Clinical and Therapeutic Outcomes by Molecular Subtype in Breast Cancer

Background: Breast cancer is the most frequent malignancy in women, with an estimated 2.3 million new cases and 685,000 deaths worldwide in 2020. Molecular subtypes defined by hormone receptor, HER2 and Ki-67 status guide treatment and prognosis. Colombian studies have described the distribution of molecular subtypes, but no study has integrated clinical, molecular, treatment and contextual factors (such as the COVID-19 pandemic and health insurance regimen) in a single cohort, and cost data disaggregated by stage and phase of care are scarce.

Design: Single-center, observational, retrospective cohort study with an umbrella design that will support subtype-specific and treatment-specific secondary analyses, plus an economic component (cost-of-illness study with a micro-costing approach from the perspective of the Colombian health system).

Population: Women 18 years or older with histologically confirmed breast cancer and documented molecular subtype determined by immunohistochemistry and/or in situ hybridization, treated and/or followed at Fundación Santa Fe de Bogotá between January 1, 2014 and December 31, 2024. The sample size (370 patients) was calculated to estimate a 10% proportion of triple-negative breast cancer with 95% confidence and 3% precision.

Subtype-specific objectives: (1) triple-negative disease: pathological response, adverse events, recurrence, progression and survival, including the impact of the COVID-19 pandemic (diagnosis before versus after March 2020) and the influence of health insurance regimen; (2) luminal A disease: treatment patterns and outcomes, including high-risk patients who were candidates for abemaciclib or ribociclib; (3) luminal B HER2-positive disease: association of anti-HER2 therapy with pathological complete response, recurrence and survival; (4) luminal B HER2-negative disease: association of high Ki-67 with adjuvant or neoadjuvant chemotherapy decisions and outcomes; (5) HER2-enriched disease: anti-HER2 therapy, response, recurrence, survival and adverse events; (6) hormone receptor-positive/HER2-negative disease: outcomes with versus without CDK4/6 inhibitors; (7) HER2-low disease: recurrence and associated factors; and (8) direct medical costs by clinical stage and phase of care.

Data collection: Data will be abstracted from institutional records (clinical databases, pathology reports, electronic medical records and oncology follow-up records) into a REDCap database with access restricted to the research team. Variables include demographics, body mass index, menopausal status, histology, molecular subtype and biomarkers (hormone receptors, HER2, Ki-67), stage and metastatic sites, comorbidities (Charlson index), performance status, treatments (surgery, radiotherapy, endocrine therapy, chemotherapy, anti-HER2 therapy, CDK4/6 inhibitors and other systemic therapies), dates of diagnosis, progression, recurrence and death, and health insurance regimen. For the economic component, resource use will be identified for case types by clinical stage, therapeutic subtype and phase of care, coded with CUPS and CUM codes and valued with national cost and price sources.

Statistical analysis: Descriptive statistics will be used for the cohort. Bivariate associations will be assessed with chi-square or Fisher exact tests and t or Mann-Whitney tests. Overall survival, progression-free survival and time to recurrence will be analyzed with Kaplan-Meier curves and log-rank tests, followed by multivariable Cox regression adjusted for age, stage, comorbidities, treatment, insurance regimen and year of diagnosis, with verification of the proportional hazards assumption. Dichotomous outcomes (pathological complete response, grade 3-4 adverse events) will be analyzed with logistic regression. Interaction terms (for example, subtype by COVID-19 period) will be explored, the 10 events-per-variable rule will be applied, and collinearity will be assessed with the variance inflation factor. Missing data will be handled with multiple imputation when compatible with missing at random, or with sensitivity analyses otherwise. Costs will be presented by stage, therapeutic subtype and phase of care, with a 3% annual discount rate for horizons longer than one year and deterministic sensitivity analyses. Analyses will be performed in R.

Ethics: The study is classified as research without risk under Colombian Resolution 8430 of 1993 (retrospective documentary research), and additional informed consent is not required. The protocol (version 1.2) was approved by the Comité Corporativo de Ética en Investigación of Fundación Santa Fe de Bogotá (CCEI-18860-2025), and amendment version 2.0 (May 14, 2026) was approved in June 2026 (CCEI-20040-2026).