McArthur, Heather L.

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by lack of estrogen receptor expression, progesterone receptor expression, and human epidermal growth factor 2 overexpression/amplification. Given its generally aggressive biology, current guidelines recommend systemic therapy for most patients, with anthracycline- and taxane-based regimens being historically preferred. However, the clinical outcomes of patients with stage I TNBC and the benefit (or lack thereof) of (neo)adjuvant chemotherapy have not been prospectively evaluated as this population has largely been excluded from prospective randomized clinical trials. As such, management decisions for stage I TNBC are typically extrapolated from trials enrolling patients with stage II or III TNBC or based on retrospective analyses. Currently, the primary factor influencing systemic therapy decisions is the anatomic stage, without other biomarkers clinically used to guide systemic therapy. This review summarizes the existing evidence supporting current and emerging systemic therapy strategies for stage I TNBC, with a special focus on treatment de-escalation and promising biomarkers that can advance personalized treatment selection.

The treatment paradigm of stage II to III triple-negative breast cancer (TNBC) is rapidly evolving, with the recent incorporation of pembrolizumab to neoadjuvant chemotherapy improving disease outcomes. Nevertheless, almost one in five patients with early-stage TNBC will relapse in 5 years, underscoring an urgent need to identify and improve outcomes for those at high risk of recurrence. Novel therapeutic strategies including antibody-drug conjugates, anti-vascular endothelial growth factor therapies, dual immune checkpoint blockade, and locoregional therapies to augment the antitumor immune response are being investigated in clinical trials. Biomarker strategies including tumor infiltrating lymphocytes, immune signatures, and circulating tumor DNA are being explored to identify patients at a high risk of relapse and to predict treatment response. In this article, we review recent advances in the management of stage II to III TNBC, highlight emerging investigational therapies and combinations, and explore novel biomarker strategies aimed at personalizing the care for patients with stage II to III TNBC.

Triple-negative breast cancer (TNBC) is characterized by the lack of estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2 overexpression. Historically, treatment options for TNBC have been limited, because of the absence of actionable targets. The addition of immune checkpoint inhibitors to chemotherapy improved outcomes for a subset of patients with metastatic PD-L1–positive disease; however, a critical need for more effective therapies remains. Antibody-drug conjugates (ADCs) have been a promising advance in the management of advanced TNBC and are reshaping the landscape as they move earlier into the treatment algorithm. A greater understanding of the molecular heterogeneity of TNBC has enabled the pursuit of more targeted and personalized therapeutic strategies. Despite this, TNBC continues to have the least favorable outcomes compared with other breast cancer subtypes. This review highlights current evidence and future challenges in advanced TNBC, including optimizing therapeutic sequencing and the ongoing need for predictive biomarkers and novel agents.

PURPOSE This guideline updates recommendations of the ASCO guideline on chemotherapy and targeted therapy for patients with human epidermal growth factor receptor 2–negative metastatic breast cancer (MBC) that is either endocrine-pretreated or hormone receptor (HR)–negative. METHODS An Expert Panel conducted a targeted systematic literature review guided by a signals approach to identify new, potentially practice-changing data that might translate into revised guideline recommendations. RESULTS The Expert Panel reviewed abstracts from the literature review and retained 14 articles. RECOMMENDATIONS Patients with triple-negative, programmed cell death ligand-1–positive MBC may be offered the addition of immune checkpoint inhibitor to chemotherapy as first-line therapy. Patients with triple-negative, programmed cell death ligand-1–negative MBC should be offered single-agent chemotherapy rather than combination chemotherapy as first-line treatment, although combination regimens may be offered for life-threatening disease. Patients with triple-negative MBC who have received at least two prior therapies for MBC should be offered treatment with sacituzumab govitecan. Patients with triple-negative MBC with germline BRCA mutations previously treated with chemotherapy may be offered a poly (ADP-ribose) polymerase inhibitor rather than chemotherapy. Patients with HR-positive human epidermal growth factor receptor 2–negative MBC for whom chemotherapy is being considered should be offered single–agent chemotherapy rather than combination chemotherapy, although combination regimens may be offered for highly symptomatic or life-threatening disease. Patients with HR-positive MBC with disease progression on an endocrine agent may be offered treatment with either endocrine therapy with or without targeted therapy or single-agent chemotherapy. Patients with HR-positive MBC with germline BRCA mutations no longer benefiting from endocrine therapy may be offered a poly (ADP-ribose) polymerase inhibitor rather than chemotherapy. No recommendation regarding when a patient's care should be transitioned to hospice or best supportive care alone is possible. Additional information is available at www.asco.org/breast-cancer-guidelines .

AbstractImmune checkpoint inhibitor therapies targeting PD‐1/PD‐L1 are now the standard of care in oncology across several hematologic and solid tumor types, including triple negative breast cancer (TNBC). Patients with metastatic or locally advanced TNBC with PD‐L1 expression on immune cells occupying ≥1% of tumor area demonstrated survival benefit with the addition of atezolizumab to nab‐paclitaxel. However, concerns regarding variability between immunohistochemical PD‐L1 assay performance and inter‐reader reproducibility have been raised. High tumor‐infiltrating lymphocytes (TILs) have also been associated with response to PD‐1/PD‐L1 inhibitors in patients with breast cancer (BC). TILs can be easily assessed on hematoxylin and eosin–stained slides and have shown reliable inter‐reader reproducibility. As an established prognostic factor in early stage TNBC, TILs are soon anticipated to be reported in daily practice in many pathology laboratories worldwide. Because TILs and PD‐L1 are parts of an immunological spectrum in BC, we propose the systematic implementation of combined PD‐L1 and TIL analyses as a more comprehensive immuno‐oncological biomarker for patient selection for PD‐1/PD‐L1 inhibition‐based therapy in patients with BC. Although practical and regulatory considerations differ by jurisdiction, the pathology community has the responsibility to patients to implement assays that lead to optimal patient selection. We propose herewith a risk‐management framework that may help mitigate the risks of suboptimal patient selection for immuno‐therapeutic approaches in clinical trials and daily practice based on combined TILs/PD‐L1 assessment in BC. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.