Cardiac Side Effects of Systemic Therapy in Early-Stage Breast Cancer (C-BREAST-01)

Prospective and Molecular Biomarker-Based Evaluation of Cardiac Side Effects in Patients With Early-Stage Breast Cancer Receiving Systemic Therapy: A Single-Center Observational Cohort Study

The goal of this observational study is to evaluate cardiac side effects in women with early-stage breast cancer who receive systemic chemotherapy and/or anti-HER2 therapy as part of their standard cancer care.

The main questions it aims to answer are:

Can changes in Global Longitudinal Strain (GLS) on echocardiography detect early cardiac dysfunction before a drop in left ventricular ejection fraction (LVEF) becomes apparent? Are changes in circulating microRNA levels in the blood associated with early cardiac dysfunction during cancer treatment? Does cardiac dysfunction occur more frequently with anthracycline-containing chemotherapy compared to anthracycline-free regimens?

Participants already receiving standard chemotherapy and/or anti-HER2 therapy as part of their routine cancer care will undergo echocardiography (LVEF and GLS), provide blood samples for microRNA analysis, and complete quality of life questionnaires at four time points: before treatment (baseline), and at 3, 6, and 12 months after starting treatment.

Study Overview

• Status: Not yet recruiting
• Conditions: Cardiotoxicity; Breast Cancer (Early Breast Cancer); Cancer Therapy-Related Cardiac Dysfunction

Detailed Description

Background:

Anthracyclines and anti-HER2 agents are cornerstone treatments for early-stage breast cancer but carry meaningful risk of cancer therapy-related cardiac dysfunction (CTRCD). Cardiotoxicity is often initially subclinical, with left ventricular ejection fraction (LVEF) decline appearing late, after irreversible myocardial damage may have occurred. The 2022 European Society of Cardiology (ESC) Cardio-Oncology Guidelines recommend Global Longitudinal Strain (GLS) as a more sensitive parameter than LVEF for early detection of cardiac dysfunction. A relative reduction in GLS can occur weeks to months before clinically apparent LVEF decline.

While echocardiography provides functional assessment of the heart, it offers limited insight into the molecular mechanisms underlying cardiac injury. Circulating microRNAs (miRNAs) are emerging as candidate biomarkers reflecting cardiomyocyte injury, oxidative stress, and fibrosis. Although several studies have evaluated cardiotoxicity from anthracyclines and anti-HER2 therapies, most have been retrospective and focused solely on LVEF changes. Prospective studies that simultaneously assess GLS and circulating miRNAs are limited, as are head-to-head comparisons of cardiac effects across different chemotherapy regimens at both functional and molecular levels.

Rationale:

This study addresses these gaps by evaluating cardiac effects of systemic therapy in early-stage breast cancer patients using both functional (echocardiographic) and molecular (miRNA) parameters in a prospective design. The findings are expected to contribute to early identification of cardiotoxicity, identification of high-risk patient subgroups, and development of personalized cardio-oncology surveillance strategies.

Study Procedures:

Patients are assessed at four time points: baseline (prior to systemic therapy initiation), Month 3, Month 6, and Month 12. At each visit, the following procedures are performed:

Echocardiographic Assessment: Transthoracic echocardiography is performed by experienced cardiologists using a standardized protocol. LVEF is measured using Simpson's biplane method, and GLS is measured using speckle-tracking analysis. Additional parameters including E/A ratio, TAPSE, and QTc interval are also recorded.

Circulating microRNA Analysis: Peripheral venous blood samples are collected in EDTA tubes during routine blood draws (no additional needle stick required). Total RNA is isolated using a commercial total nucleic acid isolation kit, and RNA concentration and purity are assessed via UV spectrophotometry. Reverse transcription is performed using a microRNA cDNA synthesis kit. Quantitative real-time PCR is performed using SYBR Green PCR kit on a LightCycler 480 II system. Expression levels of the following miRNAs are measured: miR-34a, miR-146a, miR-21, miR-155, miR-1, miR-133a, miR-208a, and miR-499. These miRNAs were selected based on their reported associations with cardiac injury, fibrosis, oxidative stress, and inflammation in the cardio-oncology literature. U6 small nuclear RNA serves as the normalization control. Relative quantification is calculated using the 2^(-ΔΔCt) method.

Cardiac Biomarkers: High-sensitivity troponin I and NT-proBNP are measured at each visit.

Routine Laboratory Assessments: Complete blood count, renal function (creatinine, eGFR), and liver function (ALT) are obtained.

