Abstract MS1-1: Immunotherapy in breast cancer: enhancing response to checkpoint blockade
Authors: Mittendorf E 
Published: March 2020

Abstract
Historically, breast tumors have been categorized as non-immunogenic in part due to a paucity of tumor infiltrating lymphocytes (TIL) when compared to other histologies. Multiple studies have now demonstrated an endogenous immune response against breast cancer with tumors having TIL present in the tumor and surrounding stroma. The extent of TIL infiltrate is dictated by the subtype of disease being highest in triple negative breast cancer (TNBC) and lowest in hormone receptor positive, HER2 negative (HR+/HER2-) disease. Recent studies have shown that immunotherapy, in the form of immune checkpoint blockade, can be effective in treating breast cancer patients. Specifically, the IMpassion 130 trial, a phase III study that enrolled over 900 patients with metastatic TNBC and randomized them to the immune checkpoint blockade agent atezolizumab plus nab-paclitaxel versus placebo plus nab-paclitaxel, demonstrated benefit to the addition of immunotherapy with respect to progression free survival as well as overall survival; a difference that was greater in patients with PD-L1 positive disease. Based on these data, the combination of atezolizumab plus nab-paclitaxel was approved for use in patients with PD-L1+ metastatic TNBC. More recently, data from a large phase III trial evaluating the use of the immune checkpoint blockade agent pembrolizumab in the neoadjuvant setting for TNBC patients showed a significant improvement in the rates of pathologic complete response. Based in part on these successes, there is significant enthusiasm for using immunotherapy to treat breast cancer patients. It must be recognized however, that a minority of patients respond. Additional work must therefore be done to expand the number of patients with TNBC who respond as well as to identify strategies for successfully employing immunotherapy for HER2+ and HR+ positive breast cancer. Development of these strategies requires understanding of the cancer immunity cycle and how it can be altered to enhance endogenous immune responses to breast cancer as well as improved understanding of the immune aspects of the tumor microenvironment and how standard of care therapies alter that microenvironment. As an example, there is emerging data showing that PARP inhibition leads to cytoplasmic DNA which activates the STING pathway leading to increased expression of release of type 1 interferons, increased MHC expression and antigen presentation and increased infiltration of effector T cells. Ongoing trials are therefore evaluating those agents in combination with immunotherapy. Our lab has shown that PARP inhibition further modifies the tumor microenvironment suggesting additional therapeutic targets. In addition, there is mounting evidence regarding potential mechanisms behind why some subtypes of breast cancer mount a robust immune response while others remain immunologically “cold”. Differences in antigen processing and presentation likely contribute and understanding how HR+ tumors “hide” from immune recognition could contribute to developing strategies to make these tumors susceptible to immunotherapy. Finally, our group has recently published data demonstrating a difference in susceptibility to immune checkpoint blockade based on age suggesting that a patient’s systemic immune status could predict therapeutic response and potentially be manipulated to enhance that response.
Citation Format: E Mittendorf. Immunotherapy in breast cancer: enhancing response to checkpoint blockade [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr MS1-1.