Dana Franklin

Ductal carcinoma in situ (DCIS) is a non-invasive precursor to invasive breast cancer. DCIS incidence continues to rise, yet its clinical management remains constrained by the absence of reliable biomarkers that can adequately distinguish indolent lesions from those with high invasive potential, to circumvent over- or under-treatment. Black women with DCIS are significantly more likely to progress to invasive breast cancer, are disproportionately diagnosed with high-grade, hormone receptor-negative lesions, and experience elevated risk of recurrence and mortality relative to White women with DCIS. These disparities persist despite comparable access to screening and treatment, suggesting underlying biological and tissue microenvironmental factors. This review synthesizes emerging evidence implicating early molecular and systemic changes that may be driving the disparity in DCIS progression. We highlight racial distinctions in interconnected pathways involving Wnt/β-catenin signaling, metabolic and nutritional dysregulation, immune microenvironment remodeling, and cellular tolerance of genomic instability. We further discuss how epigenetic alterations, obesity-associated inflammation, and immune dysregulation may arise during the pre-invasive stage that intersect with social and environmental exposures to influence racial differences in lesion fate. We spotlight candidate biomarkers disproportionately associated with aggressive disease in Black women—including KIFC1, a mediator of centrosome clustering and genomic instability tolerance, and ACKR1/DARC, a regulator of chemokine gradients and immune trafficking—as potential drivers of progression-permissive states. This review advances an integrated, equity-informed framework for DCIS progression that links early tumor evolution to coordinated alterations in genomic instability, immune regulation, metabolic signaling, and stress-adaptive pathways. Importantly, we propose that DCIS progression is governed not by isolated molecular alterations but by coordinated programs that enable survival under genomic and immunologic stress. Current clinical risk assays, which primarily capture tumor-intrinsic proliferation and hormone signaling, do not fully resolve these pathways and may therefore incompletely reflect biologically meaningful racial disparities. This synthesis underscores the need for pathway-level, microenvironment-informed, and population-representative approaches to DCIS risk stratification. Advancing such frameworks will be essential for identifying actionable biomarkers, refining early intervention strategies, and ultimately reducing racial disparities in breast cancer outcomes.

Although ductal carcinoma in situ (DCIS) diagnoses continue to climb, patient management remains constrained by limitations in recurrence prediction. Conventional histopathology and existing prognostic parameters often inadequately predict local recurrence, leading to over- or under-treatment. Additionally, discourse remains over the clinical implications of margin width as a measure of recurrence risk, demonstrating the limitations of a margin-based model, and motivating our proposal that recurrence risk is dynamic and should be defined by patient-specific, spatially resolved diagnostic biomarkers. This review introduces field cancerization as a framework that may illuminate mechanisms underlying DCIS ipsilateral recurrence and improve clinical decision-making. We propose that the potential drivers of ductal field cancerization span two stages: pre-tumorigenesis and post-tumorigenesis. Pre-tumorigenic events include non-biological and biological exposome factors. Post-tumorigenic drivers include intratumoral and microenvironment-mediated remodeling of adjacent tissues that promote malignancy. This review bridges stage-specific molecular mechanisms to potentially actionable strategies for DCIS patient management—particularly margin assessment and recurrence risk prognostication—while highlighting the critical unmet need to identify biomarkers that measure high-risk field changes. We also emphasize the need to move beyond lesion-centric management toward multivariable prognostic models that include distance-mapped field biomarkers, enabling more precise surgery, improved selection of adjuvant therapy, and safer de-escalation for low-risk patients.