Immunotherapy for triple-negative breast cancer: A molecular insight into the microenvironment, treatment, and resistance

Karn, 2017, Association Between Genomic Metrics and Immune Infiltration in Triple-Negative Breast Cancer, JAMA Oncol, 3, 1707, 10.1001/jamaoncol.2017.2140 Guestini F, McNamara KM, Ishida T, et al. Triple negative breast cancer chemosensitivity and chemoresistance: current advances in biomarkers indentification. Expert Opin Ther Targets. Jun 2016;20(6):705-20. doi:10.1517/14728222.2016.1125469 Robson, 2017, Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation, N Engl J Med, 377, 523, 10.1056/NEJMoa1706450 Bai, 2021, Triple-negative breast cancer therapeutic resistance: Where is the Achilles' heel?, Cancer Lett, 497, 100, 10.1016/j.canlet.2020.10.016 Mittendorf, 2014, PD-L1 expression in triple-negative breast cancer, Cancer Immunol Res, 2, 361, 10.1158/2326-6066.CIR-13-0127 Luen S, Virassamy B, Savas P, et al. The genomic landscape of breast cancer and its interaction with host immunity. Breast. 2016;29:241-50. doi:10.1016/j.breast.2016.07.015 Schmid P, Adams S, Rugo HS, et al. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N Engl J Med. 2018;379(22):2108-2121. doi:10.1056/NEJMoa1809615 Emens, 2020, LBA16 IMpassion130: Final OS analysis from the pivotal phase III study of atezolizumab + nab-paclitaxel vs placebo + nab-paclitaxel in previously untreated locally advanced or metastatic triple-negative breast cancer, Annals of Oncology, 31, S1148, 10.1016/j.annonc.2020.08.2244 Iwata, 2019, Subgroup analysis of IMpassion130: Atezolizumab + nab-paclitaxel (nab-P) in patients (pts) with advanced triple-negative breast cancer (TNBC) in Asian countries, Annals of Oncology, 30, 10.1093/annonc/mdz418 Crosby, 2018, Complimentary mechanisms of dual checkpoint blockade expand unique T-cell repertoires and activate adaptive anti-tumor immunity in triple-negative breast tumors, Oncoimmunology, 7, e1421891, 10.1080/2162402X.2017.1421891 Maeda, 2018, MUC1-C Induces PD-L1 and Immune Evasion in Triple-Negative Breast Cancer, Cancer Res, 78, 205, 10.1158/0008-5472.CAN-17-1636 Samanta, 2018, Chemotherapy induces enrichment of CD47(+)/CD73(+)/PDL1(+) immune evasive triple-negative breast cancer cells, Proc Natl Acad Sci U S A, 115, E1239, 10.1073/pnas.1718197115 Costa A, Kieffer Y, Scholer-Dahirel A, et al. Fibroblast Heterogeneity and Immunosuppressive Environment in Human Breast Cancer. Cancer cell. 2018;33(3):463-479 e10. doi:10.1016/j.ccell.2018.01.011 Sami, 2020, The Immunosuppressive Microenvironment in BRCA1-IRIS-Overexpressing TNBC Tumors Is Induced by Bidirectional Interaction with Tumor-Associated Macrophages, Cancer Res, 80, 1102, 10.1158/0008-5472.CAN-19-2374 Ruffell, 2014, Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells, Cancer cell, 26, 623, 10.1016/j.ccell.2014.09.006 Roux, 2019, Reactive oxygen species modulate macrophage immunosuppressive phenotype through the up-regulation of PD-L1, Proc Natl Acad Sci U S A, 116, 4326, 10.1073/pnas.1819473116 Ceeraz, 2013, B7 family checkpoint regulators in immune regulation and disease, Trends Immunol, 34, 556, 10.1016/j.it.2013.07.003 Liu, 2021, Tumor-targeted gene therapy with lipid nanoparticles inhibits tumor-associated adipocytes and remodels the immunosuppressive tumor microenvironment in triple-negative breast cancer, Nanoscale Horiz, 6, 319, 10.1039/D0NH00588F Nolan, 2017, Combined immune checkpoint blockade as a therapeutic strategy for BRCA1-mutated breast cancer, Sci Transl Med, 9, 10.1126/scitranslmed.aal4922 Staaf, 2019, Whole-genome sequencing of triple-negative breast cancers in a population-based clinical study, Nat Med, 25, 1526, 10.1038/s41591-019-0582-4 Liu, 2018, A Comprehensive Immunologic Portrait of Triple-Negative Breast Cancer, Transl