Epigenetic Therapies and Biomarkers in Breast Cancer
Abstract
Simple Summary
Abstract
1. Introduction
2. DNA Methylation and DNA Methyltransferase Inhibitors
3. Histone Modifications and Histone Deacetylase Inhibitors
4. Chromatin Remodeling, Super-Enhancers and Bromodomain and Extra-Terminal Motif Inhibitors
5. Promising Epigenetic Therapy Combinations
6. DNA Methylation Biomarkers in Breast Cancer
7. Discussion and Future Perspectives
Author Contributions
Funding
Conflicts of Interest
References
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Therapy | Phase | Patient Population | Breast Cancer Patients (n) | ORR (%) | OS (months) | PFS (months) | AE’s ≥ Grade 3–4 | Biomarkers | Ref |
---|---|---|---|---|---|---|---|---|---|
Epigenetic Therapies Alone | |||||||||
Vorinostat | II | Advancedbreast cancer | 14 | 0 | NR | NR | Diarrhoea (7%) Nausea (7%) Dehydration (7%) | NA | [8] |
Mivebresib | I | Solid organ tumours | 8/72 | 0 | NR | 1.8 |
Thrombocytopenia (35%) Anaemia (6%) | NA | [9] |
Epigenetic Therapies + Cytotoxic Agents | |||||||||
Breast | |||||||||
Vorinostat + paclitaxel + bevacizumab | I/II | Advancedbreast cancer | 44 | 55 | 29.4 | 11.9 | Neutropenia (27%) Anaemia (6%) Thrombocytopenia (2%) Diarrhoea (6%) Fatigue (19%) | HSP90 lysine 69-acetylation Acetyltubulin Acetylhistone H3 Acetylhistone H4 | [10] |
All Comer Trials | |||||||||
Hydralazine + magnesium valproate + chemotherapy | II | Solid organ tumours | 3/17 | 24 | NR | NR | Thrombocytopenia (47%) Anaemia (41%) Neutropenia (23%) Hypoalbuminaemia (23%) Infection (23%) | Histone Deacetylation DNA demethylation | [11] |
Decitabine + Carboplatin | I | Solid organ tumours | 5/35 | 3% | NR | NR | Neutropenia (46%) Leucopenia (43%) Anaemia (6%) Thrombocytopenia (3%) Fatigue (9%) Mucositis (3%) | DNA methylation (dose dependent decrease) MAGE1 CpG Demethylatio | [12] |
Vorinostat + Doxorubicin | I | Solid organ tumours | 5/32 | 8% | NR | NR | Neutropenia (25%) Thrombocytopenia (12%) Mucositis (3%) | Histone H3 H4 acetylation HDAC2 expression | [13] |
Epigenetic Therapies + Endocrine Therapy | |||||||||
Breast | |||||||||
Exemestane +/− tucidinostat | III (2:1) | Advanced ER+ breast cancer | 365 | 18% vs. 9% (p = 0.025) | NR | 7.4 vs. 3.8 (p = 0.033) | Neutropenia (51% vs. 3%) Thrombocytopenia (27% vs. 3%) Leucopenia (19% vs. 3%) | NR | [14] |
Exemestane +/− entinostat | II | Advanced ER+ breast cancer | 135 | NA | 28.1 vs. 19.8 m (HR 0.59; p = 0.036) | 4.3 vs. 2.3 | Fatigue (13%) Neutropenia (15%) Thrombocytopenia Higher rates of treatment discontinuation in the entinostat group (11% vs. 2%) | Protein lysine hyperacetylation associated with prolonged PFS in entinostat arm | [15] |
Exemestane +/− entinostat | III (1:1) | Advanced ER+ breast cancer | 608 | 5.8% vs. 5.6% | 23.4 vs. 21.7 (HR 0.99; p = 0.94) | 3.3 vs. 3.1 (HR 0.87; p = 0.030) | Neutropenia (20%) Hypophosphatemia (14%) Anaemia (8%) Leukopenia (6%) Fatigue (4%) Diarrhoea (4%) Thrombocytopenia (3%) | Higher increase in lysine acetylation in PMBCs in the entinostat arm | [16] |
Vorinostat + tamoxifen | II | Advanced ER+ breast cancer | 43 | ORR 19% | 29 | 10.3 | Thrombocytopenia 9% Neutropenia 16% Fatigue 16% VTE 7% | HDAC2 expression Histone hyperaceytlation | [17] |
Epigenetic Therapies + Targeted therapy | |||||||||
All Comers | |||||||||
5-azacytidine + erlotinib | I | Solid organ tumours | 1/30 | 7% | 7.5 | 2 | Neutropenia (27%) Neuropathy (3%) Anaemia (3%) Infection (7%) | NA | [18] |
Vorinostat + sirolimus | I | Solid organ tumours | 1/70 | 3% | 10.3 | 2 | Thrombocytopenia (31%) Neutropenia (8%) Anaemia (7%) Fatigue (3%) | NA | [19] |
Breast | |||||||||
SAHA + trastuzumab | I/II | HER2-positive and negative metastatic breast cancer | 15 | 7% | 9.3 | 1.5 | Thrombocytopenia 6% | NA | [20] |
