The Emerging Role of Tertiary Lymphoid Structures in Breast Cancer: A Narrative Review.

This narrative review aims to clarify the role of tertiary lymphoid structures in breast cancer. We examine their development, composition, and prognostic value, and current ways of recognizing them. A comprehensive literature review was performed using the PubMed/Medline, Scopus, and EMBASE databases. A significant area of interest in breast cancer research involves targeting immune checkpoint molecules, particularly in the triple-negative subtype, where treatment options remain limited. However, existing biomarkers have limitations in accurately predicting treatment response. In this context, tertiary lymphoid structures (TLSs) emerge as a prognostic biomarker and also as a promising predictive marker for response. TLSs are ectopic lymphoid formations or neo-organogenesis that can develop after prolonged exposure to inflammatory signals mediated by chemokines and cytokines. Their presence is inversely correlated with estrogen receptor (ER) and/or progesterone receptor (PR) expression, but positively associated with a higher pathologic complete response rate and improved overall survival. In certain scenarios, TLS-positive tumors were associated with improved outcomes regardless of the presence of PDL-1 (programmed cell death ligand 1) expression or TILs (tumor-infiltrating lymphocytes).

Hormone Receptor-Positive / HER2-Negative Early Breast Cancer High-Risk Population: An Algorithm for Optimization Systemic Adjuvant Treatment Based on 2022 Updates.

Prognostic and predictive factors for early and late distant distance recurrence risk in estrogen-receptor positive and HER2-receptor negative early breast cancer are well known, but not all these variables work equally for the prediction. The following are the most widely accepted variables for categorizing risk levels: clinic-pathologic features (tumor size, lymph node involvement, histological grade, age, menopausal status, Ki-67 expression, estrogen, and progesterone expression), primary systemic treatment response (pathologic response and/or Ki-67 downstaging), and gene expression signatures stratification. Treatment guidelines from cancer societies and collaborative groups, online predict-tools, real-world data and experts' opinion recommends different adjuvant strategies (chemotherapy, endocrine therapy, ovarian suppression, olaparib, or abemaciclib) depending on the low (< 10%), intermediate (10%-20%) or high-risk of distance recurrence at least in the first 5 years. Multiple randomized prospective trials were updated in 2022, that evidence allow us to perform a stratification of risk in pre- and postmenopausal women with estrogen-receptor positive and HER2-receptor negative early breast cancer based on a combination of clinic-pathologic features and genomic assays and guide the adjuvant systemic treatment recommendation for those with high risk.

LuciA-15 - a real-world prospective study of PARP inhibitors for the treatment of patients with HER-2 negative metastatic breast cancer with germline and/or somatic mutation of BRCA genes or homologous recombination repair related genes.

Background: Poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) improve progression free survival among patients with HER2 negative (HER2-ve) advanced breast cancer (ABC) and a BRCA1 or BRCA2 mutation compared to chemotherapy (CT). The objective of this prospective study was to evaluate the clinical benefit of PARPi treatment in terms of response, outcomes and survival by breast cancer type and treatment in a Latin-American population. Methods: From September 2019 to April 2023, we analyzed the data of patients with HER2-ve ABC with germline and/or somatic mutation of BRCA1 or BRCA2, or in the homologous recombination repair genes, treated with olaparib or talazoparib in daily clinical practice by oncologist from Argentina and México. real-world objective response rate (rwORR), best response rate, real-world progression-free survival (rwPFS) and real-world overall survival (rwOS) were analysed with R software and RStudio version 14.0. Results: After a median follow-up of 18.07 months (95% CI 10.53-30.07), 51 patients were treated with PARPi. Mean age at starting treatment was 47.08 years. 62.7% had ER + ve/HER2-ve and 35.3% had triple negative breast cancer (TNBC). 62.7% and 37.3% of patients received talazoparib and olaparib, respectively. BRCA 1 and 2 germline mutations were the most common alterations found in 96% of patients. 37.5% of patients received platinum-based CT in the (neo)adjuvant/metastatic setting. At the time to starting PARPi treatment, 57.5% had visceral metastasis, the median number of metastatic sites was 2 (range 1-4), the median number of lines was 2 (range 0-8), and 23.5% and 31.4% received PARPi in the 1st line and 2nd line, respectively.The rwORR was 47.0%, and the median real-world progression-free survival-1 (rwPFS1) was 7.77 months (95% CI 5.67-14.7). There was a tendency of better rwPFS1 in patients with versus without previous CT in the advance setting, 6.37 months (95% CI 5.03-8.73) and 14.30 months (95% CI 6.47-NR), respectively (p 0.084). The median rwOS was 26.97 months (95% CI 13.50-NR) and higher in the subgroup of patients naïve for CT versus previous exposure to CT in the advance setting, the median rwOS was 32.1 months (95% CI 27.0-NR) versus 13.0 (95% CI10.1-NR), respectively (p 0.022). The medium real-world progression-free survival-2 (next treatment after PARPi failure) was 4.00 months (95% CI 3.43-7.13). Treatment was discontinued due to adverse events in 4.0% of patients. Conclusion: This is the first evidence in a Latin-American population that replicates the data already published in randomised clinical trials and other scanty real-world evidence studies in this field, showing positive results in rwORR and rwPFS, and encouraging data in rwOS. Notably, there was a high proportion of patients with visceral progression even with visceral crisis and need for CT. Interestingly, there were similar rwOS results among subgroups (TNBC versus ER + ve/HER2-ve, talazoparib versus olaparib, etc).

Precision medicine in the real-world setting. Clinical activity of talazoparib in a woman with hormone receptor-positive HER2-negative metastatic breast cancer with pathogenic mutation in somatic BRCA2.

Background: Next-generation sequencing (NGS) has proven to be a key implementation to understanding biological pathways involved in cancer. In daily practice, the identification of somatic and germline mutations has allowed physicians to gather relevant information to make therapeutic decisions and benefit patients. Importantly, somatic mutations provide targeted opportunities for treatment and reveal resistance mechanisms to understand patients' tumour evolution. Scanty data in clinical trials and in a real-world setting is available regarding the utility of poly(ADP-ribose) polymerase inhibitors in pathogenic or likely-pathogenic somatic breast cancer gene 1/2 (BRCA1/2) mutations and/or germline or somatic Homologous Recombination-Related Gene mutations in advanced breast cancer (ABC). Case report: Here we report a real-life case of a 47-year-old postmenopausal woman with hormone receptor-positive (HR-positive) Epidermal growth factor receptor 2 (HER2)-negative metastatic BC that had poor response to classic therapeutic strategies for HR+/HER2- ABC. At this point, the possibility of using NGS to guide the treatment was decided in a Molecular Tumour Board (MTB), and the patient had a major response to talazoparib targeting a non-germline BRCA2 mutation. Conclusion: Undoubtedly, more information regarding the cost effectiveness of NGS is needed to develop adequate reimbursement policies for this technology. It should be highlighted that the generalisation of MTBs and the implementation of molecular screening programmes are greatly needed in our region to gain more knowledge of somatic mutations implicated in the Hispanic and Latin-American population with BC diagnosis. Recently presented results of randomised studies may support the evaluation of somatic mutations with NGS to find targeted therapies for ABC patients.