Early breast cancer: How targeted therapy, genetics and personal genomics may improve local outcomes

Background: Advances in molecular oncology and genetics start to impact surgical practice in breast cancer. Despite compliance to current guidelines for breast-conserving surgery (BCS) in early breast cancer and multimodal treatment, a subgroup of patients develops ipsilateral breast cancer (IBC) recurrence and/or contralateral breast cancer (CBC). Objective: To identify the high-risk patients for local failure (IBC/ CBC) based on genetics and genomics, to assess the impact of chemoradiotherapy and targeted therapy on IBC/CBC risk and to find out who patients might benefit from aggressive surgery like bilateral mastectomy (BM). Method: All published (1995 - 2009) data on these topics were obtained from PubMed. Results: With emphasis on long-term follow-up results after breast-conserving multimodal treatment, the rate of IBC/CBC as isolated event without any evidence of distant metastasis was substiantial in a specific subgroup. Preclinical and clinical data reveal that at highest risk of IBC/CBC are patients with inherited BRCA1/2 mutations. Particularly these patients with BRCA1/2-causing cancer may benefit from bilateral mastectomy rather than BCS. For the vast majority of patients who are those with familial non-BRCA1/ 2 (BRCA-test negative) or sporadic breast cancer, local failure risk prediction is currently unfeasible. It appears that trastuzumab in HER2-positive patients reduces IBC/CBC rates but longer follow-up data are required for definitive conclusions. Extensive genetic studies including sequencing techniques and more currently genome-wide-association (GWA) studies have already identified novel risk alleles with a series of tumor-initiating single-nucleotide polymorphisms (SNPs). However, although the genetic catalogue with genetic alterations contributing to breast carcinogenesis is nearly to be completed, next challenges include the understanding of genes functional role and the prediction of biologic networks outcomes. Conclusions: Genetic testing in patients with family history guides now decision-making between BCS and BM. In patients with (BRCA mutation testing positive, BM should be considered and discussed with the individual patient. Rapid technological advances provide promises for accurate identification of high-risk patients but multiple challenges should be overcome to predict IBC/CBC risk among familial non-BRCA or sporadic breast cancer and application of bilateral mastectomy.