Abstract 1561: Age impacts response to paclitaxel-anti-PDL1 combination therapy in triple-negative breast cancer
Authors: Spasic Milos , Goreczny Gregory J. , Guo Qiuchen , Hutchinson John N. , Freedman Rachel A. , Mittendorf Elizabeth A. , McAllister Sandra S. 
Published: July 2021

Abstract
Over half of breast cancer patients are &gt;60 years old, yet women &gt;65 represent &lt;20% of patients enrolled in clinical trials. Moreover, most preclinical breast cancer models use young mice that do not represent the age of most patients. This raises the question of whether real world practice will reflect preclinical and clinical trial results. Recently, the IMpassion031 trial, evaluating neoadjuvant nab-paclitaxel +/- anti-PD-L1 in TNBC, reported significantly improved pathological complete response rates. Given that immune function declines with age, it is critical to understand how response to immunotherapies is impacted by age. Therefore, we designed a preclinical TNBC study to understand whether age impacts response to neoadjuvant paclitaxel +/- anti-PD-L1.
Immunologically Young (~8 week old) and Aged (~12 month old) FVB/NJ mice were orthotopically injected with Met1 TNBC cells. When tumors became palpable, mice were treated with paclitaxel or vehicle control (days 7, 11, 15) and either anti-PD-L1 or isotype control (days 8, 11, 14), and sacrificed on day 16. Blinded tumor measurements were performed to quantify tumor volume and mass. Tumor sections were histologically analyzed for tumor infiltrating lymphocytes. We also analyzed peripheral blood counts, bone marrow progenitor cells, and bulk RNA sequencing of primary tumors.
Aged cancer-free mice had fewer circulating CD4+ and CD8+ T cells. Tumor growth was slower in aged mice, reflecting the fact that TNBC is more aggressive in young women. While paclitaxel reduced tumor growth in both young and aged mice, addition of anti-PD-L1 therapy further reduced tumor growth only in young mice; this benefit was lost in aged mice. Similarly, IMpassion031 trial trends suggest younger women benefit more from addition of anti-PD-L1 to chemotherapy. Tumors from aged untreated mice had more infiltrating T regulatory cells and did not exhibit the same increases in infiltrating T-cells that occured with anti-PD-L1, paclitaxel, or combination therapy in young mice. Utilizing a unique molecular barcoding approach we identified populations of tumor cells resistant to therapy in an age-depedent manner. Finally, RNA sequencing analysis is ongoing and should provide insights into mechanisms driving age-dependent therapy responses.
Our results indicate that age is a critical component of the T-cell inflamed phenotype and response to combination chemotherapy + anti-PD-L1. Our preclinical model captures immunological age and mimics therapeutic responses to neoadjuvant chemotherapy+ICB shown in clinical trials. By identifying populations of tumor cells contributing to age-dependent therapeutic responses, we gain critical insights into molecular mechanisms of tumor growth and resistance. Ultimately our work has the potential to guide age-stratified treatment strategies for patients not accurately represented in clinical trials.
Citation Format: Milos Spasic, Gregory J. Goreczny, Qiuchen Guo, John N. Hutchinson, Rachel A. Freedman, Elizabeth A. Mittendorf, Sandra S. McAllister. Age impacts response to paclitaxel-anti-PDL1 combination therapy in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1561.