Disclosure Of Potential Conflicts Of Interest
L.A. Emens reports receiving commercial research grants from Aduro Biotech, AstraZeneca, Corvus, EMD Serono, Genentech/Roche, and Merck, and is a consultant/advisory board member for Amgen, AstraZeneca, Bayer, Celgene, eTheRNA, Gritstone, Molecuvax, Peregrine, Syndax, and Vaccinex. Under a licensing agreement between Johns Hopkins University and Aduro Biotech, L.A. Emens and the University are entitled to milestone payments and royalty on the sales of the GM-CSFsecreting breast cancer vaccine. The terms of these arrangements are being managed by Johns Hopkins University in accordance with its conflict of interest policies.
Qol And Symptom Monitoring
Currently, the majority of experience with immunotherapy for breast cancer has been in the advanced/metastatic setting. Patients with metastatic breast cancer can experience an accumulation of physical symptoms and psychosocial stressors that adversely affect their QOL throughout their continued treatment. Over time, these effects usually become worse as treatment is ongoing. A robust corpus of literature has described key QOL outcomes for patients receiving chemotherapy, radiotherapy, endocrine therapy, or HER2-directed therapies. In addition, throughout a patientâs journey, multiple intrinsic and extrinsic factors may influence QOL, including AEs associated with therapy as well as other characteristics of the individual being treated . However, data are currently lacking on the QOL implications for the addition of ICIs to chemotherapy or other conventional treatments.
Ongoing trials are also evaluating ICIs in early-stage disease. Patients with early-stage breast cancer also experience both physical symptoms and psychosocial stressors that can adversely affect their QOL. Although survivors of early-stage breast cancer generally report high functioning after the conclusion of treatment, important rehabilitation problems may persist beyond 1 year after primary treatment, including difficulties with physical and recreational activities, body image, sexual interest, sexual function, and dating for those who were single.
Mechanisms Of Immune System Evasions In Breast Cancer
The tumors cells have the capability to evade the immune system through the development of different mechanisms. A less efficiently surface antigen expression and a reduced expression of the major histocompatibility complex in tumor cells, which can decrease immune detection and immune cell activation, contributes to the evolution a clone selection of low immunogenic tumor cells that escape immune system surveillance . Other mechanisms to escape immune detection are associated with changes to an immunosuppressive TME induced by regulatory T cells , myeloid-derived suppressor cells and tumor-associated macrophages . These mechanisms also include the upregulation of immune checkpoint receptors, such as cytotoxic T-lymphocyte-associated protein-4 , programmed cell death protein-1 , programmed cell death protein-Ligand 1 and T-cell immunoglobulin 3 and the presence of tumor-derived immunosuppressive factors . The previous mechanisms are probably caused by the combination of genetic instability inherent in all tumor cells along with the immunoselection process .
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Gut Microbiota And The Breast
The impairment of the normal functioning of gut microbiota in maintaining host wellness may deregulate the microbial-derived products or metabolites, causing several other disorders on local or distant organs, including in the tissue breast . In this context, some microorganisms seem to interfere with host cell proliferation and apoptosis, tissue inflammation, cell invasion, immune system function, gene expression, oncogenic signalling, mutagenesis, angiogenesis, and hormonal and detoxification pathways . In addition, human microbiotas composition also influences drug disposition, action and toxicity, including of ICI .
The gut microbiome also contributes to epigenetic deregulation, which can interact with the tumour. The microorganisms can produce low molecular weight bioactive substances such as folates, short-chain fatty acids and biotin, which can participate in epigenetic processes, including altering substrates used for methylation or synthesising the complexes that change the action of epigenetic enzymes .