Patient-Reported Outcomes: Quality of life is assessed using the EORTC QLQ-C30 (general cancer module) and EORTC QLQ-BR42 (breast cancer-specific module). Additional patient-reported assessments include the EORTC QLQ-FA12 (cancer-related fatigue), EORTC QLQ-SH22 (sexual health), PHQ-4 (anxiety/depression), PSQI (sleep quality), and FACT-Cog (cognitive function).

Adverse Event Monitoring: All treatment-emergent adverse events are graded according to CTCAE version 5.0.

Treatment:

The study does not modify treatment selection, dose, or duration. All patients receive standard-of-care systemic therapy (anthracycline-containing or anthracycline-free regimens, with or without anti-HER2 agents) determined by their treating oncologist based on disease characteristics and current clinical guidelines. For analytic purposes, patients are sub-grouped by chemotherapy regimen for comparative analyses.

Statistical Considerations:

A total of 100 patients are planned for enrollment. miRNA expression differences between groups are analyzed using REST 2009 v2.013 software and confirmed with GeneGlobe Data Analysis Center. Continuous variables not normally distributed are compared using Mann-Whitney U test (two groups) or Kruskal-Wallis test with Dunn post-hoc tests (three or more groups). Statistical significance is set at p < 0.05.

• Study Type: Observational
• Enrollment (Estimated): 100

Contacts and Locations

• Study Contact: Name: Sıla Soylu Koçoğlu, MD; Phone Number: +905012735223; Email: drsilasoylu@gmail.com
• Study Contact Backup: Name: Fatih Gürler, MD; Phone Number: +905325495597; Email: drfatihgurler@gmail.com

Study Locations

• Turkey (Türkiye)
  • Ankara
    • Ankara, Ankara, Turkey (Türkiye), 06560
      • Gazi University Faculty of Medicine
      • Contact: Sıla Soylu Koçoğlu, MD; Phone Number: +905012735223; Email: drsilasoylu@gmail.com
      • Principal Investigator: Fatih Gürler, MD
      • Sub-Investigator: Sıla Soylu Koçoğlu, MD
      • Sub-Investigator: Ayşe Arslan Kapuci, MD
      • Sub-Investigator: Serkan Ünlü, MD
      • Sub-Investigator: Elif Nur Ayrancı, MD
      • Sub-Investigator: Ahmet Eren Beşir, MD
      • Sub-Investigator: Duygu Deniz Usta Salimi, PhD
      • Sub-Investigator: Atiye Seda Yar, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Adult women with histologically confirmed Stage I-III breast cancer for whom neoadjuvant or adjuvant systemic therapy (chemotherapy and/or HER2-targeted therapy) is planned, recruited from the Medical Oncology outpatient clinic at Gazi University Faculty of Medicine Hospital, Ankara, Türkiye.

Description

Inclusion Criteria:

• Histologically confirmed diagnosis of breast cancer
• Stage I, II, or III disease
• Planned neoadjuvant or adjuvant chemotherapy and/or HER2-targeted systemic therapy
• Baseline transthoracic echocardiographic left ventricular ejection fraction (LVEF) ≥ 50%
• Age ≥ 18 years
• Able and willing to provide written informed consent

Exclusion Criteria:

• Metastatic (Stage IV) breast cancer
• Pre-existing heart failure or clinically significant cardiac disease
• Prior exposure to chemotherapy or other cardiotoxic systemic therapy
• Concurrent active malignancy other than breast cancer
• Inability or unwillingness to comply with the planned follow-up and assessment schedule

