Immunotherapy in breast cancer: A clinician's perspective

Abstract

Globally over 2 million women are diagnosed with breast cancer each year despite major advances in detection and treatment of the disease. Breast cancer is comprised of several distinct subtypes and understanding the heterogeneity of the disease has become crucial for treatment planning. Therapeutic strategies span from a hormone therapy-based focus for women with estrogen receptor positive breast cancer to targeting human epidermal growth factor (HER2) by small molecules, antibody-drug-conjugates (ADC) and monoclonal antibodies in those with HER2 overexpression. Other novel treatment strategies for select subgroups of patients include the cyclin-dependent kinase 4/6 (CDK4/6) inhibitors for women with estrogen receptor positive tumors, the poly ADP ribose polymerase (PARP) inhibitors for those with BRCA mutations, and phosphoinositide 3-kinase (PI3K) inhibitors for women with tumors harboring phophatidylinositol-4,5-bisphosphate 3 kinase catalytic subunit alpha (PIK3CA) mutations. In contrast, the treatment for women with triple negative breast cancer has until recently been solely limited to chemotherapy. The profound impact of immunotherapy on cancer treatment in general has created much hope for its potential in breast cancer. This review will focus on the current advances and the research of immunotherapy in breast cancer, particularly on immune checkpoint inhibitors, adoptive cell transfer and cancer vaccines.

Fig. 1

Adaptive immune therapies. (A) T cell activity is in part regulated through immune checkpoint cell surface receptors and ligands expressed in the microenvironment. Tumor cells and the tumor microenvironment down-regulate T cell cytokine production and proliferation by activating these checkpoints resulting in an exhausted T cell phenotype. Inhibiting antibodies that recognize and interfere with checkpoint receptor/ligand interactions (e.g. αPD-1, αPD-L1, and αCTLA-4) have been developed to promote T cell cytotoxic activity and an anti-tumor immune response. (B) Adoptive T cell therapies are derived from patient or donor T cells. T cells may be engineered through viral transduction to recognize tumor specific antigens (CAR-T cells) or by culturing T cells with tumor specific antigen and isolating activated T cells. Tumor directed T cells are then expanded and re-introduced to the patient to mount an adoptive therapy response. (C) Therapeutic cancer vaccines are generally either derived from endogenous antigens prepared from the patient's tumor or from exogenous antigens known to be tumor specific or associated with cancer or specific types of cancer. These antigens, together with adjuvants to boost immune response, are introduced to the patient to stimulate an effector and memory T cell response.

Fig. 2

Predictive and prognostic biomarkers for TNBC. Approved TNBC biomarkers include PD-L1 tumor positivity and microsatellite instability, which represent a relatively small percentage of TNBC tumors. As such, the search for predictive and/or prognostic biomarkers for the treatment of TNBC continues to be a robust area of research. These include a myriad number of clinical, tumor, microenvironment, and peripheral blood features. Abbreviation: BRCAmt, BRCA mutation; cDC, classical dendritic cell; HER2, human epidermal growth factor 2; IFN, interferon; LDH, lactate dehyolrogenase; MDSC, myeloid derived suppressor cell; peCTLs, partially exhausted cytotoxic T lymphocytes; TAM, tumor associated macrophage; TCR, T cell receptor; TMB, tumor mutation burden; TME, tumor microenviroment; Tregs, regulatory T cells.