Role of HER2 in local relapse and metastasis

HER2-positive breast carcinomas have been shown to display an early peak of relapses in the first 4 years after surgery, especially in the node-positive subgroup. To explain this observation, growth factors released at the time of surgery were investigated. The level of growth factors of the EGF family, detected in postsurgical sera from breast carcinoma patients, was found to correlate with surgical invasiveness. Indeed, following radical mastectomy, higher levels of serum EGF-like factors were found than after conservative surgery. This implicates that the growth of tumors overexpressing HER2, activated by these growth factors, should be stimulated after invasive surgery. Two retrospective analyses of the HER2 status of primary tumors included in a randomized clinical trial addressing the issue of conservative versus invasive surgery and of radiotherapy were performed by immunohistochemistry using the standardized herceptest. Survival analysis according to surgery indicated no differences in HER2-negative cases but indicated a poorer survival for HER2-positive node-positive patients who had mastectomy in comparison with those who had conservative surgery. Furthermore, local relapses in patients who had conservative surgery without radiotherapy were found to be anticipated in the HER2-positive subset. This is a 'proof of principle' that surgery by inducing growth factor release may be detrimental for patients with HER2-positive tumors. To verify these findings, a prospective analysis of the follow-up of more than 2000 patients who have had mastectomy or conservative surgery is ongoing. Preliminary data indicate a significantly worst prognosis of HER2-positive tumors after invasive surgery, above all for tumors scoring 2+ by immunohistochemistry.