The recent approvals of the immunotherapeutic agent pembrolizumab, the antibody-drug conjugate sacituzumab govitecan and the PARP inhibitors olaparib and talazoparib for select patients with metastatic triple negative breast cancer (TNBC) have spurred interest in evaluating these and other novel agents in patients with earlier stage disease. For the last several decades, a standard approach to treating early stage TNBC was to administer neoadjuvant chemotherapy, most often an anthracycline/taxane-based regimen. Pathologic complete response (pCR) rates generally ranged 30-40%. Trials such as CALGB 40603, GeparSixto and BrighTNess demonstrated that the addition of carboplatin to an anthracycline and taxane based chemotherapy could increase the pCR rates (53-58%). At the most recent ESMO conference, the BrighTNess investigators reported that the addition of carboplatin improved event free survival (EFS) after a median follow-up of 4.5 years. For patients not experiencing a pCR, the Create-X trial showed benefit of capecitabine in the adjuvant setting.As of August 2021, there is a new standard for treating early stage TNBC. Specifically, based on the KEYNOTE-522 trial, pembrolizumab, in combination with chemotherapy, is FDA approved for this indication. KEYNOTE-522 enrolled over 1170 stage 2-3 TNBC patients and randomized them to chemotherapy +/- pembrolizumab. The most recent report showed the trial met it’s co-primary endpoints of improved pCR (63% vs 56%) and EFS (84.5% vs 76.8%) after a median follow-up of 39 months. Importantly, the benefit was regardless of the PD-L1 status of the patient’s tumor. With the approval of pembrolizumab comes a number of questions: 1) which patients should receive this regimen which is associated with immune-related toxicities, some of which are lifelong, 2) what is the optimal chemotherapy backbone, 3) is a full year of pembrolizumab required and 4) are there other biomarkers to be explored that may predict response to therapy or the development of toxicity? Other studies either have or are evaluating other targeted agents in the preoperative setting for early stage TNBC. In a small study of 20 BRCA mutation carriers treated preoperatively with single agent talazoparib, investigators reported a pCR rate of 53%. A study looking at sacituzumab monotherapy in the preoperative setting has completed accrual and the results are awaited. These two trials begin to address the question of whether we can identify an “achilles” heel in TNBC and if so, will targeting it improve patient outcomes. Good correlative studies that provide improved understanding of the impact of these therapies on the TNBC microenvironment will help inform the next generation of trials; likely combination therapies.There is also the question of adjuvant therapy, particularly for those that do not experience a pCR with preoperative therapy. As stated above, the CREATE-X trial supports the use of capecitabine in patients with residual disease, however EA1131 demonstrated that outcomes are still poor for this population. More recently, for patients with BRCA-mutated cancers, the OlympiA trial showed benefit to a year of adjuvant olaparib. There is also growing interest in whether patients with residual disease who are at highest risk for recurrence can be identified using technologies looking for cell-free DNA to find those with minimal residual disease. Historically we’ve thought about TNBC for what it’s not – it is not ER, PR or HER2 positive. With multiple studies now showing benefit of specific agents in TNBC, the next several years will provide an opportunity to more extensively dissect triple negative tumors and their. microenvironment. This will allow us to learn what TNBC “is”, and which of likely multiple different therapeutic strategies will be best applied to which patients.

Citation Format: E Mittendorf. Optimizing the management of early stage TNBC [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr ES5-2.