Novel Approaches to Immunotherapy in Triple Negative Breast Cancer
15 Dec 2018-Vol. 11, Iss: 12
TL;DR: As TNBC is regarded a heterogeneous disease, the discovery of biomarkers of response to immunotherapy will increase the likelihood of response of patients with TNBC to these therapies.
Abstract: Context: Triple negative breast cancers (TNBC) constitute about 15% of breast neoplasms. In contrast to estrogen receptor (ER) or human epidermal growth factor receptor (HER2) positive breast cancers, which respond to hormonal therapy (such as tamoxifen) or anti-HER2 therapy (such as trastuzumab), respectively, the main standard therapy in either early or late stage TNBC is chemotherapy. Therefore, it is necessary to find new treatment modalities for TNBC patients. We searched the literature to find published studies on immunotherapy in triple negative breast cancer and the putative biomarkers of response to these treatments. Evidence Acquisition: We searched PubMed, Scopus, and Web of Science Core Collection with these keywords: “Triple negative breast cancer, Immunotherapy, Resistance, Response, Programmed cell death 1 receptor, CTLA-4, Tumor mutation burden, and Immune signature”. Results: TNBC is considered a heterogeneous neoplasm with regard to molecular aberrations. Analysis of genomic expression profile of TNBC has delineated 4 subtypes. TNBC tumors show high genetic instability. Tumor infiltrating lymphocytes (TILs) are detected more in TNBCs, compared to other breast cancer types. It has been shown that the amount of CD8 positive T cells in TNBCs is an independent predictor of overall survival. Up to now, two immunotherapy strategies have been used in clinical trials of TNBC, including immune checkpoint blockers and therapeutic cancer vaccines. Tumor programmed cell death ligand 1 (PDL1) expression is the most widely used immunotherapy biomarker. Tumor mutation burden (TMB) can be a promising biomarker of response to immunotherapy. The more somatic mutations a cancer cell has, the more neoantigens it probably produces. Analysis of TMB can give an estimate of tumor mutation load. Increased somatic mutation load has also been observed in tumors with impaired mismatch repair (MMR). Conclusions: As TNBC is regarded a heterogeneous disease, the discovery of biomarkers of response to immunotherapy will increase the likelihood of response to these therapies. Further in-depth investigations are needed to find novel biomarkers of response to these immunotherapies for the better management of patients with TNBC.
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TL;DR: The naturally abundant guar gum based non-viral carrier developed through conjugating by low molecular weight polyethylenimine (LPEI) using napthalic anhydride coupling agent showed very high in vitro transfection efficiency in TNBC cell compared to lipofectamine 2000 (LF2k) which could be justified by its high buffering capacity.
16 citations
TL;DR: Immunotherapy (namely, immune checkpoint inhibitors, adoptive cellular immunotherapy, CAR-T immunotherapy and some potential treatments) provides new hope in TNBC.
Abstract: In the classification and typing of breast cancer, triple-negative breast cancer (TNBC) is one type of refractory breast cancer, while chemotherapy stays in the traditional treatment methods. However, the impact of chemotherapy is short-lived and may lead to recurrence due to incomplete killing of tumor cells. The occurrence, development, and relapse of breast cancer are relevant to T cell dysfunction, multiplied expression of related immune checkpoint molecules (ICIs) such as programmed death receptor 1 (PD-1), programmed cell death 1 ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) produce immunosuppressive effect. Immunotherapy (namely, immune checkpoint inhibitors, adoptive cellular immunotherapy, CAR-T immunotherapy and some potential treatments) provides new hope in TNBC. This review focuses on the new immune strategies of TNBC patients.
14 citations
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TL;DR: A status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions.
