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Current evidence from both randomized trials and real-world studies suggests that older patients with advanced hormone receptor-positive/HER2-negative (HR+/HER2) breast cancer derive clinical benefit from the addition of CDK4/6 inhibitors to endocrine therapy. However, a higher risk for adverse events due to CDK4/6 inhibitors among older patients is evident, leading to a trend of initiating CDK4/6 inhibitors at lower dose in clinical practice, though without evidence. The aim of the IMPORTANT-trial, a pragmatic, multinational, open-label, partly decentralized randomized trial is to investigate whether lower starting dose of CDK4/6 inhibitors combined with endocrine therapy is comparable to full dose in older (≥70 years old) patients with advanced HR+/HER2- breast cancer who are assessed as vulnerable or frail based on comprehensive geriatric assessment. Clinical Trial Registration:NCT06044623 (ClinicalTrials.gov); Registration date: 13 September 2023. Article highlights Breast cancer treatment overview in older patients In patients with advanced hormone receptor- (HR-) positive/HER2-negative breast cancer, the combination of endocrine therapy with CDK4/6 inhibitors is the standard of care as initial treatment approach. Older cancer patients are underrepresented in clinical trials, including pivotal trials on CDK4/6 inhibitors. Real-world evidence studies have showed that older patients are at increased risk for adverse events when treated with implementation of CDK4/6 inhibitors; lower initial dose is common in clinical practice, though without evidence. Comprehensive geriatric assessment (CGA) seems to be a reliable tool for the optimization of treatment strategy in older cancer patients. IMPORTANT trial design IMPORTANT is pragmatic, multi-national, open-label, partly de-centralized randomized trial investigating whether a lower initial dose of CDK4/6 inhibitors combined with endocrine therapy is comparable to a full dose in older (≥70 years old) patients with advanced HR+/HER2- breast cancer that are assessed as vulnerable or frail based on CGA. Eligible patients are older female or male patients (≥70 years old) with advanced HR-positive/HER2-negative breast cancer, not amenable for curative treatment and without prior therapy for advanced disease. The follow-up strategy in terms of treatment efficacy and toxicity resembles the current follow-up strategy in clinical practice without additional blood tests or radiological examinations. The follow-up will include toxicity evaluation before each treatment cycle as well as clinical and radiological evaluation of treatment efficacy every 3 months. Patient-reported outcomes will be captured through self-questionnaires during the study period. A total of 495 patients are to be enrolled with 30-month accrual period with aim to recruit 149 patients for the fit cohort to be treated and followed, and 346 patients for the vulnerable/ frail cohort to be randomized. Categorization & randomization in IMPORTANT trial Patients will be categorized based on self-reported CGA to fit or vulnerable/frail depending on domains of age metrics that are impaired. Patients categorized as vulnerable/frail will be randomized (1:1) to -1 level lower initial dose or full dose of CDK 4/6 inhibitors combined with endocrine therapy. Stratification factors during randomization are the type of CDK4/6 inhibitor used (palbociclib vs ribociclib vs abemaciclib), the type of endocrine therapy (aromatase inhibitors vs fulvestrant) and the level of vulnerability based on CGA (vulnerable vs frail). IMPORTANT trial end points The primary end point is time-to-treatment failure; secondary end points include overall treatment utility, investigator-assessed progression-free survival, overall survival, time to chemotherapy initiation, toxicity, quality-of-life (QoL), time to QoL deterioration and cost-effectiveness. [ABSTRACT FROM AUTHOR]

