Breast cancers today are of predominantly T1 ( ？cm) or T2 ( ？cm) categories due to early diagnosis. Molecular profiling using microarrays has led to the notion of breast cancer as a heterogeneous disease both clinically and molecularly. Given the prognostic power and clinical use of tumor size, the purpose of this study was to search for molecular signatures characterizing clinical T1 and T2. In total 46 samples were included in the discovery dataset. After adjusting for hormone receptor status, lymph node status, grade, and tumor subclass 441 genes were differently expressed between T1 and T2 tumors. Focal adhesion and extracellular matrix receptor interaction were upregulated in the smaller tumors while p38MAPK signaling and immune-related pathways were more dominant in the larger tumors. The T-size signature was then tested on a validation set of 947 breast tumor samples. Using the T-size expression signatures instead of tumor size leads to a significant difference in risk for distant metastases ( ). If further confirmed, this molecular signature can be used to select patients with tumor category T1 who may need more aggressive treatment and patients with tumor category T2 who may have less benefit from it. 1. Introduction Breast cancer is by far the most frequent cancer among women, and ranks second overall [1]. Guidelines for breast cancer treatment are based upon classical clinicopathological parameters: age, tumor size, grade, lymph node status, and histological type; in addition to hormone receptor status [2]. Lymph node (N) status is the most powerful single indicator of breast cancer prognosis [3], while tumor size, categorized into four groups (T1–4) is the second strongest indicator and is independent of lymph node status [3]. Here we attempted to identify the molecular background behind this prognostic effect of tumor size. Mammographic screening has led to breast cancer diagnosis at preclinical stage and, as a consequence, most diagnosed cases present as T1 or T2, with significantly better survival in T1 tumors [4]. Nevertheless, T1 tumors may also give recurrence or metastases. Chemotherapy and hormonal treatment reduce the risk of recurrence or distant metastases by approximately 30% and according to the current guidelines whether a tumor is T1 or T2 is a critical factor in treatment decision. However, 70–80% of patients would have survived without adjuvant treatment [5]. How to distinguish the patients that would benefit from adjuvant treatment would therefore be of great value to the patient preventing possible severe side effects, and
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