Role of Immunotherapy in Breast Cancer

Abstract

The advent of immunotherapy, particularly immune checkpoint inhibitors (ICIs), has revolutionized the treatment of solid tumor malignancies. In breast cancer, the most robust data to date for ICI exist for triple-negative breast cancer (TNBC). Preclinical studies suggested increased antitumoral immune response in patients with TNBC undergoing ICI treatment. Early clinical trials investigated the use of ICI monotherapy in patients with metastatic TNBC with promising results, particularly in the first-line setting and for those patients whose tumors had high programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) expression. Subsequent trials evaluated the use of ICI in combination with conventional chemotherapy to enhance the host immune response. Pembrolizumab combined with chemotherapy in the KEYNOTE-355 study resulted in improved progression-free survival and overall survival benefits for patients with PD-L1 combined positive score > 10 metastatic TNBC. In early-stage disease, two phase III trials demonstrated increased rates of pathologic complete response at the time of surgery with the addition of neoadjuvant ICI to standard chemotherapy. The large KEYNOTE-522 trial showed improved event-free survival with neoadjuvant and adjuvant ICI. Several biomarkers have been identified, which may be predictive of response to ICI therapy including PD-1/PD-L1 expression, tumor mutational burden, tumor-infiltrating lymphocytes, and multigene assays capturing favorable immune cell signatures. For hormone receptor–positive and human epidermal growth factor receptor–positive breast cancer, there are ongoing studies evaluating ICI therapy in combination with chemotherapy and targeted agents. Finally, across all subtypes, several novel immunotherapeutic agents are under investigation including novel ICIs, cancer vaccines, adoptive cellular therapy, and oncolytic viruses.

Tumor-Associated Lymphocytes and Breast Cancer Survival in Black and White Women

“…Advances in cancer genomics have generated insights regarding immunotherapeutics in breast cancer. TNBC is more likely to respond to immunomodulation with cell cycle checkpoint inhibitors; it is hypothesized that this response is related to frequency of tumor-infiltrating lymphocytes or tumor-associated leukocytes (TALs) . Several millennia of evolutionary selection pressure on the human genome shaped by exposure to infectious pathogens in Africa have resulted in germline genetic variants associated with African ancestry that were acquired because of their association with resistance to deadly diseases.…”

Clinical utility of genomic signatures for the management of early and metastatic triple-negative breast cancer

“…The multidisciplinary management of early TNBC traditionally relies on a combination of systemic chemotherapy, surgery, and radiotherapy [10]. Considering its genomic and immunological features [14–18], TNBC has represented an appealing subtype for the implementation of ICI-based therapy, and many studies have investigated this strategy in early TNBC [19] (Table 1). Accordingly, ICIs have been implemented in the treatment algorithm of early TNBC given the Food and Drug Administration (FDA) approval of pembrolizumab in combination with chemotherapy based on the results of the phase III KEYNOTE-522 study (NCT03036488) [20].…”

Scoparone attenuates PD-L1 expression in human breast cancer cells by MKP-3 upregulation

“…Immunotherapy has recently become a crucial treatment approach for cancer, in addition to surgery, chemotherapy, radiotherapy, and hormone therapy (Schneble et al 2015 ; Waks and Winer 2019 ; Debien et al 2023 ). In particular, immune checkpoint inhibitors – which block key immunosuppressive receptors, such as programed cell death 1 (PD-1), programed death ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), – have revolutionized the treatment of solid tumors (Ribas and Wolchok 2018 ; Jacob et al 2023 ).…”