Joseph APurpose
Endocrine therapy resistance in advanced breast cancer remains a significant clinical problem that may be overcome with the use of histone deacetylase inhibitors such as entinostat. The ENCORE301 phase II study reported improvement in progression-free survival (PFS) and overall survival (OS) with the addition of entinostat to the steroidal aromatase inhibitor (AI) exemestane in advanced hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer.Patients and methods
E2112 is a multicenter, randomized, double-blind, placebo-controlled phase III study that enrolled men or women with advanced HR-positive, HER2-negative breast cancer whose disease progressed after nonsteroidal AI. Participants were randomly assigned to exemestane 25 mg by mouth once daily and entinostat (EE) or placebo (EP) 5 mg by mouth once weekly. Primary end points were PFS by central review and OS. Secondary end points included safety, objective response rate, and lysine acetylation change in peripheral blood mononuclear cells between baseline and cycle 1 day 15.Results
Six hundred eight patients were randomly assigned during March 2014-October 2018. Median age was 63 years (range 29-91), 60% had visceral disease, and 84% had progressed after nonsteroidal AI in metastatic setting. Previous treatments included chemotherapy (60%), fulvestrant (30%), and cyclin-dependent kinase inhibitor (35%). Most common grade 3 and 4 adverse events in the EE arm included neutropenia (20%), hypophosphatemia (14%), anemia (8%), leukopenia (6%), fatigue (4%), diarrhea (4%), and thrombocytopenia (3%). Median PFS was 3.3 months (EE) versus 3.1 months (EP; hazard ratio = 0.87; 95% CI, 0.67 to 1.13; P = .30). Median OS was 23.4 months (EE) versus 21.7 months (EP; hazard ratio = 0.99; 95% CI, 0.82 to 1.21; P = .94). Objective response rate was 5.8% (EE) and 5.6% (EP). Pharmacodynamic analysis confirmed target inhibition in entinostat-treated patients.Conclusion
The combination of exemestane and entinostat did not improve survival in AI-resistant advanced HR-positive, HER2-negative breast cancer.Item Open Access Early and Locally Advanced Metaplastic Breast Cancer: Presentation and Survival by Receptor Status in Surveillance, Epidemiology, and End Results (SEER) 2010-2014.(The oncologist, 2018-04) Schroeder, Mary C; Rastogi, Priya; Geyer, Charles E; Miller, Lance D; Thomas, AlexandraBackground
Metaplastic breast cancer (MBC) is a rare disease subtype characterized by an aggressive clinical course. MBC is commonly triple negative (TN), although hormone receptor (HR) positive and human epidermal growth receptor 2 (HER2) positive cases do occur. Previous studies have reported similar outcomes for MBC with regard to HR status. Less is known about outcomes for HER2 positive MBC.Materials and methods
Surveillance, Epidemiology, and End Results Program data were used to identify women diagnosed 2010-2014 with MBC or invasive ductal carcinoma (IDC). Kaplan-Meier curves estimated overall survival (OS) and multivariate Cox models were fitted. For survival analyses, only first cancers were included, and 2014 diagnoses were excluded to allow for sufficient follow-up.Results
Our MBC sample included 1,516 women. Relative to women with IDC, women with MBC were more likely to be older (63 vs. 61 years), black (16.0% vs. 11.1%), and present with stage III disease (15.6% vs. 10.8%). HER2 positive and HER2 negative/HR positive MBC tumors represented 5.2% and 23.0% of cases. For MBC overall, 3-year OS was greatest for women with HER2 positive MBC (91.8%), relative to women with TN (75.4%) and HER2 negative/HR positive MBC (77.1%). This difference was more pronounced for stage III MBC, for which 3-year OS was 92.9%, 47.1%, and 42.2% for women with HER2 positive, TN, and HER2 negative/HR positive MBC, respectively. A multivariate Cox model of MBC demonstrated that HER2 positive tumors (relative to TN) were associated with improved survival (hazard ratio = 0.32, 95% confidence interval [CI] 0.13-0.79). In a second Cox model of exclusively HER2 positive tumors, OS did not differ between MBC and IDC disease subtypes (hazard ratio = 1.16, 95% CI 0.48-2.81).Conclusion
