Combinatorial Epigenetic and Immunotherapy in Breast Cancer Management: A Literature Review
Abstract
:1. Introduction
2. Epigenetics and Epi-Drugs
3. Rationale for Epi-Drugs Combined with Immunotherapy
3.1. Targeting DNA Methylation
3.2. Targeting Histone Deacetylation
3.3. Targeting Histone Demethylation
3.4. Targeting Histone Methylation
3.5. Targeting Bromodomain in Breast Cancer
4. Conclusions
Funding
Conflicts of Interest
References
- Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018, 68, 394–424. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Perou, C.M.; Sorlie, T.; Eisen, M.B.; van de Rijn, M.; Jeffrey, S.S.; Rees, C.A.; Pollack, J.R.; Ross, D.T.; Johnsen, H.; Akslen, L.A.; et al. Molecular portraits of human breast tumours. Nature 2000, 406, 747–752. [Google Scholar] [CrossRef] [PubMed]
- Sorlie, T.; Perou, C.M.; Tibshirani, R.; Aas, T.; Geisler, S.; Johnsen, H.; Hastie, T.; Eisen, M.B.; van de Rijn, M.; Jeffrey, S.S.; et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc. Natl. Acad. Sci. USA 2001, 98, 10869–10874. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Viale, G. The current state of breast cancer classification. Ann. Oncol. 2012, 23, x207–x210. [Google Scholar] [CrossRef]
- Jackisch, C.; Harbeck, N.; Huober, J.; von Minckwitz, G.; Gerber, B.; Kreipe, H.-H.; Liedtke, C.; Marschner, N.; Möbus, V.; Scheithauer, H.; et al. 14th St. Gallen International Breast Cancer Conference 2015: Evidence, Controversies, Consensus—Primary Therapy of Early Breast Cancer: Opinions Expressed by German Experts. Breast Care 2015, 10, 211–219. [Google Scholar] [CrossRef] [Green Version]
- Network, N.C.C. Breast Cancer (Version 3, 2020). Available online: https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf (accessed on 10 November 2020).
- Reinert, T.; Barrios, C.H. Overall survival and progression-free survival with endocrine therapy for hormone receptor-positive, HER2-negative advanced breast cancer: review. Adv. Med. Oncol. 2017, 9, 693–709. [Google Scholar] [CrossRef] [Green Version]
- deGraffenried, L.A.; Friedrichs, W.E.; Russell, D.H.; Donzis, E.J.; Middleton, A.K.; Silva, J.M.; Roth, R.A.; Hidalgo, M. Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt Activity. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2004, 10, 8059–8067. [Google Scholar] [CrossRef] [Green Version]
- Baselga, J.; Campone, M.; Piccart, M.; Burris, H.A., 3rd; Rugo, H.S.; Sahmoud, T.; Noguchi, S.; Gnant, M.; Pritchard, K.I.; Lebrun, F.; et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. New Engl. J. Med. 2012, 366, 520–529. [Google Scholar] [CrossRef] [Green Version]
- André, F.; Ciruelos, E.; Rubovszky, G.; Campone, M.; Loibl, S.; Rugo, H.S.; Iwata, H.; Conte, P.; Mayer, I.A.; Kaufman, B.; et al. Alpelisib for PIK3CA-Mutated, Hormone Receptor–Positive Advanced Breast Cancer. New Engl. J. Med. 2019, 380, 1929–1940. [Google Scholar] [CrossRef]
- Comprehensive molecular portraits of human breast tumours. Nature 2012, 490, 61–70. [CrossRef] [Green Version]
- Wilcken, N.R.; Prall, O.W.; Musgrove, E.A.; Sutherland, R.L. Inducible overexpression of cyclin D1 in breast cancer cells reverses the growth-inhibitory effects of antiestrogens. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 1997, 3, 849–854. [Google Scholar]
- Finn, R.S.; Martin, M.; Rugo, H.S.; Jones, S.; Im, S.A.; Gelmon, K.; Harbeck, N.; Lipatov, O.N.; Walshe, J.M.; Moulder, S.; et al. Palbociclib and Letrozole in Advanced Breast Cancer. N. Engl. J. Med. 2016, 375, 1925–1936. [Google Scholar] [CrossRef] [PubMed]
- Tripathy, D.; Im, S.A.; Colleoni, M.; Franke, F.; Bardia, A.; Harbeck, N.; Hurvitz, S.A.; Chow, L.; Sohn, J.; Lee, K.S.; et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol. 2018, 19, 904–915. [Google Scholar] [CrossRef]
- Hortobagyi, G.N.; Stemmer, S.M.; Burris, H.A.; Yap, Y.S.; Sonke, G.S.; Paluch-Shimon, S.; Campone, M.; Blackwell, K.L.; Andre, F.; Winer, E.P.; et al. Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. N. Engl. J. Med. 2016, 375, 1738–1748. [Google Scholar] [CrossRef]
