Refining patient selection for breast cancer immunotherapy: beyond PD-L1.
01 Oct 2021-Vol. 6, Iss: 5, pp 100257
TL;DR: In this paper, the authors proposed to combine clinical, molecular and immunological features of the disease, possibly powered by artificial intelligence, for better selection of BC patients for various immunotherapies.
Abstract: Therapies that modulate immune response to cancer, such as immune checkpoint inhibitors, began an intense development a few years ago; however, in breast cancer (BC), the results have been relatively disappointing so far. Finding biomarkers for better selection of BC patients for various immunotherapies remains a significant unmet medical need. At present, only tumour tissue programmed death-ligand 1 (PD-L1) and mismatch repair deficiency status are approved as theranostic biomarkers for programmed cell death-1 (PD-1)/PD-L1 inhibitors in BC. However, due to the complexity of tumour microenvironment (TME) and cancer response to immunomodulators, none of them is a perfect selector. Therefore, an intense quest is ongoing for complementary tumour- or host-related predictive biomarkers in breast immuno-oncology. Among the upcoming biomarkers, quantity, immunophenotype and spatial distribution of tumour-infiltrating lymphocytes and other TME cells as well as immune gene signatures emerge as most promising and are being increasingly tested in clinical trials. Biomarkers or strategies allowing dynamic assessment of BC response to immunotherapy, such as circulating/exosomal PD-L1, quantity of white/immune blood cell subpopulations and molecular imaging are particularly suitable for immunotreatment monitoring. Finally, host-related factors, such as microbiome and lifestyle, should also be taken into account when planning integration of immunomodulating therapies into BC management. As none of the biomarkers taken separately is accurate enough, the solution could come from composite biomarkers, which would combine clinical, molecular and immunological features of the disease, possibly powered by artificial intelligence.
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TL;DR: A review of the main published studies on serum proteins in breast cancer and elaborate on the potential of circulating proteins to be predictive and/or prognostic biomarkers in Breast Cancer is presented in this paper .
Abstract: Breast cancer (BC) is the most common cancer and among the leading causes of cancer death in women. It is a heterogeneous group of tumours with numerous morphological and molecular subtypes, making predictions of disease evolution and patient outcomes difficult. Therefore, biomarkers are needed to help clinicians choose the best treatment for each patient. For the last years, studies have increasingly focused on biomarkers obtainable by liquid biopsy. Circulating proteins (from serum or plasma) can be used for inexpensive and minimally invasive determination of disease risk, early diagnosis, treatment adjusting, prognostication and disease progression monitoring. We provide here a review of the main published studies on serum proteins in breast cancer and elaborate on the potential of circulating proteins to be predictive and/or prognostic biomarkers in breast cancer.
10 citations
TL;DR: A review of the main published studies on serum proteins in breast cancer and elaborate on the potential of circulating proteins to be predictive and/or prognostic biomarkers in Breast Cancer is presented in this article .
Abstract: Breast cancer (BC) is the most common cancer and among the leading causes of cancer death in women. It is a heterogeneous group of tumours with numerous morphological and molecular subtypes, making predictions of disease evolution and patient outcomes difficult. Therefore, biomarkers are needed to help clinicians choose the best treatment for each patient. For the last years, studies have increasingly focused on biomarkers obtainable by liquid biopsy. Circulating proteins (from serum or plasma) can be used for inexpensive and minimally invasive determination of disease risk, early diagnosis, treatment adjusting, prognostication and disease progression monitoring. We provide here a review of the main published studies on serum proteins in breast cancer and elaborate on the potential of circulating proteins to be predictive and/or prognostic biomarkers in breast cancer.
10 citations
TL;DR: A review of the recent clinical trials that inform the integration of immune checkpoint inhibitors into treatments for triple negative breast cancer (TNBC) can be found in this paper , where the authors discuss ongoing challenges including patient selection, management of resistance to post-checkpoint inhibitor therapy, and combining immunotherapy with targeted therapies, including PARP inhibitors.
Abstract: Triple-negative breast cancer (TNBC) is the most aggressive histologic subtype of breast cancer for which, until recently, treatment options have been limited to chemotherapy. In recent years, an improved understanding of the importance of tumor-infiltrating lymphocytes and the tumor microenvironment in TNBC has led to investigation of immune checkpoint inhibitors for treatment. There is now evidence from several randomized controlled trials that supports the addition of immune checkpoint inhibitors to first-line treatment of advanced TNBC and to neoadjuvant chemotherapy for stage II-III TNBC. In parallel, the PARP inhibitors have emerged as a targeted therapy option for patients with HER2-negative breast cancer harboring mutations in BRCA1, BRCA2, and PALB2. Here, we review the recent clinical trials that inform the integration of immune checkpoint inhibitors into treatments for TNBC and discuss ongoing challenges-including patient selection, management of resistance to post-checkpoint inhibitor therapy, and combining immunotherapy with targeted therapies, including PARP inhibitors.
