Update on Classic and Novel Approaches in Metastatic Triple-Negative Breast Cancer Treatment: A Comprehensive Review
Abstract
:1. Introduction
2. Data Analysis
2.1. Study Selection
2.2. Data Collection Process
2.3. Risk of Bias Assessment
2.4. Data Source
3. Antineoplastic Agents
3.1. Chemotherapy
3.1.1. Platinum-Based Chemotherapy
3.1.2. Taxanes
3.1.3. Anthracyclines
3.1.4. Anti-Metabolites
3.1.5. Microtubule Inhibitors
3.1.6. Alkylating Agents
3.1.7. Antibody-Drug Conjugates
3.2. Immune Checkpoint Inhibitors
3.3. PARP Inhibitors
3.4. Tyrosine Kinase Inhibitors
3.5. Alternative Therapies
4. Focus on the New NCCN Clinical Practice Guidelines
5. Conclusions and Future Perspectives
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Authors | Trial Registration Code | Sample Size, n | Study Design | Study Type | Study Duration | Treatment | PFS and/or OS | Other Clinical Results |
---|---|---|---|---|---|---|---|---|
Zhang et al. (CBCSG006 trial) [14] | NCT01287624 | 240 | Phase III | RCT | 11 January–13 November | Cisplatin + gemcitabine (GP) vs. paclitaxel + gemcitabine (GT) | PFS: 7.73 (95% CI 6.46–9.00) for GP vs. 6.07 (95% CI 5.32–6.83) for GT arm OS: NS | - |
Yardley et al. (tnAcity trial) [23] | NCT01881230 | 191 | Phase II | RCT | 13 September–15 April | Nab-paclitaxel + carboplatin (nab-P/C) vs. nab-paclitaxel + gemcitabine (nab-P/G) vs. gemcitabine + carboplatin (G/C) | PFS: nab-P/C vs. nab-P/G 8.3 vs. 5.5 (HR 0.59, 95% CI 0.38–0.92); nab-P/C vs. G/C 8.3 vs. 6.0 (HR 0.58, 95% CI 0.37–0.90) OS: NS | ORR: 73% for nab-P/C, 39% for nag-P/G, 44% for G/C |
Wang et al. (GAP trial) [24] | NCT02546934 | 254 | Phase III | RCT | 16 March–19 October | Nab-paclitaxel + cisplatin (AP) vs. gemcitabine + cisplatin (GP) | PFS: 9.8 for AP vs. 7.4 for GP OS: HR 0.62 (95% CI 0.44–0.90) in favor of AP | ORR: 81.1% for AP vs. 56.3% for GP |
Cortes et al. (EMBRACE trial) [36] | NCT00388726 | 762 | Phase III | RCT | 6–8 November | Eribulin mesilate (EM) vs. treatment of physician’s choice (TPC) | OS: 13.1 (95% CI 11.8–14.3) vs. 10.6 (95% CI 9.3–12.5); HR 0.81 (95% CI 0.66–0.99) in favor of EM arm | - |
Anders et al. (LCCC 1525 trial) [47] | NCT02768701 | 40 | Phase II, single arm | SAT | 16 November–18 February | Cyclophosphamide prior to pembrolizumab | PFS: 1.8 months | ORR: 21% |
Bardia et al. (ASCENT trial) [50] | NCT02574455 | 468 | Phase III | RCT | 17 November–19 September | Sacituzumab govitecan (SG) vs. chemotherapy (CT) | PFS: 5.6 (95% CI 4.3–6.3) for SG arm vs. 1.7 (95% CI 1.5–2.6) for CT arm OS: 12.1 (95% 10.7–14.0) for SG vs. 6.7 (95% CI 5.8–7.7) for CT arm | ORR: 35% for SG vs. 5% for CT arm |
Schmid et al. (IMpassion130 trial) [60] | NCT02425891 | 902 | Phase III | RCT | 15 June–17 May | Atezolizumab + nab-paclitaxel (AT-P) vs. placebo + nab-paclitaxel (PP) | PFS: 7.5 vs. 5.0; HR 0.62 (95% CI 0.49–0.78) in favor of AT-P arm OS: NS | - |
Røssevold et al. (ALICE trial) [62] | NCT03164993 | 70 | Phase IIb | RCT | 17 August–21 December | Atezolizumab + pegylated liposomal doxorubin + cyclophosphamide (AT-CT) vs. placebo + doxorubicin + cyclophosphamide (P-CT) | PFS: 4.3 vs. 3.5; HR 0.57 (95% CI 0.33–0.99) in favor of AT-CT arm | - |