Globally, the efforts to find the best cancer treatment are demanding and very intensive. Immunotherapy has gained an important role as a second or sometimes first line of treatment for various types of cancer. PD-1/PD-L1 checkpoint inhibitors are an impending category of immunotherapy, and their mechanism, as well as their interaction with T cells, are well studied. However, our knowledge about any possible effect(s) of immunotherapy on B cells is limited. In this prospective study, we asked the question of any possible alterations of circulating B cells (numbers and subsets) occurring during immunotherapy in patients with cancer and of the potential correlation of such changes with the outcomes and with development of immune-related adverse events (irAEs). We enrolled 20 cancer patients who received PD-1 checkpoint inhibitors and 8 healthy donors (HD). Patients underwent regular clinical assessment and imaging using the iRECIST criteria for 6 months following immunotherapy. Peripheral blood samples were collected before and during PD-1 checkpoint inhibitor therapy, and flow cytometry analysis of peripheral blood mononuclear cells (PBMCs) was performed, evaluating various circulating B cell subset phenotypes, including mature naïve B cells, memory B cells, regulatory B cells (Bregs), antibody-secreting cells (ASCs), and age-related B cells (ABCs). Statistical analysis was employed to compare the differences of B cells between different groups and among sequential data within the same group. Total circulating CD19+ B cell counts remained stable across both groups (responders (R), nonresponders (NR)) and timepoints. However, there was a significant rise in mature naïve B cells and decline in memory B cells at the initiation of the treatment in the R group compared to healthy donors and to the NR group. Such changes were correlated with a good response to immunotherapy. On the contrary, higher numbers of ABCs at baseline were seen in the NR group and were correlated with resistance to treatment. As far as immune-related adverse events are concerned, no significant changes were recorded among the different B cell subpopulations evaluated in both groups. Our study provides preliminary data suggesting that B cell subset changes during immunotherapy may correlate with immune checkpoint inhibitor-induced clinical responses in patients with neoplasia. Further investigations to delineate the potential role(s) of B cells in patients undergoing immunotherapy are needed. [ABSTRACT FROM AUTHOR]

Simple Summary: Advanced hormone receptor-positive (HR+) breast cancer remains a significant clinical challenge despite novel treatment options. The standard therapeutic choice for advanced HR+ breast cancer includes endocrine therapy in combination with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. However, most of the patients eventually develop endocrine resistance leading to disease progression. Antibody–drug conjugates (ADCs) are a promising class of targeted therapeutic agents that selectively deliver highly potent cytotoxic drugs to cancer cells. This review describes their mechanism of action, preclinical and safety data as well as their indications and future perspectives in the treatment of advanced HR+ breast cancer. Breast cancer is the most common cancer type in women. The vast majority of breast cancer patients have hormone receptor-positive (HR+) tumors. In advanced HR+ breast cancer, the combination of endocrine therapy with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors is considered the standard of care in the front-line setting. Nevertheless, resistance to hormonal therapy and CDK4/6 inhibitors eventually occurs, leading to progression of the disease. Antibody–drug conjugates (ADCs) comprise a promising therapeutic choice with significant efficacy in patients with HR+ breast cancer, which is resistant to endocrine treatment. ADCs typically consist of a cytotoxic payload attached by a linker to a monoclonal antibody that targets a specific tumor-associated antigen, offering the advantage of a more selective delivery of chemotherapy to cancer cells. In this review, we focus on the ADC mechanisms of action, their toxicity profile and therapeutic uses as well as on related biomarkers and future perspectives in advanced HR+ breast cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Numerous studies have emerged into the role of small extracellular vesicles (sEVs), including exosomes in cancer and colorectal cancer in proliferation, metastasis, epithelial-to-mesenchymal transition, angiogenesis and tumor microenvironment. The available data regarding the clinical significance of gene expression of molecules, which participate in sEVs biogenesis, are extremely limited. In the present study, we evaluated the expression of the most important genes, which are implicated in sEVs biogenesis, and their association with sEVs plasma levels as well as with the clinical outcome of patients with colorectal cancer. A growing number of studies have shed light on the role of small extracellular vesicles (sEVs), including exosomes, in colorectal cancer (CRC). Available data regarding the clinical significance of molecular players in CRC, implicated in sEVs biogenesis, is limited. In this study, we assessed the expression of the most important genes which are implicated in sEVs biogenesis and their association with sEVs plasma levels, investigated with a double sandwich ELISA assay, as well as with the clinical outcome of patients with CRC. Our study shows that RAB27A, RAB27B, RAB2B, and RAB3B mRNA levels were lower in tumor tissues compared to tumor adjacent, non-malignant tissues (p < 0.001, p = 0.009, p = 0.011, and p < 0.001, respectively). In addition, high tumor expression of RAB27A, RAB27B, RAB9A, RAB11B, and STX1A was favorable of a 5-year survival (p = 0.038, p = 0.015, p = 0.008, p = 0.002, and p = 0.028, respectively). Furthermore, patients with adenomas had lower overall plasma sEVs concentrations, compared to healthy volunteers (p = 0.026), while no statistically significant differences were observed in the overall or tumor-derived plasma sEVs concentration (p = 0.885 and p = 0.330, respectively) of CRC patients. In conclusion, sEVs biogenesis has a potentially significant role in CRC, with RAB27A, RAB27B, RAB9A, RAB11B, and STX1A having a promising role in survival outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Studies have shown that JUNB and CXCR4 contribute to cell proliferation, migration and invasion, hence claiming an important role in tumor progression and metastasis, in various cancer types, including lung cancer. We have previously reported that JUNB and CXCR4 are overexpressed in circulating and disseminated tumor cells from breast cancer patients and are correlated with worse survival. In the present study, we investigated the expression of JUNB and CXCR4 in circulating tumor cells (CTCs) of non-small-cell lung cancer and small-cell lung cancer patients and determined their clinical significance. Our results showed that both JUNB and CXCR4 were overexpressed in CTCs from lung cancer patients. Furthermore, both proteins were correlated with poor survival in non-small-cell lung cancer patients, while only CXCR4 was associated with worse survival in small-cell lung cancer patients, suggesting that JUNB and CXCR4 are potentially important prognostic biomarkers for lung cancer. In the present study, we evaluated the expression of JUNB and CXCR4 in circulating tumor cells (CTCs) of lung cancer patients and investigated whether these proteins have prognostic clinical relevance. Peripheral blood from 30 patients with non-small-cell lung cancer (NSCLC) was filtered using ISET membranes, and cytospins from 37 patients with small-cell lung cancer (SCLC) were analyzed using confocal and VyCAP microscopy. Both JUNB and CXCR4 were expressed in the vast majority of lung cancer patients. Interestingly, the phenotypic patterns differed between NSCLC and SCLC patients; the (CK+/JUNB+/CXCR4+) phenotype was present in 50% of NSCLC vs. 71% of SCLC patients. Similarly, the (CK+/JUNB+/CXCR4–) was present in 44% vs. 71%, the (CK+/JUNB–/CXCR4+) in 6% vs. 71%, and the (CK+/JUNB–/CXCR4–) phenotype in 38% vs. 84%. In NSCLC, the presence of ≥1 CTCs with the (CK+/JUNB+/CXCR4+) phenotype was associated with worse progression-free survival (PFS) (p = 0.007, HR = 5.21) while ≥2 with poorer overall survival (OS) (p < 0.001, HR = 2.16). In extensive stage SCLC patients, the presence of ≥4 CXCR4-positive CTCs was associated with shorter OS (p = 0.041, HR = 5.01). Consequently, JUNB and CXCR4 were expressed in CTCs from lung cancer patients, and associated with patients' survival, underlying their key role in tumor progression. [ABSTRACT FROM AUTHOR]

Simple Summary: Tumor-infiltrating lymphocytes (TILs) have been reported to contribute to breast cancer (BC) prognosis. The aim of our study was to investigate the prognostic impact of CD8+ TILs and their subtypes in patients with early breast cancer treated with sequential, dose-dense adjuvant chemotherapy. Tumors of 627 patients were examined for total (t), stromal (s), and intratumoral (i) CD8 lymphocyte density (counts/mm2). Our results showed that high expression of sCD8, iCD8, and tCD8 correlated with higher Ki67, TILs density, ER/PgR negativity, and higher histological grade. We confirmed that patients with high iCD8+ and tCD8+ TILs had longer DFS and OS, as compared to those with low counts/mm2. Survival benefit was retained when adjusting for classical clinical and pathological characteristics, but