Oncol, 11, 311, 10.1016/j.tranon.2018.01.011 Singh, 2020, Loss of ELF5-FBXW7 stabilizes IFNGR1 to promote the growth and metastasis of triple-negative breast cancer through interferon-gamma signalling, Nat Cell Biol, 22, 591, 10.1038/s41556-020-0495-y Yamashita, 2021, MUC1-C integrates activation of the IFN-gamma pathway with suppression of the tumor immune microenvironment in triple-negative breast cancer, J Immunother Cancer, 9, e002115, 10.1136/jitc-2020-002115 Buisseret, 2018, Clinical significance of CD73 in triple-negative breast cancer: multiplex analysis of a phase III clinical trial, Ann Oncol, 29, 1056, 10.1093/annonc/mdx730 Eiger, 2020, 348P First findings from SYNERGY, a phase I/II trial testing the addition of the anti-CD73 oleclumab (O) to the anti-PD-L1 durvalumab (D) and chemotherapy (ChT) as first line therapy for patients (pts) with metastatic triple-negative breast cancer (mTNBC), Annals of Oncology, 31, S386, 10.1016/j.annonc.2020.08.450 Shuptrine, 2017, An unbiased in vivo functional genomics screening approach in mice identifies novel tumor cell-based regulators of immune rejection, Cancer Immunol Immunother, 66, 1529, 10.1007/s00262-017-2047-2 DeNardo, 2019, Macrophages as regulators of tumour immunity and immunotherapy, Nat Rev Immunol, 19, 369, 10.1038/s41577-019-0127-6 Azizi, 2018, Single-Cell Map of Diverse Immune Phenotypes in the Breast Tumor Microenvironment, Cell, 174, 1293, 10.1016/j.cell.2018.05.060 Wagner, 2019, A Single-Cell Atlas of the Tumor and Immune Ecosystem of Human Breast Cancer, Cell, 177, 1330, 10.1016/j.cell.2019.03.005 Bassez, 2021, A single-cell map of intratumoral changes during anti-PD1 treatment of patients with breast cancer, Nat Med, 27, 820, 10.1038/s41591-021-01323-8 Cortés, 2019, LBA21 - KEYNOTE-119: Phase III study of pembrolizumab (pembro) versus single-agent chemotherapy (chemo) for metastatic triple negative breast cancer (mTNBC), Annals of Oncology, 30, v859, 10.1093/annonc/mdz394.010 Cortes, 2020, Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial, Lancet, 396, 1817, 10.1016/S0140-6736(20)32531-9 Yusof, 2020, 43O Phase III KEYNOTE-355 study of pembrolizumab (pembro) vs placebo (pbo) + chemotherapy (chemo) for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC): Results for patients (Pts) enrolled in Asia, Annals of Oncology, 31, S1257, 10.1016/j.annonc.2020.10.063 Chen, 2013, Chemoimmunotherapy: reengineering tumor immunity, Cancer Immunol Immunother, 62, 203, 10.1007/s00262-012-1388-0 Falvo, 2021, Cyclophosphamide and Vinorelbine Activate Stem-Like CD8(+) T Cells and Improve Anti-PD-1 Efficacy in Triple-Negative Breast Cancer, Cancer Res, 81, 685, 10.1158/0008-5472.CAN-20-1818 Coosemans, 2019, Combining conventional therapy with immunotherapy: A risky business?, Eur J Cancer, 113, 41, 10.1016/j.ejca.2019.02.014 Miles, 2020, LBA15 Primary results from IMpassion131, a double-blind placebo-controlled randomised phase III trial of first-line paclitaxel (PAC) ± atezolizumab (atezo) for unresectable locally advanced/metastatic triple-negative breast cancer (mTNBC), Annals of Oncology, 31, S1147, 10.1016/j.annonc.2020.08.2243 Kok, 2017, Adaptive phase II randomized non-comparative trial of nivolumab after induction treatment in triple negative breast cancer: TONIC-trial, Annals of Oncology, 28, v608, 10.1093/annonc/mdx440.006 Voorwerk, 2019, Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial, Nat Med, 25, 920, 10.1038/s41591-019-0432-4 Loibl, 2019, A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study, Ann Oncol, 30, 1279, 10.1093/annonc/mdz158 Schmid, 2020, Pembrolizumab for Early Triple-Negative Breast Cancer, N Engl J Med, 382, 810, 10.1056/NEJMoa1910549 Dent, 2020, 1O KEYNOTE-522 Asian subgroup: Phase III study of neoadjuvant pembrolizumab (pembro) vs placebo (pbo) + chemotherapy (chemo) followed by adjuvant pembro vs pbo for early triple-negative breast cancer (TNBC), Annals of Oncology, 31, S1241, 10.1016/j.annonc.2020.10.021 Mittendorf, 2020, Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial, Lancet, 396, 1090, 10.1016/S0140-6736(20)31953-X Lhuillier, 2021, Radiotherapy-exposed CD8+ and CD4+ neoantigens enhance tumor control, J Clin Invest, 131, 10.1172/JCI138740 McArthur, 2020, Abstract P3-09-09: Pre-operative pembrolizumab (pembro) with radiation therapy (RT) in patients with operable triple-negative breast cancer (TNBC), Cancer Research, 80 Loi, 2016, RAS/MAPK Activation Is Associated with Reduced Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer: Therapeutic Cooperation Between MEK and PD-1/PD-L1 Immune Checkpoint Inhibitors, Clin Cancer Res, 22, 1499, 10.1158/1078-0432.CCR-15-1125 Page, 2019, A phase II study of dual immune checkpoint blockade (ICB) plus androgen receptor (AR) blockade to enhance thymic T-cell production and immunotherapy response in metastatic breast cancer (MBC), Journal of Clinical Oncology, 37, 10.1200/JCO.2019.37.15_suppl.TPS1106 Yuan, 2021, A Phase II Clinical Trial of Pembrolizumab and Enobosarm in Patients with Androgen Receptor-Positive Metastatic Triple-Negative Breast Cancer, Oncologist, 26, 99, 10.1002/onco.13583 Jiao, 2017, PARP Inhibitor Upregulates PD-L1 Expression and Enhances Cancer-Associated Immunosuppression, Clin Cancer Res., 23, 3711, 10.1158/1078-0432.CCR-16-3215 Vinayak, 2019, Open-Label Clinical Trial of Niraparib Combined With Pembrolizumab for Treatment of Advanced or Metastatic Triple-Negative Breast Cancer, JAMA Oncol, 5, 1132, 10.1001/jamaoncol.2019.1029 Li, 2020, Low-Dose Anti-Angiogenic Therapy Sensitizes Breast Cancer to PD-1 Blockade, Clin Cancer Res, 26, 1712, 10.1158/1078-0432.CCR-19-2179 Liu, 2020, Efficacy and safety of camrelizumab combined with apatinib in advanced triple-negative breast cancer: an open-label phase II trial, J Immunother Cancer, 8, e000696, 10.1136/jitc-2020-000696 Brufsky, 2019, Phase II COLET study: Atezolizumab (A) + cobimetinib (C) + paclitaxel (P)/nab-paclitaxel (nP) as first-line (1L) treatment (tx) for patients (pts) with locally advanced or metastatic triple-negative breast cancer (mTNBC), Journal of Clinical Oncology, 37, 1013, 10.1200/JCO.2019.37.15_suppl.1013 Lwin, 2020, LBA41 LEAP-005: Phase II study of lenvatinib (len) plus pembrolizumab (pembro) in patients (pts) with previously treated advanced solid tumours, Annals of Oncology, 31, S1170, 10.1016/j.annonc.2020.08.2271 Polk A, Svane IM, Andersson M, et al. Checkpoint inhibitors in breast cancer - Current status. Cancer Treat Rev. 2018;63:122-134. doi:10.1016/j.ctrv.2017.12.008 Hutchinson, 2020, Comprehensive Profiling of Poor-Risk Paired Primary and Recurrent Triple-Negative Breast Cancers Reveals Immune Phenotype Shifts, Clin Cancer Res, 26, 657, 10.1158/1078-0432.CCR-19-1773 Sceneay, 2019, Interferon Signaling Is Diminished with Age and Is Associated with Immune Checkpoint Blockade Efficacy in Triple-Negative Breast Cancer, Cancer Discov, 9, 1208, 10.1158/2159-8290.CD-18-1454 Zaretsky, 2016, Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma, N Engl J Med, 375, 819, 10.1056/NEJMoa1604958 Patel, 2017, Identification of essential genes for cancer immunotherapy, Nature, 548, 537, 10.1038/nature23477 Schwartz, 2011, The Role of Interferon Regulatory Factor-1 (IRF1) in Overcoming Antiestrogen Resistance in the Treatment of Breast Cancer, Int J Breast Cancer, 912102 Benci, 2016, Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade, Cell, 167, 1504, 10.1016/j.cell.2016.11.022 Pan, 2018, A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing, Science, 359, 770, 10.1126/science.aao1710 Huang, 2018, The RNA-binding Protein MEX3B Mediates Resistance to Cancer Immunotherapy by Downregulating HLA-A Expression, Clin Cancer Res, 24, 3366, 10.1158/1078-0432.CCR-17-2483 Hu, 2019, Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression, Nat Immunol, 20, 835, 10.1038/s41590-019-0400-7 Manguso RT, Pope HW, Zimmer MD, et al. In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nature. 