Background Current therapeutic strategies that are used to combat breast cancer vary widely and largely depend on its clinicopathological features, including tumor subtype, size, stage, lymph node involvement, the presence of hormone receptors and/or HER2, as well as the degree of proliferative activity. Recent work has focused on improving our knowledge on the molecular mechanisms that underlie this complex disease. Most of the human genome is transcribed into RNAs that do not encode proteins. These noncoding RNAs may act as mediators in the regulation of gene expression. Based on their size and function, noncoding RNAs are classified into small noncoding RNAs (sncRNAs) and long noncoding RNAs (lncRNAs). LncRNAs have been found to play key roles in relevant biological processes, including breast cancer. As such, lncRNAs have been proposed as diagnostic and prognostic biomarkers, as predictive biomarkers and as putative therapeutic targets. Conclusions In this review, we discuss the potential application of lncRNAs for the monitoring and treatment of breast cancer. We conclude that lncRNAs play important roles in the pathophysiology of this disease and may serve as putative therapeutic targets. As such, tumor-specific lncRNAs may be instrumental for improving current breast cancer clinical practices.

Background: The ideal adjuvant treatment of triple negative EBC remains to be defined. CIBOMA/2004-01_GEICAM/2003-11 is a multinational randomized phase III trial exploring adjuvant Cap after the conclusion of conventional chemotherapy in triple-negative EBC patients. Materials and Methods: Patients with operable, node-positive (or node-negative with tumour diameter ≥1 cm), hormone receptor-negative, HER2-negative EBC that have received 6–8 cycles of standard anthracycline and/or taxane-containing chemotherapy in the (neo)adjuvant setting (doxorubicin–cyclophosphamide x 4 allowed for node-negative disease), followed by radiotherapy (if indicated) are eligible. After central confirmation of triple negativity by immunohistochemistry, patients were randomised to either 8 cycles of Cap (1,000 mg/m2 bid, d1–14 q21d) or observation. Stratification factors: centre, prior taxane (yes vs. no), involved nodes (0 vs. 1–3 vs. ≥4) and phenotype (basal vs. non-basal). The primary endpoint is disease-free survival (DFS). Secondary endpoints include 5-year DFS, overall survival and safety. An optional pharmacogenetic sub-study will explore polymorphisms of thymidylate synthase and methylenetetrahydrofolate reductase in relation to efficacy and tolerability of Cap. Present Status: Recruitment of 876 randomized patients was completed in September 2011. Statistical assumptions: expected 30% reduction in the risk of recurrence at 5 years (64.7% to 73.7%, HR 0.701), power of 80% and 0.05 two-sided significance level. Final efficacy analysis will be triggered by 255 events. Baseline characteristics are well balanced and shown in the table below. 75.0% of the patients completed the 8 cycles of adjuvant Cap. Baseline patients characteristics Capecitabine (n = 448)Observation (n = 428)Median Age, years (range)51 (20-79)50 (24-83)Basal Phenotype,%70.772.2Histology,%  Ductal87.786.1Lobular1.82.3Other9.811.4Unknown0.70.2Grade,%  13.32.8218.119.0371.969.6Not determinable6.08.4Unknown0.70.2Chemotherapy received,%  Adjuvant (only)78.982.2Neoadjuvant (only)15.615.0Adjuvant + Neoadjuvant4.22.6Unknown1.30.2Postmenopausal,%69.267.3Prior Chemotherapy Agents,%  Anthracyclines without taxanes32.132.2Anthracyclines and taxanes67.267.6Unknown0.70.2 Conclusions: This randomized phase III adjuvant trial in triple negative EBC patients has completed accrual and event follow up is ongoing. The trial is sponsored by CIBOMA/GEICAM. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-1-06.

INTRODUCTION. In response to neoadjuvant therapy, pathological complete response (pCR; lack of residual disease in breast and lymph nodes), has been proposed as a prognostic marker for long-term clinical outcomes, such as disease-free (DFS) and overall survival (OS), in human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancer. In clinical practice, recognizing those patients likely to achieve such responses proves challenging to the oncologist, making the identification of new useful biomarkers vital. Here, we searched for potential biomarkers that anticipate pCR to neoadjuvant therapy in HER2-positive, hormone receptor-negative breast cancer tissue samples. METHODS. Patients with early and locally advanced breast cancer, diagnose as HER2-positive, hormone receptor-negative by immunohistochemistry (IHC) at the time of neoadjuvant treatment were included. All samples were collected from biobank at Hospital Universitario Virgen del Rocio. We defined two groups: responder (R) and non-responder (nR) and analyzed 18 samples in the discovery cohort (10 R vs 8 nR) and 12 samples in the validation cohort (6 R vs 6 nR).The RNA for the study was extracted from tissue fixed in formaldehyde and paraffin embedded. The extraction of the RNA was carried out using the commercial kit RecoverAll Total Nucleic Acid Isolation Kit from Ambion (Applied Biosystems). RNA was quantified by Qubit RNA HS Assay Kit (Molecular Probes). Before hybridization, RNA for the discovery cohort was amplified using GeneChip WT Pico Kit (Applied Biosystems).We analyzed transcript expression using ClariomD array. Differential expression between the two groups was analyzed using in-house R scripts (version 3.5.1). Data were corrected and normalized using Robust Multi-array Average method. Expression was summarized at gene level using the corresponding annotation for ClariomD BrainArray. Gene validation was performed by qPCR using TaqMan Gene Expression Assay (Applied Biosystem). RESULTS. Considering a fold change ≥ 2 and an adjusted p-value <0.05 as statistically significant, we found 53 differentially expressed transcripts: 51 downregulated transcripts (lower expression in R) and 2 upregulated transcripts (higher expression in R). The RNA was annotated as non-coding RNAs in over 25% of the cases. The distribution of such molecules was as followed: 8 long non-coding RNAs (56%); 3 non-coding RNAs (22%) and 3 pseudo-genes (22%). Regarding protein coding transcripts, gene ontology analysis revealed an enrichment of terms associated to metabolic processes and response to toxic substance.As expected, ERBB2, which encodes for HER2, appeared at the top of the list with a patent upregulation of expression in the responder group when compared with non-responder patients. To validate the data, we used qPCR and ERBB2 expression as a positive control of the results (p-value=0.0380). Our data showed a significant downregulation of UDP-glucuronosyltransferase 2B15 (UGT2B15; p-value= 0.0173), which encodes a glycosyltransferase, involved in the metabolism and elimination of toxic compounds. CONCLUSIONS. The ability to predict which patients will benefit from neoadjuvant therapy and achieve a pCR would allow for improved patient stratification and more personalized medicine. Here, we identified a set of transcript differentially expressed (FC>2; adjusted p-value<0.05) in patients that achieve pCR (R) when compared with tissue samples with residual disease (nR). We usedERBB2 expression as a positive control to validate the data and show that UGT2B15 is consistently upregulated in non-responder patients. Further work is needed to elucidate UGT2B15 role, but it is worth mentioning that an increased rate of glucuronidation has been associated with a loss of potency for the target drugs. Citation Format: Ana Gil-Torralvo, Marta Benavent, Maria A Dominguez-Cejudo, Alejandro Falcon, Begoña Vieites, Sonia Molina-Pinela, Manuel Ruiz, Álvaro Montaño, Rosario Gónzalez, Julia Martínez, Juan de la Haba, Antonio Rodríguez, Maria I Queipo, Begoña Jímenez, Javier Salvador-Bofill. Identification of UGT2B15 as a potential biomarker in response to neoadjuvant therapy in HER2+ breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-07-08.