Abstract 859: Regulation of cell cycle and NAD biosynthesis II pathways are associated with differential response to preoperative radiotherapy in locally advanced breast carcinoma

Abstract

Abstract Human breast carcinomas have heterogeneous pathologies, molecular profiles and different responses to therapy. For non-inflammatory locally-advanced breast cancer patients (LABC), preoperative radiotherapy (pRT) is currently indicated after neoadjuvant chemoherapy (CHT), if there is no response to CHT. However, there are no predictive markers of response to pRT in routine clinical practice. Furthermore, understanding of the molecular mechanisms associated to radiotherapy response could open new avenues for overcoming radio-resistance in these patients. In this retrospective study, we have analyzed genes associated with different response to pRT in a neo-adjuvant setting in LABC patients treated with preoperative RT with a total dose of 45 Gy in 15 fractions every second day to the breast and regional lymph nodes, without previous or concomitant systemic therapy. Radical mastectomy was performed 6 weeks after pRT, and adjuvant systemic therapy was administered as per protocol. Response to pRT was classified as pathological complete response (pCR) if there is no evidence of tumor in the breast after mastectomy, partial response (PR) if regression of tumor was >30%, and no response if regression was <30%. We have analyzed global gene expression profiles by Agilent 8x60K microarray platform in a set of 14 samples of formalin-fixed paraffin-embedded (FFPE) initial LABC biopsies. Unsupervised clustering analysis (Pearson correlation, un-centered metrics) over top 20% most variable genes revealed clear differences in the gene expression profile between radio-resistant and radio-sensitive tumors, despite the small sample size. We have found 165 genes significantly differentially expressed (FDR < 0.10) between responders and non-responders to pRT. To explain the biological processes and signaling pathways of radioresistance, a gene set enrichment using Ingenuity Pathways Analysis was applied. Top scoring molecular functions associated with this gene list included regulation of cellular development, cellular growth and proliferation and cell cycle. Not surprisingly, the most significantly enriched canonical pathways (Fisher's exact p-value<0.05) within the gene list of significantly differentially expressed genes between RT resistant and RT sensitive tumors were cell cycle control of chromosomal replication and pathways related to glucose metabolism and NAD biosynthesis II route. These results set basis for further understanding of molecular response to radiotherapy and highlight genes potentially useful as predictive markers of response to preoperative radiation treatment. Further confirmatory research of potentially RT sensitive/resistant genes and pathways is warranted. Citation Format: Miljana Tanic, Ana Krivokuca, Jasmina Mladenovic, Snezana Susnjar, Sinisa Radulovic, Radmila Jankovic. Regulation of cell cycle and NAD biosynthesis II pathways are associated with differential response to preoperative radiotherapy in locally advanced breast carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 859. doi:10.1158/1538-7445.AM2014-859