Does surgery induce angiogenesis in breast cancer? Indirect evidence from relapse pattern and mammography paradox

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Abstract
A significant bimodal relapse hazard pattern has been observed in two independent databases for patients untreated with adjuvant chemotherapy. This implies there is more than one mode of relapse. The earliest and most closely grouped relapses occur 8-10 months after surgery for young women with node-positive disease. Analysis of these data using computer simulation suggested that surgery probably instigated angiogenesis in dormant distant disease in approximately 20% of cases for premenopausal node-positive patients. We explore if this could explain the mammography paradox for women aged 40-49: an unexplained temporary excess in mortality for the screened population compared to controls. Calculations based on our data predict 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 trial data. Surgery-induced angiogenesis could account for the mammography paradox for women aged 40-49 and the bimodal relapse hazard pattern. According to the proposed biology, removing tumors could remove the source of inhibitors of angiogenesis or growth factors could appear in response to surgical wounding. While this needs confirmation, this could be considered when designing treatment protocols particularly for young women with positive nodes. It reinforces the need for close coordination between surgical resection and ensuing medical intervention. Women need to be advised of risk of accelerated tumor growth and early relapse before giving informed consent for mammography.