- Goetz, M.P.; Toi, M.; Campone, M.; Sohn, J.; Paluch-Shimon, S.; Huober, J.; Park, I.H.; Tredan, O.; Chen, S.C.; Manso, L.; et al. MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2017, 35, 3638–3646. [Google Scholar] [CrossRef] [PubMed]
- Belli, C.; Duso, B.A.; Ferraro, E.; Curigliano, G. Homologous recombination deficiency in triple negative breast cancer. Breast (Edinb. Scotl. ) 2019, 4, 15–21. [Google Scholar] [CrossRef]
- Telli, M.L.; Timms, K.M.; Reid, J.; Hennessy, B.; Mills, G.B.; Jensen, K.C.; Szallasi, Z.; Barry, W.T.; Winer, E.P.; Tung, N.M.; et al. Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2016, 22, 3764–3773. [Google Scholar] [CrossRef] [Green Version]
- Dirix, L.Y.; Takacs, I.; Jerusalem, G.; Nikolinakos, P.; Arkenau, H.T.; Forero-Torres, A.; Boccia, R.; Lippman, M.E.; Somer, R.; Smakal, M.; et al. Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN Solid Tumor study. Breast Cancer Res. Treat. 2018, 167, 671–686. [Google Scholar] [CrossRef] [Green Version]
- Schmid, P.; Adams, S.; Rugo, H.S.; Schneeweiss, A.; Barrios, C.H.; Iwata, H.; Dieras, V.; Hegg, R.; Im, S.A.; Shaw Wright, G.; et al. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N. Engl. J. Med. 2018, 379, 2108–2121. [Google Scholar] [CrossRef]
- Lin, C.H.; Liau, J.Y.; Lu, Y.S.; Huang, C.S.; Lee, W.C.; Kuo, K.T.; Shen, Y.C.; Kuo, S.H.; Lan, C.; Liu, J.M.; et al. Molecular subtypes of breast cancer emerging in young women in Taiwan: evidence for more than just westernization as a reason for the disease in Asia. Cancer Epidemiol. Biomark. Prev. Publ. Am. Assoc. Cancer Res. Cosponsored Am. Soc. Prev. Oncol. 2009, 18, 1807–1814. [Google Scholar] [CrossRef] [Green Version]
- Howlader, N.; Altekruse, S.F.; Li, C.I.; Chen, V.W.; Clarke, C.A.; Ries, L.A.; Cronin, K.A. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J. Natl. Cancer Inst. 2014, 106. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Waddington, C.H. The epigenotype. 1942. Int. J. Epidemiol. 2012, 41, 10–13. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Etchegaray, J.P.; Mostoslavsky, R. Interplay between Metabolism and Epigenetics: A Nuclear Adaptation to Environmental Changes. Mol. Cell 2016, 62, 695–711. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Flavahan, W.A.; Gaskell, E.; Bernstein, B.E. Epigenetic plasticity and the hallmarks of cancer. Science 2017, 357. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cheng, Y.; He, C.; Wang, M.; Ma, X.; Mo, F.; Yang, S.; Han, J.; Wei, X. Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials. Signal. Transduct. Target. Ther. 2019, 4, 62. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cavalli, G.; Heard, E. Advances in epigenetics link genetics to the environment and disease. Nature 2019, 571, 489–499. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wu, X.; Zhang, Y. TET-mediated active DNA demethylation: mechanism, function and beyond. Nat. Rev. Genet. 2017, 18, 517–534. [Google Scholar] [CrossRef]
- Tessarz, P.; Kouzarides, T. Histone core modifications regulating nucleosome structure and dynamics. Nat. Rev. Mol. Cell Biol. 2014, 15, 703–708. [Google Scholar] [CrossRef]
- Audia, J.E.; Campbell, R.M. Histone Modifications and Cancer. Cold Spring Harb. Perspect. Biol. 2016, 8, a019521. [Google Scholar] [CrossRef]
- Michalak, E.M.; Burr, M.L.; Bannister, A.J.; Dawson, M.A. The roles of DNA, RNA and histone methylation in ageing and cancer. Nat. Rev. Mol. Cell Biol. 2019, 20, 573–589. [Google Scholar] [CrossRef]
- Fujisawa, T.; Filippakopoulos, P. Functions of bromodomain-containing proteins and their roles in homeostasis and cancer. Nat. Rev. Mol. Cell Biol. 2017, 18, 246–262. [Google Scholar] [CrossRef]
- Mai, A.; Massa, S.; Rotili, D.; Cerbara, I.; Valente, S.; Pezzi, R.; Simeoni, S.; Ragno, R. Histone deacetylation in epigenetics: an attractive target for anticancer therapy. Med. Res. Rev. 2005, 25, 261–309. [Google Scholar] [CrossRef] [PubMed]
