We thank Dr. Evans for his interest in our report.1 Dr. Evans suggests that randomized prospective trials have shown definitively that development of ipsilateral breast tumor recurrence (IBTR) is a marker of risk for (and not a cause for) distant metastasis. We believe that, based on the results of existing trials, the question remains unanswered. Randomized trials have shown that radiotherapy significantly decreases IBTR after breast-conserving surgery;2–5 however, most of those studies were designed to evaluate the effect of radiation on the rate of IBTR as the primary endpoint and, thus, were not statistically powered to address the survival question. Although, in the Swedish trial, the decrease in IBTR did not translate into a decrease in distant metastases in the radiation therapy arm, in the Scottish trial, there was a trend toward fewer distant metastases in the irradiated group.4, 5 Furthermore, in the Ontario Clinical Oncology Group trial, a statistically significant increase in the relative risk for distant recurrence among patients who did not receive radiotherapy was observed (relative risk, 1.4; 95% confidence interval, 1.07–1.8; P = 0.01).3 However, the Ontario study also was not designed specifically to determine the effect of radiotherapy on distant metastases. Therefore, we cannot exclude the possibility that this result is biased due to the precipitation of screening for distant metastases by IBTRs. Finally, the Milan trial noted a poorer 10-year overall survival in patients with positive lymph nodes who were randomized to undergo quadrantectomy alone compared with quadrantectomy plus breast irradiation (34.1% vs. 19.3%, respectively; P = 0.038).6 The increase in deaths likely was due to the higher rate of locoregional recurrence in the group that did not receive radiation.
Biologically, it would be difficult to argue that malignant cells in the primary tumor can metastasize and that malignant cells in the recurrent tumor cannot. Metastases arise from the spread of malignant cells from the primary tumor site and the formation of new tumors in distant sites. The metastatic process consists of series of steps that need to be completed successfully. First, the malignant cells at the primary site need to develop access to the circulation, either through the circulatory blood system or through the lymphatic system. Then, the malignant cells need to survive in the circulation. Next, the circulating cells need to arrest in a new organ and extravasate into the new tissue. Finally, the cells need to initiate growth in the new tissue and eventually establish vascularization to sustain the new tumor. Although the metastatic process overall is quite complex, none of the individual steps appear to be unique for primary tumors, and it appears that a locally recurrent tumor also should be vulnerable to these steps. We agree that IBTR, by definition, is local persistence of a tumor. In patients who have received radiation, it is possible to speculate that, through clonal selection, these tumor cells may have accumulated further genetic alterations conferring radiation-resistance. Many oncogenes that confer a survival advantage also facilitate one or more steps in the metastatic process. Although the theory that the host can defend against circulating cells until a certain primary tumor burden is reached is interesting, it may be argued that the tumor already has escaped host defense mechanisms by recurring. Further study is needed to define the molecular alterations in primary tumors and local recurrences. However, based on our current understanding of biologic principles, it is predictable that an IBTR would have a more aggressive phenotype with a metastatic advantage.
Most studies to date have reported that IBTR after breast conservation is associated with an increased risk of distant metastases and poorer survival.7–11 Although it is very likely that patients at higher risk of systemic recurrence also are at risk for IBTR, the data are not sufficient to exclude the possibility that a portion of patients who initially are rendered free of distant disease subsequently develop an IBTR and develop a subsequent distant metastasis from the IBTR. The importance of negative surgical margins for local tumor control and survival has been documented repeatedly for several other tumor types, including sarcoma, pancreatic cancer, and rectal cancer.12–16 Because that is the case, we strongly believe that the ‘conservative’ strategy is to be aggressive about local control in breast cancer therapy.