Abstract: This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions There will be an estimated 181 million new cancer cases (170 million excluding nonmelanoma skin cancer) and 96 million cancer deaths (95 million excluding nonmelanoma skin cancer) in 2018 In both sexes combined, lung cancer is the most commonly diagnosed cancer (116% of the total cases) and the leading cause of cancer death (184% of the total cancer deaths), closely followed by female breast cancer (116%), prostate cancer (71%), and colorectal cancer (61%) for incidence and colorectal cancer (92%), stomach cancer (82%), and liver cancer (82%) for mortality Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality) Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors It is noteworthy that high-quality cancer registry data, the basis for planning and implementing evidence-based cancer control programs, are not available in most low- and middle-income countries The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts CA: A Cancer Journal for Clinicians 2018;0:1-31 © 2018 American Cancer Society
58,675 citations
Daniel C. Koboldt1, Robert S. Fulton1, Michael D. McLellan1, Heather Schmidt1 +352 more•Institutions (35)
TL;DR: The ability to integrate information across platforms provided key insights into previously defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity.
Abstract: We analysed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing and reverse-phase protein arrays. Our ability to integrate information across platforms provided key insights into previously defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at >10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA and MAP3K1 with the luminal A subtype. We identified two novel protein-expression-defined subgroups, possibly produced by stromal/microenvironmental elements, and integrated analyses identified specific signalling pathways dominant in each molecular subtype including a HER2/phosphorylated HER2/EGFR/phosphorylated EGFR signature within the HER2-enriched expression subtype. Comparison of basal-like breast tumours with high-grade serous ovarian tumours showed many molecular commonalities, indicating a related aetiology and similar therapeutic opportunities. The biological finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biological subtypes of breast cancer.
9,355 citations
TL;DR: Pembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non-small-cell lung cancer (NSCLC), with increased activity in tumors that express PD-L1 as mentioned in this paper.
Abstract: BackgroundPembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non–small-cell lung cancer (NSCLC), with increased activity in tumors that express programmed death ligand 1 (PD-L1). MethodsIn this open-label, phase 3 trial, we randomly assigned 305 patients who had previously untreated advanced NSCLC with PD-L1 expression on at least 50% of tumor cells and no sensitizing mutation of the epidermal growth factor receptor gene or translocation of the anaplastic lymphoma kinase gene to receive either pembrolizumab (at a fixed dose of 200 mg every 3 weeks) or the investigator’s choice of platinum-based chemotherapy. Crossover from the chemotherapy group to the pembrolizumab group was permitted in the event of disease progression. The primary end point, progression-free survival, was assessed by means of blinded, independent, central radiologic review. Secondary end points were overall survival, objective response rate, and safety. ResultsMedi...
7,053 citations
TL;DR: Treatment efficacy was associated with a higher number of mutations in the tumors, and a tumor-specific T cell response paralleled tumor regression in one patient, suggesting that the genomic landscape of lung cancers shapes response to anti–PD-1 therapy.
Abstract: Immune checkpoint inhibitors, which unleash a patient’s own T cells to kill tumors, are revolutionizing cancer treatment. To unravel the genomic determinants of response to this therapy, we used whole-exome sequencing of non–small cell lung cancers treated with pembrolizumab, an antibody targeting programmed cell death-1 (PD-1). In two independent cohorts, higher nonsynonymous mutation burden in tumors was associated with improved objective response, durable clinical benefit, and progression-free survival. Efficacy also correlated with the molecular smoking signature, higher neoantigen burden, and DNA repair pathway mutations; each factor was also associated with mutation burden. In one responder, neoantigen-specific CD8+ T cell responses paralleled tumor regression, suggesting that anti–PD-1 therapy enhances neoantigen-specific T cell reactivity. Our results suggest that the genomic landscape of lung cancers shapes response to anti–PD-1 therapy.
6,215 citations
Yale University1, Netherlands Cancer Institute2, Seoul National University Hospital3, Hebron University4, University of Navarra5, Mayo Clinic6, Samsung Medical Center7, Rush University Medical Center8, University of São Paulo9, Pontifical Catholic University of Chile10, Merck & Co.11, University of California, Los Angeles12
TL;DR: In this article, the authors evaluated the efficacy of pembrolizumab for patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer.
4,693 citations