- Mann, B.S.; Johnson, J.R.; Cohen, M.H.; Justice, R.; Pazdur, R. FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncology 2007, 12, 1247–1252. [Google Scholar] [CrossRef] [PubMed]
- Kaminskas, E.; Farrell, A.; Abraham, S.; Baird, A.; Hsieh, L.S.; Lee, S.L.; Leighton, J.K.; Patel, H.; Rahman, A.; Sridhara, R.; et al. Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2005, 11, 3604–3608. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- DiNardo, C.D.; Pratz, K.; Pullarkat, V.; Jonas, B.A.; Arellano, M.; Becker, P.S.; Frankfurt, O.; Konopleva, M.; Wei, A.H.; Kantarjian, H.M.; et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood 2019, 133, 7–17. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Morel, D.; Jeffery, D.; Aspeslagh, S.; Almouzni, G.; Postel-Vinay, S. Combining epigenetic drugs with other therapies for solid tumours—Past lessons and future promise. Nat. Rev. Clin. Oncol. 2020, 17, 91–107. [Google Scholar] [CrossRef] [PubMed]
- Mazzone, R.; Zwergel, C.; Mai, A.; Valente, S. Epi-drugs in combination with immunotherapy: a new avenue to improve anticancer efficacy. Clin. Epigenetics 2017, 9, 59. [Google Scholar] [CrossRef] [PubMed]
- Egger, G.; Liang, G.; Aparicio, A.; Jones, P.A. Epigenetics in human disease and prospects for epigenetic therapy. Nature 2004, 429, 457–463. [Google Scholar] [CrossRef]
- Lapidus, R.G.; Ferguson, A.T.; Ottaviano, Y.L.; Parl, F.F.; Smith, H.S.; Weitzman, S.A.; Baylin, S.B.; Issa, J.P.; Davidson, N.E. Methylation of estrogen and progesterone receptor gene 5’ CpG islands correlates with lack of estrogen and progesterone receptor gene expression in breast tumors. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 1996, 2, 805–810. [Google Scholar]
- Zhou, Q.; Atadja, P.; Davidson, N.E. Histone deacetylase inhibitor LBH589 reactivates silenced estrogen receptor alpha (ER) gene expression without loss of DNA hypermethylation. Cancer Biol. Ther. 2007, 6, 64–69. [Google Scholar] [CrossRef] [Green Version]
- Ribas, A.; Wolchok, J.D. Cancer immunotherapy using checkpoint blockade. Science 2018, 359, 1350–1355. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Emens, L.A.; Cruz, C.; Eder, J.P.; Braiteh, F.; Chung, C.; Tolaney, S.M.; Kuter, I.; Nanda, R.; Cassier, P.A.; Delord, J.P.; et al. Long-term Clinical Outcomes and Biomarker Analyses of Atezolizumab Therapy for Patients With Metastatic Triple-Negative Breast Cancer: A Phase 1 Study. Jama Oncol. 2019, 5, 74–82. [Google Scholar] [CrossRef] [PubMed]
- Schmid, P.; Cortes, J.; Pusztai, L.; McArthur, H.; Kümmel, S.; Bergh, J.; Denkert, C.; Park, Y.H.; Hui, R.; Harbeck, N.; et al. Pembrolizumab for Early Triple-Negative Breast Cancer. N. Engl. J. Med. 2020, 382, 810–821. [Google Scholar] [CrossRef] [PubMed]
- Joyce, J.A. Therapeutic targeting of the tumor microenvironment. Cancer Cell 2005, 7, 513–520. [Google Scholar] [CrossRef] [Green Version]
- Fang, H.; Declerck, Y.A. Targeting the tumor microenvironment: from understanding pathways to effective clinical trials. Cancer Res. 2013, 73, 4965–4977. [Google Scholar] [CrossRef] [Green Version]
- Gatti-Mays, M.E.; Balko, J.M.; Gameiro, S.R.; Bear, H.D.; Prabhakaran, S.; Fukui, J.; Disis, M.L.; Nanda, R.; Gulley, J.L.; Kalinsky, K.; et al. If we build it they will come: targeting the immune response to breast cancer. Npj Breast Cancer 2019, 5, 37. [Google Scholar] [CrossRef] [Green Version]
- Garcia-Aranda, M.; Redondo, M. Immunotherapy: A Challenge of Breast Cancer Treatment. Cancers 2019, 11, 1822. [Google Scholar] [CrossRef] [Green Version]
- Wagner, J.; Rapsomaniki, M.A.; Chevrier, S.; Anzeneder, T.; Langwieder, C.; Dykgers, A.; Rees, M.; Ramaswamy, A.; Muenst, S.; Soysal, S.D.; et al. A Single-Cell Atlas of the Tumor and Immune Ecosystem of Human Breast Cancer. Cell 2019, 177, 1330–1345 e1318. [Google Scholar] [CrossRef] [Green Version]
- Segovia-Mendoza, M.; Morales-Montor, J. Immune Tumor Microenvironment in Breast Cancer and the Participation of Estrogen and Its Receptors in Cancer Physiopathology. Front. Immunol. 2019, 10, 348. [Google Scholar] [CrossRef] [Green Version]