Epigenetic Target | Breast Cancer Subtype | Phase of Trial | Interventions | Status | Clinical Trials Reference |
---|---|---|---|---|---|
DNMT | Advanced HR+, HER2– Progressed on AI. | 2 | Fulvestrant + Azacitadine | Terminated | NCT02374099 |
Locally advanced, resectable HER2– | 2 | Pembrolizumab + Decitabine followed by neoadjuvant chemotherapy | Recruiting | NCT02957968 | |
Advanced HER2– | 1b | Paclitaxel + Decitabine | Unknown | NCT03282825 | |
Advanced TNBC | 2 | Carboplatin + Decitabine | Recruiting | NCT03295552 | |
Advanced, any subtype | 1b/2 | Nab-paclitaxel + Azacitadine | Completed | NCT00748553 | |
DNMT + HDAC | Advanced HER2– | 2 | Azacitadine + Entinostat | Active, not recruiting | NCT01349959 |
HDAC | Advanced HR+ | 2 | Exemestane +/− Entinostat | Active, not recruiting | NCT02115282 |
Advanced HR+ | 3 | Exemestane +/− Entinostat | Active, not recruiting | NCT03538171 | |
Advanced HR+ | 2 | Exemestane +/− Entinostat | Active, not recruiting | NCT03291886 | |
Advanced HR+, HER2– | 1b/2 | Atezolizumab + Entinostat vs. Fulvestrant | Recruiting | NCT03280563 | |
Advanced HR+ | 1 | Nivolumab + Ipilimumab + Entinostat | Active, not recruiting | NCT02453620 | |
Advanced HR+, PD1 > 10% | 2 | Tamoxifen + Pembrolizumab +/− Vorinostat | Active, not recruiting | NCT04190056 | |
Advanced HER2–and Stage I-III HER2–, with residual disease following neoadjuvant chemotherapy | 1 | Capecitabine + Entinostat | Recruiting | NCT03473639 | |
Advanced HER2+ | 1 | Lapatinib + Trastuzumab + Entinostat | Completed | NCT01434303 | |
Early stage TNBC | 2 | Neoadjuvant Anastrozole + Entinostat | Terminated | NCT01234532 | |
Advanced TNBC | 1 | Ribociclib + Belinostat | Recruiting | NCT04315233 | |
Advanced TNBC | 1/2 | Cisplatin + Nivolumab + Romidepsin | Suspended | NCT02393794 | |
BET | Advanced HR+ | 1 | Fulvestrant + Molibresib/GSK525762 | Active, not recruiting | NCT02964507 |
Advanced HR+ | 1 | Fulvestrant or Exemestane + Alobresib | Completed | NCT02392611 | |
Advanced TNBC, BRCA wildtype | 2 | Talazoparib + ZEN003694 | Active, not recruiting | NCT03901469 |
Epigenetic Biomarkers | Genes with Poor Outcomes | Genes with Improved Outcomes | Methods of Assessment |
---|---|---|---|
Prognostic Biomarkers | Hypermethylation of BRCA, PITX2, CDH1, RARB, PCDH10, PGR, GSTP1, RASSF1, PTEN, PTGER4, CDK10, HOXC10, ID4, NAT1 | Hypermethylation of ESRI and CYP1B1 | Methylight Digital Droplet MSP Bisulphite pyrosequencing Combined bisulphite restriction analysis (COBRA) EpiTYPER MethyLight Methylation-Specific PCR Headloop-MSP Digital bisulphite genomic sequencing Methylation-sensitive high resolution melting Targeted multiplex bisulphite amplicon sequencing. Whole-genome bisulphite sequencing MeDIP-seq |
Predictive Biomarkers | Hypermethylation of DAXX, MSI2, NCOR2, RXRA, C8orf46, GATA3, ITPK1, ESR1 and GET4 genes | Hypermethylation of PSAT1 promoter hypermethylation, FERD3L, TRIP10 BRCA1 Hypomethylation of ESR1-responsive enhancer elements |
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Brown, L.J.; Achinger-Kawecka, J.; Portman, N.; Clark, S.; Stirzaker, C.; Lim, E. Epigenetic Therapies and Biomarkers in Breast Cancer. Cancers 2022, 14, 474. https://doi.org/10.3390/cancers14030474
Brown LJ, Achinger-Kawecka J, Portman N, Clark S, Stirzaker C, Lim E. Epigenetic Therapies and Biomarkers in Breast Cancer. Cancers. 2022; 14(3):474. https://doi.org/10.3390/cancers14030474
Chicago/Turabian StyleBrown, Lauren Julia, Joanna Achinger-Kawecka, Neil Portman, Susan Clark, Clare Stirzaker, and Elgene Lim. 2022. "Epigenetic Therapies and Biomarkers in Breast Cancer" Cancers 14, no. 3: 474. https://doi.org/10.3390/cancers14030474
APA StyleBrown, L. J., Achinger-Kawecka, J., Portman, N., Clark, S., Stirzaker, C., & Lim, E. (2022). Epigenetic Therapies and Biomarkers in Breast Cancer. Cancers, 14(3), 474. https://doi.org/10.3390/cancers14030474