This study of the natural history of human breast cancer was based on the analysis of a series of 3000 patients treated by radical mastectomy at a single institution (Institut Gustave Roussy) at a time when adjuvant chemotherapy was not prescribed. The follow-up of the patients ranged from 15 to 30 years; for each patient the tumor size, the number of involved axillary nodes, and the histological grade were prospectively registered. A highly significant correlation was found between tumor size and the probability of distant metastatic dissemination. The distribution of tumor sizes at metastatic spread was log-normal with a median diameter equal to 3.5 cm. The patients were subdivided into 3 groups according to the histological grade. In each subgroup there was a significant correlation between tumor size and the probability of distant spread; the distributions were log-normal and the median size was markedly larger for grade 1 tumors. Moreover the proportion of grade 1 tumors was higher in small tumors than in large ones while the reverse was observed for grade 3 tumors; these data suggest that during their growth tumors progress towards higher grades. One of the chief fundamental characteristics of a tumor seems to be its propensity for axillary node invasion. The orderly pattern of nodal involvement makes it possible to calculate the tumor size at invasion of the first axillary node in each subset of patients. A strong and highly significant correlation exists between the size of the tumor at initiation of distant metastasis and at invasion of the first lymph node. However the capacity for lymphatic spread is, on average, acquired much earlier than the capacity for metastatic spread. With a simple model based on these data it was possible to compute the proportion of patients with occult metastases as a function of tumor size, histological grade, and number of involved axillary nodes. Early invasion of axillary nodes is associated with a rapid growth rate of the primary tumor (or a high S-phase fraction). However each of these variables has an independent prognostic significance; the S-phase fraction appears as one of the strongest prognostic indicators. A model of tumor growth was used to assess the impact of screening procedures on the proportion of patients with distant metastases. The predictions of the model are consistent with the results of the screening programs. The model was used to predict the influence of the interval between mammographies on the proportion of patients with distant metastases and on the size of these metastases. Since the curability of distant metastases by adjuvant chemotherapy is, to a large extent, governed by their size, the model can predict the cumulative effect of screening procedures and adjuvant chemotherapy on the proportion of patients with overt distant metastases.