- Beltra, J.C.; Manne, S.; Abdel-Hakeem, M.S.; Kurachi, M.; Giles, J.R.; Chen, Z.; Casella, V.; Ngiow, S.F.; Khan, O.; Huang, Y.J.; et al. Developmental Relationships of Four Exhausted CD8(+) T Cell Subsets Reveals Underlying Transcriptional and Epigenetic Landscape Control Mechanisms. Immunity 2020. [Google Scholar] [CrossRef]
- Leone, R.D.; Zhao, L.; Englert, J.M.; Sun, I.M.; Oh, M.H.; Sun, I.H.; Arwood, M.L.; Bettencourt, I.A.; Patel, C.H.; Wen, J.; et al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science 2019, 366, 1013–1021. [Google Scholar] [CrossRef] [PubMed]
- Aparicio, A.; Eads, C.A.; Leong, L.A.; Laird, P.W.; Newman, E.M.; Synold, T.W.; Baker, S.D.; Zhao, M.; Weber, J.S. Phase I trial of continuous infusion 5-aza-2’-deoxycytidine. Cancer Chemother. Pharmacol. 2003, 51, 231–239. [Google Scholar] [CrossRef] [PubMed]
- Appleton, K.; Mackay, H.J.; Judson, I.; Plumb, J.A.; McCormick, C.; Strathdee, G.; Lee, C.; Barrett, S.; Reade, S.; Jadayel, D.; et al. Phase I and pharmacodynamic trial of the DNA methyltransferase inhibitor decitabine and carboplatin in solid tumors. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2007, 25, 4603–4609. [Google Scholar] [CrossRef] [PubMed]
- Cohen, A.L.; Ray, A.; Van Brocklin, M.; Burnett, D.M.; Bowen, R.C.; Dyess, D.L.; Butler, T.W.; Dumlao, T.; Khong, H.T. A phase I trial of azacitidine and nanoparticle albumin bound paclitaxel in patients with advanced or metastatic solid tumors. Oncotarget 2017, 8, 52413–52419. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Munster, P.; Marchion, D.; Bicaku, E.; Schmitt, M.; Lee, J.H.; DeConti, R.; Simon, G.; Fishman, M.; Minton, S.; Garrett, C.; et al. Phase I trial of histone deacetylase inhibition by valproic acid followed by the topoisomerase II inhibitor epirubicin in advanced solid tumors: a clinical and translational study. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2007, 25, 1979–1985. [Google Scholar] [CrossRef] [PubMed]
- Yardley, D.A.; Ismail-Khan, R.R.; Melichar, B.; Lichinitser, M.; Munster, P.N.; Klein, P.M.; Cruickshank, S.; Miller, K.D.; Lee, M.J.; Trepel, J.B. Randomized phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2013, 31, 2128–2135. [Google Scholar] [CrossRef] [Green Version]
- Jiang, Z.; Li, W.; Hu, X.; Zhang, Q.; Sun, T.; Cui, S.; Wang, S.; Ouyang, Q.; Yin, Y.; Geng, C.; et al. Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer (ACE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019, 20, 806–815. [Google Scholar] [CrossRef]
- Goldstein, L.J.; Zhao, F.; Wang, M.; Swaby, R.F.; Sparano, J.A.; Meropol, N.J.; Bhalla, K.N.; Pellegrino, C.M.; Katherine Alpaugh, R.; Falkson, C.I.; et al. A Phase I/II study of suberoylanilide hydroxamic acid (SAHA) in combination with trastuzumab (Herceptin) in patients with advanced metastatic and/or local chest wall recurrent HER2-amplified breast cancer: a trial of the ECOG-ACRIN Cancer Research Group (E1104). Breast Cancer Res. Treat. 2017, 165, 375–382. [Google Scholar] [CrossRef]
- Munster, P.N.; Thurn, K.T.; Thomas, S.; Raha, P.; Lacevic, M.; Miller, A.; Melisko, M.; Ismail-Khan, R.; Rugo, H.; Moasser, M.; et al. A phase II study of the histone deacetylase inhibitor vorinostat combined with tamoxifen for the treatment of patients with hormone therapy-resistant breast cancer. Br. J. Cancer 2011, 104, 1828–1835. [Google Scholar] [CrossRef]
- Terranova-Barberio, M.; Pawlowska, N.; Dhawan, M.; Moasser, M.; Chien, A.J.; Melisko, M.E.; Rugo, H.; Rahimi, R.; Deal, T.; Daud, A.; et al. Exhausted T cell signature predicts immunotherapy response in ER-positive breast cancer. Nat. Commun. 2020, 11, 3584. [Google Scholar] [CrossRef]
- Piha-Paul, S.A.; Hann, C.L.; French, C.A.; Cousin, S.; Brana, I.; Cassier, P.A.; Moreno, V.; de Bono, J.S.; Harward, S.D.; Ferron-Brady, G.; et al. Phase 1 Study of Molibresib (GSK525762), a Bromodomain and Extra-Terminal Domain Protein Inhibitor, in NUT Carcinoma and Other Solid Tumors. Jnci Cancer Spectr. 2020, 4, pkz093. [Google Scholar] [CrossRef]
