The impact of tumor biology in selecting patients for adjuvant radiation therapy in breast cancer

It is a matter of fact that the proper patient selection is critical to the success of any kind of treatment. In breast cancer, guidelines for postoperative irradiation are based on risk factors known as prognostic for local control, such as tumour margins, size, grade, receptor status, histology, extensive intraductal component, lymph node statusand age. Other parameters, such as HER2 amplification, proliferation index, biological subtypes and systemic treatment are not still part of these guidelines. Their added value to conventional risk factors in predicting outcome is under investigation. High Ki-67 level, which is a nuclear marker of cell proliferation, is associated with worse survival, but it is also a risk factor for local recurrence. Other markers, such as p53, bcl-2, and cyclin D1, appear to be promising as predictive factors for local recurrence and survival in breast cancer. More recently, gene expression profiling studies using DNA microarrays have identified prognostic gene expression sets to predict outcome in breast cancer patients. These gene-expression signatures proved to be superior to clinicopathologic assessment in predicting distant metastases and overall survival. Recent data suggest that biologic subtypes also have an impact on locoregional recurrence. There are 4 major molecular subtypes of breast cancer identified by gene expression studies. In the clinical setting, these subtypes can be more conveniently approximated by immunohistochemical staining pattern for estrogen receptor-positive (ER+), progesterone receptor-positive (PR+), and human epidermal growth factor receptor 2-positive (HER-2+) expression. It implies that fenotype-based subtypes, although reliable surrogates, could not strictly correspond to the underlying genotype –based. The subtypes are luminal A (ER+ or PR+ and HER-2-negative), luminal B (ER+ or PR+ and HER-2+), HER-2 enriched (ER-and PR- and HER-2+) and basal like (ER- and PR- and HER-2). HER-2 and basal-like subtypes have poorer prognosis. Luminal B tumours, which express higher level of proliferation genes, have poorer outcomes than luminal A tumours. Currently there is a lack of relationship between TNM staging system and biological profiles. Effortshave to be done in integrating these informations in order to define new categories of risk, with the final goal to tailor the radiation therapy according this complex scenario, avoiding conflicting results. To date radiation therapy can be modulated better than in the past, both with respects the fractionation schedule (hypofractionation) or the amount of the treated volume (partial breast irradiation). This approach could also define patients with a so low risk for local failure to avoid adjuvant radiation therapy. In conclusion, there is a growing evidence in literature that molecular profiles can have a great impact also in locoregional management of breast cancer, but they need to be validated in datasets and confirmed in randomized trials.