Abstract

Metastatic breast cancer (BC) is an aggressive form of cancer and is an absolute challenge to treat. This review discusses the standard treatments available for metastatic BC. It further highlights the rationale for targeting oncodrivers, tumor-associated antigens, and neoantigens in BC. Explaining the significance of immune response in successful immunotherapeutic studies, it draws attention towards how adoptive cell therapy can be a useful immunotherapeutic tool. We focus on adoptive cell therapy in BC covering tumor-infiltrating lymphocyte therapy, engineered T cell receptor therapy, chimeric antigen receptor therapy, dendritic cell therapy and natural killer cell therapy. In this work, we aim to provide an overview of clinical data regarding the use of cellular immunotherapies in BC. Eventually, we conclude by proposing future adoptive cell therapy approaches, which can be used to cure BC.

In the United States, an estimated 6% of women with breast cancer (BC) are metastatic at diagnosis, with 20% to 30% of early-stage BC patients eventually progressing to metastatic disease.^1,2 Metastatic BC (MBC) is considered incurable with goals of treatment aimed at quality of life and extending survival. The 5-year survival for MBC is a mere 27% compared with more than 86% for women with local disease. Overall survival for MBC ranges from 6.3 to 55.8 months with a median of 24 months, depending on subtype.³ Over the past 30 years, all-stage BC deaths have declined by 40%, which can be partially attributed to a growing list of treatment options.⁴

Metastatic BC is a varied disease that can be characterized based on molecular subtype, which also provides prognostic information. The most common subtype is hormone receptor (HR)–positive (either estrogen receptor [ER]–positive or progesterone receptor [PR]–positive), which accounts for approximately 68% of newly diagnosed BCs. Hormone receptor–positive BC can be further divided into luminal A and luminal B based on Ki-67 expression. Subtypes that are known to be more aggressive and have worse outcomes include those overexpressing human epidermal growth factor receptor 2 (HER2) and triple-negative (HR⁻/HER2⁻).⁵ Molecular subtypes have also been found to have an impact on local and regional recurrence. Luminal A subtype has been shown to have the best prognosis with the lowest frequency of metastatic disease, consisting of bone-only disease in 45% of cases. This differs drastically to HER2⁺ and triple-negative BC (TNBC) subtypes, which present more often with visceral-only metastasis.⁶ Patients with brain metastasis compared with bone have a worse overall prognosis partly due to the fact that most systemic therapies fail to cross the blood-brain barrier, which limits treatments.⁵

One of the biggest struggles with treating MBC is the amount of intertumor and intratumor heterogenicity. These differences can be due to natural or treatment selection pressures, which can alter treatment response.⁷ Currently, the National Comprehensive Cancer Network recommends assessment of the following biomarkers in MBC: HRs, HER2, programmed death ligand 1 (PD-L1) in triple-negative, and germline BRCA1 and BRCA2 status, with the option to test for PIK3CA as a second line in ER⁺/HER2⁻ cancers and in certain circumstances testing for mismatch repair protein and tumor mutational burden.⁸ A perfect example of the importance that subtypes play in MBC is seen in the evolution of HER2⁺ disease, which used to confer a poor prognosis until anti-HER2 therapies were developed.^9,10

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