Miles et al. (IMpassion131 trial) [63] | NCT03125902 | 651 | Phase III | RCT | 17 August–19 September | Atezolizumab + paclitaxel (AT-P) vs. placebo + paclitaxel (PP) | PFS: 6.0 for AT-P arm vs. 5.7 for PP arm; HR 0.82 (95% CI 0.60–1.12) OS: NS | - |
Adams et al. (KEYNOTE-086 trial) [64] | NCT02447003 | 170 | Phase II, single arm | SAT | 15 July–16 January | Pembrolizumab | PFS: 2.0 (95% CI 1.9–2.0) OS: 9.0 (95% CI 7.6–11.2) | ORR: 5.3% in the total and 5.7% in the PD-L1+ population |
Ho et al. [65] | NCT02730130 | 17 | Phase II, single arm | SAT | 16 June–17 May | Pembrolizumab + radiotherapy | PFS: 2.6 months OS: 8.25 months | ORR: 17.6% (95% CI 4.7–44.2) |
Winer et al. (KEYNOTE-119 trial) [67] | NCT02555657 | 622 | Phase III | RCT | 15 November–17 April | Pembrolizumab (Pem) vs. chemotherapy of physician’s choice (TPC) | OS: 9.9 (95% CI 8.3–11.4) for Pem arm and 10.2 (95% CI 7.9–12.6) for TPC arm | - |
Cortes et al. (KEYNOTE-355 trial) [68] | NCT02819518 | 847 | Phase III | RCT | 17 January–18 June | Pembrolizumab (Pem) vs. chemotherapy treatment of physician’s choice (TPC) | OS: 23.0 for Pem arm (with PD-L1 CPS ≥10) vs. 16.1 for TPC arm; HR 0.86 (95% CI 0.72–1.04) | - |
Tan et al. [87] | NCT02978716 | 34 | Phase II | RCT | 17 February–18 May | Trilaciclib (Tr) prior to gemcitabine + carboplatin (G/C) vs. G/C alone | OS: 12.6 for G/C arm, not reached for Tr prior to G/C arm, and 19.8 for Tr + Tr prior to G/C arm | - |
Schmid et al. (PAKT trial) [22] | NCT02423603 | 140 | Phase II | RCT | 14 May–17 June | Capivasertib + paclitaxel (CP) vs. placebo + paclitaxel (PP) | PFS: 5.9 for CP arm vs. 4.2 for PP arm, HR 0.74 (95% CI 0.50–1.08) OS: 19.1 for CP arm vs. 12.6 for PP arm, HR 0.61 (95% CI 0.37–0.99) | - |
Garrido-Castro et al. [92] | NCT01790932 | 50 | Phase II, single arm | SAT | 12 June–14 September | Buparlisib | PFS: 1.8 (95% CI 1.6–2.3) OS: 11.2 (95% CI 6.2–25) | - |
Lehmann et al. (TBCRC 032 trial) [93] | NCT02457910 | 17 | Phase IB/II | RCT | 15 May–18 August | Enzalutamide alone (Ez) vs. enzalutamide + taselisib (Ez/T) | PFS: 3.4 months | CBR: 35.7% |
Diamond et al. [95] | NCT01639248 | 41 | Phase II, single arm | SAT | 12 July–16 October | ENMD-2076 | PFS: 1.84 (95% CI 1.73–3.73) | CBR: 16.7% (95% CI 6–32.8%) |
Brufsky et al. (COLET trial) [98] | NCT02322814 | 106 | Phase II | RCT | 15 March–16 October | Cobimetinib + paclitaxel (CoP) vs. placebo + paclitaxel (PP) | PFS: 5.5 for CoP arm vs. 3.8 for PP arm, HR 0.73 (95% CI 0.43–1.24) | ORR: 38.3% (95% CI 24.4–52.2) for CoP arm vs. 20.9% (95% CI 8.8–33.1) for PP arm |
Goldstein et al. (fRIDA trial) [131] | NCT01861054 | 123 | Phase II | RCT | 15 July–18 May | Reparixin + paclitaxel (RP) vs. placebo + paclitaxel (PP) | PFS: 5.5 for RP arm vs. 5.6 vs. PP arm | - |
Setting | Subtype/Biomarkers | Regimen |
---|---|---|
First-line | PD-L1 CPS ≥ 10 regardless of germline BRCA mutation | Pembrolizumab + chemotherapy (nab-paclitaxel, or gemcitabine and carboplatin) (Category 1) |
PD-L1 CPS < 10 and no germline BRCA1/2 mutation | Systemic chemotherapy (see Table 3) | |
PD-L1 CPS < 10 and germline BRCA1/2 mutation | PARPi (olaparib, talazoparib) or platinum (carboplatin or cisplatin) (both Category 1) | |
Second-line | Germline BRCA1/2 mutation | PARPi (olaparib, talazoparib) (Category 1) |
