Genetic Heterogeneity, Tumor Microenvironment and Immunotherapy in Triple-Negative Breast Cancer
Abstract
:1. Introduction
2. Molecular Classification of TNBC
3. Genomic and Transcriptomic Landscape of TNBC with Focus on the Immune System
3.1. Transcriptional Landscape of TNBC
3.2. Genomic Profile of TNBC Tissue
3.3. Genomic Alterations and Their Impact on Immune Surveillance
4. Novel Findings in Epigenetics, Genetics, Non-Coding RNAs, and Biomarkers in TNBC
5. Tumor Microenvironment, Tumor Infiltrating Lymphocytes (TILs) and Their Role in Disease Prognosis in TNBC
6. Current Immunotherapeutic Strategies of TNBC
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
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Lehman’s Subtypes | |
BL1 |
|
BL2 |
|
M |
|
MSL |
|
IM |
|
LAR |
|
Burstein’s Subtypes | |
MES |
|
BLIA |
|
BLIS |
|
LAR |
|
FUSCC Subtypes | |
MES |
|
IM |
|
BLIS |
|
LAR |
|
Gene | Function | Type of Change | Prognostic Significance | Predictive Significance | Mutation Frequency | References |
---|---|---|---|---|---|---|
TP53 | Regulate cell cycle progression, DNA repair, cellular senescence, apoptosis | Inactivating mutation | Poor prognostic factor | Tp53 mutation status could be a useful biomarker in stratifying BC patients responsive to immunotherapy | 60–88% | [38,39,40,41] |
PIK3CA | Regulate cell proliferation differentiation, survival | Activating mutation | Negative prognostic factor | Predictive biomarker for response to chemotherapy | 10.2–30.8% | [27,28,29,42,43,44,45] |
AKT1 | Survival, cell growth, cell cycle regulation, metabolism | Activating mutation | Poor prognostic factor | 1–7.7% | [29,42,45,46,47] | |
PTEN | Cell proliferation, migration, invasion | Inactivating mutation | Poor prognostic factor | 1–11.2% | [27,28,29,48,49] | |
VEGFA | Angiogenesis | Mutation, overexpression | 30–60% | [50,51,52] | ||
BRCA1/2 | DNA damage repair, cell cycle control, apoptosis | Inactivating mutation | Poor prognostic factor | Potential predictor for response to PARP inhibitors | 10–20% | [52,53,54,55,56,57] |
ATM | Cell cycle control, apoptosis, oxidative stress | Mutation | Poor prognostic factor | 1–10.7% | [58,59,60] | |
AURKA | Chromosome segregation, bipolar spindle microtubule formation, cytokinesis, mitosis exit | overexpression | Poor prognostic factor | 51.6–72% | [61,62,63,64] |
Subtype | Molecular Determinant | Mechanism of Action | Prognosis | References |
---|---|---|---|---|
Tc | CD3+ CD8+ | Cytotoxic killing of tumor cells Granzyne/perforin complex | Positive | [115,116] |
Th1 | CD3+ CD4+ | Activation of CD8+ T-cell mediated cell killing Production of IFN-γ, IL-2, IFN-α | Positive | [115,116] |
Th2 | CD3+ CD4+ | Activation of humoral response Production of IL-4, IL-5 | Positive | [115] |
Negative | [115,117,118] | |||
Treg | CD3+ CD4+ CD25+ Foxp3+ | Immunosuppression Induction of immune-tolerance | Negative | [119] |
B-cells, Plasma cells | CD19+ CD20+ CD38+ | Antibody-dependent cell death Presentation of tumor antigens to T-cells | Positive | [108,120] |
Production of inhibitory factors | Negative | [121] | ||
NK | CD56+CD3− | Innate immune cytotoxicity | Positive | [116] |
Subtype | Molecular Determinant | Mechanism of Action | Prognosis | References |
---|---|---|---|---|
Tumor-associated macrophages (TAMs)—M1 | CD68+ | Inflammatory response Induction of Th1 response | Positive | [110,116] |
Tumor-associated macrophages (TAMs)—M2 | CD163+ | Increasing proliferation Render poorer differentiation Promotion of angiogenesis Promotion of metastasis Secretion of IL-10 Inhibition of Th1 response | Negative | [13,116] |