- Piha-Paul, S.A.; Sachdev, J.C.; Barve, M.; LoRusso, P.; Szmulewitz, R.; Patel, S.P.; Lara, P.N., Jr.; Chen, X.; Hu, B.; Freise, K.J.; et al. First-in-Human Study of Mivebresib (ABBV-075), an Oral Pan-Inhibitor of Bromodomain and Extra Terminal Proteins, in Patients with Relapsed/Refractory Solid Tumors. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2019, 25, 6309–6319. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bolden, J.E.; Peart, M.J.; Johnstone, R.W. Anticancer activities of histone deacetylase inhibitors. Nat. Rev. Drug Discov. 2006, 5, 769–784. [Google Scholar] [CrossRef] [PubMed]
- Connolly, R.M.; Li, H.; Jankowitz, R.C.; Zhang, Z.; Rudek, M.A.; Jeter, S.C.; Slater, S.A.; Powers, P.; Wolff, A.C.; Fetting, J.H.; et al. Combination Epigenetic Therapy in Advanced Breast Cancer with 5-Azacitidine and Entinostat: A Phase II National Cancer Institute/Stand Up to Cancer Study. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2017, 23, 2691–2701. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chiappinelli, K.B.; Strissel, P.L.; Desrichard, A.; Li, H.; Henke, C.; Akman, B.; Hein, A.; Rote, N.S.; Cope, L.M.; Snyder, A.; et al. Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses. Cell 2015, 162, 974–986. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tie, C.H.; Fernandes, L.; Conde, L.; Robbez-Masson, L.; Sumner, R.P.; Peacock, T.; Rodriguez-Plata, M.T.; Mickute, G.; Gifford, R.; Towers, G.J.; et al. KAP1 regulates endogenous retroviruses in adult human cells and contributes to innate immune control. Embo Rep. 2018, 19. [Google Scholar] [CrossRef]
- Rooney, M.S.; Shukla, S.A.; Wu, C.J.; Getz, G.; Hacohen, N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell 2015, 160, 48–61. [Google Scholar] [CrossRef] [Green Version]
- Panda, A.; de Cubas, A.A.; Stein, M.; Riedlinger, G.; Kra, J.; Mayer, T.; Smith, C.C.; Vincent, B.G.; Serody, J.S.; Beckermann, K.E.; et al. Endogenous retrovirus expression is associated with response to immune checkpoint blockade in clear cell renal cell carcinoma. Jci Insight 2018, 3. [Google Scholar] [CrossRef]
- Ghoneim, H.E.; Fan, Y.; Moustaki, A.; Abdelsamed, H.A.; Dash, P.; Dogra, P.; Carter, R.; Awad, W.; Neale, G.; Thomas, P.G.; et al. De Novo Epigenetic Programs Inhibit PD-1 Blockade-Mediated T Cell Rejuvenation. Cell 2017, 170, 142–157 e119. [Google Scholar] [CrossRef] [Green Version]
- Ryan, Q.C.; Headlee, D.; Acharya, M.; Sparreboom, A.; Trepel, J.B.; Ye, J.; Figg, W.D.; Hwang, K.; Chung, E.J.; Murgo, A.; et al. Phase I and Pharmacokinetic Study of MS-275, a Histone Deacetylase Inhibitor, in Patients With Advanced and Refractory Solid Tumors or Lymphoma. J. Clin. Oncol. 2005, 23, 3912–3922. [Google Scholar] [CrossRef]
- Candelaria, M.; Gallardo-Rincon, D.; Arce, C.; Cetina, L.; Aguilar-Ponce, J.L.; Arrieta, O.; Gonzalez-Fierro, A.; Chavez-Blanco, A.; de la Cruz-Hernandez, E.; Camargo, M.F.; et al. A phase II study of epigenetic therapy with hydralazine and magnesium valproate to overcome chemotherapy resistance in refractory solid tumors. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2007, 18, 1529–1538. [Google Scholar] [CrossRef] [PubMed]
- Thomas, S.; Aggarwal, R.; Jahan, T.; Ryan, C.; Troung, T.; Cripps, A.M.; Raha, P.; Thurn, K.T.; Chen, S.; Grabowsky, J.A.; et al. A phase I trial of panobinostat and epirubicin in solid tumors with a dose expansion in patients with sarcoma. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2016, 27, 947–952. [Google Scholar] [CrossRef]
- Munster, P.N.; Terranova Barberio, M.; Pawlowska, N.; Moasser, M.; Chien, A.J.; Melisko, M.E.; Rugo, H.S.; Abri, K.; Harb, A.; Deal, T.; et al. Exhausted CD8+ cells (Tex) to predict response to PD-1 therapy in estrogen receptor (+) hormone therapy resistant breast cancer predictive of response to immune checkpoint inhibitors after epigenetic priming. J. Clin. Oncol. 2018, 36, 1044. [Google Scholar] [CrossRef]
