The role of modern parameters and their relationship with recurrence risk as assessed by Oncotype DX: real-world evidence.

Genomic analysis through various platforms is an essential tool for determining prognosis and treatment in a significant subgroup of early-stage breast cancer patients with hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative status. Additionally, combined clinical and pathological characteristics can accurately predict the recurrence score (RS), as demonstrated by the University of Tennessee risk nomogram. In this study, we aimed to identify classical clinical-pathological factors associated with high RS in a local population, including modern parameters such as current abemaciclib treatment recommendations, HER2-low status, different Ki-67 cutoff values, and samples obtained from secondary primary tumours. This is a retrospective single-institution study that analysed a total of 215 tumour samples. Among lymph node-negative patients (n = 179), age, Ki67 values, and progesterone receptor status predicted RS after multivariate analysis. HER2-low status was not associated with RS differences (p = 0.41). Among lymph node-positive patients (n = 36), MonarchE inclusion criteria (15) were not associated with a higher RS (p = 0.61), and HER2-low did not reach statistical significance. However, tumours classified as secondary primaries numerically exhibited a higher RS. Based on these findings from our real-world sample, the mere application of clinical and pathological parameters is insufficient to predict RS outcomes. Modern parameters such as HER2-low status or adjuvant abemaciclib recommendations were not associated with RS differences. Regarding the observation of secondary tumours, more evidence is needed to understand whether prior hormone therapy exposure impacts the biological risk of secondary primary tumours.

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).

Phenotypic and functional analysis in HER2+ targeted therapy of human NK cell subpopulation according to the expression of FcεRIγ and NKG2C in breast cancer patients.

Adaptive NK cells constitute an NK cell subpopulation, which expands after human cytomegalovirus (HCMV) infection. This subpopulation has stronger production of cytokines after CD16 stimulation, longer life and persistence than conventional NK cells and are, therefore, interesting tools for cancer immunotherapy. Since there is limited information on adaptive NK cells in cancer patients, we described this population phenotypically and functionally, by flow cytometry, in the context of HER2 + breast cancer (BC) directed therapy. We assessed HCMV status in 78 patients with BC. We found that, similarly to healthy donors (HD), a high proportion of BC patients were HCMV-positive, and nearly 72% of them had an adaptive NK cell subpopulation characterized by the loss of FcεRIγ intracellular adaptor protein or the presence of NKG2C receptor. However, in BC patients, FcεRIγ- and NKG2C + NK cell populations overlapped to a lesser extent than in HD. Otherwise, no profound phenotypic differences were found between BC patients and HD. Although FcεRIγ- or NKG2C + NK cell subsets from BC patients produced more IFN-γ than their FcεRIγ + or NKG2C- NK cell counterparts, IFN-γ production increased only when NK cells simultaneously expressed FcεRIγ- and NKG2C + , whereas in HD the presence of NKG2C marker was sufficient to display greater functionality. Furthermore, in a group of patients treated with chemotherapy and Trastuzumab plus Pertuzumab, FcεRIγ-NKG2C + and FcεRIγ-NKG2C- NK cells retained greater functionality after treatment than FcεRIγ + NKG2C- NK cells. These results suggest that the presence or magnitude of adaptive NK cell subsets might serve as a key determinant for therapeutic approaches based on antibodies directed against tumor antigens.

HER2-Directed Therapy in Advanced Breast Cancer: Benefits and Risks.

Around 20% of breast cancers are associated with amplification or overexpression of human epidermal growth factor receptor 2 (HER2). In this setting, anti-HER2-targeted agents are the cornerstone of cancer therapeutic strategies. This includes monoclonal antibodies, tyrosine kinase inhibitors (TKIs) and, recently, antibody-drug conjugates (ADCs). With the advent of these new alternatives, the decision-making process has become more complex, especially with regard to the treatment sequence possibilities. In spite of the fact that overall survival has significantly improved accordingly, resistance to treatment remains a challenge in HER2-positive breast cancer. The introduction of new agents has created awareness regarding new potential specific adverse events, and consequently, their increasing application pose major challenges in daily patient care. This review describes the therapeutic landscape for HER2-positive advanced breast cancer (ABC) and evaluates its benefits and risks in the clinical setting.

Cyclin-Dependent Kinase 4/6 Inhibitor Outcomes in Patients With Advanced Breast Cancer Carrying Germline Pathogenic Variants in DNA Repair-Related Genes.

PURPOSE: In recent years, unprecedented benefits have been observed with the development of cyclin-dependent kinase (CDK) 4 and 6 inhibitors for the treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. However, there is scarce evidence of their value in specific populations, such as patients carrying germline pathogenic variants in DNA repair-related genes. PATIENTS AND METHODS: We retrospectively studied the efficacy of CDK 4/6 inhibitors plus endocrine therapy in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. Three cohorts were compared, including patients harboring germline pathogenic variants in DNA repair-related genes (gBRCA1/2-ATM-CHEK2 mutated), those tested without these mutations (wild type [WT]), and the nontested subgroup. Relevant prognostic factors including age, metastatic site (visceral v nonvisceral), Eastern Cooperative Oncology Group, and prior treatment with CDK 4/6 inhibitors were stratified by univariate and multivariate Cox regression models. RESULTS: Among the total population (n = 217), 15 (6.9%) patients carried gBRCA1/2 (n = 10)-ATM (n = 4)-CHEK2 (n = 1) pathogenic variants, 45 (20.7%) were WT, and 157 (72.4%) were nontested. Gene pathogenic variant carriers were younger (P < .001). Most patients (164, 75.6%) had not received prior endocrine therapy in the advanced setting. Median progression-free survival was shorter in patients with evaluated germline pathogenic variants (10.2 months [95% CI, 5.7 to 14.7]), compared with WT and nontested patients (15.6 months [95% CI, 7.8 to 23.4], and (17.6 months [95% CI, 12.9 to 22.2]; P = .002). Consistently, a worse median overall survival was observed in the subgroup with germline pathogenic variants than in the WT group (P = .006). Multivariable analysis showed that mutation status was an independent prognostic factor of progression-free survival (P = .020) and overall survival (P = .012). CONCLUSION: In this retrospective real-world study, gBRCA1/2-ATM-CHEK2 pathogenic variants were independently associated with poor outcomes in patients with advanced breast cancer treated with CDK4/6 inhibitors.

