Abstract: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 tumourspecific biomarkers status. Among these biomarkers, programmed death-ligand 1, tumourinfiltrating lymphocytes, microsatellite instability, mismatch repair and tumour mutational burden have been widely investigated. However, novel tumour-s… Show more
“…Unbalances in this mechanism lead to an increased risk of fractures, particularly at the distal femur and proximal tibia levels [28]. This complex process is regulated by resident bone cells and other cell types of the bone microenvironment, including lymphocytes, macrophages, hematopoietic cells, and endocrine signaling molecules [29][30][31][32][33][34]. In particular, the discovery of endocrine mediators produced by the skeleton has radically changed our understanding not only of the bone biology but also of the endocrinology in general [34].…”
Section: Biological Mechanisms Of Bone Metastasismentioning
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.
“…Unbalances in this mechanism lead to an increased risk of fractures, particularly at the distal femur and proximal tibia levels [28]. This complex process is regulated by resident bone cells and other cell types of the bone microenvironment, including lymphocytes, macrophages, hematopoietic cells, and endocrine signaling molecules [29][30][31][32][33][34]. In particular, the discovery of endocrine mediators produced by the skeleton has radically changed our understanding not only of the bone biology but also of the endocrinology in general [34].…”
Section: Biological Mechanisms Of Bone Metastasismentioning
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.
“…Pioneer studies provided evidence suggesting that MSI could be considered, for clinical purposes, as a proxy of the overall genome instability generated by MMR deficiency [ 24 ]. Given the elevated frequency of MSI-high (MSI-H) status in dMMR tumors, MMR protein expression and MSI have been historically considered reliable, cost-effective, and (to some extent) interchangeable biomarkers in oncology [ 25 ]. Fig.…”
Section: The Mismatch Repair System Machinerymentioning
confidence: 99%
“…Reference methods for MMR profiling depend on IHC for the four main MMR proteins with or without sequencing assays directed towards selected microsatellite markers (e.g. Bethesda panel and MSI Analysis System) [25,62]. Despite their reliability, these diagnostic strategies have several limitations, including the relatively low sensitivity in breast cancer due to their heterogeneous protein expression [63][64][65].…”
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.
“…According to a meta-analysis which included 1556 resectable GC patients, MSI-H patients had longer five-year OS and disease-free survival (DFS) compared to patients with microsatellite stable tumors (OS, 77.5% vs. 59.3%; DFS, 71.8% vs. 52.3%) [ 14 , 39 ]. Evidence suggests that dMMR is more likely to activate an immune response and lead to the increased presence of TILs, and PD-L1 upregulation in GC [ 40 , 41 , 42 , 43 ]. In particular, PD-L1 is expressed on the surface of neoplastic cells in 15–70% of GC [ 37 ], with increased expression being associated with non-metastatic cancer tissue [ 44 ], well differentiated tumors [ 44 ] and improved OS (median OS not reached vs. 40 months; p = 0.008) [ 45 ] although its association with a favorable OS has not always been consistent [ 37 , 46 ].…”
Section: Biomarkers Of Response To Immunotherapy In Gastric Cancermentioning
Despite extensive research efforts, advanced gastric cancer still has a dismal prognosis with conventional treatment options. Immune checkpoint inhibitors have revolutionized the treatment landscape for many solid tumors. Amongst gastric cancer subtypes, tumors with microsatellite instability and Epstein Barr Virus positive tumors provide the strongest rationale for responding to immunotherapy. Various predictive biomarkers such as mismatch repair status, programmed death ligand 1 expression, tumor mutational burden, assessment of tumor infiltrating lymphocytes and circulating biomarkers have been evaluated. However, results have been inconsistent due to different methodologies and thresholds used. Clinical implementation therefore remains a challenge. The role of immune checkpoint inhibitors in gastric cancer is emerging with data from monotherapy in the heavily pre-treated population already available and studies in earlier disease settings with different combinatorial approaches in progress. Immune checkpoint inhibitor combinations with chemotherapy (CT), anti-angiogenics, tyrosine kinase inhibitors, anti-Her2 directed therapy, poly (ADP-ribose) polymerase inhibitors or dual checkpoint inhibitor strategies are being explored. Moreover, novel strategies including vaccines and CAR T cell therapy are also being trialed. Here we provide an update on predictive biomarkers for response to immunotherapy with an overview of their strengths and limitations. We discuss clinical trials that have been reported and trials in progress whilst providing an account of future steps needed to improve outcome in this lethal disease.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