was not correlated to specific BC subtype. More data are needed to empower the prognostic role of TILs and establish their use in clinical practice. Tumor-infiltrating lymphocytes (TILs) contribute to breast cancer (BC) prognosis. We investigated the prognostic impact of CD8+ TILs in patients with early breast cancer treated with adjuvant chemotherapy in a large observational clinical trial. Along with a 10 year follow-up, considering the efficacy and safety, we report the results of the translational part of our study. We examined the patients' tumors for total (t), stromal (s), and intratumoral (i) CD8 lymphocyte density (counts/mm2) on tissue-microarray cores. The impact of CD8+ TILs counts on DFS and OS, and its correlation with breast cancer subtypes and standard clinicopathological parameters, were investigated, along with efficacy and safety data. Among the 928 eligible patients, 627 had available CD8+ data. Of which, 24.9% had a high expression of sCD8, iCD8, and total CD8, which were correlated with higher Ki67, TILs density, ER/PgR negativity, and higher histological grade. The 5year DFS and OS rates were 86.1% and 91.4%, respectively. Patients with high iCD8 and tCD8 had longer DFS and OS compared to those with low counts/mm2 (DFS: HR = 0.58, p = 0.011 and HR = 0.65, p = 0.034 and OS: HR = 0.63, p = 0.043 and HR = 0.58, p = 0.020, respectively). Upon adjustment for clinicopathological parameters, iCD8 and tCD8 retained their favorable prognostic significance for DFS and OS, whereas high sCD8 was only prognostic for DFS. Menopausal status, tumor size, and nodal status retained their prognostic significance in all examined multivariate models. CD8+ TILs, and especially their intratumoral subset, represent a potential favorable prognostic factor in early BC. [ABSTRACT FROM AUTHOR]

Purpose Angiogenesis is a crucial phenomenon in the development and progression of breast cancer (BC), but the clinical significance of angiogenesis-related proteins in metastatic BC remains unknown. This study investigates the prognostic value of vascular endothelial growth factor receptors 1, 2, 3 (VEGFR1, VEGFR2, VEGFR3) as well as vascular endothelial growth factors A and C (VEGFA and VEGFC) in metastatic BC patients treated with trastuzumab-based regimens. Materials and Methods Two hundred female patients were included. Protein and mRNA expression of the studied angiogenesis-related factors were evaluated by immunohistochemistry and quantitative polymerase chain reaction, respectively. Results High expression of VEGFA, VEGFC, VEGFR1, VEGFR2, and VEGFR3 in the tumor cells was observed in 43.5%, 24.2%, 36%, 29.5%, and 43%, respectively. Stromal elements expressed high levels of VEGFA, VEGFC, VEGFR1, VEGFR2, and VEGFR3 in 78.9%, 93.3%, 90.7%, 90.2%, and 74.8% of tumors with available data. High tumor cell expression of VEGFR1 was a favorable prognosticator for survival among patients with human epidermal growth factor receptor 2 (HER2)-positive tumors (hazard ratio [HR], 0.55; p=0.013). A trend towards longer progression-free survival was detected univariately for patients with HER2-negative tumors and high expression of VEGFR2 (HR, 0.60; p=0.059). Conclusion VEGFR1 and VEGFR2 seem to have significant prognostic value in BC patients with metastatic disease treated with trastuzumab-based regimens. [ABSTRACT FROM AUTHOR]

Simple Summary: Personalized medicine has significantly changed the clinical outcome of oncogene-driven non-small cell lung cancer (NSCLC) due to the efficacy of molecular targeted therapies. Despite the advances in the management of this group of patients, the need for powerful biomarkers with the potential for a real-time assessment of the tumor genomic profile as well as for detecting and monitoring minimal residual disease (MRD) remains unmet. The aim of this article is to present the current knowledge and the future perspectives regarding the prognostic value of ctDNA in NSCLC, focusing on the most common druggable driver mutations, including those in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1), rearranged during transfection (RET), kirsten rat sarcoma virus (KRAS), B-Raf proto-oncogene (BRAF), and mesenchymal epithelial transition factor receptor (MET) genes. As we enter an unprecedented era of personalized medicine, molecular targeted therapies have the potential to induce improved survival outcome in patients with non-small cell lung cancer (NSCLC). However, a significant percentage of oncogene-driven NSCLC patients