ANGIOGENESIS AS A PREDICTOR OF LONG-TERM SURVIVAL FOR PATIENTS WITH NODE-NEGATIVE BREAST-CANCER

Background: Angiogenesis (the formation of new blood vessels) is neces sary 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 bre ast cancer who received no adjuvant therapy and who were followed for a long period of time. Our long-term goal is to identify those patient s who may or may not need adjuvant chemotherapy. Methods: Pathologic a rchival material and clinical information were analyzed for 167 patien ts treated with mastectomy from 1941 through 1987; none received adjuv ant 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%) h ad tumors of larger than 3 cm. Paraffin-embedded tissue sections were stained for expression of CD34 antigen on microvessel-associated endot helial cells by use of a monoclonal anti-CD34 antibody. Vascularity wa s defined as the number of microvessels (average of the three highest counts) per high-power microscopic field (400x magnification) in the a rea of highest vascular density. A high vascular count mas defined as 15 or more microvessels per field. Actuarial survival curves were calc ulated according to the Kaplan-Meier method and comparisons mere made with the logrank test. The Cox proportional hazards model was used for multivariate analysis. All P values were based on two-sided testing R esults: The 20-year disease-free survival (DFS) for the 167 node-negat ive 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 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 grea ter with large tumors (P =.05). The proportions of tumors with low and high MVC were 33% and 67%, respectively, if the tumor size mas 2 cm o r 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 funct ion of tumor grade (P =.2). After combining patients with tumors of nu clear grades 2 and 3 compared with those of nuclear grade 1, the 20-ye ar 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 th at included the variables tumor size, age, nuclear grade, estrogen rec eptor status, and MVC, only MVC appeared to be an independent prognost ic indicator (P =.04). Conclusions: Angiogenesis as measured by MVC is a reliable independent prognostic marker of long-term survival in pat ients with node-negative breast cancer. The prognostic usefulness of t his 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, indepen dent of tumor size or grade.