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Early-stage breast cancer patients receiving systemic therapy; Adult women with histologically confirmed Stage I-III breast cancer for whom neoadjuvant or adjuvant chemotherapy and/or HER2-targeted systemic therapy is planned, with baseline left ventricular ejection fraction ≥ 50%. Patients receive standard-of-care systemic therapy as determined by their treating oncologist; the study does not modify treatment selection, dose, or duration. For analytic purposes, patients are sub-grouped by chemotherapy regimen (anthracycline-containing vs. anthracycline-free) for comparative analyses of cardiac function and circulating microRNA changes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of cancer therapy-related cardiac dysfunction (CTRCD)	CTRCD defined per ESC 2022 Cardio-Oncology Guidelines as: an absolute LVEF reduction of ≥10 percentage points to a value below 53%, AND/OR a relative reduction in GLS of ≥15% from baseline. LVEF is measured by transthoracic echocardiography using Simpson's biplane method; GLS is measured by speckle-tracking analysis using a standardized protocol.	From baseline through Month 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in Left Ventricular Ejection Fraction (LVEF)	Absolute change from baseline in left ventricular ejection fraction (LVEF, %) measured by transthoracic echocardiography using Simpson's biplane method. LVEF is the standard echocardiographic parameter for assessing left ventricular systolic function.	Baseline, Month 3, Month 6, Month 12
Change from baseline in Global Longitudinal Strain (GLS)	Relative change from baseline in Global Longitudinal Strain (GLS, %) measured by speckle-tracking echocardiography. GLS is a sensitive marker of subclinical left ventricular dysfunction that can detect myocardial impairment before changes in LVEF become apparent.	Baseline, Month 3, Month 6, Month 12
Change in circulating microRNA expression and association with cardiac function	Relative quantification (RQ) of circulating microRNAs (miR-34a, miR-146a, miR-21, miR-155, miR-1, miR-133a, miR-208a, miR-499) measured by quantitative real-time PCR using U6 snRNA as normalization control and analyzed via the 2^(-ΔΔCt) method. Correlations between miRNA expression changes and LVEF/GLS changes are assessed.	Baseline, Month 3, Month 6, Month 12
Comparison of CTRCD incidence between anthracycline-containing and anthracycline-free regimens	Frequency of CTRCD (defined as in the primary outcome) compared between patients receiving anthracycline-containing chemotherapy regimens and those receiving anthracycline-free regimens.	From baseline through Month 12
Change from baseline in health-related quality of life: EORTC QLQ-C30	European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC QLQ-C30) is a 30-item self-report cancer-specific quality of life questionnaire. The Global Health Status / Quality of Life scale ranges from 0 to 100; higher scores indicate better quality of life. Functional scales range from 0 to 100 with higher scores indicating better functioning. Symptom scales range from 0 to 100 with higher scores indicating worse symptoms.	Baseline, Month 3, Month 6, Month 12
Change from baseline in breast cancer-specific quality of life: EORTC QLQ-BR42	European Organisation for Research and Treatment of Cancer Breast Cancer Module (EORTC QLQ-BR42) is a 42-item breast cancer-specific questionnaire used as a supplement to the QLQ-C30. Scores range from 0 to 100. For functional scales, higher scores indicate better functioning; for symptom scales, higher scores indicate worse symptoms.	Baseline, Month 3, Month 6, Month 12
Change from baseline in cancer-related fatigue: EORTC QLQ-FA12	European Organisation for Research and Treatment of Cancer Fatigue Module (EORTC QLQ-FA12) is a 12-item questionnaire measuring cancer-related fatigue across physical, emotional, and cognitive dimensions. Scores range from 0 to 100; higher scores indicate higher levels of fatigue (worse outcome).	Baseline, Month 3, Month 6, Month 12
Change from baseline in sexual health: EORTC QLQ-SH22	European Organisation for Research and Treatment of Cancer Sexual Health Questionnaire (EORTC QLQ-SH22) is a 22-item self-report questionnaire assessing sexual health in cancer patients. Scores range from 0 to 100; interpretation varies by subscale. For functional subscales higher scores indicate better function; for symptom subscales higher scores indicate worse symptoms.	Baseline, Month 3, Month 6, Month 12
Change from baseline in anxiety and depression: Patient Health Questionnaire-4 (PHQ-4)	Patient Health Questionnaire-4 (PHQ-4) is a 4-item ultra-brief self-report screening tool for anxiety and depression. Total score ranges from 0 to 12; higher scores indicate worse symptoms. Scores of 0-2 indicate none, 3-5 mild, 6-8 moderate, and 9-12 severe psychological distress.	Baseline, Month 3, Month 6, Month 12
Change from baseline in sleep quality: Pittsburgh Sleep Quality Index (PSQI)	Pittsburgh Sleep Quality Index (PSQI) is a 19-item self-report questionnaire assessing sleep quality and disturbances over the past month. Global score ranges from 0 to 21; higher scores indicate worse sleep quality. A global score greater than 5 indicates poor sleep quality.	Baseline, Month 3, Month 6, Month 12
Change from baseline in cognitive function: Functional Assessment of Cancer Therapy - Cognitive Function (FACT-Cog)	Functional Assessment of Cancer Therapy - Cognitive Function (FACT-Cog) is a 37-item self-report questionnaire assessing perceived cognitive impairment, perceived cognitive abilities, comments from others on cognitive function, and quality of life impact. Total score ranges from 0 to 148; higher scores indicate better cognitive function.	Baseline, Month 3, Month 6, Month 12

