Treatment Delay and Survival in Patients with Breast Cancer by Stage and Cardiovascular Comorbidity: A Nationwide Korean Cohort Study

Technical Summary: Treatment Delay and Survival in Patients with Breast Cancer by Stage and Cardiovascular Comorbidity

Problem Statement
The impact of treatment delay on breast cancer survival remains inconsistent across existing literature. While prior meta-analyses suggest that delays in initiating therapy (Time-to-Treatment Initiation, TTI) adversely affect outcomes, findings vary significantly when stratified by disease stage. Furthermore, the role of preexisting comorbidities, particularly cardiovascular disease (CVD), in modifying the relationship between treatment delay and survival has not been fully examined. CVD is a leading cause of death among breast cancer survivors and may render patients more vulnerable to prolonged treatment intervals due to reduced tolerance for therapy and competing mortality risks. This study addresses the need for a large-scale, stage-stratified analysis of TTI and overall survival in a Korean cohort, specifically investigating the interplay between delay, disease stage, molecular subtype, and cardiovascular comorbidity.

Methodology
This retrospective cohort study utilized the Breast Cancer Collaborative Stage-Linked Database, a dataset constructed under the Korean Clinical Data Utilization for Research Excellence (K-CURE) project. The database integrates the Korea Central Cancer Registry (KCCR) Breast CS dataset (2012–2019) with administrative and clinical data from the Cancer Public Library Database (CPLD), including health insurance claims, cause-of-death records, and health screening data.

• Study Population: The final cohort comprised 16,495 women newly diagnosed with breast cancer (stages I–IV). Patients with stage 0, unknown stage, male patients, and those with unverified eligibility or diagnosis/death in the same calendar month were excluded.
• Exposure Definition: TTI was defined as the interval between the imputed diagnosis date and the first treatment (surgery, radiotherapy, or chemotherapy) received within one year. Diagnosis and death dates were recorded only at the month level; therefore, 50 imputed datasets were generated by randomly assigning days within the recorded months to ensure stable estimates. TTI was categorized as: ≤30 days (reference), 31–60 days, ≥61 days, and no treatment within one year.
• Outcome: The primary outcome was overall survival (death from any cause), with follow-up truncated to December 31, 2021.
• Statistical Analysis: Stage-stratified Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs). Models were adjusted for age, insurance premium, residential area, molecular subtype, BMI, lifestyle factors (smoking, alcohol, physical activity), and comorbidities (CVD, diabetes, chronic kidney disease, prior malignancy). Subgroup analyses were conducted by molecular subtype and, specifically for stage III patients, by CVD status.

Key Results

• Overall Cohort by Stage: Among treated patients, TTI was not significantly associated with overall survival for Stage I, II, or IV disease. However, for Stage III disease, a treatment delay of ≥61 days was associated with a 50% higher risk of death compared to the reference group (aHR, 1.50; 95% CI, 1.04–2.16).
• Molecular Subtypes: In the overall cohort, a delay of ≥61 days was significantly associated with worse survival for Triple-Negative Breast Cancer (TNBC) (aHR, 1.75; 95% CI, 1.10–2.78) and HR+/HER2+ tumors (aHR, 1.41; 95% CI, 1.04–1.92). No significant association was found for HER2-enriched or HR+/HER2− subtypes.
• Cardiovascular Comorbidity: The association between delay and survival was most pronounced in patients with Stage III disease and preexisting CVD. In this subgroup, a delay of ≥61 days was associated with a 5.28-fold increase in the risk of death (aHR, 5.28; 95% CI, 1.78–15.68), whereas no significant association was observed in Stage III patients without CVD.
• Sensitivity Analysis: Results remained consistent when diagnosis and death dates were fixed to the first day of the recorded month.

Significance and Claims
The authors conclude that the prognostic impact of treatment delay is not uniform but is highly dependent on disease stage and patient characteristics. Specifically:

1. Stage-Specific Vulnerability: Prolonged delays (≥61 days) significantly compromise survival only in Stage III breast cancer, likely because this stage typically requires timely, curative-intent multimodal treatment, whereas early-stage disease may tolerate moderate delays and metastatic disease outcomes are driven more by tumor biology.
2. Biological and Comorbidity Interactions: The adverse effects of delay are amplified in biologically aggressive subtypes (TNBC and HR+/HER2+) and in patients with preexisting cardiovascular disease.
3. Clinical Implication: The study highlights the critical need to minimize avoidable treatment delays, particularly for high-risk groups including Stage III patients, those with aggressive molecular subtypes, and those with cardiovascular comorbidities. The authors suggest that integrated cardio-oncology care may be essential for managing these high-risk populations to mitigate the compounded risks of delayed therapy and competing mortality causes.

The paper acknowledges limitations, including the inability to distinguish breast cancer-specific deaths from non-cancer deaths due to data constraints, the potential for residual confounding, and the lack of data regarding the specific causes of treatment delays. Despite these limitations, the use of a large, nationwide linked database with multiple imputation for date uncertainty provides robust evidence for stage-specific and comorbidity-stratified survival analyses.