Neoadjuvant Treatment for Triple Negative Breast Cancer: Recent Progresses and Challenges
Abstract
:1. Introduction
2. Molecular Heterogeneity of Triple Negative Breast Cancer
3. Platinum in TNBC
4. Immune Check Point Inhibitors
5. TME Targeting for Neoadjuvant Treatment
6. PARP Inhibitors for Neoadjuvant Treatment
7. PI3K/AKT/mTOR Targeted Therapies
8. Androgen Receptor Targeting in TNBC
9. Biomarkers Predicting pCR in TNBC
9.1. Tumor Infiltrating Lymphocytes
9.2. PD-L1
9.3. Immune Gene Signatures
9.4. Combined Modality of Gene Signatures and IHCs
9.5. BRCAness or DNA Repair Defect
10. Novel Neoadjuvant Clinical Trial Approach
11. De-Escalation vs. Escalation of NAC Regimen in TNBC
12. Conclusions and Future Direction
Author Contributions
Funding
Conflicts of Interest
References
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Molecular Subtypes | Genomic Alterations | Potential Therapeutic Targets |
---|---|---|
Basal-like 1 (BL1) | Cell cycle DNA repair (ATR–BRCA pathway) Proliferation | PARP inhibitors Carboplatin, Cisplatin Other chemotherapy |
Basal-like 2 (BL2) | Growth factor signaling pathways (EGFR, MET, NGF, Wnt/β-catenin, IGF-1R) Glycolysis, gluconeogenesis Expression of myoepithelial markers | mTOR inhibitors Growth-factor inhibitors |
Immunomodulatory (IM) | Immune cell processes (CTLA4, IL12, IL7 pathways, antigen processing/presentation) Gene signature for medullary BC (rare TNBC with a favorable prognosis) | PD1/PD-L1 inhibitors Other immune checkpoint inhibitors |
Mesenchymal-like (M) | Cell motility Cell differentiation Growth factor signaling (Notch, PDGFR, FGFR, TGFβ) EMT | mTOR inhibitors EMT-targeted therapy CSC-targeted therapy AXL inhibitor |
Mesenchymal stem-like (MSL) | Low proliferation Angiogenesis genes Similar to Mesenchymal-like (M) | PI3K inhibitors Antiangiogenic therapy Src antagonist |
Luminal androgen receptor (LAR) | Androgen receptor Luminal gene expression pattern Molecular apocrine subtype | Antiandrogen blockade CDK4/6 inhibitors Immune checkpoint inhibitors |
Trials | Treatment | Number of Patients with TNBC | *pCR Rate | p-Value |
---|---|---|---|---|
GEICAM/2006–03 [40] | EC followed by T + carboplatin vs. without carboplatin | 48 vs. 46 | 30% in both arms | N/A |
GeparSixto GBG66 [36] | P and NPLD with Bev + carboplatin vs. without carboplatin | 158 vs. 157 | 53.2% vs. 36.9% | 0.005 |
GALGB 40603 Alliance [34] | (weekly) P + carboplatin, followed by ddAC (with or without Bev) vs. without carboplatin | 221 vs. 212 | 54% vs. 41% | 0.0029 |
Ando et al. [41] | (weekly) P + carboplatin followed by EC/5-FU vs. without carboplatin | 37 vs. 38 | 61.2% vs. 26.3% | 0.003 |
Zhang et al. [42] | P + carboplatin vs. P + E | 47 vs. 44 | 38.6% vs. 14.0% | 0.014 |
GeparOcto GBG84 [43] | (weekly) P and NPLD + carboplatin vs. E followed by P followed by C | 203 vs. 200 | 51.7% vs. 48.5 | 0.518 |
WSG-ADAPT-TN [44] | Nab-P + carboplatin vs. Nab-P + G | 154 vs. 182 | 45.9% vs. 28.7% | 0.002 |
BrighTNess [45] | P + carboplatin followed by AC vs. without carboplatin | 160 vs. 158 | 58% vs. 31% | 0.0001 |
Sharma et al. [39] | T + carboplatin | 190 | 55% | N/A |
Yuan et al. [38] | Nab-P +carboplatin | 67 | 48% | N/A |
Trials | Treatment | Number of Patients with TNBC | *pCR Rate | p-Value |
---|---|---|---|---|
GeparNuevo [59] | Nab P + durvalumab followed by EC + durvalumab vs. without durvalumab | 88 vs. 86 | 53.4% vs. 44.2% | 0.287 |
KEYNOTE 173 [16] | Nab P with or without Cb + pembrolizumab followed by AC | 60 | 60% | N/A |
ISPY2 [57] | (weekly) P + pembrolizumab followed by AC vs. without pembrolizumab | 29 vs. | 60% vs. 22% | N/A |
KEYNOTE 522 [15] | Cb/P + pembrolizumab followed by AC or EC + pembrolizumab vs. without pembrolizumab | 401 vs. 201 | 64.8% vs. 51.2% | <0.001 |
NeoTRIP (2019, abstract) [60] | Cb and Nab P + atezolizumab vs. without atezolizumab | 138 vs. 142 | 43.5% vs. 40.8% | 0.66 |
NeoPACT (NCT03639948) | Phase II trial of Cb and T + pembrolizumab | Recruiting with accrual goal of 100 | N/A | N/A |
Impassion 031 (NCT 03197935) [62] | Phase III trial of Nab P + atezolizumab followed by ddAC + atezolizumab (continue atezolizumab as adjuvant after surgery) | Completed accrual with 204 patients | N/A | N/A |
GeparDouze (NCT03281954) [61] | Phase III trial of (weekly) P and Cb + atezolizumab followed by AC or EC + atezolizumab | Recruiting with accrual goal of 1520 | N/A | N/A |
Trials | Treatment | Number of Patients with TNBC | *pCR Rate | p-Value |
---|---|---|---|---|
I-SPY 2 [69] | P and Cb + veliparib followed by AC vs. P followed by AC | 39 vs. 21 | 51% vs. 26% | Not reported (95% PI, 33–66% vs. 9–43%) |
BrighTNess [45] | Arm 1: P and Cb + veliparib Arm 2: P and Cb Arm 3: P All arms followed by AC | 316 vs. 169 vs. 58 | 53% vs. 58% vs. 31% | Arm 1 vs 2: 0.357 Arm 1 vs. 3: <0.0001 |
GeparOLA [71] | P+ olaparib vs. P + Cb, followed by EC | 50 vs. 27 | 56.0% vs. 59.3% | Not reported |
NCT02401347 | Phase II of talazoparib | Recruiting with accrual goal of 40 | N/A | N/A |
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Lee, J.S.; Yost, S.E.; Yuan, Y. Neoadjuvant Treatment for Triple Negative Breast Cancer: Recent Progresses and Challenges. Cancers 2020, 12, 1404. https://doi.org/10.3390/cancers12061404
Lee JS, Yost SE, Yuan Y. Neoadjuvant Treatment for Triple Negative Breast Cancer: Recent Progresses and Challenges. Cancers. 2020; 12(6):1404. https://doi.org/10.3390/cancers12061404
Chicago/Turabian StyleLee, Jin Sun, Susan E. Yost, and Yuan Yuan. 2020. "Neoadjuvant Treatment for Triple Negative Breast Cancer: Recent Progresses and Challenges" Cancers 12, no. 6: 1404. https://doi.org/10.3390/cancers12061404