Appraising the quality of meta-analysis for breast cancer treatment in the adjuvant setting: A systematic review.

INTRODUCTION: Breast cancer is the tumor with highest incidence in women worldwide and adjuvant treatment is extremely important to achieve disease control. Given the relevance of systematic reviews, their rigor should be warranted to avoid biased conclusions. Our objective was to investigate the methodological quality of meta-analysis of early breast cancer adjuvant treatment. MATERIAL AND METHODS: Comprehensive searches were performed using electronic databases from 1/1/2007 to 11/12/2018. All studies identified as a systematic review with meta-analysis investigating the efficacy of breast cancer adjuvant treatments were included. Two reviewers independently assessed titles and abstracts, then full-texts for eligibility. Quality was assessed using the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) version 2 tool. RESULTS: Of 950 citations retrieved, 66 studies (7.0%) were deemed eligible. Methodological quality was highly variable, median AMSTAR score 8.5 (IQR 7-9.5) and range 0-16. There was a weak positive correlation between journal impact factor and AMSTAR score (r = 0.17) and citation rate and AMSTAR score (r = 0.16). Cochrane Systematic Reviews were of higher quality than reviews from other journals. Overall confidence was critically low for 61 (92.4%) studies, and the least well-reported domains were the statement of conflict of interest and funding source for the included studies (4.6%), the report of a pre-defined study protocol (15.2%), and the description of details of excluded studies (6.1%). CONCLUSIONS: Our findings reinforce concerns about the design, conduction and interpretation of meta-analysis in current literature. Methodological quality should be carefully considered and journal editors, decision makers and readers in general, must follow a critical approach to this studies.

Los linfocitos estromales intratumorales (tils) como factor pronóstico en tumores primarios de mama Triple Negativos / Tumor infiltrating lymphocytes (tils) in Triple Negative breast cancer as a prognostic factor

Introducción Los tumores de mama se encuentran frecuentemente rodeados por células inflamatorias como signo de interacción entre el tumor y el huésped, siendo esta crítica para el desarrollo y progresión del cáncer. Algunas observaciones sugieren el valor pronóstico de los linfocitos estromales intratumorales (tils). Sin embargo, su evaluación no es rutinaria ya que su relevancia clínica aún no se encuentra consolidada. Objetivos Los objetivos de este trabajo son: • la evaluación de la concordancia interobservador de los linfocitos intratumorales (tils); • su relación con la sobrevida libre de enfermedad (sle); • su valoración como factor pronóstico en cáncer de mama Triple Negativo. Material y método Se seleccionaron retrospectivamente pacientes con tumores de mama Triple Negativos operados en el Instituto Alexander Fleming entre 2010-2016 sin tratamiento neoadyuvante, alcanzando una muestra de 65 pacientes. Resultados El porcentaje mediano de tils fue de 30% (12,5-50), y se consideraron como "Tumores ricos en linfocitos" (Lymphocyte Predominant Breast Cancerlpbc) a los de 19 pacientes (29,2%). Tanto la presencia de tils (p>0,01) como la definición del subtipo de lpbc (p=0,03) presentaron asociación estadísticamente significativa con la recurrencia de enfermedad. En el análisis multivariado, presentaron asociación la histología ductal y el valor de tils. Por cada 10% de aumento, disminuye 31% el riesgo de recaída. El valor de tils estratificado en 3 subgrupos (≤20; 30-40; ≥50%) presentó asociación estadísticamente significativa con la Sobrevida Libre de Enfermedad (Log Rank <0,01). Conclusiones En este trabajo se logró describir una característica tumoral y del huésped reproducible, cuya instrumentación podría generalizarle por el potencial valor pronóstico.

Introduction Breast tumors are frequently surrounded by inflammatory cells as a sign of interaction between the tumor and host, being this relationship critical for cancer development and progression. Present evidence suggests that tumor infiltrating lymphocytes (tils) may provide prognostic information. Nevertheless, tils description is not generalized as its clinical relevance is not consolidated. Objectives • evaluation of interobserver concordance of intratumoral lymphocytes (tils); • its relationship with Disease Free Survival; • its assessment as a prognostic factor in Triple Negative breast cancer. Materials end method Triple Negative breast cancer patients with surgery in Instituto Alexander Fleming, between 2010-2016, without neoadyuvant treatment, were selected retrospectively. 65 patients were selected. Results In the 65 patients selected, tils median percentage was 30% (12.5-50), and 19 (29.2%) were considered Lymphocyte Predominant Breast Cancer (lpbc). tils percentage (p>0.01) and lpbc subtype (p=0.03) presented significant association with disease recurrence. Multivariate analysis showed that ductal histology and tils percentage are associated with disease recurrence. For every 10% increment in tils, there was a 31% reduction of risk of recurrence. High tils value stratified in 3 subgroups (≤20; 30-40; ≥50%) was associated with better Disease Free Survival (Log Rank 0.01). Conclusions Due to its potential prognostic value and its technical reproducibility, we believe that this tumoral and host characteristic must be generalized.