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Editorial |
University of Oklahoma Breast Institute, 920 S. L. Young Boulevard, Williams Pavilion, Suite 2290, Oklahoma City, Oklahoma 73104
Correspondence: Address correspondence and reprint requests to: William C. Dooley, MD; E-mail: william-dooley{at}ouhsc.edu.
A recent review of the National Cancer Data Base suggested that there might be a survival benefit to resection of the primary breast cancer in patients with established metastatic disease—i.e., stage IV. Removal of a primary lesion in breast cancer rarely leads to spontaneous response or remission, as it might in renal cell carcinoma. We all remember the few women who seem to have metastatic disease blossom immediately after primary excision in breast cancer. How could it be that excision of the primary cancer will improve survival? Babiera and the M. D. Anderson group1 have performed a detailed review of this issue over the last several years at their institution. Although this is not a prospective randomized trial, it offers some insight into potential explanations for this apparent paradox of a survival benefit from incomplete tumor removal.
First, their series was limited to patients who were, for at least some time, receiving effective systemic therapies. Major improvements have been made to the effectiveness of systemic therapies against breast cancer in the last two decades. Could it possibly be that the primary site is more likely to harbor or rapidly develop chemotherapy- and hormone-resistant cells than the metastases? It could be that when metastases are responding to systemic therapies, new metastases are being shed from these resistant islands within the primary tumor.2–4 This theory has proponents and support from animal studies, much as the proposed mechanism of restoration of immune competence does, as discussed in this article.
Second, this might be just a fluke because of bias regarding which patients undergo operation: those with a better prognosis are more likely to get their tumor resected. The authors did a fairly nice job of analyzing the data from differing angles to convince us that this is unlikely as an explanation. We all know, however, that many clinicians use difficult-to-itemize factors for referral bias. This potential bias could really be excluded only with a large prospective randomized trial in which performance status and tumor characteristics were closely reviewed and stratified.
Third, there might be a dependent relationship between the primary tumor and the metastases. In the face of effective systemic therapy, it is possible that the primary tumor confers some sort of humoral resistance not native to the metastases or that at least develops more slowly within the metastases themselves. Removal of the primary tumor, then, would leave the metastases newly vulnerable to treatment if they could not rapidly accumulate this resistance factor.
Whatever the mechanism, the finding of apparent improved survival of stage IV breast cancer with primary extirpation seems real, both in national and local data series. We have assumed that surgery establishes local control and that drugs establish systemic control if the tumor has already spread before surgery. We can now be relatively sure that the relationship is more complex. The timing of surgery in stage III disease before or after chemotherapy seemed not to affect overall survival. The median time to surgery for these stage IV patients was only 24 days. In other words, soon after or shortly before effective systemic therapy began, their primary tumor was removed. We desperately need to know whether there would be less of an effect if surgery occurred later, after more systemic therapy. If a high tumor burden is associated with a more rapid resistance to systemic therapies, we now have a huge array of tools to ablate metastatic sites to add to simple primary cancer excision. Many patients did have metastatic sites resected when, presumably, they were not responding quickly to systemic therapies.
To answer all of these burning biological and clinical questions, we need wide participation in a large prospective trial of surgical extirpation of stage IV breast cancer primary tumors at varying times after diagnosis. A careful analysis of pathologic changes between diagnostic biopsies and surgical resection may yet unlock important clues as to the relationship between primary tumors and metastases and, most importantly, give us insight into strategies to maximize benefit and limit morbidity to this group of patients with terminal breast cancer.
Received for publication October 20, 2005. Accepted for publication October 26, 2005.
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