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Human Microbiota And Immunotherapy In Breast Cancer
- 1Medical Oncology Department, Hospital Professor Doutor Fernando Fonseca, Amadora, Portugal
- 2Breast Cancer Unit, CUF Oncologia, Lisbon, Portugal
- 3NOVA Medical School, Faculdade de Ciências Médicas, Lisbon, Portugal
- 4Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
- 5Comprehensive Health Research Centre , NOVA Medical School, Faculdade de Ciências Médicas, Lisbon, Portugal
- 6CINTESIS Center for Health Technology and Services Research, NOVA Medical School, Faculdade de Ciências Médicas, Lisbon, Portugal
Breast Cancer Microbiota And Immunotherapy
BC is the most common malignancy, and the incidence and the number of survivors continues to increase, with most developed countries reporting 85-90% five-year survival rates. However, patients with BC show different outcomes, according to different molecular profiles. Currently, four molecular subtypes of BC with prognostic and therapeutic relevance are well established: luminal A-like subtype, with high expression of oestrogen and progesterone receptors and low cell proliferation index luminal B-like subtype with high expression of ER and PR and high cell proliferation index HER2 overexpressing subtype and triple negative subtype . Furthermore, depending on histological subtype and stage at diagnosis, the prognoses are different, with the luminal A-like and TNBC subtypes having the best and worst prognoses, respectively.
Most BC patients are diagnosed in initial stages when the goal of treatment is to cure. In early and locally advanced BC, a multimodal approach is frequently used, incorporating surgery, radiotherapy and systemic therapy. The primary goals of treatment are to prolong survival and ameliorate the quality of life .
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Rechallenging With Ici After Irae: When Is Retreatment Appropriate
The decision to rechallenge patients with immunotherapy following an irAE depends on the perceived benefit versus risk for the patient. The risk-benefit calculation for a patient with a symptomatic irAE should be based on the severity of the event, time to recovery to grade 1 or lower toxicity, the ability to taper off steroids without recurrence of toxicity, and if immunotherapy is clearly providing clinical benefit. Most expert guidelines, including from SITC, recommend permanent cessation of immunotherapy agents for most grade 3â4 toxicities and potential rechallenge for grade 2 AEs that resolve to grade 0â1 promptly with supportive therapy. Some exceptions to this rule are continuation of therapy for stable endocrinopathies and rechallenge in cases of grade 3 colitis, as only roughly 30% of patients develop recurrent colitis after retreatment with anti-PD-1 ICI. Conversely, treatment is permanently stopped for grade 2 cardiac and neurologic complications. Currently, there are no data to suggest that patients with prior PD-1 treatment are less likely to respond to rechallenge. Although the onset of irAEs on therapy has been linked with improved OS and PFS for some tumor types, special consideration is warranted about the value of continuing therapy for patients with breast cancer as the overall clinical benefits with ICI are more modest when compared with other immune-responsive tumor types.
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Adding CNVs and fusions to a lung cfDNA assay: impact on oncology research
- Dr. Beatriz Bellosillo, Head of Pathology at Hospital del Mar, discusses her experience evaluating the Oncomine Lung cfDNA Assay
- Dr. Kelli Bramlett, Sr. Director of R& D for Clinical NGS at Thermo Fisher Scientific, presents a new white paper that showcases performance of the new variant types introduced in the evaluated assay
Evaluation of a pan-cancer cell-free assay to meet unmet research needs
- Dr. Luca Quagliata, Consultant for Molecular Pathology at the University of Basel, shares his lab’s two specific unmet needs that lead to the evaluation, adoption, and implementation of the Oncomine Pan-Cancer Cell Free Assay
From qualitative to quantitative: experiences with a cfDNA assay in metastatic breast cancer research
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The Role Of Pyroptosis And Its Crosstalk With Immune Therapy In Breast Cancer
- 1Department of Clinical Laboratory Medicine, Taizhou Central Hospital , Taizhou, China
- 2Medical College, Yangzhou University, Yangzhou, China
Pyroptosis is a brand-new category of programmed cell death that is brought on by multitudinous inflammasomes, which can recognize several stimuli to pilot the cleavage of and activate inflammatory cytokines like IL-18 and IL-1 is believed to have dual effects on the development of multiple cancers including breast cancer. However, pyroptosis has different effects on cancers depending on the type of tissues and their distinct heredity. Recently, the association between pyroptosis and breast cancer has received more and more attention, and it is thought that inducing pyroptosis could be used as a cancer treatment option. In addition, a great deal of evidence accumulating over the past decades has evinced the crosstalk between pyroptosis and tumor immunological therapy. Thus, a comprehensive summary combining the function of pyroptosis in breast cancer and antitumor immunity is imperative. We portray the prevalent knowledge of the multidimensional roles of pyroptosis in cancer and summarize the pyroptosis in breast cancer principally. Moreover, we elucidate the influence of inflammasomes and pyroptosis-produced cytokines on the tumor microenvironment of breast cancer. Taken together, we aim to provide a clue to harness pyroptosis rationally and apply it to augment immunotherapy efficiency for breast cancer.