5 citations
TL;DR: The authors in this paper focused on the mRNA vaccine for the immunotherapy of neuroblastoma and gave an overview based on the recent literature available, focusing on the characteristics such as elevated effectiveness, harmless administration, quick expansion abilities, and efficient manufacturing allows the mRNA cancer vaccines outperform other traditional vaccination platforms.
Abstract: In children, neuroblastoma seems to be the most frequent form of tumor found in the extracranial region, with a wide range of medical outcomes ranging from reduction of the tumor volume with time to even developing into a metastatic form and death, regardless of treatment. mRNA vaccines have emerged as a potential cancer treatment platform and could be used as a treatment of neuroblastoma as well. mRNA vaccines, whether naked or loaded with a carrier, proficiently express the antigens of the tumor in APCs after the process of immunization which facilitates the stimulation of the APCs and innate immune reaction. The characteristics such as elevated effectiveness, harmless administration, quick expansion abilities, and efficient manufacturing allows the mRNA cancer vaccines outperform other traditional vaccination platforms. This review focuses on the mRNA vaccine for the immunotherapy of neuroblastoma and gives an overview based on the recent literature available.
2 citations
TL;DR: Clinical trials investigating neoadjuvant ICIs for TNBC and the improvement of pCR rates are appraised and insights into the role of p CR as a surrogate endpoint and the possibility of enhancing p CR rates for women affected by early TNBC are offered.
Abstract: ABSTRACT Introduction The treatment landscape of early triple-negative breast cancer (TNBC) has recently expanded after the Food and Drug Administration (FDA) approval of pembrolizumab in combination with neoadjuvant chemotherapy. The addition of this immune checkpoint inhibitor (ICI) has shown significantly increased pathological complete response (pCR) rate and event-free survival (EFS) in the KEYNOTE-522 phase III trial. Several additional studies are ongoing with the goal of further improving the outcomes and achieving an optimal integration of ICIs in the treatment of TNBC. Areas covered The article examines pCR and survival rates in TNBC. It appraises clinical trials investigating neoadjuvant ICIs for TNBC and the improvement of pCR rates (biomarker-driven escalation of treatment, optimization of chemotherapy backbone, and addition of locoregional treatments or innovative agents). Insights into the role of pCR as a surrogate endpoint and the possibility of enhancing pCR rates for women affected by early TNBC are offered. Expert opinion The pharmacopoeia of early TNBC is growing and becoming more heterogeneous with the advent of ICIs; to enhance the clinical benefit of patients, it is necessary to develop response endpoints that consider the mechanism of action of experimental drugs, to optimize patient selection through validated biomarkers, and to compare the most promising treatment strategies in randomized clinical trials.
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Wellcome Trust Sanger Institute1, Cambridge University Hospitals NHS Foundation Trust2, Wellcome Trust3, University of British Columbia4, University of Cambridge5, Oslo University Hospital6, The Breast Cancer Research Foundation7, University of Oslo8, University of Münster9, Université libre de Bruxelles10, German Cancer Research Center11, University of Iceland12, Erasmus University Rotterdam13, Paris Descartes University14, French Institute of Health and Medical Research15, University of Paris16, Broad Institute17, University of Bergen18, University of Queensland19, University of Oviedo20, University of Glasgow21, Harvard University22, United States Department of Veterans Affairs23, Netherlands Cancer Institute24, University of Kiel25, Radboud University Nijmegen26, King's College London27, Curie Institute28, Bankstown Lidcombe Hospital29, University of New South Wales30, University of Barcelona31
TL;DR: It is shown that hypermutation localized to small genomic regions, ‘kataegis’, is found in many cancer types, and this results reveal the diversity of mutational processes underlying the development of cancer.
Abstract: All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.
7,904 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
TL;DR: A unifying conceptual framework called “cancer immunoediting,” which integrates the immune system’s dual host-protective and tumor-promoting roles is discussed.
Abstract: Understanding how the immune system affects cancer development and progression has been one of the most challenging questions in immunology. Research over the past two decades has helped explain why the answer to this question has evaded us for so long. We now appreciate that the immune system plays a dual role in cancer: It can not only suppress tumor growth by destroying cancer cells or inhibiting their outgrowth but also promote tumor progression either by selecting for tumor cells that are more fit to survive in an immunocompetent host or by establishing conditions within the tumor microenvironment that facilitate tumor outgrowth. Here, we discuss a unifying conceptual framework called "cancer immunoediting," which integrates the immune system's dual host-protective and tumor-promoting roles.
5,026 citations
TL;DR: Evaluating the efficacy of PD-1 blockade in patients with advanced mismatch repair–deficient cancers across 12 different tumor types showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor–1 (PD-1).
Abstract: The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor–1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair–deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair–deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers’ tissue of origin.
4,569 citations