Breast Cancer Tumor Size, Nodal Status, and Prognosis: Biology Trumps Anatomy

In the articles that accompany this editorial, Wo et al and Hernandez-Aya et al present two provocative clinical findings with respect to the relationship of tumor size and lymph node status to clinical outcome. Together, these articles highlight the less than perfect connection between a tumor size and its ability to colonize lymph nodes and distant organs. The first article, by Wo et al, reports that in cases of extensive lymph node involvement, very small tumors may confer a more aggressive subtype than larger tumors with the same degree of lymph node involvement. The second article, by HernandezAya et al, proposes that in triple-negative breast cancers, the worse prognosis associated with lymph node involvement may not be greatly affected by the absolute number of positive lymph nodes. Wo et al were motivated to conduct their study because of their hypothesis that very small tumors that generate extensive lymph node involvement may represent a unique subset of highly malignant breast cancers. To evaluate this idea, they used the Surveillance, Epidemiology, and End Results registry to identify 50,949 women who were diagnosed with nonmetastatic T1 and T2 invasive breast cancers and were treated with surgery and axillary lymph node dissection. In support of their hypothesis, among women who had four or more involved lymph nodes (N2), those women with smaller tumors (T1a) had a higher breast cancer–specific mortality (BCSM) than those with larger tumors (T1b). This difference was not seen in patients with fewer or no lymph nodes involved. Notably, among patients with estrogen receptor–negative cancer and four or more involved lymph nodes, patients with T1b tumors experienced significantly lower BCSM relative to patients with T1a tumors. On the contrary, no significant difference was noted among patients with T1a tumors relative to patients with T1c or T2 tumors. That is, the authors demonstrate that for very small tumors with extensive lymph node involvement, there is a decreasing BCSM as the tumors get larger. After a set threshold (Figure 2 in the article by Wo et al), however, BCSM increases as one would expect, with increasing tumor size conferring increased mortality. In another retrospective study, Hernandez-Aya et al investigated the prognostic relationship between tumor size and lymph node status in 1,711 women with triple-negative breast cancer. Their work indicates that in triple-negative breast cancers, any amount of nodal involvement denotes a worse relapse-free and overall survival. Essentially, once lymph nodes are involved, outcomes are not greatly affected by the absolute number of positive lymph nodes. In addition, when the authors compared node-negative to node-positive disease for all tumor sizes and all degrees of positive nodal involvement, there was a significant difference in outcomes. Unlike in the Wo et al study, Hernandez-Aya et al categorized patients according to T1, T2, and T3/T4, and did not additionally subcategorize the T1 tumors. Thus, it is not clear whether additional subset analysis would show that T1a tumors do particularly worse than T1b orT1c tumors. Why are these results surprising or, at least, deserving of being reported in this journal? The obvious answer is that they do not jibe with accepted—and profoundly influential—notions of malignant progression. From the beginning of our understanding of cancer as a disease of abnormal cellular growth, we have thought of malignant cellular expansion and metastases as a sequential process. By this concept, the initial defect in carcinogenesis is derangement in mitosis (or, later, the mitosis-apoptosis ratio), such that cancer cells accumulate as an abnormally large mass. With increasing cell accumulation and resulting additional changes in cell biology—now accepted as the consequence of genomic aberrancies—cells would be expected to acquire the ability to migrate, via blood and/or lymphatic channels, infiltrate organs other than their organ of origin, and proliferate in these sites as microscopic and then gross metastases. The fact that large breast cancers are more likely to be associated with axillary nodal metastases, and consequently distant metastases as well, has always been advanced as consistent with and, in fact, proof of this fundamental concept. Indeed, the push to diagnose breast cancers as early as possible after spontaneous tumor initiation, such as with mammography and now magnetic resonance imaging in selected cases, has been motivated by the idea that if a tumor can be removed before it learns metastatic behavior, distant metastases might be avoided. Hence, the success of breast screening programs to reduce mortality from this disease was the expected result and additionally increased our confidence in the malignant progression dogma. But nagging enigmas in breast cancer behavior have always added a tinge of uncertainty. One of the most disturbing is the fact that metastatic pathways seem to be predictable and unpredictable at the same time. Modern data on sentinel lymph node mapping seems to support the principle, popularized by Halsted in the nineteenth century, that the flow of cells from the breast tumor to the axilla is orderly: if the first nodes that receive lymphatic flow are free of cancer cells, it is almost certain that the rest of the axilla will be clean. However, JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L S