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“…Furthermore, actionable co-alterations in PIK3CA and DNA repair genes might lead to the activation of the human leukocyte antigen (HLA) molecules due to increased TMB and subsequent neoantigens production, particularly in the metastatic setting [ 13 , 45 , 46 ]. This subset of patients represents a possible target for immunotherapy with ICB [ 47 ]. Fig.…”
Section: Mismatch Repair Alterations In Hr+ Breast Cancermentioning
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.
“…Furthermore, actionable co-alterations in PIK3CA and DNA repair genes might lead to the activation of the human leukocyte antigen (HLA) molecules due to increased TMB and subsequent neoantigens production, particularly in the metastatic setting [ 13 , 45 , 46 ]. This subset of patients represents a possible target for immunotherapy with ICB [ 47 ]. Fig.…”
Section: Mismatch Repair Alterations In Hr+ Breast Cancermentioning
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.
“…In the early years, the therapeutic effect was witnessed in tumors with strong immunogenicity, especially melanoma [7]. But now, cancer biotherapy research has been spread into breast cancer [8], lung cancer [9] and liver cancer [10]. Meanwhile, anti-neovascularization drugs, monoclonal antibodies, cancer vaccines, gene therapy drugs and immunomodulators have been used clinically and been studied in clinical trials.…”
The activation of the cGAS-STING pathway has tremendous potential to improve anti-tumor immunity by generating type I interferons. In recent decades, we have witnessed that producing dsDNA upon various stimuli is an initiative factor, triggering the cGAS-SING pathway for a defensive host. The understanding of both intracellular cascade reaction and the changes of molecular components gains insight into type I IFNs and adaptive immunity. Based on the immunological study, the STING-cGAS pathway is coupled to cancer biotherapy. The most challenging problem is the limited therapeutic effect. Therefore, people view 5, 6-dimethylxanthenone-4-acetic acid, cyclic dinucleotides and various derivative as cGAS-STING pathway agonists. Even so, these agonists have flaws in decreasing biotherapeutic efficacy. Subsequently, we exploited agonist delivery systems (nanocarriers, microparticles and hydrogels). The article will discuss the activation of the cGAS-STING pathway and underlying mechanisms, with an introduction of cGAS-STING agonists, related clinical trials and agonist delivery systems.
“…While some studies have shown evidence of an association between immune activity and selective pressures 8,34,51,55,59 , others have claimed that there is a lack of evidence to prove this relationship 16 . Given that several studies have applied dN/dS as a metric of selection in cancer and in normal tissue 7,8,[60][61][62][63] , we aimed to prove the use of hypothesis, a recent study of longitudinal recurrence of metastasis reported a more aggressive phenotype in metastatic deposits that had higher levels of immune-selection 55 . However, whether tumor cells growing in immunecompetent tissues are more likely to colonize new niches and how long it takes those tumor cells to readapt or to find a novel escape mechanism, as has been previously observed in mice models 31,64 , remains a challenging question.…”
Immunoediting is a major force during cancer evolution that selects for clones with low immunogenicity (adaptation), or clones with mechanisms of immune evasion (escape). However, quantifying immunogenicity in the cancer genome and how the tumour-immune coevolutionary dynamics impact patient outcomes remain unexplored. Here we show that the ratio of nonsynonymous to synonymous mutations (dN/dS) in the immunopeptidome quantifies tumor immunogenicity and differentiates between adaptation and escape. We analysed 8,543 primary tumors from TCGA and validated immune dN/dS as a measure of selection associated with immune infiltration in immune-adapted tumours. In a cohort of 308 metastatic patients that received immunotherapy, pre-treatment lesions in non-responders showed increased immune selection (dN/dS<1), whereas responders did not and instead harboured a higher proportion of genetic escape mechanisms. Ultimately, these findings highlight the potential of evolutionary genomic measures to predict clinical response to immunotherapy.
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