Linking survival of HER2-positive breast carcinoma patients with surgical invasiveness

Abstract

The early peak of relapse in patients with breast carcinomas that overexpress HER2 oncoprotein and dissemination to the axillary lymph nodes might be related to proliferation of micrometastatic lesions induced by EGF family growth factors released at the time of surgery. If the levels of these growth factors have an impact on relapse, the survival of patients with positive nodes and HER2-positive tumours should be dependent on surgery wideness. To test this hypothesis, HER2 status of primary tumours from patients included in a randomized clinical trial addressing conservative quadrantectomy versus radical mastectomy was retrospectively analyzed. In HER2-negative patients, independently of node infiltration, and in HER2-positive patients without node infiltration, no differences in survival according to the type of surgery were observed. In patients with positive nodes and HER2-positive tumours the estimation of the time-dependent log-hazard ratios showed that radical mastectomy significantly increased early death rates (P = 0.037).

Introduction

Amplification and overexpression of the HER2 oncogene, encoding a transmembrane tyrosine kinase receptor of the epidermal growth factor (EGF) receptor family, has been identified in about 25% of breast carcinomas.¹ Several data2, 3, 4 have shown that HER2-positive breast carcinomas represent a particularly aggressive tumour subset with increased proliferation and metastatic potential. While there is no consensus on the prognostic value of HER2 amplification/overexpression in node-negative cases, its value in node-positive patients has been widely demonstrated.5, 6, 7, 8 Patients with breast carcinomas that overexpress HER2 oncogene and disseminate to the axillary lymph nodes display an early peak of relapse in the first years after surgery.² A simple increase in the proliferation potential of HER2-positive tumours does not satisfactorily explain the poor prognosis associated with HER2 positivity in node-positive patients and certainly cannot explain the confinement of the poor prognosis in HER2-positive/node-positive patients to the first 3–4 years after surgery. It could be possible that processes triggered by surgery itself stimulate recurrence. Some data point to the role of growth factors released during healing after surgery in preferentially stimulating HER2-positive micrometastatic lesions, which are more likely to be present in node-positive patients. Indeed, we found that growth factors of the EGF family, released during the wound healing process, stimulate the growth of HER2-positive carcinomas.⁹ These factors are released by degranulation of platelets during blood coagulation, and their serum levels correlate with the invasiveness of surgery, measured as levels of creatine phosphokinase.⁹ We reasoned that if the levels of growth factors released at surgery have an impact on early relapse, then survival of patients with node-positive and HER2-positive tumours should be poorer after mastectomy than after the less invasive quadrantectomy. However, no differences are expected in node-negative cases due to the low probability of disseminated micrometastatic foci that might be stimulated by surgically-induced growth factors. This hypothesis was tested on archival material from the Milano 1 randomized clinical trial that compared Halsted radical mastectomy with quadrantectomy, axillary dissection, and radiotherapy in patients with small cancers of the breast.