2017;547(7664):413-418. doi:10.1038/nature23270 Brockwell, 2017, Neoadjuvant Interferons: Critical for Effective PD-1-Based Immunotherapy in TNBC, Cancer Immunol Res, 5, 871, 10.1158/2326-6066.CIR-17-0150 Pedersen, 2017, Downregulation of antigen presentation-associated pathway proteins is linked to poor outcome in triple-negative breast cancer patient tumors, Oncoimmunology, 6, e1305531, 10.1080/2162402X.2017.1305531 Della Mora, 2017, Stromal peritumoral and intratumoral infiltrating lymphocytes: how immunity influences prognosis in triple negative breast cancer, Annals of Oncology, 28, vi31, 10.1093/annonc/mdx424.022 McGrail DJ, Pilie PG, Rashid NU, et al. High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types. Ann Oncol. 2021;32(5):661-672. doi:10.1016/j.annonc.2021.02.006 Karn, 2020, Tumor mutational burden and immune infiltration as independent predictors of response to neoadjuvant immune checkpoint inhibition in early TNBC in GeparNuevo, Ann Oncol, 31, 1216, 10.1016/j.annonc.2020.05.015 Emens, 2020, 296P Tumour mutational burden and clinical outcomes with first-line atezolizumab and nab-paclitaxel in triple-negative breast cancer: Exploratory analysis of the phase III IMpassion130 trial, Annals of Oncology, 31, S360, 10.1016/j.annonc.2020.08.398 Strickler, 2021, Tumor Mutational Burden as a Predictor of Immunotherapy Response: Is More Always Better?, Clin Cancer Res, 27, 1236, 10.1158/1078-0432.CCR-20-3054 Gruosso, 2019, Spatially distinct tumor immune microenvironments stratify triple-negative breast cancers, J Clin Invest, 129, 1785, 10.1172/JCI96313 Xiao, 2019, Multi-Omics Profiling Reveals Distinct Microenvironment Characterization and Suggests Immune Escape Mechanisms of Triple-Negative Breast Cancer, Clin Cancer Res, 25, 5002, 10.1158/1078-0432.CCR-18-3524 Kim, 2019, Immuno-subtyping of breast cancer reveals distinct myeloid cell profiles and immunotherapy resistance mechanisms, Nat Cell Biol, 21, 1113, 10.1038/s41556-019-0373-7 Wang, 2021, Tumor immunological phenotype signature-based high-throughput screening for the discovery of combination immunotherapy compounds, Sci Adv., 7, eabd7851, 10.1126/sciadv.abd7851 Bardia, 2019, Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer, N Engl J Med, 380, 741, 10.1056/NEJMoa1814213 Song, 2020, Pharmacologic Suppression of B7-H4 Glycosylation Restores Antitumor Immunity in Immune-Cold Breast Cancers, Cancer Discov, 10, 1872, 10.1158/2159-8290.CD-20-0402 MR, 2017, Nectin-4: a new prognostic biomarker for efficient therapeutic targeting of primary and metastatic triple-negative breast cancer, Ann Oncol, 28, 769, 10.1093/annonc/mdw678 Sohn, 2020, 322 Efficacy and safety of GX-I7 plus pembrolizumab for heavily pretreated patients with metastatic triple negative breast cancer: The Phase 1b/2 KEYNOTE-899 Study, Journal for ImmunoTherapy of Cancer, 8, A197 Bourgeois-Daigneault, 2018, Neoadjuvant oncolytic virotherapy before surgery sensitizes triple-negative breast cancer to immune checkpoint therapy, Sci Transl Med, 10, 10.1126/scitranslmed.aao1641 Toh, 2020, Early phase II study of mixed 19-peptide vaccine monotherapy for refractory triple-negative breast cancer, Cancer Sci, 111, 2760, 10.1111/cas.14510 Fabian, 2020, PD-L1 targeting high-affinity NK (t-haNK) cells induce direct antitumor effects and target suppressive MDSC populations, J Immunother Cancer, 8, e000450, 10.1136/jitc-2019-000450