- Boucheron, N.; Tschismarov, R.; Goeschl, L.; Moser, M.A.; Lagger, S.; Sakaguchi, S.; Winter, M.; Lenz, F.; Vitko, D.; Breitwieser, F.P.; et al. CD4(+) T cell lineage integrity is controlled by the histone deacetylases HDAC1 and HDAC2. Nat. Immunol. 2014, 15, 439–448. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Woods, D.M.; Woan, K.V.; Cheng, F.; Sodre, A.L.; Wang, D.; Wu, Y.; Wang, Z.; Chen, J.; Powers, J.; Pinilla-Ibarz, J.; et al. T cells lacking HDAC11 have increased effector functions and mediate enhanced alloreactivity in a murine model. Blood 2017, 130, 146–155. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wang, L.; Liu, Y.; Han, R.; Beier, U.H.; Bhatti, T.R.; Akimova, T.; Greene, M.I.; Hiebert, S.W.; Hancock, W.W. FOXP3(+) regulatory T cell development and function require histone/protein deacetylase 3. J. Clin. Investig. 2015, 125, 3304. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, B.; Samanta, A.; Song, X.; Iacono, K.T.; Bembas, K.; Tao, R.; Basu, S.; Riley, J.L.; Hancock, W.W.; Shen, Y.; et al. FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression. Proc. Natl. Acad. Sci. USA 2007, 104, 4571–4576. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yan, K.; Cao, Q.; Reilly, C.M.; Young, N.L.; Garcia, B.A.; Mishra, N. Histone deacetylase 9 deficiency protects against effector T cell-mediated systemic autoimmunity. J. Biol. Chem. 2011, 286, 28833–28843. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fang, Y.; Liao, G.; Yu, B. LSD1/KDM1A inhibitors in clinical trials: advances and prospects. J. Hematol. Oncol. 2019, 12, 129. [Google Scholar] [CrossRef] [Green Version]
- Verigos, J.; Karakaidos, P.; Kordias, D.; Papoudou-Bai, A.; Evangelou, Z.; Harissis, H.V.; Klinakis, A.; Magklara, A. The Histone Demethylase LSD1/KappaDM1A Mediates Chemoresistance in Breast Cancer via Regulation of a Stem Cell Program. Cancers 2019, 11, 1585. [Google Scholar] [CrossRef] [Green Version]
- Sheng, W.; LaFleur, M.W.; Nguyen, T.H.; Chen, S.; Chakravarthy, A.; Conway, J.R.; Li, Y.; Chen, H.; Yang, H.; Hsu, P.H.; et al. LSD1 Ablation Stimulates Anti-tumor Immunity and Enables Checkpoint Blockade. Cell 2018, 174, 549–563 e519. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Qin, Y.; Vasilatos, S.N.; Chen, L.; Wu, H.; Cao, Z.; Fu, Y.; Huang, M.; Vlad, A.M.; Lu, B.; Oesterreich, S.; et al. Inhibition of histone lysine-specific demethylase 1 elicits breast tumor immunity and enhances antitumor efficacy of immune checkpoint blockade. Oncogene 2019, 38, 390–405. [Google Scholar] [CrossRef] [PubMed]
- Tan, A.H.Y.; Tu, W.; McCuaig, R.; Hardy, K.; Donovan, T.; Tsimbalyuk, S.; Forwood, J.K.; Rao, S. Lysine-Specific Histone Demethylase 1A Regulates Macrophage Polarization and Checkpoint Molecules in the Tumor Microenvironment of Triple-Negative Breast Cancer. Front. Immunol. 2019, 10, 1351. [Google Scholar] [CrossRef] [PubMed]
- Kleer, C.G.; Cao, Q.; Varambally, S.; Shen, R.; Ota, I.; Tomlins, S.A.; Ghosh, D.; Sewalt, R.G.; Otte, A.P.; Hayes, D.F.; et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc. Natl. Acad. Sci. USA 2003, 100, 11606–11611. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Puppe, J.; Opdam, M.; Schouten, P.C.; Jozwiak, K.; Lips, E.; Severson, T.; van de Ven, M.; Brambillasca, C.; Bouwman, P.; van Tellingen, O.; et al. EZH2 Is Overexpressed in BRCA1-like Breast Tumors and Predictive for Sensitivity to High-Dose Platinum-Based Chemotherapy. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2019, 25, 4351–4362. [Google Scholar] [CrossRef] [Green Version]
- Italiano, A.; Soria, J.C.; Toulmonde, M.; Michot, J.M.; Lucchesi, C.; Varga, A.; Coindre, J.M.; Blakemore, S.J.; Clawson, A.; Suttle, B.; et al. Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 study. Lancet Oncol. 2018, 19, 649–659. [Google Scholar] [CrossRef]