In this contemporary, population-based study of women with MBC, HER2 but not HR status was associated with improved survival. Survival was similar between HER2 positive MBC and HER2 positive IDC. This suggests HER2 positive MBC is responsive to HER2-directed therapy, a finding that may offer insights for additional therapeutic approaches to MBC.Implications for practice
This population-based study reports recent outcomes, by receptor status, for women with metaplastic breast cancer. Survival in metaplastic breast cancer is not impacted by hormone receptor status. To the authors' knowledge, this is the first report indicating that women with human epidermal growth receptor 2 (HER2) positive metaplastic breast cancer have survival superior to women with HER2 negative metaplastic breast cancer and survival similar to women with HER2 positive invasive ductal carcinoma. This information can be used for counseling patients diagnosed with metaplastic breast cancer. Further understanding of HER2 positive metaplastic breast cancer could offer insights for the development of therapeutic approaches to metaplastic breast cancer more broadly.Item Open Access Effect at One Year of Adjuvant Trastuzumab for HER2+ Breast Cancer Combined with Radiation or an Anthracycline on Left Ventricular Ejection Fraction.(The American journal of cardiology, 2020-06) Andersen, Mousumi M; Ayala-Peacock, Diandra; Bowers, Jessie; Kooken, Banks W; D'Agostino, Ralph B; Jordan, Jennifer H; Vasu, Sujethra; Thomas, Alexandra; Klepin, Heidi D; Brown, Doris R; Hundley, W GregoryTo determine the impact of radiation therapy (XRT) in addition to trastuzumab (TZB) adjuvant chemotherapy for HER2+ breast cancer on left ventricular systolic function, we assessed demographics, oncologic treatment history including XRT exposure, and serial measurements of left ventricular ejection fraction (LVEF) in 135 consecutively identified women receiving TZB for treatment of adjuvant breast cancer. Longitudinal mixed effects models were fit to identify baseline to treatment changes in LVEF among those receiving TZB with or without concomitant anthracycline or XRT. Women averaged 53 ± 3 years in age, 77% were white, 62% patients had 1 or more cardiovascular risk factors at baseline, and mean duration of TZB was 11 ± 5 months. Seventy-seven women were treated with XRT and received between 4000 and 5500 cGy of radiation. The LVEF declined by an average of 3.4% after 1 year for those in the study. Relative to baseline upon completion of adjuvant TZB, LVEF remained reduced for those receiving anthracycline with or without XRT (p=0.002 for both), or XRT alone (p=0.002), but not in those without these therapies. Amongst patients treated only with XRT and TZB, LVEF declined 3.1% on average in those with left-sided disease and 6.9% on average in those with right-sided disease (p= 0.06, p= 0.008 respectively). Among women receiving TZB for adjuvant treatment of HER-2 positive breast cancer, the administration of XRT, anthracycline, or the combination of the 2 is associated with a persistent post-treatment as opposed to a temporary treatment related decline in LVEF.Item Open Access Expanding access to early phase trials: the CATCH-UP.2020 experience.(JNCI cancer spectrum, 2023-01) Baranda, Joaquina C; Diaz, Francisco J; Rubinstein, Larry; Shields, Anthony F; Dayyani, Farshid; Mehta, Amitkumar; Mehnert, Janice M; Trent, Jonathan; Mabaera, Rodwell; Mooney, Margaret; Moscow, Jeffrey A; Doroshow, James; Waters, Brittany; Ivy, Percy; Gore, Steven D; Thomas, AlexandraBackground
Disparities in cancer outcomes persist for underserved populations; one important aspect of this is limited access to promising early phase clinical trials. To address this, the National Cancer Institute-funded Create Access to Targeted Cancer Therapy for Underserved Populations (CATCH-UP.2020) was created. We report the tools developed and accrual metrics of the initial year of CATCH-UP.2020 with a focus on racial, ethnic, geographic, and socioeconomically underserved populations.Methods
CATCH-UP.2020 is a P30 supplement awarded to 8 National Cancer Institute-designated cancer centers with existing resources to rapidly open and accrue to Experimental Therapeutics Clinical Trials Network (ETCTN) trials with emphasis on engaging patients from underserved populations. Sites used patient-based, community-based, investigator-based, and program-based tools to meet specific program goals.Results