Collaborators and Investigators

• Sponsor: Fatih GURLER
• Investigators: Principal Investigator: Fatih Gürler, Gazi University

Publications and helpful links

General Publications

• Lyon AR, Lopez-Fernandez T, Couch LS, Asteggiano R, Aznar MC, Bergler-Klein J, Boriani G, Cardinale D, Cordoba R, Cosyns B, Cutter DJ, de Azambuja E, de Boer RA, Dent SF, Farmakis D, Gevaert SA, Gorog DA, Herrmann J, Lenihan D, Moslehi J, Moura B, Salinger SS, Stephens R, Suter TM, Szmit S, Tamargo J, Thavendiranathan P, Tocchetti CG, van der Meer P, van der Pal HJH; ESC Scientific Document Group. 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Eur Heart J. 2022 Nov 1;43(41):4229-4361. doi: 10.1093/eurheartj/ehac244. No abstract available.
• Kuang Z, Ge Y, Cao L, Wang X, Liu K, Wang J, Zhu X, Wu M, Li J. Precision Treatment of Anthracycline-Induced Cardiotoxicity: An Updated Review. Curr Treat Options Oncol. 2024 Aug;25(8):1038-1054. doi: 10.1007/s11864-024-01238-9. Epub 2024 Jul 27.
• Poovorawan N, Susiriwatananont T, Teerapakpinyo C, Chariyavilaskul P, Sitthideatphaiboon P, Jarutasnangkul L, Tumkosit M, Chattranukulchai P, Theerasuwipakorn N, Aporntewan C, Shuangshoti S, Manasnayakorn S, Vinayanuwattikun C, Vorasettakarnkij Y, Sriuranpong V. Long-term impact of anthracycline in early-stage breast cancer, bridging of MiRNAs profiler for early cardiotoxicity. Cardiooncology. 2025 Apr 23;11(1):39. doi: 10.1186/s40959-025-00337-2.
• Boen HM, Cherubin M, Franssen C, Gevaert AB, Witvrouwen I, Bosman M, Guns PJ, Heidbuchel H, Loeys B, Alaerts M, Van Craenenbroeck EM. Circulating MicroRNA as Biomarkers of Anthracycline-Induced Cardiotoxicity: JACC: CardioOncology State-of-the-Art Review. JACC CardioOncol. 2024 Feb 27;6(2):183-199. doi: 10.1016/j.jaccao.2023.12.009. eCollection 2024 Apr.
• Mecinaj A, Gulati G, Ree AH, Gravdehaug B, Rosjo H, Steine K, Wisloff T, Geisler J, Omland T, Heck SL. Impact of the ESC Cardio-Oncology Guidelines Biomarker Criteria on Incidence of Cancer Therapy-Related Cardiac Dysfunction. JACC CardioOncol. 2024 Jan 16;6(1):83-95. doi: 10.1016/j.jaccao.2023.10.008. eCollection 2024 Feb.
• Bernasconi R, Kuster GM. Non-coding RNAs and their potential exploitation in cancer therapy-related cardiotoxicity. Br J Pharmacol. 2025 Jan;182(2):296-315. doi: 10.1111/bph.16416. Epub 2024 May 27.

Study record dates

Study Major Dates

• Study Start (Estimated): May 10, 2026
• Primary Completion (Estimated): December 10, 2027
• Study Completion (Estimated): March 30, 2028

Study Registration Dates

• First Submitted: May 3, 2026
• First Submitted That Met QC Criteria: May 10, 2026
• First Posted (Actual): May 14, 2026

Study Record Updates

• Last Update Posted (Actual): May 14, 2026
• Last Update Submitted That Met QC Criteria: May 10, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: microRNA; Cardiotoxicity; Anthracyclines; Cardio-oncology; GLS; Anti-HER2 therapy; Early-stage breast cancer
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Wounds and Injuries; Pathologic Processes; Neoplasms by Site; Neoplasms; Heart Diseases; Chemically-Induced Disorders; Skin Diseases; Breast Diseases; Drug-Related Side Effects and Adverse Reactions; Radiation Injuries; Pathological Conditions, Signs and Symptoms; Skin and Connective Tissue Diseases; Breast Neoplasms; Cardiotoxicity
• Other Study ID Numbers: GUTF-MO-OnkoKard-2026-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: A formal IPD sharing plan has not yet been established. The study team will determine whether anonymized individual participant data can be made available upon reasonable request after study completion and publication, in accordance with applicable data protection regulations (including KVKK / GDPR), institutional policies, and ethics committee approval.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No