Abstract IA24: Setting the stage for immunotherapy in breast cancer: where are we and where are we going in the clinic?
Authors: Rugo Hope S. 
Published: August 2018

Abstract
Recent and emerging data have generated great excitement about manipulating the patient’s own immune system to attack and eliminate malignant tumors. Although the majority of success has not been in breast cancer, recent studies have increased enthusiasm about this therapeutic modality. The immune system plays a complex role in cancer biology involving both in promotion and eradication of disease. A series of immune checkpoints are hardwired into the immune system in order to modulate the duration and amplitude of the immune response, reducing collateral normal tissue damage. These immune checkpoint pathways serve as a mechanism for tumor immune invasion, particularly against T-cells generated against tumor antigens. Recently several monoclonal antibodies specifically targeted at blocking immune checkpoint receptor-ligand interactions have demonstrated unprecedented anti-tumor responses in a wide variety of immunogenic tumors that has led to U.S. FDA approval of a variety of agents, including those blocking the programmed cell death protein 1 (PD1) receptor and its ligand programmed cell death-ligand 1 (PD-L1).
Unlike many solid tumors, breast cancer has not typically been responsive to modulation of the immune system. The success of checkpoint inhibitors to date has generally relied on the immunogenicity and high mutational burden which is thought to be important in generating an antitumor immune response to neoantigens that can then be reactivated by immune checkpoint inhibitors. In breast cancer, proliferative subsets such as TNBC and HER2+ disease have a higher mutational burden, and could be more amenable to immunotherapy. Higher levels of tumor infiltrating lymphocytes (TILs) are found in TNBC and HER2 positive breast cancer and have been associated with improved outcome in both early and late stage disease settings. Expression of PD-L1 has been shown to be associated with lack of ER expression, higher TIL counts and the triple negative phenotype. Chemotherapy may increase mutational burden or expression of neoantigens through cell death, potentially increasing tumor immunogenicity and making combination studies very appealing.
Four phase I monotherapy expansion trials in patients with metastatic breast cancer have demonstrated low but durable single agent responses to PD-1 and PD-L1 inhibitors, ranging from 4.8 to 19%. Two trials included patients with TNBC, one trial included patients with any breast cancer subtype, and one trial included only patients with HR+ disease. Higher response rates are seen in TNBC, compared to hormone receptor positive disease. Variability in requirements for tumor PD-L1 expression, and variations in testing complicate cross trial comparisons. Two large single agent trials enrolling over 100 patients have recently been presented evaluating either atezolizumab or pembrolizumab as single agent therapy for TNBC. Response rates ranged from 5 to 10%, but in both trials the response rate was much higher in patients treated in the first line setting at 23-26%, potentially due to multiple mechanisms of resistance in the second or greater line setting and bringing up the question of clinical trial design.
Although rare durable responses have been seen, it is clear that combination therapy is a critical next step in the study of immunotherapy for breast cancer. Both pre-clinical and clinical data suggest that chemotherapy can enhance the host immune response, acting as an ‘immune agonist.’ A 5th phase Ib trial reported a 38% response rate in metastatic TNBC treated with atezolizumab and nab-paclitaxel in combination. Several phase III trials combining immune checkpoint inhibitors with chemotherapy as first line therapy for metastatic TNBC are ongoing, as well as a number of adjuvant and post-neoadjuvant trials. One small trial suggested that response to checkpoint inhibition might be improved with induction therapy with either a short course of radiation or chemotherapy. Additional studies are evaluating combinations with immune agonists.
Given data suggesting improved response in less heavily pretreated disease, there has been great interest in combining immune check-point inhibition with chemotherapy as neoadjuvant therapy for high risk breast cancer. Recent data from the multi-arm I-SPY2 phase II neoadjuvant trial demonstrated a marked and significant improvement in estimated pathologic complete remission when pembrolizumab was added to weekly paclitaxel before anthracyclines in both triple negative and hormone receptor positive disease. Longer exposure to pembrolizumab is currently being evaluated. Several randomized trials in the neoadjuvant setting are planned or ongoing as well.
Treatment with checkpoint inhibitors is generally well tolerated, with low rates of immune toxicity including hypothyroidism, pneumonitis, hepatitis, colitis, and hypophysitis, occurring even months after the end of therapy. In the neoadjuvant I-SPY2 trial, higher rates of adrenal insufficiency were noted, although these responded quickly to treatment. Further evaluation is needed to understand this difference.
Ongoing studies are evaluating combinations with chemotherapy, as well as a number of other targeted agents such as immune agonists, MEK inhibitors, HDAC inhibitors, HER2 targeted therapy and cyclin dependent kinase 4/6 inhibitors.
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Citation Format: Hope S. Rugo. Setting the stage for immunotherapy in breast cancer: where are we and where are we going in the clinic? [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr IA24.