Genomic Instability And Telomere Characteristics As Predictive Biomarkers Of Therapeutic Response In Triple-Negative Breast Cancer

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background. Triple negative breast cancers (TNBC) represent about 15 % of invasive breast carcinomas. These tumors are identified in clinical practice according to their “triple negative” immunophenotype (estrogen receptor, progesterone receptor and HER2 negative). TNBC show aggressive behavior and an unusual sarcoma-like pattern of metastasis. Identification of predictive biomarkers is critical to optimal therapeutic management of these tumors. TNBC are characterized by increased genomic instability. These tumors present complex pattern of numerous low-amplitude genomic gains and losses as well as shorter telomeres. Aim. Identification of predictive biomarkers of response to neoadjuvant chemotherapy in TNBC by evaluating telomeric parameters and genomic instability. Methods. We studied 38 TNBC patients treated with neoadjuvant chemotherapy according to the TVA protocol (FEC 100, docetaxel, panitumumab). DNA and RNA were extracted from snap-frozen tumor samples obtained before neoadjuvant therapy. The pathological response to treatment was evaluated according to Chevallier's and Sataloff's classifications and correlated with aCGH profiles (8x60K, Agilent) and telomere characteristics, including telomere length (qPCR) and expression (qRT-PCR) of telomerase (hTERT) and shelterin complex genes (TRF1, TRF2, POT1, TPP1, RAP1 and TIN2). Results. Telomere shortening and high hTERT expression were found in more aggressive tumors according to TNM classification (P< 0.04), and hTERT expression was also highly correlated with an increased tumor size (P= 0.0058). Short telomeres were strongly associated with incomplete histological response to neoadjuvant therapy according to Chevallier's (P= 0.0004) and Sataloff's classifications, (P= 0.0007). hTERT expression was significantly increased in cases with incomplete response (P< 0.04). Among shelterin complex genes, TRF2 and TPP1 overexpression was found in more aggressive TNBC (according to TNM classification and SBR grading, P< 0.05), but there was no correlation with pathological response. aCGH data indicated that genomic instability in non-responders was mainly represented by genomic gains. In particular, cases with incomplete therapeutic responses showed significantly larger size of gains than cases with complete responses. (P= 0.0089). Short telomeres were also associated with larger gains of genomic material (P= 0.0067). Of note, telomere shortening has been previously described as one of the mechanisms of genomic gains and amplifications. Conclusions. Telomere shortening and hTERT overexpression were observed in resistant TNBC. Genomic profile of non-responding tumors was characterized by larger genomic gains. Telomere length, hTERT expression and genomic instability profiles may represent predictive biomarkers of response to neoadjuvant chemotherapy in TNBC. Citation Format: Mathilde Gay-bellile, Nina Radosevic-Robin, Eleonore Eymard-Pierre, Fabrice Kwiatkowski, Marie-Melanie Dauplat, Maud Privat, Catherine Abrial, Patricia Combes, Gwendoline Soler, Yves-Jean Bignon, Jean-Marc Nabholtz, Philippe Vago, Frederique Penault-Llorca, Andrei Tchirkov. Genomic instability and telomere characteristics as predictive biomarkers of therapeutic response in triple-negative breast cancer. [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 550. doi:10.1158/1538-7445.AM2014-550