Advancements In Human Breast Cancer Targeted Therapy And Immunotherapy
Mayassa J. Bou-Dargham1#, Sophia Draughon1#, Vance Cantrell1, Zahraa I. Khamis1,2 , Qing-Xiang Amy Sang1,3
1. Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida, United States of America.2. Department of Chemistry and Biochemistry, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon.3. Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida, United States of America.#These authors contributed equally to this work.
Corresponding authors: E-mail: qxsangfsu.edu and zahraakhamiscom .
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Advanced Her2+ Breast Cancer
Signals of clinical efficacy have been reported with the addition of ICIs to standard of care therapies in HER2+ advanced breast cancer. Beyond immunotherapy, additional targeted agents such as trastuzumab deruxtecan and tucatinib continue to offer more options to patients with HER2+ disease. In the phase II KATE2 study, which randomized 133 patients to receive atezolizumab plus trastuzumab emtansine and 69 patients to receive placebo plus T-DM1, no statistically significant difference in overall PFS was observed between the two arms. A trend toward more favorable PFS and ORR were seen with the combination in patients with tumor infiltrating lymphocyte â¥5% and/or PD-L1+ tumors as defined by an IC score > 1 by the SP142 assay. Updated data with a median follow-up of 19.5 months for the atezolizumab arm and 18.2 months for the placebo arm revealed similar 1-year OS rates in both arms . In the PD-L1+ subgroup , the 1-year OS was numerically greater in the atezolizumab arm compared with placebo . A definitive phase III trial is planned based on this hypothesis-generating data.
Other General Concerns For Patients With Breast Cancer Treated With Immunotherapy
Curative locoregional therapy including definitive surgery and adjuvant radiation therapy have been used sequentially or concurrently with anti-PD-1 immunotherapy in the I-SPY2, KEYNOTE-522, and IMpassion031 studies. Of note, for immunotherapy in the adjuvant setting, monitoring for irAEs may be challenging if patients transfer to another healthcare provider. For example, if a patient receives adjuvant therapy at a tertiary care center, but then transfers care to a local oncologist, it is essential there is exchange of information among providers regarding the risk of toxicity and need for ongoing vigilance for irAEs. In published trials, there has not been an increased incidence of perioperative complications with immunotherapy. While rare with PD-1 agents, adrenal insufficiency is associated with ICIs, and therefore obtaining a preoperative cortisol level is recommended for patients who have received neoadjuvant checkpoint inhibitors.
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Immune System And Breast Cancer
The immune system plays an important role in normal breast development, where diverse populations of immune cells are present in the breast stroma at various stages of development and maturation, like post-natality, puberty and pregnancy .
BC is usually classified as a moderately immunogenic cancer, with the HER2+ and TNBC subtypes considered to be the most immunogenic subtypes . Immune cells have a crucial role in BC recognition and early eradication, but also in tumor progression . The process that describes the interactions between the hosts immune system and the tumors cells is denominated as immunoediting, and it englobes three phases: the elimination, the equilibrium and the escape . Mendes et al. proposed a fourth phase, the exhaustion .
Immunoediting commences by recognizing cancer cells as foreign and mounting an immune response against themthe elimination phase . This starts with breast tumorigenesis, in which the tumor tissue releases signals that activate the innate immunity cells such as Natural Killer cells, macrophages and neutrophils, all acting to eliminate the tumor cells. This process also contributes to dendritic cell maturation, that are antigen-presenting cells to T cells and that initiate a specific immune response against the tumor, mainly with the CD8+ cytotoxic T cells .
