Precision immunotherapy is a crucial approach to improve the efficacy of anti-cancer treatments, particularly in the metastatic setting. In this respect, accurate patient selection takes advantage of ...the multidimensional integration of patients' clinical information and tumour-specific biomarkers status. Among these biomarkers, programmed death-ligand 1, tumour-infiltrating lymphocytes, microsatellite instability, mismatch repair and tumour mutational burden have been widely investigated. However, novel tumour-specific biomarkers and testing methods will further improve patients' outcomes. Here, we discuss the currently available strategies for the implementation of a precision immunotherapy approach in the clinical management of metastatic solid tumours and highlight future perspectives.
HER2 status in breast cancer is assessed to select patients eligible for targeted therapy with anti-HER2 therapies. According to the American Society of Clinical Oncology (ASCO) and College of ...American Pathologists (CAP), the HER2 test positivity is defined by protein overexpression (score 3+) at immunohistochemistry (IHC) and/or gene amplification at
hybridization (ISH). The introduction of novel anti-HER2 compounds, however, is changing this paradigm because some breast cancers with lower levels of protein expression (i.e. score 1+/2+ with no gene amplification) benefited from HER2 antibody-drug conjugates (ADC). Recently, a potential for HER2 targeting in HER2 "ultra-low" (i.e. score 0 with incomplete and faint staining in ≤10% of tumor cells) and MutL-deficient estrogen receptor (estrogen receptor)-positive/HER2-negative breast cancers has been highlighted. All these novel findings are transforming the traditional dichotomy of HER2 status and have dramatically raised the expectations in this field. Still, a more aware HER2 status assessment coupled with the comprehensive characterization of the clinical and molecular features of these tumors is required. Here, we seek to provide an overview of the current state of HER2 targeting in breast cancers beyond the canonical HER2 positivity and to discuss the practical implications for pathologists and oncologists.
Breast cancer is the most common malignant tumor and the most prevalent cause of mortality in women. Advances in early diagnosis and more effective adjuvant therapies have improved the long-term ...survival of these patients. Pharmacotherapies and intrinsic tumor-related factors may lead to a wide spectrum of treatment-related disabling complications, such as breast cancer-related lymphedema, axillary web syndrome, persistent pain, bone loss, arthralgia, and fatigue. These conditions have a detrimental impact on the health-related quality of life of survivors. Here, we sought to provide a portrait of the role that rehabilitation plays in breast cancer survivors. Particular emphasis has been put in terms of recovering function, improving independence in activities of daily living, and reducing disability. This complex scenario requires a precision medicine approach to provide more effective decision-making and adequate treatment compliance.
Immunotherapy has become the standard-of-care in many solid tumors. Despite the significant recent achievements in the diagnosis and treatment of cancer, several issues related to patients' selection ...for immunotherapy remain unsolved. Multiple lines of evidence suggest that, in this setting, the vision of a single biomarker is somewhat naïve and imprecise, given that immunotherapy does not follow the rules that we have experienced in the past for targeted therapies. On the other hand, additional immune-related biomarkers that are reliable in real-life clinical practice remain to be identified. Recently, the immune-checkpoint blockade has been approved in the US irrespective of the tumor site of origin. Further histology-agnostic approvals, coupled with with tumor-specific companion diagnostics and guidelines, are expected in this field. In addition, immune-related biomarkers can also have a significant prognostic value. In this review, we provide an overview of the role of these biomarkers and their characterization in the management of lung cancer, melanoma, colorectal cancer, gastric cancer, head and neck cancer, renal cell carcinoma, urothelial cancers, and breast cancer.
Despite the remarkable advances in the diagnosis and treatment of breast cancer patients, the presence or development of metastasis remains an incurable condition. Bone is one of the most frequent ...sites of distant dissemination and negatively impacts on patient’s survival and overall frailty. The interplay between tumor cells and the bone microenvironment induces bone destruction and tumor progression. To date, the clinical management of bone metastatic breast cancer encompasses anti-tumor systemic therapies along with bone-targeting agents, aimed at slowing bone resorption to reduce the risk of skeletal-related events. However, their effect on patients’ survival remains controversial. Unraveling the biology that governs the interplay between breast neoplastic cells and bone tissue would provide means for the development of new therapeutic agents. This article outlines the state-of-the art in the characterization and targeting the bone metastasis in breast cancer, focusing on the major clinical and translational studies on this clinically relevant topic.
Breast cancer fatigue (BCF) is a complex and multidimensional condition characterized by a persistent sense of physical and/or mental stiffness, resulting in a substantial impairment of ...health-related quality of life in breast cancer survivors. Aim of this prospective cohort study was to evaluate the feasibility and the effectiveness of a 4-week rehabilitation protocol on BCF, muscle mass, strength, physical performance, and quality of life in breast cancer (BC) survivors. We recruited adult BC women with a diagnosis of BCF, according to the International Classification of Diseases 10 criteria, referred to the Outpatient Service for Oncological Rehabilitation of a University Hospital. All participants performed a specific physical exercise rehabilitative protocol consisting of 60-min sessions repeated 2 times/week for 4 weeks. All outcomes were evaluated at the baseline (T0), at the end of the 4-week rehabilitation treatment (T1), and at 2 months follow up (T2). The primary outcome measure was the Brief Fatigue Inventory (BFI); secondary outcomes included: Fat-Free Mass and Fat Mass, assessed by Bioelectrical Impedance Analysis (BIA); Hand Grip Strength Test (HGS); Short Physical Performance Battery (SPPB); 10-meter walking test (10 MWT); 6-min walking test (6 MWT); European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Thirty-six women (mean age: 55.17 ± 7.76 years) were enrolled in the study. Significant reduction of BCF was observed both after the 4-week rehabilitation treatment (T1) (BFI: 5.4 ± 1.6 vs. 4.2 ± 1.7; p = 0.004) and at the follow-up visit (T2) (BFI: 5.4 ± 1.6 vs. 4.4 ± 1.6; p = 0.004). Moreover, significant differences (p < 0.001) HGS, SPPB, 10 MWT, 6 MWT, and EORTC QLQ-C30 were found at T1, while at T2 all the outcome measures were significantly different (p < 0.05) from the baseline. The rehabilitation protocol seemed to be feasible, safe, and effective in reducing BCF, improving muscle mass and function, and improving HRQoL in a cohort of BC survivors. The results of this study could improve awareness of this underestimated disease, suggesting the definition of a specific therapeutic exercise protocol to reduce BCF.
