Elżbieta Senkus

Background: Optimal management of breast cancer (BC) patients with pathological complete response (pCR) after neoadjuvant therapy (NAT) remains debated. We performed a retrospective analysis to evaluate whether the extent of surgery influences survival outcomes in this patient population. Methods: Using the EUSOMA database, we retrospectively collected data of women with pCR after NAT, excluding those with BRCA1/2 mutations. The cohort was stratified by surgery type, i.e., breast-conserving surgery (BCS) or mastectomy. Relapse-free survival (RFS) and overall survival (OS) were compared using Cox regression. Results: Of 467 patients, 327 (70.0%) underwent BCS and 140 (30.0%) underwent mastectomy. Women treated with mastectomy were more likely to have multifocal tumors and advanced disease. After a median follow-up of 5.6 years, 7.3% of patients experienced BC recurrence. Axillary nodal involvement (cN+) and mastectomy were independently associated with recurrence, occurring in 11.4% of cN+ compared to 3.7% of cN0 patients (HR 3.02; 95% CI: 1.40–6.51; p = 0.005) and in 12.5% of mastectomy vs. 5.2% of BCS patients (HR 2.08; 95% CI: 1.05–4.11; p 0.035). cN+ patients also showed significantly higher mortality rates (9.4% vs. 1.6% of cN0; HR 6.16; 95%CI: 2.09–18.17; p = 0.001). However, surgery type did not impact OS. Conclusions: In this cohort of BC patients with pCR after NAT, BCS was not associated with a higher risk of recurrence compared with mastectomy. Baseline nodal involvement independently predicted recurrence and mortality; however, the type of surgery did not impact OS. These findings support BCS as a safe treatment option for this patient population.

Neutrophils are emerging as key regulators of tumor biology, influencing cancer progression, immune evasion, and therapeutic response. However, their transcriptomic characterization remains challenging due to low RNA content, limiting confident discrimination from other leukocyte populations at the single-cell level. To address this, we developed a robust analytical framework for single-cell RNA sequencing data, calculating a neutrophil score for each cell based on two curated neutrophil marker gene panels and excluding cells expressing non-neutrophil marker genes. White blood cells were isolated from liquid biopsies of six triple-negative breast cancer (TNBC) patients and six non-malignant donors, sequenced, and analyzed to profile 84 neutrophils isolated from TNBC patients and 128 neutrophils isolated from control donors. TNBC neutrophils displayed significant upregulation of migration-associated genes (−log₁₀ adjusted p ≈ 3) and respiratory complex genes (p < 1 × 10⁻⁹) compared with controls. These findings demonstrate significant transcriptomic differences between the TNBC and control neutrophils, revealing a part of the influence of the TNBC tumor on circulating immune cells. Moreover, this work provides a validated framework for precise neutrophil identification and functional characterization in single-cell studies and lays the foundation for dissecting their mechanistic roles in cancer progression.

Physical exercise both during and after curative cancer treatment has been shown to reduce side effects. Evidence in the metastatic cancer setting is scarce, and interventions that improve health-related quality of life (HRQOL) are much needed for patients with metastatic breast cancer (MBC). The multinational randomized controlled PREFERABLE-EFFECT trial assessed the effects of exercise on fatigue and HRQOL in patients with MBC. In total, 357 patients with MBC and a life expectancy of ≥6 months but without unstable bone metastases were recruited at eight study centers across five European countries and Australia. Participants were randomly assigned (1:1) to usual care (control group, n = 179) or a 9-month supervised exercise program (exercise group, n = 178). Intervention effects on physical fatigue (European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-FA12 scale) and HRQOL (EORTC QLQ-C30 summary score) were determined by comparing the change from baseline to 3, 6 (primary timepoint) and 9 months between groups using mixed models for repeated measures, adjusted for baseline values of the outcome, line of treatment (first or second versus third or higher) and study center. Exercise resulted in significant positive effects on both primary outcomes. Physical fatigue was significantly lower (−5.3 (95% confidence interval (CI), −10.0 to −0.6), Bonferroni–Holm-adjusted P = 0.027; Cohen's effect size, 0.22) and HRQOL significantly higher (4.8 (95% CI, 2.2–7.4), Bonferroni–Holm-adjusted P = 0.0003; effect size, 0.33) in the exercise group than in the control group at 6 months. Two serious adverse events occurred (that is, fractures), but both were not related to bone metastases. These results demonstrate that supervised exercise has positive effects on physical fatigue and HRQOL in patients with MBC and should be recommended as part of supportive care.ClinicalTrials.gov Identifier: NCT04120298.

