Breast Cancer Patients: Who Would Benefit from Neoadjuvant Chemotherapies?

Abstract

Neoadjuvant chemotherapy (NACT) was developed with the aims of shrinking tumors or stopping cancer cells from spreading before surgery. Unfortunately, not all breast cancer patients will benefit from NACT, and thus, patients must weigh the risks and benefits of treatment prior to the initiation of therapy. Currently, the data for predicting the efficacy of NACT is limited. Molecular testing, such as Oncotype DX, MammaPrint, and Curebest 95GC, have been developed to assist which breast cancer patients will benefit from the treatment. Patients with an increased level of Human Leukocyte Antigen-DR isotype, tumor-infiltrating lymphocytes, Fizzy-related protein homolog, and a decreased level of tumor-associated macrophages appear to benefit most from NACT.

Keywords: Human Leukocyte Antigen-DR (HLA-DR); breast cancer; cytotoxic T lymphocytes (CTLs); neoadjuvant chemotherapy (NACT); pathologic complete response (pCR); tumor-infiltrating lymphocytes (TILs).

Figure 1

A flow chart for multigene and biomarker assays to predict NACT response. Peripheral blood or biopsy samples can be obtained from a blood drawn or core needle biopsy. CD8⁺ T or TAM cells are isolated from PBMCs and are harvested after a density gradient centrifugation with Ficoll-Paque. Biomarker assays are completed with the aid of a flow cytometer, quantitative polymerase chain reaction (qPCR, also known as RT-PCR), immunohistochemistry (IHC), or Western Blot as needed. For multigene signature assay, it is much easier as a commercial service: obtain a special specimen transportation kit, then complete a requisition form, submit samples, and finally access and get the test results.

Figure 2

Factors decreasing CTL cell activity. Cancer cells express inhibitory molecule PD-L1, which binds to PD-1 on CTLs. This binding induces a negative regulatory pathway that limits CTL activity. Other inhibitory immune checkpoints, such as CTL-A4, and immunosuppressing molecules (i.e., IL-10, TGF-β, IDO) could also negatively impact CTL activity.

Figure 3

Role of APC/FZR1 and APC/C in cell cycle regulation. APC/C regulation of cell cycle progression occurs mainly through Cdc20 or Cdh1 temporal coordination. APC/C-Cdc20 (blue) is activated by Cdk 1 phosphorylation, inhibited by spindle assembly checkpoint (SAC) and mitotic checkpoint complex (MCC), and degrades substrates in early/middle mitosis. APC/C-Cdh1 (brown) degrades substrates during the end of mitosis and G1 phase. When cell commences to anaphase, Cdh1 is dephosphorylated by CDC14 and activates APC/C-Cdh1, which ubiquitylates substrates during anaphases and telophase. APC/C-Cdh1 degrades mitotic cyclins at G1 phase, and then it is inactivated by Emi1, Cdh1 degradation, and phosphorylation by cyclin A/Cdk2 and degradation of E2s during G1/S phase transition.