From September 2020 to August 2021, CATCH-UP.2020 sites opened 45 ETCTN trials. Weighted average trial activation time for the 7 sites reporting this was 107 days. In the initial year, sites enrolled 145 patients in CATCH-UP.2020 with 68 (46.9%) representing racial, ethnic, rural, and socioeconomically underserved populations using the broader definition of underserved encompassed in the grant charge. During the initial year of CATCH-UP.2020, a time impacted by the COVID-19 pandemic, 15.8% (66 of 417) and 21.4% (31 of 145) of patients enrolled to ETCTN trials at network and at CATCH-UP sites, respectively, were from racial and ethnic minority groups, a more limited definition of underserved for which comparable data are available.Conclusion
Targeted funding accelerated activation and accrual of early phase trials and expanded access to this therapeutic option for underserved populations.Item Open Access Incidence and Survival Among Young Women With Stage I-III Breast Cancer: SEER 2000-2015.(JNCI cancer spectrum, 2019-09) Thomas, Alexandra; Rhoads, Anthony; Pinkerton, Elizabeth; Schroeder, Mary C; Conway, Kristin M; Hundley, William G; McNally, Lacey R; Oleson, Jacob; Lynch, Charles F; Romitti, Paul ABackground
Although recent findings suggest that de novo stage IV breast cancer is increasing in premenopausal women in the United States, contemporary incidence and survival data are lacking for stage I-III cancer.Methods
Women aged 20-29 (n = 3826), 30-39 (n = 34 585), and 40-49 (n = 126 552) years who were diagnosed with stage I-III breast cancer from 2000 to 2015 were identified from the Surveillance, Epidemiology, and End Results 18 registries database. Age-adjusted, average annual percentage changes in incidence and 5- and 10-year Kaplan-Meier survival curves were estimated by race and ethnicity, stage, and hormone receptor (HR) status and grade (low to well and moderately differentiated; high to poorly and undifferentiated) for each age decade.Results
The average annual percentage change in incidence was positive for each age decade and was highest among women aged 20-29 years. Increased incidence was driven largely by HR+ cancer, particularly HR+ low-grade cancer in women aged 20-29 and 40-49 years. By 2015, incidence of HR+ low- and high-grade cancer each independently exceeded incidence of HR- cancer in each age decade. Survival for HR+ low- and high-grade cancer decreased with decreasing age; survival for HR- cancer was similar across age decades. Among all women aged 20-29 years, 10-year survival for HR+ high-grade cancer was lower than that for HR+ low-grade or HR- cancer. Among women aged 20-29 years with stage I cancer, 10-year survival was lowest for HR+ high-grade cancer.Conclusions
HR+ breast cancer is increasing in incidence among premenopausal women, and HR+ high-grade cancer was associated with reduced survival among women aged 20-29 years. Our findings can help guide further evaluation of preventive, diagnostic, and therapeutic strategies for breast cancer among premenopausal women.Item Open Access Incidence and Survival by Human Epidermal Growth Factor Receptor 2 Status in Young Women With Stage I-III Breast Cancer: SEER, 2010-2016.(Clinical breast cancer, 2020-08) Thomas, Alexandra; Rhoads, Anthony; Suhl, Jonathan; Conway, Kristin M; Hundley, William G; McNally, Lacey R; Oleson, Jacob; Melin, Susan A; Lynch, Charles F; Romitti, Paul ABackground
Young premenopausal women with breast cancer often experience more aggressive disease biology and poorer survival than older women. Diagnostic and therapeutic advances, including human epidermal growth factor receptor 2 (HER2)-directed therapy, may lessen treatment burden and improve survival for these young women, but contemporary incidence and survival data by HER2 status are limited.Patients and methods
We identified women aged 20-49 years (n = 68,530) diagnosed with stage I-III breast cancer during 2010-2016 from the United States Surveillance, Epidemiology, and End Results 18 registries database. Age-adjusted average annual percent changes in incidence (diagnosis 2010-2016) and 5-year Kaplan-Meier survival curves (diagnosis 2010-2015) were estimated by HER2 and hormone receptor (HR) status and stratified independently by cancer stage and race/ethnicity.Results
