Analysis of gene expression and methylation data for the identification of novel biomarkers in breast cancer

Context: Breast cancer treatment has experienced several changes in the last decades due to the innovation of specific prognostic and predictive biomarkers that facilitate the application of more personalized therapies to different molecular sub-groups. Presently, more women are be- ing treated with neoadjuvant (preoperative) therapy which involves chemotherapy or endocrine agents before surgery, for earlier-stage operable breast carcinoma. Following this mode of pre- operative systemic treatment could improve the surgical option and make inoperable tumors operable. It can also increase the breast conservation rate. Another key benefit of neoadjuvant therapy is monitoring response to the treatment. The good response to neoadjuvant therapy with complete pathological response (pCR) is a surrogate marker for overall survival.

Objective: 1) To investigate the association between early changes in several gene expression signatures, recapitulating several biological processes, and neoadjuvant letrozole (endocrine therapy), and to compare those to Ki67 values. 2) To interrogate the association between chemotherapy response (Pathological complete response (pCR) in this case) and gene expres- sion modules, recapitulating important biological processes such as the gene expression grade index (GGI) and ”druggable”oncogenic pathways in different breast cancer subtypes.

Data Sources: We collected publicly available gene expression data based on the review of selected literature on breast carcinoma after neoadjuvant therapy with the clinical and patho- logic characteristics.

Results: In this work we have shown, 1) Residual proliferation after short-term endocrine therapy can be used as an early surrogate marker of clinical to response to endocrine therapy in this population. 2) Different processes and pathways are associated with pCR in different BC subtypes.

Conclusions: Our analysis has several limitations such as: 1) Lacks of statistical power due to small dataset for endocrine treated patients, 2) We have included only anthracycline-based neoadjuvant chemotherapy regimens; therefore, it is not known if the associations between gene modules and pCR are anthracycline specific or indicate general chemosensitivity. More- over, patients with HER2-positive tumors did not receive preoperative trastuzumab, and it is not known how this could modulate the identified associations. But our results generate sev- eral hypotheses that should be tested in BC subtype - focused trials of targeted agents like IGF1, PARP inhibitors, and agents modulating immune response. If results are confirmed by additional validation studies, this may lead to a paradigm shift in early breast cancer treatment.