- Peng, D.; Kryczek, I.; Nagarsheth, N.; Zhao, L.; Wei, S.; Wang, W.; Sun, Y.; Zhao, E.; Vatan, L.; Szeliga, W.; et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 2015, 527, 249–253. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Huang, S.; Wang, Z.; Zhou, J.; Huang, J.; Zhou, L.; Luo, J.; Wan, Y.Y.; Long, H.; Zhu, B. EZH2 Inhibitor GSK126 Suppresses Antitumor Immunity by Driving Production of Myeloid-Derived Suppressor Cells. Cancer Res. 2019, 79, 2009–2020. [Google Scholar] [CrossRef]
- Meeks, J.J.; Shilatifard, A.; Miller, S.D.; Morgans, A.K.; VanderWeele, D.J.; Kocherginsky, M.; Hussain, M.H.A. A pilot study of tazemetostat and MK-3475 (pembrolizumab) in advanced urothelial carcinoma (ETCTN 10183). J. Clin. Oncol. 2020, 38, TPS607. [Google Scholar] [CrossRef]
- Lewin, J.; Soria, J.-C.; Stathis, A.; Delord, J.-P.; Peters, S.; Awada, A.; Aftimos, P.G.; Bekradda, M.; Rezai, K.; Zeng, Z.; et al. Phase Ib Trial With Birabresib, a Small-Molecule Inhibitor of Bromodomain and Extraterminal Proteins, in Patients With Selected Advanced Solid Tumors. J. Clin. Oncol. 2018, 36, 3007–3014. [Google Scholar] [CrossRef]
- Kagoya, Y.; Nakatsugawa, M.; Yamashita, Y.; Ochi, T.; Guo, T.; Anczurowski, M.; Saso, K.; Butler, M.O.; Arrowsmith, C.H.; Hirano, N. BET bromodomain inhibition enhances T cell persistence and function in adoptive immunotherapy models. J. Clin. Investig. 2016, 126, 3479–3494. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Adeegbe, D.O.; Liu, Y.; Lizotte, P.H.; Kamihara, Y.; Aref, A.R.; Almonte, C.; Dries, R.; Li, Y.; Liu, S.; Wang, X.; et al. Synergistic Immunostimulatory Effects and Therapeutic Benefit of Combined Histone Deacetylase and Bromodomain Inhibition in Non-Small Cell Lung Cancer. Cancer Discov. 2017, 7, 852–867. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Adeegbe, D.O.; Liu, S.; Hattersley, M.M.; Bowden, M.; Zhou, C.W.; Li, S.; Vlahos, R.; Grondine, M.; Dolgalev, I.; Ivanova, E.V.; et al. BET Bromodomain Inhibition Cooperates with PD-1 Blockade to Facilitate Antitumor Response in Kras-Mutant Non-Small Cell Lung Cancer. Cancer Immunol. Res. 2018, 6, 1234–1245. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Andrieu, G.P.; Shafran, J.S.; Smith, C.L.; Belkina, A.C.; Casey, A.N.; Jafari, N.; Denis, G.V. BET protein targeting suppresses the PD-1/PD-L1 pathway in triple-negative breast cancer and elicits anti-tumor immune response. Cancer Lett. 2019, 465, 45–58. [Google Scholar] [CrossRef] [PubMed]
- Lai, X.; Stiff, A.; Duggan, M.; Wesolowski, R.; Carson, W.E., 3rd; Friedman, A. Modeling combination therapy for breast cancer with BET and immune checkpoint inhibitors. Proc. Natl. Acad. Sci. USA 2018, 115, 5534–5539. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Subtype Incidence [21,22] | Pathological Definition 1 | Systemic Therapies |
---|---|---|
HR(+)/HER2(−) 60–70% | ER or PR >1% of cells staining | Endocrine therapy-based regimens |
First line of therapy AI + CDK4/6 inhibitor Endocrine therapy (AI, SERD, SERM) Subsequent-Line Therapy AI + CDK4/6 inhibitor mTOR inhibitor + endocrine therapy: Everolimus + endocrine therapy (exemestane, fulvestrant, or tamoxifen) PI3K inhibitor + endocrine therapy 2: Alpelisib + fulvestrant Endocrine therapy (AI, SERD, SERM) Chemotherapy PARP inhibitors 3 | ||
HER2 (+) with HR (+) or HR (−) 15% | HER2 staining: strongly positive (3+) or HER2 gene amplification by in situ hybridization assay | First line of therapy Dual HER2-blockade + Chemotherapy: Pertuzumab + trastuzumab + Taxanes Subsequent-Line Therapy Ado-trastuzumab emtansine Anti-HER2 + chemotherapy |
Triple-Negative 15% | Negative ER, PR, and HER2 | Chemotherapy Immune checkpoint inhibitor + chemotherapy Atezolizumab + albumin-bound paclitaxel PARP inhibitors 3 |
Phase(NCT No./Ref.) | Patient Population (n) | Interventions | Outcome | Status | Date Started | Estimated Completion Date |
---|---|---|---|---|---|---|
DNMT Inhibitor | ||||||
Phase I ([53]) | Breast cancer/Solid tumor (4/19) | Decitabine, continuous infusion | No responses in breast cancer | Completed | ||
Phase I ([54]) | Breast cancer/Solid tumor (5/33) | Decitabine + Carboplatin | No responses in breast cancer | Completed | ||