Monitoring Patients On Treatment
The goal of appropriate monitoring during immunotherapy treatment is to promptly detect immune-related toxicities and intervene before these toxicities cause significant morbidity or mortality. An important principle is to properly educate patients and staff about the symptoms that require prompt reporting to avoid life-threatening complications . The most frequently reported irAEs in breast cancer ICI trials are rash and pruritus , thyroid disorders , and liver function abnormalities . Incidences of irAEs reported in trials of ICI monotherapy or combination regimens for TNBC are summarized in . Particular attention should be paid to new or worsening fatigue, headaches, rash, respiratory symptoms, changes in bowel function, visual changes/eye pain, or musculoskeletal symptoms. Careful monitoring of laboratory studies is also required, including electrolytes, creatinine, glucose, liver function, and thyroid hormone levels.
Reported incidence of irAEs in published ICI clinical trials for metastatic TNBC
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Future Perspectives Of Pyroptosis In Breast Cancer
Since a closed association between pyroptosis and breast cancer as well as antitumor immunity, targeting pyroptosis or gene-related pyroptosis may be a treatment option for breast cancer patients and will undoubtedly become a focused area in the future. Meanwhile, with the development of bioinformatics, the association among pyroptosis, clinical outcome, and the effectiveness of immunotherapy are further comprehensively analyzed by evaluating genes and long non-coding RNAs linked to pyroptosis , which is also beneficial to discover new genes and mechanisms. However, there are only a limited number of experimental and clinical investigations that have investigated the link between pyroptosis and breast cancer. Recognizing the multidimensional roles of pyroptosis in breast cancer and applying it in cancer therapy research is still at an initial stage. In the short run, laboratories and medical institutions have an incentive to conduct studies and clinical tests with the mechanism that functions in initiating pyroptosis. Meanwhile, as a model of inflammatory death, the factors related to pyroptosis can form an inflammatory microenvironment and have a duple influence on encouraging and preventing tumor growth. The mechanism of pyroptosis and the associated factor in breast tumors must thus be further investigated in well-designed research to provide fresh therapeutic alternatives.
Human Microbiota And Immune System
In a specific biosphere, the set composed of microorganisms, including bacteria, viruses, fungi, archaea, and protists, is designated by microbiota. The collective genome of these biological agents is called the microbiome. There are different microbiota ecosystems in the human body, such as the gastrointestinal tract, skin, vaginal mucosa, or the oral cavity, which account for trillions of microorganisms. The relationship between these ecological communities and the human body is ancient and evolved over time to benefit both parties simultaneously, thus achieving a symbiotic balance .
Figure 1 Gut Microbiota and Immune System. Gut bacteria, through PAMPs, can upregulate the TLRs and activate inflammatory pathways, which causes a release of cytokines leading to an inflammation milieu. PAMPs can also activate APC which migrate to the mesenteric lymph nodes to stimulate T and B cells. Activation of B cells to plasma cells allows the release of IgA into the lumen. APC activate CD4 T cells to differentiate into Tregs and Th17 cells, that can migrate back to the gut or enter systemic circulation and influence immunity in different sites. APC may also stimulate CD8 T cells into effector cells that migrate from the gut to periphery.
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Tumor Antigens And Vaccines In Breast Cancer
The immune system eliminates tumors by recognizing tumor antigens processed and presented by MHC class I and MHC class II , resulting in the cross-priming and activation of T cells and tumor rejection. Breast cancer vaccines are designed to induce or amplify a population of tumor-specific T cells that can recognize and lyse breast tumors. Historically, breast cancer vaccines have incorporated shared tumor antigens that are overexpressed in tumors relative to normal tissues, or are restricted to mammary tissue . Shared tumor antigens are typically recognized as self by the immune system. To avoid autoimmunity, thymic selection results in the deletion of high-avidity T cells specific for these tumor antigens, leaving in place a population of lower avidity T cells for recruitment to the tumor-specific immune response.