Triple-negative breast cancer (TNBC) is associated with an elevated risk of recurrence and poor prognosis. Historically, only chemotherapy was available as systemic treatment, but immunotherapy and targeted therapies currently offer prolonged benefits. TNBC is a group of diseases with heterogeneous treatment sensitivity, and resistance is inevitable and early for a large proportion of the intrinsic subtypes. Although senescence induction by anticancer therapy offers an immediate favorable clinical outcome once the rate of tumor progression reduces, these cells are commonly dysfunctional and metabolically active, culminating in treatment-resistant repopulation associated with worse prognosis. This heterogeneous response can also occur without therapeutic pressure in response to damage or oncogenic stress, playing a relevant role in the carcinogenesis. Remarkably, there is preclinical and exploratory clinical evidence to support a relevant role of senescence in treatment resistance. Therefore, targeting senescent cells has been a scientific effort in many malignant tumors using a variety of targets and strategies, including increasing proapoptotic and decreasing antiapoptotic stimuli. Despite promising results, there are some challenges to applying this technology, including the best schedule of combination, assessment of senescence, specific vulnerabilities, and the best clinical scenarios. This review provides an overview of senescence in TNBC with a focus on future-proofing senotherapy strategies.

Real-world assessment of the effect of impact of tumor size on pathological complete response rates in triple negative breast cancer after neoadjuvant chemotherapy Bruno Henrique Rala de Paula, Sanjeev Kumar, Fabiola Marques Morosini, Debora Evelyn Martins Calábria Cardoso, Carlos Augusto Moreira de Sousa, Susanne Crocamo

Breast cancer is a heterogeneous disease with distinct clinical and molecular characteristics. Scientific advances in molecular subtype differentiation support the understanding of cellular signaling, crosstalk, proliferation, survival, migration, and invasion mechanisms, allowing the development of new molecular drug targets. The breast cancer subtype with super expression and/or amplification of human growth factor receptor 2 (HER2) is clinically aggressive, but prognosis significantly shifted with the advent of anti-HER2 targeted therapy. Zoledronic-acid (ZOL) combined with a neoadjuvant Trastuzumab-containing chemotherapy regimen (Doxorubicin, Cyclophosphamide followed by Docetaxel, Trastuzumab) increased the pCR rate in a RH-positive/ HER2-positive subgroup, according to the phase II Zo-NAnTax trial. To verify genes that could be related to this response, a microarray assay was performed finding 164 differentially expressed genes. Silico analysis of these genes showed signaling pathways related to growth factors, apoptosis, invasion, and metabolism, as well as differentially expressed genes related to estrogen response. In addition, the RAC3 gene was found to interact with the MVD gene, a member of the mevalonate pathway. Taken together, these results indicate that RH-positive/ HER2-positive patients present gene alterations before treatment, and these could be related to the improvement of pCR.

To evaluate the association of sociodemographic, clinical, and pathological factors with response and survival in triple negative breast cancer (TNBC) undergoing neoadjuvant chemotherapy (NACT). Clinical-pathological and sociodemographic data were obtained from medical records of 235 eligible women with TNBC diagnosed between 2010 and 2014 undergoing NACT and surgery at the Brazilian National Cancer Institute. They have been assessed for pathological complete response (pCR), event-free survival (EFS), and overall survival (OS). Both univariate and multivariate Cox regression analyses were performed. The median follow-up was 64.3 months. Most patients had advanced clinical stage (III: 85.1%; cT3/T4: 86.4%; cN1-3: 74.4%) and high-grade tumors (72.1%). Clinical staging (III vs II, adjusted hazard ratio [HR] = 2.95, P = .012) significantly influenced the pCR rate. Alcohol intake negatively influenced EFS (adjusted HR = 1.67, P = .006) and OS (adjusted HR = 1.89, P = .005). Women with pCR showed better EFS (crude HR = 0.15, P < .001) and OS (crude HR = 0.12, P < .001) compared with non-pCR. The ypT (<0.001) and ypN (<0.001) gradually influenced survival outcomes. Clinical stage III were associated with lower response rate and worse survival. Alcohol intake, pCR, and burden of post-NACT residual disease have shown considerable influence on survival outcomes.