With increasing age decade, proportions of HER2-/HR+ cancer increased, whereas proportions of HER2+/HR+, HER2+/HR-, and HER2-/HR- decreased. The greatest increases in incidence during 2010-2016 were observed for HER2+ among women aged 20-49 years and HER2-/HR- among women aged 20-29 years. Incidence decreased for HER2-/HR- among women aged 40-49 years. Five-year survival was lowest for HER2-/HR- status compared to other receptor-based subtypes among women aged 20-49 years. HER2+ status was more beneficial for 5-year survival than HR+ status among women aged 20-29 years, with the opposite observed among women aged 30-49 years, particularly those aged 40-49 years.Conclusion
HER2+ breast cancer increased among premenopausal women and was also associated with higher early survival within each HR status. HER2-/HR- cancer also increased among women aged 20-29 years and was associated with lower early survival. Our contemporary data provide important insights to help inform preventive and therapeutic strategies for premenopausal women.Item Open Access Late Recurrence Following Early Breast Cancer.(Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2022-05) Thomas, Alexandra; Parsons, Heather A; Smith, Karen LisaThe Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in the Journal of Clinical Oncology, to patients seen in their own clinical practice.Item Open Access Myocardial Function in Premenopausal Women Treated With Ovarian Function Suppression and an Aromatase Inhibitor.(JNCI cancer spectrum, 2021-08) Jordan, Jennifer H; D'Agostino, Ralph B; Ansley, Katherine; Douglas, Emily; Melin, Susan; Sorscher, Steven; Vasu, Sujethra; Park, Sung; Kotak, Anuj; Romitti, Paul A; O'Connell, Nathanial S; Hundley, William G; Thomas, AlexandraPremenopausal women with high-risk hormone receptor (HR)-positive breast cancer often receive ovarian function suppression (OFS) with aromatase inhibitor therapy; however, abrupt menopause induction, together with further decrements in estrogen exposure through aromatase inhibition, may affect cardiovascular microcirculatory function. We examined adenosine-induced changes in left ventricular (LV) myocardial T1, a potential subclinical marker of LV microcirculatory function in premenopausal women undergoing treatment for breast cancer. Twenty-one premenopausal women (14 with HR-positive breast cancer receiving OFS with an aromatase inhibitor and 7 comparator women with triple-negative breast cancer [TNBC] who had completed primary systemic therapy) underwent serial resting and adenosine cardiovascular magnetic resonance imaging measurements of LV myocardial T1 and LV volumes, mass, and ejection fraction. All statistical tests were 2-sided. After a median of 4.0 months (range = 3.1-5.7 months), the stress to resting ratio of LV myocardial T1 declined in women with HR-positive breast cancer (-1.3%, 95% confidence interval [CI] = -3.4% to 0.7%) relative to those with TNBC (3.2%, 95% CI = -1.2% to 7.6%, P = .02). After accounting for age, LV stroke volume, LV ejection fraction, diastolic blood pressure, and breast cancer subtype women with HR-positive breast cancer experienced a blunted T1 response after adenosine relative to women with TNBC (difference = -4.7%, 95% CI = -7.3% to -2.1%, Pdifference = .002). Over the brief interval examined, women with HR-positive breast cancer receiving OFS with an aromatase inhibitor experienced reductions in adenosine-associated changes in LV myocardial T1 relative to women who received nonhormonal therapy for TNBC. These findings suggest a possible adverse impact on LV myocardial microcirculatory function in premenopausal women with breast cancer receiving hormone deprivation therapy.Item Open Access Rare subtypes of triple negative breast cancer: Current understanding and future directions.