Any | Sacituzumab govitecan (Category 1) | |
No germline BRCA1/2 mutation and HER2 IHC 1+ or 2 + /ISH negative | Fam-trastuzumab deruxtecan-nxki (Category 1) | |
Third-line and beyond | Biomarker positive | Targeted agents (see Table 4) |
Any | Systemic chemotherapy (see Table 3) |
Preferred Regimens | Other Recommended Regimens | Useful in Certain Circumstances |
---|---|---|
Anthracyclines (doxorubicin or liposomal doxorubicin) | Cyclophosphamide | AC (doxorubicin and cyclophosphamide) |
Taxanes (paclitaxel) | Docetaxel | EC (epirubicin and cyclophosphamide) |
Anti-metabolites (capecitabine or gemcitabine) | Nab-paclitaxel | CMF (cyclophosphamide and methotrexate and fluorouracil) |
Microtubule inhibitors (vinorelbine or eribulin) | Epirubicin | Docetaxel and capecitabine |
Ixabepilone | GT (gemcitabine and paclitaxel) | |
Carboplatin and paclitaxel or nab-paclitaxel | ||
Gemcitabine and carboplatin |
Biomarker | Detection Method | FDA-Approved Agents |
---|---|---|
NTRK fusion | FISH, NGS, PCR (tissue block) | Larotrectinib or entrectinib (Category 2A) |
MSI-H/dMMR | IHC, NGS, PCR (tissue block) | Pembrolizumab or dostarlimab-gxly (Category 2A) |
TMB-H (≥ 10 mut/Mb) | NGS | Pembrolizumab (Category 2A) |
RET-fusion | NGS | Selpercatinib (Category 2A) |
Antineoplastic Agents | Main Mechanism of Action |
---|---|
Chemotherapeutic agents | |
Platinum-based chemotherapy | Covalent binding to DNA, leading to the formation of DNA cross-links |
Taxanes | Binding to microtubules, preventing their depolymerization |
Anthracyclines | Disruption of DNA by poisoning topoisomerase |
Microtubule inhibitors | Inhibition of the AKT/mTOR signaling pathway |
Alkylating agents | Direct action on DNA, resulting in crosslinking and strand breaks |
Antibody–drug conjugates | Delivery of deactivated cytotoxins to specific cancer cells |
Immune checkpoint inhibitors | Targeted inhibition of the bindings between cancer cell checkpoint ligands and their complementary receptors on the CD8+ cell |
PARP inhibitors | Inhibition of DNA repair pathways, leading to apoptosis of cancer cells, especially in homologous recombination deficient cells |
Tyrosine kinase inhibitors | Phosphorylation of specific amino acids on substrate enzymes, causing altered signal transduction |
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Greco, S.; Fabbri, N.; Spaggiari, R.; De Giorgi, A.; Fabbian, F.; Giovine, A. Update on Classic and Novel Approaches in Metastatic Triple-Negative Breast Cancer Treatment: A Comprehensive Review. Biomedicines 2023, 11, 1772. https://doi.org/10.3390/biomedicines11061772
Greco S, Fabbri N, Spaggiari R, De Giorgi A, Fabbian F, Giovine A. Update on Classic and Novel Approaches in Metastatic Triple-Negative Breast Cancer Treatment: A Comprehensive Review. Biomedicines. 2023; 11(6):1772. https://doi.org/10.3390/biomedicines11061772
Chicago/Turabian StyleGreco, Salvatore, Nicolò Fabbri, Riccardo Spaggiari, Alfredo De Giorgi, Fabio Fabbian, and Antonio Giovine. 2023. "Update on Classic and Novel Approaches in Metastatic Triple-Negative Breast Cancer Treatment: A Comprehensive Review" Biomedicines 11, no. 6: 1772. https://doi.org/10.3390/biomedicines11061772