Tumor-Associated Neutrophils (TANs) N1 | CD66b+ CD15- | Direct lysis of tumor cells Induction of antitumor cytotoxicity | Positive | [116,122] |
Tumor-Associated Neutrophils (TANs) N2 | CD66b+ CD15+ | Promotion of tumor proliferation Promotion of tumor migration Promotion of tumor invasion and metastasis Inhibition of antitumor immunity | Negative | [116,123,124] |
Cancer-associated fibroblasts (CAFs) | α-SMA | Reduction in antitumor immunity Enhancement of proliferation and invasion Promotion of neoangiogenesis Reshape the extracellular matrix Formation of an immunosuppressive microenvironment | Negative | [116] |
Cancer-Associated Adipocytes (CAAs) | Depends on the type. e.g.: UCP1, MYF5, EVA1, CD137, TBX1 | Secretion of CCL2, CCL5, IL-1, IL-6, TNF-α, VEGF Promote tumor cell proliferation and invasion Promote angiogenesis | Negative | [116,125] |
Immunomodulators | Study Details | Results | References |
---|---|---|---|
Atezolizumab | Atezolizumab intravenously (15 or 20 mg/kg, or at a 1200-mg flat dose), every 3 weeks in metastatic TNBC (required ≥5% PD-L1 positivity) (n = 116); NCT01375842 | Efficacy, manageable safety profile, well tolerated, adverse events: fatigue, nausea, diarrhea, hypothyroidism, asthenia, decreased appetite, arthralgia, pruritus, or rush | [138,139] |
Pembrolizumab | Pembrolizumab (200 mg) administered intravenously over 30 min every 3 weeks for up to 2 years in TNBC women (n = 170) with PD-L1-positive tumors (61.8%) and received ≥3 previous lines of therapy for metastatic disease (43.5%); NCT02447003 | Manageable safety profile and durable antitumor activity, well-tolerated; common adverse events: fatigue, nausea, hypothyroidism, decreased appetite, diarrhea, asthenia, pruritus, arthralgia, or hyperthyroidism | [140] |
Intravenous pembrolizumab at 10 mg/kg every 2 weeks to TNBC patients with advanced PD-L1-positive (n = 111); NCT01848834 | Clinical activity and potentially acceptable safety profile of pembrolizumab; mild toxicities: arthralgia, fatigue, myalgia, and nausea | [152] | |
Intravenous pembrolizumab (200 mg once every 3 weeks for 35 cycles) (n = 312) or single-drug chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine) (n = 310) in TNBC patients stratified according to PD-L1 positivity/negativity; NCT02555657 | Not significant effect for improving overall survival; common adverse events: anaemia, decreased white blood cells or neutrophil count, and neutropenia | [153] | |
Pembrolizumab (200 mg in first cycle), then eight cycles of pembrolizumab in combination with a taxane with or without carboplatin for 12 weeks, and then doxorubicin and cyclophosphamide for 12 weeks before surgery in patients with high-risk, early-stage TNBC (n = 60); NCT02622074 | Toxicity and promising antitumor activity related to positive correlation with tumor PD-L1 expression and stromal tumor-infiltrating lymphocyte levels; common adverse events: neutropenia | [154] | |
Atezolizumab and nab-paclitaxel (FDA-approved combination for unresectable locally advanced or metastatic PD-L1 positive TNBC) | Intravenous atezolizumab (800 mg) on days 1 and 15 of each cycle every 2 weeks and intravenous nab-paclitaxel (125 mg/m2) on days 1, 8, and 15 of each cycle (3 weeks on, 1 week off) in women (n = 33) with stage IV or locally recurrent TNBC and 0 to 2 lines of prior chemotherapy in the metastatic setting; NCT01633970 | Standard treatment, safe and clinically active; common adverse events: neutropenia, fatigue, alopecia, diarrhea, peripheral sensory neuropathy, peripheral neuropathy, and nausea | [141,142] |