(NPJ breast cancer, 2023-06) Thomas, Alexandra; Reis-Filho, Jorge S; Geyer, Charles E; Wen, Hannah YRare subtypes of triple-negative breast cancers (TNBC) are a heterogenous group of tumors, comprising 5-10% of all TNBCs. Despite accounting for an absolute number of cases in aggregate approaching that of other less common, but well studied solid tumors, rare subtypes of triple-negative disease remain understudied. Low prevalence, diagnostic challenges and overlapping diagnoses have hindered consistent categorization of these breast cancers. Here we review epidemiology, histology and clinical and molecular characteristics of metaplastic, triple-negative lobular, apocrine, adenoid cystic, secretory and high-grade neuroendocrine TNBCs. Medullary pattern invasive ductal carcinoma no special type, which until recently was a considered a distinct subtype, is also discussed. With this background, we review how applying biological principals often applied to study TNBC no special type could improve our understanding of rare TNBCs. These could include the utilization of targeted molecular approaches or disease agnostic tools such as tumor mutational burden or germline mutation-directed treatments. Burgeoning data also suggest that pathologic response to neoadjuvant therapy and circulating tumor DNA have value in understanding rare subtypes of TNBC. Finally, we discuss a framework for advancing disease-specific knowledge in this space. While the conduct of randomized trials in rare TNBC subtypes has been challenging, re-envisioning trial design and technologic tools may offer new opportunities. These include embedding rare TNBC subtypes in umbrella studies of rare tumors, retrospective review of contemporary trials, prospective identification of patients with rare TNBC subtypes entering on clinical trials and querying big data for outcomes of patients with rare breast tumors.Item Open Access Reproducibility assessment of a biomechanical model-based elasticity imaging method for identifying changes in left ventricular mechanical stiffness.(Journal of medical imaging (Bellingham, Wash.), 2022-09) Miller, Caroline E; Jordan, Jennifer H; Douglas, Emily; Ansley, Katherine; Thomas, Alexandra; Weis, Jared APurpose
Cardiotoxicity of antineoplastic therapies is increasingly a risk to cancer patients treated with curative intent with years of life to protect. Studies highlight the importance of identifying early cardiac decline in cancer patients undergoing cardiotoxic therapies. Accurate tools to study this are a critical clinical need. Current and emerging methods for assessing cardiotoxicity are too coarse for identifying preclinical cardiac degradation or too cumbersome for clinical implementation.Approach
In the previous work, we developed a noninvasive biomechanical model-based elasticity imaging methodology (BEIM) to assess mechanical stiffness changes of the left ventricle (LV) based on routine cine cardiac magnetic resonance (CMR) images. We examine this methodology to assess methodological reproducibility. We assessed a cohort of 10 participants that underwent test/retest short-axis CMR imaging at baseline and follow-up sessions as part of a previous publicly available study. We compare test images to retest images acquired within the same session to assess within-session reproducibility. We also compare test and retest images acquired at the baseline imaging session to test and retest images acquired at the follow-up imaging session to assess between-session reproducibility.Results
We establish the within-session and between-session reproducibility of our method, with global elasticity demonstrating repeatability within a range previously demonstrated in cardiac strain imaging studies. We demonstrate increased repeatability of global elasticity compared to segmental elasticity for both within-session and between-session. Within-subject coefficients of variation for within-session test/retest images globally for all modulus directions and a mechanical fractional mechanical stiffness anisotropy metric ranged from 11% to 28%.Conclusions
Results suggest that our methodology can reproducibly generate estimates of relative mechanical elasticity of the LV and provides a threshold for distinguishing true changes in myocardial mechanical stiffness from experimental variation. BEIM has applications in identifying preclinical cardiotoxicity in breast cancer patients undergoing antineoplastic therapies.