Phase I (NCT00748553/[55]) | Breast cancer/Solid tumor (1/16) | Azacitidine + nab-paclitaxel | 1 PR in Breast cancer | Completed | ||
Phase II (NCT01349959) | Hormone-resistant breast cancer (27) and TNBC (13) | Azacitidine + Entinostat | 1 PR (1/27, 4%) in hormone-resistant breast cancer No responses in TNBC | Completed | ||
Phase II (NCT02811497) | Unspecified solid tumor including ER(+) HER2(−) breast cancer | Azacitidine + Durvalumab | Overall response rate | Active, not recruiting | September 2016 | January 2022 |
Phase II (NCT02957968) | HER2(−) breast cancer | Decitabine + Neoadjuvant Pembrolizumab | Changes of tumor infiltrating lymphocytes | Recruiting | January 2017 | February 2023 |
HDAC Inhibitor | ||||||
Phase II (NCT00404508) | Breast cancer/Solid tumor (3/15) | Valproate + Hydralazine + chemotherapy | 1 SD (1/3, 33%) in breast cancer | Completed | ||
Phase I ([56]) | Breast cancer/Solid tumor (10/44) | Valproate + Epirubicin | 3 SD (3/10, 30%) and 3 PR (3/10, 30%) in breast cancer | Completed | ||
Phase I (NCT00878904) | Breast cancer/Solid tumor (5/37) | Panobinostat + Epirubicin | 2 PR (2/5, 40%) in breast cancer | Completed | ||
Phase II (NCT00676663/[57]) | ER(+) breast cancer (130) | Entinostat + Exemestane | PFS: 4.3 vs. 2.3 months OS: extend 28.1 vs. 19.8 months | Completed | ||
Phase III (NCT02482753/[58]) | ER(+) breast cancer (365) | Tucidinostat + Exemestane | PFS: 7.4 vs. 3.8 months Common hematological adverse events | Completed | ||
Phase II (NCT00258349/[59]) | HER2(+) breast cancer (16) | Vorinostat + Trastuzumab | No response | Completed | ||
Phase II (NCT00365599/[60]) | HR(+) breast cancer (43) | Vorinostat + Tamoxifen | Objective response: 8/43, 19% | Completed | ||
Phase II (NCT02395627/[61]) | ER(+) breast cancer (34) | Vorinostat + Tamoxifen + Pembrolizumab | Objective response: 1/27 (4%) Clinical benefits: 5/27 (18%) | Terminated | ||
Phase II (NCT02453620) | HER2(−) breast cancer | Entinostat + Nivolumab + Ipilimumab | AE | Active, not recruiting | November 2015 | December 2020 |
Phase II (NCT03280563) | HR(+) HER2(−) breast cancer | Entinostat + Atezolizumab | Objective response | Recruiting | December 2017 | October 2022 |
Phase II (NCT04190056) | ER(+) breast cancer | Vorinostat + Tamoxifen + pembrolizumab | Overall response rate | Not yet recruiting | December 2020 | June 2026 |
Phase I (NCT04296942) | TNBC or HR(−) HER2(+) breast cancer | Entinostat + BN-Brachyury + Adotrastuzumab emtansine + M7824 | Overall response rate | Not yet recruiting | November 2020 | January 2022 |
LSD1 Inhibitor | ||||||
Phase I (NCT03505528) | HER2(−) breast cancer | Phenelzine + Nab-paclitaxel | Dose-limiting toxicity (not reported yet) | Completed | ||
BET Inhibitor | ||||||
Phase I/II (NCT01587703/[62]) | TNBC/NUT carcinoma or Solid tumor (5/65) | Molibresib | 1 SD (1/5, 20%) and 1 PR (1/5, 20%) in breast cancer Thrombocytopenia (51%) | Completed | ||
Phase I (NCT02391480/[63]) | TNBC/Solid tumor (8/72) | Mivebresib | Grade 3 or 4 AE: 57% 1 SD (1/8, 16%) in breast cancer | Completed | ||
Phase II (NCT03901469) | TNBC | ZEN003694 +Talazoparib | Dose-limiting toxicities Objective response | Recruiting | June 2019 | January 2022 |
Phase I/II (NCT02419417) | Unspecified advanced cancer | BMS-986158 + Nivolumab | AE | Recruiting | June 2015 | July 2023 |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Lee, Y.-T.; Chuang, Y.-M.; Chan, M.W.Y. Combinatorial Epigenetic and Immunotherapy in Breast Cancer Management: A Literature Review. Epigenomes 2020, 4, 27. https://doi.org/10.3390/epigenomes4040027
Lee Y-T, Chuang Y-M, Chan MWY. Combinatorial Epigenetic and Immunotherapy in Breast Cancer Management: A Literature Review. Epigenomes. 2020; 4(4):27. https://doi.org/10.3390/epigenomes4040027
Chicago/Turabian StyleLee, Yu-Ting, Yu-Ming Chuang, and Michael W. Y. Chan. 2020. "Combinatorial Epigenetic and Immunotherapy in Breast Cancer Management: A Literature Review" Epigenomes 4, no. 4: 27. https://doi.org/10.3390/epigenomes4040027