Analysis of breast-cancer relapse patterns from two independent databases provides indirect evidence for the theory that surgery to remove the primary tumor may initiate formation of a new blood supply (angiogenesis) in formerly dormant metastases, accounting for a pattern of early relapse in younger women.
The study, published online by the International Journal of Surgery, analyzed data from 1,173 women in three clinical trials who had surgery for breast cancer, but no further treatment. The researchers found two relapse peaks: one at 18 months, and another 5 years. Closer analysis showed that 20 percent of premenopausal, node-positive patients (whose cancer had spread to the lymph nodes) relapsed within the first 10 months after removal of the primary tumor.
The researchers, led by Michael Retsky, PhD, an investigator in the Vascular Biology Program at Children's Hospital Boston, believe their observations may help to explain the so-called "mammography paradox" among women aged 40 to 49: a counterintuitive temporary excess in mortality for the screened population compared to controls. Calculations based on their data predict that surgery-induced angiogenesis would accelerate disease by a median of two years and produce 0.11 early deaths per 1000 screened young women in the third year of screening. The predicted timing, as well as the magnitude of excess mortality, agree with the actual trial data and relapse patterns.
Although the study did not look at biological mechanisms of relapse, primary tumors have been shown to secrete angiogenesis inhibitors, which naturally inhibit the growth of metastases, so surgery to remove the primary tumor might eliminate this inhibition. Alternatively, surgery might spur release of angiogenesis promoters through a wound-healing mechanism.
"Cancer outgrowth after surgery has been observed for over 100 years, and the mechanisms have not been fully identified," comments Retsky. "Our analysis suggests that biology may be the underlying cause, rather than something going wrong during surgery. It also suggests that while most young women benefit from early detection of breast cancer, a small percentage will relapse and die early of metastatic disease. The paper suggests remedial steps that might prevent the sudden growth from occurring.
"The results of this study could also be considered when designing treatment protocols for young women with positive nodes, since it may not be a coincidence that adjuvant chemotherapy works best for those patients," he adds. "Young women need to be advised of the risk of accelerated tumor growth and early relapse before giving informed consent for mammography."
Coauthors include Romano Demicheli, MD, PhD of Milan, Italy and William Hrushesky, MD of Colombia, SC.