Phosphatase and tensin homolog (PTEN) loss is associated with tumorigenesis, tumor progression, and therapy resistance in breast cancer. However, the clinical value of PTEN as a biomarker in these ...patients is controversial. We sought to determine whether the benefit of traditional biomarkers testing is improved by the analysis of PTEN status for the identification of high-risk breast cancer.
A cohort of 608 patients with breast cancer was included in this study. Based on the expression on the neoplastic cells compared to the normal internal controls by immunohistochemistry (IHC), cases were classified as PTEN-low (PTEN-L) or PTEN-retained (PTEN-WT). The former constituted the study group, while the latter the control group. Analysis of gene expression was performed on publicly available genomic data and included 4265 patients from the METABRIC and MSK cohorts retrieved from cBioPortal. The Shapiro-Wilk test was used to analyze the normal distributions of continuous variables. Relationships between PTEN status and the clinicopathologic and molecular features of the patient population were assessed using Fisher's exact test or Chi-squared/Wilcoxon rank-sum test. Survival curves were built according to the Kaplan-Meier method.
Alteration in PTEN status was significantly different at protein and gene levels, where the reduced protein expression was observed in 280/608 cases (46.1%) from our group, while genetic aberrations in only 315/4265 (7.4%) cases of the METABRIC and MSK cohorts. PTEN-L tumors were significantly enriched for hormone receptors (HR) and HER2 negativity (n = 48, 17.1%) compared to PTEN-WT tumors (n = 22, 6.7%; p = 0.0008). Lack of HR with or without HER2 overexpression/amplification was significantly associated with worse overall survival (OS) in PTEN-L but not in PTEN-WT breast cancers (p < .0001). Moreover, PTEN-L protein expression but not gene alterations was related to the outcome, in terms of both OS and disease-free survival (p = 0.002).
The combined analysis of PTEN, HER2, and HR status offers relevant information for a more precise risk assessment of patients with breast cancer.
Celiac disease (CD) is a multiorgan autoimmune disorder of the chronic intestinal disease group characterized by duodenal inflammation in genetically predisposed individuals, precipitated by gluten ...ingestion. The pathogenesis of celiac disease is now widely studied, overcoming the limits of the purely autoimmune concept and explaining its hereditability. The genomic profiling of this condition has led to the discovery of numerous genes involved in interleukin signaling and immune-related pathways. The spectrum of disease manifestations is not limited to the gastrointestinal tract, and a significant number of studies have considered the possible association between CD and neoplasms. Patients with CD are found to be at increased risk of developing malignancies, with a particular predisposition of certain types of intestinal cancer, lymphomas, and oropharyngeal cancers. This can be partially explained by common cancer hallmarks present in these patients. The study of gut microbiota, microRNAs, and DNA methylation is evolving to find the any possible missing links between CD and cancer incidence in these patients. However, the literature is extremely mixed and, therefore, our understanding of the biological interplay between CD and cancer remains limited, with significant implications in terms of clinical management and screening protocols. In this review article, we seek to provide a comprehensive overview of the genomics, epigenomics, and transcriptomics data on CD and its relation to the most frequent types of neoplasms that may occur in these patients.
The clinical outcome of patients with a diagnosis of hormone receptor (HR)+ breast cancer has improved remarkably since the arrival of endocrine therapy. Yet, resistance to standard treatments is a ...major clinical challenge for breast cancer specialists and a life-threatening condition for the patients. In breast cancer, mismatch repair (MMR) status assessment has been demonstrated to be clinically relevant not only in terms of screening for inherited conditions such as Lynch syndrome, but also for prognostication, selection for immunotherapy, and early identification of therapy resistance. Peculiar traits characterize the MMR biology in HR+ breast cancers compared to other cancer types. In these tumors, MMR genetic alterations are relatively rare, occurring in ~3 % of cases. On the other hand, modifications at the protein level can be observed also in the absence of gene alterations and vice versa. In HR+ breast cancers, the prognostic role of MMR deficiency has been confirmed by several studies, but its predictive value remains a matter of controversy. The characterization of MMR status in these patients is troubled by the lack of tumor-specific guidelines and/or companion diagnostic tests. For this reason, precise identification of MMR-deficient breast cancers can be problematic. A deeper understanding of the MMR biology and clinical actionability in HR+ breast cancer may light the path to effective tumor-specific diagnostic tools. For a precise MMR status profiling, the specific strengths and limitations of the available technologies should be taken into consideration. This article aims at providing a comprehensive overview of the current state of knowledge of MMR alterations in HR+ breast cancer. The available armamentarium for MMR testing in these tumors is also examined along with possible strategies for a tailored pathological characterization.
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