Tumor-infiltrating lymphocytes (TILs) are pivotal in the immune response against breast cancer (BC), with their prognostic and predictive significance varying across BC subtypes. In triple-negative BC (TNBC), higher TIL levels correlate with improved prognosis and treatment response, guiding therapeutic strategies and potentially offering avenues for treatment de-escalation. In metastatic TNBC, TILs identify patients with enhanced immunotherapy response. HER2+ BC, similar to TNBC, exhibits positive correlations between TILs and treatment response, especially in neoadjuvant settings. Luminal BC generally has low TILs, with limited prognostic impact. Single hormone receptor-positive BCs show distinct TIL associations, emphasizing subtype-specific considerations. TILs in ductal carcinoma in situ (DCIS) display ambiguous prognostic significance, necessitating further investigation. Standardizing TIL assessment methods is crucial for unlocking their full potential as biomarkers, guiding treatment decisions, and enhancing patient care in BC.

Invasive lobular breast cancer (ILC) differs from invasive breast cancer of no special type in many ways. Evidence on treatment efficacy for ILC is, however, lacking. We studied the degree of documentation and representation of ILC in phase III/IV clinical trials for novel breast cancer treatments. Trials were identified on Pubmed and clinicaltrials.gov. Inclusion/exclusion criteria were reviewed for requirements on histological subtype and tumor measurability. Documentation of ILC was assessed and ILC inclusion rate, central pathology and subgroup analyses were evaluated. Inclusion restrictions concerning tumor measurability were found in 39/93 manuscripts. Inclusion rates for ILC were documented in 13/93 manuscripts and varied between 2.0 and 26.0%. No central pathology for ILC was reported and 3/13 manuscripts had ILC sub-analyses. ILC is largely disregarded in most trials with poor representation and documentation. The current inclusion criteria using RECIST v1.1, fall short in recognizing the unique non-measurable metastatic infiltration of ILC.

Opinion statement: Approximately 15–20% of breast cancers (BC) demonstrate HER2 overexpression/gene amplification. Historically, before the era of HER2-directed therapies, this subtype was associated with poor prognosis. Anti-HER2 agents dramatically changed the natural course of disease and significantly prolonged patients’ survival. In recent years, a number of new anti-HER2 therapies have been developed, and their approvals offer new therapeutic options for patients with advanced HER2-positive breast cancer. At present, HER2 pathway blocking drugs used in the treatment of metastatic breast cancer worldwide include trastuzumab and pertuzumab in the first-line treatment; trastuzumab deruxtecan and trastuzumab emtansine in the second line; and tucatinib, neratinib, lapatinib, and margetuximab in further lines of treatment of advanced HER2 positive breast cancer. Additionally, there are many clinical trials underway evaluating drugs blocking the HER2 pathway in advanced disease setting. This article presents new treatment options, discussing the most important findings from clinical trials and real-world reports, clinical benefits and risks of treatment, as well as efficacy of re-treatment with trastuzumab in metastatic breast cancer. New data challenge the current standards, and a number of questions arise regarding the optimal sequence of anti-HER2 targeted therapies, the optimal combination, including endocrine agents in luminal HER2 positive tumors and treatment of special patient population such as patients with brain metastases (BM).

Circulating tumor cells (CTCs) and circulating cancer-associated fibroblasts (cCAFs) have been individually considered strong indicators of cancer progression. However, technical limitations have prevented their simultaneous analysis in the context of CTC phenotypes different from epithelial. This study aimed to analyze CTCs and cCAFs simultaneously in the peripheral blood of 210 breast cancer patients using DAPI/pan-keratin (K)/vimentin (V)/alpha-SMA/CD29/CD45/CD31 immunofluorescent staining and novel technology—imaging flow cytometry (imFC). Single and clustered CTCs of different sizes and phenotypes (i.e., epithelial phenotype K+/V− and epithelial–mesenchymal transition (EMT)-related CTCs, such as K+/V+, K−/V+, and K−/V−) were detected in 27.6% of the samples and correlated with metastases. EMT-related CTCs interacted more frequently with normal cells and tended to occur in patients with tumors progressing during therapy, while cCAFs coincided with CTCs (mainly K+/V− and K−/V−) in seven (3.3%) patients and seemed to correlate with the presence of metastases, particularly visceral ones. This study emphasizes the advantages of imFC in the field of liquid biopsy and highlights the importance of multimarker-based analysis of different subpopulations and phenotypes of cancer progression-related cells, i.e., CTCs and cCAFs. The co-detection of CTCs and cCAFs might improve the identification of patients at higher risk of progression and their monitoring during therapy.