Intravenous atezolizumab (840 mg) on day 1 and day 15 of every 28-day cycle and intravenous nab-paclitaxel (100 mg/m2 of body surface area) on days 1, 8, and 15 until progression or unacceptable toxicity in TNBC patients (n = 451) and placebo group (n = 451); NCT02425891 | Higher overall survival in the patients treated with Atezolizumab and nab-paclitaxel (21·0 months) when compared with placebo group (18·7 months); common adverse events: neutropenia, peripheral neuropathy, decreased neutrophil count, and fatigue; Treatment-related deaths (n = 2) due to autoimmune hepatitis and septic shock | [155] | |
Atezolizumab and entinostat | Atezolizumab (1200 mg) + entinostat (5 mg) in patients with advanced TNBC (n = 81); NCT02708680 | Not prolonged progression-free survival, greater toxicity of combination when compared to atezolizumab or placebo treated group | [156] |
Niraparib combined with Pembrolizumab | Oral niraparib (200 mg of once daily) in combination with intravenous pembrolizumab (200 mg on day 1) of each 21-day cycle) in patients with advanced or metastatic TNBC (n = 55) irrespective of BRCA mutation status or PD-L1 expression; NCT02657889 | Promising antitumor activity, especially with higher response rates in patients with tumor BRCA mutations; common adverse events: anemia, thrombocytopenia, and fatigue | [157]. |
Pembrolizumab combined with radiotherapy | Pembrolizumab (200 mg) was given intravenously within 3 days of first radiotherapy, then every 3 weeks +/−3 days until disease progression in metastatic TNBC patients (n = 17); NCT02730130 | Well-tolerated combination, stable disease (n = 1) and decreased tumor burden (n = 3); common adverse events: mild fatigue, myalgia, and nausea | [158] |
Pembrolizumab combined with eribulin | Intravenous administration of pembrolizumab (200 mg on day 1 of 21-day cycles) with intravenous eribulin (1.4 mg/m2 on day 1 and day 8) in patients with metastatic TNBC (n = 160); NCT02513472 | Well-tolerated combination with promising antitumor activity, higher objective response rate in patients with PD-L1-positive tumors; common adverse events: fatigue, nausea, peripheral sensory neuropathy, alopecia, and constipation | [159] |
Pembrolizumab combined with Imprime PGG | Pembrolizumab (200 mg on D1 of each cycle) and Imprime (4 mg/kg IV days 1, 8, 15 of each 3-week cycle) in patients with metastatic TNBC, Simon 2 stage study (n = 12 Stage 1, n = 32 Stage 2); NCT02981303 | Well-tolerated combination, innate immune activation through increased CD86 on circulating monocytes and CD8 T cell activation (PD1+/Ki67+/HLA-DR+) | [160] |
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Kudelova, E.; Smolar, M.; Holubekova, V.; Hornakova, A.; Dvorska, D.; Lucansky, V.; Koklesova, L.; Kudela, E.; Kubatka, P. Genetic Heterogeneity, Tumor Microenvironment and Immunotherapy in Triple-Negative Breast Cancer. Int. J. Mol. Sci. 2022, 23, 14937. https://doi.org/10.3390/ijms232314937
Kudelova E, Smolar M, Holubekova V, Hornakova A, Dvorska D, Lucansky V, Koklesova L, Kudela E, Kubatka P. Genetic Heterogeneity, Tumor Microenvironment and Immunotherapy in Triple-Negative Breast Cancer. International Journal of Molecular Sciences. 2022; 23(23):14937. https://doi.org/10.3390/ijms232314937
Chicago/Turabian StyleKudelova, Eva, Marek Smolar, Veronika Holubekova, Andrea Hornakova, Dana Dvorska, Vincent Lucansky, Lenka Koklesova, Erik Kudela, and Peter Kubatka. 2022. "Genetic Heterogeneity, Tumor Microenvironment and Immunotherapy in Triple-Negative Breast Cancer" International Journal of Molecular Sciences 23, no. 23: 14937. https://doi.org/10.3390/ijms232314937