will relapse even after definitive treatment, whereas chronic and durable response to targeted therapies is a less common event in advanced-stage lung cancer. This phenomenon could be attributed to minimal residual disease (MRD), defined as a population of disseminated tumor cells that survive during the course or after treatment, eventually leading to recurrence and limiting patient survival. Circulating tumor DNA (ctDNA) is a powerful biomarker for MRD detection and monitoring and is a non-invasive approach of treating cancer, and especially NSCLC, based on a real-time assessment of the tumor genomic landscape. In this review, we present the key findings of studies that have used ctDNA with regard to its prognostic value and in respect to the most common druggable driver mutations of genes in NSCLC, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1), rearranged during transfection (RET), Kirsten rat sarcoma virus (KRAS), B-Raf proto-oncogene (BRAF), and mesenchymal epithelial transition factor receptor (MET). [ABSTRACT FROM AUTHOR]

The onset and progression of cancer are strongly associated with the dissipation of adhesion forces between cancer cells, thus facilitating their incessant attachment and detachment from the extracellular matrix (ECM) to move toward metastasis. During this process, cancer cells undergo mechanical stresses and respond to these stresses with membrane deformation while inducing protrusions to invade the surrounding tissues. Cellular response to mechanical forces is inherently related to the reorganization of the cytoskeleton, the dissipation of cell-cell junctions, and the adhesion to the surrounding ECM. Moreover, the role of focal adhesion proteins, and particularly the role of vinculin in cell attachment and detachment during migration, is critical, indicating the tight cell-ECM junctions, which favor or inhibit the metastatic cascade. The biomechanical analysis of these sequences of events may elucidate the tumor progression and the potential of cancer cells for migration and metastasis. In this work, we focused on the evaluation of the spreading rate and the estimation of the adhesion strength between breast cancer cells and ECM prior to and post-treatment with anti-tumor agents. Specifically, different tamoxifen concentrations were used for Er+ breast cancer cells, while even concentrations of trastuzumab and pertuzumab were used for HER2+ cells. Analysis of cell stiffness indicated an increased elastic Young's modulus post-treatment in both MCF-7 and SKBR-3 cells. The results showed that the post-treatment spreading rate was significantly decreased in both types of breast cancer, suggesting a lower metastatic potential. Additionally, treated cells required greater adhesion forces to detach from the ECM, thus preventing detachment events of cancer cells from the ECM, and therefore, the probability of cell motility, migration, and metastasis was confined. Furthermore, post-detachment and post-treatment vinculin levels were increased, indicating tighter cell-ECM junctions, hence limiting the probability of cell detachment and, therefore, cell motility and migration. [ABSTRACT FROM AUTHOR]

Cellular senescence (CS) is a major homeostatic biological process, which plays a key role in normal tissue development and provides protection from stressful cell insults. The role of CS in mammary-gland development and breast cancer is not well understood. While there is a lack of experimental data on the role of CS in the development of the pre-pubertal mammary gland, there is evidence for a biphasic senescence response in adult normal-mammary-epithelial cells, where the bypass of the first senescence barrier (M0) seems to be a key step in the development of premalignant lesions, with genetic abnormalities that resemble in situ breast carcinoma. Further, there is accumulating evidence for the role of cellular senescence in breast-cancer response, regarding treatment and patient outcome. Here, we review the current literature on cellular senescence, in epithelial-mammary cells, breast-cancer cells, and breast-tumor-microenvironment-resident cells. Furthermore, we discuss its putative role in breast-cancer response, regarding treatment and disease progression. In addition, we provide preliminary evidence of CS in breast-cancer-microenvironment cells, such as tumor-associated fibroblasts and tumor-infiltrating lymphocytes, by employing the novel GL13 lipofuscin stain, as a marker of cellular senescence. [ABSTRACT FROM AUTHOR]