Of five main randomized trials testing the addition of an anti-programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) agent to neoadjuvant chemotherapy 12, 13, 14, 15, 16, three showed an improvement in pCR rate with immunotherapy 12, 13, 14, 17 (Table 1). Results from several randomized trials designed with this purpose are now available, igniting a rapid change of practice in early TNBC. From this perspective, there was strong rationale for ICI administration to the earliest possible time in the disease course, namely before surgical resection. Notably, evidence suggest a superior efficacy of ICIs in TNBC when administered early in the disease course, possibly due to the progression of immune escape mechanisms during the advancement of disease 10, 11. Indeed, checkpoint inhibition with atezolizumab (now withdrawn in the U.S.) and with pembrolizumab has been approved for advanced-stage, PD-L1 positive TNBC based on the improvement in outcomes observed when combined with frontline chemotherapy 8, 9. However, the emergence of cancer immunotherapy is now revolutionizing the way we treat this disease.ĭespite lacking canonical targets for biologic treatment, TNBC is characterized by a relatively high tumor mutational burden (TMB) compared to other subtypes of BC, a feature which has been linked with increased responsiveness to immunotherapy with immune-checkpoint inhibitors (ICIs) 7. Multiple novel agents have been tested in the last decades to improve the prognosis of early TNBC, with none entering clinical practice, except for the recent approval of adjuvant olaparib for the subset of high-risk TNBC patients harboring germline BRCA1 or BRCA2 pathogenic variants 6. Conversely, only follow up is recommended for patients achieving pathological complete response (pCR) at surgery, despite the fact that the risk of relapse remains clinically relevant. Indeed, patients with residual disease after neoadjuvant chemotherapy are at the highest risk of recurrence 4 and derive a significant benefit from the addition of adjuvant capecitabine 5. Poly-chemotherapy remains the standard treatment for early TNBC, most often administered preoperatively to assess tumor sensitivity and adapt post-operative systemic treatment accordingly 3. Thus, intensive treatment strategies have been developed, to reduce the odds of recurrence after tumor removal. It is commonly diagnosed at a younger age compared with other breast cancer (BC) subtypes, and has a poor prognosis in case of metastatic relapse, with a median overall survival (OS) of less than two years 2. Triple negative breast cancer (TNBC) has long been a challenging disease to treat due to its aggressive behavior and the lack of actionable targets 1.
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The next decade of clinical research will be key to overcome these challenges, and ultimately learn how to optimally integrate immunotherapy in the treatment landscape of TNBC. Lastly, extensive efforts are needed to minimize the impact on patients of immune-related adverse events and financial toxicity. Moreover, the best integration of pembrolizumab with further recent advancements (capecitabine, olaparib) is yet to be defined. Indeed, we desperately need strategies to identify upfront patients deriving benefit from the addition of immunotherapy. This landmark advancement has however raised several important scientific questions. The addition of pembrolizumab to neoadjuvant chemotherapy has indeed shown to significantly improve event-free survival for stage II–III TNBC, leading to its establishment as new standard of care in this setting. Recent advancements, however, are rapidly reshaping the treatment algorithms for this disease. For decades, the systemic treatment of localized triple negative breast cancer (TNBC) has exclusively relied on chemotherapy.
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