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ABSTRACT
Introduction
The use of immune checkpoint inhibitors (ICI) targeting the PD-1/PD-L1 pathway has changed the landscape in the treatment of triple negative breast cancer (TNBC). The ICI pembrolizumab in combination with chemotherapy now forms a standard of care for the treatment of advanced PD-L1 positive TNBC and as part of neoadjuvant therapy for high-risk early-stage disease. Evidence in this space is rapidly advancing.
Areas covered
This review aims to highlight the evolving role of immunotherapy in TNBC management and to discuss current challenges. The studies in this review were searched from PubMed and ClinicalTrials.gov.
Expert opinion
The KEYNOTE-522 trial demonstrated that the addition of peri-operative pembrolizumab to neoadjuvant chemotherapy improves patient outcomes in early-stage TNBC. However, critical questions remain including how to select which patients truly gain benefit from the addition of pembrolizumab; the optimal duration of therapy, and the optimal adjuvant therapy depending on pathologic response.
Article highlights
Pembrolizumab in combination with chemotherapy improves overall survival in PD-L1 positive patients with untreated advanced TNBC.
The addition of peri-operative pembrolizumab to neoadjuvant carboplatin-containing chemotherapy (anthracycline/cyclophosphamide/paclitaxel/carboplatin) improves rates of pathological complete response and 5-year event-free survival (independent of pCR) in patients with high-risk early-stage TNBC, regardless of PD-L1 status.
Other ICIs have been investigated in advanced and early-stage TNBC with mixed results.
Reliable predictive biomarkers are needed to guide patient selection for ICI therapy and minimize immune-related and financial toxicity. Currently, there are no validated predictive biomarkers for use of peri-operative pembrolizumab in early-stage disease.
The necessity for continuing adjuvant pembrolizumab after neoadjuvant chemoimmunotherapy is currently unknown and under investigation: could patients with a pCR safely have adjuvant immunotherapy de-escalated?
Residual invasive disease (non-pCR) after neoadjuvant ICI indicates resistance, a poorer prognosis, and the need to escalate adjuvant treatment. The optimal adjuvant therapy for these patients is unknown but may include chemotherapy, PARP inhibitors, ICIs, and antibody-drug conjugates, alone or in combination.
Abbreviations list
| AC | = | doxorubicin-cyclophosphamide |
| ADC | = | antibody drug conjugate |
| CI | = | confidence interval |
| CPS | = | combined positive score |
| ctDNA | = | circulating tumor DNA |
| Dato-DXd | = | datopotamab deruxtecan |
| DDFS | = | distant disease-free survival |
| DFS | = | disease-free survival |
| DRFS | = | distant recurrence-free survival |
| DXd | = | deruxtecan |
| EC | = | epirubicin-cyclophosphamide |
| EFS | = | event free survival |
| ER | = | estrogen receptor |
| ESMO | = | European Society for Medical Oncology |
| HER2 | = | human epidermal growth factor receptor 2 |
| HR | = | hazard ratio |
| FDA | = | Food and Drug Administration |
| IC | = | immune cell |
| ICI | = | immune checkpoint inhibitor |
| iDFS | = | invasive disease-free survival |
| IRAE | = | immune-related adverse events |
| NACT | = | neoadjuvant chemotherapy |
| OS | = | overall survival |
| PARP | = | poly-adenosine diphosphate-ribose polymerase |
| PARPi | = | poly-adenosine diphosphate-ribose polymerase inhibitor |
| pCR | = | pathological complete response |
| PD-1 | = | programmed cell death 1 |
| PD-L1 | = | programmed cell death ligand 1 |
| PFS | = | progression-free survival |
| PR | = | progesterone receptor |
| RCB | = | residual cancer burden |
| SABCS | = | San Antonio Breast Cancer Symposium |
| SG | = | sacituzumab govitecan |
| TIL | = | tumor-infiltrating lymphocyte |
| TNBC | = | triple negative breast cancer |
Declaration of interest
RH De Boer has received speakers’ honorarium from MSD Australia. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
A reviewer on this manuscript has disclosed they have received honoraria from MSD and Roche and are a Coordinating Investigator of a neoadjuvant trial with nAtezolizumab in TNBC. Peer reviewers in this manuscript have no other relevant financial relationships or otherwise to disclose.