Angiogenesis as a Predictor of Long-term Survival for Patients With Node-Negative Breast Cancer

BACKGROUND Angiogenesis (the formation of new blood vessels) is necessary for tumor growth and metastasis. PURPOSE We investigated whether angiogenesis as measured by microvessel count (MVC) predicts clinical outcome in a series of patients with axillary lymph node-negative breast cancer who received no adjuvant therapy and who were followed for a long period of time. Our long-term goal is to identify those patients who may or may not need adjuvant chemotherapy. METHODS Pathologic archival material and clinical information were analyzed for 167 patients treated with mastectomy from 1941 through 1987; none received adjuvant treatment. The median follow-up time among living patients was 15.4 years (range, 2.6-35.8 years). Ninety-six (58%) patients had a tumor size of 2 cm or less, 52 (31%) had tumors of 2.1-3 cm, and 19 (11%) had tumors of larger than 3 cm. Paraffin-embedded tissue sections were stained for expression of CD34 antigen on microvessel-associated endothelial cells by use of a monoclonal anti-CD34 antibody. Vascularity was defined as the number of microvessels (average of the three highest counts) per high-power microscopic field (400 x magnification) in the area of highest vascular density. A high vascular count was defined as 15 or more microvessels per field. Actuarial survival curves were calculated according to the Kaplan-Meier method and comparisons were made with the logrank test. The Cox proportional hazards model was used for multivariate analysis. All P values were based on two-sided testing. RESULTS The 20-year disease-free survival (DFS) for the 167 node-negative patients treated with mastectomy and no adjuvant therapy was 74.8% (95% confidence interval [CI] = 64.7%-82.0%). The 20-year DFS was 93.1% (95% CI = 79.9%-97.7%) if the MVC was low versus 68.9% (95% CI = 56.8%-78.0%) if the MVC was high (P = .018). This difference was maintained irrespective of tumor size: for tumor size of 2 cm or less (93.3% [95% CI = 75.3%-98.3%] versus versus 67.8% [95% CI = 50.1%-80.3%]) and for tumor size of larger than 2 cm (92.3% [95% CI = 56.6%-98.9%] versus 70.9% [95% CI = 54.6%-81.6%]). However, the likelihood of a high MVC was greater with large tumors (P = .05). The proportions of tumors with low and high MVC were 33% and 67%, respectively, if the tumor size was 2 cm or less, and 20% and 80%, respectively, if tumor size was larger than 2 cm. There was no significant difference in the 20-year DFS as a function of tumor grade (P = .2). After combining patients with tumors of nuclear grades 2 and 3 compared with those of nuclear grade 1, the 20-year DFS was 93.9% (95% CI = 77.2%-98.4%) for low MVC versus 66.9% (95% CI = 52.2%-78.0%) for high MVC (P = .02). In a multivariate analysis that included the variables tumor size, age, nuclear grade, estrogen receptor status, and MVC, only MVC appeared to be an independent prognostic indicator (P = .04). CONCLUSIONS Angiogenesis as measured by MVC is a reliable independent prognostic marker of long-term survival in patients with node-negative breast cancer. The prognostic usefulness of this marker is maintained after more than 15 years of follow-up. A low MVC identifies a subgroup of patients with DFS of 92% or more, independent of tumor size or grade.