A molecular marker found in the tissue surrounding breast tumors could help identify patients at risk of lymph node metastasis, potentially supporting more personalized decisions about breast cancer surgery.
In a study published in npj Precision Oncology, researchers found that expression of vascular endothelial growth factor C (VEGF-C) in stromal cells was associated with lymph node involvement, independently of established clinical and pathological risk factors. Notably, VEGF-C expression in the cancer cells themselves provided no additional predictive value.
The findings highlight how the tumor microenvironment, rather than tumor cells alone, may provide clinically useful information about cancer progression.
Looking beyond the tumor cells
Determining whether breast cancer has spread to nearby lymph nodes remains important for treatment planning. Sentinel lymph node biopsy (SLNB) is routinely used to assess nodal involvement, but even this relatively minimally invasive procedure carries risks, including lymphedema, pain, and restricted arm mobility.
Recent clinical trials have demonstrated that selected patients with early-stage breast cancer can safely avoid SLNB. However, identifying patients who are unlikely to harbor lymph node metastases remains a challenge.
To investigate whether VEGF-C could improve risk assessment, researchers analyzed primary breast tumor samples from a prospectively enrolled patient cohort. They examined the protein’s expression separately in cancer cells and surrounding stromal cells, which include immune cells, fibroblasts, and endothelial cells.
Using immunohistochemistry alongside an automated digital pathology pipeline, the team found that higher stromal VEGF-C expression was consistently associated with lymph node metastasis. The association remained significant after accounting for established predictors, including tumor size and vascular invasion.
In contrast, VEGF-C expression in malignant cells showed little relationship with nodal status.
A potential addition to breast cancer risk models
VEGF-C promotes the formation of lymphatic vessels, which can provide routes for cancer cells to spread. Previous research has implicated VEGF-C-producing tumor-associated macrophages in this process, suggesting that the protein’s cellular source may be critical to its biological activity.
The researchers incorporated stromal VEGF-C measurements into a modified version of an existing lymph node prediction model. Although the improvement in overall predictive accuracy was modest, VEGF-C provided potentially useful information when vascular invasion was unavailable.
This distinction could be clinically relevant because vascular invasion, an established predictor of lymph node involvement, is difficult to assess reliably in diagnostic core needle biopsies.
The automated image analysis approach also produced results comparable to manual assessment, suggesting a possible route toward more standardized biomarker evaluation.
Toward more personalized surgical decisions
Despite its promise, stromal VEGF-C is not yet ready to guide clinical decisions. The biomarker was assessed retrospectively in archived tumor specimens, and its predictive performance still needs validation in independent cohorts and preoperative biopsy samples.
The researchers emphasize that “stromal VEGF-C should be considered complementary to, rather than a replacement for, established pathological predictors.”
Whether incorporating the marker into risk models would meaningfully change surgical decisions or improve patient outcomes remains to be established.
